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1843

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No Resistance Detected in four Phase 3 Clinical Studies in HCV Genotype 1 -6 of Sofosbuvir + Ribavirin with or without Peginterferon

Evguenia S. Svarovskaia1, Hadas S. Dvory1, Christy Hebner1, Brian Doehle1, Viktoria Gontcharova1, Ross Martin1, Edward J. Gane2, Ira M. Jacobson3, David R. Nelson4, Eric Lawitz5, B. Nebiyou Bekele1, Diana M. Brainard1, William T. Symonds1, John G. McHutchison1, Michael D. Miller1, Hongmei Mo1;
1Gilead Sciences Inc, Foster City, CA; 2University of Auckland, Auckland City Hospital, Auckland, New Zealand; 3Weill Cornell Medical College, New York, NY; 4University of Florida, Gainesville, FL; 5Texas Liver Institute, San Antonio, TX

Introduction: SOF combination therapy was demonstrated to be well tolerated and effective in the treatment of HCV genotype (GT) 1-6 in four Phase 3 studies: NEUTRINO, FISSION, POSITRON, and FUSION. We performed resistance testing of the patients that did not achieve SVR thru follow-up week 12 after treatment with SOF-containing regimens from these 4 studies. Methods: Subjects who did not achieve SVR 12 due to virologic failure or early discontinuation were included in the resistance analysis. The HCV NS5B gene was amplified from patient plasma samples at baseline and post-BL time points. PCR products were analyzed using standard population sequencing and deep sequencing with an assay cut-off of 1%. PCR products from patient samples were also cloned into a replicon vector and tested for susceptibility to SOF and RBV. Results: Baseline NS5B population sequences were successfully obtained for 1292/1305 patients. None of the 1292 patients had the SOF-associated NS5B substitution S282T detectable at baseline. There were no statistically significant correlations between the presence of any NS5B variant at baseline and treatment outcome. Among all SOF-treated patients in the Phase 3 studies, 226/991 subjects qualified for resistance testing. All but one of these had post-treatment relapse, with the remaining patient experiencing viral breakthrough associated with nonadherence. Full length NS5B was successfully amplified and deep sequencing results obtained from 208/226 patients at post-treatment Week 4, 12, or 16. In addition, a short NS5B fragment flanking amino acid position 282 was successfully deep and/or population sequenced for an additional 17 patients. Notably, the S282T substitution was not detected by deep sequencing in any the 225 patients analyzed. There were a number of NS5B substitutions observed in more than 2 patients across the 4 Phase 3 studies. All of the substitutions were at residues considered to be polymorphic. Phenotypic analyses demonstrated no reduction in susceptibility to SOF or RBV with these substitutions. Altogether, phenotypic data were obtained for 110 patients. No reduction in SOF susceptibility was observed compared to baseline samples or replicon control references. Conclusions: SOF has an exceptionally high resistance barrier. Natural variation of HCV sequence within NS5B did not appear to affect treatment outcome to the SOF-containing regimens studied. By deep sequencing and phenotypic analyses, no resistance was detected in any patient not achieving SVR12 following SOF+RBV or SOF+PEG/RBV treatment in 4 Phase 3 studies.

Disclosures:

Evguenia S. Svarovskaia - Employment: Gilead Sciences Inc; Stock Shareholder: Gilead Sciences Inc

Christy Hebner- Employment: Gilead Sciences, Inc. Brian Doehle - Employment: Gilead Sciences Ross Martin - Employment: Gilead Sciences

Edward J. Gane - Advisory Committees or Review Panels: Roche, AbbVie, Novar-tis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche

Ira M. Jacobson - Consulting: Vertex, Abbott, Achillion, Boehringer Ingelheim, Bristol Myers Squibb, Enanta, Gilead, Glaxo Smithkline, Idenix, Kadmon, Novar-tis, Presidio, Roche / Genentech, Merck, Janssen; Grant/Research Support: Abbott, Achillion, Vertex, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Novartis, Pfizer, Roche / Genentech, Schering / Merck, Tibotec / Janssen; Speaking and Teaching: Vertex, Bristol Myers Squibb, Gilead, Roche / Genentech, Schering / Merck

David R. Nelson - Advisory Committees or Review Panels: Merck; Grant/Research Support: Abbot, BMS, Beohringer Ingelheim, Gilead, Genentech, Merck, Bayer, Idenix, Vertex, Jansen

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

B. Nebiyou Bekele - Employment: Gilead Sciences Diana M. Brainard - Employment: Gilead Sciences, Inc. William T. Symonds - Employment: Gilead

John G. McHutchison - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Michael D. Miller- Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sciences, Inc.

Hongmei Mo - Employment: Gilead Science Inc

The following people have nothing to disclose: Hadas S. Dvory, Viktoria Gontcharova

1844

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Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination is Highly Effective in Subjects with Baseline NS5A Inhibitor and NS3 Protease Inhibitor Resistance-Associated Variants: The Lonestar Trial

Eric Lawitz2, Christy Hebner1, Phil S. Pang1, Robert H. Hyland1, Michael D. Miller1, Hongmei Mo1, Fred Poordad2, Fernando E. Membreno2;
1 Clinical Virology, Gilead Sciences, Inc., Foster City, CA; 2The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX

Background: Variants in the HCV NS5A viral protein conferring reduced susceptibility to NS5A inhibitors naturally occur in 5–15% of the treatment-naïve genotype 1 (GT 1) population. In addition, the NS3 protease inhibitor (PI) resistance-associated variants (RAVs) emergent in subjects who experience virologic failure on PI-containing regimens can persist for a significant duration after treatment completion. In this study, the baseline prevalence and effects of NS5A inhibitor and PI RAVs on virologic response to once daily sofosbuvir/ledipasvir fixed dose combination ± ribavirin (FDC±RBV) in the LONESTAR trial were investigated. Methods: Sixty treatment-naïve (TN; 53 GT 1a, 7 GT 1 b) and 40 protease inhibitor (PI) treatment-experienced (TE; 34 GT 1a, 6 GT 1 b) subjects were treated with FDC±RBV for 8 or 12 weeks in the LONESTAR study. Baseline plasma samples from all 100 subjects were analyzed by deep sequencing to detect the presence of GT 1 NS5A RAVs with an assay cutoff of 1 %. The presence of NS5A RAVs and PI RAVs were examined at baseline for 100 and 99 subjects, respectively, using deep sequencing with a 1% assay cutoff. Results: NS5A deep sequencing data were successfully obtained for all 100 subjects. 9 subjects (8 GT 1a, 1 GT 1 b) had detectable NS5A RAVs at baseline with 5/9 having RAVs present at high levels (>91%). M28T, Q30L/H/R, and Y93C/H NS5A variants were observed in GT 1 a subjects while Y93H was detected in the single GT 1 b subject. Of these 9 subjects, 7/9 subjects achieved SVR 12 following treatment with FDC±RBV, while only 2/9 subjects experienced virologic relapse. Analysis of PI RAVs demonstrated that baseline PI RAVs were detected in 29 out of these 99 subjects, with 26 of 40 (65%) treatment-experienced subjects and 3 of 59 (5%) treatment-naive subjects having detectable RAVs. The R155K mutation, either alone or in combination, was the most frequently observed RAV, detected in 79% of GT 1a TE subjects with detectable NS3 RAVs. No virologic failures have occurred to date in any of the 29 subjects with detectable PI RAVs at baseline following 12 weeks of treatment with SOF/LDV or SOF/LDV+RBV. The Q80K variant was detected in 46/99 subjects (29/59 treatment-naïve, 17/34 treatment-experienced). The majority of PI treatment-experienced subjects had the Q80K variant in combination with other PI RAVs (13/17 subjects). 48/49 subjects with detectable Q80K achieved SVR with only one Q80K subject experiencing relapse. Conclusions: NS5A RAVs do not preclude subjects from achieving SVR with once daily FDC±RBV. These regimens were equally effective in subjects with and without baseline PI RAVs and the Q80K variant.

Disclosures:

Eric Lawitz - Advisory Committees or Review Panels: AbbVie, Achillion Pharmaceuticals, BioCryst, Biotica, Enanta, Idenix Pharmaceuticals, Janssen, Merck & Co, Novartis, Santaris Pharmaceuticals, Theravance, Vertex Pharmaceuticals; Grant/Research Support: AbbVie, Achillion Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Idenix Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Merck & Co, Novartis, Presidio, Roche, Santaris Pharmaceuticals, Vertex Pharmaceuticals ; Speaking and Teaching: Gilead, Kadmon, Merck, Vertex

Christy Hebner- Employment: Gilead Sciences, Inc.

Phil S. Pang - Employment: Gilead Sciences

Robert H. Hyland - Employment: Gilead Sciences, Inc

Michael D. Miller - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sciences, Inc.

Hongmei Mo - Employment: Gilead Science Inc

Fred Poordad - Advisory Committees or Review Panels: Abbott, Achillion, BMS, Inhibitex, Boeheringer Ingelheim, Pfizer, Genentech, Idenix, Gilead, Merck, Vertex, Salix, Janssen, Novartis; Grant/Research Support: Abbott, Anadys, Achillion, BMS, Boehringer Ingelheim, Genentech, Idenix, Gilead, Merck, Phar-massett, Vertex, Salix, Tibotec/Janssen, Novartis

The following people have nothing to disclose: Fernando E. Membreno

1845

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Efficacy and safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in cirrhotics according to the age. Data from the CUPIC cohort (ANRS CO20)

Christophe Hezode1, Hélène Fontaine2, Cecile Dufour3, Dominique G. Larrey4, Fabien Zoulim5, Victor de Ledinghen6, Valerie Canva-Delcambre7, Laurent Alric8, Marc Bourlière9, Stanislas Pol2, Thierry Poynard10, Ghassan Riachi11, Pierre-Henri Bernard12, Jean-Jacques Raabe13, Jerome Gournay14, Sophie Metivier15, Jean-Michel Pawlotsky16, Didier Samuel17, Yoann Barthe3, Fabrice Carrat3, Jean-Pierre Bronowicki18; '1 Hepatologie, Hôpital Henri Mondor, Creteil, France; 2Hepatologie, Hôpital Cochin, Paris, France; 3UMR-S 707, Paris, France; 4Hôpital Saint-Eloi, Montpellier, France; 5INSERM U871, Lyon, France; 6Hôpital Haut Lêvèque, Bordeaux, France; 7Hôpital Claude Huriez, Lille, France; 8Medecine interne, Hôpital Purpan, Toulouse, France; 9Fondation Hôpital Saint Joseph, Marseille, France; 10Hepatologie, Hôpital de la Pitié-Salpêtrière, Paris, France;
11Hôpital Charles Nicolle, Rouen, France; 12Hôpital Saint André, Bordeaux, France; 13Hôpital Bon Secours, Metz-Thionville, France; 14CHU de Nantes, Nantes, France; 15Hepatologie, Hôptal Purpan, Toulouse, France; 16Virolo-gie, Hôpital Henri Mondor, Creteil, France; 17Hôpital Paul Brousse, Villejuif, France; 18Hôpital de Brabois, Nancy, France

Background: Safety and efficacy of triple therapy in older cirrhotics is not documented in phase III trials. This analysis was done to evaluate the efficacy and safety of triple therapy in cirrhotics included in the CUPIC cohort. Methods: 674 genotype 1 treatment-experienced patients with compensated cirrhosis

(Child A) were prospectively included and received 12W TVR/PEG-IFN-2a/RBV+36W PEG-IFN/RBV, or 4W PEG-IFN-2b/RBV+44W BOC/PEG-IFN/RBV. The analysis is restricted to 511 patients reaching W60 of follow-up. Results: Patients were categorized according to age: 1 22 (23.9%) patients aged>65 and 389 (76.1%) patients aged<65. Safety and efficacy data are shown in the table. Conclusions: In this large cohort of cir-rhotics, triple therapy can be used successfully to treat older patients, However, severe anemia was more frequent needing more frequent blood transfusion in older patients. These patients should be clearly treated but carefully monitored.

criteriaTVR <65 n=221TVR ≥65 n=78TVRpBOC <65 n=168BOC ≥65 n=44BOC P
  1. * W4 for TVR, W8 for BOC

  2. ** W12 for TVR, W16 for BOC

RVR*, n (%)135(61)37 (47)0.0569(41)13(30)0.22
EVR**, n (%)182(82)61 (78)0.40108(64)19 (43)0.02
EOT, n (%)124(56)46 (59)0.6994 (56)15 (34)0.01
SVR12, n (%)95 (43)37 (47)0.5170 (42)10(23)0.02
Death, n (%)5(2)3(4)0.433(2)01
Severe infection, n (%)19(9)9(12)0.495(3)3(7)0.36
Hepatic decompensation, n (%)10(5)5(6)0.543(2)6(14)0.003
Grade3/4 anemia n (%)22(10)16(21)0.02810(6)7(16)0.054
Blood transfusion, n (%)26 (12)27 (35)<0.00115(9)9(20)0.056

Disclosures:

Christophe Hezode - Speaking and Teaching: Roche, BMS, MSD, Janssen, abb-vie, Gilead

Hélène Fontaine - Independent Contractor: gilead, BMS, MSD, Roche

Dominique G. Larrey - Board Membership: ROCHE, MSD, TIBOTEC/JANSSEN, ABBOTT, BOEHRINGER, BMS, GILEAD; Consulting: BAYER, SANOFI, PFIZER, SERVIER, HELSINN, MMV, BIAL, TEVA; Grant/Research Support: Roche, Boehringer, BMS, GILEAD; Independent Contractor: ABBOTT

Fabien Zoulim - Advisory Committees or Review Panels: Gilead; Consulting: Roche; Grant/Research Support: Gilead, Scynexis, Roche; Speaking and Teaching: Novartis, Roche, Janssen, Bristol Myers Squibb, Gilead

Victor de Ledinghen - Advisory Committees or Review Panels: Merck, Janssen, Gilead, Echosens, Boehringer Ingelheim, Abbvie; Grant/Research Support: Roche, Gilead, Janssen; Speaking and Teaching: Roche, Echosens

Laurent Alric - Board Membership: Schering Plough, Schering Plough, Schering Plough, Schering Plough; Speaking and Teaching: Roches, BMS, Gilead, Roches, BMS, Gilead, Roches, BMS, Gilead, Roches, BMS, Gilead

Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough, Bohringer inghelmein, Merck, Schering-Plough, Bohringer inghelmein, Merck ; Board Membership: Bristol-Myers Squibb, Gilead, Bristol-Myers Squibb, Gilead; Consulting: Roche, Novartis, Tibotec, Abott, glaxo smith kline, Roche, Novartis, Tibotec, Abott, glaxo smith kline

Stanislas Pol - Board Membership: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis; Grant/Research Support: Glaxo Smith Kline, Gilead, Roche, MSD; Speaking and Teaching: Sanofi, Bristol-Myers-Squibb, Boehringer Ingelheim, Tibotec Janssen Cilag, Gilead, Glaxo Smith Kline, Roche, MSD, Novartis

Thierry Poynard - Advisory Committees or Review Panels: Merck; Speaking and Teaching: BMS; Stock Shareholder: Biopredictive

Sophie Metivier - Speaking and Teaching: Roche, BMS, Janssen, MSD

Jean-Michel Pawlotsky - Consulting: Abbott, Achillion, Boehringer-Ingelheim, Bristol-Myers Squibb, Idenix, Gilead, Janssen, Madaus-Rottapharm, Merck, Novartis, Roche; Grant/Research Support: Gilead; Speaking and Teaching: Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, Madaus-Rottapharm, Merck, Janssen-Cilag, Novartis, Abbott

Didier Samuel - Consulting: Astellas, MSD, BMS, Roche, Novartis, Gilead, LFB, Janssen-Cilag

Fabrice Carrat - Grant/Research Support: Janssen, Merck, Gilead, BMS, Roche

Jean-Pierre Bronowicki - Consulting: Merck, Janssen, Boehringer Ingelheim, Gilead, BMS, Bayer, Novartis, GSK, Merck, Janssen, Boehringer Ingelheim, Gilead, BMS, Bayer, Novartis, GSK; Speaking and Teaching: Roche, Merck, Janssen, BMS, Bayer, Roche, Merck, Janssen, BMS, Bayer

The following people have nothing to disclose: Cecile Dufour, Valerie Canva-Del-cambre, Ghassan Riachi, Pierre-Henri Bernard, Jean-Jacques Raabe, Jerome Gournay, Yoann Barthe

1846

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IFNL4-ΔG Genotype and Racial Differences in Treatment Response in Virahep-C

Ruth M. Pfeiffer1, Charles D. Howell2, Sabrina Chen3, Alan S. Wang1, Wei Tang1, Kathy Ryan2, Ludmila Prokunina-Olsson1, Thomas R. O'Brien1;
1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD;2 Department of Medicine, University of Maryland School of Medicine, Baltimore, MD; 3Information Management Services, Silver Spring, MD

Background: Standard therapy for chronic hepatitis C genotype 1 is an HCV protease inhibitor combined with pegylated-IFN-α and ribavirin. African American (AA) patients are less responsive to IFN-based therapy than European American (EA) patients and this racial difference has been explained, in part, by differences in rs12979860 ['IL28B'] genotype. Previously, we reported that the IFNL4-ΔG genetic variant, which generates the novel interferon lambda 4 protein, is a better predictor of treatment response than rs1 2979860 for AA patients (Nature Genetics, 2013). We examined whether differences in IFNL4-ΔG genotype explain racial differences in response to pegy-lated-IFN-α/ribavirin among Virahep-C participants. Methods: Treatment-naïve patients with HCV genotype 1 infection received pegylated-IFN-α-2a plus weight-based ribavirin for 48 weeks. Study end points included decrease in HCV RNA levels from baseline (ÑRNA) and sustained virologic response (SVR). IFNL4-ΔG (ss469415590) genotyping was performed by Taq-Man assay. We used linear regression to examine ÑRNA at day 28. Logistic regression was used to calculate an odds ratio (OR), 95% confidence interval (95% CI) and p-value for the association of race with SVR. Models included race, IFNL4-ΔG genotype, gender, education, age, liver fibrosis stage, BMI, baseline HCV RNA, AST/ALT, pegylated-IFN-α adherence and ribavirin adherence. Results: Among 169 AA participants, 91% carried the unfavorable IFNL4-ΔG allele compared to 54% among 182 EA subjects. At day 28, overall median ÑRNA (log10 IU/ml) was 1.24 in AA and 2.31 in EA patients (p=4x10-8), however, for each 10IFNL4-ΔG genotype group ÑRNA over the first 28 days of treatment was similar for AA and EA participants (data not shown) and, in a linear regression model, ÑRNA at day 28 did not differ by race (slope parameter [EA vs AA], 0.06; p=0.64). The proportion of individuals who achieved SVR varied markedly by IFNL4-ΔG genotype (TT/TT, 61.2%; ΔG /TT, 37.9%; ΔG/ΔG, 22.8%; p=3×10-7). SVR was achieved in 28.2% of AA and 51.9% of EA patients (unadjusted OR [EA vs AA], 2.75; 95% CI, 1.76–4.28, p=8x10-6); however, in a logistic regression model that included IFNL4-ΔG genotype and other variables, the adjusted OR for the association of race with SVR was 1.57 (95% CI, 0.85–2.90; p=0.15). In the multivariable models, IFNL4-ΔG genotype was the strongest predictor of both ÑRNA at day 28 and SVR. Conclusions: When IFNL4-ΔG genotype and other determinants of treatment response are considered, ÑRNA during the first 28 days of pegylated-IFN-α/ribavirin treatment does not differ between EA and AA patients, and racial differences in SVR are largely or fully explained.

Disclosures:

Charles D. Howell - Advisory Committees or Review Panels: Vertex, Inc., Roche-Genetech, Vertex, Inc., Roche-Genetech, Vertex, Inc., Roche-Genetech, Vertex, Inc., Roche-Genetech; Grant/Research Support: Abbott, Eisai, Inc., Abbott, Eisai, Inc., Abbott, Eisai, Inc., Abbott, Eisai, Inc., Boehringer Ingelheim, Bristol Meyer Squibb, Gilead Sciences; Speaking and Teaching: Roche-Genetech, SNAP Meeting Solutions, Medical Education Resources, Consensus Medcial Communications, Roche-Genetech, SNAP Meeting Solutions, Medical Education Resources, Consensus Medcial Communications, Roche-Genetech, SNAP Meeting Solutions, Medical Education Resources, Consensus Medcial Communications, Roche-Genetech, SNAP Meeting Solutions, Medical Education Resources, Consensus Medcial Communications

Thomas R. O'Brien - Patent Held/Filed: National Cancer Institute

The following people have nothing to disclose: Ruth M. Pfeiffer, Sabrina Chen, Alan S. Wang, Wei Tang, Kathy Ryan, Ludmila Prokunina-Olsson

1847

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Cost Effectiveness of HCV triple therapy with protease inhibitors; the true cost of SVR

Nidhi Sethi, Annie Vong, Saima Firdoos, Meredith Rourke, Nezam H. Afdhal;
Department of Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

The aim of this study was to evaluate the true direct cost of treatment with IFN/RBV/PI in an unselected sequential population of patients treated at a tertiary care center for HCV genotype 1. PATIENTS: 198 patients completed IFN/RBV/PI therapy and were included in this study. Patients had a mean age of 55 years, 69% were male, 41% had cirrhosis, 28% treatment-naïve, 31% relapsers, and 41% partial or null responders. There were 39% genotype 1 a patients, 22% genotype 1b, and remaining 39% were not subtyped. 80% of patients were high viral load > 800,000IU at baseline. Telaprevir was used in 65% and boceprevir in 35% and 88% received PEG alfa 2a. METHODS: The cost of treatment was measured using WAC price for medications, average hospital costs per day for each diagnosis codes based on US inpatient hospital charges. All costs were adjusted to 2013 dollars. Number and cost of OP visits were based on standard average costs at BIDMC for level 3 follow up visit. RESULTS: SVR was achieved in 90 patients (46%). 14% experienced relapse, 19% breakthrough or non-response, and 21% discontinued secondary to side effects. Common side effects were anemia (54%), depression (23%), rash (25%), neutropenia (20%), thrombocytopenia (< 50,000 platelets per cc; 1 6%). 1 9% of patients had at least one hospi-talization and 1 decompensated (<1%). For the treatment of cytopenias, 37% of patients required erythropoietin stimulating agents, 16% received GCSF, 2% required eltrombopag and 15% required blood transfusion. SVR was achieved in 49% of prior naïve and relapsers, and 31% of prior treatment failures. The mean overall cost of treatment was $83,376 per patient. The cost per SVR was $183,428. Breakdown of costs for different patient categories and side effects are given below. CONCLUSION: Costs per SVR are substantially greater when considering all components of real-world management, and depend significantly on stage of disease and side effects. New all oral regimens with better tolerability, higher efficacy and shorter duration will bring significant savings to overall cost of care.

VariableMean Cost/PatientMean Cost/SVR
Cirrhosis (n =81)90,216332,158
No cirrhosis (n= 117)78,641153,349
Anemia < 8.5g/dl (n= 42)106,672194,792
Anemia < l0g/dl (n=63)95,371187,761
No anemia (n=89)63,808210,330
Hospitalization (n- 38)87,963289,952
No hospitalization (n=160)82,286190,808
Prior Naives and Relapsers (n=l17)86,768178,102
Prior Treatment Failure (n=81)78,477254,265

Disclosures:

Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott

The following people have nothing to disclose: Nidhi Sethi, Annie Vong, Saima Firdoos, Meredith Rourke

1848

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Comparative Effectiveness of Boceprevir- and Telaprevir-Based Therapy in US Veterans

Lisa I. Backus1,2, Pamela S. Belperio1,3, Troy A. Shahoumian1, Ramsey Cheung4,5, Larry A. Mole1;
1 Population Health Group/Office of Public Health, Veterasn Health Administration Palo Alto, Palo Alto, CA; 2Department of Medicine, Veterans Health Administration Palo Alto, Palo Alto, CA; 3Veterans Health Administration Greater Los Angeles, Los Angeles, CA; 4Division of Gastroenterology and Hepatology, Veterans Health Administration Palo Alto, Palo Alto, CA; 5Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA

Purpose: Compare sustained virologic response (SVR) rates for boceprevir- (BOC) and telaprevir (TVR)-based regimens in routine medical practice among Veterans. Methods: Veterans were prospectively identified from the Veterans Affairs' Clinical Case Registry and included in the cohort if they had HCV genotype 1 and initiated VA-prescribed peginterferon/ribavirin and either BOC or TVR prior to January 201 2. We determined SVR at least 12 weeks after the end of treatment (EOT) with data available through April 2013. Patients with HIV-coinfection, hepatocellular carcinoma, liver transplant or undetectable HCV RNA results at EOT but no test ≧12 weeks after EOT were excluded. To adjust for selection bias, inverse probability-of-treatment weighting (IPTW) in marginal structural models and multivariate regression models of the entire cohort and matched-pairs were used to evaluate the association of antiviral choice (BOC or TVR) and other baseline covariates with SVR. Results: Of 791 veterans with HCV RNA results available, SVR was achieved in 46% (279/612) of patients receiving BOC-and 49% (87/179) receiving TVR-based treatment (p=0.69). SVR rates for subgroups did not differ (Table). TVR use was marginally associated with an increased likelihood of SVR by IPTW (OR 1.45, 95%CI 1.01–2.09, p=0.043) but was not significantly associated with SVR in the multivariable analysis of the matched-pairs (OR 1.30, 95%CI 0.83–2.04, p=0.26). Prior null response was a significant independent predictor of reduced likelihood of SVR in all multivariable models constructed. Conclusions: In this comparative effectiveness analysis SVR rates were lower than those reported in clinical trials and highest in prior relapsers. No substantial differences in likelihood of SVR were observed among BOC- and TVR-treated patients after accounting for differences in patient characteristics.

SubgroupBOC %SVR (n/N)TVR %SVR (n/N)P value
All patients46% (276/612)49% (87/179)0.69
Al] cirrhotic41% (59/144)41% (30/73)0.91
All naive50% (180/362)52% (46/88)0.79
-- Naive non-cirrhotic51% (151/296)57% (30/53)0.54
-- Naive cirrhotic44% (29/66)46% (16/35)1.00
All prior null responders17% (10/58)19% (7/37)0.86
- Prior null responder non-cirrhotic18% (7/38)20% (4/20)0.95
-- Prior null responder cirrhotic15% (3/20)18% (3/17)1.00
All prior partial responders3l% (20/64)50% (12/24)0.19
-- Prior partial responder non-cirrhotic34% (15/44)54% (7/13)0.44
-- Prior partial responder cirrhotic25% (5/20)45% (5/11)0.39
All prior relapsers54% (59/110)72% (21/29)0.13
~ Prior relapser non-cirrhotic51% (38/75)79% (15/19)0.06
-- Prior relapser cirrhotic60% (21/35)60% (6/10)1.00

Disclosures:

The following people have nothing to disclose: Lisa I. Backus, Pamela S. Belperio, Troy A. Shahoumian, Ramsey Cheung, Larry A. Mole

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Analysis of the Durability of Response and Persistance of Resistance Associated Variants during Long Term Follow Up after Boceprevir + Pegylated Interferon/Rib-avirin Therapy - 3 Year Analysis

Anita Y. Howe, Jianmin Long, Seth Thompson, Richard J. Barnard, Katia Alves, John A. Howe, Janice Wahl;
Virology, Merck Research Laboratory, Kenilworth, NJ

Background The HCV-NS3 protease inhibitor boceprevir (BOC) combined with peginterferon alfa-2a/b plus ribavirin (PR) is an effective treatment approved for HCV genotype 1 (G1) infection. In this analysis, the durability of SVR obtained after BOC/PR therapy in subjects enrolled from Phase 2 and 3 trials was assessed. In addition, the persistence of resistance associated amino acid variants (RAVs) was studied in patients that experienced virologic failure. Methods All subjects in boceprevir Phase 2/3 programs were eligible to enroll in the 3 year follow-up study, regardless of their treatment outcome. For patients who had achieved SVR, long term durability was monitored using Roche COBAS Taqman HCV Test v2.0 (LOD = 9.3 IU/mL). For those who failed to achieve SVR and had detectable RAVs, viral resistance pattern was examined over time by population sequencing. Patient visits were every 3 months in year 1 and every 6 months thereafter. Results Of the 1335 subjects participating in this study 1 148 received BOC and 696 of these subjects achieved SVR in the Phase 2/3 trials before enrollment into the long term follow up study. Among the BOC treated subjects 3/696 experienced viral relapse during long-term follow-up resulting in a relapse rate of 0.4% or 1.3 relapse/1,000 person-years. In the Phase 2/3 studies, about 60% (474/789) of the non-SVR subjects had detectable RAVs. At the time of analysis (31DEC2012) in subjects enrolled in the long-term follow-up study and with up to 3 years follow-up data, 228/314 (73%) had no detectable RAVs at all BOC RAV loci by population sequencing. The median time for RAVs to become undetectable was 1.11 (1.05 - 1.2) years. For the RAVs analyzed the longest median time to return to wild-type was 13 months for T54S, R155K, and T54S/R155K, and the shortest time for return to wild-type was 6 and 8 months for T54A and V36M/R155K, respectively. Overall, the rate of RAVs return to wild-type was similar between genotype 1a and 1b. The median time forG1a and G1b RAV return to wild-type at the key boceprevir associated loci was 1.17 and 1.04 years, respectively. Conclusion SVR assessing 24 week after completing treatment is an excellent predictor of long term response/clearance with boceprevir containing regimens. Only 3/696 BOC treated subjects enrolled in the 3 year long term follow up study relapsed. In an analysis of resistance in patients enrolled in the long-term follow-up trial, the detection of RAVs declined over time. The rate of decline in detection of specific RAVs likely reflects differences in the in vivo fitness of different viral variants.

Disclosures:

Anita Y. Howe - Employment: Merck Research Laboratory

Jianmin Long - Employment: Merck Sharp & Dohme Corp.

Seth Thompson - Employment: Merck; Stock Shareholder: Merck

Richard J. Barnard - Employment: Merck and Co; Stock Shareholder: Merck and Co

Katia Alves - Employment: Merck & Co., Inc. John A. Howe - Stock Shareholder: Merck Janice Wahl - Employment: Merck & Co,

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The dose impact of telaprevier on the efficacy and the safety in chronic hepatitis C patients treated with the triple therapy: Interim results of a prospective randomized trial

Tsugiko Oze1, Naoki Hiramatsu1, Naoki Morishita1, Naoki Harada1, Ryoko Yamada1, Masanori Miyazaki1, Takayuki Yakushi-jin1, Akira Yamada2, Masahide Oshita3, Akira Kaneko4, Shinji Tamura5, Harumasa Yoshihara6, Yasuharu Imai7, Takuya Miyagi1, Yuichi Yoshida1, Tomohide Tatsumi1, Akinori Kasahara1, Norio Hayashi8, Tetsuo Takehara1;
1Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan; 2Sumitomo Hospital, Osaka, Japan; 3Osaka Police Hospital, Osaka, Japan; 4NTT West Osaka Hospital, Osaka, Japan; 5Minoh City Hospital, Minoh, Japan; 6Osaka Rosai Hospital, Sakai, Japan; 7Ikeda Municipal Hospital, Ikeda, Japan; 8Kansai Rousai Hospital, Amagasaki, Japan

Background & Aim: Although triple therapy with telaprevir (TVR), pegylated interferon (Peg-IFN) plus ribavirin (RBV) have improved antiviral efficacy in chronic hepatitis C (CH-C) patients with hepatitis C virus (HCV) genotype1, the severe adverse effects caused by TVR, such as anemia, renal dysfunction and eruption, are great issue to be resolved. However, appropriate dosage of TVR has not been sufficiently examined prospectively. Patients & Methods: We conducted a prospective, randomized, multicenter, open-label non-inferiority study to compare the antiviral efficacy and safety of treatment with a regimen of TVR; 2250mg + Peg-IFN + RBV (group A) vs. TVR; 1500mg + Peg-IFN + RBV (group B) at Osaka University Hospital and other institutions participating in the Osaka Liver Forum. A total of 81 CH-C patients with HCV genotype 1 were randomized into two groups and treated with triple therapy for 24 weeks. TVR was administered orally at a dose of 750 mg (group A) or 500 mg (group B) every 8 hours after food. The primary efficacy endpoint was sustained virologic response (SVR), defined as an undetectable serum HCV-RNA level (<15 IU/ml) at 12 weeks after the end of treatment, by intention-to-treat analysis. Viral break through (VBT) was defined a more than 1 log increase of HCV-RNA from nadir. The primary safety endpoint was treatment-related withdrawal rate. Interim analysis was assessed among the 66 patients who started triple therapy by September 2012. Results: Baseline characteristic factors were outlined below; group A, 19 males, 13 females, mean age 61.1 ± 7.1 y.o., naïve patients 11, relapser 16, non-responder 5, HCV-RNA (median) 6.9 Log IU/ml; group B, 19 males, 15 females, mean age 61.5 ± 8.5 y.o., naïve patients 12, relapser 16, non-responder 6, HCV-RNA (median) 6.8 Log IU/ml. Among all patients, the mean HCV-RNA level at week 2 and 4 were 1.0 ± 0.8 and 0.2 ± 0.5 log IU/ml in group A and 1.0 ± 0.6 and 0.1 ± 0.4 log IU/ml in group B. Among all patients, RVR, EVR, ETR and SVR rates were 80%, 97%, 97% and 90% in group A, and 87%, 91%, 91% and 81% in group B; among naive patients, 73%, 91%, 91% and 88% in group A, and 83%, 92%, 92% and 82% in group B. There were no patients with VBT in both groups. The withdrawal rate of all drugs until 12 weeks and the withdrawal rate of TVR were 1 2% (4/33) and 33% (11/33) in group A, and 9% (3/34) and 24% (8/34) in group B. Conclusion: These preliminary data demonstrate that lower dose of TVR can result in almost same SVR rate and low treatment-related withdrawal rate compared to higher dose of TVR in patients with CH-C genotype 1 treated with triple therapy.

Disclosures:

Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD K.K.

The following people have nothing to disclose: Tsugiko Oze, Naoki Hiramatsu, Naoki Morishita, Naoki Harada, Ryoko Yamada, Masanori Miyazaki, Takayuki Yakushijin, Akira Yamada, Masahide Oshita, Akira Kaneko, Shinji Tamura, Haru-masa Yoshihara, Yasuharu Imai, Takuya Miyagi, Yuichi Yoshida, Tomohide Tat-sumi, Akinori Kasahara, Norio Hayashi

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Peginterferon alfa-2a with or without Low Dose Rib-avirin for Hemodialysis Patients with Hepatitis C Virus Genotype 2 Infection: A Randomized Trial

Chen-Hua Liu1, Chung-Feng Huang2, Chun-Jen Liu1, Chia-Yen Dai2, Cheng-Chao Liang3, Jee-Fu Huang2, Peir-Haur Hung4, Hung-Bin Tsai5, Meng-Kun Tsai6, Shih-I Chen7, Sheng-Shun Yang8, Tung-Hung Su1, Hung-Chih Yang1, Pei-Jer Chen1, Ding-Shinn Chen1, Wan-Long Chuang2, Ming-Lung Yu2, Jia-Horng Kao1;
1Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 2Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan; 4Internal Medicine, Chiayi Christian Hospital, Chiayi, Taiwan; 5Traumatol-ogy, National Taiwan University Hospital, Taipei, Taiwan; 6Surgery, National Taiwan University Hospital, Taipei, Taiwan; 7Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin, Taiwan; 8Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

Background: Combination therapy with peginterferon plus low dose ribavirin is more effective than peginterferon monotherapy for hemodialysis patients with hepatitis C virus genotype 1 (HCV-1) infection. The safety and efficacy of combination therapy or monotherapy remain unclear for hemodialysis patients with HCV-2 infection. Methods: A total of 172 treatment-naïve HCV-2 hemodialysis patients were randomly assigned to receive 24 weeks of peginterferon alfa-2a (1 35 μg/week) plus low dose ribavirin (200 mg/day) (n = 86) or peginterferon alfa-2a (135 μg/week) monotherapy (n = 86). The primary endpoint was sustained virologic response (SVR) by intention-to-treat (ITT) analysis. The secondary endpoint was treatment-related withdrawal rate. Results: The SVR rate of combination therapy was superior to monotherapy (74% vs. 44%, p < 0.001). The higher SVR rate of the combination therapy than the monotherapy was attributed to the lower relapse rate (1 2% vs. 48%, p < 0.001). Furthermore, treatment-related withdrawal rates were comparable between the two groups (9% vs. 10%, p = 1.00). Patients treated with combination therapy had a higher rate of protocol-defined anemia, defined as hemoglobin < 8.5 g/dL (71% vs. 29%, p < 0.001) and needed a high dosage of erythropoietin (14,180 IU/week vs. 6,120

IU/week, p < 0.001) than those with monotherapy. Multivari-ate analysis showed that patients with combination therapy (OR: 8.03 [3.09–20.87], p < 0.001) and RVR (OR: 18.14 [6.86–47.98], p < 0.001) were independent factors predictive of SVR. Conclusions: Combination therapy with peginterferon plus low dose ribavirin is more effective than peginterferon monotherapy in HCV-2 infected hemodialysis patients. Furthermore, it provides comparable safety profiles to peginterferon monotherapy. High dose erythropoietin is required to maintain the hemoglobin level within the safety range during the combination therapy.

Disclosures:

Pei-Jer Chen - Advisory Committees or Review Panels: BMS, GSK, BMS, GSK, Medigene; Independent Contractor: J & J; Speaking and Teaching: Roche, Roche

Ding-Shinn Chen - Consulting: BMS, GSK, Gilead, Roche, Merck, BMS, GSK, Gilead, Roche, Merck

Ming-Lung Yu - Advisory Committees or Review Panels: ABBOTT, MSD; Grant/Research Support: ABBOTT, ROCHE, MSD; Speaking and Teaching: ABBOTT, ROCHE, MSD, GILEAD, BMS, GSK

The following people have nothing to disclose: Chen-Hua Liu, Chung-Feng Huang, Chun-Jen Liu, Chia-Yen Dai, Cheng-Chao Liang, Jee-Fu Huang, Peir-Haur Hung, Hung-Bin Tsai, Meng-Kun Tsai, Shih-I Chen, Sheng-Shun Yang, Tung-Hung Su, Hung-Chih Yang, Wan-Long Chuang, Jia-Horng Kao

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Pre-treatment IP-10 levels and IL28B genotype as predictive markers for SVR in treatment-naïve patients with genotype 1 HCV infection treated with telaprevir/pegin-terferon/ribavirin in the OPTIMIZE study

Leen Vijgen1, Inge Dierynck1, Katrien Janssen1, Willem Talloen2, Luc Gys2, Greet Vanhoof2, Donghan Luo3, Sandra De Meyer1, James Witek3, Jeroen Aerssens1;
1Janssen Infectious Diseases BVBA, Beerse, Belgium; 2Janssen Pharmaceutica NV, Beerse, Belgium; 3Janssen Research & Development LLC, Titusville, NJ

IL28B genotype and pre-treatment serum interferon-gamma inducible protein 10 (IP-10) levels are complementary predictors of sustained virologic response (SVR) in patients with chronic HCV treated with peginterferon and ribavirin (PR). The role of these markers in predicting SVR in prior PR treatment-failure patients was previously reported using data from the telaprevir (TVR) Phase 3 REALIZE study. The predictive role of IL28B genotype and pre-treatment plasma IP-10 levels in achievement of SVR in a TVR-based regimen in treatment-naïve patients was evaluated in the TVR Phase 3 OPTIMIZE study. Baseline (BL) plasma IP-10 levels were assessed in samples from 651/740 patients in OPTIMIZE (322/369 patients in TVR bid/PR arm, 329/371 patients in TVR q8h/PR arm). For all patients IL28B genotype was determined by real-time PCR. Mul-tivariate logistic regression (MLR) and receiver operator characteristic (ROC) analyses were used to evaluate associations between SVR and BL characteristics (IP-10, IL28B genotype, HCV RNA level, HCV geno/subtype, fibrosis stage, low-density lipoprotein and alanine transaminase) and/or on-treatment factor, extended rapid virologic response (eRVR). Median BL IP-10 level was 371 pg/ml (range: 61–18284 pg/ml). BL IP-10 levels were significantly lower in patients who achieved SVR compared with non-SVR patients (median IP-10: 318 versus 521 pg/ml for SVR and non-SVR groups, respectively, p<0.0001). BL IP-10 and IL28B genotype were associated with SVR in addition to BL factors HCV RNA level, HCV geno/subtype and fibrosis stage (Table). BL log10 IP-10 (ROC area under the curve [AUC]=0.68) and IL28B genotype (AUC=0.62) alone, or both combined (AUC=0.72) had similar or higher predictive capacity for SVR than HCV RNA level, HCV geno/subtype and fibrosis stage combined (AUC=0.68). When added to the latter model, log10 IP-10 and IL28B improved the predictability for

SVR (AUC=0.75). Addition of eRVR further improved the predictive capacity of the model (AUC=0.86). BL plasma IP-10 levels and IL28B genotype were shown to be predictive markers of SVR in treatment-naïve patients treated with a TVR-based regimen. These markers improved the predictability for SVR when combined with other BL factors such as HCV RNA level, HCV geno/subtype and fibrosis stage.

BL characteristicsMLR, Odds Ratio (95% Confidence Interval)
Log10 IP-100.32(0.16–0.64)
IL28B CT vs CC0.26 (0.15–0.45)
IL28B TT vs CC0.20(0.10–0.40)
HCV RNA level0.54 (0.38–0.79)
HCV geno/subtype la vs lb0.61 (0.41–0.90)
Fibrosis stage F3 vs F41.94 (1.02–3.69)
Fibrosis stage F0-F2 vs F42.78 (1.68–4.61)

Disclosures:

Leen Vijgen - Employment: Janssen Infectious Diseases BVBA

Inge Dierynck - Employment: Janssen Infectious Diseases, Johnson & Johnson; Stock Shareholder: Janssen Infectious Diseases, Johnson & Johnson

Katrien Janssen - Employment: Janssen Pharmaceutica NV

Greet Vanhoof - Employment: Janssen R1 D, a division of Janssen Pharmaceutica NV

Donghan Luo - Employment: Tibotec Inc.; Stock Shareholder: Johnson & Johnson

Sandra De Meyer - Employment: Janssen Infectious Diseases bvba (J&J); Stock Shareholder: J&J

James Witek - Employment: Johnson & Johnson; Stock Shareholder: Johnson & Johnson

Jeroen Aerssens - Employment: Janssen Infectious Diseases bvba; Stock Shareholder: Johnson & Johnson

The following people have nothing to disclose: Willem Talloen, Luc Gys

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Pooled Clinical Trial Analyses of Detectable Baseline HCV NS3/4A Resistance Associated Variants on the Efficacy of Boceprevir + Pegylated Interferon/Ribavirin Therapy

John A. Howe, Jianmin Long, Stuart Black, Robert Chase, Patricia McMonagle, Stephanie Curry, Anita Y. Howe;
Infectious Diseases, Merck, Kenilworth, NJ

Background Resistance to direct-acting antivirals (DAAs) represents a new challenge in the treatment of chronic hepatitis C (HCV). The impact of boceprevir (BOC) resistance associated variants (RAVs) detected before treatment (Baseline RAVs) on the efficacy of BOC + pegylated interferon / ribarvirin regimens was assessed. Methods Data from the phase II study (P03523) and phase III studies (P05101, P05216, P05411, P05685 and P06086), were pooled and baseline population sequencing data (detection limit 15–20%) was available from plasma samples for 2241/2352 subjects who received boceprevir. The frequency of RAVs detected was analyzed as a function of IL28B genotype (rs12979860), CC versus CT/TT, and poor interferon (IFN) response (< 1-log10 viral load decrease) versus IFN response (≧1-Iogl0 viral load decrease) at the end of the 4-week P/R lead-in. Results RAVs were detected in 178/2241 (8%) subjects; 153/1498 (10%) subjects with genotype 1a virus and 25/742 (3%) subjects with genotype 1 b virus. Baseline variants were detected at 8/11 of NS3 loci examined: V36, T54, V55, V107, R155, V158, I170 and M175; but not at 3/11of NS3 loci: A156, D168 and V170. SVR was 64% (1326/2063) for subjects without baseline RAVs compared to 65% (115/178) SVR for subjects with baseline RAVs. In addition, there appeared to be no impact of Baseline RAVs on SVR when assessed according to IL28B genotype. Among the subjects with poor IFN response and baseline RAVs detected 22% (8/36) achieved SVR, compared to the numerically higher 37% (174/474) SVR rate for subjects with poor IFN response and no baseline RAVs detected. Baseline RAVs detected in the SVR subjects with poor IFN response were V55I (1/8), V55A (1/8) and I170V (5/8) and V107I (1/8). These RAVs, except V55A, had a limited effect on BOC susceptibility in replicon assays (< 2-fold shift). Most subjects with poor IFN response and Baseline RAVs that conferred > 3-fold reduction in BOC replicon activity including: V36M (1/28), T54S (2/28), V55A (10/28) and R155K (3/28), did not achieve SVR. The remaining poor IFN responders that were non-SVR had V55I (2/28), V107I (1/28) or I170V (14/28) at baseline. SVR rates for IFN responders with or without Baseline RAVs detected were 78% (93/120) and 76% (1012/1367) subjects, respectively. For IFN responders with Baseline RAVs no correlations between distribution of variants and treatment outcome were apparent. Conclusions Overall, SVR rate was not compromised among subjects with RAVs detected at baseline. SVR rates for poor IFN responders were reduced when Baseline RAVs were detected, predominantly by RAVs that conferred a > 3-fold reduction in BOC susceptibility.

Disclosures:

John A. Howe - Stock Shareholder: Merck

Jianmin Long - Employment: Merck Sharp & Dohme Corp.

Stuart Black- Employment: Merck

Robert Chase - Employment: Merck, Inc

Patricia McMonagle - Employment: Merck and Co.

Stephanie Curry- Employment: Merck

Anita Y. Howe - Employment: Merck Research Laboratory

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Detectable but not quantifiable hepatitis C virus RNA during antiviral treatment with pegylated interferon alpha and ribavirin can predict the probability of relapse

Marc Puigvehí1, José A. Carrión1, Alexandre Viu2, Virginia Plasen-cia2, Montserrat Garcia-Retortillo1, Nuria Canete1, Maria Teresa Broquetas1, Susanna Coll1, Margarita Salvadó2, Ricard Solà1;
1 Liver Section, Hospital del Mar. IMIM. Universitat Autònoma de Barcelona, Barcelona, Spain; 2Laboratori de Referència de Catalunya, Barcelona, Spain

BACKGROUND: The clinical relevance of detectable, but not quantifiable, hepatitis C virus (HCV) RNA has been recently described in the response-guided therapy with telaprevir and boceprevir. The aim of our study was to investigate the influence of detectable HCV RNA to predict relapse after treatment with pegylated interferon (Peg-IFN)-alpha plus Ribavirin (RBV). METHODS: From 2007 to 2011 we analyzed 665 chronic hepatitis C (CHC) treated patients with Peg-IFN-alpha plus RBV. The duration of antiviral treatment and ribavirin dose were performed according to guidelines recommendations. The HCV RNA was measured by Roche COBAS TaqMan HCV 2.0 assay at baseline and at weeks 4, 12 and 24 of treatment and week 24 after end of treatment. We considered 3 different levels of HCV RNA quantification: quantifiable (≧ 25 IU/mL), detectable but lower the limit of quantification (LLOQ) (10–25 IU/mL), and inferior to the limit of detection (ILD) (<10 IU/mL) reported as “target not detected”. RESULTS: We identified 411 (61.8%) patients with HCV RNA < 25 IU/mL at week 24 of treatment. One hundred and seventy five (42.6%) patients were infected by genotype 1, 188 (45.7%) by genotype 2/3 and 48 (11.7%) patients by genotype 4. The probability of relapse after treatment in HCV infected patients with genotype 1 and

HCV RNA LLOQ at weeks 4, 12 and 24 was 8,3%, 25% and 75%, respectively. These probabilities were 11,9%, 25 % and 25% for genotype 2/3 infected patients. CONCLUSION: Detectable but not quantifiable HCV RNA can predict the probability of relapse in patients receiving Peg-IFN-alpha plus RBV.

 Patients (n)SVR (n,%)Relapse (n, %)P
Week 4    
LLOQ5953 (89.8)6 (10.2) 
ILD111107(96.4)4 (3.6).08
Week 12    
LLOQ4532(71.1)13(28.9) 
ILD296262 (88.5)34 (11.5)0.003
Week 24    
LLOQ2410(41.7)14(58.3) 
ILD387321 (82.9)66 (17)<.0001

Disclosures:

Ricard Solà - Advisory Committees or Review Panels: Roche, Roche, Roche, Roche; Consulting: Bristol-Meyers Squibb, Gilead, Novartis, Tibotec-Jansen-Cilag, Bristol-Meyers Squibb, Gilead, Novartis, Tibotec-Jansen-Cilag, Bristol-Meyers Squibb, Gilead, Novartis, Tibotec-Jansen-Cilag, Bristol-Meyers Squibb, Gilead, Novartis, Tibotec-Jansen-Cilag; Grant/Research Support: Roche, Gilead, Scherin-Plough, Roche, Gilead, Scherin-Plough, Roche, Gilead, Scherin-Plough, Roche, Gilead, Scherin-Plough; Speaking and Teaching: Roche, Bristol-Meyers Squibb, Gilead, Novartis, Roche, Bristol-Meyers Squibb, Gilead, Novartis, Roche, Bristol-Meyers Squibb, Gilead, Novartis, Roche, Bristol-Meyers Squibb, Gilead, Novartis

The following people have nothing to disclose: Marc Puigvehí, José A. Carrión, Alexandre Viu, Virginia Plasencia, Montserrat Garcia-Retortillo, Nuria Canete, Maria Teresa Broquetas, Susanna Coll, Margarita Salvadó

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Shortened treatment duration in treatment-naive genotype 6 chronic hepatitis C patients with rapid virological response: A randomized controlled trial

Cai Qing-Xian1, Zhao Zhixin1, Chaoshuang Lin1, Xu Min2, Wei Min3, Huang Mingshou4;
1 The third affiliated hospital of Sun yat-sen University, Guangzhou, China; 2The Eighth People's Hospital of Guangzhou, Guangzhou, China; 3Zhongshan second people's hospital, Zhongshan, China; 4Panyu People's Hospital, Zhongshan, China

Background: Recent study implied chronic hepatitis C genotype 6 responses better to the 48-week treatment with pegylated interferon and ribavirin than genotype 1. However, the treatment is associated with many side effects and costly. Shorter treatment for chronic hepatitis C genotype 6 is necessary to be assessed. Method: In this multicenter, open label, randomized controlled trial(NCT01263860) conducted at 3 liver centers in South china, patients with chronic hepatitis C genotype 6 were treated with pegylated interferon alfa 2a (180ug/week)and ribavirin(800–1200mg based on weight) for 4 weeks. Those who were HCV RNA negative at week 4 by COBAS AMPLICOR HCV test(15 IU/ml detection limit) were defined as rapid virologic responders and randomized to either an additional 20 or 44 weeks (24-week or 48-week treatment group) combination treatment. Primary outcome measurement was sustained virologic response(SVR) rate by per protocol(PP) analysis . This was non-inferiority trial. The smallest difference considered to be clinically important is 10%. Thus to state “non-inferiority” the 95% confidence interval of the observed difference between the groups shall not overlap 10%. Result: From December 2010 to January 2013, two hundred and forty two treat-ment-naïve chronic hepatitis C genotype 6 were enrolled. One hundred and fifty two (152/242, 62.8%) patents achieved rapid virologic response and were randomized 1:1 to 24-week or 48-week treatment group. Until June 2013, sixty patients in 24-week group and 55 in 48-week group had finished the treatment and follow-up. The PP analysis showed that 93.3%(56/60) in 24-week group and 94.5%(52/55) in 48-week groups achieved SVR(p=0.78). The patients in the 48-week group were more likely to suffer from hematological abnormalities (68.3% vs 45.5%, P=0.013) than those in 24-week group, but other adverse events were comparable between the two groups. Conclusion: For patients of chronic hepatitis C genotype 6 who have an RVR, the duration of combination treatment with pegylated interferon alfa 2a and ribavirin could be shortened to 24 weeks.

Disclosures:

The following people have nothing to disclose: Cai Qing-Xian, Zhao Zhixin, Chaoshuang Lin, Xu Min, Wei Min, Huang Mingshou

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Safety and efficacy of triple therapy containing boceprevir (BOC) or telaprevir (TVR) plus peginterferon alfa-2a / ribavirin in patients with advanced fibrosis or cirrhosis in real-life setting

Stefan Mauss1, Andreas Schober2, Christine John3, Thomas Lutz4, Gero Moog5, Harald-Robert Bruch6, Gerlinde Teuber7, Stefan Christensen8, Renate Heyne9, Stefan Pape10, Uwe Naumann11, Martin Roessle12, Willi Schiffelholz13, Hanns-Friedrich F. Loehr14, Ulrich Alshuth15, Dietrich Hueppe16; 1 Center for HIV and Hepato-gastroenterology, Duesseldorf, Germany; 2Center of Gastroen-terology, Goettingen, Germany; 3Center of Gastroenterology, Berlin, Germany; 4Infektiologikum, Frankfurt/M, Germany; 5Center of Gastroenterology, Kassel, Germany; 6Center of Gastroenterology, Bonn, Germany; 7IFS, Interdisziplinaeres Facharztzentrum Sachsenhausen, Frankfurt/M, Germany; 8Center for Interdisciplinary Medicine (CIM), Muenster, Germany; 9Liver and study center Checkpoint, Berlin, Germany; 10Center of Gastroenterology, Pader-born, Germany;
1 1 Center for Addiction-Medicine, Hepatology and HIV, Praxiszentrum Kaiserdamm, Berlin, Germany; 12Gastrointestinal and Endocrinological Center, Freiburg, Germany; 13Center of Gastroenterology, Augsburg, Germany; 14Center of Gastroenterology, Wiesbaden, Germany; 15Virology, Roche Pharma AG, Gren-zach-Wyhlen, Germany; 16Center of Gastroenterology, Herne, Germany

BACKGROUND: Data from the French CUPIC study[1] and an Austrian cohort[2] showed that patients with F3 or F4 fibrosis status had a modest treatment outcome and a high rate of severe events, particularly in patients with platelet count <100,000/mm3 and serum albumin <35 g/L. Here, the impact of these baseline factors on treatment efficacy was analysed in the noninterventional “PAN” cohort, conducted by Association of German Gastroenterologists in Private Practice (bng) and Roche. METHODS: Patients infected with HCV genotype 1, APRI Score >1.5 initiating treatment with BOC or TVR from October 2011 to March 2012 were included in this cross sectional analysis if documentation of baseline factors was completed. RESULTS: 204 patients were analysed, 45 with BOC and 159 with TVR triple therapy. 47.1% of patients had liver cirrhosis (at least one result of sonography, histology, elastog-raphy or clinical appearance). 56.4% male, mean age 53.6 years, BMI 27.1 kg/m2. 65.2% of patients had ALT >3xULN, 33.3% platelets <100,000/μl and 17.1% albumin < 35 g/L. Genotype-subtypes distribution was 1a 29.9%, 1b 52.0%, unknown/other 18.1%; High viral load (HCV-RNA >400,000 IU/ml) 74,4%. 147/204 patients (72.1%) were pretreated with 61 relapsers, 86 non-responders. Treatment discontinuation rate increased over time until week 48: 2.9% at week 4, 12.7% at week 8, 17.2% at week 12, 30.9% at week 24, and 33.3% before week 48. 53.4% of patients discontinued treatment before week 48. Percentages of virological response are the following (undetectable or <10 IU/ml): 43.5% at week 4 (n=154), 59.0% at week 8 (n = 117), 67.1% at week 12 (n = 152), 53.7% at week 24 (n = 162), 83.9% at week 48 (n=56). Preliminary data of 88 patients having reached an observational period of 60 of 72 weeks reveal 65.9 % treatment discontinuation and 25.0% SVR. Because of anemia dosing of ribavirin was modified in 39.2% of patients and of Peg-IFN in 20.1%. 15.7% of patients had SAEs. The risk of SAE increased to 28.6% with platelet count <100,000/mm3 and serum albumin <35 g/L. Of all SAEs anemia (3.4%), infections (5.0%) and hepatic decomensation (4.5%) were most frequent. One patient died of unknown reasons. CONCLUSION: In our cohort patients with advanced liver disease had a poor safety profile, in particular if they had platelet count <100,000/mm3 and serum albumin <35 g/L. This observation confirms the findings from the CUPIC study. Due to the high discontinuation the chance of achieving SVR is low. [1] Hezode et al., J Hepatol. 2013 May 10. pii: S0168-8278(13)00290-0. doi: 10.1016/j.jhep.2013.04.035. [2] Rutteretal, Oral presentation, EASL2013, #65

Disclosures:

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Thomas Lutz - Advisory Committees or Review Panels: Gilead, MSD, Abbott, BMS, Janssen Cilag; Grant/Research Support: Boehringer Ingelheim, Gilead, GlaxoSmithKline, Schering-Plough, Roche, MSD, Abbott, Janssen Cilag; Speaking and Teaching: Boehringer Ingelheim, GlaxoSmithKline, Roche, BMS

Gerlinde Teuber- Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Stefan Christensen - Advisory Committees or Review Panels: Roche, BMS, Abbott, Janssen, Schering Plough, ViiV, Gilead, MSD, Boehringer Ingelheim; Speaking and Teaching: Gilead, MSD, Roche, BMS, Schering Plough, ViiV, Boehringer Ingelheim, Janssen

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

Ulrich Alshuth - Employment: Roche

Dietrich Hueppe - Advisory Committees or Review Panels: Roche, MSD, Novatis, Gilead, BMS

The following people have nothing to disclose: Andreas Schober, Christine John, Gero Moog, Harald-Robert Bruch, Renate Heyne, Stefan Pape, Martin Roessle, Willi Schiffelholz, Hanns-Friedrich F. Loehr

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Renal dysfunction during peg-IFN + RBV + TVR treatment

Tsukasa Nakamura1, Motoyuki Kohjima1, Tsuyoshi Yoshimoto1, Shinichi Tsuruta1, Tomoko Ohashi1, Kunitaka Fukuizumi1, Nao Fujimori1 , Ken Kawabe1, Kazuhiro Haraguchi1, Akira Aso1, Yorinobu Sumida1, Naohiko Harada1, Kazufumi Dohmen2, Hideyuki Nomura3, Munechika Enjoji4, Makoto Nakamuta1;
1Gastroen-terology, Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan; 2Internal Medicine, Chihaya Hospital, Fukuoka, Japan; 3Internal Medicine, Shin-Kokura Hospital, Kitakyushu, Japan; 4Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan

Background: Telaprevir (TVR) is an NS3/4A protease inhibitor that is used for the treatment for chronic HCV patients in combination with peg-IFN and ribavirin (RBV). Although TVR were usually used 2250 mg/day tid, we sometimes need to reduce the dose of TVR for undersized patients or aged women. Furthermore, break of the therapy is required because of a number of adverse events like renal dysfunction as well as serious anemia or rash. In this study, we have examined the factor involved in renal dysfunction during the treatment, and analyzed the HCV kinetics during the therapy with respect to the dose of TVR. Methods: The patients with HCV genotype 1 b have been treated with peg-IFNα2b + RBV + TVR from 2011 (n=115). We have used the reduced-dose of TVR (1500 mg/day bid) for patient aged 65 or over. We examined the factor involved in renal dysfunction during the treatment, and compared viral response in each dosage of TVR. Results: eGFR was dropped off for every patient from early course of the treatment (day 3). FENa was lower than 1 at day3 and day7 of treatment, while the FENa was similar between patients with and without renal dysfunction. Urinary β2-microglobulin was elevated drastically, and the urinary β2-microglobulin was significantly higher in patients with renal damage. The degree of exacerbation for renal function was milder in patients with reduced TVR dose despite of their lower eGFR at the baseline, and patients with reduced dosage of TVR had significantly lower risk of renal damage. Univariate analysis identified two parameters that correlated significantly with the pathogenesis of renal damage; serum creatinine (p =0.033) and TVR starting dosage (p <0.0001). In multivariate analysis, TVR dosage (2250 mg; OR 121.2, p <0.0001) and eGFR at the initiation of treatment (<90ml/min/m2; OR 32.6, p =0.0003) were selected as a significant contribution factor for the development of renal dysfunction. The viral kinetics of HCV and SVR rate for the treatment was similar between patients with different dose of TVR. Conclusion: Failure of renal tubule as well as pre-renal dysfunction causes renal damage during peg-IFN + RBV + TVR treatment. The reduction of TVR could prevent renal dysfunction during the therapy, and will not affect response for the peg-IFN + RBV + TVR therapy.

Disclosures:

The following people have nothing to disclose: Tsukasa Nakamura, Motoyuki Kohjima, Tsuyoshi Yoshimoto, Shinichi Tsuruta, Tomoko Ohashi, Kunitaka Fukuizumi, Nao Fujimori, Ken Kawabe, Kazuhiro Haraguchi, Akira Aso, Yorinobu Sumida, Naohiko Harada, Kazufumi Dohmen, Hideyuki Nomura, Munechika Enjoji, Makoto Nakamuta

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Predictors and outcome of Week 4 response <1log10 in patients with chronic HCV genotype 1 (G1) infection undergoing peginterferon (PegIFN) α-2b / Ribavirin (RBV) treatment in German real-world

Stefan Mauss1, Dietrich Hueppe2, Elmar Zehnter3, Michael P. Manns4, Gerlinde Teuber5, Tarek Dahhan6, Ulrike Meyer7, Thomas Witthoeft8, Bernd Moeller9, Nektarios Dikopoulos10, Jochen Brack11, Bernd Dreher12, Dagmar Hartmann12, Manfred Bilzer12; 1Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; 2Medical Group Practice, Herne, Germany; 3Gastroentero-logical Practice, Dortmund, Germany; 4Medical School of Hannover, Hannover, Germany; 5Gastroenterological Practice, Frankfurt, Germany; 6Medical Practice, Fellbach, Germany; 7Med-ical Practice, Berlin, Germany; 8Gastroenterological Practice, Stade, Germany; 9Medical Practice, Berlin, Germany; 10Health Centre Langenau, Langenau, Germany;
11Hospital Nord Ochsen-zoll, Hamburg, Germany; 12MSD Pharma GmbH, Haar, Germany

Background: The ability to predict week 4 virologic response to PegIFN/RBV may be helpful when considering treatment with HCV protease inhibitors. Controlled randomized studies demonstrated the association between week 4 response <1 log10 and poor SVR rates of ~5% and ~33% after treatment with PegIFN/RBV alone or in combination with protease inhibitors. This analysis assessed baseline predictors and outcome of week 4 response <1log10 in patients (pts) undergoing PegIFN α-2b/RBV treatment in German real-life. log10Methods: Data from pts treated for G1 infection with PegIFN α-2b 1.5 μg/kg/week + RBV (800-1200 mg/day) for up to 48 weeks in a large observational real-life study at 285 sites in Germany were retrospectively analyzed. The present analysis was restricted to 792 pts with documented outcome and available quantification of HCV-RNA at baseline and week 4. Results: 280 of 792 pts (35.4%) achieved week 4 virologic response <1log10. SVR, non-response, relapse and week 12 null-response rates <2log1010 were 16.1%, 65.0%, 45.8% and 70.0% in contrast to 50.0%, 20.7%, 24.0% and 8.8% in pts who attained a week 4 response ≧1 log10 (each p<0.0001). Pts with week 4 response <1log10 were more likely to be aged >50 years and to have platelet counts <150/nL, while no significant differences were obtained for gender, BMI, baseline viral load and initial dosing of PegIFN α-2b and RBV (Table). Factors significantly associated with week 4 response <1log10 in a multiple logistic regression analysis included older age >50 years (vs <50 years, odds ratio: 1.54; p<0.0088) and platelets <150/nL (vs ≧150 /nL; odds ratio 1.94; p=0.0008), but not gender, BMI, baseline viral load and PegIFN α-2b/RBV dosing. Conclusions: The present analysis confirms poor SVR rates in G1-infected pts who achieve a week 4 response <1log10 under PegIFN/RBV treatment in real-life. Age >50 years and baseline platelet counts <150/nL are predictors of HCV-RNA decline <1log10 in treatment week 4. Treatment lead-in with PegIFN/RBV in real-life allows targeting of pts poorly responsive to IFN-based dual therapy which may benefit from more intensive combinations with potent DAAs.

  Week 4 HCV-RNA declineP-value
  1. *<50 vs >50 years; #<600000 vs >600000 IU/ml; §<150 vs >150/nL; Mean±SD or % (n/N) is displayed.

OutcomeSVR Non-response Relapse Week 12 response <21og10 ≥21ogl016.1 (45/280)65.0 (182/280)45.8 (38/83) 70.0 (170/243) 30.0 (73/243)50.0(256/512) 20.7 (106/512)24.0 (81/337) 8.8 (36/408) 91.2 (372/408)<0.0001 <0.0001 <0.0001 <0.0001
CharacteristicsGender Female Male Age Age <50 years ≥50 years35.3(123/348)35.4 (157/444) 46.4±11.2 (N=280) 31.7(163/514) 42.1 (117/278)64.7 (225/348) 64.6 (287/444) 43.5±12.3 (N=512) 68.3(351/514) 57.9 (161/278)0.9964 0.0011 0.0036*
 Baseline viral load <600000 lU/ml≥600000 Ill/ml Baseline platelet count <150/nl≥150/nl37.9(138/364)33.3 (142/426)49.3 (70/142) 32.3 (208/644)62.1 (226/364)66.7 (284/426) 50.7 (72/142) 67.7 (436/644)0.1799#0.0001§
 BMI (kg/m2)25.2±4.1 (N=278)25.5±4.5 (N=509)0.3568
 Peglntron dosing (μg/kg/week) RBV dosing (mg/kg/day)1.5±0.2 (N=279) 13.8±2.0 (N=279)1.5±0.2 (N=510) 13.6±2.1 (N=507)1.0000 0.1942

Disclosures:

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Dietrich Hueppe - Advisory Committees or Review Panels: Roche, MSD, Gilead, Novartis, BMS

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Gerlinde Teuber- Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Bernd Dreher - Employment: MSD

Dagmar Hartmann - Employment: MSD Germany

Manfred Bilzer - Consulting: MSD Germany

The following people have nothing to disclose: Elmar Zehnter, Tarek Dahhan, Ulrike Meyer, Thomas Witthoeft, Bernd Moeller, Nektarios Dikopoulos, Jochen Brack

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Serious Adverse Drug Reactions Related to Telaprevir: Analysis of Food and Drug Administration Reported Events

Bryan L. Love1, Rasha Arabyat2, Vishvas Garg2, Dennis W. Raisch2, Charles L. Bennett1;
1 South Carolina College of Pharmacy, Columbia, SC; 2The University of New Mexico College of Pharmacy, Albuquerque, NM

BACKGROUND: The approval of hepatitis C (HCV) protease inhibitors has ushered in a new era of therapy for chronic HCV infection. Telaprevir, in combination with peginterferon and rib-avirin, is approved for treatment of both naïve and treatment-experienced patients. The purpose of this study was to examine the frequency of serious adverse drug reactions (SADRs) associated with telaprevir from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: We searched FAERS for telaprevir-associated SADRs between May 23, 2011 and June 30, 2012. Empirical Bayes geometric means (EBGMs) were estimated to investigate the dispropor-tionality reporting signals for specific SADRs from telaprevir administration. SADRs of interest included thromboembolic events [myocardial infarction (MI), deep vein thrombosis (DVT), pulmonary embolism (PE), cerebrovascular accident (CVA)], severe cutaneous reactions, anemia, thrombocytopenia, neu-tropenia, and hepatic failure. Duplicate case reports were matched (based on age, sex, race, and event date) and excluded from the analysis. A significant signal was defined as EBGM 0.05 lower boundary confidence interval (CI) >2 and number of events >3. RESULTS: A total of 560 SADRs of interest were reported in 480 patients who received a telaprevir-based treatment regimen (table 1). Hematologic toxicities were reported most frequently . A total of 14 cases of hepatic failure were reported with 8 of these resulting in death. Significant signals were found for telaprevir-associated anemia, thrombocytopenia, and neutropenia. Severe cutaneous reactions were reported in 24 unique patients; however, this did not meet the pre-specified criteria to be a significant signal. CONCLUSIONS: Hematologic toxicities were disproportionately reported with telaprevir-based treatment regimens in our analysis. These findings are consistent with those observed during clinical trials.

Table 1: Summary of FDA Reported Cases

Adverse EventReported CasesEBGM (95% CI)
MI140.13 (0.08 to 0.22)
CVA190.15 (0.09 to 0.23)
DVT/PE140.55(0.31 to 0.89)
Hepatic Failure140.99 (0.57 to 1.62)
Severe Cutaneous Reactions242.62 (1.73 to 3.87)
Neutropenia2482.64 (2.32 to 2.98)
Thrombocytopenia1662.76 (2.37 to 3.21)
Anemia615.49 (4.16 to 6.95)

Disclosures:

Bryan L. Love - Grant/Research Support: Bristol-Myers-Squibb

The following people have nothing to disclose: Rasha Arabyat, Vishvas Garg, Dennis W. Raisch, Charles L. Bennett

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Roche 454 Ultradeep Pyrosequencing Reveals Complex Resistance Patterns Post Protease Inhibitor Failure

Malcolm J. Macartney1, Clare L. Booth1, Tim C. Conibear1, Ana Garcia-Diaz1, Adele L. McCormick1, Geoffrey Dusheiko2, Michael Jacobs2, William M. Rosenberg2, Daniel P. Webster1, Dianne N. Irish1, Tanzina Haque1;
1Virology, Royal Free Hospital, London, United Kingdom; 2Directorate of Hepatology, Nephrology and Transplantation, Royal Free Hospital, London, United Kingdom

Background: Through an expanded access programme, we treated 58 chronically infected hepatitis C virus (HCV) patients with telaprevir or boceprevir combined with pegylated-inter-feron/ribavirin. Twenty-one patients failed treatment: 18 patients, all treated with telaprevir, had evidence of resistance mutations by population sequencing. We used the Roche 454 GS Junior ultra-deep pyrosequencing (UDPS) platform to quantify the presence of resistant variants in follow-up samples taken up to a year after telaprevir exposure. Methods: Pre-treatment, at failure and post-treatment follow-up samples were tested by UDPS from 12 patients. Nested PCR using “bar-coded” nested primers was followed by processing in line with Roche 454 protocols. UDPS encompassed amino acids 9 to 190 of HCV protease gene in a single sequencing reaction. Roche AVA software was used to quantify the presence of wild type and resistant variants. Results: In all 12 patients, resistant variants were detectable by UDPS up to 394 days post-telaprevir (median 199 days) at levels between 36 and 100% of the virus population. There was no correlation between time off-therapy and levels of resistant variants at follow-up. In patients where >95% of HCV sequences contained resistant variants at V36 and R155 on the same genome at failure, >90% of sequences continued to show both resistant variants on the same genome up to 293 days post-treatment (median 173 days). In patients where these resistant variants comprised <95% of the population at failure, dual-resistant variants on the same genome comprised a maximum of 15% of the population after a median of 311 days. In patients with a single resistant variant at failure, V36 or R155, resistant variants at the same position comprised >90% of the population a median of 168 days later. Conclusions: We demonstrate the long-term persistence of HCV expressing dual-resistance variants on the same genome, comprising >90% of the population up to 329 days post- telaprevir, even though such variants are associated with lower levels of relative replicative capacity. Persistence of these variants at such high levels has significant implications for future oral-only regimens where resistance rather than lack of response is likely to be a major cause of treatment failure.

Disclosures:

Geoffrey Dusheiko - Advisory Committees or Review Panels: Janssen, Merck, Merck; Grant/Research Support: Janssen

Michael Jacobs - Advisory Committees or Review Panels: Janssen, Gilead, Boehringer Ingelheim; Speaking and Teaching: Janssen, Gilead

William M. Rosenberg - Advisory Committees or Review Panels: Merk, Gilead, Merk, Gilead, GSK; Board Membership: iQur Limited, iQur Limited; Speaking and Teaching: siemens, Roche, siemens, Roche

The following people have nothing to disclose: Malcolm J. Macartney, Clare L. Booth, Tim C. Conibear, Ana Garcia-Diaz, Adele L. McCormick, Daniel P. Webster, Dianne N. Irish, Tanzina Haque

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IFNL4 ss469415590 polymorphism and response to interferon-based therapy of hepatitis C in HIV-positive patients with acute and chronic hepatitis C

Benjamin Krämer1, Hans Dieter Nischalke1, Christoph Boesecke1, Patrick Ingiliz2, Esther Voigt3, Stefan Mauss4, Hans-Jürgen Stell-brink5, Axel Baumgarten2, Juergen K. Rockstroh1, Ulrich Spengler1, Jacob Nattermann1;
1Department of Internal medicine I, Univeritiy of Bonn, Bonn, Germany; 2Medical Center for Infectious Diseases (MIB), Berlin, Germany; 3Praxis am Ebertplatz, Köln, Germany; 4Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; 5Infektionsmedizinisches Centrum, Hamburg, Germany

Introduction: Two recent study suggested that a polymorphism (ss469415590, ΔG/TT) creating (ΔG) or disrupting (TT) an open reading frame in a new gene, designated IFNL4 is a better predictor of response to interferon/ribavirin therapy than rs12979860 in HCV mono-infected patients. However, no data was shown regarding the impact of this frameshift on response to HCV therapy in HIV(+) patients. Therefore, we assessed the influence of the IFNL4 ss469415590 variant on response to interferon-based combination therapy in HIV/HCV co-infected patients. Methods: IFLN4 and IL28B genotyping was performed in 285 HIV/HCV co-infected Caucasian patients, including 153 subjects with chronic and 132 patients with acute hepatitis C. As a control 162 HIV(-)/HCV(+), 145 HIV(+)/HCV(-), and 157 HIV(-)/HCV(-) healthy individuals were analyzed. For statistical comparisons between the groups, chi2 statistics and Mann-Whitney U test were used. Results: IFNL4 ss469415590 genotype distribution did not differ significantly between HIV(+) patients with acute and chronic hepatitis C. Moreover, distribution of IFNL4 genotypes in HIV/HCV patients was similar to that seen in healthy individuals but differed significantly from that in HCV or HIV mono-infected patients. The IFNL4-creating allele was almost perfectly correlated with the unfavourable IL28B rs12979860[T] allele in healthy controls (r2 = 0.99) and HIV(+)/HCV(-) patients (r2 = 0.96) and well correlated in patients with HIV/HCV co-infection (r2 = 0.88) and HCV mono-infection (r2 = 0.88). All distributions were in accordance with the Hardy-Weinberg equilibrium. Data on treatment responses were available in 79 HIV(+) patients with acute and in 127 HIV(+) individuals with chronic HCV infection. In contrast to HIV(+) individuals with acute HCV the IFNL4 genotype was significantly associated with treatment response in HIV(-) and HIV(+) patients chronically infected with HCV with higher SVR rates in carriers of a T/T genotype (HIV(-): p=0.00002; HIV(+): p=0.04). In a multivariate analysis the IFNL4 genotype could be confirmed as an independent predictor of response to therapy only in HIV(-)/HCV(+) patients. In HIV(+) patients with chronic hepatitis HCV load and the IL28B polymorphism were significantly associated with treatment response, whereas the IFNL4 polymorphism was removed from the final model by regression analysis. Conclusion: Taken together our data suggest that the IFNL4 genotype is a better predictor of treatment response than the IL28B genotype in HIV(-)/HCV(+) patients but not in HIV(+) individuals co-infected with HCV, suggesting that effects of the IFNL4 may differ in HIV(+) and HIV(-) patients.

Disclosures:

Christoph Boesecke - Speaking and Teaching: MSD, Boehringer, Gilead, BMS, Roche, Abbott

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Hans-Jürgen Stellbrink - Advisory Committees or Review Panels: Abbott, Gilead Sciences, Boehringer Ingelheim, Janssen Cilag, Bristol-Myers Squibb, Merck, Sharp & Dohme, ViiV Healthcare; Consulting: Abbott, Gilead Sciences, Boehringer Ingelheim, Janssen Cilag, Bristol-Myers Squibb, Merck, Sharp & Dohme, ViiV Healthcare; Grant/Research Support: GlaxoSmithKLine, Pfizer, Gilead Sciences, Boehringer Ingelheim, Janssen Cilag, Merck, Sharp & Dohme; Speaking and Teaching: Abbott, Gilead Sciences, Boehringer Ingelheim, Janssen Cilag, Bristol-Myers Squibb, Merck, Sharp & Dohme, ViiV Healthcare

Juergen K. Rockstroh - Advisory Committees or Review Panels: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Abbott, ViiV, Vertex, Tibotec, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Pfizer, Abbott, ViiV, Vertex, Tibotec; Board Membership: Human Genome Sciences; Consulting: Bionor, Abbvie, Novartis, Abbott, Novartis; Grant/Research Support: Abbott, Merck, Abbott, Merck; Speaking and Teaching: Abbott, Gilead, GlaxoSmithK-line, Abbvie, Roche, Merck, ViiV, Abbott, Gilead, GlaxoSmithKline, Roche, Merck, ViiV

The following people have nothing to disclose: Benjamin Krämer, Hans Dieter Nis-chalke, Patrick Ingiliz, Esther Voigt, Axel Baumgarten, Ulrich Spengler, Jacob Nattermann

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Using Laboratory Data to Predict Long-Term Morbidity and Mortality in Chronic Hepatitis C Patients in the U.S. Veterans Health Administration

Jeffrey McCombs1, Tara Matsuda1,2, Ivy Tonnu-Mihara2, Sammy Saab3, Patricia Hines4, Gil L' Italian4, Timothy Juday4, Yong Yuan4;
1Clinical Pharmacy and Pharmaceutical Economics and Policy, Univ Southern California, Los Angeles, CA; 2Veterans Health Administration Hospital, Long Beach, CA; 3David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA; 4Global Health Economics and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ

Objective: Hepatitis C virus [HCV] patients and their physicians frequently delay treatment balancing the risk of adverse liver-related outcomes against their concerns about safety and efficacy of treatment. This study developed risk prediction models which track a patient's changing liver event risk over time based on laboratory test data. Methods: Study patients were selected from the VHA's HCV Clinical Case Registry [CCR] covering the period 1999-2012 if they had a detectable viral load [>25 IU/ml] and a recorded viral genotype. The primary outcomes were death and a composite of incident compensated cirrhosis, de-compensated cirrhosis, hepatocellular cancer (HCC) or a liver-related hospitalization. Cox proportional hazards models were estimated using dependent variables for time to an abnormal value for a wide range of common laboratory tests. Other risk factors include age, gender, race, ethnicity, genotype, time to treatment and time to viral load suppression. Results: 128,769 patients out of 360,857 unique patients registered in the VA HCV CCR database met all study inclusion criteria. Treatment rates were low [24.3%] and few treated patients [16.4%] achieved at least one undetectable viral load level. Abnormal values for five laboratory tests were associated with increased risk across all primary outcomes: AST/ALT ratio, albumin, gamma-glutayltransferase [GGT], platelets, and alpha fetoprotein. The estimated hazard ratios for the composite outcome were 1.36 for AST/ALT ratio [95% CI: 1.25-1.48]; 2.36 for albumin [95% CI:2.08–2.67]; 1.56 for GG T[95% CI: 1.42–1.70]; 3.81 for platelet count [95% CI:3.45–4.20]; and 4.63 for alpha fetoprotein [95% CI:3.60–5.97]. The estimated hazard ratios for all-cause mortality were 2.02 for AST/ALT ratio [95% CI:1 .84–2.20]; 4.30 for albumin [95% CI:3.94–4.70]; 1.21 for GGT [95% CI:1 .11–1.32]; 1.61 for platelet count[95% CI:1 .48–1.75]; and 2.52 for alpha fetoprotein [95% CI:2.15–2.95]. Conclusion: Clinicians need new strategies to manage HCV patients who they believe may not develop liver complications in the short-term and for whom standard therapy is delayed to avoid treatment burden. Disease progression evolves over time, changing the parameters of the treatment decision. Our results identified five common laboratory tests which were correlated with changes in the risk of disease progression over time. Untreated HCV patients can be routinely monitored and treatment decisions revisited for patients with changing risk assessments.

Disclosures:

Jeffrey McCombs - Consulting: BMS; Grant/Research Support: BMS

Tara Matsuda - Grant/Research Support: BMS

Sammy Saab- Advisory Committees or Review Panels: BMS, Gilead, Merck, Vertex, Genentech; Grant/Research Support: Merck, Gilead; Speaking and Teaching: BMS, Gilead, Merck, Vertex, Genentech, Salix, Onyx, Bayer, Kadman; Stock Shareholder: Salix, Johnson and Johnson

Patricia Hines - Employment: Bristol-Myers Squibb

Timothy Juday - Employment: Bristol-Myers Squibb; Stock Shareholder: Bristol-Myers Squibb

Yong Yuan - Employment: Bristol Myers Squibb Company

The following people have nothing to disclose: Ivy Tonnu-Mihara, Gil L' Italian

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People who inject drugs (PWID): Difficult to get into services, easy to cure

Jan Tait1, Brian P. Stephens1, Morgan Evans2, Shirley Cleary1, John F. Dillon1;
1 Dept of Gastroenterology, Ninewells Hospital and Medical School, Dundee, United Kingdom; 2Dept of Infectious Diseases, Ninewells Hospital and Medical School, Dundee, United Kingdom

Background and Aim Within the UK the main source off hepatitis c infection is injecting drug use. If the hepatitis epidemic is to be addressed then robust integrated care pathways need to be in place to ensure that treatment outcomes for injectors are the same as for non injectors. Since 2009 our centre has had a programme in place which offers BBV testing routinely to PWID and has pathways in place to facilitate referral, care and treatment. Methods This was a prospective cohort study of all treatment naive individuals who were treated for hepatitis C in our region from 2009 to the end of 2012. Data collected included risk factors, injecting drug history, evidence of fibrosis, referral and treatment outcomes. Results 347 individuals were included in the study and divided into 2 cohorts. Cohort A included 251 individuals who have a recent history of injecting drug use. The mean age was 33.3 years, 66.1% were on methadone substitution drug treatment. Cohort B included 96 individuals. The mean age was 42.3 years and their risk factors included sexual transmission, blood products, born in high prevalence country, tattoos and piecing. The genotype spread was not significant between the 2 groups however the viral load was significantly lower in group A. In addition PWID had less cirrhosis and lower amount of fibrosis (Table 1). At the end of the study 51 were still on treatment. In Cohort A, 13 were non responders, 178 completed treatment and 21 were non adherent to full course of treatment. In Cohort B, 8 were non responders, 2 died, 2 stopped due to medical complications, 67 completed full course and 5 were non adherent. 25 are in the post treatment phase .The overall SVR was 73.6% in the PWID cohort and 64.1% in the non drug user's cohort. Conclusions The study has shown that recent injecting drug users can have similar or even better treatment outcomes than non injectors. The numbers who adhered to a full course of treatment were similar in both cohorts. Many PWIDs had low viral loads and less prevalence of fibrosis/cirrhosis, so that while this group of patients may be difficult to reach they are younger, have less fibrosis/cirrhosis and are therefore easier to cure if there are effective pathways of care in place.

Table 1. Outcomes of individuals per cohort
 Male sexGenotype 2/3LVL <600,000CirrhosisNo/min fibrosisTreat in-completeSVR
Cohort A190/251 (75.6%)153/251 (60.9%)135/251 (53.7%)27/251 (10.7%)145/251 (57.7%)21/212 (9.9%)137/186 (73.6%)
Cohort B63/96 (65.6%)51/96 (53.1%)39/96 (40.6%)21/96 (21.8%)41/96 (42.7%)5/84 (5.9%)52/81 (64.1%)
p value0.0780.2240.0310.0140.0160.3640.143

Disclosures:

The following people have nothing to disclose: Jan Tait, Brian P. Stephens, Morgan Evans, Shirley Cleary, John F. Dillon

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The natural history of the acquisition of HCV in chaotic PWID

Brian P. Stephens1, Jan Tait1, Morgan Evans2, John F. Dillon1;
1Dept of Gastroenterology, Ninewells Hospital and Medical School, Dundee, United Kingdom; 2Dept of Infectious Diseases, Ninewells Hospital and Medical School, Dundee, United Kingdom

Background & Aims The main transmission route of Hepatitis C virus (HCV) in the U.K. is intravenous drug use, with the highest proportion of new infections being diagnosed in people who inject drugs (PWID). The aims of the study were to evaluate HCV prevalence and seroconvertion within our current PWID population. Methods This prospective cohort study examines the results of HCV Dry Blood Spot (DBS) tests carried out in our region from July 2009 to April 2013.Tests were offered to individuals at needle exchange & drug treatment services. Test results were examined to determine prevalence and individuals, who were negative on their first test but continued to inject illicit drugs were offered routine re-testing after a 12 month time period. Results During the study 1554 tests were performed. 992 (63.8%) were males. Their mean age was 32 years. 1247 had one test and 256 individuals returned for repeat test(s). 387/1247 (31%) were HCV antibody positive on their first test. HCV PCR was established in 341 cases and 219 (64.2%) were positive; therefore 35.8% spontaneously resolved their infection. There was no significant difference between male and female antibody positive and PCR positive tests. 256 individuals have had 281 repeat tests throughout the study 26 repeat tests were discounted as duplicate positive result were identified. The time lapse for retesting varied from 1 to 3 years due to the chaotic nature of the patient cohort, despite all being offered yearly testing. 59 new diagnoses were established on these repeat tests. The HCV antibody positive rate over each time period is detailed in table 1. Conclusion DBS testing is an effective method of testing to establish HCV status within an often chaotic group of PWID. Due to the variance in the time periods of re-testing, it is difficult to draw accurate conclusions on the true annual rate of seroconvertion among PWID; however opportunistic testing can highlight recently acquired HCV infections. Early diagnosis may reduce the rate of onward transmission and provide additional motivation for initiating behaviour change in this chaotic population while allowing specific harm reduction advice to be provided to those most at risk of infection. In addition, routine testing highlights acute and recent infections and can be important for making decisions about treatment.

Table 2. Repeat HCV test
Retested as positiveNumbers testedHCV antibody positivePrevalence
After 1 year18232 
After 2 years772228.6%
After 3 years18527.8%

Disclosures:

The following people have nothing to disclose: Brian P. Stephens, Jan Tait, Morgan Evans, John F. Dillon

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Safety and Efficacy of Telaprevir (TVR) or Boceprevir (BOC) in Patients with Cirrhosis: Interim Results of a Longitudinal, Observational Study

Nezam H. Afdhal1, Nancy Reau2, Gregory T. Everson3, Giuseppe Morelli4, Anna S. Lok5, Kenneth E. Sherman6, Rolland C. Dick-son7, Fredric Regenstein8, Edward A. Mena9, Thomas Stewart10, Michael W. Fried10, PaulJ. Pockros11; 1Hepatology, Harvard Medical School, Boston, MA; 2University of Chicago Medical Center, Chicago, IL; 3University of Colorado, Denver, CO; 4University of Florida, Gainesville, FL; 5University of Michigan Health Sciences, Ann Arbor, MI; 6University of Cincinnati, Cincinnati, OH; 7Dart-mouth-Hitchock Medical Center, Lebanon, NH; 8St. Lukes Hospital, Kansas City, MO; 9HMRI Liver Institute, Pasadena, CA; 10University of North Carolina, Chapel Hill, NC;
11Scripps Clinic, La Jolla, CA

Recent reports suggest that treatment with TVR or BOC triple therapy is associated with a higher incidence of adverse events in cirrhotic populations. The aim of the present study was to evaluate the safety and efficacy of triple therapy in patients with cirrhosis compared to non-cirrhotics. METHODS: HCV-TARGET (HCVT) is a consortium of academic and community medical centers in a longitudinal observational study of patients treated with DAAs. Demographic, clinical, adverse events, and viro-logical data are collected throughout treatment and post-treatment follow-up from sequentially enrolled patients. RESULTS: Of 2,212 pts enrolled in HCVT to date, 970 began treatment prior to July 2012 and have had the opportunity to complete at least 26 weeks of treatment are in the analysis. One-third of the cir-rhotics have esophageal varices and mean MELD score was 8.2, although 12% had MELD >10 at baseline. Treatment d/c of all HCV drugs was similar between cirrhotics and non-cirrhotics (28% vs 23%), although cirrhotics more frequently d/c'd due to adverse event (13% vs 7.5%). Pts with lower PLT or ALB where more likely to d/c treatment; Log odds ratio of discontinuation per 25 unit decrease platelets: 0.11, 95% CI (0.03, 0.19); per unit decrease in albumin: 0.59, 95% CI (0.16, 1.03). Decompensating event defined as hepatic encephalopa-thy, variceal bleeding, new onset ascites occurred in 12%. SVR results for 524 patients that had a determination of virological outcome within a window 6 weeks after stopping therapy (SVR6) are provided in table. CONCLUSIONS: Patients with cirrhosis treated with triple therapy regimens across the U.S. had higher rates of adverse events, including evidence of hepatic decompensation. All-cause treatment discontinuation was associated with features of liver dysfunction and portal HTN. SVR6 rates were lower than non-cirrhotics.

CharacteristicCirrhosis (n=408)Non Cirrhosis (n=531)
Mean Age5654
Male AA66% 13%57% 22%
Varices33%1%
Platelets122k202K
MELD8.2(6–21) 12%> 10N/A
Prior Treatment (Incl REL)63%54%
Anemia65% 23% <8.5g/dl61% 16%<8.5g/dl
RBV Dose Reduction58%46%
EPO / Transfusion37% / 13%32% / 8%
Decomp12%1%
Infection25%22%
Discontinuation all HCV meds28%23%
Discontinue secondary to SAE13%7.5%
BOC SVR6 Naive/ EXP45% (5/ 11)/ 20% (6/30)72% (26/36) 35% (19/55)
TVR SVR6 Naive / EXP47% (36/76)/ 56% (70/124)78% (64/82)/ 64% (70/110)

Disclosures:

Nezam H. Afdhal - Consulting: Merck, Vertex, Idenix, GlaxoSmithKline, Spring-bank, Gilead, Pharmasett, Abbott; Grant/Research Support: Merck, Vertex, Idenix, GlaxoSmithKline, Springbank, Gilead, Pharmasett, Abbott

Nancy Reau - Advisory Committees or Review Panels: Genentech, Kadmon, Jannsen, Vertex, Idenix; Consulting: IHEP; Grant/Research Support: Vertex, Gilead, abbott

Gregory T. Everson - Advisory Committees or Review Panels: Roche/Genentech, Merck, HepC Connection, Roche/Genentech, Merck, HepC Connection; Board Membership: HepQuant LLC, PSC Partners, HepQuant LLC, PSC Partners; Consulting: Roche/Genentech, BMS, Gilead, Roche/Genentech, Bristol-Myers Squibb, Abbott; Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, GSK, Schering-Plough, Bristol-Myers Squibb, Tibotec, GlobeImmune, Pfizer, Abbott, Conatus, Zymogenetics, PSC Partners, Roche/Genentech, Pharmassett, Vertex, GSK, Schering-Plough, Tibotec, GlobeImmune, Pfizer, Gilead, Conatus, Zymogenetics, PSC Partners, Abbott; Management Position: HepQuant LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado, Univ of Colorado

Anna S. Lok - Advisory Committees or Review Panels: Gilead, Immune Targeting System, MedImmune, Arrowhead, Bayer, GSK, Janssen, Novartis; Grant/Research Support: Abbott, BMS, Gilead, Merck, Roche

Kenneth E. Sherman - Advisory Committees or Review Panels: Kadmon, Bioline, Janssen/Tibotec, Fibrogen, MedPace, Merck; Grant/Research Support: Merck, Genentech/Roche, Gilead, Anadys, Briston-Myers Squibb, Vertex, Boehringer-Ingelheim, Novartis

Rolland C. Dickson - Advisory Committees or Review Panels: Biotest

Fredric Regenstein - Grant/Research Support: Bristol-Myers Squibb, Roche/Genentech, Merck; Speaking and Teaching: Salix, Gilead, Vertex, Merck

Edward A. Mena - Advisory Committees or Review Panels: Vertex, Gilead, BMS, Kadmon; Speaking and Teaching: Merck, Genetech

Michael W. Fried - Advisory Committees or Review Panels: GlaxoSmithKline; Consulting: Roche/Genentech, Janssen, Vertex, Merck, Bristol Myers Squibb, Abbott, Merck, Gilead, Novartis; Grant/Research Support: Roche/Genentech, Janssen, Vertex, Merck, Bristol Myers Squibb, Abbott, Merck, Gilead

Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genentech, BMS, Gilead, Vertex, Abbott Labs, Genentech, BMS, Gilead, Vertex; Consulting: Genentech, Lumena, Boehinger Ingelheim, Regulus, Beckman Coulter, Hologic Genprobe, Biotest, Genentech; Grant/Research Support: Novartis, Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim, Lumena, Beckman Coulter, Abbott labs, Mochida Pharmaceuticals, Novartis, Genentech, Merck, BMS, Gilead, Vertex; Speaking and Teaching: Genentech, Merck, Gilead, Vertex, Genentech, BMS, Gilead, Vertex

The following people have nothing to disclose: Giuseppe Morelli, Thomas Stewart

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The Frequency and Management of Adverse Events in Chronic Hepatitis C (HCV) Treated with Boceprevir or Telaprevir: Real World Experience from the HCV-TARGET Longitudinal Observational Study

Stuart C. Gordon1, Andrew J. Muir2, Joseph K. Lim3, Brian Pearl-man4, Curtis K. Argo5, Guy W. Neff6, Ananthakrishnan Ramani7, Benedict Maliakkal8, Maribel Rodriguez-Torres9, Thomas Stewart10, Michael W. Fried10, K. Rajender Reddy11; 1Henry Ford Health System, Detroit, MI; 2Duke University Medical Center, Durham, NC; 3Yale University, New Haven, CT; 4Atlanta Medical Center, Atlanta, GA; 5University of Virginia Health System, Char-lottesville, VA; 6Tampa General Medical Group, Tampa, FL; 7Columbia Memorial Hospital, Hudson, NY; 8Strong Memorial Hospital/ University of Rochester, Rochester, NY; 9Fundación de Investigación de Diego, San Juan; 10University of North Carolina at Chapel Hill, Chapel Hill, NC;
1 1 University of Pennsylvania Hospital, Philadelphia, PA

Frequency and the severity of adverse events (AEs) as reported in the registration trials for boceprevir (BOC) and telaprevir (TVR) may not reflect the post-approval experience. The present analysis defines the safety of these agents and the management of side effects according to local practice patterns across the U.S. METHODS: HCV-TARGET (HCVT) is a consortium of academic and community centers performing a longitudinal observational study of patients treated with direct acting antiviral containing therapy. Demographic, clinical, adverse events and virological data are collected on treatment and in follow-up from sequentially enrolled patients. HCV treatment is administered per local standard of care. RESULTS: Of 2,212 patients enrolled to date, 928 began treatment prior to July 2012, have completed at least 26 weeks of treatment, and are included in this analysis (Table). Patient characteristics: mean age 55 years, male (61%), Caucasian/Black race (77%/ 18%), cirrhosis (43%), median platelets = 165K (range 25K to 472K) and prior treatment experience (57%). AEs requiring a prescription treatment or dosage change occurred in 80% and 73% treated with TVR or BOC, respectively. SAEs occurred in 8% (TVR) and 13% (BOC); 3 patients died (liver failure, sepsis, MI). In multi-variate analysis, severe anemia (Hgb <9.0) was associated with lower baseline hemoglobin (Log odds ratio -0.35; 95%CI -0.52, -0.18), female sex (0.92; 95%CI 0.42, 1.41), and higher baseline creatinine (1.27; 95%CI 0.49, 2.05). Rash was more frequent with TVR (51%) than with BOC (25%), treatment discontinuation of all drugs was in 4% (TPV) and 2% (BOC). DRESS occurred in 2 patients on TVR. Hepatic decompensation events or addition of concomitant meds to treat such events occurred in 5% of the cohort. Premature discontinuation of all HCV drugs due to AE occurred in 10%. Conclusions: Patients treated with triple therapy across a diverse spectrum of medical practices had more advanced disease than in registration trials. Predictors of severe anemia were lower baseline hemoglobin, female gender, and higher baseline creatinine. Treatment was associated with frequent adverse events, although relatively low rates of AE-related treatment discontinuation suggest attentive management of AEs.

CharacteristicTVR (n=704)BOC (n=224)
Anemia: Nadir Hgb <10g/dl or <8.5 g/dl32%/20%38%/15%
SAE Anemia2%5%
Anemia Management (Total population) RBVdose reduction/ EPO use /Transfusion51%/33%/11%43%/40%/9%
Anorectal symptoms/ Dysgeusia30%/20%6%/7%
Skin Rash/ Severe skin rash/SAE skin rash51%/2%/l%25%/0%/0%
Any infection/ SAE infection24%/423%/3
Decompensating event6%3%

Disclosures:

Stuart C. Gordon - Advisory Committees or Review Panels: Tibotec; Consulting: Merck, CVS Caremark, Gilead Sciences, BMS; Grant/Research Support: Roche/Genentech, Merck, Vertex Pharmaceuticals, Gilead Sciences, BMS, Abbott, Intercept Pharmaceuticals, Exalenz Sciences, Inc.

Andrew J. Muir - Advisory Committees or Review Panels: Merck, Vertex, Gilead, BMS, Abbott, Achillion; Consulting: Profectus, GSK; Grant/Research Support: Merck, Vertex, Roche, BMS, Gilead, Achillion, Abbott, Pfizer, Salix, GSK

Joseph K. Lim - Consulting: Merck, Vertex, Gilead, Bristol Myers Squibb, Boehringer-Ingelheim; Grant/Research Support: Abbott, Boehringer-Ingelheim, Bristol Myers Squibb, Genentech, Gilead, Janssen/Tibotec, Vertex, Achillion

Brian Pearlman - Grant/Research Support: BI, BMS, J&J, Abbott; Speaking and Teaching: Merck, Kadmon Pharmaceuticals, Vertex

Curtis K. Argo - Consulting: Wellstat Diagnostics; Independent Contractor: Genen-tech/Roche

Guy W. Neff - Consulting: Genentech, Vertex, Salix; Speaking and Teaching: Genentech, Vertex, Salix, BMS, Merck

Ananthakrishnan Ramani - Employment: columbia memorial hospital; Grant/Research Support: Forest; Speaking and Teaching: Merck, VIIV, Gilead

Maribel Rodriguez-Torres - Consulting: Hoffman La Roche, Abbott Labs, Phar-masset, Akros, Bristol-Myers Squibb, Merck, Vertex, Inhibitex, Genentech, Janssen R&D Ireland, Santaris; Grant/Research Support: Anadys, Novartis, Hoffman-LaRoche, Glaxo Smith Kline, Inhibitex, Bristol-Myers Squibb, Vertex, Idera, Phar-masset, Sanofi-Aventis, Merck, Abbott, Pfizer, Human Genome Sciences, Gilead, Johnson & Johnson, Zymogenetics, AKROS, Scynexis, Santaris, Boehringher, Idenix, Genentech, Beckman Coulter, Mochida Pharmaceutical

Michael W. Fried - Consulting: Genentech, Merck, Abbvie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Grant/Research Support: Genentech, Merck, AbbVie, Vertex, Janssen, Bristol Myers Squibb, Gilead; Patent Held/Filed: HCCPlex

K. Rajender Reddy - Advisory Committees or Review Panels: Genentech-Roche, Merck, Janssen, Vertex, Gilead, BMS, Novartis, Idenix; Grant/Research Support: Genentech-Roche, Merck, BMS, Ikaria, Gilead, Hyperion, Janssen, AbbVie

The following people have nothing to disclose: Benedict Maliakkal, Thomas Stewart

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Successful Interferon Therapy Reverses Enhanced Hepatic Progenitor Cell Activation in Patients with Chronic Hepatitis C

Hidenao Noritake, Yoshimasa Kobayashi, Yukimasa Ohba, Ken-suke Kitsugi, Shin Shimoyama, Satoru Yamazaki, Takeshi Chida, Shinya Watanabe, Kazuhito Kawata, Kinya Kawamura;
Hepatol-ogy Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan

Background: Hepatic progenitor cells (HPC) are activated to differentiate toward biliary and hepatocytic lineages, giving rise to ductular reaction (DR). Enhanced accumulation of activated HPC is related to the risk of progression to HCC. HPCs have been suggested as targets of malignant transformation in chronic liver diseases, including chronic hepatitis C virus (HCV) infection. Interferon (IFN) therapy reduces the risk of progression to HCC in HCV patients. Sustained virological responders have the greatest benefit in terms of reducing the risk of HCC. However, the underlying mechanisms remain unclear. Aims: The aim of this study was to examine the effect of IFN therapy on HPC activation in HCV patients with sustained virological response (SVR) compared to those with non-SVR. Methods: Immunohistochemical detection of cytokeratin 7 (CK7) was performed to evaluate HPC activation in paired pre- and post-treatment liver biopsies from 18 HCV patients with SVR to IFN-based therapy and from 23 patients with non-SVR, and in normal liver tissue obtained from surgical resection specimens of 10 patients. HPC activation was evaluated by quantifying the immunoreactivity of CK7 in portal and periportal areas using computer-assisted image analysis. Results: Pretreatment HCV livers showed increased CK7 immunoreactivity compared with normal livers (HCV: median, 1.38%; normal: median, 0.69%, P=0.006); the portal and periportal CK7-immunoreac-tive areas comprised anatomical bile ducts and DR in pretreatment HCV livers, whereas the immunoreactive areas comprised anatomical bile ducts only without DR in normal livers. The CK7-immunoreactivity in pretreatment HCV livers was positively correlated with the degrees of hepatic necroinflammation and fibrosis (necroinflammation: r=0.386, P=0.017; fibrosis: r=0.472, P=0.003). In the patients with SVR, CK7-immunore-activity was attenuated after IFN treatment (median, 1.57% pre-IFN vs. 0.69% post-IFN, P=0.001), whereas IFN treatment did not improve CK7-immunoreactivity in non-SVR patients (median, 1.32% pre-IFN vs. 1.63% post-IFN, P=0.738). By multiple logistic regression analysis, SVR was a significant independent factor for normalization of CK7-immunoreactivity (<0.8%) (odds ratio = 9.4; 95% CI=2.2–39.1, P=0.002). Conclusions: Enhanced HPC activation occurs in chronic HCV infection. Successful IFN therapy can reverse enhanced HPC activation in chronic hepatitis C. Reduction of HPC activation in patients with successful IFN treatment may contribute to reducing the risk of HCC development.

Disclosures:

The following people have nothing to disclose: Hidenao Noritake, Yoshimasa Kobayashi, Yukimasa Ohba, Kensuke Kitsugi, Shin Shimoyama, Satoru Yamazaki, Takeshi Chida, Shinya Watanabe, Kazuhito Kawata, Kinya Kawamura

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Genome-wide association analysis to evaluate genetic variations associated with rash development in telapre-vir phase 2 and 3 studies

James C. Sullivan1, Darin Takemoto1, Jeroen Aerssens2, Kevin Kel-liher1, Brian Hare1, Leif Bengtsson1, Raymond A. Rubin1, David B. Goldstein3, Martyn Botfield1;
1Vertex Pharmaceuticals Incorporated, Cambridge, MA; 2Janssen Infectious Diseases BVBA, Beerse, Belgium; 3Human Genome Research Institute, Duke University School of Medicine, Durham, NC

In the Phase 3 telaprevir studies, rash events during the telapre-vir treatment phase were more frequent and greater in severity in patients receiving telaprevir (T) in combination with pegin-terferon and ribavirin (PR) compared with PR alone, with severe (Grade > 3) rash occurring in 3.7% (66/1797) of T/PR-treated patients as compared with 0.4% (2/493) in PR-treated patients. Identifying genetic risk factors associated with development of rash in telaprevir-treated patients could potentially help inform clinical treatment decisions. As such, this retrospective analysis sought to identify genetic variations that may correlate with development of telaprevir-related severe rash. De-identified DNA samples isolated from blood of patients with genotype 1 chronic hepatitis C (HCV) infection who had been enrolled in the telaprevir Phase 2 and 3 studies were used. A total of 556 DNA samples were utilized; 60 were from patients who experienced severe (Grade > 3) rash, and 496 were from patients who did not experience rash during 12 weeks of telaprevir combination treatment. After employing industry standard data quality control metrics, 58 'severe rash' samples and 477 'no rash' samples were used for genome-wide association (GWA) testing. GWA utilized single nucleotide polymorphisms (SNPs) generated using the Affymetrix 6.0 SNP chip. All SNP loci that passed quality control criteria were assessed for association with rash using logistic regression after correcting for age and population stratification, as were all copy number variants that could be inferred from the SNP data. There was no significant association between any genomic variation and rash in patients treated with telaprevir. The SNP with the greatest association (rs17576821) had an odds ratio of 4.851 (Uncorrected p=lxl0-7; Bonferroni-corrected p=0.089). A sensitivity analysis using only SNPs in the extended major histocompatibility complex region revealed that there was no significant association between any SNP and the development of rash with telaprevir in this limited subset of the data. The genomic variations identified in this analysis did not show a significant association with telaprevir-related severe rash. However, these findings do not preclude the possibility of genomic variation being associated with severe rash, and the methodology utilized in this investigation may have utility for other GWA analyses.

Disclosures:

James C. Sullivan - Employment: Vertex Pharmaceuticals Incorporated; Stock Shareholder: Vertex Pharmaceuticals Incorporated

Darin Takemoto - Employment: Vertex Pharmaceuticals; Stock Shareholder: Vertex Pharmaceuticals

Jeroen Aerssens - Employment: Janssen Infectious Diseases bvba; Stock Shareholder: Johnson & Johnson

Kevin Kelliher - Employment: Vertex Pharmaceutical Inc.; Stock Shareholder: Vertex Pharmaceutical Inc.

Brian Hare - Employment: Vertex Pharmaceuticals; Stock Shareholder: Vertex Pharmaceuticals

Leif Bengtsson - Employment: Vertex, Vertex, Vertex, Vertex; Stock Shareholder: Vertex, Vertex, Vertex, Vertex

Raymond A. Rubin - Employment: Vertex Pharmaceuticals

David B. Goldstein - Advisory Committees or Review Panels: Astra Zeneca, NIH, Biogen, Gordon Research Conference; Board Membership: Knome; Consulting: glaxo smithkline, Severe Adverse Events Consortium, Roche, Gilead Sciences, Inc, Scienta Advisors; Employment: Duke University; Grant/Research Support: UCB, NIH, Biogen, Henry M Jackson Foundation, SAIC, Inc, Bill & Melinda Gates Foundation, Eisai, Inc; Patent Held/Filed: patent IL28B findings, patent ITPA findings, Merck & Company; Speaking and Teaching: Current Biology magazine, Illu-mina, Regeneron, Dermatology Society; Stock Shareholder: Pfizer

Martyn Botfield - Employment: Vertex Pharmaceuticals; Stock Shareholder: Vertex Pharmaceuticals

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Ribavirin Resets the STAT4-Dependent IFN-γ Responsiveness of Natural Killer Cells in Hepatitis C

Jens M. Werner, Elisavet Serti, Xenia Chepa-Lotrea, Jonathan D. Stoltzfus, Golo Ahlenstiel, Jordan J. Feld, T. Jake Liang, Yaron Rot-man, Barbara Rehermann;
Liver Diseases Branch, NIDDK, National Institutes of Health, Bethesda, MD

BACKGROUND: Ribavirin (RBV) is an important component of IFN-α-based treatment regimens for hepatitis C and newer regimens with direct acting antivirals. While RBV's mechanism of action is largely unknown it was suggested that it affects the induction of interferon-stimulated genes. We have previously shown that NK cells can be used as sensitive biomarkers of IFNα/β receptor signaling. In HCV patients NK cells are activated due to chronic stimulation by endogenous type I IFN (Gastroenterology 2010; 138:325–35), resulting in increased pSTAT1-dependent cytotoxicity and decreased pSTAT4-depend-ent IFN-γ production of NK cells. IFN-α-based treatment exacerbates this phenotype (Gastroenterology 2011 ;141:1231–9; Hepatology 2012;55:39–48). AIM: We asked whether RBV improves IFN-γ production of NK cells in response to IFNα. METHODS: 54 HCV patients were randomized to receive either 4 weeks of RBV (n=22) or no pretreatment (n=32) prior to standard PegIFN/RBV. NK cells were studied at week -4

(start of RBV therapy), 0 hours (start of PegIFN/RBV therapy) and weeks 1, 2, 4 and 12 thereafter for pSTAT 1 /pSTAT4 levels, cytotoxicity, and IFN-γ production by flow cytometry. RESULTS: RBV pretreatment resulted in a modest reduction of HCV RNA levels by 0.5 log10 (P=0.0001) and ALT levels by 38% (P<0.0001). NK cells became less activated as evidenced by decreased cytotoxicity P=0.049), which was correlated with decreased pSTAT1 (Rho=0.45, P=0.045) and decreased ALT levels (Rho=0.52, P=0.0159). NK cell IFN-γ production decreased more than cytotoxicity (P=0.001) and was correlated with both decreased pSTAT4 levels (Rho=0.58, p=0.019) and decreased viral titer (Rho=0.61, p=0.004). None of these changes were observed in the control group that did not receive RBV. In vitro and in vivo pretreatment with RBV improved the responsiveness of NK cells to subsequent stimulation with IFN-α. Specifically, RBV pretreatment of PBMCs improved STAT4 signaling upon subsequent stimulation with IFN-α (P=0.008). Similarly, PBMCs of RBV-treated patients showed improved STAT4 signaling upon in vitro stimulation with IFN-α (P=0.0093). Accordingly, patients who were pretreated with RBV had a better pSTAT4-dependent IFN-γ response upon subsequent PegIFN/RBV therapy than those who did not receive RBV pretreament. The differential IFN-γ production was maintained for at least 12 weeks and correlated with the second phase virological response. CONCLUSION: RBV modulates NK cell function in vitro and in vivo. RBV improves the NK cell responsiveness to IFN-α, resulting in enhanced STAT4 signaling and IFN-γ production. This may contribute to decreased HCV replication and ultimately HCV clearance.

Disclosures:

Jordan J. Feld - Advisory Committees or Review Panels: Roche, Merck, Vertex, Gilead, Abbott, Tibotec, Theravance, Achillion; Speaking and Teaching: Merck, Roche, Abbott

The following people have nothing to disclose: Jens M. Werner, Elisavet Serti, Xenia Chepa-Lotrea, Jonathan D. Stoltzfus, Golo Ahlenstiel, T. Jake Liang, Yaron Rotman, Barbara Rehermann

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Efficacy of pegylated interferon and ribavirin combination therapy for patients with hepatitis C virus infection after curative resection or ablation for hepatocellular carcinoma

Naoki Harada1, Naoki Hiramatsu1, Tsugiko Oze1, Naoki Mor-ishita1, Ryoko Yamada1, Masanori Miyazaki1, Takayuki Yakushi-jin1, Sadaharu Iio2, Akira Yamada3, Toshifumi Ito4, Taizo Hijioka5, Masami Inada6, Kazuhiro Katayama7, Shinji Tamura8, Atsuo Inoue9, Eijirou Hayashi10, Michio Kato11, Hayato Hikita1, Ryotaro Sakamori1, Takuya Miyagi1, Tomohide Tatsumi1, Tatsuya Kanto12, Akinori Kasahara1, Norio Hayashi13, Tetsuo Takehara1; 1Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan; 2Higashiosaka city general hospital, Higashiosaka, Japan; 3Sumitomo Hospital, Osaka, Japan; 4Osaka Koseinenkin Hospital, Osaka, Japan; 5National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Japan; 6Toyonaka Municipal Hospital, Toyonaka, Japan; 7Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka, Japan; 8Minoh City Hospital, Minoh, Japan; 9Osaka General Medical Center, Osaka, Japan; 10Kinki Central Hospital of Mutual Aid Association of Public School Teachers, Itami, Japan;
1 1National Organization Minami Wakayama Medical Center, Tanabe, Japan; 12National Center for Global Health and Medicine, Tokyo, Japan; 13Kansai Rosai Hospital, Amagasaki, Japan

Background and Aim: Approximately half of patients with chronic hepatitis C virus (HCV) infection who receive curative resection or ablation for hepatocellular carcinoma (HCC) experience HCC recurrence within 3 years. In this study, we aimed to investigate the anti-viral effect of pegylated interferon (Peg-IFN) plus ribavirin combination therapy and the impact of this therapy on HCC recurrence. Patients & Methods: This retrospective multicenter study was conducted at Osaka University Hospital and at institutions participating in the Osaka Liver Forum. A total of 99 patients with chronic HCV infections who received curative resection or radiofrequency ablation for primary HCC, met the Milan criteria and were treated with Peg-IFN plus ribavirin therapy between December, 2004 and December, 2009 were enrolled in this study (75 males, 24 females; mean age, 65.0 ± 5.9 y.o.; 79 HCV genotype 1, 20 genotype 2; platelet counts 12.7 ± 3.2 x 104 /μl). The antiviral and adverse effects of this therapy were examined. An analysis of HCC recurrence was performed for 40 patients who had received curative treatment for a single HCC and who were observed for a period of 27.6 ±18.1 months. The factors associated with HCC recurrence were examined using a log-rank test for univariate analysis and a Cox proportional-hazards model for multivariate analysis. Results: The discontinuation rate of the Peg-IFN plus ribavirin combination therapy was 25% (25/99). The major causes for discontinuation of this therapy included HCC recurrence (36%), fatigue (16%), anemia (8%), interstitial pneumonia (8%), appetite loss (8%), etc. Among the patients who completed the therapy, the sustained virologic response (SVR) rates were 35% for the genotype 1 patients and 56% for the genotype 2 patients. HCC recurrence occurred for 18 of the 40 patients considered, and the log-rank test indicated that recurrence was significantly associated with lower platelet counts (< 12 x 104/mm3 vs. > 12 x 104/mm3, p = 0.024) and a SVR (SVR vs. non-SVR, p = 0.023). These two factors served as independent factors of HCC recurrence in the Cox proportional-hazards model (platelet counts< 12 x 104/mm3 vs. > 12 x 104/mm3, HR = 3.19, p = 0.019; SVR vs. non-SVR, HR = 0.190, p = 0.029). The cumulative incidence of HCC recurrence at 3 years was 15.3% in the SVR patients and 58.2% in the non-SVR patients. Conclusion: Patients with HCV infection after curative treatment for HCC should be considered as candidates for anti-viral therapy to reduce the incidence of HCC, especially patients with lower platelet counts. Careful HCC surveillance should be performed for these patients.

Disclosures:

Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD K.K.

The following people have nothing to disclose: Naoki Harada, Naoki Hiramatsu, Tsugiko Oze, Naoki Morishita, Ryoko Yamada, Masanori Miyazaki, Takayuki Yakushijin, Sadaharu Iio, Akira Yamada, Toshifumi Ito, Taizo Hijioka, Masami Inada, Kazuhiro Katayama, Shinji Tamura, Atsuo Inoue, Eijirou Hayashi, Michio Kato, Hayato Hikita, Ryotaro Sakamori, Takuya Miyagi, Tomohide Tatsumi, Tat-suya Kanto, Akinori Kasahara, Norio Hayashi

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cost-saving approach to triple therapy for hepatitis C using the OPTIM prognostic tool to predict virologic response to 4 weeks of peginterferon and ribavirin in genotype 1 patients

Juan Turnes1, Itziar Oyagüez2, Ramon Planas3, Javier García-Samaniego4, Moisés Diago5, Javier Crespo6, Jose Luis Calleja7, Ricard Solá8, Miguel A. Casado2, Manuel Romero-Gomez9;
1Com-plejo Hospitalario de Pontevedra, Pontevedra, Spain; 2Pharma-coeconomics & Outcomes Research Iberia, Madrid, Spain; 3Hospital Germans Trias I Pujol, Badalona, Spain; 4Hospital Carlos III & CIBERehd, Madrid, Spain; 5Hospital General de Valencia, Valencia, Spain; 6Hospital Marqués de Valdecilla, Santander, Spain; 7Hospital Puerta de Hierro, Madrid, Spain; 8Hospital El Mar, Barcelona, Spain; 9Hospital de VaIme & CIBERehd, Sevilla, Spain

BACKGROUND In hepatitis C patients receiving bocepreviror telaprevir based-triple therapy, virological response at week 4 after double peginterferon + ribavirin (P+R) therapy could predict the possibility of achieving sustained viral response. A prognostic tool has been recently developed to predict rapid viral response (RVR) and/or a decline of 1 log10 HCV-RNA (D1 L) at week 4 of double therapy in naïve patients (Romero-Gómez et al. J Hepatol 2013;58:894A). The aim of this study was to assess the economic impact on total costs for different strategies using or not the current tool. METHODS A cost-analysis was performed to assess the differences of 48 weeks treatment cost with or without prognostic tools implementation. A decision tree (Figure 1) was designed to predict RVR and D1 L. Time horizon lasted less than 1 year, and therefore any discount rate was applied. Pharmaceutical costs were calculated according to Summary Product Characteristics recommendations, and assuming the whole recommended duration. The study was carried out from the perspective of the Spanish National Health Service. Triple therapy costs were calculated as average cost of boceprevir and telaprevir treatments for 48 weeks (€36,218.62). Alternative scenarios were tested modifying sensitivity and positive predictive value of prognostic tools with 95% CI limits, and triple therapy costs. RESULTS Total cost (€, 2013) for hepatitis C therapy per patient was estimated to be €36,218.62 along 48 weeks. The implementation of prognostic tool was associated to €10,720.15 savings per patient in the base case scenario. The total savings per patient in alternative scenarios ranged from €9,716.08 to €12,326.86. Assuming €1,000,000 of fixed budget, the implementation of the prognostic tool would enable a cost reduction of 29,6% that could allow the treatment of additional 12 patients in base case scenario within the existing budget. CONCLUSIONS The model showed that the implementation of this tool could be a cost-saving strategy compared to universal triple therapy for hepatitis C that could contribute to a more efficient allocation of the available resources.

Disclosures:

Juan Turnes - Advisory Committees or Review Panels: Roche; Speaking and Teaching: Roche, Janssen, MSD, BMS, Gilead

Itziar Oyagüez - Consulting: Janssen Cilag, Roche

Ramon Planas - Advisory Committees or Review Panels: Novartis, Abbott, BMS, Novartis, Abbott, BMS, Novartis, Abbott, BMS, Novartis, Abbott, BMS; Grant/Research Support: Roche, Guilead, Roche, Guilead, Roche, Guilead, Roche, Guilead

Javier García-Samaniego - Consulting: Boehringer-Ingelheim

Moisés Diago - Grant/Research Support: ROCHE, MSD, GILEAD, BMS, JANSSEN, ABBVIE, GLAXO, BOERINGHER

Javier Crespo - Board Membership: MSD, Roche, Janssen, Gilead

Miguel A. Casado - Consulting: Gilead, Novartis, Gilead, Novartis, Gilead, Novartis, Gilead, Novartis, Janssen-Cilag, Roche

Manuel Romero-Gomez - Advisory Committees or Review Panels: Roche Farma,SA., MSD, S.A., Janssen, S.A., Abbott, S.A.; Grant/Research Support: Ferrer, S.A.

The following people have nothing to disclose: Jose Luis Calleja, Ricard Solá

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Predictive factors of survival in liver retransplantation for hepatitis C recurrence: the importance of HCV therapy

Alice T. Song1,2, Rodolphe Sobesky3,4, Carmen Vinaixa4,5, Jérôme Dumortier6, Sylvie Radenne7, Francois Durand8, Yvon Calmus9, Géraldine Rousseau10, Marianne Latournerie1 1, Cyrille Feray12, Valérie Delvart4, Bruno Roche4, Stéphanie Haïm-Boukoza1, Anne-Marie Roque-Afonso1, Denis X. Castaing4, Edson Abdala2, Jean-Charles Duclos-Vallee1,4, Marina Berenguer5, Didier Samuel4,1;
1Unit 785, Inserm, Villejuif, France; 2Hospital clinicas, Sao Paulo, Brazil; 3UMR-S785, Univ Paris-Sud, Villejuif, France; 4Centre Hepato-Biliaire, AP-HP Hopital Paul Brousse, Villejuif, France; 5La Fe Hospital, Valencia, Spain; 6Hopital Edouard Herriot, Lyon, France; 7Hopital de la Croix Rousse, Lyon, France; 8AP-HP, Hopital Beaujon, Clichy, France; 9 AP-HP, Hopital Saint Antoine, Paris, France; 10AP-HP, Hopital Pitie Salpetriere, Paris, France; 11CHU Pontchaillou, Rennes, France; 12AP-HP, Hopital Henri Mondor, Creteil, France

Background: Hepatitis C (HCV) recurrence after liver transplantation is the main cause of mortality and graft loss in patients transplanted with detectable viral load. In patients with established cirrhosis and graft failure, liver retransplantation (reLT) is the only therapeutic option. The procedure of reLT for patients with HCV-related disease is debatable in the context of organ shortage. Objectives: We aimed to identify risk factors associated with survival in patients retransplanted for HCV recurrence and to apply a survival score recently published by Andres et al. (Transplantation 2012;93:717–722). We also aimed to compare reLT cases with those with graft failure due to HCV recurrence without reLT. Methods: This is a retrospective, multicentric and comparative study. Two groups were analyzed: reLT patients due to HCV-related disease and patients with Metavir F4 or fibrosis cholestatic hepatitis (FCH) on the first graft. Kaplan-Meier analysis were used to estimate the 3, 5 and 10-year survival rates. We assessed variables potentially associated to prognosis and variables with significant results in the univariate analyses were used to design multivariate evaluation. Results: Between 1994 to 2012, we analyzed 108 patients retransplanted for HCV recurrence and 164 patients presenting fibrosis F4 or FCH post-transplant with decompensation. Overall survival was 55%, 47% and 43% at 3, 5, and 10 years, respectively in reLT patients, compared to 27%, 18% and 9% à 3, 5, and 10 years in patients with graft failure without reLT (p<0.0001). For 102 reLT patients the mean score was 43.4±6.6. In univariate analysis, an Andres score < 40 was associated with better survival (p=0.019). In our cohort, Five years survival was 40% in patients with Andres score > 40, better than 5 years survival of 27% published in Andres cohort. In multivariate analysis, factors associated with better survival were: negative HCV viremia before reLT (p=0.0052), antiviral therapy after reLT (p<0.0001), non-split graft (p=0.0217), non-genotype 1 (p=0.017) and retransplantation donor age <60 years (p=0.0027). Conclusions: Overall survival after reLT for HCV recurrence was 55%, 47% and 43% at 3, 5, and 10 years, respectively, significantly better than in patients with decompensated cirrhosis on the graft without reLT (p<0001). In multivariate analysis, antiviral therapy pre and post-retrans-plantation, non-split graft, non-genotype 1, and lower retransplantation donor age represent major prognostic factors for better survival in retransplantation for HCV recurrence. In our cohort, the Andres score overestimates the mortality.

Disclosures:

Jérôme Dumortier - Board Membership: Novartis, Astellas, Roche; Consulting: Novartis; Grant/Research Support: Novartis, Astellas, Roche, MSD, GSK

Francois Durand - Advisory Committees or Review Panels: Astellas, Novartis; Speaking and Teaching: Gilead

Marina Berenguer - Advisory Committees or Review Panels: Novartis, Astellas, Janssen, BMS

Didier Samuel - Consulting: Astellas, BMS, Gilead, Janssen-Cilag, LFB, MSD, Novartis, Roche, Biotest

The following people have nothing to disclose: Alice T. Song, Rodolphe Sobesky, Carmen Vinaixa, Sylvie Radenne, Yvon Calmus, Géraldine Rousseau, Marianne Latournerie, Cyrille Feray, Valérie Delvart, Bruno Roche, Stéphanie Haïm-Boukoza, Anne-Marie Roque-Afonso, Denis X. Castaing, Edson Abdala, Jean-Charles Duclos-Vallee

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Treatment Of Hepatitis C Genotype 1 Patients With Severe Fibrosis Or Compensated Cirrhosis: Efficacy Results To Week 16 On 1587 Patients From The International Telaprevir Early Access Program

Paulo R. Abrão Ferreira1, Massimo Colombo2, Petr Urbanek3, Simone I. Strasser4, Christophe Moreno5, Inmaculada Fernández6, Djamal Abdurakhmanov7, Adrian Streinu-Cercel8, Giovanni B. Gaeta9, Anke Verheyen10, Wafae Iraqi11, Ralph DeMasi12, Andrew Hill13, Joerg M. Läuffer14, Isabelle Lonjon-Domanec11, Heiner Wedemeyer15;
1INFECTIOUS DISEASE, FEDERAL UNIVER-SYTI OF SÃO PAULO, São Paulo, Brazil; 2Department of Medicine, Division of Gastroenterology, Universita' degli Studi di Milano, Milan, Italy; 3Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic; 4Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia; 5Liver Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium; 6Sección de Aparato Digestivo, Hospital Universitario 12 de Octubre, Madrid, Spain; 7I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation; 8Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases “Prof.Dr. Matei Bals”, Bucharest, Romania; 9Viral Hepatitis Unit, Department of Infectious Diseases, Second University, Naples, Italy; 10Janssen Pharmaceutica, Beerse, Belgium; 11Janssen Pharmaceuticals, Paris, France; 12Janssen Research & Development LLC, Titusville, NJ; 13MetaVirology Ltd, London, United Kingdom; 14Janssen-Cilag AG, Zug, Switzerland; 15Medi-zinische Hochschule Hannover, Hannover, Germany

Background and aims: HEP3002 is an ongoing, open-label, early access program of telaprevir (TVR) in 16 countries, for patients with genotype 1 hepatitis C with severe fibrosis or compensated cirrhosis. Methods: Patients were treated with TVR, pegylated interferon-alpha and ribavirin (PR) for 12 weeks, followed by PR. Liver biopsy or non-invasive tests showing severe fibrosis (Metavir F3 or Ishak 3–4) or cirrhosis (Metavir F4 or Ishak 5–6) and platelet count >90,000/mm3 were required at entry. This interim (ITT) analysis included 16 week data from the first 1587 patients. Results: Mean age was 53 years and mean weight 78kg; 64% were male and 98% Caucasian, 66% had HCV RNA levels >800,000 IU/mL, 47%/53% had severe fibrosis/cirrhosis, 22% had genotype 1a, 20% were treatment naïve, 34% prior relapsers, 43% prior non-responders and 3% had prior viral breakthrough. HCV RNA responses (percent undetectable) at Weeks 4 and 12 (ITT analysis) are shown below. Overall, 40/1587 patients (2.5%) met the stopping rule for early discontinuation of TVR. In a multivariate analysis, four baseline factors were associated with a higher chance of eRVR: baseline viral load <800,000 IU/mL (OR=1.47, 95% CI 1.18–1.85), Genotype 1b (OR=1.52, 95% CI 1.16–1.96), alpha-fetoprotein (AFP) <10 pg/mL (OR=2.36, 95% CI 1.82–3.23) and naïve, relapser or prior partial response versus prior null response (OR=2.0, 95% CI1.56–2.5). The rates of eRVR were 20/50 (40%), 77/235 (33%), 262/500 (52%), 349/584 (60%) and 173/200 (79%) for patients with 0, 1, 2, 3 or 4 of these predictive factors, respectively. Conclusions: In this TVR early access program for patients with severe fibrosis or compensated cirrhosis, 82% of patients had undetectable HCV RNA by Week 12 (ITT), while 55% had eRVR. The strongest predictors of eRVR were baseline HCV RNA, sub-genotype, AFP and prior response.

Percent HCV RNA not detected / WeekWeek 4 (RVR)Week 4+12 (eRVR)Week 12
  1. RVR: rapid virologic response; eRVR: extended RVR

Naϊve (n=321)65%60%85%
Relapser (n=531)70%70%88%
Partial responder (n=203)59%53%80%
Null responder (n=436)46%41%72%
Overall (n=l587)60%55%82%

Disclosures:

Paulo R. Abrão Ferreira - Grant/Research Support: ABBOTT, ROCHE, BMS, JANSSEN; Speaking and Teaching: ROCHE, BMS, JANSSEN

Massimo Colombo - Advisory Committees or Review Panels: BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, Janssen Cilag, Achillion; Grant/Research Support: BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD; Speaking and Teaching: Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX, Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX

Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie, Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb, MSD, Roche Products Australia, Gilead, Janssen

Djamal Abdurakhmanov - Grant/Research Support: Roche; Speaking and Teaching: BMS, Jansenn, MSD, Novartis

Giovanni B. Gaeta - Advisory Committees or Review Panels: Janssen, Boheringer Ing; Speaking and Teaching: BMS, Gilead, Roche, MSD, Novartis

Anke Verheyen - Consulting: Janssen Pharmaceutica

Wafae Iraqi - Employment: Janssen

Ralph DeMasi - Management Position: Johnson and Johnson

Andrew Hill - Consulting: Janssen

Joerg M. Läuffer - Employment: Janssen; Stock Shareholder: Janssen

Isabelle Lonjon-Domanec - Employment: Janssen

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

The following people have nothing to disclose: Petr Urbanek, Christophe Moreno, Inmaculada Fernández, Adrian Streinu-Cercel

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Efficacy and safety of therapy with Telaprevir (DAA) in genotype 1 coinfected patients with advanced fibrosis. Six month follow-up data

Miguel A. von Wichmann1, Ana Moreno2, Enrique Ortega3, Jose Antonio Mira4, Marisa Montes5, María J. Tellez6, Carmen Quereda2, José A. Iribarren1, Miguel García Deltoro3, Manuel Márquez Solero7, Joseba Portu8, Juan J. Gonzalez-García5, Koldo Aguirrebengoa9, José-Ramón Blanco10, Juan Berenguer11, Luis F. López Cortés12, Angela M. Camacho13;
1 Infectious Diseases Unit, Hosp Univ Donostia, San Sebastián, Spain; 2Hosp Univ Ramón y Cajal, Madrid, Spain; 3Hosp Gral Univ de Valencia, Valencia, Spain; 4Hosp Univ de Valme, Sevilla, Spain; 5Hosp Univ La Paz, Madrid, Spain; 6Hosp Clínico San Carlos, Madrid, Spain; 7Hosp Univ Virgen de la Victoria, Madrid, Spain; 8Hosp Univ Txagorritxu, Vitoria, Spain; 9Hosp Univ de Cruces, Barakaldo, Spain; 10Hosp San Pedro CIBIR, Logroño, Spain; 11Hosp Univ Gregorio Marañón, Madrid, Spain; 12Hosp Univ Virgen del Rocío, Sevilla, Spain; 13Hosp Univ Reina Sofía, Cordoba, Spain

Background: Triple therapy with telaprevir in clinical trials, in naïve coinfected patients, genotype 1, with mild fibrosis has shown comparable efficacy to HIV negative patients. There is very limited experience in more difficult to treat populations, as patients who failed to treatment and advanced fibrosis. We present the preliminary data of patients with advanced fibrosis not included in clinical trials in several spanish cohorts. Methods: All patients with advanced fibrosis who started treatment with telaprevir, and have at least 6 months of follow-up, were included. We used transient elastography for the staging of liver fibrosis (> 9.5 kPa for F3 and> 12.5 for F4). All were treated with pegylated IFN alpha2a or 2b, ribavirin weight adjusted; only 2 patients with lead-in. Toxicity was grade with the ACTG scale. Results: We studied 86 HCV genotype 1 coinfected patients, F3/F4: 19,8%/80,2%, Male/Female: 73/13, mean age 48,7+5,1 years, weight 73+13,4 kg, CD4 mean 716/mm3, HIV.viral load <20 copies/mL in 87%. All but three were on ART: 47 included raltegravir, 28 boosted atazanavir, 20 etravirine and 90% with nucleosides. HCV genotypes were: genotype1a/1b/mixed/nt: 43/30/2/11, HCV-VL >800K IU/mL: 72%, IL28B: CC 31%. The majority of patients have been previously treated of chronic HCV infection (79%): null responders, partial responders, relapsers, 22,1%/24,4%/29%. The HCV viraemia became negative (ITT) in the fourth week of triple therapy in 70,9%, 82,6% at week 12 and 67,4% at week 24. In NR/PR/relapsers VL under 15 IU/mL at week 24, was observed in: 47,3%, 66,6% and 84% respectively; in naïves 66,6%. Treatment was terminated prematurely in 25 (29%) (failure 10, rebound in 6, toxicity and side effects 4). There were two cases of decompensation, and 11 bacterial infections, one with hospitalization, 3 people died, one liver related. Severe adverse events (death, liver decompensation or admission) happened in 4/66 patients with more than 100.000 platelets/mm3 and 1/20 under 100.000 platelets/ mm3. Hematological toxicity grade 3–4 appeared in: 27% in Hb, 29% neutropenia and 66% in platelets. EPO and derivatives were used in 18,6% of patients, 9,3% received transfusions and G-CSF in 11,6%. Conclusions: Preliminary data available in this hard to treat population show an adequate efficacy profile with relevant toxicities. Expertise in follow-up with this therapy seems advisable in patients with cirrhosis. Thrombocytopenia is multifactorial in HIV + patients and has a lower predictive value of severe complications than described in HIV- patients.

Disclosures:

Miguel A. von Wichmann - Grant/Research Support: Abbott, Janssen, MSD, Bristol-Myers Squibb, Gilead, ViiV healthcare, Roche Farma

Enrique Ortega - Board Membership: Gilead, Jannsen, VIIV

María J. Tellez - Advisory Committees or Review Panels: BMS, ViiV, AbbVie, MSD, GILEAD

Miguel García Deltoro - Advisory Committees or Review Panels: Janssen, MSD, Gilead, VIIV, BMS; Board Membership: Janssen, VIIV; Consulting: Janssen, MSD, Gilead, Boehringuer, VIIV, BMS; Grant/Research Support: Janssen, VIIV

Joseba Portu - Grant/Research Support: Janssen, Gilead, Abbott, MSD, ViiV

Juan J. Gonzalez-García - Board Membership: ROCHE, MSD, ABBOTT, JANSSEN and CILIAG; Speaking and Teaching: ROCHE, MSD, ABBOTT, JANSSEN and CILIAG

Juan Berenguer - Advisory Committees or Review Panels: Abbvie, BMS, GILEAD, JANSSEN, MSD; Grant/Research Support: BMS, MSD, ViiV Healthcare, ViiV Healthcare; Speaking and Teaching: Abbvie, BMS, GILEAD, JANSSEN, MSD

Luis F. López Cortés - Grant/Research Support: Abbott laboratories (Spain), Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag España, Merck Sharp & Dohme, Roche Pharma, ViiV Healthcare

The following people have nothing to disclose: Ana Moreno, Jose Antonio Mira, Marisa Montes, Carmen Quereda, José A. Iribarren, Manuel Márquez Solero, Koldo Aguirrebengoa, José-Ramón Blanco, Angela M. Camacho

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Predictive factors of premature discontinuation of triple therapy in the International Telaprevir Early Access Program

Giovanni B. Gaeta1, Massimo Colombo2, Paulo R. Abrão Fer-reira3, Simone I. Strasser4, Petr Urbanek5, Christophe Moreno6, Inmaculada Fernández7, Djamal Abdurakhmanov8, Adrian Streinu-Cercel9, Anke Verheyen10, Wafae Iraqi11, Ralph DeMasi12, Andrew Hill13, Joerg M. Läuffer14, Isabelle Lonjon-Domanec11, Heiner Wedemeyer15;
1Dept Infectious Dis, Second University, Naples, Italy; 2Department of Medicine, Division of Gastroenterol-ogy Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlin-ico, Universita' degli Studi di Milano, Milan, Italy; 3Outpatient Clinic to HIV and Viral Hepatitis Division of Infectious Disease, Federal University of São Paulo, São Paulo, Brazil; 4Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia; 5Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic; 6Department of Gastroenterology and Hepatopancre-atology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; 7Hospital Universitario 12 de Octubre, Sección de Aparato Digestivo, Madrid, Spain; 8I.M. Sechenov First Moscow State Medical University, E. M. Tareev Clinic for Nephrology, Internal and Occupational Medicine, Moscow, Russian Federation; 9 Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases “Prof.Dr. Matei Bals”, Bucharest, Romania; 10Janssen Pharmaceutica, Beerse, Belgium; 11Janssen Pharmaceuticals, Paris, France; 12Janssen Research & Development LLC, Titusville, NJ; 13MetaVirology Ltd, London, United Kingdom; 14Janssen-Cilag AG, Zug, Switzerland; 15Medizinische Hochschule Hannover, Hannover, Germany

Background and aims: HEP3002 is an ongoing, open-label, early access program of telaprevir (TVR) in 16 countries, for patients with genotype 1 hepatitis C with severe fibrosis or compensated cirrhosis. The second interim analysis included data from 1587 patients while taking TVR. The aim of this study was to identify the factors associated with early discontinuation of TVR. Methods: Patients were treated with TVR, pegylated inter-feron-alpha (Peg-IFN, P) and ribavirin (RBV, R) for 12 weeks, followed by PR. Liver biopsy or non-invasive tests showing severe fibrosis or cirrhosis and platelet count >90,000/mm3 were required at entry. Fibroscan was performed at baseline in 1040/1587 patients. Multivariate analysis was carried out to determine the significant predictors of TVR discontinuation for adverse events (AEs) up to Week 16, for the first 1587 patients in the program. Fibroscan, haemoglobin, platelets, log10AFP and weight-adjusted RBV dose were analysed as continuous variables. Results: Mean age was 53 years and mean weight 78kg; 64% were male and 98% Caucasian, 66% had HCV RNA levels ≥800,000 IU/mL, 47%/53% had severe fibro-sis/cirrhosis, 22% had genotype 1a. Overall, 20% were treatment naïve, 34% prior relapsers, 43% prior non-responders and 3% had prior viral breakthrough. Out of 1587 patients who began treatment, 285 patients (18%) discontinued TVR, of whom 193 patients (12%) discontinued for AEs; the most common AEs leading to discontinuation were rash (5%) and anaemia (3%). The two most significant baseline predictors of stopping TVR for AEs before Week 12 were lower baseline log10 platelet count [OR=12.5, 95% CI 4.3–33.3, p<0.001) and a higher initial weight-adjusted dose of RBV (OR=1.17, 95% CI 1.08–1.26, p<0.001). Patients with Genotype 1b subtype infection were also more likely to discontinue TVR for AEs, but this association was less strong (OR=1.7, 95% CI 1.23–2.63, p=0.013). In the multivariate analysis, there were no significant correlations between discontinuation of TVR for AEs and either Fibroscan results (kPa, continuous scale), baseline haemoglobin, the type of Peg-IFN used, fibrosis stage (F3 or F4), gender or age. Conclusions: In this TVR early access program for patients with severe fibrosis or compensated cirrhosis, the rate of discontinuation of TVR for AEs was 12%. The main factors associated with early discontinuation of TVR for AEs were lower platelets at baseline and a higher weight-adjusted dose of RBV.

Disclosures:

Giovanni B. Gaeta -Advisory Committees or Review Panels: Janssen, Merk, BMS, Novartis, Gilead, Roche, Janssen, Merk, BMS, Novartis, Gilead, Roche, Janssen, Merk, BMS, Novartis, Gilead, Roche, Janssen, Merk, BMS, Novartis, Gilead, Roche

Massimo Colombo - Advisory Committees or Review Panels: BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, Janssen Cilag, Achillion; Grant/Research Support: BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD; Speaking and Teaching: Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX, Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX

Paulo R. Abrão Ferreira - Grant/Research Support: ABBOTT, ROCHE, BMS, JANSSEN; Speaking and Teaching: ROCHE, BMS, JANSSEN

Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie, Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb, MSD, Roche Products Australia, Gilead, Janssen

Djamal Abdurakhmanov - Grant/Research Support: Roche; Speaking and Teaching: BMS, Jansenn, MSD, Novartis

Anke Verheyen - Consulting: Janssen Pharmaceutica

Wafae Iraqi - Employment: Janssen

Ralph DeMasi - Management Position: Johnson and Johnson

Andrew Hill - Consulting: Janssen

Joerg M. Läuffer - Employment: Janssen; Stock Shareholder: Janssen

Isabelle Lonjon-Domanec - Employment: Janssen

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

The following people have nothing to disclose: Petr Urbanek, Christophe Moreno, Inmaculada Fernández, Adrian Streinu-Cercel

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Treatment of Patients with Dual Hepatitis C and B by Peginterferon Alfa and Ribavirin Reduced Risk of Hepatocellular Carcinoma and Mortality: A Population-Based Survey

Chun-Jen Liu1,2, Yu-Tseng Chu3, Wen-Yi Shau1,3, Raymond N. Kuo3, Pei-Jer Chen1,2, Mei-Shu Lai3;
1Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; 2Department of Internal Medicine and Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan; 3Insti-tute of Health Policy and Management, National Taiwan University College of Public Health, Taipei, Taiwan

Objective: Whether peginterferon alfa and ribavirin combination therapy reduce risk of hepatocellular carcinoma (HCC) or improve survival in patients dual-infected with hepatitis C (HCV) and hepatitis B virus (HBV) is unknown. Since now it is ethically impossible to conduct a randomized trial to learn the long-term efficacy. We rely upon the large database to explore the effectiveness of combination therapy among dual-infected patients. Design: Data for this population-based retrospective cohort study was obtained from the treatment program, Cancer Registry, National Health Insurance, and death certification. We examined the risk of HCC, mortality, and adverse events in 1,096 treated and 18,988 untreated HCV/HBV dually-infected patients. Outcomes were analyzed using the bias corrected inverse probability weighting by propensity scores (IPW). Outcomes of HCV/HBV dually-infected and HCV mono-infected patients receiving the same treatment were compared using new user design with IPW estimators to adjust for confounding. Results: After adjustment, combination therapy significantly reduced the risk of HCC (hazard ratio [HR] 0.76, 95% confidence interval [95%CI] 0.59–0.97), liver-related mortality (HR 0.47, 95%CI 0.37–0.6), and all-cause mortality (HR 0.42, 95%CI 0.34–0.52). Nevertheless, the underlying HBV infection was still a risk factor for HCC and mortality after treatment. Treatment was associated with an increase in the incidence of thyroid dysfunction (HR 1.9, p<0.001) and mood disorders (HR 1.81, p=0.005). Conclusions: This is the first evidence showing that combination therapy decreased the risk of HCC and improved survival in HCV/HBV dually-infected patients despite a slight increase in the incidence of thyroid and mood disorders.

Disclosures:

Pei-Jer Chen - Advisory Committees or Review Panels: BMS, GSK, BMS, GSK, Medigene; Independent Contractor: J & J; Speaking and Teaching: Roche, Roche

The following people have nothing to disclose: Chun-Jen Liu, Yu-Tseng Chu, Wen-Yi Shau, Raymond N. Kuo, Mei-Shu Lai

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Suppressive genes expressions of interferon signaling pathway in peripheral blood mononuclear cells associated with IL28B genetic variants and virological response to PEG-IFN, RBV plus NS3/4 protease inhibitor

Kentaro Matsuura1,2, Sayuki Iijima1, Tsunamasa Watanabe1, Etsuko Iio1,3, Mio Endo3, Noboru Shinkai3, Kei Fujiwara3, Shun-sukeNojiri3, Takashi Joh3, Yasuhito Tanaka1;
1 Department of Virology and Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; 2Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD; 3Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

Background/Aims: It has been reported that pretreatment intra-hepatic interferon stimulated genes (ISGs) expressions were associated with IL28B genetic variants and virological response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C (CHC). However, the mechanisms of them are not clear. We examined the associations between ISGs or IFN-lambda expressions in peripheral blood mononuclear cell (PBMC) and IL28B genotypes or the response to PEG-IFN, RBV plus NS3/4 protease inhibitor (PI) therapy. Methods: We enrolled total 50 CHC individuals with genotype 1 treated with PEG-IFN/RBV/PI, 31 had IL28B favorable genotype. PBMCs were obtained at baseline, 8, and 24 hours (h) after the initial administrations of PEG-IFN/RBV/PI, and RNA were extracted from PBMCs. Then mRNA expression levels of ISGs and IFN-lambda, ISG15, A20, zc3h12a, RNF125, Mx, IL1β, IL10, IRF1, SOCS1, SOCS2, SOCS3, OAS, PKR, IL28A, IL28B, IL29, were measured by real-time PCR. Written informed consent was obtained from each patient and the study was approved by the institutional ethical committee in accordance with the 1975 Declaration of Helsinki. Results: All the 31 patients with IL28B favorable genotype and 12 of 19 with unfavorable genotype resulted in sustained virological response (SVR). A20, SOCS1, SOCS3, and IRF1 expression levels at 8 h were significantly higher in the patients with IL28B unfavorable genotype than in those with favorable one (p=0.007, 0.026, 0.0004, 0.0006, respectively), whereas ISG15, IL28A, IL28B, and IL29 expression levels had no differences according to IL28B genotypes. In particular, the relative expressions of SOCS3 and IRF1 at 8h/baseline were significantly higher in the patients with IL28B unfavorable genotype (p=0.005, 0.03, respectively). There were significant correlations among A20, SOCS1, SOCS3, and IRF1 expression levels at baseline and 8 h, but were no correlations between these genes and ISG15 or IL28B. Compared these genes expression levels at 8 h between SVR and non-SVR groups in the patients with IL28B unfavorable genotype, A20, SOCS3 and IRF1 expression levels tended to be higher in non-SVR than in SVR. Particularly, the relative expression of IRF1 at 8h/baseline was significantly higher in non-SVR than in SVR (p<0.05). Conclusions: A20, SOCS1, SOCS3, and IRF1 were known to be suppressive genes in interferon signaling pathway. These genes expressions in PBMCs after the initial administrations of PEG-IFN/RBV/PI were different according to IL28B genotypes or treatment response. Therefore, these suppressive genes may play important roles in the eradication of hepatitis C virus.

Disclosures:

Yasuhito Tanaka - Advisory Committees or Review Panels: Nippon Boehringer Ingelheim Co ., Ltd.; Grant/Research Support: Chugai Pharmaceutical CO., LTD., MSD, Mitsubishi Tanabe Pharma Corporation, Dainippon Sumitomo Pharma Co., Ltd., DAIICHI SANKYO COMPANY, LIMITED, Bristol-Myers Squibb

The following people have nothing to disclose: Kentaro Matsuura, Sayuki Iijima, Tsunamasa Watanabe, Etsuko Iio, Mio Endo, Noboru Shinkai, Kei Fujiwara, Shunsuke Nojiri, Takashi Joh

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Renal impairment is frequent in chronic hepatitis C patients under triple therapy with telaprevir or boceprevir

Stefan Mauss1, Christoph Eisenbach2, Renate Heyne3, Gero Moog4, Thomas Lutz5, Uwe Naumann6, Michael Geissler7, Stefan Pape8, Matthias Mordeja9, Christoph Herold10, Karl-Georg Simon11, Konrad Isernhagen12, Ulrich Alshuth13, Peter Buggisch14, Dietrich Hueppe15;
1Center for HIV and Hepatogastroenterology, Duesseldorf, Germany; 2Dept. of Gastroenterology, University of Heidelberg, Heidelberg, Germany; 3Liver and study center Checkpoint, Berlin, Germany; 4Center of Gastroenterology, Kassel, Germany; 5 Infektiologikum, Frankfurt/M, Germany; 6Center for Addiction-Medicine, Hepatology and HIV, Praxiszentrum Kaiser-damm, Berlin, Germany; 7Department of Oncology and Gastroenterology, Municipal Hospital Esslingen, Esslingen, Germany; 8Center of Gastroenterology, Paderborn, Germany; 9Center for Gastroenterology and Hepatology, Hildesheim, Germany; 10Center of Internal Medicine, Nuremberg, Germany; 11 Center of Gastroenterology, Leverkusen, Germany; 12Practice for general medicine, Koeln, Germany; 13Virology, Roche Pharma AG, Gren-zach-Wyhlen, Germany; 14ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany; 15Center of Gastroenterology, Herne, Germany

In clinical trials with telaprevir (TVR) and boceprevir (BOC) renal impairment was not reported as a relevant adverse event. The PAN study is a non-interventional study enrolling patients treated with peginterferon alfa-2a/ribavirin (PEG/RBV) with or without TVR or BOC. Here we restrict the analysis to hepatitis C virus genotype 1 patients having completed 12 (n=895) or 24 weeks (n=591) of treatment. For estimation of glomerular filtration rate (eGFR) the CKD-EPI formula was chosen. Patients on TVR 38/575 (6.6%) and BOC 10/211 (4.7%) experienced more frequently a decrease in eGFR to <60 mL/min compared to patients treated with PEG/RBV only 1 /109 (0.9%) (p<0.05). Risk factors associated with eGFR <60 ml/min were age (p<0.001), arterial hypertension (p<0.001), Diabetes mellitus (p<0.05), higher serum creatinine at baseline (p<0.001) and being on triple therapy with TVR or BOC (p<0.05). Patients with an eGFR of <60 ml/min had a lower absolute mean haemoglobin at week 12 compared to patients with an eGFR >60 ml/min (9.7 g/dL ± 1.4 g/dL versus 11.0 g/dL ± 1.7 g/dL, p<0.001). Most patients on TVR with an eGFR <60 ml/min showed an increase in renal function after planned discontinuation of TVR at week 12. In conclusion renal impairment has not been reported as safety signal in clinical trials with TVR or BOC. However, in this large cohort including patients with risk factors for renal impairment a marked decline in renal function was observed in about 5% of patients on triple therapy. In addition to being a safety concern as such, substantial RBV dose reductions have to be considered in these patients as anaemia was more pronounced in patients with reduced renal function. The reversibility of renal impairment after the planned discontinuation of TVR argues for a causal relationship.

Disclosures:

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Christoph Eisenbach - Advisory Committees or Review Panels: Roche; Speaking and Teaching: Bristol Myers Squibb, Roche, Gilead

Thomas Lutz - Advisory Committees or Review Panels: Gilead, MSD, Abbott, BMS, Janssen Cilag; Grant/Research Support: Boehringer Ingelheim, Gilead, GlaxoSmithKline, Schering-Plough, Roche, MSD, Abbott, Janssen Cilag; Speaking and Teaching: Boehringer Ingelheim, GlaxoSmithKline, Roche, BMS

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

Christoph Herold - Speaking and Teaching: Roche Pharma Gemany, BMS Pharma Germany, MSD Pharma Germany, Gilead Pharma Germany, Novartis Pharma Germany, Roche Pharma Gemany, BMS Pharma Germany, MSD Pharma Germany, Gilead Pharma Germany, Novartis Pharma Germany

Karl-Georg Simon - Speaking and Teaching: Roche, Janssen-Cilag, BMS

Konrad Isernhagen - Advisory Committees or Review Panels: Janssen, Gilead; Speaking and Teaching: Roche, MSD

Ulrich Alshuth - Employment: Roche

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

Dietrich Hueppe - Advisory Committees or Review Panels: Roche, MSD, Novatis, Gilead, BMS

The following people have nothing to disclose: Renate Heyne, Gero Moog, Michael Geissler, Stefan Pape, Matthias Mordeja

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Telaprevir triple therapy in multimorbid chronic hepatitis C genotype 1 patients under hemodialysis

Johannes Wiegand1, Benjamin Maasoumy2, Peter Buggisch3, Anna Buslau4, Ingolf Schiefke5, Thomas Berg1, Heiner Wede-meyer2, Christoph Sarrazin4, Holger Hinrichsen6;
1Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany; 2Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany; 3IFI Liver Center, Hamburg, Germany; 4Department of Gastroenterology, University Hospital Frankfurt, Frankfurt, Germany; 5Department of Gastroenterology, Hospital St. George, Leipzig, Germany; 6Private Practice for Gastroenterology and Hepatology, Kiel, Germany

Introduction Telaprevir (TVR) triple therapy leads to improved sustained virologic response (SVR) rates compared to dual therapy with peginterferon/ribavirin in genotype 1 chronic hepatitis C virus (HCV) infection, however, it is accompanied by side effects and drug-drug-interactions. Patients with hemodialysis were not included in TVR registration trials because of renal insufficiency and multiple comorbidities. We therefore describe TVR feasibility and tolerability in multimorbid HCV infected patients under hemodialysis. Methods Multicenter retrospective analysis of clinical data from chronic HCV genotype 1 infected patients under hemodialysis. Results Seven patients (male/female n=5/2, median age 51 years, median baseline HCV-RNA 162.131 IU/ml, IL28B (rs12979860) CC/CT/TT/unavailable n=3/2/1/1, naïve/relapse/nonre-sponder/breakthrough n=4/1/1/1, Child A cirrhosis n=2, arterial hypertension n=6, cardiovascular diseases n=5) received 2250 mg/d TVR plus peginterferon alfa-2a/ribavirin (P/R) for 10 (n=2) or 12 (n=5) weeks followed by subsequent dual P/R therapy. Three cases were treated with an additional lead-in phase (n=1 ribavirin mono, n=2 P/R). Peginterferon alfa-2a was initially dosed with 135 (n=1) or 180 (n=6) μg/week, ribavirin with 200–1000 mg/week. All but one patient received erythropoietin. HCV-RNA was negative after 4 and 12 weeks of triple therapy in all cases. One patient became already HCV-RNA negative at week 6 of the P/R lead-in phase. All cases (n=4), who have completed therapy so far, received a sustained virologic response after a total treatment duration of 24/24/27/47 weeks, respectively. Intervention for anemia management was necessary in all patients and handled with ribavirin dose reduction, erythropoietin increase, and/or transfusion in n=6/5/2 cases. Peginterferon dosage had to be reduced in two individuals. Pruritus/rash, anal dis-comfort/ulceration, or diarrhea were observed in n=2/3/3 individuals. Four serious adverse events necessitating hospitali-sation occurred in three patients (Norwalk virus infection, stroke, severe anemia, hypertensive crisis). Concomitant medication was adjusted prior to TVR treatment in two cases (stop of statin and calcium-antagonist). Stopping the calcium-antagonist favored the hypertensive crisis. Conclusion Telaprevir triple therapy with individually modified ribavirin and peginterferon dosing is feasible in multimorbid HCV infected patients on hemodialysis. Because of a high number of serious adverse events patients should be thoroughly counseled prior to therapy and closely monitored on treatment.

Disclosures:

Benjamin Maasoumy - Advisory Committees or Review Panels: Abbott Molecular; Speaking and Teaching: MSD, Roche Diagnostics, Roche Pharma

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

Ingolf Schiefke - Board Membership: Baxter; Grant/Research Support: Roche, MSD, Gilead

Thomas Berg - Advisory Committees or Review Panels: Gilead, BMS, Roche, Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS, Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche, Tibotec; Vertex, Jannssen, Schering Plough, Boehringer Ingelheim, Novartis; Speaking and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Schering Plough, Novartis, Merck, Bayer

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Christoph Sarrazin - Advisory Committees or Review Panels: Boehringer Ingelheim, Vertex, Janssen, Merck/MSD, Gilead, Roche, Boehringer Ingelheim, Achillion, Janssen, Merck/MSD, Gilead, Roche; Consulting: Merck/MSD, Novartis, Merck/MSD, Novartis; Grant/Research Support: Abbott, Intermune, Roche, Merck/MSD, Gilead, Janssen, Abbott, Roche, Merck/MSD, Vertex, Gilead, Janssen; Speaking and Teaching: Bristol-Myers Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Falk, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Falk, Boehringer-Ingelheim

Holger Hinrichsen - Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: Janssen

The following people have nothing to disclose: Johannes Wiegand, Anna Buslau

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Leukocyte decline >2500/μl induced by pegylated inter-feron alfa-2b (Peg2b)/Ribavirin (RBV) treatment predicts favorable SVR rates in patients with HCV genotype 1 (G1), but not HCV genotype 2/3 (G2/3) infection

Gerlinde Teuber1, Stefan Mauss2, Dietrich Hueppe3, Elmar Zehn-ter4, Michael P. Manns5, Tarek Dahhan6, Ulrike Meyer7, Thomas Witthoeft8, Bernd Moeller9, Nektarios Dikopoulos10, Jochen Brack11, Dagmar Hartmann12, Bernd Dreher12, Manfred Bilzer12;
1Gastroenterological Practice, Frankfurt, Germany; 2Medical Group Practice, Düsseldorf, Germany; 3Medical Group Practice, Herne, Germany; 4Gastroenterological Practice, Dortmund, Germany; 5Medical School of Hannover, Hannover, Germany; 6Medical Practice, Fellbach, Germany; 7Medical Practice, Berlin, Germany; 8Gastroenterological Practice, Stade, Germany; 9 Medical Practice, Berlin, Germany; 10Health Centre Langenau, Lange-nau, Germany; '11 Hospital Nord Ochsenzoll, Hamburg, Germany; 12MSD Pharma GmbH, Haar, Germany

Background: The decline of leukocytes during antiviral treatment of chronic HCV infection may reflect pharmacodynamic effects of pegylated interferons. We therefore investigated the possible association between leukocyte decline related to Peg2b and the virologic outcome of patients (pts) treated for HCV G1 and G2/3 infection. Methods: Data from pts treated for HCV G1 (N = 1890) and G2/3 (N=1306) infection with Peg2b 1.5 μg/kg/week+RBV (800–1200 mg/day) for up to 48 weeks in a large observational real-life study at 285 sites in Germany were retrospectively analyzed. Results: 1890 pts with G1 infection (44.1 ±12.3 years, female 43%, 52.2% with baseline viral load >600000 IU/ml) had baseline and at least one leukocyte measurement during therapy. Overall sustained virologic response (SVR) following Peg2b/RBV treatment was 42.3%. A significant (P<0.0001) difference in SVR rates was obtained comparing pts with maximal leukocyte declines >2.500/μL from baseline (45.6%) with those who experienced leukocytes declines <2.500/μL (32.7%, Table). Higher SVR rates in pts with leukocyte declines >2.500/μL were significantly (P=0.0067) associated with lower non-response rates of 32.0% in comparison to 39.1% in the presence of a leukocyte decline ≤2.500/ μL, while relapse rates did not differ (22.5% vs 23.0%, P=0.87). Furthermore, pts with leukocyte declines >2500/ μL had significant reduction in week 4 and week 12 null-response rates: 46% and 34% of pts with leukocyte decline <2.500/μL achieved a week 4/12 HCV-RNA decline <1log10/ <2log10, in contrast to only 32% (p=0.008) and 25% (p=0.0027) of pts with leukocyte declines >2.500/μL. Leukocyte declines >2.500/μL were significantly associated with higher SVR rates in difficult-to-treat pts with G1 infection. Interestingly, the cohort of 1306 pts with G2/3 infection showed a trend towards higher SVR rates when leukocytes decreased by >2.500/μL, but differences did not reach significance (data not shown). Conclusions: A leukocyte decline >2.500/μL triggered by Peg2b/RBV treatment of HCV infection is a favorable factor predicting high SVR and low non-response rates in pts with HCV G1 infection, but not HCV G2/3 infection.

 Maximal leukocyte decline 
 ≤2500/μl>2500/μlP-value
Gl,SVR, % (n/N)   
Overall32.7(137/419)45.6 (652/1430)<0.000l
Female36.7(72/196)51.1 (309/605)0.0005
Male29.1 (65/223)41.6 (343/825)0.0007
Age <50 years35.8 (88/246)48.9 (480/982)0.0002
Age ≥50 years28.3 (49/173)38.4 (172/448)0.0188
LVL <600000 IU/ml38.8(73/188)55.9 (356/637)<0.0001
LVL ≥600000 IU/ml26.4(57/216)37.3(279/747)0.0029

Disclosures:

Gerlinde Teuber -Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Dietrich Hueppe -Advisory Committees or Review Panels: Roche, MSD, Gilead, Novartis, BMS

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Dagmar Hartmann - Employment: MSD Germany Bernd Dreher - Employment: MSD Manfred Bilzer - Consulting: MSD Germany

The following people have nothing to disclose: Elmar Zehnter, Tarek Dahhan, Ulrike Meyer, Thomas Witthoeft, Bernd Moeller, Nektarios Dikopoulos, Jochen Brack

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Mechanism of renal dysfunction in the early phase of telaprevir-based triple therapy

Sadatsugu Sakane1, Hisashi Ishida1, Keisuke Fukutomi1, Keiichi Kimura1, Aya Sugimoto1, Kenji Hibino1, Takeshi Tamura1, Tetsuya Iwasaki1, Ryuichiro Iwasaki1, Hiroko Hasegawa1, Yuko Sakak-ibara1, Takuya Yamada1, Masafumi Yamato2, Shoichi Nakazuru1, Takashi Toyama1, Takahito Ito2, Eiji Mita1;
1Department of Gas-troenterology and Hepatology, Osaka National Hospital, Osaka, Japan; 2Department of Nephrology, Osaka National Hospital, Osaka, Japan

BACKGROUND Telaprevir therapy in combination with rib-avirin and pegylated-interferon α2b for hepatitis C patients often induces renal dysfunction from the first week in Japan. The mechanism of this early renal dysfunction is poorly understood and needs to be clarified. METHODS For 26 patients with HCV genotype 1, the serum sodium (SNa), creatinine (SCr), cystatin-C (Cys-C), plasma osmolarity (POsm), urinary sodium (UNa), creatinine (UCr), and urinary osmolarity (UOsm) levels were measured at days 4, 8, 15. The estimated glomerular filtration rate (eGFR) was calculated with the enzymatic MDRD formula. The fractional excretion of sodium percentage (FENa%) was calculated as ([UNa/SNa]/[UCr/SCr])xl 00. Differences in quantitative values were analyzed by the Mann-Whitney U test. Correlation between values was tested with the Pearson correlation coefficient. RESULTS Baseline data were: SNa 140±2 mEq/L, SCr0.78±0.11 mg/dL, Cys-C 0.87±0.10 mg/L, eGFR 79±17 ml/min/1.73m2, POsm 289±5 mOsm, UNa 97±41 mEq/L, UCr 109±53 mg/dL, UOsm 560±179 mOsm, FENa% 0.55±0.26%. At day 4, the mean eGFR of the patients decreased to 68±15 ml/min/1.73 m2. SCr and Cys-C significantly rose to 0.96±0.14 mg/dL and 1.05±0.13 mg/L, respectively. These kidney function levels recovered to almost the initial levels at day 8. POsm and UOsm decreased to 285±4 mOsm and 387±69 mOsm, respectively. To distinguish between the two main causes of acute renal dysfunction, pre-renal mechanism and acute tubular necrosis, we compared the eGFR decrease with UNa and FENa% at day 4 and found a significant correlation with UNa (r = -0.45, p = 0.02) and also with FENa% (r = -0.39, p = 0.04). Serum renin activity levels and serum aldosterone levels were also measured for 14 patients. Serum renin activity levels increased in all patients with a mean value change from 2.9±4.4 to 4.8±2.6 ng/dL. Serum aldosterone levels increased in all but one patient with a mean value change from 148±36 to 221 ±90 pg/mL. CONCLUSION In this study, eGFR significantly decreased at day 4 and the eGFR decrease showed significant correlation with UNa and FENa%. Also, serum renin activities and serum aldosterone levels significantly increased. These findings indicate that the pre-renal mechanism is responsible for the eGFR decline. Additionally, decreases of POsm and UOsm indicate that renal blood flow is reduced by some mechanisms other than dehydration. Since patients with renal dysfunction in the early phase of therapy can be at additional risk of adverse events, high fluid intake or fluid transfusion should be promoted to maintain renal blood flow.

Disclosures:

Sadatsugu Sakane - Grant/Research Support: MSD

Takahito Ito - Consulting: Takeda Pharmaceutical Co.; Grant/Research Support: Chugai Pharmaceutical Co., Asahi Kasei Pharmaceutical Co.

Eiji Mita - Grant/Research Support: MSD

The following people have nothing to disclose: Hisashi Ishida, Keisuke Fukutomi, Keiichi Kimura, Aya Sugimoto, Kenji Hibino, Takeshi Tamura, Tetsuya Iwasaki, Ryuichiro Iwasaki, Hiroko Hasegawa, Yuko Sakakibara, Takuya Yamada, Masafumi Yamato, Shoichi Nakazuru, Takashi Toyama

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People who inject drugs on a stable opiod maintenance therapy with a chronic hepatitis C genotype 1 infection respond as well as patients with other route of infection to an antiviral triple combination therapy

Stefan Christensen1, Uwe Naumann2, Joerg H. Goelz2;
1Infectious Diseases, Center for Interdisciplinary Medicine (CIM), Muenster, Germany; 2Infectious Diseases, Center for HIV/HCV and addiction medicine, Berlin, Germany

Introduction: People who inject drugs (PWID) on a stable opioid maintenance therapy (OMT) have proven good adherence to combination therapy with pegylated interferon (PegIFN) and ribavirin (RBV) in chronic hepatitis C (HCV) infection. So far, only less experience is reported with the challenging triple combination therapy containing telaprevir (TVR) or boceprevir (BOC) together with PegIFN and RBV in this patient group. Methods: Out of a prospective cohort of 151 chronic HCV Genotyp 1 infected patients from two centers in Germany, who started triple combination therapy with TVR or BOC and PegIFN plus RBV from July 2011 on, data of 128 patients, who reached at least week 24 of therapy until Mai 2013 is reported. These patients were divided up in three groups. PWID on OMT n=37, former intravenous drug users (IVDU) n=32 and patients with other route of infection (Others) n=59. Usual baseline characteristics were documented and data of response and side effects collected during and after HCV therapy. Virological treatment response was defined as HCV-RNA < 15 IU/ml at a certain time point. Week 4 response data was defined as being 4 weeks on triple combination treatment. Results: Mean age was 47 to 50 years in all three Groups. 56,8% of patients in the OMT, 53,1% in the IVDU group and 27,1 % of the group of Others were treatment naive. Genotype 1a was found predominately in the OMT group, 67,6% versus 50% in the IVDU and 27,1% in the group of Others. IL28B-Polymorphism C/C was well matched, 21,6% in the OMT, 15,6% in IVDU and 17% in the Others. Most patients were treated with TVR and PegIFN 2a as part of regimen, 73% and 83,8% in the OMT, 65,6% and 87,5% in the IVDU, 69,5% and 93,2% in the Other group. Virological response rates are shown in table 1. At week 2481,1% in the OMT group, 90,6 % in the IVDU and 74,6% in the group of others had a HCV-PCR < 15 IU/ml, defined as treatment response. Conclusion: Triple combination therapy of PWID on OMT from 2 centers in Germany shows no difference in response rates in comparison to former intravenous drug users or patients with other route of HCV infection in the first 24 weeks. OMT seems to be a good setting for initiation of triple combination therapy of chronic HCV-infection Genotype 1 in PWID.

Table 3. Virological response rates for different patients groups during antiviral triple therapy (ITT / nc = failure)
  ALLOMTIVDUOthers
 n=128373259
HCV-PCR <15 IU/ml (%)Week 475,87384,472,9
 Week 885,289,287,581,4
 Week 1284,483,893,879,7
 Week 2480,581,190,674,6

Disclosures:

Stefan Christensen -Advisory Committees or Review Panels: Roche, BMS, Abbott, Janssen, Schering Plough, ViiV, Gilead, MSD, Boehringer Ingelheim; Speaking and Teaching: Gilead, MSD, Roche, BMS, Schering Plough, ViiV, Boehringer Ingelheim, Janssen

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

The following people have nothing to disclose: Joerg H. Goelz

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Antihyperlipidemic medications induce a reduction of the viral load in patients chronically infected with hepatitis C virus: a meta-analysis

Georgios Grammatikos1, Harald Farnik1, Dimitra Bon2, Ted Bader3, Stefan Zeuzem1, Eva Herrmann2;
1Medizinische Klinik I, University Hospital Frankfurt, Frankfurt, Germany; 2Institut für Bio-statistik und mathematische Modellierung, University Hospital Frankfurt, Frankfurt, Germany; 3Health Sciences Center, University of Oklahoma, Oklahoma, OK

Several studies investigating the role of statins and fibrates in chronic hepatitis C virus (HCV) infection offered so far conflicting evidence regarding the antiviral potency of these medications, while combination of these drugs with pegylated interferon and ribavirin improved in some trials therapeutic outcome. However, it remains particularly unclear whether the use of antihyperlipidemic medications in the clinical setting is able to suppress HCV-viral load. In the present study, we performed a meta-analysis to determine the primary impact of these antihyperlipidemic medications as monotherapy on the viral load of patients chronically infected with HCV. Methods: We conducted a literature search to identify trials that included patients with HCV monoinfection, treated with statins or fibrates as monotherapy with the primary end point of our meta-analysis being the quantitative change of HCV-RNA induced by these medications. Logarithmic changes of the viral load (ΔlogVL) and confidence intervals (CI's) were calculated according to the DerSimonian-Laird estimate. Statistical heterogeneity was assessed with the I-square statistic. Results: 8 observational studies evaluated the potency of bezafibrate and different statins as monotherapy to induce a significant reduction of HCV-RNA in HCV-monoinfected patients (n= 281). The overall chance to achieve a reduction of the HCV viral load was 19% higher (95% CI, 11%-28%, P=0.025) when antihyperlipidemic medications were clinically applied. Bezafibrate featured the highest antiviral efficacy (45% higher chance, 95% CI, 17%-72%, P=0.001) among all medications and fluvastatin (20% higher chance, 95% CI, 9–31%, P<0.001) among all statins tested. A significant correlation of the duration of antihyperlipidemic treatment to ΔlogVL-changes was observed as well (P=0.0216). However significant heterogeneity was observed within our results (I-square=51%, P for heterogeneity 0.0257). Conclusions: Based on meta-analysis fibrates and statins induce a reduction of HCV-viral load, while the duration of the clinical application of antihyperlipidemic medications associated significantly with ΔlogVL-changes. Randomized clinical trials are warranted to evaluate the prospective clinical use of statins and fibrates as adjunct medications in interferon-free anti-HCV-antiviral regimes.

Disclosures:

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingel-heim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

The following people have nothing to disclose: Georgios Grammatikos, Harald Farnik, Dimitra Bon, Ted Bader, Eva Herrmann

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Effect of thrombocytopenia on treatment tolerability and outcome in chronic hepatitis C patients with advanced hepatic fibrosis receiving (peg)interferon-based antiviral treatment

Raoel Maan1, Adriaan J. van der Meer1, Bettina E. Hansen1, Jordan J. Feld2, Heiner Wedemeyer3, Jean-Francois Dufour4, Hooman Farhang Zangneh2, Frank Lammert5, Michael P. Manns3, Stefan Zeuzem6, Harry L. Janssen1,2, Robert J. de Knegt1, Bart J. Veldt1;
1Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 2Liver Centre, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada; 3Department of Gastroenterology, Hepatology and Endocrinology, Medical School Hannover, Hannover, Germany; 4Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland; 5Department of Medicine II, Saarland University Medical Center, Homburg, Germany; 6Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany

Introduction Patients with chronic hepatitis C virus (HCV) infection and advanced fibrosis will likely remain dependent on (peg)interferon (IFN) containing treatment regimens to achieve optimal sustained virological response (SVR) rates. However, IFN-therapy is associated with thrombocytopenia (TCP), which may lead to dose reductions and early discontinuation, in particular in patients with advanced fibrosis or cirrhosis and TCP at baseline. Methods We assessed the occurrence of IFN-induced TCP, IFN dose reductions, SVR and bleeding complications in all consecutive chronic HCV patients with biopsy-proven advanced hepatic fibrosis (Ishak 4–6) who initiated IFN-based therapy between 1990 and 2003 in 5 large hepatology units in Europe and Canada. Results In total, 860 interferon-based treatments were administered to 546 patients; median age was 48 (IQR 42–56) years, 376 (69%) were males, and 400 (73%) presented with cirrhosis. Baseline platelets (PLT in 10Λ9/L) were ≧150 in 395 (46%) and < 150 in 377 (44%) treatments; TCP was moderate (PLT 75–150) in 324 (86%) and severe (PLT<75) in 53 (14%). TCP-induced IFN dose reductions occurred in 15 (28%) with severe TCP, in 46 (12%) with moderate TCP and in 3 (1%) with normal PLT (p<0.001); IFN was discontinued due to TCP in 8 (15%) with severe TCP, 8 (2%) with moderate TCP and 1 (<1%) with normal PLT (p<0.001). Overall, 22% of treatments with an IFN dose reduction and 6% of treatments that were discontinued due to TCP resulted in SVR, and 17% of treatments in patients with severe baseline TCP, 19% with moderate TCP, and 29% with normal PLT resulted in SVR. Bleeding complications occurred in 8 treatments (15%) among patients with severe TCP, 30 (9%) with moderate TCP and 15 (4%) with normal PLT (p<0.001). Bleeding episodes concerned epistaxis, gingival bleeds and haematuria in 48%, 19% and 15%, respectively). Two bleeding complications required hospitaliza-tions, none were fatal. PLT<50 at previous visit were associated with bleeding: the risk of bleeding was 1.2% if PLT were >50, 6.6% if PLT were 25–50, and 14% if PLT were <25 at previous visit. In multivariate analysis, adjusted for age and baseline PLT, cirrhosis (OR 3.0, 95%CI 1.4–6.7, p=0.005), female gender (OR 1.6, 95%CI 1.1–2.4, p=0.024) and PLT<50atthe previous visit (OR 5.3, 95%CI3.4–8.1, p<0.001) were associated with bleeding. Conclusion Patients with chronic HCV, advanced fibrosis and baseline TCP commonly experienced dose reductions and early discontinuation of IFN-based therapy, leading to lower SVR rates. On-treatment platelet counts <50 were associated with a 5-fold increased risk of bleeding complications.

Disclosures:

Adriaan J. van der Meer - Speaking and Teaching: MSD

Jordan J. Feld - Advisory Committees or Review Panels: Roche, Merck, Vertex, Gilead, Abbott, Tibotec, Theravance, Achillion; Speaking and Teaching: Merck, Roche, Abbott

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Jean-Francois Dufour - Advisory Committees or Review Panels: Bayer, BMS, Gilead, Jansse, Novartis, Roche

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris

Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche, Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag

Bart J. Veldt - Board Membership: GSK

The following people have nothing to disclose: Raoel Maan, Bettina E. Hansen, Hooman Farhang Zangneh, Frank Lammert

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Efficacy and safety of triple therapy with Peginterferon, Ribavirin, and Boceprevir within Early Access Program in Spanish patients with hepatitis c genotype 1 with severe fibrosis. SVRw12 Analisys

Jose Luis Calleja1, Juan Manuel Pascasio2, Belén Ruiz-Antorán3, Francisco Gea4, Rafael Bárcena5, Juan R. Larrubia6, Jose Manuel Sousa2, Xavier Forns7, R. Perez-Alvarez8, Ricard Sola9, Manuel Romero-Gomez10, Juan de la Revilla1, Juan I. Arenas11, Manuel B. Delgado12, Javier Crespo13, J. M. Navarro14, Conrado M. Fernandez-Rodriguez15, Ramon Planas16, Maria Buti17;
1Gastroen-terology, University Puerta de Hierro- Majadahonda Hospital, Madrid, Spain; 2Gastroenterology, Virgen del Rocio University Hospital, Sevilla, Spain; 3Clinical Pharmacology, University Puerta de Hierro- Majadahonda Hospital, Madrid, Spain; 4Gastroen-terology, University Hospital La Paz, Madrid, Spain; 5Gastroen-terology, University Hospital Ramon y Cajal, Madrid, Spain; 6Gastroenterology, University Hospital de Guadalajara, Guadalajara, Spain; 7Gastroenterology, University Hospital Clinic, Barcelona, Spain; 8Gastroenterology, University Hospital Central de Asturias, Oviedo, Spain; 9Gastroenterology, Hospital del Mar, Barcelona, Spain; 10Gastroenterology, University Hospital de Valme, Sevilla, Spain; 11Gastroenterology, Hospital Donostia, San Sebastian, Spain; 12Gastroenterology, University Hospital a Coruña, Coruña, Spain; 13Gastroenterology, University Hospital Marques de Valdecilla, Santander, Spain; 14Gastroenterology, Costa del Sol Hospital, Malaga, Spain; 15Gastroenterology, University Hospital Fundacion Alcorcon, Madrid, Spain; 16Gastroenterology, Hospital Germans Trias i Pujol, Barcelona, Spain; 17Gastroenterology, Hospital Vall Hebron, Barcelona, Spain

BACKGROUND AND AIMS. We report the safety and effectiveness profiles of treatment with boceprevir in combination with Peginterferon alfa / Ribavirin in patients genotype 1 hepatitis C with severe fibrosis (FibroScan®> 9.5 Kpa) in clinical practice. METHODS. Prospective multicentre national registry including patients with hepatitis C genotype 1, both naïve and treatment experienced, who had bridging fibrosis or cirrhosis treated with peginterferon alfa-2a or alfa-2b, ribavirin, and boceprevir as early access program, RESULTS. For the 187 patients the mean age was 54 years. 68% were male, 13/77% 1 a/1 b genotype and baseline viral load of 6.6 log (mean 3,906,012 ± 6,309,961). 80% of the patients had F4 and 23% had oesophageal varices, 22% were treatment naive and 78% had undergone prior treatment with PegIFN+rib-avirine (34% prior relapsers, 29% partial responders and 37% null responders). 16% of the patients had baseline levels <90,000 platelets. 65 patients (34.8%) developed at least one serious adverse event (SAEs 103) (Table 1). An increase in relative risk (>3) of SAEs, infections and hepatic decompensation was observed in patients with albumin <3.5g/dl and/or biliru-bin >2mg/dl. In the Intent to Treat analysis (n=132) the percentage of patients with SVRw12 HCV was 38.6%, 39.2% for treatment-naïve patients, 66.7% for relapsers, 27.3% for partial responders and 21.7% for null responders. In patients with 1 log decrease at week 4 (lead-in), the percentage of SVRw12 was 55%, 44% for treatment naïve patients, 77% for relapsers, 40% for partial responders and 45% for null responders. In the patients initiating boceprevir (n =103) the response was 49.5%, 44% for treatment-naïve patients, 68.6% for relapsers, 40% for partial responders and 35.7% for null responders. CONCLUSIONS. Triple therapy using boceprevir with PEG-IFN/RBV in patients with severe fibrosis/cirrhosis is effective, with sustained viral response (SVRw12) rates nearly 40%, but is associated with serious adverse events in 35% of the patients. SVR rates were also 40% in previous null responders who achieved > 1log10 decreased after a lead-in phase.

  1. *N=1 32 (Patients with 60 weeks of follow-up)

Patients, n (% patients with at least one event)(n=187)
Serious adverse events (SAEs)65 (34.8%)
Premature discontinuation* Due to SAEs Discontinuing patient care Virological failure65 (49.2%) 17 (12.9%) 9 (6.8%) 39 (29.5%)
Death Septic shock. Multi-organ failure secondary to pneumonia2 (1.07%)
Dose modification (PeglFN)42 (22.5%)
Infection / Infection Grade 3–456(29.9%)/17(9.1%)
Hepatic decompensation (Grade 3/4)10 (5.4%)
Anaemia Hg <10.0 g/dL Hb <8.0 g/dL EPO use Blood transfusion Ribavirin dose adjustment86 (46.0%) 8 (4.3%) 48 (25.7%) 14 (7.5%) 87 (46.5%)
Neutropenia N < 1.000/mm3 N < 500/mm3 Use G-CSF106 (56.7%) 13 (7.0%) 6 (3.2%)
Thrombopenia platelets <50.000 platelets <25.00046 (24.6%) 8 (4.3%)

Disclosures:

Rafael Bárcena - Advisory Committees or Review Panels: MSD, Janssen; Consulting: MSD, Novartis

Xavier Forns - Consulting: Tibotec/Jansen, MSD, Boheringher Ingelheim; Grant/Research Support: Roche, MSD, Gilead

Ricard Sola -Advisory Committees or Review Panels: Roche, Bristol-Myers Squibb, Gilead, Novartis, Jansen, MSD; Speaking and Teaching: Roche, Bristol-Myers Squibb, Gilead, Novartis, Schering-Plough, Jansen, MSD

Manuel Romero-Gomez - Advisory Committees or Review Panels: Roche Farma,SA., MSD, S.A., Janssen, S.A., Abbott, S.A.; Grant/Research Support: Ferrer, S.A.

Javier Crespo - Board Membership: MSD, Roche, Janssen, Gilead

Ramon Planas - Advisory Committees or Review Panels: Novartis, Abbott, BMS, Novartis, Abbott, BMS, Novartis, Abbott, BMS, Novartis, Abbott, BMS; Grant/Research Support: Roche, Guilead, Roche, Guilead, Roche, Guilead, Roche, Guilead

Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead, Janssen, Vertex, Novartis

The following people have nothing to disclose: Jose Luis Calleja, Juan Manuel Pascasio, Belén Ruiz-Antorán, Francisco Gea, Juan R. Larrubia, Jose Manuel Sousa, R. Perez-Alvarez, Juan de la Revilla, Juan I. Arenas, Manuel B. Delgado, J. M. Navarro, Conrado M. Fernandez-Rodriguez

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Romiplostim's Effect to Optimize SVR with Telaprevir, Ribavirin, And Peg Interferon-alfa 2a in Thrombocy-topenic Cirrhotics with Chronic Hepatitis C. A Placebo Controlled Prospective Clinical Trial: RESTRAINT C Trial

Patrick Basu1,2, NirajJ. Shah3, Ravi Siriki2, Md A. Rahman2, Sak-ina Farhat1;
1Columbia University School of Physicians and Surgeons, New York, NY; 2NSLIJHS/ Hofstra North Shore LIJ School of Medicine, NY, New York, NY; 3James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, NY, New York, NY

Objectives: Treating CHC (Chronic hepatitis C) cirrhotic patients with thrombocytopenia is often challenging; requiring dose reduction or even discontinuation of treatment to avoid complications. Significant dose reduction affects the response guided therapy (RGT); adversely affecting outcomes. Throm-bopoietin (TPO) agonists are used to avoid disruption or therapeutic failure to optimize SVR (Sustained Virological response). This study evaluated the use of TPO agonist in thrombocytopenia in cirrhotics with treatment experienced CHC-GT1 (CHC-Genotype 1) on treatment with Telaprevir, Ribavirin (RBV) and Peg Interferon-alfa 2a (p-IFNα-2a). Methods: Total of Forty five (n=45) cirrhotic treatment experienced CHC-GT1 patients with a mean MELD of 16 and mean platelet count 95 thousand were recruited and subdivided into three groups. Group A- (n=15) Received placebo plus reduced dose of p-IFNα-2a with RBV and Telaprevir. Group B (n=15) Received Romiplostim 500 mcg lead in 1 month prior to initiation of therapy and SOC with Telaprevir. Group C (n=15) Received Elthrombopag 50mg orally daily lead in prior 15 days and SOC with Telaprevir for 12 weeks. RGT was analyzed with serial platelet counts, hemo-globin/hematocrit, absolute neutrophils count and platelet antibodies. HCV RNA quantitative count was measured at 1ST, 2ND, 4TH, 12TH 24TH, 36TH and 60th weeks for SVR. Results: See table. ( VRVR- Very Rapid Virological Response, ETVR- End to treatment Virological Response, R- Relapser, PR-Partial Responder, BT- Break through ) Conclusion: This study demonstrates the efficacy of Romiplostim in thrombocytopenic cirrhotics with treatment experienced CHC-GT1 in optimizing SVR (Group A- 53%, Group B- 67% and Group C- 60%). A larger trial is needed to validate.

Results

 AVR 1 weekVRVR 2 weeksRVR 4 weeksEVR 12 weeksMTVR 24 weeksETVR 36 weeksETVR 48 weeksSVR 60 weeksSVR 72 weeks
Group A R=7 PR= 8 BT =05/15 (33%)7/15 ( 47%)9/15 (60%)10/15 (66%)10/15 (66%) 9/15 (60%) 8/15 (53%)
Platelet count K90 1121019398 BT1/15(7%)102RI/15 (7%)84
Group B R=8 PR= 6 BT =19/15 (60%)10/15 (66%)11/15 (77%)12/15 (80%)ETVR 12/15 (80%) SVR 9/15 (60%)  
Platelet count K68 2109096220 Rl/15(7%)180 58
Group C R=7, PR= 6BT =27/15 ( 47%)8/15 (53%)9/15 (60%)9/15 (60%) 10/15(66%) 9/15 (60%) 
Platelet count K128 1011029080108 131

Disclosures:

Md A. Rahman - Employment: NSLIJ FOREST HILLS HOSPITAL

The following people have nothing to disclose: Patrick Basu, Niraj J. Shah, Ravi Siriki, Sakina Farhat

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ITPA polymorphisms are associated with hemoglobin decline during pegylated interferon and ribavirin therapy in chronic hepatitis C

Raoel Maan1, Adriaan J. van der Meer1, Willem Pieter Brouwer1, Milan J. Sonneveld1, Robert Roomer1, Annemiek A. van der Eijk1, Zwier M. Groothuismink1, Bettina E. Hansen1, Harry L. Janssen1,2, Andre Boonstra1, Robert J. de Knegt1;
1Department of Gatroen-terology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 2Liver Centre, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada

Introduction Pegylated interferon (pegIFN) and ribavirin (RBV) remain essential in the treatment of chronic hepatitis C virus (HCV) infection, frequently causing anemia. We assessed the relation between single-nucleotide polymorphisms(SNPs) in the ITPA gene or near the IL28B gene and the pegIFN and RBV induced decline in hemoglobin(Hb) among chronic HCV-infected patients. Methods All consecutive Caucasian patients with chronic HCV infection who were treated with pegIFN and RBV between 2000 and 2009 were included if a sample was available for genetic testing. The SNPs rs11 27354(ITPA-1),rs7270101 (ITPA-2) and rs12979860(IL28B) were determined in DNA, which was purified from serum, using competitive allele-specific PCR. Decline in Hb (mmol/L) was assessed at week 4 (+/-7 days) of pegIFN and RBV therapy. Results In total, 225 patients were included. Median age was 45.0(IQR 39.0–50.5) years, 151(67%) patients were male, 110(49%) had HCV genotype 1, and 43(19%) had cirrhosis. Sustained virological response (SVR) was attained by 126(56%) patients. IL28B CC/CT/TT genotype was present in 38/47/15%, respectively. Sixty-two(79%) patients with IL28B CC-genotype attained SVR, compared to 60(46%) patients with IL28B CT/TT genotype (p<0.001). In multivariate logistic regression analyses, adjusted for age, gender, HCV genotype (1/4 vs 2/3), and cirrhosis, IL28B CC-genotype was independently associated with SVR (OR 5.0 compared to CT/TT-genotype,95%CI 2.4–10.8, p<0.001). Polymorphisms in the ITPA gene were not associated with SVR. ITPA-1 CC/CA/AA and ITPA-2 AA/AC/CC genotype were present in 59/40/1% and 77/20/3%, respectively. The two ITPA SNPs were not in linkage disequilibrium (<1%). Pre-treatment median Hb was 9.3(IQR 8.7–9.9) which declined by a median of 1.6(IQR 1.0–2.3) after 4 weeks of therapy (p<0.001). The median decline was 1.7(IQR 1.1–2.4) for patients with ITPA-1 CC-genotype and 0.65(IQR 0.43–1.1) for patients with ITPA-1 CA/AA-genotype (p=0.001). Similar results were obtained for ITPA-2 (AA versus AC/CC,p<0.001). IL28B was not associated with Hb decline. In multivariate linear regression analysis, adjusted for gender, pre-treatment Hb and platelet count, RBV dose and cumulative pegIFN dose, ITPA-1 CA/AA-genotype (Beta -1.1,95%CI -1.5--0.70,p<0.001) and ITPA-2 AC/CC-genotype (Beta -0.82,95%CI -1.1- -0.5, p<0.001) were independently associated with the decline in Hb at week 4 of therapy. Conclusion We confirmed that genetic variants in the ITPA gene protected against pegIFN and RBV treatment-induced anemia in Caucasian patients with chronic HCV infection in contrast to a genetic variant near IL28B, which was associated with SVR.

Disclosures:

Adriaan J. van der Meer - Speaking and Teaching: MSD

Milan J. Sonneveld - Speaking and Teaching: Roche

Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris

Andre Boonstra - Grant/Research Support: BMS, Janssen Pharmaceutics, Merck

Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche, Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag

The following people have nothing to disclose: Raoel Maan, Willem Pieter Brouwer, Robert Roomer, Annemiek A. van der Eijk, Zwier M. Groothuismink, Bet-tina E. Hansen

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Age is a strong predictor of SVR in patients infected with Hepatitis C genotype 3

Kjetil Isaksen1, Lars Aabakken2, Per K. Sandvei4, Lars Karlsen1, Olav Dalgard3;
1Institute of Medicine, Stavanger University Hospital, Stavanger, Norway; 2Dept of Gastroenterology, Rikshospitalet University Hospital, Oslo, Norway; 3Dept of Medicine, Akershus University Hospital, Oslo, Norway; 4Dept of Gastroenterology, Ost-fold Central Hospital, Fredrikstad, Norway

BACKGROUND: In the era of direct acting antivirals, hepatitis C virus (HCV) genotype 3 has emerged as the most difficult HCV genotype to treat. Our understanding of which patients with genotype 3 that are most at risk of treatment failure is not complete. The aim of the present study was to identify predictors of relapse and non-response in genotype 3 patients. METHODS: In this retrospective observational study, consecutive patients infected with genotype 3 receiving at least one dose of pegylated interferon alfa and ribavirin (peg/RBV) between 2002 and 2012 were included at three Norwegian outpatients clinics. Patients treated with pegIFN alfa 2a, received 180 mcg/kg/week while those receiving pegIFN alfa 2b received 1.5 mcg/kg/week. RBV was administered to patients dosed minimally as 800 mg/day. Viral genotype was determined with a hybridisation technique. Liver fibrosis was assessed using the APRI score. An APRI score of >2 was classified as advanced fibrosis (Metavir stage 3–4). SVR defined as HCV RNA not detectable 24 weeks after end of treatment was the main outcome variable and all analysis was performed as “intention to treat”. RESULTS: 351 peg/RBV treatments were analyzed,treat-ment duration was 24 weeks in 46% of patients and 12–16 weeks (all had RVR) in 38 % of patients. In an intention to treat analysis the overall SVR was achieved in 261 (74.4%) treatments, relapse followed in 58 (16.5%) treatments while non-response was registered in 32 cases (9.1%). In a univariate analysis age >40 years and advanced fibrosis was associated with reduced SVR rates, while baseline viral load, gender and type of pegIFN were not. In a logistic mulitivariate analysis with SVR as dependent variable only age <40 years independently predicted SVR (OR 3.895 c.i: 2.1–6.9). Broken into age segments (table 1), SVR in the group aged <30 was 91% compared to 48.8% in age group >50 (p<0.001). CONCLUSIONS: In patients with genotype 3 treated with peg/RBV, age was the only independent predictor of SVR. In those younger than 30 years SVR was achived in 9 of 10 while only 5 of 10 older than 50 years achieved SVR.

Table 4. HCV Genotype 3, treatment response according to age
 Age <30 n=78Age 31–40 n= 124Age 41–50 n= 107Age >50 n=41
SVR n. (%)71 (91)100(80.6)69 (64.5)20 (48.8)
Relapse n. (%)4(5.1)14 (11.3)24 (22.4)16(39)
Non Response n. (%)3 (3.8)10 (8.1)14(13.1)5(12.2)
HCV, hepatitis C virus. SVR,sustained virologic response, n, number

Disclosures:

Olav Dalgard - Advisory Committees or Review Panels: MSD, Janssen Cilag; Grant/Research Support: MSD, Roche

The following people have nothing to disclose: Kjetil Isaksen, Lars Aabakken, Per K. Sandvei, Lars Karlsen

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Pretreatment prediction of sustained virological response and telaprevir-resistant variants by ultra-deep sequencing in HCV genotype 1 patients treated with triple therapy

Norio Akuta, Fumitaka Suzuki, Tasuku Hara, Taito Fukushima, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Satoshi Saitoh, Mariko Kobayashi, Yasuji Arase, Kenji Ikeda, Hiromitsu Kumada;
Hepatology, Tora-nomon Hospital, Tokyo, Japan

BACKGROUND: Prediction of treatment efficacy and telaprevir-resistant variants after triple therapy of telaprevir/peginterferon (PEG-IFN)/ribavirin is difficult. METHODS: The predictive factors of sustained virological response (SVR) to 12- or 24-week regimen of triple therapy (T12PR12 or T12PR24) were investigated in 182 Japanese patients infected with HCV genotype 1 b. It was also evaluated whether the emergence of telaprevir-resistant variants could be predicted at baseline by ultra-deep sequencing technology, using the Ion PGM™ Sequencer (Life Technologies). Resistant variants included V36A/C/M/L/G, T54A/S, R155K/T/I/M/G/L/S/Q, A156V/T/S/I/G, and V170A. Especially, patients, who did not achieve SVR, were analyzed at baseline and at the time of re-elevation of viral loads. Furthermore, using the control experiment based on plas-mid encoding HCV NS3 sequence, amino acid mutations were defined as amino acid substitutions at frequency of more than 0.2% among the total coverage. RESULTS: Overall, SVR was achieved by 76%. Multivariate analysis identified IL28B rs8099917 (genotype TT), substitution of aa70 (Arg70), response to prior treatment (Naive or Relapse), PEG-IFN dose (≧1.3 μg/kg), and treatment regimen (T12PR24) as significant determinants of SVR. Especially, in T12PR24, treatment efficacy was high in the patients with genotype TT who accomplished SVR (91%), irrespective of substitution of aa70. In the patients having genotype non TT, those of Arg70 gained high SVR (72%); and SVR (14%) were the worst in patients who possessed three factors of genotype non TT, Gln70(His70), and non response to ribavirin combination therapy. 17 consecutive patients, who did not achieve SVR, could be analyzed resistant variants by ultra-deep sequencing. In 5 of 17 patients, resistant variants at baseline were detected, but de novo high frequency variants emerged according to treatment. In 11 patients, resistant variants were not detected at baseline, but de novo resistant variants were detected according to treatment. In only one patient, resistant variants of T54A increased from very low frequency at baseline (0.2% of 53,127 coverage) to high frequency during treatment (99.9% of 45,240 coverage). Thus, in 16 of 17 patients, de novo resistant variants were detected according to treatment, regardless of variants frequencies at baseline. CONCLUSIONS: This study identified that treatment efficacy could be predicted by combination of host, viral, and treatment factor. The present study showed that it might be difficult to predict at baseline the emergence of telaprevir-resistant variants after commencement of triple therapy, even with the use of ultra-deep sequencing.

Disclosures:

Norio Akuta - Patent Held/Filed: SRL. Inc.

Kenji Ikeda - Speaking and Teaching: Dainippon Sumitomo Pharmaceutical Company

Hiromitsu Kumada - Speaking and Teaching: Bristol-Myers Squibb,Pharma International

The following people have nothing to disclose: Fumitaka Suzuki, Tasuku Hara, Taito Fukushima, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Tetsuya Hosaka, Masahiro Kobayashi, Satoshi Saitoh, Mariko Kobayashi, Yasuji Arase

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Fluvastatin does not exhibit antiviral effect on PEG-IFN/Ribavirin/Telaprevir therapy for genotype 1 b chronic hepatitis C

Norio Itokawa1, Masanori Atsukawa1, Noritomo Shimada2, Ai Nakagawa1, Chisa Kondo1, Yoko Matsushita3, Takeshi Fukuda3, Yoshiyuki Narahara3, Katsuhisa Nakatsuka3, Katsuhiko Iwakiri3, Choitsu Sakamoto3;
1Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan; 2Shinmatsudo Central General Hospital, Mat-sudo, Japan; 3Nippon Medical School, Sendagi Tokyo, Japan

Purpose: Combination therapy with PEG-IFN/Ribavirin/Telaprevir is the standard of care for genotype 1b chronic hepatitis C,high-viral-load. Previously, we reported that fluvastatin (FLV) combined with PEG-IFN/Ribavirin therapy significantly improved the SVR rate. In present study, we analyzed factors contributing to the therapeutic effects of PEG-IFN/Ribavirin/Telaprevir therapy, including the effects of the concomitant addition of FLV. Methods: This prospective open-label randomized controlled study enrolled 107patients infected with HCV genotype 1 b, high viral load. After written informed consent was obtained from patients, they were randomly allocated to two arms: groups with and without FLV, and PEG-IFN/Ribavirin/Telaprevir therapy was performed. This study was conducted after the protocol was approved by the Drug Ethics Review Board. Results: The subjects consisted of 57males and 50 females, with median age of 60 years (28 to 70). The pretreatment state was naïve in 56 patients, relapse in 34, NVR in 17, core aa70 substitution (wild type=72/mutant type=35), and IL28B genotype (rs8099917) in 107 (TT=71/ non-TT=36). The RVR, EVR, and SVR 12 rates were 78.5% (84/107), 97.1% (104/107), and 84.2% (80/95), respectively. The SVR12 rates in the groups with and without FLV were 77.3 (34/44) and 87.5% (42/48), respectively; there was no significant difference (p=0.202). As factors contributing to SVR, core aa70, core aa91, IL28B genotype, 25(OII)D3, relapser,white blood cell count, platelet count, albumin level, LDL-C level,and hemoglobin level were extracted on univariate analysis. Multivariate analysis identified the IL28B genotype (p=0.022,Odds: 102.422, 95%CI: 1.921–5460-347) as an independent factor contributing to SVR. On subanalysis, there were no add on effects of FLV even in male, IL28B major genotype, core aa70 wild type, or relapse patients who responded to PEG-IFN/Ribavirin therapy. In addition, although the use of FLV decreased relapse rate in PEG-IFN/Ribavirin therapy, there were no differences in the relapse rate in PEG-IFN/Rib avirin/Telaprevir therapy. Conclusion: PEG-IFN/Ribavirin/Telaprevir therapy for genotype 1b chronic hepatitis C high-viral-load, were highly effective. The IL28B genotype was the most important independent factor contributing to SVR. There were no add-on effects of FLV in patients receiving PEG-IFN/Ribavirin/Telaprevir therapy.

Disclosures:

Choitsu Sakamoto - Grant/Research Support: Pfizer, Astellas, Esai, AstraZeneca, Otsuka, Daiichisankyo; Speaking and Teaching: Pfizer, Astellas

The following people have nothing to disclose: Norio Itokawa, Masanori Atsukawa, Noritomo Shimada, Ai Nakagawa, Chisa Kondo, Yoko Matsushita, Takeshi Fukuda, Yoshiyuki Narahara, Katsuhisa Nakatsuka, Katsuhiko Iwakiri

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Ifn Type I and Ifn type III Gene Expression Shows Differential Relationship with HCV Loads in Liver Tissues

Nobukazu Yuki1, Tadashi Yamasaki2, Michio Kato3, Toshikazu Yamaguchi2;
1 Department of Gastroenterology, Osaka National Hospital, Osaka, Japan; 2BML, Inc., Kawagoe, Japan; 3Depart-ment of Gastroenterology, Minamiwakayama National Hospital, Tanebe, Japan

BACKGROUND & AIMS: IFN type I and type III bind to different cellular receptors with disparate tissue distribution patterns and thus would be predicted to serve divergent biological roles. There is mounting evidence that the genotype around the type III IFN-λ3 gene is associated with HCV response to IFN-based treatment. Recent studies further showed that IFN type III and not type I drive hepatic ISG expression and induce an antiviral state in hepatitis C. Thus far, IFN type I and type III gene expression has not been well studied with regard to hepatic HCV loads. METHODS: Liver positive- and negative-strand HCV RNAs were quantified by strand-specific TaqMan PCR in 49 patients with hepatitis C genotype 1 before PEG-IFN and rib-avirin treatment. The results were correlated with hepatic mRNA expression of type I IFN-β(n=49) and type III IFN-λ2 and -λ3 (n=43). The rs8099917, rs8103142 and rs11881222 polymorphisms were determined by InvaderPlus assay in 26 patients. RESULTS: IFN-βexpression showed no relationship with hepatic HCV loads regardless of IFN responsiveness. In contrast, IFN-λ2 and -λ3 expression was positively correlated with liver positive-strand HCV RNA (r=0.853; P<0.001 and r=0.686; P=0.009, respectively) and negative-strand HCV RNA (r=0.731; P=0.009 and r=0.608; P=0.027, respectively) in IFN nonresponders not achieving HCV clearance by week 24 (n=13, per protocol analysis), but not in responders (n=24). IFN nonresponders showed marginally higher expression of IFN-β(median 3.1; range 0.6–27.5 vs. median 2.0; range 0.5–7.8; P=0.067), IFN-λ2 (median 0.59; range 0.16–7.46 vs. median 0.46; range 0.16–2.93; P=0.157) and IFN-λ3 (median 0.69; range 0.17–6.57 vs. median 0.45; range 0.16–3.18; P=0.060) compared with responders, whereas the expression levels were not associated with the IFN-λ3 (IL28B) SNPs. CONCLUSIONS: IFN nonresponders showed HCV replication-related induction of IFN type III but not IFN type I. Given that hepatic ISG expression is drived by IFN type III, these observations may partly explain high levels of hepatic ISG expression in nonresponders.

Disclosures:

The following people have nothing to disclose: Nobukazu Yuki, Tadashi Yamasaki, Michio Kato, Toshikazu Yamaguchi

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Comparison of adverse outcomes of telaprevir or boceprevir in combination with peginterferon alfa/rib-avirin versus peginterferon alfa/ribavirin: postmarket-ing experience in Canada

Morris Sherman1, Alnoor Ramji2, David Sealey3;
1Medicine, Toronto General Hospital, Toronto, ON, Canada; 2Medicine, University of British Columbia, Vancouver, BC, Canada; 3Janssen Inc, Toronto, ON, Canada

PURPOSE: We compared the incidence and management of adverse events (AEs) experienced by patients in Canada during postmarketing treatment for HCV genotype 1 with boceprevir (B) or telaprevir (T) in combination with PegIFN-alfa/ribavirin (PR) versus PR alone. METHODS: Gastroenterologists, hepatol-ogists and infectious disease specialists were invited to complete an online questionnaire to capture safety-related outcomes of their most recent patients who started therapy from June 2011 to November 2012, and at least 3 months prior to data capture. Authors were blinded to the identities of physicians and patients. Patients had to have tested positive for anti-HCV antibody and HCV RNA level ≧10,000 IU/mL for at least 6 months. Patients infected with other HCV genotypes or HIV were excluded. RESULTS: A total of 28 physicians reported data on 217 patients treated with PR (n=83), B+PR (n=61), or T+PR (n=73). The majority of patients (77%) were treatment-naïve. Baseline METAVIR scores in these groups were as follows: F0 F2, 63%, 49%, 56%; F3-F4, 24%, 46%, 42%, respectively. The incidence of any AE in the groups was 52%, 69%, and 82%. The incidence of the following AEs was higher in patients treated with B+PR/T+PR than with PR: anemia (51%/66% vs. 45%), rash (10%/41% vs. 7%), and anorectal events (2%/25% vs. 0%). Management of anemia in patients treated with PR, B+PR, and T+PR included ribavirin dose adjustment (11%, 33%, 49%), epoetin alfa (13%, 28%, 16%), transfusion (2%, 7%, 4%), and/or acute care (2%, 7%, 8%). Differences in the usage of epoetin alfa may be explained by differences in clinical course, use of other management strategies, and/or reimbursement limitations. Compared to PR, B+PR/T+PR were associated with a higher number of ribavirin dose adjustments, greater reductions in hemoglobin, and administration of higher doses of epoetin alfa for longer periods of time. T+PR was associated with higher incidence of grade >2 rash than B+PR/PR (14% vs. 2%/4%), requiring more frequent treatment with antihistamines and corticosteroids. One T+PR patient with rash received acute care and was admitted to hospital. Compared to B+PR and PR, T+PR was associated with a higher number of office visits within two months of initiation, as well as longer time spent with the physician per visit. Overall, 1%, 5%, and 5% of patients treated with PR, B+PR, and T+PR discontinued therapy due to treatment-associated AEs. CONCLUSION: Patients in Canada treated with B orT in combination with PR experienced more frequent and severe AEs which required medical intervention and discontinuation of treatment. Treatment with B and T also increased utilization of medical resources.

Disclosures:

Morris Sherman - Advisory Committees or Review Panels: Merck, Tibotec, Roche, Gilead, Celsion, Janssen; Speaking and Teaching: Gilead, Bristol Myers Squibb, Bayer

Alnoor Ramji - Advisory Committees or Review Panels: Roche, Merck, Gilead, vertex, Janssen, Boehringer Ingelheim; Grant/Research Support: BMS, Roche, Merck, Gilead, Vertex, Novartis, Abbvie, Boehringer Ingelheim

David Sealey- Employment: Janssen Inc.

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Real world experience with triple therapy for HCV GT1 patients in difficult to treat patients: Severe adverse events and treatment failure in cirrhotic patients with advanced portal hypertension

Joerg Petersen, Karen Olah, Stefan Unger, Thore Lorenzen, Frieder Kuhlendahl, Andreas Plettenberg, Albrecht Stoehr, Christine Czaja-Harder, Katharina Voelker, Urs Ehehalt, Karsten Wursthorn, Peter Buggisch;
Liver Unit at Asklepios Klinik Hamburg, IFI Institute for Interdisciplinary Medicine, Hamburg, Germany

Background and aim: Newly approved HCV GT1 triple regimens are complex and associated with additional toxicities. Besides RCT results, only limited data are available for BOC und TVR under real life conditions in difficult to treat patients with non-response and advanced liver disease. Methods: Data from 152 patients who initiated triple therapy apart from clinical studies or Early-Access-Programs with BOC (n=73) or TVR

(n=79) at the IFI Institute were obtained from medical record review and analysed on an intention to treat basis. Hemoglobin level < 9g/dl or a >4.5g/dl decrease from baseline defined severe anemia, fibrosis scores of >3 by Fibroscan or ARFI defined advanced fibrosis. Results: Median age of the study group was 56yrs with 30% of more than 60yrs, 67% males, 89% Caucasian, GT1a 39%, GT1 b 60%, IL28 C/C 11%, non C/C 88%. 42% of patients showed advanced fibrosis, 24% with complete cirrhosis and platelets of <120.000/ul, 13% with patelets of less than 100.000/ul and albumine less than 39g/l. 26% were treatment-naïve, of 74% of patients with prior Treatment failure 50% were non-responders. In this ongoing study, severe adverse events (SAEs) were reported in 65% and 59% of patients during BOC and TVR therapy, respectively. All patients with cirrhosis and all patients above 60yrs of age developed SAEs. Severe anemia occurred in 65% of patients, 38% of patients received blood transfusions, all patients above 60yrs and all cirrhotic patients received blood transfusions (Epo off label). Discontinuation rate because of SAEs or virological failure was 33% (BOC) and 32% (TVR). All patients with platelets less than 100.000/ul and albumin less than 39g/l experienced SAEs and treatment failure. Hospitalisation due to SAEs in F3/F4 patients was 25% for BOC and 27% for TVR patients. SVR12 rates for the entire cohort were 57% for BOC and 62% for TVR patients; for all naïve and relapse patients <F3 65% (BOC) and 72% (TVR); for all F4 cirrhotics 35% (BOC) and 31% (TVR); and for null responder cirrhotics 13% (BOC) and 10% (TVR). Interestingly, virological failure was more often related to virological break throughs compared to failure in reaching primary stopping rules at week 4 (TVR) or 12 (BOC). Conclusions: For patients of older age and with liver cirrhosis reflected by low platelets and albumin the safety profile is poor for both drugs. Cirrhotic patients with portal hypertension and less than 100.000 platelets/ul and less than 39g of albumine/l should not be considered for triple therapies.

Disclosures:

Joerg Petersen - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead, Novartis, Merck, Bristol-Myers Squibb, Gilead, Novartis, Merck; Grant/Research Support: Roche, GlaxoSmithKline, Roche, GlaxoSmithKline; Speaking and Teaching: Abbott, Tibotec, Merck, Abbott, Tibotec, Merck

Albrecht Stoehr- Board Membership: MSD, Böhringer Ingelheim; Speaking and Teaching: Janssen, MSD, Gilead, Abbvie, Böhringer Ingelheim

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

The following people have nothing to disclose: Karen Olah, Stefan Unger, Thore Lorenzen, Frieder Kuhlendahl, Andreas Plettenberg, Christine Czaja-Harder, Katharina Voelker, Urs Ehehalt, Karsten Wursthorn

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OPtimization of treatment for patients with chronic hepatitis C infected with HCV-genotype 2 or 3: 12 vs. 24 weeks of Treatment EXtension for patients without rapid virological response (OPTEX)

Markus Cornberg1,14, Benjamin Heidrich1,14, Hans-Jörg Cordes2, Hartwig Klinker3, Bernd Moeller4, Uwe Naumann5, Martin Roessle6, Michael R. R. Kraus7, Klaus H. Boeker8, Christoph Roggel9, Marcus Schuchmann10, Albrecht Stoehr11, Andreas Trein12, Svenja Hardtke14,1, Andrea Gonnermann13, Armin Koch13, Heiner Wedemeyer1,14, Michael P. Manns1,14;
1Gastroen-terology,Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 2Vitanus GmbH, Frankfurt, Germany; 3Dept. of Internal Medicine II, University of Würzburg, Würzburg, Germany; 4Leberzentrum, Berlin, Germany; 5Praxiszentrum Kaiser-damm, Berlin, Germany; 6Praxiszentrum Gastroenterologie, Freiburg, Germany; 7Medical Dep II, Hospital Bughausen, Burghausen/Altötting, Germany; 8Leberpraxis, Hannover, Germany; 9Gastroenterology, Minden, Germany; 10Johannes Gutenberg University Mainz, Mainz, Germany; 11Institut für Interdisziplinäre Medizin; IFI, Hamburg, Germany; 12doctor's practice, Stuttgart, Germany; 13Biometry, Hannover Medical School, Hannover, Germany; 14HepNet Study-House, German Liver Foundation, Hannover, Germany

Background: Patients with HCV genotype 2/3 (G2/3), especially those with genotype 3 and unfavourable predictors of response remain a challenge in the treatment of chronic hepatitis C. Most DAAs are not effective and the progression to cirrhosis in genotype 3 patients is faster. The current standard treatment still consists of pegylated Interferon alpha (P) and rib-avirin (R) for 24 weeks. Patients with rapid virological response (RVR) show response rates >80% even with shorter treatment duration. However, SVR in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. The objective of OPTEX was to compare the efficacy of treatment duration of 36 versus 48 weeks (treatment extension of 12–24 weeks) in non-RVR patients with G2/3 who were treated with standard P-2b and R. Methods: A total of 1004 cHCV-G2/3 patients treated with standard P/R were recruited into a German HepNet multicenter patient-screening registry. Of those, 313 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial to study treatment extension of additional 24 weeks (group A) versus additional 12 weeks (group B) with 1.5 μg/kg P-2b and 800–1400 mg R. The primary endpoint was defined as sustained virological response rates (SVR) compared to a historical control treated for 24 weeks only. Secondary endpoints are EOT response and tolerability. End of follow-up will be available in September 2013, thus relapse rates and SVR data will be presented at AASLD. Results: Only 99 non-RVR patients (n=51 Group A, n=48 Group B) could be enrolled into the OPTEX trial which was stopped before the target enrollment of 150 patients due to slow recruitment. Baseline factors did not differ between groups. The total cohort included 66% males with a mean age of 45 (SD=8.8) years; 17 patients had G2 and 82 patients G3; 62% of patients had high baseline HCV RNA >600.000 IU/ml. 40 patients in group A and 38 patients in group B had at least one adverse event. 4 patients had severe adverse events (3 in group A and 1 in group B) (p=0.402). Based on the ITT analysis, 84% [74%; 94%] patients of Group A and 83% [73%; 94%] patients of Group B were HCV RNA negative at EOT. Conclusions: Approximately 30% of G2/3 patients did not achieve RVR in a real life patient registry. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy was well tolerated and 36 versus 48 weeks treatment did not result in higher drop out rates. EOT was similar and final SVR data will be reported at the meeting.

Disclosures:

Markus Cornberg - Advisory Committees or Review Panels: Merck (MSD Ger-mamny), Roche, Gilead, Novartis; Grant/Research Support: Merck (MSD Ger-mamny), Roche; Speaking and Teaching: Merck (MSD Germamny), Roche, Gilead, BMS, Novartis, Falk

Hartwig Klinker - Advisory Committees or Review Panels: Bristol-Myers Squibb, Merck Sharp & Dohme, Abbott, ViiV, Janssen, Boehringer, Hexal; Grant/Research Support: Gilead, Abbott, Roche, Janssen, Novartis, Bristol-Myers Squibb, Boehringer; Speaking and Teaching: Roche, Gilead, Bristol-Myers Squibb, Novartis, ViiV, Merck Sharp & Dohme

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

Michael R. R. Kraus - Advisory Committees or Review Panels: Schering-Plough, Roche; Consulting: Schering-Plough, Roche

Klaus H. Boeker - Speaking and Teaching: MSD, Roche, Janssen, Gilead, BMS, Falk Foundation, Novartis

Marcus Schuchmann - Advisory Committees or Review Panels: Roche, BMS, Norgine, Boehringer; Speaking and Teaching: Gilead, Merck, Falk

Albrecht Stoehr- Board Membership: MSD, BAöhringer Ingelheim; Speaking and Teaching: Janssen, MSD, Gilead, Abbvie, Böhringer Ingelheim

Andreas Trein - Advisory Committees or Review Panels: Abbott, BMS, Boehringer, GSK, MSD / Essex; Grant/Research Support: Abbott, GSK; Speaking and Teaching: Abbott, BMS, Boehringer, Gilead, GSK, MSD / Essex, Roche, ViiV

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

The following people have nothing to disclose: Benjamin Heidrich, Hans-Jörg Cordes, Bernd Moeller, Martin Roessle, Christoph Roggel, Svenja Hardtke, Andrea Gonnermann, Armin Koch

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Chronic Hepatitis C: Peg-Interferon and /or ribavirin (PR) dose modifications during triple antiviral therapy have no impact on SVR rate: a single center experience

Gaelle Le Folgoc1, Valerie Oules1, Laurence Lecomte1, Christelle Ansaldi1, Paul Castellani1, Annie Benmenni1, Aurelie Riso1, Souad Ben Ali1, Christine P. Hernandez1, Sabrina Siame1, Adhoute Xavier1, Isabelle Portal2, Guillaume Penaranda3, Marc Bourlière1;
1Hepato Gastro Enterologie, Hopital Saint Joseph, Marseille, France; 2Hepato Gastro Enterologie, Hopital de la Conception, Marseille, France; 3Biostatistics, Alphabio, Marseille, France

Background and Aims: Triple therapy with boceprevir (BOC) or telaprevir (TVR) associated with PR lead to an increase of sustained virological response (SVR) and increase of adverse events, leading to dose modification. Our aim was to study if PR dose modification has an impact on SVR rate. Methods: Retrospective analysis including data collected from 174, genotype 1 patients treated, in our department, with triple therapy with TVR (84 subjects) or BOC (90 patients), according to French recommendations. In this cohort, there are 100 patients with severe fibrosis (F3 or F4) and 74 with mild or moderate fibro-sis. 35 naive and 139 treatment-experienced CHC patients were followed until minimum 12 weeks post-treatment (SVR 12). Results: 49% patients had a SVR with triple therapy, 39% with TVR and 58% with BOC. SVR rate is higher in naive patients (71%) than in treatment-experienced (43%) patients. SVR rate is 72% in relapsers, 10%in partial responders and 20% in null responders. 62% of patients had dose modification during treatment and 39% had no dose modification. SVR rate for those 2 groups is respectively 57% and 36%. In the TVR group, dose modification was done in 66% of patients leading to a

SVR rate of 49% versus 21% in those without PR dose modification. In the BOC group, dose modification was done in 58% of patients leading to an SVR of 65% versus 47% in those without PR dose modification. Results are the same if we compare patients according to their status: naive, relapser, partial non-responder or null responder. RVR (HCV RNA undetectability at W4 with TVR and W8 with BOC) is reached in 66% of patients with TVR and 65% with BOC. SVR rate in RVR patients is 54% with TVR and 80% with BOC in those with dose modification versus 25% with TVR and 85% with BOC in those without dose modification. Conclusion: PR dose modifications during triple regimen have no impact on SVR rate.

Disclosures:

Marc Bourlière - Advisory Committees or Review Panels: Schering-Plough, Bohringer inghelmein, Merck, Schering-Plough, Bohringer inghelmein, Merck ; Board Membership: Bristol-Myers Squibb, Gilead, Bristol-Myers Squibb, Gilead; Consulting: Roche, Novartis, Tibotec, Abott, glaxo smith kline, Roche, Novartis, Tibotec, Abott, glaxo smith kline

The following people have nothing to disclose: Gaelle Le Folgoc, Valerie Oules, Laurence Lecomte, Christelle Ansaldi, Paul Castellani, Annie Benmenni, Aurelie Riso, Souad Ben Ali, Christine P. Hernandez, Sabrina Siame, Adhoute Xavier, Isabelle Portal, Guillaume Penaranda

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Genotype distribution, response to treatment with inter-feron α2α/ribavirin and compliance rates between chronic HCV infected i.v. drug users in substitution programs with buprenorphine and methadone

Dimitrios Dimitroulopoulos1, Eleftheria Petroulaki2, Dimitrios Kypraios1, Stefanos Bassioukas1, Klisthenis X. Tsamakidis1, Dimitrios Xinopoulos1;
1Gastroenterology, “Agios Savvas” Hospital, Athens, Greece; 2National Greek Organization Against Drugs (OKANA), Athens, Greece

Introduction: Chronic HCV infection (HCV) is the most common infectious disease among intravenous drug users. Aims: To determine and compare compliance rates between two groups of chronic HCV patients from the National Greek Organization Against Drugs (OKANA) in substitution programs with buprnor-phine or methadone, treated with pegylated interferon plus rib-avirin during 24 or 48 weeks of therapy and 24 weeks of follow up. Also, to evaluate the genotype distribution and the efficacy of treatment in each group. Methods: 97 consecutive chronic HCV infected patients, members of the OKANA program, were treated with pegylated interferon α-2α in combination with oral ribavirin for 24 or 48 weeks according to their genotype. 45 were in buprnorphine maintenance (Group A, 36 males, 9 females) and 65 in methadone maintenance (Group B, 52 males, 13 females). During the study, all patients were followed up periodically by hepatologists, internists and psychiatrists. Results: The genotyping distribution in each group was for Group A 1a: 4 (8.9%), 1b: 8 (17.8%), 2: 4 (8.9%), 3a: 22 (48.9%) and 4: 7 (15.6%) and for Group B 1a: 0 (0%), 1 b: 9 (13.8%), 2: 8 (12.3%), 3a: 39 (60%) and 4: 9 (13.8%). There was no statistically significant difference between the two groups regarding the distribution of viral genotypes (p=0.137). The rest of baseline characteristics, including the viral load, were similar between the two groups with exception of ALT levels that was significantly higher in patients from group B (p=0.034). 34/45 patients (75,6%) from group A and 31/65 (47,7%) from group B completed therapy (p=0.006). Thirty-two (71,1 %) patients from group A and 27 (41,5%) from group B were followed up until the end of the follow-up period (p=0.004). At the end of the follow-up, sustained virologic response (SVR) was achieved in 23/45 (51.1%) patients from group A and 21/65 (32.3%) from group B (p= 0.075). Based on viral genotype results were accordingly: For Group A: SVR for genotypes 1, 4 were 36.8% and for genotypes 2,365.4% (p=0.111). For group B SVR rates for genotypes 1, 4 was 22,2% and for genotypes 2,336.2% (p=0.436). Conclusion: Buprenorphine maintenance achieves a significantly higher compliance rate than methadone in patients with chronic HCV infection treated with pegylated interferon and ribavirin. After 24 weeks of follow-up, response rates were similar for patients who were compliant to treatment for both groups.

Disclosures:

The following people have nothing to disclose: Dimitrios Dimitroulopoulos, Eleftheria Petroulaki, Dimitrios Kypraios, Stefanos Bassioukas, Klisthenis X. Tsamakidis, Dimitrios Xinopoulos

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Multicenter Prospective Study to Evaluate the Efficacy of Triple Therapy with Telaprevir in Patients with Genotype 1 b HCV According to the Algorithm Based on Drug Adherence and IL28B Gene as Well as Response-Guided Therapy: the AG & RGT Trial

Kayoko Sugawara, Mie Inao, Nobuaki Nakayama, Satoshi Mochida;
Department of Gastroenterology and Hepatology, Saitama Medical University, Moroyama-Machi, Japan

[Background and Aim] A previous Japanese trial revealed that treatment adherence of to both ribavirin (RBV) and Peg-IFN, as well as IL28B SNPs are crucial to achieve SVR after triple therapy with telaprevir (TPV) in patients with HCV hepatitis. Also, RGT has been shown to improve the percentage of SVR in such patients. Thus, we per-formed a prospective multicenter study to optimize the efficacy of triple therapy ac-cording to an algorithm based on adherence, IL28B polymorphism and viral response during the therapy. [Methods] A total of 273 patients (126 treatment-naïve patients, 91 patients with re-lapse and 48 non-responders [NR] to previous RBV/Peg-IFN therapy) were enrolled. All patients were diagnosed as having chronic hepatitis due to genotype 1 b HCV with serum RNA levels of greater than 5 Log IU/mL. They received TPV at the daily dose of either 2,250 or 1,500 mg for 12 weeks. The duration of RBV (600–1,000 mg/day) plus Peg-IFN-a2b (60–150 mg/week) therapy was determined according to the following al-gorithm. The therapy was administered for 24 weeks in patients showing RVR with fa-vorable IL28B alleles (TT:rs8099917) and in those showing adherence of 80% or more for both RBV and Peg-IFN until 24 weeks regardless of the alleles. In contrast, the therapy was prolonged to 48 weeks in patients showing adherence of less than 80% for either drug and unfavorable alleles (CT or CC) despite achieving RVR and in those not achieving RVR and showing cEVR, and to 72 weeks in those showing pEVR. [Results] The duration of combined RBV plus Peg-IFN therapy was determined in 240 patients, since the duration of therapy did not reach 24 weeks in the remaining 33 pa-tients. Combination therapy was discontinued at 24 weeks in 129 patients (47%) ac-cording to the algorithm, and the SVR ratio in these patients was 92% (naïve: 94%; re-lapse: 98%; NR: 78%). The therapy was prolonged in 66 patients (22%), including to 48 and 72 weeks in 64 and 2 patients, respectively, and SVR was obtained in 77% of pa-tients after completion of the prolonged therapy. In contrast, in 45 patients (17%), the therapy was discontinued due to adverse effects of TPV, however, SVR was achieved in 40% of these patients. Consequently, the percentage showing SVR among the patients in whom the therapy had already been completed was calculated as 82% (naïve: 83%; relapse: 86%; NR: 64%) through ITT analysis. [Discussion & Conclusion] A high SVR rate was obtained by triple therapy undertaken according to the algorithm established based on the drug adherence, IL28B gene poly-morphism and response during the therapy (AG & RGT), even in non-responders to previous RBV plus Peg-IFN therapy.

Disclosures:

Satoshi Mochida -Grant/Research Support: Chugai, MSD, Tioray Medical, BMS; Speaking and Teaching: MSD, Toray Medical, BMS, Tanabe Mitsubishi

The following people have nothing to disclose: Kayoko Sugawara, Mie Inao, Nobuaki Nakayama

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Telaprevir-Induced, but not Pegylated Interferon-Associ-ated, Retinopahy as a Noteworthy Adverse Effect in Patients with Chronic Hepatitis C during the Triple Antiviral Therapy

Kayoko Sugawara, Mie Inao, Nobuaki Nakayama, Satoshi Mochida;
Department of Gastroenterology and Hepatology, Saitama Medical University, Moroyama-Machi, Japan

[Background and Aim] Retinopathy consists of cotton wool spots and/or hemorrhage is one of the important adverse effects during combined ribavirin (RBV) plus Peg-IFN therapy. In general, such lesions may develop through microcirculatory disturbance by Peg-IFN, but the incidence of the lesions during triple therapy with telaprevir (TPV) is to be elucidated. Thus, we examined ophthalmologic appearance in patients receiving triple therapy. [Methods] Subjects were 94 chronic hepatitis C patients receiving triple therapy with Peg-IFN-a2b (60–150 g/week), RBV (600–1,000 mg/day) and TPV (1,500 or 2,500 mg depending on age and body weight). The oophthalmologic examination was done pro-spectively by specialists immediately before and every month during the therapy. [Results & Discussion] Retinopathy was found in 39 patients (41.5%), and the therapy was discontinued in 8 patients (8.5%), because the lesions located beside optic nerve papilla and/or macula may affect visual acuity. Considering that the frequency of reti-nopa-thy during combined RBV plus Peg-IFN therapy was 19% in Japanese historical controlled patients, TPV may enhance retinopathy development. This hypothesis was clarified through clinical course of one patient; a 65-years-old man receiving Peg-IFN-2b (100 g/week), RBV (800 mg/day) and TPV (2,250 mg/day). He had no history of previous IFN therapy, diabetes, hypertension and renal diseases. The baseline ophthalmologic examination showed no lesions on both fundi. In this patient, daily doses of RBV and TPV were reduced (800 mg and 1,500 mg, respectively) duce to hyperuricemia and renal impairment found Day 4. The scheduled ophthalmologic ex-amination revealed cotton wool spots on the fundus in both eyes, which might deterio-rate visual acuity. Thus, TPV intake was discontinued, while Peg-IFN-2b and RBV therapy were continued, and cotton wool spots disappeared then later. Then, the patient took TPV again at daily doses of 750 mg by his decision, and cotton wool spots reap-peared on right fundus, but the extent of the lesions were minimal, suggesting that TPV, but not RBV and Peg-IFN-2b were responsible for retinopathy development. [Conclusion] Ophthalmologic examinations should be done carefully during triple therapy with TPV, since the incidence was higher than that in combined PBV plus Peg-IFN therapy. Discontinuation or dose reduction of TPV is recommended for patients showing retinopathy that may affect visual acuity without discontinuation of combined Peg-IFN plus RBV therapy.

Disclosures:

Satoshi Mochida -Grant/Research Support: Chugai, MSD, Tioray Medical, BMS; Speaking and Teaching: MSD, Toray Medical, BMS, Tanabe Mitsubishi

The following people have nothing to disclose: Kayoko Sugawara, Mie Inao, Nobuaki Nakayama

1899

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IL28B genotype and IFNL4 ss469415590 ΔG variant are both associated with response to pegylated IFN-α and ribavirin therapy in Chinese patients with chronic hepatitis C

Huiying Rao1, Lai Wei1, Ruifeng Yang1, Xin-Yue Chen2, ShangJia3, ZhiLiang Gao4, Qing Xie5, Xiaoguang Dou6, Xiaoyuan Xu7, Guozhong Gong8, Guofeng Chen9, Jun Li10, Dazhi Zhang1 1, Junqi Niu12, Hong Chen13, Yinong Feng14, Jinlin Hou15, Hong You16, Yun Wu17, Peili . Zhao18; 1Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China; 2Beijing YouAn Hospital, Capital Medical University, Beijing, China; 3Henan Province People's Hospital, Zhengzhou, China; 4Sun Yat-Sen University, Guangzhou, China; 5Shanghai Jiao Tong University Ruijin Hospital, Shanghai, China; 6China Medical University, Shenyang, China; 7Peking University First Hospital, Beijing, China; 8The Second Xiangya Hospital of Central South University, Changsha, China; 9Military 302 Hospital of China, Beijing, China; 10Nanjing Medical University, Nanjing, China;
1 1 The Second Affiliated Hospital Chongqing Medical University, Chongqing, China; 12Jilin University, Changchun, China; 13Lanzhou University, Lanzhou, China; 14Shanxi Medical University, Taiyuan, China; 15Nanfang Medical University, Guangzhou, China; 16Beijing Friendship hospital, Beijing, China; 17The Affiliated Hospital of Inner Mongolia Medical Hospital, Huhehaote, China; 18The Third Hospital of Qinhuangdao, Qinhuangdao, China

Correspondence to Lai Wei, Peking University People's Hospital, Beijing, Peoples Republic of China, weilai@pkuph.edu.cn Background and Aim: Upstream of IFNL3 (IL28B), recent study discovered a new transiently induced region that harbors a din-ucleotide variant ss469415590 (TT or ΔG). Ss469415590 [ΔG] is a frame shift variant that creates a novel gene, designated IFNL4. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry. The study aimed to assess the associations of ss469415590, rs12979860 and rs8099917 with the response to pegIFN-α/RBV therapy in Chinese individuals. Methods: Patients were treated with Peg-IFN α-2a 180ug/wk plus Ribavirin. Patients with undetectable HCV RNA (<15 IU/mL) at week 12 are assigned to complete total 48 week combination therapy. Patients with detectable HCV RNA at week 12 are randomized to receive either a total duration 72 weeks or 96 weeks treatment. Rs12979860 and rs8099917 genotypes were determined by iPLEX system (MassARRAY® SNP Genotyping; Sequenom), and ss469415590 genotypes were tested by sequencing. Results: A total of 438 patients with 252 (57.5%) male from 18 Chinese hospitals were enrolled. The mean age was 41.3±13.4 years. 83.3% patients were genotype1, 13.5% patients were genotype2/3 and 14 (3.2%) patients were genotype6. 82.5% patients were ss469415590 TT/TT genotype and 1 7.5% were ΔG/TT or ΔG/ΔG genotype.81.2% patients were rs12979860 CC genotype and 18.8% were CT or TT genotype. For genotype 6, only one patient was ss469415590 ΔG/TT and 13 patients were TT/TT. For genotype1, genotype2/3 and genotype6 patients, sustained viral response (SVR) rates were 83.7%, 90.2%, and 100%, respectively. Patients for the TT/TT allele at ss469415590 had significantly higher SVR rates compared to patients with the ΔG/TT or ΔG/ΔG genotype (88.7% vs 67.1%). For genotype genotype2/3 patients, SVR rate were 91.2% in ss469415590 TT/TT patients, and 80% in ΔG/TT patients (n=5). We observed a very similar association for ss469415590 and for rs12979860 and rs8099917 with various measures of treatment response (week 4 response, week 12 response, and SVR). Conclusion: Ss469415590 were in strong linkage disequilibrium with rs12979860 and rs8099917. The association patterns between host genotype with SVR rates were similar at ss469415590, rs12979860 and rs8099917 in Chinese patients.

Disclosures:

Lai Wei - Consulting: Gilead; Grant/Research Support: BMS, Roche, Novartis; Speaking and Teaching: Gilead

Ji nlin Hou - Consulting: Roche, Novartis, GSK, BMS, Roche, Novartis, GSK, BMS; Grant/Research Support: Roche, Novartis, GSK, Roche, Novartis, GSK

The following people have nothing to disclose: Huiying Rao, Ruifeng Yang, Xin-Yue Chen, Shang Jia, ZhiLiang Gao, Qing Xie, Xiaoguang Dou, Xiaoyuan Xu, Guozhong Gong, Guofeng Chen, Jun Li, Dazhi Zhang, Junqi Niu, Hong Chen, Yinong Feng, Hong You, Yun Wu, Peili . Zhao

1900

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Real-Life Data of Telaprevir-Based Triple-Therapy in Patients with Chronic Hepatitis C GT1 in Germany - A 48 Week Interim Analysis

Thomas Berg1, Peter Buggisch2, Dietrich Hueppe3, Stefan Mauss4, Heiner Wedemeyer5, Holger Hinrichsen6, Klaus H. Boeker7, Ger-linde Teuber8, Thomas Lutz9, Kerstin Stein10, Maximilian Schuier11, Nicole Forestier11; 1Gastroenterology/Hepatology, Universitaet-sklinik, Leipzig, Germany; 2Ifi-Institut, Hamburg, Germany; 3Gas-troenterologische Gemeinschaftspraxis, Herne, Germany; 4Medizinisches Versorgungszentrum, Duesseldorf, Germany; 5Medizinische Hochschule, Hannover, Germany; 6Gastroenterolo-gische-Hepatologisches Zentrum, Kiel, Germany; 7Leberpraxis, Hannover, Germany; 8Medizinisches Versorgungszentrum, Frankfurt, Germany; 9Infektiologikum, Frankfurt, Germany;
10Univer-sitätsklinikum, Magdeburg, Germany; 11 Janssen-Cilag, Neuss, Germany

PURPOSE: Telaprevir (TVR)-based triple therapy in patients with chronic Hepatitis C (HCV) in daily practice in Germany is investigated in this non-interventional study to evaluate the safety and efficacy of the treatment under real-life conditions. METHODS: Prospective study, investigating TVR-based triple therapy in therapy-naive and pretreated patients with chronic HCV GT 1 in Germany. Data from 589 patients completing 48 weeks (W) of treatment (74% of the planned total) at 76 sites were included in this analysis. RESULTS: At baseline the mean age of the patients was 49.4 (SD 10.9) years, and 62% were male. Two-thirds of patients were pretreated (thereof, 39% were prior relapsers, 31% null or partial responder). The median HCV RNA level before initiation of TVR-based therapy was 1,200,000 IU/ml. 15% of patients reported cirrhosis at start of therapy (n=88 ); 8% of patients were coinfected with HIV (n=45 ) and 7% of patients were under stable drug substitution (n= 44). At week 4, 61%* of patients (65% therapy-naïve, 68% relapsers; 46% null and 55% partial responder) showed virological response. At W12, 88%* of patients had unde-tectable HCV RNA ( 91% of therapy-naïve, 91% relapsers; 70% null and 81% partial responder) and 75%* of patients (88% therapy-naïve, 82% relapsers; 36% null and 71% partial responder) had undetectable HCV RNA levels at the end of treatment. 53%* of patients with cirrhosis responded at W4, 83%* W12, and 63%* at the end of treatment. In total, 32% of patients terminated therapy prematurely. Main reasons for premature termination were lack of efficacy and incidence of side effects (14% and 12%, respectively). Most commonly reported AEs were general disorders and administration site conditions (73%), followed by skin and subcutaneous tissue disorders (70%), gastrointestinal disorders (65%) and blood and lymphatic system disorders (49%). AEs were mostly rated as mild (60%) or moderate (36%). 18% of patients (25% with cirrhosis) experienced serious adverse events (SAE) until W48. In total, 32 (12%) cases of anemia and 19 (8%) cases of rash were considered as SAEs. CONCLUSIONS: This interim analysis confirms the antiviral efficiency of TVR-based triple-therapy in GT1 HCV in a real life setting showing eRVR rates of more than 60% in treatment naïve and pre-treated patients. As observed in clinical trials, adverse events were reported frequently. * % based on number of patients with HCV-RNA measurements

Disclosures:

Thomas Berg - Advisory Committees or Review Panels: Gilead, BMS, Roche, Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS, Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche, Tibotec; Vertex, Jannssen, Schering Plough, Boehringer Ingelheim, Novartis; Speaking and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Schering Plough, Novartis, Merck, Bayer

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

Dietrich Hueppe -Advisory Committees or Review Panels: Roche, MSD, Gilead, Novartis, BMS

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Holger Hinrichsen -Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: Janssen

Klaus H. Boeker - Speaking and Teaching: MSD, Roche, Janssen, Gilead, BMS, Falk Foundation, Novartis

Gerlinde Teuber - Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Thomas Lutz - Advisory Committees or Review Panels: Gilead, MSD, Abbott, BMS, Janssen Cilag; Grant/Research Support: Boehringer Ingelheim, Gilead, GlaxoSmithKline, Schering-Plough, Roche, MSD, Abbott, Janssen Cilag; Speaking and Teaching: Boehringer Ingelheim, GlaxoSmithKline, Roche, BMS

Maximilian Schuier - Employment: Janssen-Cilag GmbH

The following people have nothing to disclose: Kerstin Stein, Nicole Forestier

1901

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Effect of interferon-λ 4 on treatment response to peg-interferon-α-2a and ribavirin in patients with chronic hepatitis C

Albert Stättermayer, Harald Hofer, Karoline Rutter, Sandra Bein-hardt, Thomas-Matthias Scherzer, Petra E. Steindl-Munda, Peter Fer-enci;
Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria

Background: The IL28B genotype in rs12979860 predicts success of peginterferon/ribavirin therapy in patients with chronic hepatitis C (CHC). Recently a dinucleotide frame-shift variant ss469415590 (TT/ΔG) was described which generates the novel interferon lambda 4 protein (IFNL4). Individuals carrying the IFNL4 ss469415590-ΔG allele (Prokunina-Olsson et al, Nature Genetics, 201345:164–71) have an impaired clearance of HCV infection and response to IFN-α therapy. IFNL4 leads in-vitro to elevated levels of interferon-stimulated genes (ISG). The aim of our study was to determine the role of IFNL4 for response to peg-interferon-α-2a and ribavirin (PEG/RBV) in a population of patients with chronic hepatitis C. We specifically selected rs12979860 CC patients not responding to therapy and T-allele carriers with SVR. Methods: 310 Caucasian PEG/RBV treated patients (male/female=185/125; age: 41.0±11.5; GT1: n=166, GT2: n = 11, GT3: n=96, GT4: n=37) were selected: 53 CC-carrier patients who failed antiviral treatment, and 211 TC- and 46 TT-carriers with SVR. Rs12979860, rs8099917 (n=272) and ss469415590 were analyzed by RT-PCR-system (StepOnePlus, Applied Biosystems, Foster City, USA). Results: Of the 53 nonresponders with CC in

IL28B, all had the TT/TT dinucleotide in IFNL4 (r^2=1.000, p<0.001). In the 257 TC/TT carrying patients with SVR there was only a weak correlation between IL28B and IFNL4 (r^2=0.371, p<0.001): 94 patients had IFNL4 TT/TT, 157 had TT/ΔG and only six had the unfavorable ΔG/ΔG (table). Conclusion: Our data suggest, that testing for IFNL4 before treatment might give additional information on the likelihood to achieve a SVR in patients carrying the unfavorable rs12979860 T-allele.

IL28BN IFNL4 SVR
rsl2979860 TT/TTTT/ΔGAG/ΔG 
CC5353000
TC211931171211
TT46140546
rs8099917     
TT1389345092
TG12245761119
GG12012012

Disclosures:

Harald Hofer - Speaking and Teaching: Janssen, Roche, MSD

Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, Roche, MSD, Vertex, Salix, Madaus Rottapharm, Tibotec, Böhringer Ingelheim, Achilleon, GSK; Grant/Research Support: MSD, Vertex, Madaus Rottapharm; Patent Held/Filed: Madaus Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix

The following people have nothing to disclose: Albert Stättermayer, Karoline Rut-ter, Sandra Beinhardt, Thomas-Matthias Scherzer, Petra E. Steindl-Munda

1902

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Non-virological factors predicting patient adherence during antiviral treatment of genotype 1 /4 infection in real world: role of gender and age

Thomas Witthoeft1, Ralph Link2, Stefan Christensen3, Heiner W. Busch3, Wolfgang Gickler4, Hermann Steffens5, Christine John6, Stefanie Holm7, Armand von Lucadou8, Elmar Zehnter9, Hans-Jörg Cordes10, Dietrich Hueppe11, Harald W. Blaak12, Dagmar Hart-mann12, Manfred Bilzer12; 1Gastroenterological Practice, Stade, Germany; 2St. Josefshospital, Offenburg, Germany; 3Center for Interdisciplinary Medicine (CIM), Münster, Germany; 4DRK Krankenhaus Neuwied, Neuwied, Germany; 5Practice of Internal Medicine, Berlin, Germany; 6Practice of Internal Medicine, Berlin, Germany; 7Practice of Internal Medicine, Hannover, Germany; 8Practice of Internal Medicine, Nürnberg, Germany; 9Gastroen-terological Practice, Dortmund, Germany; 10Interdisziplinäres Facharztzentrum Sachsenhausen (IFS), Frankfurt, Germany;
1 1 Medical Group Practice, Herne, Germany; 12MSD SHARP & DOHME GMBH, Haar, Germany

Background: Only few data are available on adherence to combination HCV therapy with pegylated interferon (PegIFN)/ribavirin (RBV) in real-world settings, despite its acknowledged importance. Such information might help clinicians to improve adherence and thereby virologic response to PegIFN/RBV therapy, also in combination with new antivirals. Methods: In this prospective observational multicenter study (@dhere study) 746 treatment-naïve patients with chronic HCV infection were treated with PegIFN alfa-2b (Peg-2b) 1.5 μg/kg/week + RBV (800–1200 mg/day) for up to 48 wks at 42 sites in Germany. Patients who received at least 80% of each of the 2 medications for at least 80% of the expected duration of therapy were classified as adherent. Multivariate logistic regression was used to determine factors predicting adherence to HCV treatment. The analysis was restricted to 480 patients with HCV genotype1/4 infection. SVR was defined as undetectable serum HCV-RNA 24 weeks after end of treatment. Results: Overall SVR rate of patients with G1 /4 infection was 47.1% in contrast to 76.4% and 22.5% in adherent/non-adherent patients, respectively. Using logistic regression, a number of patient visits ≧12 during antiviral treatment was identified as major factor independently associated with a higher likelihood of adherence (OR 19.3, p<0.0001). Compared to female patients (OR 11.8, p=0.0004) this association was most prominent in male patients (OR 27.3, p=0.0003). Peg2b/RBV-related adverse events were identified as less important predictor of adherence (OR 2.52, p=0.006). Again this effect was most prominent and only significant in male patients (OR 2.35, p=0.0113) when compared with female patients (OR 1.31, p=0.55). Recommendation of supportive psychotherapy was independently associated with a lower likelihood of adherence (OR 0.41, p<0.035). This association was particularly relevant for patients <50 years (OR 0.31, p=0.001), but not for patients >50 years (OR 1.49, p=0.51). Other factors such as detailed demonstration of Peg-2b pen device before therapy (OR 0.99, p=0.57), consumption of soft drugs (OR 0.94, p=0.78) or alcohol (OR 0.28, p=0.052) and the experience of physicians by number of HCV patients treated per year (OR 1.01, p=0.89) or specialization (gastroenterology vs hepatology: OR 0.56; p=0.56; other vs hepatology: OR 0.54, p=0.45) were not significantly associated with adherence. Conclusions: Adherence to HCV treatment with Peg-2b/RBV increases the likelihood of SVR in patients with HCV genotype G1/4 infection. Non-virologic factors influencing treatment adherence depend on gender and age.

Disclosures:

Stefan Christensen -Advisory Committees or Review Panels: Roche, BMS, Abbott, Janssen, Schering Plough, ViiV, Gilead, MSD, Boehringer Ingelheim; Speaking and Teaching: Gilead, MSD, Roche, BMS, Schering Plough, ViiV, Boehringer Ingelheim, Janssen

Heiner W. Busch - Advisory Committees or Review Panels: Essex, Tibotec; Speaking and Teaching: Tibotec, MSD, Roche, Boehringer Ingelheim, BMS, Gilead

Armand von Lucadou - Speaking and Teaching: Essex, Roche

Dietrich Hueppe - Advisory Committees or Review Panels: Roche, MSD, Novatis, Gilead, BMS

Harald W. Blaak - Employment: MSD Sharp & Dohme GmbH Dagmar Hartmann - Employment: MSD Germany Manfred Bilzer - Consulting: MSD Germany

The following people have nothing to disclose: Thomas Witthoeft, Ralph Link, Wolfgang Gickler, Hermann Steffens, Christine John, Stefanie Holm, Elmar Zehnter, Hans-Jörg Cordes

1903

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Increased ribavirin biodisponibility associated with telaprevir use in HCV patients treated with PEG-IFN/rib-avirin/telaprevir triple therapy

François Bailly1, Pierre Pradat1, Marianne Maynard-Muet1, Mathilde Leclercq1, Victor Virlogeux1, Patrick Miailhes3, Giorgiana Hatu1, Majid Amiri1, Fanny Lebossé1, Fabien Zoulim1, Marie-Claude Gagnieu2;
1Hepatology, Hospices Civils de Lyon, Hopital de la Croix-Rousse, Lyon, France; 2Pharmacology, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France; 3Infectious Diseases, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France

Introduction: In patients with hepatitis C virus (HCV) infection, anemia is a commonly observed side effect of ribavirin (RBV)-based therapy often resulting in dose reduction and/or treatment withdrawal. Previous studies indicate that anemia is about twice more frequent in patients receiving telaprevir with PEG-IFN/RBV than in those receiving PEG-IFN/RBV alone. The objective of this pilot study was to measure the impact of telaprevir on RBV plasma exposure and to assess concomitant renal function. Methods: 14 HCV patients (among whom 4 cir-rhotics) non-responders to a previous course of PEG-IFN/RBV therapy and re-treated by triple therapy combining PEG-IFN/RBV and telaprevir were analyzed. RBV trough plasma concentration as well as RBV biodisponibility (assessed by the ratio concentration/posology/bodyweight) were measured before triple therapy initiation (during previous treatment), during the early phase (W2+/-2), the later phase (W8+/-2), and after telaprevir cessation (post W16). Renal function was assessed by measuring the glomerular filtration rate (GFR) using the MDRD formula. Results: Four weeks after triple therapy initiation, RBV biodisponibility was significantly increased (median increase 0.089 mg/l/poso/kg; p=0.012). In parallel, renal function was impaired with a median GFR decrease of 29.9 mL/min/1.73 m2 (p=0.005). Between W4 and W8, RBV biodisponibility continued to increase (p=0.022) and decreased significantly at telaprevir discontinuation (p=0.012) with a concomitant restoration of renal function (GFR increase of 28 mL/min/1.73 m2; p=0.025). Eight patients had a RBV dose reduction between W4 and W8. All still increased their RBV biodisponibility despite a reduced plasma concentration in three of them. Conclusion: The assessment of RBV biodisponibility measures the actual exposure to RBV whereas the trough plasma concentration varies with posology. Our results indicate a reversible increase of RBV biodisponibility after telaprevir exposure which might be linked to the impairment of the glomerular filtration rate. This also suggests a RBV-telaprevir pharmacological interaction, a possible source of severe anemia observed under triple therapy. The persistence of a high RBV biodisponibility despite RBV dose reductions recommended for severe anemia could explain why these dose reductions do not impact the virological response. These results could prompt physicians to continue the RBV pharmacological monitoring especially in the context of novel forthcoming treatment strategies.

Disclosures:

François Bailly- Board Membership: MSD, BMS, GILEAD; Speaking and Teaching: ROCHE, JANSSEN

Fabien Zoulim - Advisory Committees or Review Panels: Gilead; Consulting: Roche; Grant/Research Support: Gilead, Scynexis, Roche; Speaking and Teaching: Novartis, Roche, Janssen, Bristol Myers Squibb, Gilead

The following people have nothing to disclose: Pierre Pradat, Marianne Maynard-Muet, Mathilde Leclercq, Victor Virlogeux, Patrick Miailhes, Giorgiana Hatu, Majid Amiri, Fanny Lebossé, Marie-Claude Gagnieu

1904

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Efficacy of antiviral treatment of chronic hepatitis C with PEG-IFNα-2B and RIBAVIRIN in combination with METFORMIN in patients with HCV-1 genotype and insulin resistance

Olga O. Khafisova1,2, Olga Tarasova1,2, Nataliya Mazurchik1,2, Pavel P. Ogurtsov1,2;
1The centre of Liver Researches, Peoples' Friendship University of Russia, Moscow, Russian Federation;2 Hospital Therapy, People's Friendship University of Russia, Moscow, Russian Federation

Insulin resistance (IR) - an important prognostic factor reducing the effectiveness of the antiviral therapy in patients with chronic hepatitis C. Using of metformin as a drug which normalize the level of insulin resistance in CHC patients, treated with Peg-IFNα-2b+ribavirin increases its efficacy, which is particularly important for patients with genotype 1 HCV. Aim: to estimate the frequency of the SVR in patients with chronic hepatitis C (HCV-1) and IR, receiving standard therapy in combination with metformin. Patients and methods: Since November 2009 we conducted a prospective study aimed to estimate the frequency of the SVR in 133 Russian patients with chronic hepatitis C (HCV-1), receiving standard therapy (PegIFNα-2b+ribavirin) in combination with metformin (in IR patients only). We studied IR using the method of “homeostatic model” (Homeostasis Model Assessment). HOMA-index (HOMA-IR) is calculated based on the indices of insulin and glucose in one portion of serum: HOMA-IR = fasting insulin level (MkME/mL)xfasting glucose (mmol/L)/22.5. The criterion for the presence of IR value was considered HOMA-IR>2. All patients were assigned to the standard combination therapy PegIFN-α-2b at a dose of 1.5 mcg/kg/weekand ribavirin in a dose of 15 mg/kg/day. 28 of 70 patients with chronic hepatitis C (HCV-1) and IR were given metformin at a dose of 20 mg/kg/day. Results: 133 patients were analyzed:63 patients without IR and 70 patients with IR.28 patients received metformin. Metformin was administered together with the antiviral treatment, or 3–6 months before the starting of antiviral treatment and continue throughout the course of therapy. Patients in the second (control) group did not receive metformin (n=42). Patients receiving and not receiving metformin did not differ significantly by gender and age, the average viral load and the degree of liver fibrosis (measured using FibroScan®502). Among the patients with HCV-1 without IR, SVR rate was 46% (n=29/63), and in patients with HCV-1 with IR (not receiving metformin), SVR was achieved in 42% of patients(n=18/42), p=0,33. In patients with HCV-1 and IR, receiving metformin, the SVR rate was 64% (n=18/28), p=0,001. Thus, correction of IR with using of metformin has led to an increase in its efficacy by 1.5 times. Significant reduction of glucose levels in patients with IR receiving metformin wasn't noted. Thus, metformin is not only effective but also safety for use in patients with chronic hepatitis C as a medication reducing IR. Conclusion: adding metformin 20 mg/kg/day as a third component of antiviral therapy is safe and improves its efficiency (42%vs64%) in patients with HCV-1 and IR.

Disclosures:

Pavel P. Ogurtsov - Consulting: MSD

The following people have nothing to disclose: Olga O. Khafisova, Olga Tarasova, Nataliya Mazurchik

1905

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Efficacy and safety of eRVR patients treated with telaprevir, peginterferon alfa-2A and ribavirin: SVR Data from the German non-interventional PAN Study

Stefan Christensen1, Klaus H. Boeker2, Christoph Eisenbach3, Marcus Schuchmann4, Thomas Lutz5, Renate Heyne6, Gero Moog7, Stefan Mauss8, Maria-Christina Jung9, Gerlinde Teuber10, Franz Emke11, Uwe Naumann12, Margareta Frank Doss13, Armand von Lucadou14, Ulrich Alshuth15, Dietrich Hueppe16; 1 Center for Interdisciplinary Medicine (CIM), Muenster, Germany; 2Center for Hepatology, Hannover, Germany; 3Dept. of Gastroenterology, University of Heidelberg, Heidelberg, Germany; 4Dept Med 1, Gastroenterology and Hepatology, Johannes Gutenberg Univ Mainz, Mainz, Germany; 5Infektiologikum, Frankfurt/M, Germany; 6Liver and study center Checkpoint, Berlin, Germany; 7Center of Gastroenterology, Kassel, Germany; 8Center for HIV and Hepatogas-troenterology, Duesseldorf, Germany; 9Liver Center, Munich, Germany; 10IFS, Interdisziplinaeres Facharztzentrum Sachsen-hausen, Frankfurt/M, Germany;
1 1 Center of Gastroenterology, Osnabrueck, Germany; 12Center for Addiction-Medicine, Hepatology and HIV, Praxiszentrum Kaiserdamm, Berlin, Germany; 13Center of Gastroenterology, Marburg, Germany; 14Center for Internal Medicine, Nuremberg, Germany; 15Virology, Roche Pharma AG, Grenzach-Wyhlen, Germany; 16Center of Gastroenterology, Herne, Germany

Introduction: In pivotal trials shortening of telaprevir (TVR) based triple therapies was possible in up to 58%*. Drawbacks in real-life are complex guidelines and need of profound knowledge of treatment practices for different patient populations. Here we analyse whether this is feasible under real life conditions. Methods: The PAN study is a non-interventional study conducted by the Association of German Gastroenterologists in Private Practice (bng) in cooperation with Roche. Patients selected for the analysis were treated with TVR plus peginterferon alfa-2a/ribavirin (Peg-IFN/RBV). The analysis was restricted to treatment naïve patients infected with genotype-1 who started treatment before March 31st, 2012 and had documentation of at least 24 treatment-weeks completed. Results: Overall 269 patients were included in the present analysis. Mean age 46.6 years, mean BMI was 25.6 kg/m2, 60.2% were male, 97.0% were Caucasian, 8.9% had one diagnostic measure consistent with cirrhosis, and the mean HCV-RNA was 6.1 log 10 IU/mL. 33.5% and 48.0% of the patients were infected with HCV G1a and G1b, respectively. For 18.5% the subtype is unknown. Percentages of all virological responses defined as HCV-RNA undetectable or <10 IU/ml are given in the table. However, in real life in only 168/240 (70.0%) of HCV-RNA determinations were done at the appropriate date. In a subset of patients having already reached week 24 after EOT 47/87 patients had valid HCV-RNA at w4 and w12 with 41/47 (87.2%) achieving eRVR. Of 34/41 (82.9%) reached SVR. RBV or Peg-IFN dose modifications occurred in the first 10 weeks of treatment. Rates of haemoglobin <8.5 g/dL or > 8.5 but <10 g/dL within the first 12 weeks (13.1% and 34.0%) did not differ from those thereafter (9.0% and 26.2%). Rash and rash like symtoms were more likely within the first 12 weeks (42.0%) than thereafter(4.5%). Conclusion: Real world experiences with TVR plus Peg-IFN/RBV are generally consistent with the results of the published phase 3 trials, if treatment complies with the recommendations in the label. However in this cohort documenting treatment initiated early after approval of TVR substantial proportion of patients did not receive shortened duration due to inadequate therapy management. *Jacobsen et al., N Engl J Med 2011 ;364:2405–16

Table 5. Virological responses during different time points of treatment
 Visits completedvalid HCV-RNA (=100%)Discontin-uations in total (%)viral load undetectable and/or <10 IU/ml (%)valid HCV-RNA at w4 and wl2 (=100%)viral load undetectable and/or <10 IU/ml (%)
week 42692102.968.1  
week 1226919315.079.816864.9
week 2426920122.971.615575.5
EoT week 241219215.280.46786.6
follow up nter 24w tx877812.882.14783.0

Disclosures:

Stefan Christensen -Advisory Committees or Review Panels: Roche, BMS, Abbott, Janssen, Schering Plough, ViiV, Gilead, MSD, Boehringer Ingelheim; Speaking and Teaching: Gilead, MSD, Roche, BMS, Schering Plough, ViiV, Boehringer Ingelheim, Janssen

Klaus H. Boeker - Speaking and Teaching: MSD, Roche, Janssen, Gilead, BMS, Falk Foundation, Novartis

Christoph Eisenbach - Advisory Committees or Review Panels: Roche; Speaking and Teaching: Bristol Myers Squibb, Roche, Gilead

Marcus Schuchmann - Advisory Committees or Review Panels: Roche, BMS, Norgine, Boehringer; Speaking and Teaching: Gilead, Merck, Falk

Thomas Lutz - Advisory Committees or Review Panels: Gilead, MSD, Abbott, BMS, Janssen Cilag; Grant/Research Support: Boehringer Ingelheim, Gilead, GlaxoSmithKline, Schering-Plough, Roche, MSD, Abbott, Janssen Cilag; Speaking and Teaching: Boehringer Ingelheim, GlaxoSmithKline, Roche, BMS

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Gerlinde Teuber - Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

Margareta Frank Doss - Grant/Research Support: Roche Pharma AG Armand von Lucadou - Speaking and Teaching: Essex, Roche Ulrich Alshuth - Employment: Roche

Dietrich Hueppe - Advisory Committees or Review Panels: Roche, MSD, Novatis, Gilead, BMS

The following people have nothing to disclose: Renate Heyne, Gero Moog, Maria-Christina Jung, Franz Emke

1906

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Triple Treatment Of HIV/HCV Coinfected Patients In The German Daily Routine - An Interim Analysis From The PAN Study

Axel Baumgarten1, Stefanie Holm2, Thomas Lutz3, Dietmar Schranz4, Stefan Mauss5, Heribert Hillenbrand6, Arend Moll7, Stefan H. Scholten8, Wolfgang Schmidt9, Joerg H. Goelz10, Bettina Hintsche11, Dorothea M. Schleehauf10, Stefan Fenske12, Christoph Stephan13, Daniel Prziwara14, Siegfried Koeppe15, Manfred Bog-dan16, Hans Jaeger17;
1 mib Dienstleistung GmbH, Berlin, Germany; 2Private Practice Dres. Kuhlmann/Holm/Heiken, Hannover, Germany; 3Infektiologikum, Frankfurt/M, Germany; 4Private Practice Dres. Schranz/Fischer, Berlin, Germany; 5Center for HIV and Hepatogastroenterology, Duesseldorf, Germany; 6Center of Medicine, City Ost, Berlin, Germany; 7Center for HIV and Hepatology, Berlin, Germany; 8 Center of Medicine Hohenstaufenring, Cologne, Germany; 9MVZ Aerzteforum Seestrasse, Berlin, Germany; 10Cen-ter for Addiction-Medicine, Hepatology and HIV, Praxiszentrum Kaiserdamm, Berlin, Germany; 11 Center for Infectiology and Hepatology, Berlin, Germany; 12ICH Grindelpraxis, Infektionsepidemiol-ogisches Centrum, Hamburg, Germany; 13Department of Infectious Disease, J. W. Goethe University Hospital, Frankfurt/M, Germany; 14Paxisteam Mitte, Berlin, Germany; 15Private Practice, Berlin, Germany; 16Virology, Roche Pharma AG, Grenzach-Wyhlen, Germany; 17HIV Research and Clinical Care Centre, MVZ Karlsplatz, Munich, Germany

PURPOSE: So far there is only little experience in treating HCV/HIV coinfected patients with HCV triple therapy beyond controlled studies where patients are highly selected. Here we report the 12 week results of 75 patients treated in german routine. Methods: The non-interventional study PAN documents daily routine of peginterferon alfa-2a/ribavirin (PEG/RBV) treated patients under surveillance of the German Association of Gastroenterologists (Berufsverband Niedergelassener Gas-troenterologen BNG). Here we analyzed 75 patients coinfected with HCV/HIV: 42 treated with Telaprevir (TVR) + Peginterferon alfa 2a/Ribavirin (PEG/RBV), 5 with Boceprevir (BOC)+PEG/RBV and 28 with PEG/RBV. All patients, who have a documented visit at week 12 of therapy have been included. Data cut off was 1. April 2013. Results: Baseline characteristics are shown in the table. HCV-RNA at week 12 was undetectable in 75,8%, 80.0%, 55,6% of TVR, BOC and PEG/RBV treated patients respectively (adjusted to available HCV-RNA values). HIV-RNA at baseline was <50 copies/ml in 88,9% of TVR, 75% of BOC and 76,2% of PEG/RBV patients. At week 12 HIV-RNA was <50 copies/ml in 100% of TVR, 75% of BOC and 87,5% of PEG/RBV patients. No unexpected safety signals were observed while HIV-treatment was ongoing in 94,3% at baseline and 91,7% of patients at week 12. Adverse Events: Anemia was reported in 9,5%, 20%, 21,4%, skin disorder in 14,3%, 0%, 10,7% and rash in 9,5%, 0%,14,3% in TVR, BOC and PEG/RBV patients respectively. Conclusion: Daily outine of HIV/HCV coinfected patients includes also patients with cirrhosis and AIDS-defining events. So far 12 weeks results indicate a comparable efficacy and safety to Phase-III trials without affecting efficacy of HIV-therapy. TVR seems to be preferred in daily routine for HIV coinfected patients in this study because of drug-drug-interactions. These results have to be interpreted with caution due to low patient numbers and short observation time.

Table 6. Baseline Characteristics
 PEG/RBV/TVR (n=42) PEG/RBV/BOC (n=5) PEG/RBV (n=28) 
  1. *At least one result of sonography, histology, elastography or clinical appearance.

 N%N%N%
male40/4295,2%5/5100,0%28/28100,0%
cirrhosis*5/4211,9%0/50,0%1/283,6%
treatment naiv10/4223,8%4/580,0%19/2867,9%
AIDS-defining Events8/3920,5%1520,0%3/2611,5%
HIV-RNA Viral load < 50 (copies/ml)32/3688,9%3/475,0%16/2176,2%
CD-4 < 50/μl0/350%0/40,0%0/220,0%
CD-4 50 - 350/μ15/3514,3%0/40,0%4/2218,2%
CD-4 >350/μ130/3585,7%4/4100,0%18/2281,8%

Disclosures:

Thomas Lutz - Advisory Committees or Review Panels: Gilead, MSD, Abbott, BMS, Janssen Cilag; Grant/Research Support: Boehringer Ingelheim, Gilead, GlaxoSmithKline, Schering-Plough, Roche, MSD, Abbott, Janssen Cilag; Speaking and Teaching: Boehringer Ingelheim, GlaxoSmithKline, Roche, BMS

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Stefan H. Scholten - Advisory Committees or Review Panels: Abbott, Abbvie, Boehringer Ingelheim, BMS, Janssen, Pfizer; Grant/Research Support: Abbott, Abbvie, Boehringer Ingelheim, BMS, Gilead, Janssen, MSD, Pfizer, Roche; Speaking and Teaching: Abbott, Boehringer Ingelheim, BMS, Gilead, Janssen, MSD, Roche

Siegfried Koeppe - Advisory Committees or Review Panels: Jansen, Abbvie, ViiV, MSD; Board Membership: Boehringer ; Speaking and Teaching: Gilead

Manfred Bogdan - Management Position: Roche Pharma, Germany

The following people have nothing to disclose: Axel Baumgarten, Stefanie Holm, Dietmar Schranz, Heribert Hillenbrand, Arend Moll, Wolfgang Schmidt, Joerg H. Goelz, Bettina Hintsche, Dorothea M. Schleehauf, Stefan Fenske, Christoph Stephan, Daniel Prziwara, Hans Jaeger

1907

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Predictive impacts of α-fetoprotein levels on development of hepatocellular carcinoma during interferon therapy for chronic hepatitis C

Yasuto Takeuchi, Fusao Ikeda, Tetsuya Yasunaka, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto;
Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

Background and aims: Interferon suppresses development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. However, predictive factors of HCC development during the therapy are still uncertain. Methods: The present study enrolled consecutive patients with chronic hepatitis C who received pegylated interferon and ribavirin in our hospitals between 2005 and 2011, and examined predictive values of alpha-fetoprotein (AFP) levels on HCC development. Cumulative incidence of HCC development was estimated by the Kaplan-Meier method. The factors associated with HCC development were analyzed in the proportional hazards models. The patients matched of age, sex, platelet count, and alanine aminotransferase were selected with Propensity score for comparisons. Results: Among 1255 patients enrolled in the study, 665 patients obtained sustained viral response (SVR). During a mean follow-up period of 5.2 years after the therapy, HCC was detected in 89 patients including 20 SVR patients. Multivariate analysis revealed that old age and high AFP level before the therapy were independent factors associated with HCC development among SVR patients (P = 0.028, and 0.0009, respectively). The best cutoff value of AFP level was 5ng/ml by using the receiver operatorating characteristic curve. The patients with AFP >5ng/ml before the therapy had significantly higher cumulative incidence of HCC than those <5ng/ml (P <0.0001). Among those with AFP >5ng/ml before the therapy, the cumulative incidence of HCC was significantly lower in patients whose AFP levels 1 year after the therapy decreased below 5ng/ml than those with AFP >5ng/ml (P= 0.010). Similar results were obtained among non-SVR patients; the cumulative incidence of HCC was also significantly higher in patients with AFP >5ng/ml before the therapy, especially in those whose AFP levels remained higher than 5ng/ml (P= 0.015). Conclusions: AFP levels before interferon therapy and the changes of AFP levels after the therapy are useful predictors of HCC development in patients with chronic hepatitis C.

Disclosures:

Kazuhide Yamamoto - Advisory Committees or Review Panels: Shionogi Pharmaceutical Co; Grant/Research Support: Tanabe Mitsubishi Co, MSD, Chugai Pharmaceutical Co, Esai Co

The following people have nothing to disclose: Yasuto Takeuchi, Fusao Ikeda, Tet-suya Yasunaka, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki

1908

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Telaprevir + peginterferon alfa-2a and ribavirin in treat-ment-naïve patients with genotype 1 HCV and mild to moderate liver disease

Stefan Zeuzem1, Ralph DeMasi2, Graham R. Foster3, Maria Buti4, Joerg M. Läuffer5, Donghan Luo2, James Witek2, Mario Rizzetto6;
1 Department of Internal Medicine I, J.W. Goethe University Hospital, Frankfurt, Germany; 2Janssen Research & Development LLC, Titusville, NJ; 3Queen Mary,, University of London, Barts Health, London, United Kingdom; 4Hospital Valle Hebron, Barcelona, Spain; 5Janssen-Cilag AG, Zug, Switzerland; 6University of Torino, Torino, Italy

Background: The safety and efficacy of telaprevir (T) + peginterferon and ribavirin (PR) over PR in the treatment of patients (pts) with HCV infection has been demonstrated in clinical studies. Here we provide detailed characterization of the safety and efficacy of T+PR in pts with genotype 1 (G1) chronic HCV infection and mild-to-moderate liver disease (F0-F2), and explore treatment response by disease stage. Methods: This retrospective analysis included treatment-naïve pts (n=1642) who participated in the telaprevir pivotal studies and received 12 wk of T (750mg q8h or 1125mg bid) + PR (P, 180μg/wk; R, 1000 or 1200mg/day), followed by PR alone for an additional 12 or 36 wk. Data was pooled and retrospectively analyzed overall and by fibrosis stage (Metavir score determined by liver biopsy). Multivariable logistic regression (MLR) analyses comparing outcomes across fibrosis stages were performed. Results: Key characteristics and selected safety and efficacy endpoints for the 1642 pts included in the analysis are summarized (Table). Distribution of pts by fibrosis stage was: F0-F1: 630 (38%); F2: 580 (35%); F3: 247 (15%); and F4: 185 (11%). F0-F1 and F2 pts had more favorable prognostic factors and were more likely to receive 24 wk PR than F3/F4 pts. Safety and efficacy parameters varied by fibrosis stage, with F0-F1 and F2 pts having similar outcomes but more favorable outcomes than pts with more advanced disease (eg SVR: F0-F1 + F2, 79%; vs F3, 68%; vs F4, 54%; p<0.0028, MLR). The gain in efficacy of T+PR for F2 over F3/F4 was unaccompanied by excess risk of untoward clinical or laboratory events. Conclusions: Pooled analyses of 1642 pts with G1 chronic HCV infection suggests a favorable risk-benefit ratio for T+PR, resulting in additive efficacy along with a similar or superior safety/tolerability profile for F2 relative to F3/F4 pts. Together with comparative F2 data demonstrating efficacy of T+PR over PR (79% vs 49%), these results support the treatment of F2 pts with T+PR vs PR alone.

 F0-1 (N=630)F2 (N=580)F3 (N=247)F4 (N=185)Total (N=1,642
  1. ‡Any Rash SSC clinical adverse event; Hb = Hemoglobin; RVR = Rapid Viral Response; eRVR = Extended Rapid Viral Response; AE = Adverse Event; SAE = Serious AE; *includes ≤8.5 g/dL

24 weeks PR (%)6657535560
Age, years (mean)4449535348
Gender(% male)5261706960
Race (% White)9D86858587
Viral load (%≧800K IU/L)7884878782
Subtype (%1a)5666686862
RVR7373615769
SVR(FDA Snapshotanalysis)8079685475
Grade 2–4 AEs7579158879
SeriousAEs910111710
Discontinuation due to AE712131511
Grade 2–4 rash SSC AE ‡1918262520
Grade 2–4 anemia SSC AE‡3132373933
Hb<10g/dL*4243475544
Hb≤8.5g/dL1212192114

Disclosures:

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingel-heim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Ralph DeMasi - Employment: Janssen Pharmaceuticals

Graham R. Foster - Advisory Committees or Review Panels: GlaxoSmithKline, Novartis, Boehringer Ingelheim, Tibotec, Chughai, Gilead, Janssen, Idenix, GlaxoSmithKline, Novartis, Roche, Tibotec, Chughai, Gilead, Merck, Janssen, Idenix, BMS; Board Membership: Boehringer Ingelheim; Grant/Research Support: Chughai, Roche, Chughai; Speaking and Teaching: Roche, Gilead, Tibotec, Merck, BMS, Boehringer Ingelheim, Gilead, Janssen

Maria Buti - Advisory Committees or Review Panels: Boerhinger Inghelm, Boer-hinger Inghelm; Speaking and Teaching: MSD, Bristol-Myers Squibb, Novartis, Gilead, Janssen, MSD, Bristol-Myers Squibb, Novartis, Gilead, Janssen

Joerg M. Läuffer - Employment: Janssen; Stock Shareholder: Janssen

Donghan Luo - Employment: Tibotec Inc.; Stock Shareholder: Johnson & Johnson

James Witek - Employment: Johnson & Johnson; Stock Shareholder: Johnson & Johnson

Mario Rizzetto - Advisory Committees or Review Panels: Merck, Janssen, BMS

1909

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Adherence to interferon-containing therapy among Veteran Affairs hepatitis c patients

Onur Baser2,3, Li Wang3, Stephanie K. Cline1, Derek A. Misurski1, Katherine L. Gooch1;
1Global Health Economics and Outcomes Research, AbbVie Pharmaceuticals, North Chicago, IL; 2Depart-ment of Internal Medicine, University of Michigan, Ann Arbor, MI; 3STATinMED Research, Ann Arbor, MI

Background: Treatment completion rates for interferon-containing therapies (ICT) among veterans infected with hepatitis C (HCV) have previously been reported as low as 22.5%. Furthermore, these completion rates were found to be negatively impacted by diagnoses of pre-existing depression. As these rates were derived from observations occurring between 1998 and 2003, the majority of patients received non-pegylated ICT (73.1%). Given the greater uptake of pegylated ICT over the past decade, treatment patterns in a cohort of Veteran Affairs HCV patients were re-assessed. Methods: Data from the US Veterans Health Administration (VHA) Medical SAS® Dataset (years 2008 to 2011) were used to identify incident HCV patients (based on ICD-9 codes) who were ≧18 years of age and had >2 years of continuous enrollment (>1 year before and after first diagnosis). Receipt of ICT was based on National Drug Codes and treatment initiation had to occur subsequent to the first observed diagnosis of HCV. Discontinuations were defined as a lapse of >60 days between ICT claims. Adherence was measured by the proportion of days covered (PDC) defined as the number of days following ICT initiation where ICT were received, divided by total days of recommended treatment. Being adherent to ICT was defined as a PDC>0.8. Logistic regression analyses were used to determine associations, including demographic and pre-existing comorbidity information, with a PDC>0.8 outcome. Results: A total of 135, 712 HCV patients met the enrollment criteria of which 5,379 (4%) received ICT (of these, 1 % received non-pegylated ICT; 99% received pegylated ICT). The average age was 56.7 years for all HCV patients and 54.5 years for those treated during the study timeframe. Among treated patients, 1,388 (25.8%) completed >80% of their recommended duration of treatment. The average PDC was 40% (PDC = 0.4). Adherence to ICT was associated with being in the 35–54 year old age group (OR = 3.86; 95% CI 1.95–7.66), being in the 55–64 year old age group (OR = 3.75; 95% CI 1.90–7.41), and negatively associated with having a diagnosis of pre-existing depression (OR = 0.84; 95% CI 0.71–0.99). Conclusions: Results from this study suggest that the utilization of and adherence to ICT remains low in veteran HCV patients, despite the use of pegylated ICT. Depression was significantly associated with poor adherence.

Disclosures:

Onur Baser - Consulting: STATinMED Research

Li Wang - Consulting: STATinMED Research

Stephanie K. Cline - Employment: AbbVie Pharmaceuticals; Stock Shareholder: AbbVie Pharmaceuticals

Derek A. Misurski - Employment: AbbVie; Stock Shareholder: AbbVie Katherine L. Gooch - Employment: Abbvie

1910

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Prediction for Severity of Ribavirin-induced Anemia by ITPA Enzyme Activity and ATP Concentration in Human Erythrocyte

Yoichi Tanaka1, Hiroaki Yokomori2, Masaya Oda3, Wataru Ando1, Takako Komiyama1;
1 Clinical Pharmacy, Kitasato University, Tokyo, Japan; 2General Internal Medicine, Kitasato University Medical Center, Saitama, Japan; 3Internal Medicine, Sanno Medical Center, Tokyo, Japan

Background and Aims: One of the most important treatment-limiting adverse effects in the treatment for chronic infection with the hepatitis C virus is ribavirin (RBV)-induced hemolytic anemia. Relation between genetic mutation of inosine triphosphate pyrophosphatase (ITPA) and RBV-induced anemia has been recently reported, and an accumulation of inosine triphosphate has been considered to protect patients against RBV-induced anemia during treatment for chronic hepatitis C infection. One possible biological mechanism is decreasing ATP level in erythrocyte and increasing vulnerability by oxidative damage on the erythrocyte membrane during RBV administration. We investigated the relationship changing hematological data with erythrocyte ATP concentration and ITPA enzyme activity in patients with Peg-Interferon (Peg-IFN) and RBV therapy. Methods: Twenty-five Japanese patients with chronic hepatitis C and treated with Peg-IFN and RBV therapy for 24 - 72 weeks were included in this prospective study. ITPA enzyme activity in erythrocyte was determined by HPLC method. ATP concentration in erythrocyte was determined by luciferase assay. ITPA genotyp-ing (rs1127354 and rs7270101) was analyzed by TaqMan probe assay. The correlation between ITPA enzyme activity, ATP concentration in erythrocyte and degree of hemoglobin (Hb) reduction over the course of therapy were investigated. Results: The median ITPA enzyme activity value (μmoL/h/gHb) for genotype rs1127354 CC (n = 19), CA (n = 5), and AA (n = 1) were 227.2, 44.7, and 4.7 respectively. No mutation at rs7270101 was shown in this population. The correlation between ITPA enzyme activity and quantitative Hb reduction at therapeutic week 2, 4, 6, 8 were shown significantly inverse relation, and values of correction coefficient were -0.416, -0.519, -0.499, -0.417 respectively (Pearson's correlation coefficient, p < 0.05). The ATP concentration in erythrocyte significantly correlates with quantitative Hb reduction (Pearson's correlation coefficient, r = 0.313, p < 0.05). Conclusion: Erythrocyte ITPA enzyme activity value in the ITPA genetic mutations is significantly lower than in the wild-type. Low ITPA enzyme activity is associated with diminishing Hb reduction rate in early period of Peg-IFN and RBV therapy. Moreover, low ATP concentration in erythrocyte associated with increasing extent of Hb reduction. These results are suggesting that intensity of Hb reduction in early period of therapy is affected by ATP levels in erythrocyte. Erythrocyte ITPA enzyme activity value and ATP concentrations in the first one to two months period of therapy are possible prediction markers for the severity in RBV-induced anemia.

Disclosures:

The following people have nothing to disclose: Yoichi Tanaka, Hiroaki Yokomori, Masaya Oda, Wataru Ando, Takako Komiyama

1911

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Efficacy and safety results of treatment of patients over 65 years old with genotype 1 hepatitis C with severe fibrosis or compensated cirrhosis: the International Telaprevir Early Access Program

Christophe Moreno1, Heiner Wedemeyer2, Inmaculada Fernández3, Paulo R. Abrão Ferreira4, Simone I. Strasser5, Petr Urbanek6, Djamal Abdurakhmanov7, Adrian Streinu-Cercel8, Giovanni B. Gaeta9, Filip Beeldens10, Wafae Iraqi11, Ralph DeMasi12, Andrew Hill13, Joerg M. Läuffer14, Isabelle Lonjon-Domanec11, Massimo Colombo15; 1 Department of Gastroenterology and Hepatopancre-atology, Erasme Hospital, Brussels, Belgium; 2Medizinische Hochschule Hannover, Hannover, Germany; 3Hospital Universi-tario 12 de Octubre, Sección de Aparato Digestivo, Madrid, Spain; 4Outpatient Clinic to HIV and Viral Hepatitis Division of Infectious Disease, Federal University of São Paulo, São Paulo, Brazil;5Royal Prince Alfred Hospital, University of Sydney, Sydney, NSW, Australia; 6Department of Internal Medicine, First Medical Faculty, Charles University, and Central Military Hospital Prague, Prague, Czech Republic; 7I.M. Sechenov First Moscow State Medical University, E. M. Tareev Clinic for Nephrology, Internal and Occupational Medicine, Moscow, Russian Federation; 8Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases “Prof.Dr. Matei Bals”, Bucharest, Romania; 9Viral Hepatitis Unit, Department of Infectious Diseases, Second University, Naples, Italy; 10Janssen Pharmaceutica, Beerse, Belgium;
1 1Janssen Pharmaceuticals, Paris, France; 12Janssen Research & Development LLC, Titusville, NJ; 13MetaVirology Ltd, London, United Kingdom; 14Janssen-Cilag AG, Zug, Switzerland; 15Department of Medicine, Division of Gastroenterology, Fon-dazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Universita' degli Studi di Milano, Milan, Italy

Background and aims: HEP3002 is an ongoing, open-label, early access program (EAP) of telaprevir (TVR) in 16 countries, for patients with genotype 1 hepatitis C with severe fibrosis or compensated cirrhosis. Methods: Patients were treated with TVR, pegylated interferon-alpha and ribavirin (PR) for 12 weeks, followed by PR. Liver biopsy or non-invasive tests showing severe fibrosis were required at entry. This interim (ITT) report describes the 16 week data for the first 128 patients enrolled on to the program who were over the age of 65 years. Results: For patients >65 years old, mean age was 68 years and mean weight 73kg; 47% were male and 99% Caucasian, 66% had HCV RNA levels >800,000 IU/mL, 39%/61% had severe fibrosis/cirrhosis, 11% had genotype 1a. Fifteen patients were aged 70 years or older (protocol violators), 20% were treatment naïve, 27% prior relapsers, 50% prior non-responders and 2% had prior viral breakthrough. Up to Week 16, 35/128 patients (27%) discontinued TVR (29 (23%) for adverse events). 80% of patients developed grade 1–4 anaemia (Hb <11 g/dL or >2.5 g/dL reduction), with 45% severe cases (Hb <9 g/dL or >4.5 g/dL reduction); 86 patients (67%) dose reduced ribavirin; 11 (9%) discontinued treatment for anaemia. In a multivariate analysis of the whole trial, patients aged >65 years were significantly more likely to develop anaemia (p<0.001). By Week 16, 41% of patients developed grade 1–3 rash versus 32% in the overall trial population. There were 2% severe rash cases (all grade 3) and one Stevens-Johnson syndrome; 4 patients (3%) discontinued treatment for rash. 31 patients (24%) developed a serious adverse event (SAE) versus 12% in the overall trial population. HCV RNA responses at Weeks 4 and 12 (ITT analysis) are shown below for patients aged >65 years (n=128) and the overall trial population (n=1573). Conclusions: In this TVR early access program for patients with severe fibrosis or compensated cirrhosis, 81% of patients over the age of 65 years had undetectable HCV RNA by Week 12 (ITT), which was comparable to the overall trial population. Patients aged >65 years had a significant increased risk of anaemia on treatment, compared with the overall population.

Percent HCV RNA undetectableWeek 4Week 12
  1. *There were 8 patients (non-responders and viral breakthrough) not included in the main four categories.

HCV RNA suppression*>65 years N=128Overall N=1573>65 years N=128Overall N=1573
Naϊve (n=26)65%65%85%85%
Relapser (n=35)54%70%83%88%
Partial responder (n=15)73%59%80%80%
Null responder (n-44)43%46%77%72%
Overall (n=l28)55%60%81%82%

Disclosures:

Christophe Moreno - Board Membership: JANSSEN, Janssen Therapeutics; Consulting: Gilead, MSD; Grant/Research Support: ROCHE, Janssen, Novartis, Astel-las, MSD; Speaking and Teaching: MSD, BMS, JANSSEN

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Paulo R. Abrão Ferreira - Grant/Research Support: ABBOTT, ROCHE, BMS, JANSSEN; Speaking and Teaching: ROCHE, BMS, JANSSEN

Simone I. Strasser - Advisory Committees or Review Panels: Janssen, AbbVie, Roche Products Australia, MSD, Bristol-Myers Squibb, Gilead, Norgine, Bayer Healthcare; Speaking and Teaching: Bayer Healthcare, Bristol-Myers Squibb, MSD, Roche Products Australia, Gilead, Janssen

Djamal Abdurakhmanov - Grant/Research Support: Roche; Speaking and Teaching: BMS, Jansenn, MSD, Novartis

Giovanni B. Gaeta - Advisory Committees or Review Panels: Janssen, Boheringer Ing; Speaking and Teaching: BMS, Gilead, Roche, MSD, Novartis

Filip Beeldens - Employment: Janssen Research and Development

Wafae Iraqi - Employment: Janssen

Ralph DeMasi - Employment: Janssen Pharmaceuticals

Andrew Hill - Consulting: Janssen

Joerg M. Läuffer - Employment: Janssen; Stock Shareholder: Janssen

Isabelle Lonjon-Domanec - Employment: Janssen

Massimo Colombo - Advisory Committees or Review Panels: BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, GILEAD, Janssen Cilag, Achillion; Grant/Research Support: BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD, BRISTOL-MEYERS-SQUIBB, ROCHE, GILEAD; Speaking and Teaching: Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX, Glaxo Smith-Kline, BRISTOL-MEYERS-SQUIBB, SCHERING-PLOUGH, ROCHE, NOVARTIS, GILEAD, VERTEX

The following people have nothing to disclose: Inmaculada Fernández, Petr Urbanek, Adrian Streinu-Cercel

1912

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Only a small portion of all HCV GT1 patients is cured by HCV Protease Inhibitor based Triple Therapies: An analysis of the first 208 evaluated patients in a tertiary referral center

Benjamin Maasoumy, Kerstin Port, Antoaneta A. Markova, Beatriz Calle Serrano, Lisa Sollik, Janina Kirschner, Carola Mix, Michael P. Manns, Heiner Wedemeyer, Markus Cornberg;
Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

Background: Phase III studies showed a remarkable increase of SVR rates up to 88% in the optimal setting if an HCV protease inhibitor (PI), either Boceprevir orTelaprevir, was added to Peg-Interferon alfa and Ribavirin (P/R). However, not all HCV patients are eligible for PI/P/R therapy and pivotal trials do not necessarily reflect real world, where more patients present with advanced liver disease or significant comorbidities. The aim of our study was to analyze efficacy and effectiveness of P/R/PI for the treatment of chronic HCV GT1 infection in a real world setting of a tertiary referral center. Methods: All 208 consecutive HCV GT1 infected patients who were referred to our center between June and November 2011 were included. We analysed efficacy of PI/P/R therapy in all patients that received antiviral treatment and effectiveness in the overall cohort. Results: After a careful evaluation treatment was not initiated in 103 out of the 208 patients. Most frequently safety concerns were relevant (64%). However, low treatment urgency and no patient wish were also important factors. 19 patients were treated at local centers or randomized into phase 2/3 trials and not further considered for our analysis. We initiated a triple therapy concept in 86 patients, of those 86% had F3/F4-fibro-sis and only 27% were treatment-naïve. Some patients were treated despite the presence of relative contraindications, i.e. 16% had a platelet count <90/nl. Only 42 patients (49%) completed treatment, while the same number of patients (49%) had to discontinue therapy, 23 due to virological failure and 19 due to intolerance, of which the majority experienced a relapse (84%). Two patients were lost to follow up. Overall only 33 patients achieved SVR12. Three patients are still ahead of SVR12 assessment but HCV RNA negative at EOT. SVR rates were similar for BOC and TLV. However, only 38–42% of all treated (efficacy) and not more than 17–19% of all initially evaluated patients (effectiveness) will be cured by currently available triple therapy. Conclusions: At least 50% of patients managed in a tertiary referral center are currently not eligible for P/R/PI. Those selected for triple therapy mainly present with advanced liver fibrosis or cirrhosis and are previous nonre-sponders to P/R. Here, efficacy of PI/P/R is limited. As a result majority of patients is not cured by currently available triple therapies which limits the overall effectiveness. Both limited efficacy as well as limited eligibility should be considered to estimate advantages of future IFN free treatment options.

Disclosures:

Benjamin Maasoumy-Advisory Committees or Review Panels: Abbott Molecular; Speaking and Teaching: MSD, Roche Diagnostics, Roche Pharma

Kerstin Port - Speaking and Teaching: Roche

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Markus Cornberg - Advisory Committees or Review Panels: Merck (MSD Ger-mamny), Roche, Gilead, Novartis; Grant/Research Support: Merck (MSD Ger-mamny), Roche; Speaking and Teaching: Merck (MSD Germamny), Roche, Gilead, BMS, Novartis, Falk

The following people have nothing to disclose: Antoaneta A. Markova, Beatriz Calle Serrano, Lisa Sollik, Janina Kirschner, Carola Mix

1913

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ITPA genotyping before triple therapy enables identification of chronic hepatitis C patients with a higher risk of developing early severe anemia when on therapy

Sílvia Camós6, Francisco Rodriguez-Frias6,3, Irene Belmonte Mula6, Maria Homs3, David Tabernero3, Andrea Caballero6, María Cuaresma2, Amparo Escudero1, Felicidad Rodriguez1, María Teresa Ferrer2, Miguel Angel Serra1, Juan Manuel Pascasio2, Josep Quer5, Rafael Esteban4, Maria Buti4,3;
1Digestive Diseases, Hospital Clínico de Valencia, Valencia, Spain; 2Digestive Disease, H.U. Virgen del Rocío, Sevilla, Spain; 3Centro de Investigación Bio-médica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Universitari Vall d'Hebron, Barcelona, Spain; 4Hepatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain; 5VHIR, Hospital Universitari Vall d'Hebron, Barcelona, Spain; 6Biochemistry, Hospital Universitari Vall d'Hebron, Barcelona, Spain

Introduction Anemia is the most common and severe adverse effect of triple therapy including the PIs boceprevir (BOC) or telaprevir (TVP) for the treatment of chronic hepatitis C (CHC), particularly in patients with cirrhosis. Deficiency of inosine triphosphatase (ITPA) enzymes detected by polymorphisms, such as rs1127354 (C/A) and rs7270101 (A/A), are associated with a lower risk of developing anemia in patients with CHC treated with peginterferon and ribavirin. Aims To determine ITPA polymorphisms in patients under triple therapy including BOC or TVP and correlate them with the risk of early severe anemia. Material and methods Blood samples from 96 genotype 1 CHC patients treated with triple therapy including TVP (N=55) and BOC (N=41) were studied. Both ITPA polymorphisms were genotyped by real-time PCR and melting curves (LightCycler, Roche). Anemia was defined based on two criteria: decrease in Hb >3 g/dL and Hb <10 g/dL at week 4 of PI treatment. Results ITPA non-deficient polymorphisms (homozy-gous for the major allele) were detected in 63 patients (66%) and polymorphisms with some ITPA deficit (one or more minor alleles) were detected in 33 cases (34%). The table shows the results at week 4 of PI treatment. Genotypes with ITPA deficiency >70% were less likely to develop anemia than those with <40% deficiency (p<0.001). Only 1 patient (7%) with >70% deficiency presented a drop in Hb >3 g/dL, versus 44 cases (54%) with deficits <40%. Hb <10 g/dL was detected in 23 patients (13%) and all of them had genotypes with deficits <40% (p<0.001). Conclusion Patients with ITPA deficiency have a lower risk of developing early severe anemia when receiving triple therapy. ITPA genotyping enables identification of at-risk patients who might require more frequent monitoring and dose reductions.

rsl127354 Major allele Crs7270101 Major allele AITPA DeficiencyNumber of casesHb>3g/dL decline at week 4 PIHb<10g/dLat week 4 PI
C/CA/A0%63 (66%)40 (60%)21 (33%)
C/CA/C40%19(20%)4(21%)2(11%)
C/AA/A70%8 (8%)1 (13%)0
C/AA/C90%6 (6%)00

Disclosures:

Rafael Esteban - Speaking and Teaching: MSD, BMS, Novartis, Gilead, Glaxo, MSD, BMS, Novartis, Gilead, Glaxo, Janssen

Maria Buti - Advisory Committees or Review Panels: Gilead, Janssen, Vertex; Grant/Research Support: Gilead, Janssen; Speaking and Teaching: Gilead, Janssen, Vertex, Novartis

The following people have nothing to disclose: Sílvia Camós, Francisco Rodriguez-Frias, Irene Belmonte Mula, Maria Homs, David Tabernero, Andrea Caballero, María Cuaresma, Amparo Escudero, Felicidad Rodriguez, María Teresa Ferrer, Miguel Angel Serra, Juan Manuel Pascasio, Josep Quer

1914

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Treatment of chronic Hepatitis C genotype 1 (G1) infection with Boceprevir (Victrelis®) in the German real-life setting: high early virologic response rates in treatment-naïve patients from the NOVUS observational study

Peter Buggisch1, Hanns F. Loehr2, Gerlinde Teuber3, Hermann Stef-fens4, Michael R. R. Kraus5, Christine John6, Peter R. Geyer7, Bernd Weber8, Thomas Witthoeft9, Andreas Herrmann10, Mark Hoesl11, Uwe Naumann12, Tarek Dahhan13, Dagmar Hartmann14, Bernd Dreher14, Manfred Bilzer14; 1ifi Institute, Hamburg, Germany; 2Gastroenterological Practice, Wiesbaden, Germany; 3Gastroen-terological Practice, Frankfurt, Germany; 4Practice of Internal Medicine, Berlin, Germany; 5Medical Department II, Klinikum Burghausen, Burghausen, Germany; 6Practice of internal Medicine, Berlin, Germany; 7Gastroentorological Practice, Fulda, Germany; 8Medical Practice, Kassel, Germany; 9Gastroenterological Practice, Stade, Germany; 10Friedrich-Schiller-University, Jena, Germany;
1 1Gastroenterological Practice, Nürnberg, Germany; 12Center of Medicine, Berlin, Germany; 13Gastroenterological Practice, Fellbach, Germany; 14MSD Pharma GmbH, Haar, Germany

Background: Triple therapy with the HCV protease inhibitor boceprevir (Victrelis®) in combination with pegylated interfer-ons (PegIFN) and ribavirin (RBV) has recently been approved as new standard of care for patients with chronic hepatitis C genotype 1 (G1) infection. The non-interventional observational NOVUS study was conducted to investigate the efficacy and safety of this novel and more complex therapeutic approach in the German real-life setting. Methods: From April 2012 until May 2013, 374 patients with HCV G1 infection were recruited in the ongoing NOVUS study by 85 practices and hospital ambulances in Germany. According to German label, treatment with PegIFN/RBV together with boceprevir for 24 to 44 weeks after a 4 weeks lead-in period with PegIFN/RBV was recommended, but due to the character of this study, the responsible physicians treated patients according to their discretion. In the present interim analysis with focus on the first 8 weeks of treatment documented data of 180 previously untreated patients were regarded. Results: Median age of patients was 46 years and 44% were older than 50 years. 56% were male, median BMI was 26.2 kg/m2, 4.4% and 1.1% were coinfected with HIV and HBV and 16% were opioid user under stable substitution. HCV G1 subtypes were distributed as follows: G1a 33%, G1b 47%, unknown 20%. High baseline viral load >800000 IU/mL was found in 54% of patients. Liver cirrhosis was apparent in 4%, while 17% had baseline platelet count <150/nL. Mean duration of lead-in was 31 ±7 days. At the end of treatment week (TW) 4a HCV-RNA decline >1log10was achieved by 83% of patients. Among patients with evaluable data 76% (98/129) had undetectable HCV-RNA at TW8. As early responder, these patients were eligible for shorter treatment duration. Importantly, HCV-RNA levels at TW8 were not collected in 51 of 180 patients (28.3%). AtTW8 the proportion of patients with hemoglobin values below 10 g/dL was 21.9%. Conclusions: First results from the NOVUS observational trial show promising early virologic response rates at the end of

TW8 allowing shortage of triple therapy with boceprevir to 24 weeks in approximately 75% of previously untreated patients. These findings underline the importance of week 8 HCV-RNA levels which are currently not collected in a significant proportion of patients undergoing boceprevir triple therapy. Results of this ongoing study will be presented together with week 12 response rates which are still under investigation.

Disclosures:

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

Gerlinde Teuber-Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Michael R. R. Kraus - Advisory Committees or Review Panels: Schering-Plough, Roche; Consulting: Schering-Plough, Roche

Bernd Weber - Advisory Committees or Review Panels: Molteni Farmaceutici; Speaking and Teaching: Roche Pharma AG, Janssen Cilag, Reckitt Benckiser, Sandoz, Lundbeck Pharma, Sanofi-Aventis

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

Dagmar Hartmann - Employment: MSD Germany Bernd Dreher - Employment: MSD Manfred Bilzer - Consulting: MSD Germany

The following people have nothing to disclose: Hanns F. Loehr, Hermann Steffens, Christine John, Peter R. Geyer, Thomas Witthoeft, Andreas Herrmann, Mark Hoesl, Tarek Dahhan

1915

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Cost-effectiveness analysis of telaprevir triple therapy for treatment-naïve patients with chronic hepatitis C based on the combined efficacy data of the ADVANCE and OPTIMIZE studies

Maria Buti2, Blanca Gros1, Itziar Oyagüez1, Raul J. Andrade3, Miguel Angel Serra4, Juan Turnes5, Miguel A. Casado1;
1Pharma-coeconomics & Outcomes Research Iberia, Madrid, Spain; 2Hos-pital Vall d' Hebrón, Barcelona, Spain; 3Hospital Virgen de la Victoria, Málaga, Spain; 4Hospital Clinico de Valencia, Valencia, Spain; 5Complejo Hospitalario de Pontevedra, Pontevedra, Spain

BACKGROUND The standard treatment of hepatitis C virus (HCV) genotype 1 infected patients is the combination of telaprevir with pegylated interferon-alfa and ribavirin (PR). This treatment is associated to higher efficacies but also to higher average treatment costs and incidence on existing adverse events (AE) vs. PR. The aim of this study was to assess the incremental cost effectiveness ratio (ICER) of telaprevir triple therapy (T/PR) as first-line therapy in treatment-naïve patients vs. dual therapy. METHODS A cost-utility analysis based on a Markov-model that simulates patient outcomes was used to estimate lifetime costs and quality-adjusted life-years (QALYs) of T/PR and PR from the perspective of the Spanish National Health System. One-year transition probabilities between health states (mild, moderate, and bridging fibrosis; compensated and decompen-sated cirrhosis; hepatocellular carcinoma; liver transplantation and post-liver transplantation) and utilities were obtained from published sources. Reference cohort was a 49-year aged with clinical profile (mild 41.1%, moderate 35.5%, bridging fibrosis 14.2% and cirrhosis 9.2%). T/PR used a response guided approach for 24 or 48 weeks. Results on efficacy (sustained virological response: 74.6% [T/PR], 44.0% [PR]) and AE were obtained from ADVANCE and OPTIMIZE trials. Total cost (€, 2013) included: medication, adverse events and disease management costs by health state. Pharmaceutical costs were based on local ex-factory prices with mandatory deductions. Resource use provided by an expert panel was used to estimate AE management and health state costs. Unitary resource costs were obtained from a local cost database. Costs and benefits were discounted at 3% annually. Both one-way and probabilistic analyses were performed. RESULTS T/PR showed better outcomes (14.44 QALYs) and higher costs (€50,724) than PR therapy (13.71 QALYs and €37,599). The lifetime ICER resulted €17,887/QALY gained for T/PR vs PR. This ICER increased up to €26,707/QALY gained for a 20-year horizon, and ranged from €19,711 to €16,048/QALY gained with ±25% variation of transition probabilities, and from €9,889 to €28,056/QALY gained when alternative discount rates (0% and 6%, respectively) were applied. The analysis showed also that T/PR could avoid 14 cirrhosis and 5 liver transplants per 1,000 patients compared to PR alone. On the probabilistic analysis the probability of an ICER below a €30,000/QALY gained threshold was 98%. CONCLUSIONS Telaprevir triple therapy is a cost-effective option compared with PR alone for treatment-naïve patients with genotype 1 HCV, based on the combined results of ADVANCE and OPTIMIZE studies.

Disclosures:

Maria Buti - Speaking and Teaching: MSD, Gilead, BMS, Janseen

Blanca Gros - Consulting: Janssen Cilag

Itziar Oyagüez - Consulting: Janssen Cilag, Roche

Juan Turnes - Advisory Committees or Review Panels: Roche; Speaking and Teaching: Roche, Janssen, MSD, BMS, Gilead

Miguel A. Casado - Consulting: Gilead, Novartis, Gilead, Novartis, Gilead, Novartis, Gilead, Novartis, Janssen-Cilag, Roche

The following people have nothing to disclose: Raul J. Andrade, Miguel Angel Serra

1916

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Body weight reduction by life-style intervention can improve early virologic responses of peginterferon/rib-avirin therapy in chronic hepatitis C patients with insulin resistance: A randomized controlled trial

Shinji Iwane, Toshihiko Mizuta, Yasunori Kawaguchi, Hirokazu Takahashi, Noriko Oza, Satoshi Oeda, Takuya Kuwashiro, Hiroshi Isoda, Yuichiro Eguchi, Iwata Ozaki;
Internal Medicine, Saga Medical School, Saga, Japan

Background: Insulin resistance (IR) impairs the virologic response to peginterferon/ribavirin (PEG-IFN/RBV) therapy for chronic hepatitis C (CHC) patients. We previously reported that early and sustained virologic response rates in IR patients with genotype 1 and a high viral load were almost 20% with PEG-IFN/RBV treatment. Although HCV can cause IR, we reported that visceral fat accumulation is more important in the onset of IR in CHC patients. Therefore, we conducted a randomized controlled trial to examine whether life-style diet intervention can enhance the anti-viral effect of PEG-IFN/RBV therapy. Methods: Sixty CHC patients with genotype 1 b, a high viral load and a >2 homeostasis model assessment-insulin resistance (HOMA-IR) value participated in the study. Patients were randomly allocated to either group A (life-style modification to decrease weight), or group B (no modification, used as control). There were no differences in BMI (25.2 ± 2.8 and 24.3 ± 2.7), visceral fat area (cm2) (108.0 ± 48.0 and 98.2 ± 32.7), viral load (logIU/mL) (6.6 ± 0.5 and 6.5 ± 0.3), HOMA-IR value (3.4 ± 1.2 and 3.1 ± 1.3) and hepatic functions between groups. Before anti-viral treatment, group A received diet and exercise adjustments for 3–6 months, with the aim of achieving a 5% weight loss from a subject's initial body weight. All patients were treated with standard PEG-IFNα-2b/RBV for 48 weeks, or 72 weeks in late virologic response cases. HCV-RNA levels were monitored every 4 weeks during treatment. Results: Virologic response rates in groups A and B were 0% and 3% at 4 weeks, 19% and 12% at 8 weeks, 42% and 24% at 12 weeks (EVR), 88% and 70% at end of treatment (ETR) and 34% and 29% at 24 weeks after completing therapy (SVR), respectively. There were no significant differences between groups at any point. Further subdividing group A into two with (A1) or without (A2) 5% or more weight loss after intervention, EVR was 52% (A1) and 27% (A2), ETR was 93% (A1) and 82% (A2) and SVR was 33% (A1) and 36% (A2). EVR in group A1 was significantly higher than that in group B (p=0.01), but SVR was comparable. Conclusions: This prospective study indicates that body weight reduction by life-style intervention forCHC patients with insulin resistance might improve the early viral response to PEG-IFN/RBV treatment. However, more additive or alternative approach is required as improvement in final viral eradication could not be achieved.

Disclosures:

The following people have nothing to disclose: Shinji Iwane, Toshihiko Mizuta, Yasunori Kawaguchi, Hirokazu Takahashi, Noriko Oza, Satoshi Oeda, Takuya Kuwashiro, Hiroshi Isoda, Yuichiro Eguchi, Iwata Ozaki

1917

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Early plasma exposure after a first dose of ribavirin in HIV-HCV coinfected patients compared with HCV monoinfected patients

Giorgiana Hatu1, Pierre Pradat1, Emmanuel Pourcelot2, Marianne Maynard-Muet1, François Bailly1, Patrick Miailhes3, Fabien Zoulim1, Marie-Claude Gagnieu2;
1 Hepatology, Hospices Civils de Lyon, Hopital de la Croix-Rousse, Lyon, France; 2Pharmacology, Hospices Civils de Lyon, Hôpital Edouard Herriot, Lyon, France; 3Infectious Diseases, Hospices Civils de Lyon, Hôpital de la Croix-Rousse, Lyon, France

Introduction: In patients with hepatitis C virus (HCV) infection treated with pegylated interferon/ribavirin (PEG-IFN/RBV), the rate of sustained virological response (SVR) was shown to be associated with early RBV exposure measured by the RBV area under the concentration-time curve (AUC). In HIV-HCV coin-fected patients, the impact of AUC on virological response is poorly documented and should be validated to optimize the SVR rate which remains lower than in HCV monoinfected patients. Methods: 86 HCV patients treated by PEG-IFN/RBV were included among whom 23 (27%) had HIV coinfection. We determined early RBV plasma exposure (expressed as AUC from 0 to 4h) after a 600 mg first dose of RBV. Serum samples were collected before the first dose of RBV, and after 30min, 1, 2, and 4 hours. Results: 72% of patients were males and 85% were infected by HCV genotype 1 or 4. Among HIV-HCV coin-fected patients, median CD4 cell count was 543/mm3 and all were under triple antiviral therapy (cART). Coinfected patients had a significantly lower RBV-AUC0–4h (median: 1469 μg*h/L [range 936–3677]) compared with monoinfected patients (2030 μg*h/L [851–7700]; p=0.018). This RBV under-exposure in coinfected patients persisted after normalization of AUC to RBV dose per kilogram of body weight (182 μg*h/L [11 0–425] versus 271 μg*h/L [82–1091], p=0.001). This RBV under-exposure was associated with a CD4 level below the 33% threshold (≈500/mm3) with a lower AUC compared with patients with CD4>33% (1270 μg.h/L vs 1840 μg.h/L respectively; p=0.047). However, no association was observed between AUC and liver disease severity (fibrosis score) and between AUC and type of cART. Conclusion: HIV-HCV coinfected patients receiving PEG-IFN/RBV combination therapy show a lower initial RBV exposure which could explain the lower SVR rate observed in these patients. These results seem to be associated with patients' immunological status. Similar AUC values are indeed observed in HCV monoinfected patients and in HIV-HCV coinfected patients with normal CD4 levels. Specific

RBV dose adjustments based on the immunological status could be suggested for HIV-HCV coinfected patients treated with PEG-IFN/RBV and should be validated in new forthcoming RBV-based therapeutic strategies.

Disclosures:

François Bailly- Board Membership: MSD, BMS, GILEAD; Speaking and Teaching: ROCHE, JANSSEN

Fabien Zoulim - Advisory Committees or Review Panels: Gilead; Consulting: Roche; Grant/Research Support: Gilead, Scynexis, Roche; Speaking and Teaching: Novartis, Roche, Janssen, Bristol Myers Squibb, Gilead

The following people have nothing to disclose: Giorgiana Hatu, Pierre Pradat, Emmanuel Pourcelot, Marianne Maynard-Muet, Patrick Miailhes, Marie-Claude Gagnieu

1918

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The Belgian experience in treatment of persons who used drugs with the new standard of care in genotype 1 HCV infected patients: an interim analysis

Amber Arain1,2, Stefan Bourgeois3, Chantal de Galocsy4, Pierre Deltenre5, Jean Henrion5, François G. D'Heygere6, Christophe Georges6, Boris Bastens7, Lode Van Overbeke8, Rita Verrando9, Liesbeth Bruckers10, Catharina Mathei11,12, Frank Buntinx13, Hans Van Vlierberghe14, Sven Francque15, W. Laleman16, Christophe Moreno17, Frederik Nevens16, Geert Robaeys1,16; 1 Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium; 2Faculty of Medicine and Life Sciences, Limburg Clinical Research Program, Hasselt University, Hasselt, Belgium; 3Department of Gastroenterology and Hepatology, ZNA Stuyven-berg, Antwerp, Belgium; 4Department of Gastroenterology and Hepatology, Hôpitaux Iris Sud Bracops, Brussels, Belgium; 5Depart-ment of Gastroenterology and Hepatology, Hôpital de Jolimont, Haine-Saint-Paul, Belgium; 6Department of Gastroenterology and Hepatology, AZ Groeninge, Kortrijk, Belgium;7 Department of Gastroenterology and Hepatology, Clinique Saint-Joseph, Clinique de l'Espérance, Liège, Belgium; 8Department of Gastroenterology and Hepatology, AZSt Maarten, Mechelen, Belgium; 9Medisch Sociaal Opvangcentrum Limburg, Genk, Belgium;
10Center for Statistics (CenStat), Hasselt University, Hasselt, Belgium; 11Free Clinic, Antwerp, Belgium; 12Department of Public Health and Primary Care KULeuven, KU Leuven, Leuven, Belgium; 13Department of General Practice, KU Leuven, Leuven, Belgium; 14Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium; 15Department of Gastroenterology and Hepatology, UZ Antwerp, Antwerp, Belgium; 16Department of Hepatology, UZLeuven, Leuven, Belgium; 17Hepatology and Liver Transplantation Unit, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium

Background: In HCV genotype (GT) 1 infected patients direct acting agents in combination with pegylated interferon and ribavirin are the standard of care. There remains some doubt if this new standard of care is also applicable in HCV infected persons who used drugs (PWUD). Aim: To compare compliance and viral outcome in GT1 infected PWUD treated with bocepre-vir and telaprevir vs Persons Who Used no Drugs. Methods: We studied treatment completion and early (EVR) and sustained (SVR) viral response in a retrospective treatment cohort study in real life in GT1 HCV infected PWUD treated with telaprevir or boceprevir in combination with pegylated interferon and ribavirin in 11 hepatology centres in Belgium. Not all those centres were integrated in a multidisciplinary system organized for treatment of substance users. Results: Up to now data on antiviral treatment with boceprevir and telaprevir were collected in 144 HCV infected patients: 65 (45.1%) infected after substance use (19 actively using substances during antiviral treatment (heroin, cocaine, cannabis), 25 actively using benzodi-azepines, 20 in a substitution maintenance program, 44 former substance users) and 79 not infected after substance use (controls). The moments of evaluation of EVR and SVR were reached up to now in resp. 63 and 29 PWUD and resp. 67 and 40 of controls. In the group of patients infected after substance use there were significantly less females (23 vs. 48%) (p=0.01) compared to controls, they were significantly younger (45 vs. 53 y) (p<0.0001) at start of treatment and were significantly more infected by GT 1a HCV (p<0.0001). Race, viral load, liver fibrosis in liver biopsy, rate of treatment with boceprevir and telaprevir were not statistically different. Treatment completion, reasons for stopping treatment (side effects, non compliance), EVR and SVR did not differ between the two groups (p=0.11, 0.62, 0.08, 0.11 resp.). Administration of methadone and active use of substances and benzodiazepines during treatment did not significantly influence EVR (n=18, p= 0.07; n=18, p=0.20 and n=23, p=0.16 resp.) and SVR (n=11, p= 0.25; n=7, p=0.32 and n=8, p=0.08 resp.). However, there was a tendency to lower EVR (77%, n=27) and SVR (30%, n=10) in PWUD who actively used substances or benzodiazepines in comparison to controls (92%, n=67 and 67%, n=24 resp.). One PWUD (0.01%) died during antiviral treatment due to overdose of substances. This seemed not to be related to treatment with DAA therapy. Conclusion: At this moment there are no arguments to exclude HCV infected PWUD from treatment with boceprevir and telaprevir.

Disclosures:

Stefan Bourgeois - Consulting: Roche, MSD; Speaking and Teaching: Janssen

Pierre Deltenre - Consulting: Schering-Plough, BMS, Janssen-Cilag; Grant/Research Support: Schering-Plough; Speaking and Teaching: Schering-Plough, BMS

Frederik Nevens - Grant/Research Support: Ipsen, Roche, MSD, Astellas, CAF

Geert Robaeys - Advisory Committees or Review Panels: Gilead; Speaking and Teaching: Merck, Janssens

The following people have nothing to disclose: Amber Arain, Chantal de Galocsy, Jean Henrion, François G. D'Heygere, Christophe Georges, Boris Bastens, Lode Van Overbeke, Rita Verrando, Liesbeth Bruckers, Catharina Mathei, Frank Buntinx, Hans Van Vlierberghe, Sven Francque, W. Laleman, Christophe Moreno

1919

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treatment discontinuation with pegylated interferon a lf a-2a plus ribavirin in prison inmates with and without personality disorder. Subanalysis of PERSEO study

Andres Marco1, Pablo Saiz de la Hoya2, José Joaquín Antón3, Jose DeJuan4, Inmaculada Faraco5;
1Men's Penitentiary Centers of Barcelona, Barcelona, Spain; 2Penitentiary Center of Albolote, Granada, Spain; 3Penitentiary Center of Fontcalent, Alicante, Spain; 4Penitentiary Center of Córdoba, Cordoba, Spain; 5Peni-tentiary Center of Sevilla, Sevilla, Spain

Aim: To determine treatment discontinuation with pegylated interferon alfa-2a plus ribavirin in prison inmates with and without personality disorder (PD), its causes and potential predictive factors. Methods: A prospective multicenter study in 25 Spanish prisons. Treatment discontinuation was evaluated in inmates treated in 2011 for chronic hepatitis due to HCV with pegin-terferon alfa-2a (Pegasys®) plus ribavirin. The study was approved by a clinical research ethics committee and by the penitentiary administrations. Informed consent was obtained from all participants. The Personality Diagnostic Questionnaire-4+ (PDQ-4+) was used, which is validated in Spain to diagnose PD according to DSM-IV criteria. Causes for discontinuation were collected, and to assess predictive factors, a bivariate and multivariate analysis were performed using logistic regression, calculating the adjusted odds ratio (AOR) with 95% confidence intervals. Results: A total of 257 patients were enrolled.

PD was studied in 195 patients (75.9%) because the PDQ-4+ was incomplete or invalid in 62. There were no differences between patients with and without and evaluable PDQ-4+. Mean age was 40 years, 92.3% were men, 79.1 % intravenous drug users and 25.3% HIV-coinfected. Prevalence of PD was 72.3%. The most prevalent disorders were antisocial (46.7%), borderline (30.8%) and paranoid (29.2%) PD. 51.3% had more than one PD. Treatment was discontinued in 76 patients (30.5%): 38.2% was due to a treatment-related cause (lack of efficacy and/or adverse effects), 32.9% to a penitentiary cause (excarcelation or transfer between prisons) and 28.9% to a patient-related cause (voluntary discontinuation or nonatten-dance to visits and/or blood tests). Overall, discontinuation was higher in genotypes 1–4 (AOR=2.65; CI:1 .36–5.14) and those who did not have PD (AOR=2.27; CI = 1 .17–4.41). Patient-related discontinuation was also higher in cases without PD (14.3% vs 5.8% in cases with PD; AOR=2.89; CI=1.03–8.15). Discussion: Treatment discontinuation was moderate and only 8.8% was due to patient-related causes. Cases with PD discontinued less often than cases without PD. Conclusion: Discontinuation is not a cause for not including patients with PD in treatment.

Disclosures:

The following people have nothing to disclose: Andres Marco, Pablo Saiz de la Hoya, José Joaquín Antón, Jose De Juan, Inmaculada Faraco

1920

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Significant improvements of non-invasive liver fibrosis tests in a short term follow up of 12 to 24 weeks after successful triple therapy of patients with chronic hepatitis C genotype 1 infection

Christoph Hoener zu Siederdissen, Benjamin Maasoumy, Kerstin Port, Katja Deterding, Janet Cornberg, Janina Kirschner, Michael P. Manns, Heiner Wedemeyer, Markus Cornberg;
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

BACKGROUND and AIM: Triple therapy of pegylated interferon alpha (P), ribavirin (R) and a HCV protease inhibitor (PI) is the new standard of care for patients with chronic hepatitis C genotype 1 (GT1). Sustained virological response (SVR) has been shown to improve survival and lower the incidence of HCC. Some data suggest even regression of liver cirrhosis after SVR. However, data are limited, especially for triple therapy. We aim to evaluate the impact of SVR after triple therapy including PIs on liver fibrosis by non-invasive fibrosis measures in a real-world setting. METHODS: Eighty-six patients with GT1 were treated with P/R/PI in a real-world setting (Maasoumy et al., PloS One 2012). 72 patients received a non-invasive fibrosis evaluation with fibroscan before treatment. A second fibroscan was performed 12–24 weeks after the end of treatment. APRI-Score was calculated at both time points. By now, complete data from 34 patients is available (18 male, median 58 years, median baseline fibroscan 14.4 kPa, median APRI score 1.4). 12 patients were lost to follow up, 6 died or developed HCC and for 20 patients a second fibroscan is planned for the upcoming follow-up visit. RESULTS: 19 patients achieved SVR, while 15 patients failed to respond to therapy. Change between pre- and post- treatment fibrosis scores was significantly different between the SVR and non-SVR group (p < 0.01 for fibroscan and APRI-Score). The non-SVR group showed an increase in liver stiffness measured by fibroscan (median +1,9 kPA), whilst the APRI-Score remained stable (-0,2). In contrast, SVR patients experienced an improvement of the fibroscan result (-4,7kPA) and APRI-Score (-0,5). To exclude the effect of liver inflammation on liver stiffness values, patients with ALT

>3xULN on baseline were excluded from a subsequent analysis. Still, the results for fibroscan (p < 0.05) and APRI-Score (p < 0.05) remained significant with 11 patients in the SVR group and 9 patients in the non-SVR group. Two patients in the non-SVR group progressed to cirrhosis based on the fibroscan criteria of >14.5 kPA. In comparison, 5 out of 10 SVR patients with cirrhosis at baseline demonstrated a regression to values below 14.5 kPA after therapy (11.3 kPa on follow-up). This was also confirmed by using the APRI-Score, with 5 patients having an APRI-Score > 2 at baseline and none at follow-up. CONCLUSION: Successful triple therapy of hepatitis C leads to a significant improvement of non-invasive fibrosis markers even in a short term follow up of 12 to 24 weeks after end of treatment. These findings even suggest the possibility for regression of liver cirrhosis after SVR.

Disclosures:

Benjamin Maasoumy - Advisory Committees or Review Panels: Abbott Molecular; Speaking and Teaching: MSD, Roche Diagnostics, Roche Pharma

Kerstin Port - Speaking and Teaching: Roche

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Markus Cornberg - Advisory Committees or Review Panels: Merck (MSD Ger-mamny), Roche, Gilead, Novartis; Grant/Research Support: Merck (MSD Ger-mamny), Roche; Speaking and Teaching: Merck (MSD Germamny), Roche, Gilead, BMS, Novartis, Falk

The following people have nothing to disclose: Christoph Hoenerzu Siederdissen, Katja Deterding, Janet Cornberg, Janina Kirschner

1921

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Cost-Effectiveness Modeling Study of boceprevir for the treatment of patients with genotype 1 chronic hepatitis C virus infection in Hong Kong

Shannon A. Ferrante1, Man-Fung Yuen2, Vincent W. Wong3, Ching-Kong Loo4, Jagpreet Chhatwal5, Elamin Elbasha1;
1Health Economic Statistics, Merck Research Laboratories, Merck & Co, Inc., North Wales, PA; 2Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pok Fu Lam, Hong Kong; 3Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong; 4Department of Medicine, Kwong Wah Hospital, Yau Ma Tei, Hong Kong; 5Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA

Background: SPRINT-2 and RESPOND-2 demonstrated that boceprevir (BOC) in addition to peginterferon and ribavirin (PR) was more efficacious than the dual therapy of peginterferon and ribavirin in the treatment of patients with chronic hepatitis C virus genotype 1 (HCV G1). The objective of this study was to evaluate the cost-effectiveness of BOC-based treatment strategies compared with dual therapy in both treatment-naive and treatment-experienced patients in Hong Kong. Methods: A Markov-model was developed to estimate the lifetime clinical benefits and the cost-effectiveness of BOC-based regiments compared with dual therapy from the Hong Kong payer perspective. Efficacy data was obtained from SPRINT-2 and RESPOND-2. Disease progression rates, liver transplantation rates, and health state utilities used in the model were from published studies. Cost estimates were provided by the hospital authority. Future costs and quality-adjusted life years (QALYs) were discounted at 3%. Results: BOC-based therapy is projected to result in relative reductions of 41–42% and 44–50% in the lifetime incidence of severe liver disease complications (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation, and liver-related mortality) in treatment naive and treatment experienced patients. In addition, the modeling study predicts that QALYs will increase by 0.89 and 2.10 in the treatment-naive and treatment-experienced populations. The corresponding incremental cost-effectiveness ratios were HK$ 145,500 and HK$67,956 per QALY compared to dual therapy. Conclusion: The results of the model suggest that adding boceprevir to dual therapy is projected to be a highly cost-effective strategy (assuming a threshold of HK$821,337 per QALY) in the treatment of both treatment naive and treatment experienced patients infected with chronic HCV G1 in Hong Kong.

Disclosures:

Shannon A. Ferrante - Employment: Merck & Co, Inc

Man-Fung Yuen - Advisory Committees or Review Panels: GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Bristol-Myers Squibb, Pfizer; Grant/Research Support: Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science, Roche, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Science

Vincent W. Wong - Advisory Committees or Review Panels: Otsuka, Roche Pharmaceuticals, Gilead, Abbott; Speaking and Teaching: Bristol-Myers Squibb, Novartis Pharmaceuticals, Echosens

Jagpreet Chhatwal - Consulting: Merck & Co., Inc.; Grant/Research Support: NIH/National Center for Advancing Translational Sciences

Elamin Elbasha - Employment: Merck & Co., INC

The following people have nothing to disclose: Ching-Kong Loo

1922

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A Prospective Pilot Trial Of 3 Different COBAS Taqman Assays Of HCV RNA For DAA Treatment Shows Differences In Week 4 And 12 RGT Results

Paul J. Pockros1, Bryan Still1, Mary Lou Souders1, Andrea C. Sch-erschel1, Mary Helen Broussard1, Kevin Lok2, Bryan R. Cobb2;
1 Div of Gastro/Hepatology, Scripps Clinic, La Jolla, CA; 2Medical and Scientific Affairs, Roche Molecular Systems, Pleasanton, CA

Background: HCV RNA results from the phase 3 trials of DAAs were performed using the Roche COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System with a LLOQ of 25 IU/mL and a LOD ~10 IU/mL in G1 patients. However, this assay is generally not available to practicing providers. The assay used in most reference laboratories and hospitals is the COBAS® Ampliprep/ COBAS® TaqMan® HCV Test -v 1.0 with an LLOQ of 43 IU/ml and LOD of 7.1 IU/mL for G1. RGT definitions for both Telaprevir and Boceprevir are based upon undetectability of viral loads using the High Pure System assay. A new version 2.0 Ampliprep assay with LLOQ and LOD of 15 IU/ml is now approved in EU and US. We compared these 3 assay results simultaneously in a group of patients initiating DAA therapy in a single US site. Methods: All HCV RNA plasma specimens from 34 G1 patients were processed in the usual fashion and specimens were separated into 2 aliquots. One aliquot was be frozen at -70 F and stored and the second was processed by automated methodology and tested by the COBAS® Ampliprep. Results of this assay were used in patient management decisions for RGT. The frozen specimens (n=45) were tested by the Roche COBAS® TaqMan® HCV Test, v2.0 for Use with the High Pure System assay and the the COBAS® Ampliprep/ COBAS® TaqMan® HCV Test, v2.0. Results: 4 patients had results that were < 43 IU/ml by Ampliprep but undetectable by one of the other assays at week 4 (n=3) or 12 (n=1). This would have changed RGT in 3 of the patients. The rest of the patients had a detectable result by at least one assay and each test specific discrepancy varied by patient but in all cases, the patients were undetectable by 12 weeks. Our results are consistent with those of a recent multi-center study from Germany which also showed a lack of concordence between the 3 assay results, primarily at week 4. Conclusions: Results varied between “detectable but below the LLOQ” and “not detected” more frequently at the first RGT time point and these differences were clinically significant in 3 cases. Differences became less apparent with longer treatment duration. These variations may have resulted in prolonged therapy in some patients treated with DAA regimens.

Disclosures:

Paul J. Pockros - Advisory Committees or Review Panels: Janssen, Merck, Genen-tech, BMS, Gilead, Vertex, Abbott Labs, Genentech, BMS, Gilead, Vertex; Consulting: Genentech, Lumena, Boehinger Ingelheim, Regulus, Beckman Coulter, Hologic Genprobe, Biotest, Genentech; Grant/Research Support: Novartis, Intercept, Janssen, Genentech, BMS, Gilead, Vertex, Boehinger Ingelheim, Lumena, Beckman Coulter, Abbott labs, Mochida Pharmaceuticals, Novartis, Genentech, Merck, BMS, Gilead, Vertex; Speaking and Teaching: Genentech, Merck, Gilead, Vertex, Genentech, BMS, Gilead, Vertex

Andrea C. Scherschel - Advisory Committees or Review Panels: Jensen, Gilead; Speaking and Teaching: Vertex, Kadmon

Bryan R. Cobb - Employment: Roche Molecular Diagnostics

The following people have nothing to disclose: Bryan Still, Mary Lou Souders, Mary Helen Broussard, Kevin Lok

1923

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Long term efficacy of Interferon a-2b/Peg-Iinterferon a-2b monotherapy in b-thalassemics with chronic hepatitis C

Christos K. Triantos1, Alexandra Kourakli2, Nikolaos Gatselis3, Maria Kalafateli1, Polikseni Lambropoulou2, Anne-Lise De Lastic2, Konstatinos Thomopoulos1, Athanasios Tsamandas4, Mirto Christofidou5, Eleni Jelastopulu6, Vasiliki Nikolopoulou1, Argiris Symeonidis2, George N. Dalekos3, Chrisoula Labropoulou-Karatza C7;
1Department of Gastroenterology, University Hospital of Patras, Patra, Greece; 2Hematology Division/Thalassemia & Hemoglo-binopathies Unit, Department of Internal Medicine, University Hospital of Patras, Patras, Greece; 3Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece; 4Department of Pathology, University Hospital of Patras, Patras, Greece; 5Department of Microbiology, University Hospital of Patras, Patras, Greece; 6Department of Public Health, School of Medicine, University of Patras, Patras, Greece; 7Department of Internal Medicine, University Hospital of Patras, Patras, Greece

Background: Hepatitis C virus (HCV) infection and iron overload are the main causes of liver disease in patients with β-Tha-lassemia major (βTM). Since there is concern about ribavirin treatment in these patients, monotherapy with standard or pegy-lated interferon (PegIFN) remains the first-line treatment. The long-term impact of antiviral treatment/retreatment in this group is still unknown. Recent data suggest that polymorphisms in the interleukin-28B (IL28B) gene are associated with sustained viro-logical response (SVR). Aim: To assess the long-term efficacy of monotherapy with IFN-a2b/Peg IFN-a2b (one or multiple treatment courses) in HCV-infected thalassemic patients and the predictive factors for SVR. Methods: 48 βTM, HCV-infected patients received IFN-a2b (n=34) or PegIFN-a2b (n=14) [M/F: 19/29, median age: 22 years (12–45), median ALT: 107 IU/ml (33–331), median BMI: 23.1 (17.3–30.4), median serum fer-ritin: 1926.5 ng/ml (373–10820) and previous splenectomy: 23 (47.9%)].Liver histology: Ishak stage >4: 13/39 (27.1%), and grade: 6 (3–10), siderosis grade 3–4: 23/43 (47.9%). Median follow-up: 165.5 months (8–237). Patients either received IFN-a2b (70.8%) or PegIFN-a2b (29.2%). Genotypes: 1 (47.2%), 2 (5.6%), 3 (25%) and 4 (22%) in 36/48. IL28B genotype was determined by means of in-house real-time PCR, using genomic DNA, extracted from frozen serum samples, in conjunction with minor groove binder probes: CC: 27%, CT: 62.2%, TT: 10.8%. Results: Totally, 15/48 (31.3%) patients achieved SVR following the first treatment course; 13 (27.1%) received multiple courses: 2 (n=7), 3 (n=4), 4 (n=1), 5 (n=1). From those patients, who failed to achieve SVR (n=33) with the first course, retreatment resulted in SVR in 3/16 (18.75%). SVR at the end of follow-up was achieved in 18 patients (38.3%). Splenectomy (p=0.008) and fibrosis grade>4 (p=0.037) were negative predictive factors for SVR (first course), whereas splenectomy (p=0.024) and age >18 (p=0.02) for SVR at the end of follow-up. In HCV-genotype 1, 100% of patients with CC IL28B genotype achieved SVR versus 18.2% of patients with CT or TT (p=0.07). Conclusions: Interferon treatment of HCV-infected βTM patients is as efficient as for non-thalassemics. Predictive factors for SVR are splenectomy, age and fibrosis. All the HCV-genotype1 patients with CC IL28B achieved SVR in this cohort.

Disclosures:

The following people have nothing to disclose: Christos K. Triantos, Alexandra Kourakli, Nikolaos Gatselis, Maria Kalafateli, Polikseni Lambropoulou, Anne-Lise De Lastic, Konstatinos Thomopoulos, Athanasios Tsamandas, Mirto Christofidou, Eleni Jelastopulu, Vasiliki Nikolopoulou, Argiris Symeonidis, George N. Dalekos, Chrisoula Labropoulou-Karatza C

1924

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Acoustic radiation force impulse imaging for evaluation of antiviral treatment response in chronic hepatitis C

Toshiki Kan, Keisuke Osakabe, Naoto Kawabe, Senju Hashimoto, Masao Harata, Yoshifumi Nitta, Michihito Murao, Takuji Nakano, Yuko Arima, Hiroaki Shimazaki, Masashi Ohki, Kazunori Nakaoka, Takagawa Yuka, Toru Nishikawa, Naohiro Ichino, Ken-taro Yoshioka;
Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan

Purpose: Interferon (IFN) treatment has been demonstrated to reduce liver fibrosis by liver biopsies and by transient elastog-raphy (TE) which can assess liver fibrosis noninvasively. Acoustic radiation force impulse (ARFI) is another noninvasive method for assessing liver fibrosis. However reduction of liver fibrosis after antiviral therapy has not been well evaluated by ARFI. The aim of the present study is to measure velocity of shear wave (Vs) by ARFI before and after IFN treatment and to evaluate the reduction of liver fibrosis after IFN treatment in patients with chronic hepatitis C. Methods: Vs measurement by ARFI was performed with a Siemens ACUSON S2000 before treatment, at end of treatment (EOT), and 1 year after EOT in 81 patients with chronic hepatitis C treated by IFNs with or without ribavirin. Results: In the patients with sustained virolog-ical response (SVR)(n=37), Vs significantly decreased at EOT [1.13 (1.06–1.27) meters/second (m/s), p= 0.0071], 1 year after EOT [1.06 (0.97–1.17), p=0.0002] compared with baseline [1.25 (1.01–1.40)]. Vs significantly decreased 1 years after EOT compared with the values at EOT in SVR patients (p=0.0112). In the patients with relapse (relapsers)(n=21), Vs did not significantly decrease at EOT [1.28 (1.14–1.55) m/s] or 1 year after EOT [1.38 (1.15–1.73)] compared with baseline [1.45 (1.17–1.58)]. Vs significantly increased 1 years after EOT compared with the values at EOT in relapsers (p=0.0431). In the patients with no virological response (NVR; null respon-ders or partial responders)(n=21), Vs did not significantly decrease at EOT [1.53 (1.25–1.84) m/s], 1 year after EOT [1.54 (1.19–1.80)] compared with baseline [1.64 (1.20–1.97)]. In genotype 1 patients, baseline Vs tended to be lower in SVR patients [n = 18; 1.28 (0.97–1.38)] than in non-SVR patients [n=38; 1.52 (1.19–1.77)](p=0.0629). Conclusions: IFN treatment reduced Vs in SVR patients and reduction of Vs continued till 1 years after EOT. In relapsers, Vs incresed 1 years after EOT compared with the values at EOT. In genotype 1 patients, baseline Vs tended to be lower in SVR patients than in non-SVR patients. Vs measurement is useful in evaluation of the response to IFN treatment and also in prediction of the response.

Disclosures:

Kentaro Yoshioka - Grant/Research Support: Chugai, Schering-Plough, Bristol Myers Squibb, Tanabe Mitsubishi, Taiho, Otsuka, Ajinomoto, Tore Medical, Torii, Boston Scientific

The following people have nothing to disclose: Toshiki Kan, Keisuke Osakabe, Naoto Kawabe, Senju Hashimoto, Masao Harata, Yoshifumi Nitta, Michihito Murao, Takuji Nakano, Yuko Arima, Hiroaki Shimazaki, Masashi Ohki, Kazunori Nakaoka, Takagawa Yuka, Toru Nishikawa, Naohiro Ichino

1925

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Treatment of chronic Hepatitis C by pegylated interferon alfa-2b (Peg2b) and Ribavirin (RBV): age and gender dependent frequency of hematological alterations in a German real-life cohort

Gerlinde Teuber1, Stefan Mauss2, Dietrich Hueppe3, Elmar Zehn-ter4, Michael P. Manns5, Tarek Dahhan6, Ulrike Meyer7, Thomas Witthoeft8, Bernd Moeller9, Nektarios Dikopoulos10, Jochen Brack11, Dagmar Hartmann12, Bernd Dreher12, Manfred Bilzer12;
1Gastroenterological Practice, Frankfurt, Germany; 2Medical Group Practice, Düsseldorf, Germany; 3Medical Group Practice, Herne, Germany; 4Gastroenterological Practice, Dortmund, Germany; 5Medical High School Hannover, Hannover, Germany; 6Medical Practice, Fellbach, Germany; 7Medical Practice, Berlin, Germany; 8Gastroenterological Practice, Stade, Germany; 9Med-ical Practice, Berlin, Germany; 10Health Centre Langenau, Lange-nau, Germany; 11Hospital Nord Ochsenzoll, Hamburg, Germany; 12MSD Pharma GmbH, Haar, Germany

Background: Peg2b in combination with RBV has been extensively explored for its efficacy in the treatment of chronic Hepatitis C. Its use is accompanied by a variety of hematological side effects which may hamper reaching and maintaining the dose needed for maximal therapeutic effect. Data regarding the frequency of hematological side effects caused by Peg2b/RBV in real-life are still scarce. Methods: Data from patients (pts) infected with HCV genotype (G) 1 (N = 1873) and G2/3 (N=1323) treated with Peg2b 1.5 μg/kg/week+weight-based RBV (800–1200 mg/day) for up to 48 weeks in a large observational real-life study at 285 sites in Germany were retrospectively analyzed. Pts who had baseline and at least one hemoglobin (Hb), leukocyte and platelet measurement during therapy were included in the analysis Results: After starting Peg2b/RBV treatment 33.5%, 10.7%, 0.8% and 0.1% of G1 infected pts had an Hb decline grade 1, 2, 3 and 4, respectively (Table). Frequencies of Hb declines grade 1 and 2 were significantly higher in females and pts older than 50 years. Grade 1 to 4 declines in leukocytes occurred in 42.4%, 13.8%, 3.5% and 0.1% of treated pts. Again females and pts older than 50 years showed higher frequencies of grade 2 and 3 leukocyte declines. No difference was seen between females and males in platelet declines, while frequencies of grade 1 to 3 platelet declines were significantly higher in pts older than 50 years. Compared to pts with G1 infection grade 1 and 2 declines in Hb (23.0%/5.0%) and leukocytes (38.1%/9.0%) occurred significantly less frequent in G2/3 pts in contrast to similar alterations in platelet counts (15.9%/4.6%). Conclusions: During Peg2b/RBV treatment of chronic HCV infection in real-life Hb and leukocyte declines occur more frequently in G1 infected pts, females and pts older than 50 years. In contrast, alterations in platelet count occur in a similar frequency in pts with G1 and G2/3 infection and depend on age, but not on gender.

Hematological alterations in pts with G1 infection

 Grade 1 (Mild)Grade 2 (Moderate)Grade 3 (Severe)Grade 4 (Life-threatening)
  1. * P<0.02

Hb,g/dl(%)9.5-<11.08.0-<9.56.5-<8.0<6.5
All33.510.70.80.1
Female/male41.7/27.3*15.0/7.3*1.1/0.60.1/0
Age <50/>50 yrs28.6/43.4*8.2/15.7*0.4/1.6*0/0.2
Leukocyte, 103 /μl (%)2.0-< 3.01.5-<2.01.0-<1.5<1.0
All42.413.83.50.1
Female/male42.3/42.618.0/10.5*4.8/2.5*0.2/0
Age ≤50/>50 yrs41.6/44.212.2/16.8*2.8/5.0*0.1/0
Platelets, 10 3/μl(%)70-<10050-<7025-<50<25
All17.05.63.40.6
Female/male15.2/18.45.5/5.63.3/3.50.2/0.9
Age ≤50/>50 yrs15.5/20.0*4.2/8.3*2.3/5.6*0.8/0.3

Disclosures:

Gerlinde Teuber - Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Dietrich Hueppe -Advisory Committees or Review Panels: Roche, MSD, Gilead, Novartis, BMS

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Dagmar Hartmann - Employment: MSD Germany Bernd Dreher- Employment: MSD Manfred Bilzer - Consulting: MSD Germany

The following people have nothing to disclose: Elmar Zehnter, Tarek Dahhan, Ulrike Meyer, Thomas Witthoeft, Bernd Moeller, Nektarios Dikopoulos, Jochen Brack

1926

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Virologic response to boceprevir plus peginterferon alfa-2a (40KD) and ribavirin in treatment-naive patients with chronic hepatitis C and HCV genotype 1 infection: interim analysis of data from the international TriCo study

Peter Ferenci1, Robert Flisiak2, Florin A. Caruntu3, Gabriella Lengyel4, Marc Hohmann5, Fernando Tatsch6;
1 Department of Internal Medicine III, Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; 2Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bia-lystok, Poland; 3National Institute for Infectious Diseases “Matei Bals“, Bucharest, Romania; 42nd Department of Medicine, Sem-melweis University, Budapest, Hungary; 5IST GmbH, Mannheim, Germany; 6F. Hoffmann-La Roche Ltd, Basel, Switzerland

Background:Despite recent advances in antiviral therapy for CHC, first-generation protease inhibitor-based triple therapy will likely remain the treatment of choice in financially constrained countries for the foreseeable future. There are limited prospectively collected data on the use of boceprevir (BOC) in combination with PegIFN alfa-2a/RBV. This study aimed to explore the efficacy and safety of BOC administered in combination with PegIFN alfa-2a/RBV. The aim of this interim analysis is to report virologic response (VR) rates at the end of the 4-week PegIFN alfa-2a/RBV lead-in and at Week 4 of triple therapy. Methods:TriCo is an international prospective, open-label study of response-guided therapy with BOC in treatment-naive G1-infected patients with or without compensated cirrhosis. All patients receive a 4-week PegIFN alfa-2a/RBV lead-in after which BOC 800mg tid is added. Noncirrhotic patients with a >l-log10 drop in HCV RNA by Week 4 either continue triple therapy for 24 weeks then stop all therapy at Week 28 (if HCV RNA undetectable at Weeks 8 and 24) or continue triple therapy for 32 weeks, stop BOC at Week 36, and continue PegIFN alfa-2a/RBV to Week 48 (if HCV RNA detectable at Week 8 and undetectable at Week 24). Noncirrhotic patients with a <1-log10 drop in HCV RNA by Week 4 and all cirrhotic patients continue triple therapy until Week 48 and then stop all therapy. Treatment is stopped for futility if HCV RNA is &ge;100 IU/mL at Week 12 or is detectable at Week 24. VR is defined as undetectable HCV RNA by Roche COBAS®TaqMan®2.0 HCV Test (LOQ=25 IU/mL; LOD=10–15 IU/mL for G1). Results:A total of 165 patients have been enrolled (mean age 46 yrs, 50% male, 13% cirrhotic, 86% G1b, 21% rs12979860 CC, 44% rs8099917 TT) and were included in the Week 8 interim analysis. A total of 133 patients (81%) had a &ge; 1-log10 drop in HCV RNA at Week 4, and totals of 6 (4%), 12 (7%), 68 (41%) and 100 (61%) patients had undetectable HCV RNA at Weeks 2, 4, 6 and 8, respectively. VR increased after the addition of BOC, including in patients with difficult-to-treat characteristics such as unfavourable IL28B genotype (rs12979860 non-CC) or cirrhosis (Table). Week 28 data will be presented at the meeting. Conclusions:This interim analysis shows that more than 80% of patients achieve a >1-log10 drop in HCV RNA by Week 4 with PegIFN alfa-2a/RBV treatment, and that addition of BOC leads to an increase in Week 8 VR rates both overall and in patients with difficult-to-treat characteristics. F. Hoffmann-La Roche Ltd-funded

Virologic response, n/N (%)Week 4 (end of PegIFN/RBV lead-in)Week 8
IL2SB (rsl2979860) CC vs. non-CC6/35 (17) vs. 6/129(5)30/35 (86) vs. 70/129 (54)
No cirrhosis vs. cirrhosis12/144 (8) vs. 0/21 (0)91/144(63) vs. 9/21 (43)

Disclosures:

Peter Ferenci - Advisory Committees or Review Panels: Roche, Idenix, Roche, MSD, Vertex, Salix, Madaus Rottapharm, Tibotec, Böhringer Ingelheim, Achilleon, GSK; Grant/Research Support: MSD, Vertex, Madaus Rottapharm; Patent Held/Filed: Madaus Rottapharm; Speaking and Teaching: Roche, Gilead, Roche, Gilead, Salix

Robert Flisiak - Advisory Committees or Review Panels: Gilead, Merck, Roche, Bristol Myers Squibb, Janssen, Novartis, Achillion, Abbvie; Grant/Research Support: Roche, Bristol Myers Squibb, Janssen, Novartis, Gilead, Vertex, Merck; Speaking and Teaching: Janssen, Merck, Roche, Bristol Myers Squibb, Gilead

Marc Hohmann - Advisory Committees or Review Panels: F. Hoffmann-La Roche Ltd; Employment: IST GmbH

Fernando Tatsch - Employment: F. Hoffmann-La Roche Ltd; Stock Shareholder: F. Hoffmann-La Roche Ltd, Novartis

The following people have nothing to disclose: Florin A. Caruntu, Gabriella Lengyel

1927

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Evaluating fluvastatin in combination with the standard of care( PegIFN-ribavirin) to treat Egyptian patients with Hepatitis C virus

Moataz S. Seyam1, Haitham A. Gabr2, Zakaria A. Salama3, Mohammed A. Mokhles2, Raghda N. Marzaban3, Ahmed F. Soli-man3;
1Hepatology and gastroenterology, Theodor Bilharz Research Institute, Cairo, Egypt; 2General medicine, National Research Center in Cairo, Cairo, Egypt; 3Endemic Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt

Background and Aim : Cholesterol biosynthesis plays a critical role in hepatitis C virus (HCV) life cycle and statins are proved to suppress replication of HCV-1 b replicons .Thus we aimed to evaluate the efficacy and safety of fluvastatin as an adjuvant therapy to the approved standard of care (SOC) for genotype 4 patients; Pegylated Interferon(Peg IFN) and Ribavirin. Patients and methods:60 chronic HCV patients were enrolled and randomly assigned to receive either triple therapy, Fluvastatin 80 mg/day + SOC (group I) or the SOC (group II), all planed for 48 weeks . Patients were subjected to pretreatment liver biopsy, HCV-RNA quantification at weeks (0, 4, 12, 48 and 72) and monthly assessment of biochemical, including lipid profile, and hematological tests. Results: Three patients were dropped in group II during early treatment period. Rapid virological response (RVR) was achieved in 16(53.3%) patients and 12(44.4%) patients in groups I and II respectively with no statistical significant difference (p=0.5). Early virological response (EVR) was achieved in 27(90%) patients and 24 (88.9%) patients in groups I and II respectively (p=0.8). Finally, sustained virological response (SVR) was achieved in 22(73.3%) patients and 18(66.7%) patients in groups I and II respectively with no statistical significant difference (p=0.58). A significantly higher percentage of group I patients 26(86.7%) showed complete early virological response than group II patients 19(70.4%) (P=0.05) .Neither groups showed manifestations of hepatotoxicity . Conclusion: Fluvastatin is a safe adjuvant therapy with the SOC, yet, it proved significant higher virological response than the SOC only in terms of complete early virological response.

Disclosures:

The following people have nothing to disclose: Moataz S. Seyam, Haitham A. Gabr, Zakaria A. Salama, Mohammed A. Mokhles, Raghda N. Marzaban, Ahmed F. Soliman

1928

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The effect of pegylated interferon and ribavirin in chronic hepatitis C patients on hemodynamic changes in hepatic and splenic arteries

Ehab E. Abdel-Khalek1, Hasan M. Elaskalany1, Talal Amer2, Ahmed Eldeeb1, Mahmoud M. Yousef1;
1 Internal Medicine, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 2Diagnostic Radiology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Background: Pegylated interferon in combination with ribavirin is the standard of care for patients with chronic hepatitis C. In this group of patients, the hemodynamic changes in the hepatic and splenic arteries have not been thoroughly investigated before and after treatment. Our objective was to assess the effect of pegylated interferon and ribavirin on the hemodynamic changes in the hepatic and splenic arteries evaluated by pulsed-wave Doppler ultrasonography. Methods: 253 patients with chronic hepatitis C viral infection who were treated with pegylated interferon plus ribavirin were included in this study. Hepatic artery resistive index (HARI), hepatic artery pulsatility index (HAPI), splenic artery resistive index (SARI), and splenic artery pulsatility index (SAPI) were evaluated by pulsed-wave Doppler ultrasonography (Hitachi EUB-7500 ultrasound scanner, Hitachi medical corporation, Tokyo, Japan). Results: in patients who have achieved a sustained virological response, HARI showed a significant decrease 24 weeks after the end of treatment (P = 0.003), while HAPI showed a nonsignificant decrease (P = 0.071). SARI and SAPI showed a significant decrease 24 weeks after the end of treatment (P < 0.001). Conclusions: pulsed-wave Doppler ultrasonography is a noninva-sive and easily performed method for evaluating the effects of interferon therapy in patients with chronic hepatitis C, this technique is useful for measuring HARI, HAPI, SARI, SAPI before and after interferon administration in order to evaluate the changes over time, thus assessing the effectiveness of interferon therapy

Disclosures:

The following people have nothing to disclose: Ehab E. Abdel-Khalek, Hasan M. Elaskalany, Talal Amer, Ahmed Eldeeb, Mahmoud M. Yousef

1929

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Boceprevir Plus Peginterferon Alfa-2B and Ribavirin in Russian Patients With Hepatitis C Virus Genotype 1 Infection: Treatment Week 8 Interim Analysis

Vasily Isakov1, Igor Nikitin2, Vladimir P. Chulanov3, Pavel P. Ogurtsov4, Ekaterina Lukyanova5, Jianmin Long6, Janice Wahl6, Frans A. Helmond6;
1 Department of Gastroenterology & Hepatol-ogy, Institute of Nutrition, Moscow, Russian Federation; 2Central Clinical Hospital of the Russian Academy of Sciences, Moscow, Russian Federation; 3Clinical Diagnostics and Research Center, Central Research Institute of Epidemiology, Moscow, Russian Federation; 4Center for Liver Research, Peoples' Friendship University of Russia, Moscow, Russian Federation; 5MSD Pharmaceuticals LLC, Moscow, Russian Federation; 6Merck Research Laboratories, Kenilworth, NJ

Purpose: To evaluate addition of boceprevir (BOC) to peginterferon and ribavirin (PR) in Russian patients with chronic hepatitis C virus (HCV) genotype (G) 1 infection. Methods: This is an ongoing, randomized, placebo-controlled, double-blind study in treatment-naive (TN) and treatment-experienced (TE) patients (N = 238). Patients were randomized (2:1) to receive BOC/PR or PR, stratified by previous treatment (TN versus TE) and IL28B status (CC allele versus non-CC allele). All patients received PR for 4 weeks then BOC/PR response-guided therapy (RGT) or PR for 44 weeks. Duration of RGT was based on treatment week (TW) 8 viral load. In the BOC arm, TN patients with detectable HCV-RNA at TW24 and TE patients with detectable HCV-RNA atTW12 were discontinued. This interim analysis is based on TW8 virologic response. Results: Most patients were TN (61%), male (59%), white (99%), and had HCV G1b infection (98%). Relatively few patients were TE (39%), cirrhotic (4%), and had the IL28B CC polymorphism (14%). Mean age was 38 years and mean baseline viral load was 572,000 IU/mL. Compared to patients enrolled in the BOC phase 3 studies, more Russian patients were aged <40 years (62% vs. 13%), had baseline viral load <800,000 IU/mL (60% vs. 14%), and had HCV G1 b infection (98% vs. 35%). Rates of undetectable HCV-RNA at TW4 were similar in the BOC RGT and PR treatment arms (14% vs. 13%) and higher in the BOC RGT than the PR arm at TW6 (69% vs. 28%) and TW8 (87% vs. 42%; P <0.01). Rates of undetectable HCV-RNA at TW8 in the BOC RGT and PR arms were: 91% vs. 48% in TN patients; 82% vs. 33% in TE patients; 100% vs. 100% in IL28B CC patients; and 85% vs. 33% in IL28B non-CC patients. Rates of undetectable HCV-RNA at TW8 in the BOC RGT and PR arms were: 67% vs. 0% in TW4 “null responders” (<1 log HCV-RNA decline); 96% vs. 51% in TW4 “partial responders” (detectable and >1 log HCV-RNA decline); and 100% vs. 100% in patients with “rapid virological response” (undetectable) at TW4. The safety profile of BOC/PR treatment was similar to that observed in the previous BOC/PR studies with a higher incidence of anemia, neutrope-nia, and dysgeusia in the BOC arm compared to the PR arm. Conclusions: In both treatment arms, rates of undetectable HCV-RNA at TW8 were higher than observed in phase 3 studies, but the treatment effect (approximately 40%) was similar. The higher response rate in this study may in part be explained by favorable baseline factors compared to the phase 3 study populations. The interferon response at TW4 was highly predictive for the response at TW8. Regulatory approval has been obtained for boceprevir in Russia based on the TW8 interim analysis.

Disclosures:

Vasily Isakov - Advisory Committees or Review Panels: Abbvie, Bristol-Myers Squibb, Gilead, Janssen, Merck, Vertex; Consulting: Bristol-Myers Squibb, Merck; Speaking and Teaching: Bristol-Myers Squibb, Janssen, Merck

Vladimir P. Chulanov - Grant/Research Support: Bristol Myers Squibb; Speaking and Teaching: Bristol Myers Squibb, Hoffman la Roche, MSD

Pavel P. Ogurtsov - Consulting: MSD

Ekaterina Lukyanova - Employment: Merck/MSD

Jianmin Long - Employment: Merck Sharp & Dohme Corp.

Janice Wahl - Employment: Merck & Co,

Frans A. Helmond - Employment: Merck (self), Bayer (spouse)

The following people have nothing to disclose: Igor Nikitin

1930

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Comparison of simeprevir plus peginterferon/ribavirin and telaprevir plus peginterferon/ribavirin for patients with HCV Genotype 1

Tomoaki Nakajima, Mutuumi Kimura, Tomohiro Arakawa, Yasuaki Kuwata, Itaru Ozeki, Takahiro Sato, Takumi Ohmura, Shuhei Hige, Yoshiyasu Karino, Joji Toyota;
Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan

Background and Aim: Telaprevir (TVR), the first-generation protease inhibitor, is effective with PEG-IFN/Ribavirin (RBV) for hepatitis C patients. However, we have reported that TVR causes a reduction in renal function, with a reduction in the excretion of RBV, and the serum RBV concentration rises and the increased RBV concentration leads to hemolytic anemia (AASLD2012). In this study, we investigated the effects and adverse events of the triple therapy with simeprevir (TMC435), the second-generation protease inhibitor, in comparison with TVR. Methods: 27 HCV genotype 1 patients (13 males, average age 56.4 yrs, 15 IL28B (rs12979860) CC, 15 ITPA CC, 16 core aa70 wild) were assigned to simeprevir for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group A), while 71 patients (32 males, average age 56.4 yrs, 44 IL28B CC, 55 ITPA CC, 41 core aa70 wild) were assigned to TVR for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group B). Simeprevir was administered at a dose of 100mg (or 50mg) per day for 12 weeks (or 24weeks) and TVR was administered at a dose of 1500mg or 2250mg per day for 12 weeks. SVR4 (SVR at 4 weeks after treatment) was evaluated in the full analysis set. The serum RBV concentration was measured by HPLC method at weeks 1, 2 and 4. Results: SVR4 rate was 88.9% in Group A and 80.8% in Group B. Adherence to PEG-IFN during 12 weeks was high in both groups (93.6% vs. 90.4%), but adherence to RBV/protease inhibitor (simeprevir or TVR) was higher in Group A than Group B (93.9%/96.8% vs. 52.7%/78.8%, p<0.05). Average hemoglobin level (g/dl) at weeks 0/1/2/3/4 was 14.1/13.9/12.8/12.3/12.2 in

Group A and 13.7/13.5/12.4/11.5/11.0 in Group B (p<0.05 at weeks 3/4) and average eGFR level (ml/min/1.73m2) at weeks 0/1/2/4 was 80.3/83.2/86.4/84.9 in Group A and 85.8/68.5/71.4/66.6 in Group B (p<0.05 at weeks 1/2/4). The serum RBV concentration (ng/ml) at weeks 1/2/4 was 1194.7/2173.1/1945.7 in Group A and 1300.0/2165.7/2219.7 in Group B. Only in cases without dose reduction of RBV during 4 weeks, the RBV concentration ratio (at weeks 4/at weeks 2) was 0.91 and 1.44 in Groups A and B, respectively (p<0.001), and was higher in Group B as a result of impaired renal function. Conclusions: Simeprevir plus PEG-IFN/RBV resulted in less adverse events, higher adherence to RBV and higher SVR4 rate than TVR plus PEG-IFN/RBV.

Disclosures:

Joji Toyota - Speaking and Teaching: MSD

The following people have nothing to disclose: Tomoaki Nakajima, Mutuumi Kimura, Tomohiro Arakawa, Yasuaki Kuwata, Itaru Ozeki, Takahiro Sato, Takumi Ohmura, Shuhei Hige, Yoshiyasu Karino

1931

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Low initial viremia predicts SVR to a similar extent as the IL28B genotype in hemodialysed patients with HCV infection, genotype 1

Jan Sperl1, Sona Frankova1,4, Vaclav Hejda2, Miroslava Volfova3, Milan Jirsa4, Dusan Merta5, Renata Bartakova1, Ondrej Viklicky6, Julius Spicak1;
1 Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2Department of Internal Medicine, Medical School Plzen, Plzen, Czech Republic; 3Hepato-Gastroenterology HK, Hepato-Gastroen-terology HK, Hradec Kralove, Czech Republic; 4Laboratory of Experimental Hepatology, Center for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 5Department of Anesthesiology and Intensive Care, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 6Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

Introduction: Optimal treatment strategies for hemodialysed (HD) patients with chronic HCV infection remain controversial. HCV eradication improves long-term survival after kidney transplantation, but antiviral treatment delays transplantation by at least one year. In treatment strategy decisions, overall life expectancy as well as the probability of sustained virological response (SVR) should be considered. We hypothesized that predictive factors of SVR in HD patients may differ from those in general HCV population. Patients' characteristics: We evaluated 33 HD kidney transplant candidates treated for chronic HCV infection, 23 males and 10 females, of average age 51 years. All patients had HCV genotype 1. The mean hemodial-ysis period was 3 years (range 1–19 years). Pretreatment liver biopsy was performed in 24 patients, 8 of whom had fibrosis stage 3 or 4 and 16 patients had stage 1 or 2. Results: We found that the distribution of IL28B genotypes was as follows: CC 30%, CT 63.5%, TT 6.5%. The mean initial viremia was 8.87x105 IU/mL (range 1.2x101 -7.2x106 IU/mL). All patients were treated with peginterferon α-2a; patients with hemoglobin level > 10 g/dL were concurrently treated with ribavirin at reduced doses. The anticipated treatment period was 48 weeks. Twenty-two patients (66.6%) achieved SVR. The planned 48-week treatment period was completed in only 21 patients, whereas 12 patients stopped treatment prematurely due to adverse events. All patients with IL28B CC genotype achieved SVR. In addition, SVR was observed in all but one patients with low initial viremia less than 100,000 IU/mL (OR 17.5, 95%, CI 1.88–16.3, P<0.001). Additional variables predicting SVR were the following: rapid virological response (P<0.001), early virological response (P<0.001) and ribavirin administration (p=0.02). Age, sex, fibrosis stage or HD duration did not determine SVR. Conclusions: In conclusion, our data strongly suggest that in HD patients, low pretreatment viremia predicts SVR with similar reliability as IL28B genotype. Therefore, low pretreatment viremia may substantially influence the treatment decision in HCV patients before enlistment for kidney transplant.

Disclosures:

The following people have nothing to disclose: Jan Sperl, Sona Frankova, Vaclav Hejda, Miroslava Volfova, Milan Jirsa, Dusan Merta, Renata Bartakova, Ondrej Viklicky, Julius Spicak

1932

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Ribavirin priming pegylated-Interferon combination therapy in chronic hepatitis C patients: study of plasma Ribavirin trough concentrations, anaemia, viral kinetic and genetic variability

Paloma Muñoz-de-Rueda1,2, Alicia Martín-Lagos1, Rosa Quiles1,2, Ana Gila1,2, Ana Belen Martín1, Esther-José Pavón-Castillero1, Elena Ruiz Escolano1, Sergio Manuel Jiménez-Ruiz1, Angeles Ruiz-Extremera3,2, Javier Salmeron1,2;
1 Unit of clinical management of digestive tract, Hospital Universitario San Cecilio, Granada, Spain; 2CIBERehd, Granada, Spain; 3Pediatric Service, Hospital Universitario San Cecilio, Granada, Spain

Aim: Ribavirin (RBV) remains essential to chronic hepatitis C (CHC) treatment. We aimed to investigate the influence of RBV priming to steady state before combined peg-IFN/RBV on viral kinetics, ALT levels, anaemia, RBV trough concentrations (RBV Ctrough), genetic variability within HCV-core, -NS5B and -NS5A, and response to antiviral therapy. Methods: Prospective cohort study. 27 CHC genotype 1 naïve patients received 4 weeks of RBV monotherapy followed by pegIFN-α-2a and RBV for 48 weeks (group A). The results were compared with a control/historical group (group B) of 27 patients undergoing combined treatment for 48 weeks. The study of mutations being done in the majority sequence of core, NS5B and NS5A (ISDR and PKRbd). Results: No differences in main baseline characteristics were found between the treatment arms. Rapid, early and sustained virological response values were 44%, 89% and 52%, respectively, in group A, and 41%, 89% and 48% in group B, with no statistically significant differences. However, in the 4-week combined treatment, group A patients showed a greater decrease in HCV-RNA (2.3 log 10 IU/mL vs 1.2 log10IU/mL; P=0.04), lower levels of Hb (12.48±1.7 g/dL vs 13.6±1.9 g/dL; P=0.039), lower levels of ALT (23.5±1.3 U/L vs 60.11 ±18 U/L; P<0.001) and higher mean RBV Ctrough (3.28±1.26 mg/L vs 1.76±0.69 mg/L; P=0.001). Did not observe variation, with respect to the baseline, in the number of mutations at week 4 of RBV monotherapy in the NS5B, ISDR, or PKRbd, however we observe a decrease of silent mutations in core region (P=0.04) (Table 1). Conclusions: A 4-week course of induction therapy, priming with RBV, does not improve SVR rates in HCV genotype 1 naïve infected patients. However, the greater reductions in viral load, Hb and ALT, and higher RBV Ctrough values at week 4 of combined treatment could reflect the greater effectiveness of the treatment. Also, RBV monotherapy does not cause an increase in the number of mutations in the majority sequence of the regions core, NS5B and NS5A (ISDR and PKRbd).

Mutations CoreBaseline4-week RBV monoterapyP
  1. Test U Mann-Whitney

Silent9.8±1.97.9±1.50.04
Non-Silentl.2±0.21.2±0.21
Mutations NS5B  P
Silent34.5±4.233.8±4.40.7
Non-Silent7.5+1.47.211.40.9
Mutations NS5A-ISDR  P
Silent10.4±1.39.911.40.5
Non-Silent3.6±0.73.310.70.9
Mutations NS5A-PKRbd  P
Silent18.74±2.318.4812.40.5
Non-Silent6.74±1.15.6210.90.3

Disclosures:

The following people have nothing to disclose: Paloma Muñoz-de-Rueda, Alicia Martín-Lagos, Rosa Quiles, Ana Gila, Ana Belen Martín, Esther-José Pavón-Castillero, Elena Ruiz Escolano, Sergio Manuel Jiménez-Ruiz, Angeles Ruiz-Extremera, Javier Salmeron

1933

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Thyroid dysfunction triggered by Peginterferon alfa-2b (peg-2b)/ Ribavirin (RBV) occurs frequently in patients with HCV mono-infection, but rarely in patients with HCV/HIV coinfection

Stefan Mauss1, Axel Baumgarten2, Dietrich Hueppe3, Hans-Jörg Cordes4, Elmar Zehnter5, Michael P. Manns6, Juergen K. Rock-stroh7, Gerlinde Teuber8, Uwe Naumann9, Christian Hoffmann10, Thomas Witthoeft11, Bernd Moeller12, Dagmar Hartmann13, Bernd Dreher13, Manfred Bilzer13; 1Medical Group Practice, Düsseldorf, Germany; 2Praxis Driesener Strasse, Berlin, Germany; 3Medical Group Practice, Herne, Germany; 4Medical Practice, Berlin, Germany; 5Gastroenterological Practice, Dortmund, Germany; 6Med-ical High School Hannover, Hannover, Germany; 7Department of Internal Medicine I, University of Bonn, Bonn, Germany; 8Gas-troenterological Practice, Frankfurt, Germany; 9Center of Medicine, Berlin, Germany;
10Infektionsmedizinisches Centrum (ICH), Hamburg, Germany; '1 1 Gastroenterological Practice, Stade, Germany; 12Medical Practice, Berlin, Germany; 13MSD Pharma GmbH, Haar, Germany

Background: Thyroiditis leading to thyroid dysfunction in patients (pts) undergoing treatment for chronic HCV infection has been attributed to interferon-stimulated immune mechanisms similar to that implicated in the antiviral response induced by interferons. Furthermore, an association between interferon-induced thyroid dysfunction and favorable SVR rates has been demonstrated. The present retrospective analysis aimed to determine factors influencing the frequency of thyroid dysfunctions in pts treated with Peg2b/RBV for HCV infection in real-world. Methods: Data from 3290 pts with HCV mono-infection and 259 pts with HCV/HIV-coinfection from two German observational real-life studies were retrospectively analyzed. Pts were treated with Peg2b 1.5 μg/kg/week plus RBV (800–1200 mg/day) for up to 48 weeks. Thyroid dysfunction was estimated by serum TSH levels. TSH levels below or above the normal range were classified as abnormal. This analysis was restricted to pts with normal TSH values at baseline and at least one TSH measurement during therapy. Results: From 2471 pts with HCV mono-infection and normal TSH at baseline, 501 patients (20.3%) developed abnormal TSH during Peg2b/RBV treatment. The incidence of TSH abnormalities was comparable in pts infected with HCV genotype (G) 1 (21.2%, 304/1436),

G2 (21.1%, 40/190) and G3 (18.6%, 157/845). TSH abnormalities were associated with female gender as indicated by a higher incidence of 26.5% vs 16.9% (female vs male) (p<0.0001), 26.3% vs 17.4% (p=0.145) and 22.4% vs 16.2% (p=0.0298) in pts with G1, G2 and G3 infection, respectively. In contrast, no association was found between the incidence of thyroid dysfunction and age (<50 vs >50 years), baseline viral load (<600.000 IU/mLvs ≧600.000 IU/mL) and platelet count (<150/nL vs ≧150/nL) as indicator of severe fibrosis or cirrhosis. Interestingly, only 7 of 143 pts (4.9%) with HCV/HIV-coinfection and documented TSH data developed thyroid dysfunction. Regarding gender, thyroid dysfunction became apparent in 1 of 27 female pts (3.7%) and in 6 of 11 6 male pts (5.2%) coinfected with HIV. Conclusions: Induction of thyroid dysfunction during treatment of HCV mono-infection occurs most frequently in female pts independent of HCV genotype and age. In contrast, IFN-triggered thyroid dysfunction occurs rarely in pts with HCV-HIV-coinfection. Whether this phenomenon reflects less responsiveness to IFN in this patient subgroup remains to be elucidated.

Disclosures:

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Dietrich Hueppe -Advisory Committees or Review Panels: Roche, MSD, Gilead, Novartis, BMS

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Juergen K. Rockstroh - Advisory Committees or Review Panels: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Abbott, ViiV, Vertex, Tibotec, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Pfizer, Abbott, ViiV, Vertex, Tibotec; Board Membership: Human Genome Sciences; Consulting: Bionor, Abbvie, Novartis, Abbott, Novartis; Grant/Research Support: Abbott, Merck, Abbott, Merck; Speaking and Teaching: Abbott, Gilead, GlaxoSmithK-line, Abbvie, Roche, Merck, ViiV, Abbott, Gilead, GlaxoSmithKline, Roche, Merck, ViiV

Gerlinde Teuber - Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

Christian Hoffmann - Advisory Committees or Review Panels: Boehringer-Ingel-heim, MSD, Janssen-Cilag, AbbVie, Gilead Sciences, Hexal AG; Speaking and Teaching: Boehringer-Ingelheim, MSD, Janssen-Cilag, AbbvVie, Gilead Sciences, Bristol Myers-Squibb

Dagmar Hartmann - Employment: MSD Germany Bernd Dreher- Employment: MSD Manfred Bilzer - Consulting: MSD Germany

The following people have nothing to disclose: Axel Baumgarten, Hans-Jörg Cordes, Elmar Zehnter, Thomas Witthoeft, Bernd Moeller

1934

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An Egyptian experience for the study of Baseline Predictors of Sustained virological response to HCV treatment in Egyptian patients infected with viral hepatitis C genotype 4

Mahasen Mabrouk, Rabab M. Salama, Hadeel G. Abdel el Moniem El Sayed;
Endemic medicine department, Kasr Al Aini hospital - Faculty of Medicine- Cairo University, Cairo, Egypt

Introduction Egypt represents the highest prevalence of HCV worldwide. Identifying Predictive factors for response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection especially those with genotype 4 may provide information to optimize and/or individualize the treatment of HCV genotype 4 infected patients, thus improving antiviral response. Aim:

To analyze the data from Egyptian chronically infected patients with HCV treated for 48 weeks with a course of Peg interferon alfa-2a and alpha-2b plus Ribavirin, to determine the baseline factors associated with SVR. Patients and Methods: Retrospective data of 3719 patients with chronic HCV who had received pegylated interferon /Ribavirin therapy in the context of the national program at Cairo-Fatemia Hospital, Egypt were retrieved. Different baseline demographic, laboratory, histo-logical (grade and stage (Metavir score)) and virological parameters were recorded before initiating treatment and response to treatment was evaluated by PCR at 12, 48 and 72 weeks of treatment. Results: The estimated sustained virological response (SVR) at week 72 was 54%. On doing Univariate and multivariate analysis of the base line factors related to SVR, the significant factors affecting response were male gender, the grade of inflammation (grade 2, 3) and base line ALT> 40 u/l with a p value < 0.01, < 0, 05 and < 0.01 respectively, as well as Viremia if > 600 IU with p < 0.05, baseline AFP> 10 ng/ml and stage of fibrosis (F2, F3, F4,) with at p <0.01. Conclusion: Male gender, low grade of inflammation, lower stages of fibrosis and lower level of viremia at base line were found to be the predictive factors that may play a significant role in achievement of sustained virological response to HCV treatment. Univariate and multivariate logistic regression analysis for baseline factors associated with failure of treatment

Disclosures:

The following people have nothing to disclose: Mahasen Mabrouk, Rabab M. Salama, Hadeel G. Abdel el Moniem El Sayed

1935

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Preliminary Experience Of Hepatitis C Genotype 1 Treatment Response With Either Telaprevir Or Bocepre-vir Based Regimen In Patients With End Stage Renal Disease On Dialysis

Kalyan R. Bhamidimarri1, Seth N. Sclair1, Melissa Franco1, Anish Patel2, Violet Copado3, Omer Junaidi3, Cynthia Levy1, Paul Martin1, Madhavi Rudraraju3;
1 Hepatology, University of Miami-Miller School of Medicine, Miami, FL; 2Gastroenterology and Hepatology, San Antonio Military Medical Center, Sam Houston, TX; 3Hepatology, Methodist Specialty and Transplant Hospital, San Antonio, TX

Introduction: Limited data exists regarding the use of telaprevir or boceprevir based regimens to treat hepatitis C (HCV) in patients with end stage renal disease (ESRD) on dialysis. Aim: To evaluate HCV treatment response with the use of telaprevir (T) or boceprevir (B) based regimens in dialysis patients. Methods: We analyzed 15 HCV genotype 1 patients with ESRD from two transplant centers, of whom 9 were undergoing evaluation for kidney- and 6 for combined liver-kidney transplantation. All patients received pegylated interferon alpha 2a (P), ribavirin (R) and either boceprevir (B) 800mg thrice daily or telaprevir (T) 750mg thrice daily. All patients treated with BPR received 1 month lead-in, P 180 micrograms weekly and R 200mg thrice weekly whereas those treated with TPR received no lead-in, P 135micrograms weekly and R 200mg- daily (12.5%), twice weekly (50%) and thrice weekly (37.5%) at the discretion of the clinician. There were several dose reductions Results: The cohort characteristics include mean age of 56 years, 73% male, 53% African-American, 60% genotype 1a, 40% cirrhosis, 100% IL28b non-CC and baseline hemoglobin of 12.3 gm/dl. There were 3 well-compensated cirrhotic patients in each group. Blood transfusion, ribavirin dose reductions, and growth factor use were higher in the TPR group compared to BPR. There was 1 virologic breakthrough in BPR that occurred within 8 weeks and 3 in the TPR group that occurred during 12–28weeks of treatment. Thirteen of the 15 patients completed response guided therapy, of which 9 achieved end of treatment response. Conclusions: Telaprevir or boceprevir based HCV treatment in this difficult-to-treat group of ESRD patients is feasible, although side effects are frequent. The overall on-treatment virologic response observed is 60% according to intention to treat. The telaprevir group had more viral break-thoughs and higher anemia grades compared to the boceprevir group.

Treatment Differences In Telaprevir And Boceprevir Groups

 BPR N=7TPR N=8
African-American42%62%
Treatment Naive71%62%
Cirrhosis43%37%
RVR eRVR6/7 6/78/8 7/8
End of Treatment Response (EOTR)4/7 2/7- ongoing Rx (Undetectable at 32 weeks)5/8
Viral Breakthrough1 (at week 8)3 (at week 12, 18, 28)
Hospitalizations28%37%
Anemia > 2gm/dl, > 4gm/dl42%, 0%50%, 25%
PRBC Transfusion14%25%
Erythropoetin Use42%75%

Disclosures:

Cynthia Levy - Advisory Committees or Review Panels: Johnson & Johnson, Novar-tis; Consulting: Lumena; Speaking and Teaching: Bayer, Vertex

Paul Martin - Consulting: Roche, BMS, Gilead, Vertex, Roche, BMS, Gilead, Vertex, Roche, BMS, Gilead, Vertex, Roche, BMS, Gilead, Vertex; Speaking and Teaching: Roche, BMS, Roche, BMS, Roche, BMS, Roche, BMS

The following people have nothing to disclose: Kalyan R. Bhamidimarri, Seth N. Sclair, Melissa Franco, Anish Patel, Violet Copado, Omer Junaidi, Madhavi Rudraraju

1936

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Comparative effectiveness and safety of boceprever and telaprevir for chronic genotype 1 hepatitis C in a community setting: interim analysis

Aimee R. Loucks2, Jim Chan3, Rita L. Hui3, Michele M. Spence4, Jean-Luc Szpakowski1;
1 Gastroenterology, Kaiser Permanente, Fremont, CA; 2Drug Information Services, California Regions, Kaiser Permanente, Oakland, CA; 3Pharmacy Outcomes Research Group, California Regions, Kaiser Permanente, Oakland, CA; 4Pharmacy Outcomes Research Group, California Regions, Kaiser Permanente, Downey, CA

Purpose The purpose of this study is to compare the effectiveness and safety of triple therapy with boceprevir (BOC) and telaprevir (TEL) and to determine how patient demographics and clinical characteristics affect outcomes. Methods Data was collected at a California integrated health care delivery system from patients undergoing treatment for hepatitis C genotype 1. All patients were treated with a triple drug regimen consisting of pegylated interferon, ribavirin, and either BOC or TEL. Patients at least 18 years of age who initiated treatment between June 2011 and November 2012 were included in this analysis. Exclusion criteria included co-infection with hepatitis B or human immunodeficiency virus and receipt of a liver transplant. The primary effectiveness endpoint for this trial was rapid virologic response (RVR),defined as an undetectable viral load after four weeks of treatment with BOC or TEL. Secondary effectiveness endpoints include end-of-treatment response (ETR) and sustained virologic response (SVR). The primary safety endpoint was premature discontinuation due to medication-related intolerance or adverse event. Patient demographics were analyzed using t-tests for continuous variables and Chi-square test for categorical variables. Effectiveness endpoints were analyzed using logistic regression and Cox-proportional hazard modeling. Discontinuation rates were evaluated using Chi-square test. Results: A total of 830 patients were included in this study. Of these, 42.2% (n=350) were treated with BOC and 57.8% (n=480) were treated with TEL. There were no significant differences in baseline characteristics between groups. RVR was achieved by 40.3% of BOC-treated and 43.3% of TEL-treated patients. There was no significant difference in RVR between BOC and TEL (Odds Ratio [OR]: 0.832, 95% Confidence Interval [CI]: 0.624–1.110); however, patients who were treatment experienced (OR:0.670, 95% CI: 0.501–0.896) and patients with cirrhosis were less likely to respond (OR:0.536, 95% CI: 0.379–0.759). Of the patients enrolled in this study, 92.3% (n=766) either completed a full course of therapy or discontinued therapy early for intolerance or treatment futility. There was no significant difference in rates of discontinuation due to intolerance or adverse effects between patients taking BOC or TEL (21.0% vs. 17.4%, p=0.226). Conclusion There was no significant difference in RVR between BOC and TEL. Discontinuation rates due to adverse effects and intolerance were not significantly different between groups. The study is ongoing with collection of data on ETR and SVR.

Disclosures:

The following people have nothing to disclose: Aimee R. Loucks, Jim Chan, Rita L. Hui, Michele M. Spence, Jean-Luc Szpakowski

1937

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Treatment of HCV genotype 1 chronic hepatitis with pegylated-interferon plus ribavirin with or without boceprevir or telaprevir: a meta-analysis of randomized controlled trials on the role of response predictors

Nicola Coppola1, Mariantonietta Pisaturo1, Caterina Sagnelli2, Evangelista Sagnelli1, Italo F. Angelillo3;
1Mental Health and Public Medicine, Second University of Naples, Naples, Italy; 22. Department of Clinical and Experimental Medicine and Surgery “F. Magrassi e A. Lanzara”, Second University of Naples, Naples, Italy; 33. Department of Experimental Medicine, Second University of Naples, Naples, Italy

Aims: to compare the efficacy of Pegylated-interferon (Peg-IFN) α-2a or α-2b and Ribavirine given as dual therapy vs. triple therapy (Peg-IFN and Ribavirine plus Boceprevir or Telaprevir) in patients with HCV-1 chronic hepatitis naïve to anti-HCV therapy or relapser to dual therapy to identify most adequate treatment strategies for patients' subgroups with high rate of Sustained Viral Response (SVR). Methods: included in the meta-analysis were studies meting these criteria: original data from randomized trials on the efficacy of dual versus triple therapy in patients naïve or relapser at least one primary outcome clearly defined, as SVR with or without Rapid Virological Response (RVR), with genotype 1a or 1 b, low or high HCV viral load, IL28-B CC or non-CC, mild or severe fibrosis; odds ratio estimates of relative risk (RR) and 95% confidence intervals (CIs); English language; published within May 2013. Results: Seven original studies and 3 post-hoc analysis met inclusion criteria, allowing a meta-analysis on 3,652 patients. Triple therapy was more effective than dual therapy, disregarding IL-28B genotype, HCV sub-genotype, liver fibrosis and baseline HCV load. In the 1,045 patients who achieved RVR, SVR was more frequently obtained with dual therapy (RR=1.11; 95% CI=1 .04–1.19, p=0.002) than with triple therapy. In naïve patients with low baseline HCV load dual and triple therapy obtained similar SVR rates (RR=0.93; 95% CI=0.83–1 .04, p=0.206). Conclusion: Triple therapy provides a significantly higher SVR rate than dual therapy, but dual therapy obtains a significantly higher SVR rate in patients with RVR. The data stress the clinical relevance of a 4 weeks lead-in phase in DAA-based treatment

Disclosures:

The following people have nothing to disclose: Nicola Coppola, Mariantonietta Pisaturo, Caterina Sagnelli, Evangelista Sagnelli, Italo F. Angelillo

1938

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Analysis of the transcriptome and immune function of monocytes during PEG-IFN-and ribavirin therapy in chronic HCV infection

Jun Hou1, Zwier M. Groothuismink1, Ludi Koning1, Wilfred van IJcken2, Harry L. Janssen1,3, Robert J. de Knegt1, Andre Boonstra1;
1Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Rotterdam, Netherlands; 2Bio-mics Center, Erasmus University Medical Center, Rotterdam, Rotterdam, Netherlands; 3Liver Clinic, Toronto Western and General Hospital University Health Network Toronto, Toronto, ON, Canada

Introduction: Although numerous in vitro studies have been performed to dissect action mechanism and target cells of IFN-alpha, detailed in vivo studies focused on monocytes in chronic HCV patients have not been performed during PEG-IFN and ribavirin therapy. Method: This study enrolled 14 chronic HCV (genotype 1) patients who received PEG-IFN-alpha weekly plus daily ribavirin for 48 weeks. Peripheral blood was collected at baseline and 12 weeks after start of therapy. Monocytes were phenotyped by flow cytometry, and purified by MACS. The function of monocytes was evaluated upon stimulation with various TLR agonists and assessed by multiplex cytokine assay. Monocytes from 6 patients were subjected to RNA sequencing (RNA-Seq). Results: Mean viral load and ALT levels at baseline were 2.3±1.9x106 IU/ml and 82.4±42.8 U/l, respectively. After 12 weeks of IFN-based treatment HCV RNA was unde-tectable in all patients (<615 IU/ml). Ten out of 14 patients showed normalization of ALT levels at week 12. The percentage of monocytes increased from 7.9±2.2% to 10.0±3.9% at week 12 (p<0.05). Stimulation of monocytes with LPS or R848 presented a similar cytokine profile, although stimulation with R848 induced higher production of GM-CSF, IL-1 b, IL-6, TNF and CCL2 as compared to LPS-stimulation. Importantly, monocytes displayed a hyperactive state upon IFN-based therapy with respect to TLR-induced cytokine production, as evidenced by increased levels of various pro-inflammatory cytokines and chemokines (FC>10). Detailed RNA-seq analysis of monocytes of HCVpatients showed that the TLR7 signaling pathway was induced by IFN-based therapy, as demonstrated by up-regulated expression of TLR7, MYD88, IRF7. In contrast, the expression of other TLR, CD1c, CLEC4C, CLEC9A was absent or retained at low levels during therapy. Moreover, transcription of CCL2, CCL4, ISG15, ISG20 and IL-10 was significantly induced by therapy. With RNA-seq we identified a group of IFNa modulated genes and biological pathways. Conclusion: The differentially expressed genes and pathways identified in this study may serve as potential targets for novel anti-HCV therapy. Our study provides important evidence that, as a consequence of PEG-IFN and ribavirin therapy, circulating monocytes are altered. Although more functional studies need to be performed, IFN-induced expression of TLR7 in chronic HCV patients may contribute to antiviral responses by induction of ISG and other immunomodulators. In addition, evaluation of the functional consequences of IFN-induced expression of TLR7 on monocytes is important for therapeutic development of TLR agonists to treat chronic viral hepatitis.

Disclosures:

Ludi Koning - Speaking and Teaching: Gilead

Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris

Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche, Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag

Andre Boonstra - Grant/Research Support: BMS, Janssen Pharmaceutics, Merck

The following people have nothing to disclose: Jun Hou, Zwier M. Groothuismink, Wilfred van IJcken

1939

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Baseline Predictors of HCV-RNA Rebound after Initial Response to Boceprevir (BOC) or Telaprevir (TPV)-based Triple Therapy in Patients with Severe Fibrosis Treated in the “Real Life”

Ana Moreno1, Carmen Quereda1, María J. Pérez-Elías1, Fernando García-Hoz2, José L. Casado1, Miguel A. Rodriguez-Sagrado3, Santos del Campo Terrón2, Fernando Dronda1, Javier Moreno2, Maria L. Mateos4, Agustín Albillos2, Santiago Moreno1, Rafael Bárcena2;
1 Infectious Diseases, Hospital Ramón y Cajal, Madrid, Spain; 2Liver-Gastroenterology, Hospital Ramón y Cajal, Madrid, Spain; 3Pharmacy, Hospital Ramón y Cajal, Madrid, Spain; 4Microbiology, Hospital Ramón y Cajal, Madrid, Spain

Background: the large CUPIC cohort in cirrhotic patients reports SVR rates after triple therapy around 40%, despite high rates of negative HCV-RNA during the first 24 weeks, and we lack information on baseline predictors of HCV-RNA rebound among responders. Objective and Methods: to describe the overall rate of HCV-RNA negativization and baseline predictors of viral rebound in 94 consecutive patients with F3/F4 fibrosis during the first year use of BOC or TPV after approval at a tertiary center in Madrid, Spain (January-December 2012). Results: TPV 66% (n=62), BOC 34% (n=32). Most were cirrhotic (86%, n=81), pretreated (77%, n=72): null responders (26%), partial responders (37%), relapsers (31%), previous breakthrough (6%). 73% male, mean age 52±8 years, 11% IL28B TT, 39% HIV/HCV-coinfected (n=37). 80% completed at least 12 weeks of triple therapy, with overall lead-in use in 36% (n=34). Baseline HCV-RNA was 6,12±0,7 log 10 IU/ml. The overall rate of HCV-RNA negativization was 81% (n=76). After a median follow-up of 28 weeks, the rate of viral rebound was 25% (n=19). By univariate analysis, baseline factors precluding HCV-RNA rebound were negative HCV-RNA at week 2 (0% vs 30%, p=0.031) or week 4 (10% vs 43%, p=0.001) and, among treated patients, prior relapse (5% vs 44%, p=0.002), whereas IL28B TT genotype (71% vs 20%, p=0.009) and a Child-Pugh score >6 (45% vs 19%, p=0.022) led to higher rates of HCV-RNA rebound. HIV-coinfection (35% vs 20%, p=0.16), genotype 1 a (42% vs 21 %, p= 0.17), peg-IFN adjustment during the first 12 weeks (39% vs 21%p=0.13), and higher baseline MELD (9±2 vs 8±2, p=0.13) or HCV-RNA (6,29±0,39 vs 6,0±0,80 log 10 IU/ml, p=0.14) showed a trend to increase the probability of HCV-RNA rebound. Cirrhosis vs F3 (p=0.27), prior peg-IFN/RBV therapy (p=0.23), gender (p=1) or age (p=0.24), peg-IFN-α2a vs α2b (p=0.77), TPV vs BOC use (p=0.27), RBV dose (p=0.99) or RBV dose-adjustment (p=0.45) did not affect viral rebound. After multivariate analysis, negative HCV-RNA at week 4 (HR 8.802, 95%CI 1.527–50.749, p=0.015) and prior relapse after peg-IFN/RBV in pretreated subjects (HR 18.222, 95%CI 1.612–206.011, p=0.019) remained as protective factors of viral rebound, whereas IL28B TT genotype showed a trend to independently lead to HCV-RNA rebound (p=0.13). Conclusions: in patients with severe fibrosis receiving triple therapy in the clinical setting, despite high rates of HCV-RNA negativization, HCV-RNA rebound reaches 25%. Early HCV-RNA kinectics and prior relapse after standard peg-IFN/RBV allow to identify those patients with the highest probability of SVR, whereas IL28B TT genotype remains as an unfavourable factor for SVR.

Disclosures:

Rafael Bárcena - Advisory Committees or Review Panels: MSD, Janssen; Consulting: MSD, Novartis

The following people have nothing to disclose: Ana Moreno, Carmen Quereda, María J. Pérez-Elías, Fernando García-Hoz, José L. Casado, Miguel A. RodriguezSagrado, Santos del Campo Terrón, Fernando Dronda, Javier Moreno, Maria L. Mateos, Agustín Albillos, Santiago Moreno

1940

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High-dose versus standard-dose weight-based ribavirin in combination with peginterferon alfa-2a for patients infected with hepatitis C virus genotype 1 or 4

Ludi Koning1, Joost Drenth2, Johannes T. Brouwer3, M. N. Apari-cio4, J. G. den Hollander5, L. C. Baak6, Pieter Honkoop7, M. Klemt-Kropp8, Harry L. Janssen1,9, Bettina E. Hansen1, Robert J. de Knegt1;
1Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, Netherlands; 2Gastroenterology & Hepatology, University Medical Center Nijmegen St. Radboud, Nijmegen, Netherlands; 3Gastroenterology & Hepatology, Reinier De Graaf Medical Center, Delft, Netherlands; 4Gastroenterology & Hepatology, Canisius Wilhelmina Hospital, Nijmegen, Netherlands; 5Internal Medicine, Maasstad Hospital, Rotterdam, Rotterdam, Netherlands; 6Gastroenterology & Hepatology, Hospital Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands; 7Gas-troenterology & Hepatology, Albert Schweitzer Hospital, Dordrecht, Netherlands; 8Gastroenterology & Hepatology, Medical Center Alkmaar, Alkmaar, Netherlands; 9Liver Centre, Toronto Western Hospital, University Health Network, Toronto, ON, Canada

INTRODUCTION Optimal ribavirin dosages are essential in achieving SVR in hepatitis C patients on dual therapy. Ribavirin will remain a cornerstone of antiviral therapy, also with the Direct Acting Antivirals. Our aim was to investigate high-dose ribavirin in combination with peginterferon alfa-2a to improve outcome in treatment naïve hepatitis C patients with genotype 1 or 4 and a high viral load (>400.000 IU/ml). METHODS We conducted a prospective, randomized, multi-center study to assess efficacy and safety of peginterferon alfa-2a (PEG-IFN) and high dose ribavirin (HDR) (25–29 mg/kg/day) vs. PEG-IFN and standard dose ribavirin (SDR)(12–15 mg/kg/day). 110 treatment-naïve patients with either genotype 1 (N= 99) or 4 (N = 11) and viral load >400.000 IU/ml were randomized 1:1 to receive 48 weeks of antiviral treatment. RESULTS Mean viral decline from baseline to week 4/12 was higher in the HDR group (2.4/3,3 vs. 2.0/2.8 log, p=0.05/0.009). In multivariate analysis, SVR was not associated with sex, age, race, cirrhosis (F3/F4 or kPa≧12), and HCV genotype. Anemia (Hb <6.8mmol/l) occurred in 39/52 (75%) patients in the HDR group and in 26/56 (46.4%) patients in the SDR group (p=0.002) requiring per protocol institution of a weekly fixed dose of epoietin beta 30.000IU. Moderate anemia (Hb <5.0mmol/l) was seen in 9/52(17.3%) patients in the HDR group and 1/56 (1.8%) patient in the SDR group (p=0.005). Severe anemia (Hb<4.0mmol/l) occurred in only one patient in the HDR group and was managed with multiple dose reductions of ribavirin and repeated red blood cell transfusions. 26 severe adverse events (SAE's) in 23 patients were reported. Most common were neutropenia (N = 10) and infections (N=7). One patient in the SDR group died during treatment from urosepsis. CONCLUSIONS High-dose ribavirin improves viral decline in the first 24 weeks of treatment and tended to improve SVR.

High dose ribavirin induces more anemia, which is manageable with appropriate administration of epoietin beta.

Virological response for both study arms (intention to treat)

 High dose ribavirin n=52Standard dose ribavirin N=58p-value
RVR (HCV RNA negative week 4)20 (38.5 %)21 (36.2%)0.81
EVR (HCV RNA negative week 12)45 (86.5%)40 (69.0 %)0.028
>2log drop at week 1249 (94.2 %)44 (75.9 %)0.008
HCV RNA negative week 2446 (88.5 %)42 (72.4 %)0.036
HCV RNA negative week 4839/51 (76.5%)37/57 (64.9%)0.19
Viral break through5/47 (10.6%)4/42 (9.5%)0.86
SVR (week 24 follow up)28/50 (56.0 %)25/57 (43.9 %)0.21

Disclosures:

Ludi Koning - Speaking and Teaching: Gilead

Harry L. Janssen - Consulting: Abbott, Bristol Myers Squibb, Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris; Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris

Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche, Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag

The following people have nothing to disclose: Joost Drenth, Johannes T. Brouwer, M. N. Aparicio, J. G. den Hollander, L. C. Baak, Pieter Honkoop, M. Klemt-Kropp, Bettina E. Hansen

1941

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Patient burden of peginterferon alfa (alfa)-based therapy among patients with chronic hepatitis C infection in Japan: Report from a 2013 national survey study

Marco DiBonaventura1, Yong Yuan2, Anupama Kalsekar2, Lewis Kopenhafer1, Ann C. Tang3, Timothy W. Victor1, Gilbert L'Italien2, Kazuaki Chayama4, Joji Toyota5, Hiromitsu Kumada6;
1Health Outcomes Practice, Kantar Health, New York, NY; 2Global Health Economics and Outcomes Research, Bristol-Myers Squibb, Lawrenceville, NJ; 3Health Economics and Outcomes Research, Bristol-Myers K.K., Tokyo, Japan; 4Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan; 5Depart-ment of Hepatology, Hokkaido P.W.F.A.C Sapporo-Kosei General Hospital, Tokyo, Japan; 6Department of Hepatology, Toranomon Hospital, Tokyo, Japan

Despite their efficacy, current treatments for hepatitis C (HCV) impose a significant burden on the patient due to their poor tol-erability profile. The aim of this study is to characterize the patient burden of HCV treatments in Japan. Data were obtained from a 2013 cross-sectional Internet survey of 733 HCV patients in Japan (68% male; mean age=55.0yrs). Patients using peginterferon alfa-based therapy (alfa patients) (n=188) were compared with untreated patients (n=365) and, among alfa patients, those with and without adverse events (AEs) were also compared using regression modeling. Outcomes included the Hepatitis Quality of Life Questionnaire and the Work Productivity and Activity Impairment questionnaire. 13.8% of alfa patients reported using triple therapy (alfa+ RBV+ TVR). Alfa patients reported significantly worse mental (MCS; Adjusted means=44.1 vs. 48.0, p<.05) and physical (PCS; Adjusted means=50.1 vs. 52.0, p<.05) component summary scores and greater overall work impairment (Adjusted means=25.6% vs. 32.7%, p<.05) relative to untreated patients. Alfa patients reported several AEs: fatigue (78.7%), flu-like symptoms (72.9%), depression/sadness (61.7%), dyspnea (60.6%), muscle weakness (59.6%), anemia (57.5%), headache (55.9%), and skin rash (54.8%). A statistically significant burden was observed for all AEs (see Table). A significant and clinically relevant burden of alfa-based therapies on patients with HCV in Japan was observed, which can partially be explained by frequent AEs, such as fatigue, flu-like symptoms and others. Additional treatment options which may avoid the AEs associated with current treatment options may significantly ease patient burden.

Adjusted means of those with and without AEs among patients on alfa-based therapy.

 MCSPCSOverall work impairment
  1. *p<.05 relative to those without the respective AE

Fatigue42.0*49.0*38.9%*
No fatigue48.552.919.5%
Flu-like symptoms41.8*48.9*38.5%*
No flu-like symptoms47.552.223.4%
Depression39.9*49.0*44.7%*
No depression48.951.219.0%
Dyspnea40.6*48.1*42.3%*
No dyspnea47.652.522.4%
Muscle weakness40.1*48.2*42.1%*
so rRevie wPanels:MS48.252.223.0%
enCila41.9*49.336.2%
No anemia45.350.532.9%
Headache39.7*48.2*43.8%*
No headache47.951.921.2%
Skin rash40.1*48.4*42.4%*
No skin rash47.351.623.0%

Disclosures:

Marco DiBonaventura - Consulting: Bristol-Myers Squibb

Yong Yuan - Employment: Bristol Myers Squibb Company

Anupama Kalsekar- Employment: Bristol Myers Squibb

Lewis Kopenhafer - Employment: Kantar Health

Ann C. Tang - Employment: Bristol-Myers Suqibb

Gilbert L'Italien - Employment: Bristol Myers Squibb; Stock Shareholder: Bristol Myers Squibb

Kazuaki Chayama - Consulting: Abbvie; Grant/Research Support: Dainippon Sumitomo, Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, Toray, BMS, MSD; Speaking and Teaching: Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, KYORIN, Nihon Medi-Physics, BMS, Dainippon Sumitomo, MSD, ASKA, Astellas, AstraZeneca, Eisai, Olympus, GlaxoSmithKline, ZERIA, Bayer, Minophagen, JANSSEN, JIMRO, TSUMURA, Otsuka, Taiho, Nippon Kayaku, Nippon Shinyaku, Takeda, AJINOMOTO, Meiji Seika, Toray

Joji Toyota - Speaking and Teaching: MSD

Hiromitsu Kumada - Speaking and Teaching: Bristol-Myers Squibb,Pharma International

The following people have nothing to disclose: Timothy W. Victor

1942

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Low platelet count and low serum albumin identify patients with a poor risk benefit ratio for triple therapy including Boceprevir or Telaprevir for chronic HCV genotype 1 infection

Benjamin Maasoumy1, Kerstin Port1, Antoaneta A. Markova1, Beat-riz Calle Serrano1, Magdalena Rogalska-Taranta1,2, Lisa Sollik1, Janina Kirschner1, Carola Mix1, Michael P. Manns1, Heiner Wede-meyer1, Markus Cornberg1;
1Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 2Infectious Diseases and Hepatology, Medical University in Bia-lystok, Bialystok, Poland

Background: Pivotal trials of HCV protease inhibitor (PI) boceprevir (BOC) and telaprevir (TLV) included only a small percentage of patients with liver cirrhosis and/or significant comor-bidities. First data from observational studies suggest that safety and efficacy of PI containing triple therapy might be limited in real life settings. Therefore a careful patient selection is crucial to ensure a reasonable risk/benefit ratio. We aimed to identify baseline predictors for treatment failure (TF) and serious adverse events (SAEs) in a real life cohort of patients treated with a triple therapy concept at a tertiary referral center. Methods: Between June and November 2011 a group of 86 HCV GT1 patients were selected for treatment with a triple therapy concept at our hepatitis outpatient clinic and included in this study. Baseline parameters were analysed retrospectively for association with TF or SAEs. Results: Mean age was 54yrs, mean platelets 158/nl. Only 27% were treatment-naïve, 86% had F3/F4-fibrosis. So far, data for final treatment outcome (SVR12) are available for 81 patients. Overall, 48 patients (59%) experienced a TF. HCV GT1a (OR 3.7;p<0.05), baseline serum albumin (S-ALB) <40g/dl (OR 5.5;p<0.01) and a platelet count <110/nl (OR 6.2;p<0.01) were significantly associated with TF. In contrast, patients with IL28B CC (OR 6.5;p<0.05) and age<40yrs (OR 12.7;p<0.01) had higher chances for SVR. TF was independent from BOC or TLV. Mean treatment duration was 31 months. During this time 38 SAEs were documented in 24 patients. Most common SAE was severe anemia (37%) followed by severe infections (16%). Three deaths occurred, two due to GI sepsis, possibly associated to antiviral therapy. Predictive factors for SAEs during therapy were a pre-treatment FibroScan result >30kPa (OR 4.4;p<0.05), platelet counts <110/nl (OR 7.5;p<0.001) and S-ALB <40g/dl at baseline (OR 7.7;p<0.001). Patients with baseline platelets >110/nl and S-ALB >40g/dl had a reasonable risk/benefit ratio with 0.2 SAEs per achieved SVR. In contrast, in those 12 patients with both risk factors eleven SAEs were documented but only a single patient achieved SVR (11 SAEs per SVR). Conclusions: Safety and efficacy of PI containing triple therapy is limited in the real world of a tertiary referral center. We here identified S-ALB <40g/dl and platelet count <110/nl as the most valuable baseline predictors to identify patients with a poor risk/benefit ratio. More efficient and safer treatment options are expected in the near future. Thus patients with such risk factors should only be considered for currently available treatment options in the presence of other strong positive predictors.

Disclosures:

Benjamin Maasoumy-Advisory Committees or Review Panels: Abbott Molecular; Speaking and Teaching: MSD, Roche Diagnostics, Roche Pharma

Kerstin Port - Speaking and Teaching: Roche

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achi ll ion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

Markus Cornberg - Advisory Committees or Review Panels: Merck (MSD Ger-mamny), Roche, Gilead, Novartis; Grant/Research Support: Merck (MSD Ger-mamny), Roche; Speaking and Teaching: Merck (MSD Germamny), Roche, Gilead, BMS, Novartis, Falk

The following people have nothing to disclose: Antoaneta A. Markova, Beatriz Calle Serrano, Magdalena Rogalska-Taranta, Lisa Sollik, Janina Kirschner, Carola Mix

1943

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Analysis of the usefulness of HCV core amino acid substitution, serum IP-10 level and IFNL4 genotype as the predictive factor of anti-HCV effect in triple therapy including protease inhibitor

Yoshiyasu Karino1, Tomoaki Nakajima1, Itaru Ozeki1, Shuhei Hige1, Mutuumi Kimura1, Tomohiro Arakawa1, Yasuaki Kuwata1, Takahiro Sato1, Takumi Ohmura1, Joji Toyota1, Hidenori Ochi2, Daiki Miki2, Kazuaki Chayama3;
1 Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan; 2Integrative Medical Science, RIKEN Center, Hiroshima, Japan; 3Medicine & Molecular Science, Hiroshima University, Hiroshima, Japan

Background and aims: The clinical effect of the hepatitis C improved by an appearance of Triple therapy including protease inhibitors drastically, but a poor effect case still exists. We examined the predictability of the anti-HCV effect by aa substitution of HCV core 70 which is the virus factor and serum IP -10 and IFNL4 gene which are the host factors. Methods: 112 patients (male: 61 cases, female: 51 cases, median age: 59 years old) with genotype 1 who received triple therapy of peg-interferon/ribavirin/ protease inhibitor were examined. All cases were genotype 1 b except one genotype 1 a case. Twenty-five cases of them received triple therapy including simeprevir (100mg/day). And 89 cases of them received triple therapy including telaprevir (TVR). The initial TVR doses (1500mg/day or 2250mg/day) were adjusted according to the Japanese guidelines for the treatment of hepatitis B and C. In all cases, aa substitution of HCV core 70 and dinucleotide variant of IFNL4 (ss469415590: TT or ΔG) were measured. Serum IP-10 was measured using stored serum immediately before the initiation of therapy. We used HCV RNA negative conversion of the fourth week (RVR) and 12 weeks of sustained viral response (SVR12) for an index of the antivirus effect. Results: of 112 cases, 43 cases had aa substitution of HCV core 70 (mutant), 65 cases hadn't, and 4 cases couldn't classified. Serum IP-10 showed a wide distribution (median: 433pg/ml, range: 131–4840). IFNL4 was genotyped as TT/TT (64 cases), TT/ΔG (46 cases) and ΔG/ΔG (2 cases), and divided in two groups (TT: major genotype, non-TT: non-major genotype). About the achievement of RVR, core aa 70 wild was 81.5% and mutant was 79.0% (NS), IFNL4 major was 87.5% and non-major was 70.8% (P=0.028). About the achievement of SVR12, core aa 70 wild was 81.4% and mutant was 80.6% (NS), IFNL4 major was 91.4% and non-major was 67.5% (P=0.0027). As for the value of serum IP-10, there was not a difference whether achieved RVR or did not and whether achieved SVR12 or did not (541.2 vs 559.5, 556.0 vs 552.7, respectively). Even limiting to IFNL4 non-major cases, SVR12 rate did not have a difference between core aa 70 wild cases and mutant cases (65% vs 70%). Conclusions: Amino acid substitution of HCV core 70 and serum IP-10 level did not become the effective prediction factor in Triple therapy including protease inhibitors, may be because of powerful anti-HCV effect of triple therapy. IFNL4 genotype is a useful predictive factor of clinical effect, but can expect approximately 70% of SVR rate even if it is IFNL4 non-major genotype.

Disclosures:

Joji Toyota - Speaking and Teaching: MSD

Kazuaki Chayama - Consulting: Abbvie; Grant/Research Support: Dainippon Sumitomo, Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, Toray, BMS, MSD; Speaking and Teaching: Chugai, Mitsubishi Tanabe, DAIICHI SANKYO, KYORIN, Nihon Medi-Physics, BMS, Dainippon Sumitomo, MSD, ASKA, Astellas, AstraZeneca, Eisai, Olympus, GlaxoSmithKline, ZERIA, Bayer, Minophagen, JANSSEN, JIMRO, TSUMURA, Otsuka, Taiho, Nippon Kayaku, Nippon Shinyaku, Takeda, AJINOMOTO, Meiji Seika, Toray

The following people have nothing to disclose: Yoshiyasu Karino, Tomoaki Nakajima, Itaru Ozeki, Shuhei Hige, Mutuumi Kimura, Tomohiro Arakawa, Yasuaki Kuwata, Takahiro Sato, Takumi Ohmura, Hidenori Ochi, Daiki Miki

1944

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Frequency of Core/NS5A amino acid substitutions and impact on PegIFN/Ribavirin dual therapy in European patients infected with HCV genotype 1 a/b

Kai-Henrik Peiffer, Simone Susser, Dany Perner, Caterina Fueller, Stefan Zeuzem, Christoph Sarrazin;
J. W. Goethe University, Medi-zinische Klinik 1, Frankfurt am Main, Germany

Background/Aims: HCV genotype (GT) 1 infected patients treated with dual therapy (PegIFN/R) achieve SVR in approx. 50%. Several studies mainly from Japan show significant correlations between mutations in HCV NS5A/Core and response to PegIFN/R treatment in GT1 b infected patients. Four or more mutations in IFN-sensitivity determining region (ISDR) enhance IFN-response. Despite lower incidences of these mutations in Europe this correlation was also observed in large European GT1 b cohorts but has not been examined in GT1a infected patients so far. However, amino acid substitutions in Core at position 70 (R to Q) and 91 (L to M) correlate with virologic failure in Japanese patients. Frequency and impact in European and GT1a infected patients is largely unknown. Methods: Pre-treatment samples were obtained from 71 HCV GT1 a and 109 GT1 b infected patients who received PegIFN/R combination therapy (INDIV-2 cohort). Substitutions in core (aa1–191) and in ISDR (aa2209–2248), according to HCV-J prototype sequence, were determined by population-based sequencing. Absence of mutations in ISDR was defined as wild-, 1–3 mutations as intermediate- and >4 mutations as mutant-type. Findings were correlated with treatment outcome. Results: Replacement of glutamine at a70 in HCV core was found in 25% (27/107) of GT1 b but could not be found in GT1 a (0/71) samples. Methio-nine polymorphism at a91 was found in the majority of GT1 b (72%) but only rarely (1 %) in GT1 a samples. Likelihood of treatment failure was not significantly increased in GT1 b infected patients with the 70Q or the 91M substitutions in comparison to patients with arginine and leucine at these locations (59 vs. 50% (p=0.503) and 51 vs. 52% (p=1.0), respectively). Also the combination of both substitutions (70Q/91M) did not show an increased risk for virologic failure (50%). Wild-type ISDR was found in 19% of GT1 a and 42% of GT1 b infected patients. An intermediated-type was found in 72% of GT1a and 57% of GT1 b infected patients. A mutant-type was found only in few patients (1% in GT1 b and 9% in GT1a). Overall, likelihood of treatment failure to PegIFN/R did not significantly differ in the examined groups (wild: 63% vs. intermediate: 60% vs. mutant: 71%) and irrespective of the genotype. Conclusion: Substitutions at a70 and a91 in HCV core were found frequently in HCV GT1 b infected patients but did not correlate with treatment failure to dual therapy in our European cohort. In GT1a samples these mutations were not frequently observed. ISDR mutant-types were found infrequently in both genotypes (GT1a > 1 b). Likelihood of treatment failure did not significantly vary in wild-, intermediate- and mutant-types.

Disclosures:

Stefan Zeuzem - Consulting: Abbvie, Achillion Pharmaceuticals, Boehringer Ingel-heim GmbH, Bristol-Myers Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen, Roche Pharma AG, Vertex Pharmaceuticals, Presidio, Santaris, Inc

Christoph Sarrazin - Advisory Committees or Review Panels: Boehringer Ingel-heim, Vertex, Janssen, Merck/MSD, Gilead, Roche, Boehringer Ingelheim, Achillion, Janssen, Merck/MSD, Gilead, Roche; Consulting: Merck/MSD, Novartis, Merck/MSD, Novartis; Grant/Research Support: Abbott, Intermune, Roche, Merck/MSD, Gilead, Janssen, Abbott, Roche, Merck/MSD, Vertex, Gilead, Janssen; Speaking and Teaching: Bristol-Myers Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Falk, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Falk, Boehringer-Ingelheim

The following people have nothing to disclose: Kai-Henrik Peiffer, Simone Susser, Dany Perner, Caterina Fueller

1945

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Telaprevir-Based-Therapy in HIV/HCV with advanced liver fibrosis in a community setting

Moises Garcia, Mary Busalacchi, Anton Strunets;
Aurora Health Care, Milwaukee, WI

Hepatitis C virus (HCV) co-infection is common among HIV patients. Effective HIV treatment has resulted in drammatic survival; however, HCV-related liver disease is a major cause of mortality. Teleprevir (TVR) is a HCV NS3/4A protease inhibitor, in combination with PEG-IFN/RBV is approved in HCV monoin-fected patients. However, its safety and efficacy in patients with HCV and HIV-1 con-infection are unknown especially when advance liver fibrosis is present. We report our experience using TVR based therapy in HIV/HCV co-infected patients with advance liver fibrosis in an community clinic in Milwaukee. PATIENTS: 90 patients with HIV were followed. Out of this group 16 patients (23%) ages 40–63 were coinfected with HCV. 12 patients (13%) with HIV-1 on highly active retroviral regimens (HAART) with HCV genotype 1 and advanced liver fibrosis were treated with TVR plus PEG-IFN-α2a-ribavirin for 24–48 weeks. In order to be considered for treatment, patient must have been on HAART, have undetectable HIV viral load for at least 6 months, be free of any active opportunistic infection, active drug abuse, opioids abuse, acute psychosis or depression, and have variceal and hepatocellular carcionoma screening. They were treated independently of the CD4 count. RESULTS: Sustained virologic response (SVR) occurred in 75% (9 out of 12) of patients. Two of the non-responders withdrew before completing the treatment both due to non-compliance with follow-ups. One patient was a true non-responder. All patients had anemia and received erythropoetin with simulta-neouse adjustment in Ribavirin dose. 58% (7 in 12) received blood transfusions. Pruritus, and hemorrhoids were observed in 41% (5 in 12) of all patients. Rapid HCV suppression (as defined by undetectable HCV RNA levels by week 4) were seen in all responders. There was a significant reduction on CD4, WBC, Hemoglobin and platelets counts during treatment. 8 out of 12 patients used protease inhibitor-based HAART. Two patients developed mild liver decompensation but achieved SVR with a shorter duration of therapy. CONCLUSION: Treatment of HIV/HCV co-infected patient with advanced liver fibrosis is possible with TVR-based therapy in a community clinic setting with higher SVR than described in historical controls on PEG-RBV regimen with significant but manageable rates of com-pications.

Disclosures:

The following people have nothing to disclose: Moises Garcia, Mary Busalacchi, Anton Strunets

1946

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The effect of interferon/ribavirin/telaprevir therapy on innate immune responses (natural killer cells) and on adaptive immune responses (helper T cell (Th1, Th2 and Th17) and regulatory T cell) in chronic hepatitis C patients

Ikuo Nakamura1,2, Takeharu Asano2, Shinichi Asabe2, Katsutoshi Sugimoto1, Yasuharu Imai1, Fuminori Moriyasu1, Michio Imawari3;
1Department of Gastoenterology and Hepatology, Tokyo Medical University, Tokyo, Japan; 2Saitama Medical Center, JIchi Medical University, Saitama, Japan; 3Shinyurigaoka General Hospital, Kawasaki, Japan

Aim : HCV is one of the most important agents of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. So far, the combination therapy of pegylated-interferon, ribavirin and protease inhibitor is one of the most effective treatment for chronic hepatitis C. The response of this treatment (SVR vs Non-SVR) might be related to the immune responses, that are composed of innate and adaptive immune responses. The aim of this study is to examine the effect of the therapy on innate immune responses (NK activity, frequency of NK cell (CD56dim and CD56brightNK cell) in peripheral blood) and adaptive immune responses (frequency of helper T cell (Th1, Th2 and Th17) and regulatory T cell (Treg) and FoxP3(+)Treg in peripheral blood) in chronic hepatitis C patients. Patients and Methods : In twenty three chronic hepatitis C patients, the combination therapy of pegylated-interferon and ribavirin with or without telaprevir was performed. Just before and at 3 months of the therapy and 6 months after the therapy, NK cell activity and the frequency of NK cell (CD3-/CD56+), CD56dimNK cell and CD56brightNK cell in peripheral blood were estimated by Cr release assay(E/T=20) and flowcytometry. Additionally, the frequency of helper T cell (Th1 (CD4+/IFNγ+), Th2(CD4+/IL4+) and Th17(CD4+/IL17+)), Treg (CD4+/CD25+ and CD4+/CD25+/FoxP3+) were estimated by flowcytometry. Statistical analysis was performed by ANOVA and Mann-Whitney U test. Informed consent was obtained from each patient. Results : The analysis by AOVA showed that NK activity significantly improved at 6 months after the treatment compared with before therapy(p<0.05). It also showed that frequency of CD56brightNK cell was significantly increased at 6 months after the treatment (p<0.05) . Furthermore, frequency of Th1 and that of Th2 cells were significantly increased at 6 months after the treatment (p<0.05, p<0.01). And frequency of FoxP3(+) Treg cell was significantly increased at 6 months after the therapy (p<0.05). In addition, NK activity ratio (6 months after the Tx/ before Tx) in SVR group was higher compared with that in Non-SVR group by analysis using Mann-Whitney U test(p<0.05). Conclusion : The combination therapy of pegylated-interferon and ribavirin with or without telaprevir in chronic hepatitis C patients improved NK activity in innate immune responses by increasing the frequency of CD56brightNK cell. In addition, this therapy changed the frequency of Th and FoxP3(+) Treg cells in adaptive immunity. Further analyses on these effect in immune responses might be useful for the development of more effective therapy for chronic hepatitis C.

Disclosures:

Michio Imawari - Advisory Committees or Review Panels: Shionogi Pharmaceutical Co.; Consulting: Ajinomoto; Speaking and Teaching: Tanabe Mitsubishi Pharmaceutical Co., Yansen Pharma, Dainippon Sumitomo Pharmaceutical Co., Taisho Toyama Pharmaceutical Co., Tohre, Meiji Seika Pharma, GSK, MSD, Dai-ichi Sankyo, Chugai Pharmaceutical Co., Takeda Pharmaceutical Co., Ehzai

The following people have nothing to disclose: Ikuo Nakamura, Takeharu Asano, Shinichi Asabe, Katsutoshi Sugimoto, Yasuharu Imai, Fuminori Moriyasu

1947

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24 week treatment of former relapse, HCV genotype 1 infected patients with telaprevir in combination with peginterferon alfa 2a/ribavirin - experiences under real life conditions

Klaus H. Boeker1, Ralph Link2, Axel Baumgarten3, Albrecht Stoehr4, Renate Heyne5, Martin Roessle6, Eckart Schott7, Rainer Ullrich8, Peter Erren9, Christoph Herold10, Wolfgang Schmidt1 1, Karl-Georg Simon12, Michael Geissler13, Willi Schiffelholz14, Ulrich Alshuth15, Dietrich Hueppe16, Stefan Mauss17; 1Center for Hepa-tology, Hannover, Germany; 2MZV Offenburg, Offenburg, Germany; 3mib Dienstleistung GmbH, Berlin, Germany; 4ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany; 5Liver and study center Checkpoint, Berlin, Germany; 6Gastrointestinal and Endocrinological Center, Freiburg, Germany; 7Dept. of Gastroen-terology, Hepatology, Charité Campus Virchow Klinikum, Berlin, Germany; 8Center of Gastroenterology, Krefeld, Germany; 9MVZ Portal 10, Muenster, Germany; 10Center of Internal Medicine, Nuremberg, Germany;
1 1MVZ Aerzteforum Seestrasse, Berlin, Germany; 12Center of Gastroenterology, Leverkusen, Germany; 13Department of Oncology and Gastroenterology, Municipal Hospital Esslingen, Esslingen, Germany; 14Center of Gastroenterology, Augsburg, Germany; 15Virology, Roche Pharma AG, Grenzach-Wyhlen, Germany; 16Center of Gastroenterology, Herne, Germany; 17Center for HIV and Hepatogastroenterology, Duesseldorf, Germany

Introduction: Although in pivotal trials of telaprevir (TVR) a shorter treatment duration of 24 weeks was not explored for relapse patients, FDA and EMA approved reduction of treatment duration to 24 weeks, if patients achieve an extended RVR (eRVR) *. Are the physicians aware of this option and is a continuous monitoring of these patients doable under real life conditions? Methods: Between October 2011 and April 2013 >1900 genotype 1 patients treated with TVR containing triple therapy were included in the non-interventional study PAN conducted by the Association of German Gastroenterologists in Private Practice (bng) and Roche. Data of 287 former relapse patients with simultaneous start of TVR and peginterferon alfa 2a/ribavirin before April 2012 and with complete data up to week 24 were analyzed. Precision of measuring HCV-RNA at week 4 was set to +/- 5d and of week12 to +/- 10d. Results: Demographic mean data were: age 51.5 yrs, male gender 65.5%, BMI 26.7 kg/m2, ALT 96.7 IU/l. 15.3% of patients had liver cirrhosis (at least one result of sonography, histology, elastography or clinical appearance). 66.6% of patients had high viral load (>400,000 IU/ml), distribution of GT-1 subtypes was 24.0% 1a, 50.9% 1 b, 0.7% other and 24.4% unknown. Virological responses, treatment discontinuation and valid HCV-RNA measurement rates are shown in the table. Only 181 /268 (67.8%) Patients on therapy had a valid HCV-RNA determination at week 4 and 12 to assess eRVR. Of those 67/77 (87.0%) reached an eRVR. In a subgroup of patients having already reached week 24 after EOT 48 of 51 patients with a HCV-RNA value at w4 and w12 had eRVR and of them 91.7% achieved SVR. Rates of anemia < 10 g/dl and < 8.5 g/dl were 27.5% and 6.7% during the first 12 weeks and 25.9% and 10.2% after week 12. Conclusion: In accordance with a parallel study in treatment naïve patients in this cohort ~25% of patients in weeks 4, 12 and 24 had no valid or assignable HCV-RNA as recommended in the label. Here is a clear potential to optimize monitoring and therapy regime resulting in an improved treatment outcome. Patients who achieve eRVR had low discontinuation rates in total and high chance to reach SVR. So adequate monitoring of treatment and shortening therapy is associated with high treatment efficacy in daily routine. * J Liu et al, Hepatology 2013;57:897–902

Virological efficacy of week 4, 12, 24 , 24 as EoT and Follow-up after 24 weeks of treatment

 Visits completedvalid HCV-RNA (=100%Discontin-uations in total (%)viral load undetectable and/or<10 IU/ml(%)valid HCV-RNA at w4and w12 (=100%viral load undetectable and/or<10IU/ml(%)
week 42872083.870.7  
week 122872146.686.018170.2
week 2428721414.584.618175.1
Eot week 24107818.691.46195.1
follow up after 24 wtx83776.587.05188.2

Disclosures:

Klaus H. Boeker - Speaking and Teaching: MSD, Roche, Janssen, Gilead, BMS, Falk Foundation, Novartis

Albrecht Stoehr - Board Membership: MSD, Böhringer Ingelheim; Speaking and Teaching: Janssen, MSD, Gilead, Abbvie, Böhringer Ingelheim

Eckart Schott - Advisory Committees or Review Panels: Gilead, Roche, Bayer, BMS; Speaking and Teaching: Gilead, Novartis, Roche, MSD, Bayer, Falk, BMS

Christoph Herold - Speaking and Teaching: Roche Pharma Gemany, BMS Pharma Germany, MSD Pharma Germany, Gilead Pharma Germany, Novartis Pharma Germany, Roche Pharma Gemany, BMS Pharma Germany, MSD Pharma Germany, Gilead Pharma Germany, Novartis Pharma Germany

Karl-Georg Simon - Speaking and Teaching: Roche, Janssen-Cilag, BMS Ulrich Alshuth - Employment: Roche

Dietrich Hueppe - Advisory Committees or Review Panels: Roche, MSD, Novatis, Gilead, BMS

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

The following people have nothing to disclose: Ralph Link, Axel Baumgarten, Renate Heyne, Martin Roessle, Rainer Ullrich, Peter Erren, Wolfgang Schmidt, Michael Geissler, Willi Schiffelholz

1948

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Elevated glucose, metabolic syndrome and diabetes predict lower treatment response to triple therapy with telaprevir in HCV

Elmar Jaeckel1, Christine John2, Renate Heyne3, Gerlinde Teuber4, Willi Schiffelholz5, Stefan Christensen6, Christoph Antoni7, Stefan Pape8, Martin Roessle9, Hanns-Friedrich F. Loehr10, Klaus H. Boeker11, Andreas Schober12, Thomas Lutz13, Harald-Robert Bruch14, Stefan Mauss15, Hermann Steffens16, Ulrich Alshuth17, Michael P. Manns18;
1Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany; 2Center of Gastroenterology, Berlin, Germany; 3Liver and study center Checkpoint, Berlin, Germany; 4IFS, Interdisziplinaeres Facharztzentrum Sachsenhausen, Frankfurt/M, Germany; 5Center of Gastroenterology, Augsburg, Germany; 6Center for Interdisciplinary Medicine (CIM), Muenster, Germany; 7II. Medizinische Uni-versitaetsklinik, Universitaetsmedizin Mannheim, Mannheim, Germany; 8Center of Gastroenterology, Paderborn, Germany; 9Gastrointestinal and Endocrinological Center, Freiburg, Germany; 10Center of Gastroenterology, Wiesbaden, Germany; 11Center for Hepatology, Hannover, Germany; 12Center of Gastroenterology, Goettingen, Germany; 13Infektiologikum, Frankfurt/M, Germany; 14Center of Gastroenterology, Bonn, Germany; 15Center for HIV and Hepatogastroenterology, Duesseldorf, Germany; 16Practice for internal Medicine, Berlin, Germany; 17Virology, Roche Pharma AG, Grenzach-Wyhlen, Germany; 18Dept. of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany

Background: While markers of the metabolic syndrome were associated with a lower treatment to dual therapy with PEG-interferon alfa-2a 180μg/ ribavirin, similar associations were not seen in phase III studies involving triple therapy with telaprevir. These data were generated by a German-wide, observational study conducted by the German gastroenterologists in private practice in cooperation with Roche since 2011. Within this observational study metabolic risk factors are investigated in patients receiving triple therapy of telaprevir, PEG-interferon alfa-2a and 180μg/ ribavirin. Results: Within this interim analysis data of 421 patients who completed follow-up were evaluated for metabolic risk markers. 63.2% were male, median age was 48.7 years, median BMI 25.9 kg/m2, 25.2% of patients had an BMI >28. Duration of infection was 17.2 years, 20.7% of patients had blood glucose levels >100mg/dL. Rapid (RVR), early (EVR) or sustained virological response were defined as HCV-RNA negative or <10IU/mL at week 4 or 12 during or at least 12 weeks after therapy, respectively. RVR rates were decreased for patients with a HbA1c>6% (30.8 vs. 67.3%), diabetes (40.9 vs. 66.0%) and HDL-levels below 40mg/dl (35.7 vs. 67.1%). Metabolic markers pre therapy had no significant influence on EVR rates. Astonishingly, metabolic markers had a marked influence on SVR rates in this real world setting, which was not reported before. Patients with pre-diabetic alterations of glucose metabolism showed already reduced SVR rates: SVR was reduced for patients with fasting glucose levels >100mg/dl (43.9 vs. 64.1%) or HbA1c> 6.0% (30.8 vs. 59.7%). Overt diabetes decreased SVR rates 27.3% compared to 55.7% in patients without diabetes. In addition SVR was also reduced by other signs of the metabolic syndrome: SVR was reduced with triglyceride levels >150 mg/dl (37.5 vs. 55.8%), HDL levels <40 mg/dl (23.5 vs. 60.5%) and presence of hypertension (43.8 vs. 56.8%). Conclusions: Alterations in glucose metabolism, diabetes and the metabolic syndrome are substantially decreasing the SVR rate in patients being treated for their HCV infection with a telaprevir based triple therapy. These results from a real world observational trial were not reported in the phase III trials. They identify hard to treat patients for which other therapies will be needed in the future.

Disclosures:

Elmar Jaeckel - Consulting: Roche Pharma AG

Gerlinde Teuber - Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Stefan Christensen -Advisory Committees or Review Panels: Roche, BMS, Abbott, Janssen, Schering Plough, ViiV, Gilead, MSD, Boehringer Ingelheim; Speaking and Teaching: Gilead, MSD, Roche, BMS, Schering Plough, ViiV, Boehringer Ingelheim, Janssen

Christoph Antoni - Speaking and Teaching: Roche, MSD, BMS

Klaus H. Boeker - Speaking and Teaching: MSD, Roche, Janssen, Gilead, BMS, Falk Foundation, Novartis

Thomas Lutz - Advisory Committees or Review Panels: Gilead, MSD, Abbott, BMS, Janssen Cilag; Grant/Research Support: Boehringer Ingelheim, Gilead, GlaxoSmithKline, Schering-Plough, Roche, MSD, Abbott, Janssen Cilag; Speaking and Teaching: Boehringer Ingelheim, GlaxoSmithKline, Roche, BMS

Stefan Mauss - Advisory Committees or Review Panels: Roche, Gilead, BMS, Janssen, Boehringer Ingelheim; Speaking and Teaching: Janssen, Roche, MSD, Gilead, BMS, Boehringer Ingelheim

Ulrich Alshuth - Employment: Roche

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

The following people have nothing to disclose: Christine John, Renate Heyne, Willi Schiffelholz, Stefan Pape, Martin Roessle, Hanns-Friedrich F. Loehr, Andreas Schober, Harald-Robert Bruch, Hermann Steffens

1949

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KIR, HLA, and a genetic variant of IL28B are associated with a virological response to PEG-IFN/RBV therapy for chronic hepatitis C

Takeji Umemura1, Yuichi Nozawa1, Satoru Joshita1, Yoshihiko Kat-suyama2, Eiji Tanaka1, Masao Ota3;
1Medicine, Shinshu University School of Medicine, Matsumoto, Japan; 2Pharmacy, Shinshu University Hospital, Matsumoto, Japan; 3Legal Medicine, Shinshu University School of Medicine, Matsumoto, Japan

Background & Aims: Natural killer cell responses have been shown to play a crucial role in the innate immune system for virus clearance. Since the killer immunoglobulin-like receptor (KIR), in combination with its cognate human leukocyte antigen (HLA) ligand, is associated with treatment-induced and spontaneous clearance of hepatitis C virus (HCV) infection, we examined the impact of KIR, HLA, and IL28B SNP on the response to pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in a Japanese population. Methods: We investigated 16 KIR genotypes along with HLA-B and -C ligands and a genetic variant of IL28B (rs8099917) in 115 chronic hepatitis C genotype 1b patients who underwent PEG-IFN and RBV therapy. Results: Sustained virological response (SVR) rates were significantly decreased in patients with KIR2DL2 and KIR2DS2 (P = 0.015; odds ratio [OR] 0.30 and P = 0.025; OR 0.32, respectively). In contrast, the centrometric A/A haplotype of KIR was associated with an SVR (P = 0.015; OR 3.95). Univariate analysis showed that IL28B TT genotype, KIR3DL1-HLA-Bw4, KIR2DL2/HLA-C1, white blood cell count, hemoglobin level, and HCV RNA viral load were all associated with an SVR. Mul-tivariate logistic regression analysis subsequently identified IL28B TT (P = 0.00013; OR 6.44), KIR3DL1/HLA-Bw4 (P = 0.016; OR 2.93), and KIR2DL2/HLA-C1 (P = 0.002; OR 0.14) as independent predictive factors of an SVR. In patients with the IL28B TT genotype, the SVR rates in those with and without KIR3DL1/HLA-Bw4 were 67% and 56%, respectively, whereas in patients with IL28B non-TT, the SVR rates in those with and without KIR3DL1/HLA-Bw4 were 41% and 14% (P = 0.0023). Conversely, in patients with IL28B non-TT genotype, the SVR rates in those with and without KIR2DL2/HLA-C1 were 0% and 33%, respectively, but in patients with IL28B TT, the SVR rates with and without KIR2DL2/HLA-C1 improved to 40% and 68% (P = 0.001). We also noted a significant correlation between the frequency of KIR2DL2 and serum aminotransferase. Conclusions: Combinations of KIR3DL1/HLA-Bw4, KIR2DL2/HLA-C1, and a genetic variant of the IL28B gene are predictive of the response to PEG-IFN and RBV therapy in Japanese patients infected with genotype 1 b HCV.

Disclosures:

Eiji Tanaka - Grant/Research Support: MSD pharmaceutical company, Chugai pharmaceutical company, Glaxo Smith Kline Chugai pharmaceutical company, Bristol Mayers Chugai pharmaceutical company, Sumitomo pharmaceutical company, Banyu pharmaceutical company, Takeda pharmaceutical company, Oht-suka pharmaceutical company, Daiichi Sankyo Ohtsuka pharmaceutical company, Tanabe Mitsubishi Ohtsuka pharmaceutical company, Ajinomoto pharmaceutical company; Speaking and Teaching: MSD pharmaceutical company, Chugai pharmaceutical company, Bristol Mayers Chugai pharmaceutical company, Sumitomo pharmaceutical company, Ohtsuka pharmaceutical company, Tanabe Mitsubishi Ohtsuka pharmaceutical company, Ajinomoto pharmaceutical company

The following people have nothing to disclose: Takeji Umemura, Yuichi Nozawa, Satoru Joshita, Yoshihiko Katsuyama, Masao Ota

1950

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Prevalence of resistance mutations against NS3 protease inhibitors in patients with hepatitis C virus genotype 1 b and response to telaprevir plus pegylated-interferon-alpha 2b and ribavirin combination therapy

Kazuhiko Hayashi, Yoshiaki Katano, Takashi Honda, Teiji Kuzuya, Yoji Ishizu, Masatoshi Ishigami, Hidemi Goto;
Gastroenterology, Nagoya University, Nagoya, Japan

OBJECTIVES: Telaprevir (TPV), a NS3 protease inhibitors has improved the sustained virological response (SVR) rate in combination with peginterferon (Peg-IFN) and ribavirin (RBV) but has induced resistance variants. These mutations became important problems. The viral population would be dominated by the strains with the resistant mutations during the course of treatment. It has been suggested that generation of resistance mutations against TPV is the result by selection of preexisting minor resistant strains because development of resistance mutations emerge shortly after starting therapy. This might be one reason for treatment failure. However, little was known about these mutations and effect on response to TPV combination therapy. The aim of this study was to investigate whether the preexisting of resistance variants against TPV by direct sequencing and ultradeep amplicon pyrosequencing affect the response to TPV plus Peg-IFN and RBV combination therapy. METHODS: Fifty seven patients with HCV genotype 1b were enrolled. Patients received Peg-IFN -alpha 2b once each week plus oral RBV and TPV daily for 24 weeks. Identification of resistance mutations in the NS3 region by the ultradeep amplicon pyrosequencing using GS FLX Titanium technology was performed. Alignment to reference strain and SNP candidate detection were performed using GS Amplicon Variant Analzer. The NS3 region was also examined by direct sequencing. Detection of the SNPs of IL28B was done by a real-time PCR system. RESULTS: There are 4 patients had resistant variants (V36I, T54S, T54S, and S138L) to TPV before therapy by direct sequence. The minor resistance variants (V170M, V36D+T54I) detected by ultradeep sequencing were found in 2 patients without mutation by direct sequence. Of the 57 patients, 48 (84.2%) showed rapidly virologic response (RVR), with HCV-negativity, at 4 weeks. TPV resistance mutations by both direct and ultradeep sequencing were not related to RVR on univariate analysis. 73.3% patients achieved SVR. There were no significant differences in SVR according to IL28B genotypes and drug resistance mutations. Three patients were reappeared HCV and one of 3 patients had emerged T54S mutation which was resistance to TPV. One patient had viral breakthrough at week 8 and detected V36M variants. The resistant variants by both direct and ultradeep sequencing at pretreatment could not be found in all patients who acquired resistant variants through the therapy. CONCLUSIONS: The identification of drug-resistant HCV variants by direct and ultradeep sequencing at pretreatment was not associated with response to Peg-IFN, RBV and TPV therapy in patients with HCV genotype 1 b.

Disclosures:

Kazuhiko Hayashi - Grant/Research Support: MSD, Astra Zenaca

Hidemi Goto - Grant/Research Support: MSD, Roche, Bayer, Bristol-Myers

The following people have nothing to disclose: Yoshiaki Katano, Takashi Honda, Teiji Kuzuya, Yoji Ishizu, Masatoshi Ishigami

1951

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Muscle adiposity influences viral response to pegylated interferon plus ribavirin treatment in patients with genotype 1 chronic hepatitis C

Michiaki Okada, Toshihiko Mizuta, Yoichiro Kitajima, Yasunori Kawaguchi, Shinji Iwane, Yasushi Ide, Yuichiro Eguchi, Keizo Anzai, Iwata Ozaki;
Internal Medicine, Saga University Hospital, Saga, Japan

Background: Resent studies have indicated that insulin resistance (IR) is associated with the virologic response of interferon treatment to chronic hepatitis C (CHC). We previously reported that visceral adiposity could worsen antiviral effect of pegylated interferon plus ribavirin (PEG-IFN+RBV) treatment (AASLD 2010). Therefore, we examined whether skeletal muscle steato-sis as an ectopic adiposity, which is known to be associated with IR, could influence the efficacy of PEG-IFN+RBV treatment. Patients and Methods: Ninety-one CHC patients with genotype 1 b and high viral load treated with PEG-IFN+RBV for 48 weeks were examined. Visceral fat area (VFA) was measured at the umbilical level on abdominal CT. We quantified skeletal muscle steatosis by using the attenuation rate of multifidus muscle/subcutaneous fat (intra-muscular adipose tissue content, IMAC), which also evaluated by same CT slice. We used two methods to evaluate IR: HOMA-IR and the whole-body insulin sensitivity index (WBISI). Age, sex, BMI, AST, ALT, γ-GTP, glucose tolerance class, HOMA-IR, WBISI, VFA, histological inflammation, fibrosis and steatosis and IMAC were analyzed for their association with the sustained virologic response (SVR) using logistic regression models. Results: Overall, the SVR rate was 49.5%. Age <60 (OR: 4.2, P = 0.005), HOMA-IR <2 (OR: 3.8, P = 0.013), WBISI >6 (OR: 3.5, P = 0.008), fibrosis stage 0–2 (OR: 3.6, P = 0.062), VFA <80 (OR: 3.3, P = 0.027) and IMAC <-0.4 (OR: 3.6, P = 0.002) were closely associated with SVR by univariate analysis. Multivariate analysis showed that age (OR: 3.7, P = 0.004), WBISI (OR: 4.3, P = 0.004), and IMAC (OR: 3.4, P = 0.015) were independently associated with SVR. Conclusions: Skeletal muscle steatosis might cause resistance to PEG-IFN+RBV treatment in CHC patients. This result suggests that exercise and/or diet might improve response to antivairal therapy.

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Disclosures:

The following people have nothing to disclose: Michiaki Okada, Toshihiko Mizuta, Yoichiro Kitajima, Yasunori Kawaguchi, Shinji Iwane, Yasushi Ide, Yuichiro Eguchi, Keizo Anzai, Iwata Ozaki

1952

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Composition of serum fatty acids may be associated with the antiviral effects of interferon-based therapy in patients with hepatitis C virus infection

Teruki Miyake1, Masashi Hirooka1, Yoshio Tokumoto1, Takao Watanabe1, Teru Kumagi1, Masanori Abe1, Shinya Furukawa2, Morikazu Onji3, Bunzo Matsuura1, Yoichi Hiasa1;
1 Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan; 2Department of Public Health, Ehime University Graduate School of Medicine, Toon, Japan; 3Sai-seikai imabari hospital, Imabari, Japan

Background and aims: Hepatitis C virus (HCV) core protein has effects on fatty acid synthesis, and fatty droplets in the liver are related to development of hepatitis. Although there have been reports on the role of fatty acids in the liver of patients with HCV infection, the relationship between serum fatty acid level and efficacy of interferon (IFN)-based antiviral therapy against HCV remains unclear. This study aimed at evaluating whether the serum fatty acid levels affect the virological response of IFN-based therapy in HCV infection patients, and at identifying these effects using an in vitro assay. Methods: We enrolled 55 patients (27 men and 28 women, mean age 53.6±11.2 years) with HCV infection who received IFN-based therapy at Ehime University Hospital. We evaluated patient characteristics, laboratory data including fatty acids levels, and viral factors that may be associated with the anti-HCV effects of IFN-based therapy, and then confirmed this association using transfected cultured cells expressing H77orJFH1 HCV clones in vitro. Results: Multivariate logistic regression analysis showed that serum palmitic acid levels before treatment and the HCV genotype were significant predictors of rapid virological response, early virological response, and sustained virological response. High palmitic acid levels inhibited the anti-HCV effects of IFN-based therapy. The effect of palmitic acid on HCV replication was assessed in vitro. In both cell lines, HCV RNA levels were not altered by the addition of palmitic acid alone. However, addition of palmitic acid weakened the anti-HCV effects of IFN and ribavirin (RBV) (P = 0.028 and P = 0.038 for H77 and JFH1, respectively; Wilcoxon test). Moreover, other saturated fatty acids such as myristic acid and stearic acid and unsaturated fatty acids such as oleic acid did not have any effects on HCV replication or efficacy of treatment with IFN and RBV. Conclusion: The serum palmitic acid level is an independent predictor of the virological response to IFN-based antiviral therapy. Thus, the efficacy of IFN-based antiviral therapy in patients with HCV infection may be enhanced by the alteration of serum palmitic acid levels.

Disclosures:

The following people have nothing to disclose: Teruki Miyake, Masashi Hirooka, Yoshio Tokumoto, Takao Watanabe, Teru Kumagi, Masanori Abe, Shinya Furukawa, Morikazu Onji, Bunzo Matsuura, Yoichi Hiasa

1953

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Drug-Drug Interactions between Boceprevir and Cal-cineurin Inhibitors in Genotype 1 Hepatitis C Virus Liver Transplant Recipients

Travis B. Dick, Alissa A. Raines;
Department of Pharmacy, Inter-mountain Medical Center, Murray, UT

Recurrent hepatitis C virus (HCV) is the most frequent complication following liver transplant for patients with HCV. Boceprevir (BOC) is a protease inhibitor FDA approved to treat genotype 1 HCV and improves treatment outcomes in combination with pegylated interferon and ribavirin in the non-transplant population, but no studies exist in liver transplant recipients. BOC inhibits cytochrome P450 enzymes which can affect calcineurin inhibitor concentrations. At our center, we implemented a HCV treatment protocol consisting of cyclosporine (CsA) monotherapy for rejection prevention followed by a 4 week lead-in with pegylated interferon alfa-2a and weight-based ribavirin. BOC was added at week 5 and continued in combination with interferon and ribavirin for an additional 44 weeks. The purpose of this study is to describe the drug-drug interactions of BOC and calcineurin inhibitor therapy in post liver transplant recipients undergoing protease inhibitor based triple therapy for HCV. Six liver transplant recipients, all HCV genotype 1 and previous non-responders to interferon and ribavirin therapy were enrolled in the protocol. At the time of BOC initiation, calcineurin inhibitor doses were decreased empirically to avoid supratherapeutic concentrations. Upon discontinuation of BOC, calcineurin inhibitor doses were increased empirically and trough concentrations were monitored closely. Five patients received CsA monotherapy to prevent rejection while 1 received tacrolimus due to an increase in liver function tests with associated cholestasis while on CsA. In this case an empiric decrease in tacrolimus dose of 75% was associated with an increase in tacrolimus concentration of 18% after BOC initiation. Upon BOC discontinuation, a 100% increase in tacrolimus dose was associated with an increase in tacrolimus trough concentration of 6%. Table 1 describes changes in CsA doses and associated trough concentrations upon both initiation and discontinuation of BOC therapy. In conclusion, the drug-drug interaction between both CsA and tacrolimus with BOC is significant and unpredictable. We recommend judicious monitoring of calcineurin inhibitor concentrations when both starting and stopping BOC therapy to avoid calcineurin inhibitor toxicity and/or rejection.

Table 7. Changes in CsA doses and concentrations at the beginning and end of BOC therapy.
TimingAverage Empiric Dose Adjustment % (Range %)*Associated CsA Trough Change % (Range %)*
  1. *Negative numbers denote decreases and positive numbers increases.

BOC initiation (n=5)-22 (-50 to 50)3 (-45 to 19)
BOC discontinuation (n=4)31 (-25 to 50)-20 (-87 to 36)

Disclosures:

The following people have nothing to disclose: Travis B. Dick, Alissa A. Raines

1954

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Retreatment of chronic Hepatitis C genotype 1 (G1) infection with Boceprevir (Victrelis®) in the German real-life setting: interim analysis from the non-interventional NOVUS study

Peter Buggisch1, Hanns F. Loehr2, Gerlinde Teuber3, Hermann Stef-fens4, Michael R. R. Kraus5, Christine John6, Peter R. Geyer7, Bernd Weber8, Thomas Witthoeft9, Andreas Herrmann10, Mark Hoesl11, Uwe Naumann12, Tarek Dahhan13, Dagmar Hartmann14, Bernd Dreher14, Manfred Bilzer14; 1ifi Institute, Hamburg, Germany; 2Gastroenterological Practice, Wiesbaden, Germany; 3Gastroen-terological Practice, Frankfurt, Germany; 4Practice of Internal Medicine, Berlin, Germany; 5Medical Department II, Klinikum Burghausen, Burghausen, Germany; 6Practice of internal Medicine, Berlin, Germany; 7Gastroentorological Practice, Fulda, Germany; 8Medical Practice, Kassel, Germany; 9Gastroenterological Practice, Stade, Germany; 10Friedrich-Schiller-University, Jena, Germany;
1 1Gastroenterological Practice, Nürnberg, Germany; 12Center of Medicine, Berlin, Germany; 13 Gastroenterological Practice, Fellbach, Germany; 14MSD Pharma GmbH, Haar, Germany

Background: Triple therapy with the HCV protease inhibitor boceprevir (Victrelis®) in combination with pegylated interfer-ons (PegIFN) and ribavirin (RBV) has recently been approved as new standard of care for previously untreated and treatment-experienced patients with chronic Hepatitis C genotype 1 (G1) infection. The non-interventional observational NOVUS study was conducted to investigate the efficacy and safety of this novel and more complex therapeutic approach in the German real-life setting. Methods: From April 2012 until May 2013, 374 patients with G1 infection were recruited in the ongoing NOVUS study by 85 practices and hospital ambulances in Germany. The present interim analysis was restricted to 95 treatment-experienced patients undergoing triple therapy with boceprevir who completed 8 weeks of retreatment including a 4 week lead-in period with PegIFN/RBV. Results: Overall, 33%, 17%, 20% and 8% of the treatment-experienced patients had a previous relapse, partial response, null-response and breakthrough while previous virologic response was unknown in 18%. Median age of patients was 53 years and 62% were older than 50 years. 56% were male, median BMI was 26.0 kg/m2, 6.3% and 2.1% were coinfected with HIV and HBV and 8.4% were opioid user under stable substitution. HCV G1 subtypes were distributed as follows: G1a 31%, G1b 47%, unknown 20%. High baseline viral load >800.000 IU/ml was found in 54% of patients. 8.4% had one diagnostic measure consistent with liver cirrhosis, while 22% had baseline platelet count <150/nL. Mean duration of lead-in with PegIFN/RBV was 30±6 days. At the end of treatment week (TW) 4, a HCV-RNA decline >1 log10 was achieved by 70% of patients. Among patients with evaluable data, 62.3% (43/69) had undetectable HCV-RNA at TW8. The proportion of patients with hemoglobin values below 10 g/dL at TW8 was 21.0%. Conclusions: This interim analysis from the NOVUS observational study shows promising early virologic response rates after completion of 8 weeks of retreatment of HCV G1 infection with boceprevir in real-life. Results of this ongoing study will be presented together with week 12 response rates which are still under investigation.

Disclosures:

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

Gerlinde Teuber - Advisory Committees or Review Panels: MSD, Gilead Sciences, Roche Pharma; Speaking and Teaching: MSD, Gilead Sciences, Janssen-Cilag, Roche Pharma

Michael R. R. Kraus - Advisory Committees or Review Panels: Schering-Plough, Roche; Consulting: Schering-Plough, Roche

Bernd Weber - Advisory Committees or Review Panels: Molteni Farmaceutici; Speaking and Teaching: Roche Pharma AG, Janssen Cilag, Reckitt Benckiser, Sandoz, Lundbeck Pharma, Sanofi-Aventis

Uwe Naumann - Speaking and Teaching: MSD, Roche, BMS, Abbott, VIIV, Janssen

Dagmar Hartmann - Employment: MSD Germany Bernd Dreher - Employment: MSD Manfred Bilzer - Consulting: MSD Germany

The following people have nothing to disclose: Hanns F. Loehr, Hermann Steffens, Christine John, Peter R. Geyer, Thomas Witthoeft, Andreas Herrmann, Mark Hoesl, Tarek Dahhan

1955

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Antiviral activity and safety of a reduced dose of telaprevir with peginterferon and ribavirin in patients with chronic HCV genotype 1 b infection

Akihiko Oshige1, Akio Ido1, Seiichi Mawatari1, Kunio Fujisaki2, Susumu Hasegawa2, Masafumi Hashiguchi2, Takeshi Hori3, Kazuhiro Sakurai3, Hiroka Onishi3, Kaori Ohno1, Eriko Toyokura1, Kazuaki Tabu1, Dai Imanaka1, Kotaro Kumagai1, Tsutomu Tamai1, Akihiro Moriuchi1, Hirofumi Uto1, Makoto Oketani1, Hirohito Tsub-ouchi4;
1Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; 2Department of Gastroenterology, Kirishima Medical Center, Kirishima, Japan; 3Department of Gastroenterology, Kagoshima Teishin Hospital, Kagoshima, Japan; 4HGF tissue repair and regenerative medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

Background: Antiviral activity and adverse events (AEs) of combination therapy with telaprevir, peginterferon alfa-2b and ribavirin (TPR) were evaluated in patients with chronic hepatitis C virus (HCV) genotype 1 b infection. Methods: The subjects were 56 patients with chronic infection with genotype 1 b HCV who received telaprevir (TVR), peginterferon alfa-2b (Peg-IFN), and ribavirin (RBV) for 12 weeks, followed by Peg-IFN and RBV for 12 weeks. Of these patients, 39 (66.1 %) meeting the criteria of age >60 years old, female, body weight <50 kg, and Hb <14 g/dL received a reduced dose of TVR (1500 mg/day). Results: Of the 56 patients, 42 (75.0%) received TPR for 24 weeks, while 14 (25.0%) discontinued the treatment because of viral breakthrough (3.6%) or AEs, including anemia (7.1%) and skin manifestations (7.1%). Of the patients treated with TPR for 24 weeks, 28 (90.3%) exhibited a sustained viral response 12 weeks after the treatment (SVR12). There was no significant difference in the rate of SVR12 between males and females or between patients aged <60 and >60 years old. A decrease in the initial dose of TVR did not reduce the incidences of AEs and cessation, but patients given a low dose of TVR had a higher rate of SVR12 (1500 vs. 2250 mg/day TVR: 90.5% vs. 90.0%, p=0.97). The rates of SVR12 were significantly higher in patients with the IL28B rs8099917 TT allele compared to those with IL28B TG or GG alleles (100% vs. 66.7%, p<0.05) and in those with wild type HCV core 70aa compared to mutant HCV core 70aa (100% vs. 71.4%, p<0.05). Patients with the ITPA rs1127354 CC allele showed a significantly greater decrease in Hb in weeks 2 and 4 of TPR treatment, in comparison with those with ITPA CA or AA alleles (% decrease in Hb in patients with ITPA CC vs. CA or AA: -13.5% vs. -4.0% in week 2, p<0.001; and -25.2% vs. -12.9%, p<0.001 in week 4). Among all 56 patients, 26 (46.4%) and 47 (83.9%) had increased serum levels of creatinine and uric acid, respectively, a few days after initiation of TPR treatment. Of 19 patients with hyperuricemia in whom uric acid clearance was examined, 18 showed a decrease in urinary excretion of uric acid, indicating that TVR has an effect on renal function that may be associated with hyperuricemia, even without an increase in serum creatinine. Conclusions: A reduced initial dose of TVR did not reduce the incidences of AEs and cessation, but antiviral activity was also unaffected by the dose reduction. An ITPA single nucleotide polymorphism was associated with anemia at an early stage of TPR treatment. It is also important to monitor the levels of serum creatinine and uric acid a few days after the start of this treatment.

Disclosures:

Makoto Oketani - Grant/Research Support: Bristol-Myers Squibb

Hirohito Tsubouchi -Grant/Research Support: MSD, Chugai Pharmaceutical, Kan Research Institute, Daiichi-Sankyo, Eisai, Tanabe Mitsubishi; Speaking and Teaching: MSD, Tanabe Mitsubishi

The following people have nothing to disclose: Akihiko Oshige, Akio Ido, Seiichi Mawatari, Kunio Fujisaki, Susumu Hasegawa, Masafumi Hashiguchi, Takeshi Hori, Kazuhiro Sakurai, Hiroka Onishi, Kaori Ohno, Eriko Toyokura, Kazuaki Tabu, Dai Imanaka, Kotaro Kumagai, Tsutomu Tamai, Akihiro Moriuchi, Hirofumi Uto

1956

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Sustained virologic esponse to Telaprevir or Boceprevir in previously non responder HCV genotype 1 patients with severe liver fibrosis : results of a prospective multi-centric study

Laurent Alric1,2, Mathieu Guivarch1, Emilie Berard1, Sophie Metivier1, Karl Barange1, Florence Nicot1, Florence Abravanel1, Delphine Bonnet1;
1 Digestive, CHU Purpan, Toulouse, France; 2UMR 152, Toulouse, France

Aims : to assess in the real life practice the sustained virologic response (SVR) to Telaprevir (TELA) or Boceprevir (BOCE) in combination with PegIFN+ ribavirin in HCV genotype 1 patients with severe liver fibrosis (F3 or F4) previously nonre-sponder to PegIFN+ribavirin. Patients and methods : 125 consecutive patients were treated prospectively during 48 weeks with TELA or BOCE + PegIFN+ribavirin by a network of hepato-gastroenterology practitioners from academic hospital, general hospital and private clinic. The free choice of triple therapy was given to each investigator according to the standard treatment schedules without randomization. METAVIR score of fibrosis was F3 (n=35, 28%), F4 (n=90, 72%) Child score A in 98.4%. HCV genotype 1 subtype was 1a (31.2%), 1b (56.8%), 1 (12%). At base line HCV RNA value was 6.3 ±0.7 Log UI/ mL. Previous response to PegIFN+ribavirin was null response : 62.9%, relapse: 37.1 %. A triple therapy was given with TELA in 90 patients (72%) and with BOCE in 35 patients (28%). SVR was assessed in intent to treat, 24 weeks after the end of therapy. Results: the overall SVR rate was 59.2% and was significantly higher in the TELA group 66.3% than in the BOCE group 44.1 % (p = 0.026, OR = 2.49 [1.1, 1.5] in uni-variate analysis. SVR was significantly greater in previously relapsers (80.4%) to PegIFN+ribavirin than null responders (47.4%), p<0.0005, OR = 4,5 [1.9,10.7]. A decrease of HCV RNA level(Log UI/mL), 4 weeks after TELA or BOCE therapy was greater (- 5.96 ± 0.9) in patients with SVR than in those without SVR (- 4.49 ± 1.8), p<0.001, OR = 2.22 [1.54,3.18]. SVR was not significantly influenced by : subtype 1a vs 1 b, IL28B genotype, viral load at baseline, liver fibrosis F3 vs F4, a decrease of Ribavirin dosage or anemia. In multivariate analysis, SVR was significantly associated with only 2 factors : previous response to PegIFN+ribavirin therapy (relapsers vs non responders), (OR = 4.57 [1.6,1.29], p<0.0042) or the drop of HCV RNA 4 weeks after TELA or BOCE therapy, (OR = 2.17 [1.4,3.1] p<0.001). These 2 factors were also associated to SVR in TELA or BOCE subgroups. Conclusions : In real life practice, difficult to treat patients have a SVR of 59.2% after TELA or BOCE triple therapy. SVR was only influenced by the type of response to previous PegIFN therapy or the extent of HCV RNA drop after 4 weeks of protease inhibitors therapy. The trend of a difference of SVR between BOCE and TELA treatment needs to be confirmed in a large randomized study.

Disclosures:

Sophie Metivier - Speaking and Teaching: Roche, BMS, Janssen, MSD

The following people have nothing to disclose: Laurent Alric, Mathieu Guivarch, Emilie Berard, Karl Barange, Florence Nicot, Florence Abravanel, Delphine Bonnet

1957

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Paradoxical progression of anemia at delayed phase of triple therapy with telaprevir for ITPA non-CC patients with chronic hepatitis C

Shuhei Hige, Yoshiyasu Karino, Mutuumi Kimura, Tomohiro Arakawa, Tomoaki Nakajima, Yasuaki Kuwata, Itaru Ozeki, Takahiro Sato, Takumi Ohmura, Joji Toyota;
Hepatology, Sapporo-Kosei General Hospital, Sapporo, Japan

Backgrounds and aims:ITPAgene polymorphism was found to be associated with anemia induced by PEG-IFN and ribavirin (RBV) combination therapy. Recently, telaprevir (TVR) has been introduced into the new combination therapy. However, the impact of TVR on the occurrence of anemia has not been fully elucidated. While hemoglobin (Hb) reduction is thought to be mild for patients with anemia-protective type of ITPA SNP, we have found those cases showed unexpected progression of anemia during triple therapy with TVR. In this study, we investigated the mechanism of this paradoxical progression of anemia. Methods: Seventy genotype-1 b patients were treated with PEG-IFNα-2b, RBV and TVR (P/R/T). Another 70 patients who had received PEG-IFN and RBV (P/R) combination therapy were selected to match the condition of gender, age and ITPA genotypic status. (39 males, mean age of 56.3 and 54 ITPA-CC cases in each group.) Genotypes of IL28B(rs1297860) and ITPA(rs1127354) were measured by real-time PCR. Concentration of TVR and RBV was measured by HPLC. Initial dose of PEG-IFNα-2b and RBV was determined based on body weight (BW) or the ratio of systemic clearance relative to bioavailabil-ity (CL/F). Dose of TVR was assigned 2250mg or 1500mg daily. Results: Mean Hb levels at 0/4/8/12 weeks were 13.7/10.8/10.0/10.1 g/dl for ITPA-CC cases and 13.6/12.0/10.0/9.5 for ITPA-non-CC cases for P/R/T. Initial dosage of TVR per BW was correlated with TVR concentration at week 1 (r=0.51, p<0.01) and the degree of decrease in glomerular filtration rate during the 1st week (r=0.25, p<0.01). Change in CL/F during the 1st week was correlated with RBV concentration at week 1 (r=0.30 p<0.01). Mean RBV levels at 1/2/4 weeks were 1147/1780/2387 ng/ml for overall P/R cases, 1382/2179/2164 for ITPA-CC P/R/T cases and 1009/2109/2563 for ITPA-non-CC P/R/T cases. Mean RBV adherence for the first 4 weeks for 100%, 92.5% for non-CC and CC P/R cases and 86.5% and 55.4% for non-CC and CC P/R/T cases. Five of 16 (31.3%) of ITPA-non-CC patients discontinued the P/R/T therapy by 12weeks while no ITPA-non-CC patients stop the P/R therapy. Conclusion: In the triple therapy with telaprevir, patients with anemia-protective type of ITPA SNP tended to show the progression of anemia relatively late because the dose adjustment of drugs delayed owing to maintained Hb levels despite of high RBV concentration. Attention should be paid especially to skinny or elderly cases.

Disclosures:

Joji Toyota - Speaking and Teaching: MSD

The following people have nothing to disclose: Shuhei Hige, Yoshiyasu Karino, Mutuumi Kimura, Tomohiro Arakawa, Tomoaki Nakajima, Yasuaki Kuwata, Itaru Ozeki, Takahiro Sato, Takumi Ohmura

1958

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Does Vitamin B12 Supplementation Works for Sustained Viral Response Rates in Patients with Chronic Hepatitis C?

Goktug Sirin, Omer Senturk, Altay Celebi, Sadettin Hülagu;
Gas-troenterology, Kocaeli University Medical Faculty Hospital, Kocaeli, Turkey

INTRODUCTION: Vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication in invitro conditions. AIMS: We aimed that to evaluate the effect of vitamin B12 on viro-logical response parameters and whether is the discriminative efficacy of pretreatment B12 serum levels (s-B12) on end-of-treatment viral response (ETVR) and SVR (sustained viral response ) in patients with HCV. Thirty-two patients with HCV were randomly assigned to receive pegylated interferon alpha-2a (Peg- IFN) plus ribavirin (Standard dual antiviral therapy;SDAT1) or STAD plus vitamin B12 (STAD1+B12). Another thirty-two patients with HCV were randomly assigned to receive pegylated interferon alpha-2b (Peg-IFN) plus ribavirin (Standard dual antiviral therapy;SDAT2) or STAD plus vitamin B12 (STAD2+B12). Viral response,as, undetectable serum HCV RNA was assessed 4 weeks after starting therapy (rapid viral response;RVR), 12 weeks after starting therapy (complete early viral response; cEVR) and 24( for genotype 2) or 48 (for genotype 1 )weeks after starting therapy (ETVR), and 24 weeks after completing therapy (sustained viral response; SVR). Serum samples for B12 analysis were collected and stored at -80 °C immediately prior to the start of treatment. The B12 levels in serum samples were analysed at the Kocaeli University Laboratory using clinical routine methods. Genotyping for the interleukin 28 B (IL-28 B) polymorphism was performed in all of the HCV genotype 1 patients (58/64). RESULTS: Distribution of genotype IL-28 B did not differ between the four groups. SVR difference were not detected between the four groups of patients. cEVR and ETVR were minimally higher in both STAD+B12 groups, and RVR in STAD1+B12 group; but this was not statistically significant . Pretreatment s-B12 levels were correlated to ETVR using univariate analysis. S-B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s-B 12 was 321 pM in ETR and 228 pm in non-respon-ders (NR) (P = 0.010). The results of the multivariate analysis were as follows: Pretreatment s-B12 > 385vs<385 pm: OR 28.6 CI 2.42–321, P = 0.008. Fibrosis stage 3–4 vs 0–2: OR 0.36 CI 0.064–1.23, P = 0.051 .The SVR rate was significantly higher in carriers of IL-28 B CC genotype polymorphism and in patients who have low baseline viral load. CONCLUSION: B12 is involved in suppression of viral replication during anti-HCV treatment. But vitamin B12 supplementation does not significantly improves SVR rates, although cEVR and ETVR were minimally higher,but were not statistically significant, in both STAD+B12 groups.

Disclosures:

The following people have nothing to disclose: Goktug Sirin, Omer Senturk, Altay Celebi, Sadettin Hülagu

1959

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Triple anti-viral C therapy with Boceprevir or Telaprevir in HIV/HCV coinfected patients after liver transplantation

Teresa Maria Antonini1,2, Elina Teicher3,4, Stéphanie Haïm-Boukoza5,2, Audrey Coilly1,2, Mylene Sebagh6,2, Valerie Furlan7, Laurence Bonhomme-Faivre8, Anne-Marie Roque-Afonso5,3, Daniel Vittecoq4, Didier Samuel1,2, Anne-Marie Taburet7, Jean-Charles Duclos-Vallee1,3;
1Centre Hepato-Biliaire, AP-HP, Hopital Paul Brousse, Villejuif, France; 2Unit 785, Inserm, Villejuif, France; 3UMR-S785, Univ Paris-Sud, Villejuif, France; 4Service des Maladies Infectieuses, AP-HP, Hopital de Bicetre, Villejuif, France; 5Ser-vice de Virologie, AP-HP, Hopital Paul Brousse, Villejuif, France; 6Laboratoire Anatomie Pathologique, AP-HP, Hopital Paul Brousse, Villejuif, France; 7Pharmacie Clinique, AP-HP, Hopital de Bicetre, Villejuif, France; 8Pharmacie Clinique, AP-HP, Hopital Paul Brousse, Villejuif, France

Background: HCV recurrence affects post-transplant survival of HIV/HCV coinfected patients. Protease inhibitors (PI), Boceprevir (BOC) and Telaprevir (TPV), in combination with peg-inter-feron/ribavirin improved sustained virological response rate in HCV genotype 1 patients. Aim: To describe the results of triple anti-viral C therapy in HIV/HCV coinfected patients after liver transplantation (LT). Patients and Methods: Between January 2011 and November 2012, 7 HIV/HCV coinfected patients (genotype 1a n=4, 1 b n=3), male: 86%, mean age 50 years [44–56]), with severe HCV recurrence (F2 n = 1, according to METAVIR score or fibrosing cholestatic hepatitis (n = 6)) were treated by anti-viral C triple therapy with BOC (n=2) or TPV (n=5) immediately (n=3) or after a 4-weeks lead-in phase (n=4). The delay between LT and PI initiation was 28 months [2–77]. Five pts (72%) were non- responders to a previous course of dual therapy after LT. Immunosuppression was based on cyclosporine (n=5) and tacrolimus (n=2), mycophenolate mofetyl was combined to calcineurine inhibitors in 4 pts. In all patients HIV viral load (VL) was undetectable before landing triple therapy. Results: At baseline, total bilirubin, GGT, ALAT, haemoglobin, HCV VL and CD4 count were 45 μmol/L [10–136], 500 IU/L [153–1135], 126 IU/L [37–282], 13 g/dL [11.5–14], 7log10 IU/mL [6.2 to 8.6] and 222 giga/L [60–380], respectively. After 4 weeks (w) of PI, a rapid virological response was observed in 4 pts (57%) (BOC n = 0, TPV n = 4). Before BOC or TPV introduction cART when containing PI (n=3), was changed to avoid drug-drug interaction (n=2). After 12 w of PI, an extended rapid virological response was observed in 4 (57%) TPV pts. One pt had early discontinuation of triple therapy (w12) because of null non- response in the BOC group and 3 pts (BOC n=2, TPV n=1) experienced early discontinuation of therapy at 4, 8 and 15 w of triple therapy because of severe infection (pneumonia n=2, herpetic keratitis n=1). All pts had anemia (nadir haemoglobin 8.7 g/dL), requiring erythropoietin (EPO) and ribavirin reduction (mean reduction of 400 mg per day), 4 pts required red blood cell transfusions. The tacrolimus dose was reduced by 18,7 fold [22.5–15] with TPV, no pt received tacrolimus and BOC. The ciclosporine dose was reduced by 0,15 fold [0–0,3] and 6 fold [3–7.5] with BOC and TPV, respectively. Conclusion: An extended rapid virological response was observed in 57% (4 pts) in our study (SVR=1, ongoing therapy n=2). Anemia was most common adverse event (100%). Interactions between PI, calcineurin inhibitors and cART were manageable.

Disclosures:

Audrey Coilly - Speaking and Teaching: Gilead, BMS, Janssen, MSD, Roche, Novartis, Astellas

Didier Samuel - Consulting: Astellas, BMS, Gilead, Janssen-Cilag, LFB, MSD, Novartis, Roche, Biotest

The following people have nothing to disclose: Teresa Maria Antonini, Elina Teicher, Stéphanie Haïm-Boukoza, Mylene Sebagh, Valerie Furlan, Laurence Bonhomme-Faivre, Anne-Marie Roque-Afonso, Daniel Vittecoq, Anne-Marie Taburet, Jean-Charles Duclos-Vallee

1960

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NS3-resistance in advanced HCV patients treated with BOC/TRV-based therapy: impact on virological failure of baseline and early time points

Valeria Cento1, Velia Chiara Di Maio1, Daniele Di Paolo2, Daniele Armenia1, Valeria Micheli3, Monica Tontodonati4, Francesco Paolo Antonucci1, Maria Concetta Bellocchi1, Ada Bertoli2, Francesco De Leonardis2, Giordano Madeddu5, Carlo Magni6, Cesare Sar-recchia2, Lorenzo Nosotti7, Annalisa Tortora8, Antonio Di Biagio9, Laura Ambra Nicolini9, Giustino Parruti10, Sergio Babudieri5, Giu-liano Rizzardini6, Mario Angelico2, Carlo Federico Perno1, Francesca Ceccherini-Silberstein1;
1 University of Rome Tor Vergata, Rome, Italy; 2University Hospital of Rome “Tor Vergata”, Rome, Italy; 3 Unit of Microbiology, Hospital Sacco of Milan, Milan, Italy; 4G. D'Annunzio″ University, Chieti-Pescara, Infectious Disease Clinic, Chieti, Italy; 5University of Sassari, Italy, Sassari, Italy; 6Divi-sion of Infectious Disease, Hospital Sacco of Milan, Milan, Italy; 7San Gallicano Hospital, Rome, Italy; 8Catholic Hospital “Gemelli”, Rome, Italy; 9S. Martin Hospital, Genoa, Italy; 10Pescara General Hospital, Pescara, Italy

Background: Aim of this study is to investigate the clinical relevance of baseline and early genotypic-resistance-test in HCV-infected patients with advanced-disease treated with triple-therapy. Methods: 96 patients (GT1a/1 b/1g=35/60/1; previous nonresponders/relapsers/naïve/unknown=57/25/11/3; with cir-rhosis=45) were treated with pegIFN/ribavirin+boceprevir (BOC, N=29) or telaprevir (TVR, N=67). IL-28-genotype was available for 70 patients (14.3%=CC; 70.0%=CT; 15.7%=TT). NS3-protease resistance associated variants (RAVs) at baseline, early time points during treatment (48h-2weeks) and viral failure were analyzed by population sequencing (PS) and ultra-deep 454-pyrosequencing (UDPS, cutoff=0.1%; in a subgroup of patients). Results: In this interim analysis, the median(IQR) follow-up time for patients treated with BOC was 37(21–57)weeks and with TVR 29(21–50)weeks. Viral failure was observed in 27/96(28.1%) patients, always with RAVs and in association with previous non-response to pegIFN/ribavirin (21/27 patients, 77.8%). HCV-RNA value at week-2 (available for 44 TVR-treated patients) was predictive of viral failure: 0/9 patients with undetectable HCV-RNA failed treatment vs. 2/20 patients with HCV-RNA<100IU/ml and vs. 8/15 with >100IU/ml (p=0.002). By PS, 6/79 (7.6%) patients presented baseline RAVs (5=T54S, and 1=V36L). Within 2 weeks, 7 patients showed ex novo RAVs, one patient already having T54S baseline (1=T54A48h, 1=V36M48h, 1 =T54Sbase-line+R155K48h, 2=A156T72h, 1 =A156V+R155Tw1, 1=V36M+R155Kw2). Out of 10 TVR-treated patients with baseline/early resistance, 6 failed treatment, while 4 are still on follow-up. Out of 2 BOC-treated patients with baseline/early resistance, none reached end-of-treatment. Overall, baseline/early presence of RAVs was associated with slower virological response (p=0.056) and ultimately failure (p=0.04). Baseline-UDPS, on 32 patients, confirmed PS results, and additional minority RAVs were found only in 1 TVR-treated patient (T54A, 0.3% prevalence) still undetectable at week-23. At early time points (24–48h), additional minority RAVs were found in 1/14 patients analyzed (V36A48h 2.5%, R155K48h 4.1%, with a mutational load: V36A=182 IU/ml, R155K=298 IU/ml) who experienced viral breakthrough at week-16 of TVR treatment with V36M+R155K. Conclusions: In the context of a PI-regimen, especially for patients with advanced disease and/or previous non response to pegIFN/ribavirin, early (48h-2week) HCV-RNA determination and NS3-sequencing can provide critical information on treatment outcome, rapidly identifying patients with higher risk of viral failure and thus requiring a closer monitoring during treatment.

Disclosures:

Giuliano Rizzardini - Grant/Research Support: msd, gilead, abbott; Speaking and Teaching: bms

Mario Angelico - Advisory Committees or Review Panels: Gilead; Grant/Research Support: Roche; Speaking and Teaching: GSK, Roche, Gilead, Novartis

Francesca Ceccherini-Silberstein - Consulting: Gilead; Grant/Research Support: Merck Sharp & Dohme, Janssen

The following people have nothing to disclose: Valeria Cento, Velia Chiara Di Maio, Daniele Di Paolo, Daniele Armenia, Valeria Micheli, Monica Tontodonati, Francesco Paolo Antonucci, Maria Concetta Bellocchi, Ada Bertoli, Francesco De Leonardis, Giordano Madeddu, Carlo Magni, Cesare Sarrecchia, Lorenzo Nosotti, Annalisa Tortora, Antonio Di Biagio, Laura Ambra Nicolini, Giustino Par-ruti, Sergio Babudieri, Carlo Federico Perno

1961

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Hepatitis C Treatment in Active Injection Drug Users

Brian R. Edlin1,2, Michael R. Carden2,3, Elizabeth V. Getter4, Andrew H. Talal5, Brandon Aden2, Srikanth Goli1, Stephen J. Fer-rando2, Ann B. Beeder2;
1 Institute for Infectious Diseases, National Development and Research Institutes, New York, NY; 2Center for the Study of Hepatitis C and Department of Public Health, Weill Cornell Medical College, New York, NY; 3Deceased, New York, NY; 4Beth Israel Medical Center, New York, NY; 5State University of New York, Buffalo, NY

Background: Few studies have reported antiviral treatment of active illicit drug users, and they are rarely offered treatment. Methods: In collaboration with community-based needle exchange programs in New York, we developed a program to treat hepatitis C in persons who were actively using illicit drugs, combining hepatitis C care, substance abuse treatment, psychiatric care, and intensive case management aimed at reducing the barriers to antiviral treatment. An Intensive Case Manager assessed clients' unmet needs, helped them secure housing and other resources, provided ongoing education about hepatitis C and its treatment, delivered motivational enhancement therapy and ongoing counseling and support, accompanied participants to appointments, and coordinated care from providers of multiple disciplines. Staff from needle exchange programs and our tertiary care medical center crossed institutional boundaries to provide state-of-the-art hepatitis C care in community-based locations. Results: Of 43 active drug users enrolled during 2005–2011, the median age was 37 years (range, 18–62); 32 (74%) were men, 22 (51%) white, 11 (26%) African American, 11 (26%) Latino; 31 (72%) had been homeless and 21 (49%) in jail or prison in the past 6 months; 33 (77%) had used heroin and 26 (60%) cocaine or crack in the past 30 days; 34 (79%) had co-occurring psychiatric conditions; the median Beck depression score was 23 (moderate depression). Of the 43, 9 were HCV RNA(-), 3 were lost to follow-up, 9 declined antiviral therapy, 1 had a medical contraindication, and the remaining 21 received peginterferon-ribavirin. Acceptance of antiviral therapy was associated with reductions in perceived barriers to treatment. Of the 21 treated patients, 14 (67%) had chronic and 7 (33%) acute HCV infection; genotypes were 1 (N = 13), 2 (N=1) and 3 (N=7). Fifteen (71%) achieved a sustained virologic response (SVR). Although we did not require abstinence, 10 (48%) of the 21 patients stopped (n=9) or substantially curtailed (n=1) their use of illicit drugs on their own initiative. After 45.1 person-years of follow-up, 1 became reinfected (incidence, 2.2/100 person-years).

Conclusions: With appropriate support, active illicit drug users often chose to undergo interferon-based antiviral treatment, despite considerable barriers and ongoing drug use. Most (71%) achieved SVRs. Reinfection was uncommon. Although small, this study suggests that active drug users can be successfully treated for hepatitis C. Funding: NIH grants #R01-DA09532, R01-DA016159, R01-DA021550, M01 RR000047, UL1-RR024996; NYS Department of Health AIDS Institute. No industry funding or conflicts of interest.

Disclosures:

Andrew H. Talal -Advisory Committees or Review Panels: Merck and Co, Gilead; Board Membership: Pfizer; Grant/Research Support: Merck and Co, Vertex, Gilead, Abbott Molecular

The following people have nothing to disclose: Brian R. Edlin, Michael R. Carden, Elizabeth V. Getter, Brandon Aden, Srikanth Goli, Stephen J. Ferrando, Ann B. Beeder

1962

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Telaprevir is less tolerable than boceprevir - a randomized, pragmatic head-to-head trial

Perica Davitkov1,2, Apoorva Chandar1,2, Amy Hirsch1, Anita Com-pan1, Marina G. Silveira1,3, Donald D. Anthony1,2, Robert A. Bonomo1,2, Yngve Falck-Ytter1,2;
1GI, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH; 2IM, University Hospitals, Case Medical Center, Cleveland, OH; 3IM, Case Western Reserve University, School of Medicine, Cleveland, OH

Improved genotype 1 hepatitis C viral response rates of the two currently available protease inhibitors (PI) boceprevir and telaprevir comes at a cost of an increased rate of severe adverse events compared to peg-interferon and ribavirin alone. However, the comparative safety and effectiveness of boceprevir vs. telaprevir are unknown and have not been studied in direct head-to-head randomized controlled trials (RCT). Methods 50 patients were enrolled in an open-label, pragmatic RCT receiving usual care at a VA Medical Center liver clinic and randomly assigned to either boceprevir or telaprevir in combination with peg-interferon alpha 2a and weight based ribavirin. Allocation was concealed. Patients were stratified based upon the presence of cirrhosis or whether they were treatment naïve or treatment experienced. Tolerability was assessed at each visit and reasons for discontinuation or severity of adverse events of protease inhibitor treatment documented and adjudicated using a blinded adjudication committee. Primary outcomes included a) composite of early termination due to PI related adverse events in addition to severe adverse events either leading to hospitalization (e.g., severe rash or infection), severe anemia (hemoglobin of <8.5), or death; b) viral response rates. Results The majority of enrolled patients were men (98%) with an average age of 59 years. Forty four percent were African American, 48% were Caucasian and 4% were Hispanic or Latino. Liver biopsy results showed advanced fibro-sis or cirrhosis (stage 3 and 4) in 13 (26%) patients. Higher rates of treatment discontinuations and / or severe PI associated adverse events were seen in 10 of 25 (40%) patients randomized to telaprevir compared to 2 of 25 (8%) patients randomized to boceprevir (RR: 5; 95% CI: 1.2, 20); 8 patients stopped telaprevir treatment early due to toxicity (mostly due to rashes), one patient required hospital admission due to progressive rash and one patient developed severe anemia. Of the two patients on boceprevir who stopped treatment early, one experienced severe rash and the other severe dysguesia. Early complete viral response rates did not appear to be different between groups (telaprevir vs. boceprevir: RR 1.23; 95% CI: 0.76, 1.99). Conclusions Compared to boceprevir, use of telaprevir in standard triple antiviral regimens within a Midwestern VA patient population is associated with a significantly higher rate of severe adverse events leading to treatment discontinuation, hospitalization or severe anemia. 2627/2700 characters

Disclosures:

The following people have nothing to disclose: Perica Davitkov, Apoorva Chan-dar, Amy Hirsch, Anita Compan, Marina G. Silveira, Donald D. Anthony, Robert A. Bonomo, Yngve Falck-Ytter

1963

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Impact of adherence to triple therapy with telaprevir according to IL28B genotype in Japanese patients infected with chronic hepatitis C genotype 1

Shiho Miyase1, Yuko Morishita1, Katsuki Haraoka1, Yoshihiro Ouchida1, Shigetoshi Fujiyama1, Yutaka Sasaki2;
1 Department of Gastroenterology and Hepatology, Kumamoto Shinto General Hospital, Kumamoto, Japan; 2Department of Gastroenterology and Hepatology, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan

Background: The genotype of single nucleotide polymorphisms near the interleukin 28B (IL28B) gene modulates virological response to triple therapy (telaprevir (TVR) combined with peginterferon (PegIFN) plus ribavirin (RBV)) in patients with chronic hepatitis C virus (HCV) genotype 1 infection. On the other hand, decreased drug exposure because of discontinuation of therapy or missed doses may result in worse virological response rates. We evaluated the role of adherence to TVR-based triple therapy on the viral response according to the IL28B (rs8099917) genotype. Methods: We conducted a prospective study at our institution, and enrolled consecutive Japanese adults (>20 years of age) who were infected with HCV genotype 1. The patients initiated 12 weeks of TVR combined with PegIFN α-2b plus RBV followed by 12 weeks of PegIFN α-2b plus RBV. Adherence to the triple therapy was assessed by calculating the actual doses of TVR, PegIFN, and RBV received as a percentage of the expected dose. We evaluated the response to triple therapy and analyzed it in relation to baseline characteristics, including drug adherence and IL28B rs8099917 genotype. Results: We examined 67 patients, 43 (64.2%) of whom carried the genotype TT and 24 (35.8%) carried genotype TT/TG. The mean patient age was 57.2 years, and 28 patients (41.8%) were older than 60 years. The sustained virological response (SVR) rates were higher in patients with the TT genotype than in those with the TG/GG genotype (97.7% vs. 58.3%, P < 0.001). TG/GG genotype carriers who achieved > 80% adherence to the triple therapy for the first 4 weeks were associated with a significantly higher SVR rate than those who achieved < 80% adherence (92.3% vs. 18.2%, P < 0.001), whereas there were similarly high SVR rates in patients with the TT genotype (100.0% vs. 95.2%, P = 0.488). The SVR rates were not significantly associated with drug adherence for the first 12 weeks (P = 0.104) or the total 24 weeks (P = 0.239) in patients with the TG/GG genotype. Multivariate logistic regression analysis revealed that the TT genotype (odds ratio, 99.91; 95% confidence interval, 7.58–100.0) and achievement of 80% adherence to triple therapy for the first 4 weeks (odds ratio, 55.56; 95% confidence interval, 4.44–100.0) were independent predictors of SVR. Conclusion: Drug adherence during the early phase of triple therapy more strongly affects the SVR rate for patients with the IL28B rs8099917 TG/GG genotype than it does for patients with the TT genotype.

Disclosures:

Yutaka Sasaki - Grant/Research Support: Ajinomoto Pharmaceutical Company, MSD Pharmaceutical Company, Mitsubishi-Tokyo-Tanabe Pharmaceutical Company

The following people have nothing to disclose: Shiho Miyase, Yuko Morishita, Katsuki Haraoka, Yoshihiro Ouchida, Shigetoshi Fujiyama

1964

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Impact of Single Nucleotide Polymorphisms of IL28B rs 12979860 on SVR in Treatment Chronic Hepatitis C Genotype 6 in Vietnamese Patients

Thu Thuy Pham Thi, Tan Dat Ho;
Hepatology, Medic Medical Center, Ho Chi Minh, Viet Nam

Background: Genetic variation in the interleukin 28B (IL28B) gene has been associated with the response to Peginterferon-alfa/ribavirin therapy in hepatitis C virus (HCV) genotype 1-infected patients. The importance of IL28B single nucleotide polymorphisms (rs12979860) for HCV genotype 6 infected patients is unknown. Aims: -To determine the relationship between IL28B single nucleotide polymorphisms (SNPs) and sustained virologic response (SVR) rates to combination therapy of Peginterferon alfa and Ribavirin. - Comparing SNPs allele frequencies in relation to other factors such as age, BMI, gender, AST/ALT ratio, viral load, EVR, RVR and fibroScan. Method: The study is designed as a retrospective review of the medical records of chronic HCV patients with genotype 6. SNP of IL28B (rs12979860) was identified by real-time polymerase chain reaction analysis of samples from 102 patients who were treated with Peginterferon alfa and Ribavirin . The duration of treatment was 48 weeks. Results: Patients with CC had higher rates of rapid virologic response (RVR) (84.09% vs. 50%, p=0.010), but SVR rates were similar between those with CC and CT (87.5% vs. 71.4%, p=0.20). Patients with CT had higher rates of relapse (28.57% vs. 9%), but the difference was not statistical meaningful. In the multivariable analysis (IL28B, age, BMI, gender, AST/ALT ratio, viral load, EVR, RVR and fibroScan), only RVR predicted SVR, IL28B polymorphism did not affect the SVR. RVR remains the best predictor of SVR. Conclusion: An IL28B polymorphism was associated with an RVR in patients infected with genotype 6. But IL28B did not predict SVR. The relapse rate of patients with CT seemed to be higher than that of patients with CC. So determination of how IL28B will be used for treatment decisions in patients with genotype 6 remains to be further studied.

Disclosures:

The following people have nothing to disclose: Thu Thuy Pham Thi, Tan Dat Ho

1965

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Long-term UDCA treatment of non-responder patients with chronic hepatitis C

Inmaculada Castillo1, Javier Bartolomé1, Juan A. Quiroga1, Guiller-mina Barril2,1, Vicente Carreño1;
1Fundación Estudio Hepattitis Virales, Madrid, Spain; 2Nephrology, Hospital La Princesa, Madrid, Spain

In patients with chronic hepatitis C who have not responded to antiviral therapy and are not eligible for further antiviral treatments or refuse to be treated, there is a need to slow the progression of liver disease. Ursodeoxycholic acid (UDCA) treatment may be of benefit in these patients as it decreases levels of liver enzymes. A total of 70 patients with chronic hepatitis C histologically proven and who have not responded to different antiviral regimens have been receiving 20mg/Kg/daily of UDCA (Usrobilane, Laboratorios Aldo-Unión, Barcelona, Spain) for a mean time of 63 ± 37 months (range: 16 to 222 months). Patients have been followed every 3 months during the first year of treatment and every 4–6 months thereafter. At entry, all patients had abnormal values of

ALT and were serum HCV-RNA positive while 71% and 53% had increased levels of AST and GGTP, respectively. After 3 months of treatment, 8 patients (11.4%) normalized liver enzymes and have remained within normal ranges during the whole treatment (79 ±38 months). A second liver biopsy was obtained after 90 month of continuous treatment with UDCA during a programmed interventional laparoscopy from one of these responder patients. In this liver biopsy it was found a significant histological improvement with disappearance of fibro-sis with respect to a previous liver biopsy obtained 11 years before. Another 29 patients (41.5%) have presented fluctuating values of liver enzymes but AST. ALT and GGTP levels have significantly decreased at the last analyzed sample (77 ± 41 months of treatment) with respect to the basal sample (p < 0.01). The remaining 33 patients (47.1%) have persisted with constant abnormal levels of liver enzymes during the whole treatment (47 ± 24 months), although AST, ALT and GGTP were significantly lower (p < 0.05) in the last follow-up sample. No significant differences were found in the basal biochemical parameters between the three groups of patients except in ALT levels that were significantly higher (p < 0.01) in patients who have not responded to UDCA treatment (129 ± 52 IU/L) than in those with fluctuating ALT values (70 ± 40 IU/L) and than in complete responder patients (61 ±12 IU/L). Serum HCV-RNA levels has not changed in any group. Mild transient side effects (abdominal distension, stomach discomfort and/or diahrrea) were reported by 20% of the patients but none required treatment discontinuation. In summary, long-term UDCA treatment has beneficial effects in chronic hepatitis C patients who have not responded to antiviral treatment as it decreases liver enzymes and therefore it may delay liver damage progression.

Disclosures:

The following people have nothing to disclose: Inmaculada Castillo, Javier Bar-tolomé, Juan A. Quiroga, Guillermina Barril, Vicente Carreño

1966

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Real-world efficacy and safety of 28 week-therapy containing boceprevir, peginterferon alfa-2a and ribavirin in treatment-naive patients: first SVR data of German non-interventional PAN Study

Peter Buggisch1, Andreas Schober2, Harald-Robert Bruch3, Christoph Antoni4, Hanns-Friedrich F. Loehr5, Andreas Herrmann6, Hermann Steffens7, Gero Moog8, Joachim Haessner9, Hans-Georg Hoerster10, Christine John11, Hans-Joachim Schlueter12, Ralph Link13, Renate Heyne14, Ulrich Spengler15, Ulrich Alshuth16, Klaus H. Boeker17;
1ifi-Institute for Interdisciplinary Medicine, Hamburg, Germany; 2Center of Gastroenterology, Goettingen, Germany; 3Center of Gastroenterology, Bonn, Germany; 4II. Medizinische Universitaetsklinik, Universitaetsmedizin Mannheim, Mannheim, Germany; 5Center of Gastroenterology, Wiesbaden, Germany; 6Dept. of Internal Medicine II, University Hospital, Jena, Germany; 7Practice for internal Medicine, Berlin, Germany; 8Center of Gastroenterology, Kassel, Germany; 9Center of Internal Medicine, Wolfsburg, Germany; 10Center of Gastroenterology, Moenchengladbach, Germany; 11Center of Gastroenterology, Berlin, Germany; 12Center for internal Medicine, Dortmund, Germany; 13MZV Offenburg, Offenburg, Germany; 14Liver and study center Checkpoint, Berlin, Germany; 15Dept. of Internal Medicine I, University Hospital Bonn, Bonn, Germany; 16Virology, Roche Pharma AG, Grenzach-Wyhlen, Germany; 17Center for Hepatol-ogy, Hannover, Germany

Introduction: Boceprevir (BOC) is approved in Germany in combination with peginterferon alfa plus ribavirin in chronic hepatitis C patients infected with HCV genotype 1. The efficacy and safety of BOC is well characterized in randomized clinical trials but real world experiences are limited so far. The PAN study is a non-interventional study conducted by the Association of German Gastroenterologists in Private Practice (bng) in cooperation with Roche. Methods: Patients are eligible for inclusion in the PAN non-interventional study if they are prescribed boceprevir or telaprevir plus peginterferon alfa-2a/ribavirin (Peg-IFN/RBV). Here we restrict the analysis to treatment naïve patients receiving BOC plus Peg-IFN/RBV who completed 24–28 weeks of treatment including the 4 week lead-in phase with Peg-IFN/RBV. Patients who initiated BOC < 21 days or >43 days after starting Peg-IFN/RBV were excluded from the analysis. All patients started treatment until March 31st, 2012. Results: Overall 134 patients were included in the present analysis. Patients had a mean age of 46.3 years and a mean BMI of 27.0 kg/m2, 62.7% were male, 95.5% were Caucasian, 9.7% had one diagnostic measure consistent with cirrhosis, and the mean baseline HCV-RNA was 6.0 log 10 IU/mL. 34.3% and 47.0% of the patients were infected with HCV G1 a and G1b, respectively (18.7% unknown subtype). Of 33 patients with valid HCV-RNA measurement at w8 and w2424 were below limit of detection and so recommended for shorter treatment, of them 87.5% achieved SVR. However, in real life in only 51 /74 (68.9%) of HCV-RNA determinations were done at the appropriate date. Because of decreasing hgb level during treatment 31.3% and 11.9% of the patients required dose modifications of ribavirin and peginterferon alfa-2a, respectively, with a peak between weeks 8 and 10. Fatigue (61.2%), headache (24.6%), skin disorder (24.6%), nausea (23.9%), and anaemia (19.4%) were predominant adverse events reported. Conclusion: The present analysis reveals that more than two third of patients can shorten the duration of bocepre-vir-based treatment and that these patients have high chance to achieve SVR. Therefore, valid week 8 HCV-RNA values are crucial for treatment decisions and it is highly recommended to address this aspect in medical education.

 Visits completedvalid HCV-RNA (=100%)Discontinuations in total (%)viral load undetectable and/or <IO IU/ml (%)valid HCV-RNA a- 2a and w24 (=100%)viral load undetectable and/or <IO IU/ml (%)
week 4134104011.5  
week 8134871.170.1  
week 1213495.179.6  
week 2413410216.778.47468.9
EoT week 28705420.475.9  
follow up after 28w tx605219.269.23366.7

Disclosures:

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

Christoph Antoni - Speaking and Teaching: Roche, MSD, BMS Ulrich Alshuth - Employment: Roche

Klaus H. Boeker - Speaking and Teaching: MSD, Roche, Janssen, Gilead, BMS, Falk Foundation, Novartis

The following people have nothing to disclose: Andreas Schober, Harald-Robert Bruch, Hanns-Friedrich F. Loehr, Andreas Herrmann, Hermann Steffens, Gero Moog, Joachim Haessner, Hans-Georg Hoerster, Christine John, Hans-Joachim Schlueter, Ralph Link, Renate Heyne, Ulrich Spengler

1967

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Peg-IFN + RBV + TVR treatment for patients with liver cirrhosis

Motoyuki Kohjima1, Tsuyoshi Yoshimoto1, Tsukasa Nakamura1, Shinichi Tsuruta1, Tomoko Ohashi1, Kunitaka Fukuizumi1, Nao Fujimori1 , Ken Kawabe1, Kazuhiro Haraguchi1, Akira Aso1, Yorinobu Sumida1, Naohiko Harada1, Kazufumi Dohmen2, Hideyuki Nomura3, Munechika Enjoji4, Makoto Nakamuta1;
1Gastroenterology, Clinical Research Center, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan; 2Internal Medicine, Chihaya Hospital, Fukuoka, Japan; 3Internal Medicine, Shin-Kokura Hospital, Kitakyushu, Japan; 4Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan

Background: Telaprevir (TVR) is an NS3/4A protease inhibitor that is used for the treatment for chronic HCV patients in combination with peg-IFN and ribavirin (RBV). Although the safety of the therapy seems to be similar in the patients with liver cirrhosis and without cirrhosis in phase III trials, the efficacy of the treatment for cirrhotic patients is still unclear. Here, we examined the effect of peg-IFN + RBV + TVR triple therapy for cirrhotic patients. Methods: The patients with HCV genotype 1 b have been treated with peg-IFNα2b + RBV + TVR (n=115). We compared HCV kinetics, sustained virological response (SVR) 12w, and 24w rate between the patients with and without liver cirrhosis (n=35 and n=80, respectively) in each allele. Results: During peg-IFNa2b + RBV + TVR treatment, the response of HCV was rapid and similar between IL-28B rs8099917 TG/GG and TT allele until 3 weeks when HCV-RNA was decreased drastically, while positive rate for HCV-RNA at 4 weeks and 6 weeks of treatment was significantly higher in patients with intractable IL-28B TG/GG allele than that with TT allele (p=0.03 and p=0.026, respectively). Response rate (SVR12w, SVR24w) were significantly higher for the patients with IL-28B TT allele (96.0% and 97.6%) than TG/GG allele (65.0% and 64.3%) (p=0.0005 and p=0.0006, respectively). In multivariate analysis, predictive factors associated with SVR were IL-28B allele (genotype TT; OR 22.0, p <0.0001), gender (male; OR 9.43, p =0.0187), and liver damage (non-LC; 7.34, p =0.0152). When we compared the viral response, HCV-RNA at 2 and 3weeks of treatment was significantly higher for patients with liver cirrhosis than non-cirrhotic patients. SVR12w and SVR24w were good for patients with liver cirrhosis (71.4% and 78.6%, respectively) but lower than patients without cirrhosis (93.9% and 92.7%, respectively). We needed to reduce the dose of peg-IFN for cirrhotic patients, while the rate of severe complication (infection, severe anemia, and renal dysfunction) were similar between both groups. Conclusion: The response of HCV-RNA was different between IL-28B allele, and patients with IL-28B rs8099917 TG/GG allele showed poor SVR rate than patients with TT allele. Liver damage as well as gender and genotype variation of IL-28B is a strong predictive factor during peg-IFNa2b + RBV + TVR treatment. The viral response and safety of the treatment for cirrhotic patients is good enough in this study, while some report questioned the safety profile of the treatment for cirrhotic patients. We should evaluate the indication of triple therapy for the patients with liver cirrhosis carefully.

Disclosures:

The following people have nothing to disclose: Motoyuki Kohjima, Tsuyoshi Yoshimoto, Tsukasa Nakamura, Shinichi Tsuruta, Tomoko Ohashi, Kunitaka Fukuizumi, Nao Fujimori, Ken Kawabe, Kazuhiro Haraguchi, Akira Aso, Yorinobu Sumida, Naohiko Harada, Kazufumi Dohmen, Hideyuki Nomura, Munechika Enjoji, Makoto Nakamuta

1968

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IL28b gene and very early viral kinetics (Week-1) predict sustained virological response to triple therapy in chronic hepatitis C patients with genotype 1 b and high viral load

Tatsuya Ide1, Koichi Takaguchi2, Hidenori Toyoda3, Takashi Kumada3, Noritomo Shimada4, Keizo Kato4, Akihito Tsubota5, Namiki Izumi6, Michio Sata1;
1Division of Gastroenterology, Kurume University School of Medicine, Kurume, Japan; 2Depart-ment of Hepatology, Kagawa Prefectural Central Hospital, Taka-matsu, Japan; 3Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan; 4Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Japan; 5Institute of Clinical Medicine and Research, Jikei University School of Medicine, Kashiwa, Japan; 6Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan

Background and Aims: Triple therapy with telaprevir, peg-inter-feron, and ribavirin leads to a high sustained virological response (SVR) rate in patients infected with HCV genotype 1 b and a high viral load. However, this therapy has many severe side effects. Therefore, early prediction of SVR is very important. On the other hand, it has already been reported that genetic variation near the IL28b gene is associated with SVR in this triple therapy. We investigated the very early viral kinetics of HCV according to IL28b and whether viral kinetics in response to triple therapy can predict SVR. Patients and Methods: Criteria for patient inclusion were chronic hepatitis with HCV genotype 1 b and pretreatment HCV RNA >5.0 log IU/ml. Treatment was started with triple therapy that continued for 12 weeks. After that, peg-interferon and ribavirin were continued for 12 weeks, with treatment for a total 24 of weeks. In this study, patients who completed treatment were enrolled. The patients who discontinued the treatment were excluded. A total of 149 patients were enrolled. Among these, 86 patients have been assessed for SVR up until the present. HCV RNA levels were measured before and 1, 4, and 12 weeks after the start of therapy and at 12 weeks after therapy by real-time PCR. SVR was defined as undetectable HCV RNA at 12 weeks after the therapy. Genetic polymorphism in one tagging SNP located near the IL28B gene (rs8099917) was determined. Results: The IL28b gene, HCV RNA levels at week-1, substitution of amino acid 70 in the core region, and gamma-GTP were significant predictive factors of SVR. Of the 86 patients, 59 had the TT type of the IL28b gene and 27 patients had the non-TT type (TG or GG). Of the 59 TT type patients, 57 (96.6%) achieved SVR. On the other hand, of the 27 non-TT-type patients, 12 (44.4%) achieved SVR. In these non-TT-type patients, the HCV RNA level at week-1 was the most important factor for predicting SVR. In the patients whose HCV RNA levels were less than 2.0 log IU/ml at week-1, the SVR rate was 71.4% (10/14). However, in those whose levels were above 2.0 log at week-1, the SVR rate was only 15.4% (2/13). In summary, the SVR rate of TT-type and non-TT-type patients with HCV RNA levels less than 2.0 log at week-1 was 91.8%, and that of non-TT-type patients with HCV RNA above 2.0 log at week-1 was 15.4%. Conclusion: In patients who completed the triple therapy, IL28b and HCV RNA levels at week-1 can be used to predict the SVR rate.

Disclosures:

Namiki Izumi - Speaking and Teaching: MSD Co., Chugai Co., Daiichi Sankyo Co., Bayer Co., Bristol Meyers Co.

Michio Sata - Speaking and Teaching: MSD K.K., Chugai Pharmaceutical Co., Ltd.

The following people have nothing to disclose: Tatsuya Ide, Koichi Takaguchi, Hidenori Toyoda, Takashi Kumada, Noritomo Shimada, Keizo Kato, Akihito Tsub-ota

1969

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Protease-Inhibitor (PI) Triple Therapy (TT) in Mildly Decompensated Cirrhotics: Predictors of Treatment Discontinuation, Worsening Decompensation and Sustained Virologic Response

Varun Saxena1, Helen S. Yee2,1, Lisa Catalli1, Elizabeth M. Wayne1, Joshua Chua2, Alexander Monto2,1, Norah Terrault1;
1 Gastroenterology, University of California San Francisco, San Francisco, CA;2Gastroenterology, San Francisco VA Medical Center, San Franscisco, CA

Background: Registration trials of PI-TT excluded patients (pts) with clinical or laboratory evidence of decompensation. Risks and benefits of TT in cirrhotics with Child-Pugh (CP) >6, including those on the waiting list for liver transplant (LT), are incompletely known. Aims: To assess virologic responses (VRs) and safety of TT in mildly decompensated (CP>6) cirrhotics. Methods: Two-center retrospective cohort of all CP>6 cirrhotics treated with PI-TT [peginterferon/ribavirin (P/R) with telaprevir (70%) or boceprevir (30%)] since PI approval. For safety outcomes, all compensated cirrhotics (CP=5) treated with TT during the same time period were used for comparison. Results: 61 TT treated pts (median age 60yrs, 28% female, 66% G1A, 19%IL28B-CC, 28% previous null/partial responders) with mildly decompensated cirrhosis [CP 6 (range 6–11), MELD 10 (range 6–20] were followed for median 174d (IQR: 92–332) from start of PI (N=31 evaluable for SVR12), CP>6 pts achieved RVR in 35%, EOTR in 60% (28/47) and SVR12 in 35% (11/31). In univariate analysis, SVR12 was associated with IL28B-CC, treatment (Rx) naïve/relapse status, RVR, lower baseline total bilirubin (TB) and higher baseline platelet count (PLT). For SVR12, baseline TB>1.8 had a NPV of 100% (95% CI: 86%-100%), baseline PLT <100K had a NPV of 78% (95% CI: 52%-93%) and lack of RVR had a NPV of 83% (95% CI: 59%-96%). Compared to cirrhotics with CP=5 (n=45), CP>6 pts required more P/R dose reductions (48% vs 94%), GCSF use (20% vs 44%), eltrombopag use (4% vs 34%) (all p<0.01) and transfusions (7% vs 21%, p=0.06). 9 (15%) CP>6 pts stopped TT early due to adverse events and 11 (18%) due to virologic failure. Among pts stopping Rx early, 50% (10/20) experienced decompensation (MELD increased >2) in the CP>6 group vs 15% (2/13) in CP=5 group; decompensation was associated with higher baseline TB [OR: 2.65, p=0.05)]. Finally, 6 pts on the wait-list were treated for median of 121d TT (IQR 54–160) with the goal of preventing recurrent HCV post-LT; 4/6 achieved undetectable viral load pre-LT and 2/6 achieved post-LT VR (pTVR) at 4 weeks. Conclusions: Among CP>6 pts, PI-TT achieves SVR12 in only 35% and among those stopping Rx early, 50% decompensate further. Baseline TB was predictive of non-SVR and, further decompensation if Rx stopped early. Thus, risk may outweigh benefit in this subgroup. Pre-transplant TT to prevent HCV recurrence yielded pTVR rates similar to those historically reported with P/R. These results highlight the modest benefit and significant risk of PI-TT and points to the urgent need for safer and more effective therapies for decompensated cirrhotics.

Disclosures:

Lisa Catalli - Advisory Committees or Review Panels: Gilead, Kadmon

Norah Terrault-Advisory Committees or Review Panels: Eisai, Biotest; Consulting: BMS; Grant/Research Support: Eisai, Biotest, Vertex, Gilead, AbbVie, Novartis

The following people have nothing to disclose: Varun Saxena, Helen S. Yee, Elizabeth M. Wayne, Joshua Chua, Alexander Monto

1970

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Examination of the optimal dose of RBV in the PEG-IFN/RBV/TVR combination therapy

Yoshiyasu Karino, Mutuumi Kimura, Tomohiro Arakawa, Tomoaki Nakajima, Yasuaki Kuwata, Itaru Ozeki, Takahiro Sato, Takumi Ohmura, Shuhei Hige, Joji Toyota;
Hepatology, Sapporo Kosei General Hospital, Sapporo, Japan

Backgrounds: As for the ribavirin (RBV) dose in the triple therapy involving telaprevir (TVR), a weight base is recommended. But because of renal functional disorder by TVR, RBV blood concentration rises and causes severe anemia in comparison with peg-interferon (PEG-IFN)/RBV therapy. We examined an optimal dose of RBV in the PEG-IFN/RBV/TVR therapy using the post-marketing cases. Methods: The objects are 69 hepatitis C cases that were observed until more than 12 weeks of therapy or dosage cancellation. PEG-IFN was assigned by the weight base. TVR and RBV doses were adjusted according to the Japanese guidelines for the treatment of hepatitis B and C, established in 2012. The subject details were as follows: TVR dose (1500mg/day: 32 cases, 2250mg/day: 37 cases), age 61 (2–70) years old, 42 males (60.1%), body weight 63.3 (46–88.1) kg, hemoglobin 13.8 (11.1–15.9) g/dl and total clearance of RBV (CL/F) 12.95 (5.56–27.7) L/hr. If severe anemia was present during the triple therapy, the dosage of RBV, followed by that of TVR, was adjusted. As tentative plan dose of RBV, we used the following formula: tentative RBV dose = body weight base RBV dose -200mg -200mg (if CL/F is less than 11L/hr). This formula was led from the phenomena that the anemia developed highly in PEG-IFN/RBV/TVR therapy compared with PEG-IFN/RBV, and in the low CL/F cases anemia was more remarkable (EASL ILC 2013). We compared adherence of the RBV dosage between actual dose and tentative dose. The RBV blood concentration was measured serially in the possible cases. Results: Dose reduction or cancellation of RBV was necessary for 61 cases (88.4%). According to the TVR dose, reduction and discontinuation or cancellation was 40.6% and 43.8% in 1500mg/day group and 59.5% and 32.4% in 2250mg/day group. RBV reduction free cases were only 8 (11.6%). Ten cases agreed actual dose and tentative RBV dose, actual dose exceed tentative dose in other 59 cases. Of agreed 10 cases, 4 cases (40%) completed RBV dosing without reduction and 6 cases completed with reduction. On the contrary, of disagreed 59 cases, only 4 cases (6.8%) completed RBV dosing without reduction, 29 cases (49.2%) completed with reduction and 26 cases (44%) discontinued or cancelled RBV dosing. Serial RBV blood concentration (median) at week 1, week 2, week 4, week 8 and week 12 of therapy were (1267, 2484, 2193, 1483, 1230 ng/ml) in disagreed cases and (1000,2004, 1946, 2322, 2312 ng/ml) in agreed cases. The agreed cases showed high RBV blood concentration in later periods (P<0.05). Conclusions: To avoid cancellation of RBV dosing and obtain maximal clinical effect, dose setting of RBV in consideration of CL/F is expected.

Disclosures:

Joji Toyota - Speaking and Teaching: MSD

The following people have nothing to disclose: Yoshiyasu Karino, Mutuumi Kimura, Tomohiro Arakawa, Tomoaki Nakajima, Yasuaki Kuwata, Itaru Ozeki, Takahiro Sato, Takumi Ohmura, Shuhei Hige

1971

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Tolerance of Telaprevir or Boceprevir retreatment for chronic hepatitis C in patients with severe hepatic fibro-sis. Results in a prospective multicentric cohort

Mathieu Guivarch, Emilie Berard, Anais Palacin, Karl Barange, Sophie Metivier, Florence Nicot, Florence Abravanel, Delphine Bonnet, Laurent Alric;
Digestive, CHU Purpan, Toulouse, France

Aims: Safety profile of triple therapy with Boceprevir (BOCE) orTelaprevir (TELA) in patients with severe liver fibrosis has yet to be determined because a low number of patients were included in studies. The aim of this work was to prospectively evaluate tolerance and common adverse events (AE) in a cohort of patients retreated for hepatitis C with severe liver fibrosis. Patients and methods: 125 consecutive patients infected with hepatitis c genotype 1 who failed in previous conventional dual therapy (prior null response n=79, 62.9%, prior relapse n=46, 37.1%) with severe hepatic fibrosis evaluated F3 ( n=35, 28%) or F4 (n= 90, 72%), CHILD A for 98.4% of them were treated with Peg-IFN + ribavirin and TELA ( n=90, 72%) or BOCE (n=35, 28%) for 48 weeks. Patient's mean age was 56.2± 9.7 year and 64.8% of them were men. All adverse events during treatment and the following 24 weeks were reported. At baseline mean haemoglobin was 15.1 ± 1.6 g/dl and platelets was 165.6 ± 64.9103/mm3. Results: At baseline 24 % (n=26) patients had an exclusion criteria for the REALIZE or RESPOND-2 study. Oesophageal varices were observed in 25.4% (n= 30). Adverse events, >grade 1, occurred for 102 patients (81.6%) and were significatively more important with TELA (n= 89, 87.8%) than with BOCE (n=23, 65.7%) (OR 3.747 [1.46; 9.5] p=0.0059). During treatment 64 patients (51.2%) had a serious adverse event (SAE), > grade 3. SAE were: thrombopenia > grade 3 (n= 42, 65.6%), neutropenia > grade 3 (n= 21, 32.8%), anemia > grade 3 (28.1%), severe infection (n=4, 6.3%), asthenia > grade 3 (n= 3, 4.7%), rash skin > grade 3 (n= 2, 3.1%), liver failure > grade 3 (n=2, 3.1 %). No death was reported during treatment. Multivariate analysis identified two factors associated with SAE: female gender (OR 3.289 [1.1; 9.8] p=0.0334) and platelets counts <1001 03/mm3. There was no incidence of fibrosis stage (F3 vs F4) and choice of inhibitors of protease (TELA vs BOCE) on the occurrence of SAE. Blood transfusion was needed for 17 patients (13.6%) and EPO for 64 patients (51.2%). There were no difference between TELA and BOCE group for EPO use or blood transfusion. Treatment discontinuation for SAE occurs for 11 patients (8.8%) Conclusions: More AE (all grade >1) occurred with triple therapy with TELA than with BOCE in patients with severe liver fibrosis treated in town-hospital health network. There was no difference in the occurrence of SAE between TELA or BOCE groups. Patients with initial platelets count <1001 03/mm3 or female gender may require a closer monitoring because of an increased risk of SAE.

Disclosures:

Sophie Metivier - Speaking and Teaching: Roche, BMS, Janssen, MSD

The following people have nothing to disclose: Mathieu Guivarch, Emilie Berard, Anais Palacin, Karl Barange, Florence Nicot, Florence Abravanel, Delphine Bonnet, Laurent Alric

1972

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Safety and efficacy of boceprevir with peginterferon alfa-2a and weight based ribavirin in liver transplant recipients with genotype 1 hepatitis C virus

Alissa Raines1, Travis B. Dick1, EdwardJ. Frech2, Robert G. Jones2, MarkE. Boschert2, Gordon E. Harmston2,3;
1Pharmacy, Intermoun-tain Medical Center, Murray, UT; 2Utah Gastroenterology, Salt Lake City, UT; 3Transplantation, Intermountain Medical Center, Murray, UT

Hepatitis C virus (HCV) recurs universally in liver transplant recipients (LTR). Antiviral therapy is challenging due to potential for interferon-induced rejection and drug interactions between calcineurin inhibitors and protease inhibitors. Boceprevir (BOC) is a protease inhibitor FDA approved to treat HCV genotype 1, but studies are lacking in LTR. The purpose of this case series was to describe the safety and efficacy of BOC based HCV therapy in LTR. Cyclosporine monotherapy was used to prevent rejection. Peginterferon alfa-2a and weight-based ribavirin (P/R) were given for 4 weeks followed by BOC with P/R for an additional 44 weeks. Six LTR, all HCV genotype 1 previous non-responders, were treated. To date, 2 patients with end-of-treatment response achieved sustained virologic response (SVR) at week 24. Mean nadir hemoglobin was 6.4 + 0.5 without bleeding and all 6 patients required darbepoeitin, blood transfusions, and ribavirin dose adjustments to maintain hemoglobin > 8.5. Dose adjustments of interferon and weekly filgrastim were needed universally to maintain an ANC > 750. Mean ANC prior to BOC initiation was 1119 + 911 and after BOC initiation the nadir was 323 +116. One patient experienced bacteremia then recovered and later developed cystitis while remaining on therapy. One patient expired from sepsis in the setting of neutropenia while on therapy. While combination therapy of P/R and BOC appears efficacious for the treatment of HCV genotype 1, it should be used cautiously in LTR due to serious risk of cytopenias. We propose postponing HCV treatment in LTR until novel HCV medications are commercially available. If BOC triple therapy is initiated in LTR, frequent monitoring is required to manage toxicities and alter dosing of HCV medications.

CharactersisticPatient Number/Total (%)
SVR4 & SVR242/2(100)
Awaiting SVR2/4 (50)
Viral breakthrough1/6(17)
Extended rapid viroiogic response1/6(17)
Infection2/6 (33)
Boceprevir discontinued early due to ADE4/6 (67)
Death as a result of sepsis1/6(17)
ANC < 750/uL6/6(100)
Hemoglobin < 7.5 g/dL6/6(100)
Platelets < 50,000/uL2/6 (33)
Rejection0/6 (0)
SCr rise > 0.5 mg/dL from baseline4/6 (67)

Disclosures:

The following people have nothing to disclose: Alissa Raines, Travis B. Dick, Edward J. Frech, Robert G. Jones, Mark E. Boschert, Gordon E. Harmston

1973

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Long-term clinical outcome of Mexican patients with Chronic Hepatitis C infection after Sustained Virological Response to antiviral therapy

Rocio Torres Ibarra, David R. Castelo Lopez, Enrique Alcala Martinez;
Hospital de Infectologia, Centro Medico Nacional “La Raza”, Instituto Mexicano del Seguro Social (IMSS), Distrito Federal, Mexico

A) BACKGROUND / AIM: The key end point for antiviral therapy efficacy in chronic hepatitis C (CHC) is the absence of detectable virus at six months after treatment. The reappearance rate during a long-term follow-up of Mexican patients with sustained virological response (SVR) is unknown. We aim to assess the histopathological, biochemical and virological outcomes after a minimum of five-year follow-up time in CHC patients with SVR after therapy. B) METHODS: A total of 188 patients with CHC who achieved an SVR after antiviral therapy from a single Mexican medical center were included in this retrospective study which spans almost 14 years of experience at this center. Most of these patients were treated with subcutaneous injections of either PEG-IFN-α 2a or 2b plus ribavirin orally while some of the earlier patients received Standard Inter-feron alpha-2b. All of them were followed for at least five years and Liver Function Tests (LFT) and HCV RNA assays were performed every 6 months during this follow-up period after a SVR. A liver biopsy was performed prior to and after treatment and in some cases as a follow-up biopsy years after treatment. We analyzed data from medical records, pathology reports and viral load results from adult patients treated and followed in this hospital. C) RESULTS: Among these 188 patients with CHC who achieved SVR, 53.7% (n=101) were female, mean age at treatment was 43.3 (± 12) years, mean follow-up period was 69 (± 9) months. Genotype distribution was: 68% for genotype 1 (n=128), 27.6% for genotype 2, 3.7% for genotype 3 (n=7) and just one patient with genotype 4. Comparative liver biopsies were performed in 146 patients (77.6%) prior to and after treatment with these findings: 73.3% (n=107) had significant reduction of necroinflammatory scores (Knodell and Metavir) with paired T-test (p=<0.001). LFT were drawn at first evaluation and during follow-up, we found that 119 patients (63.3%) had abnormal Alanine Transaminase (ALT) levels at baseline and after the 5-year follow-up only 30 patients (16%) had these abnormal levels. At the end of the follow-up 185 patients (98.4%) had undetectable HCV RNA levels. Only 3 patients experienced virological recurrence, all of them at 12 months after treatment. D) CONCLUSIONS: Long-term outcome in Mexican patients with adequate response to therapy is good, based on impact on LFT and liver biopsy results. Late virological relapse rate was very low and similar to earlier data on other ethnicities.

Disclosures:

The following people have nothing to disclose: Rocio Torres Ibarra, David R. Castelo Lopez, Enrique Alcala Martinez

1974

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Triple Therapy for Chronic Hepatitis C Virus (HCV) Infection: A Comparison of Outcomes in Patients with Minimal versus Advanced Fibrosis

Lauren E. Ayres1, Jacob Langness2, Sarah Tise2, James R. Burton2, Gregory T. Everson2;
1 University of Colorado School of Medicine, Aurora, CO; 2Hepatology, University of Colorado Hospital, Aurora, CO

Background: Patients with advanced fibrosis (METAVIR F3/F4) from hepatitis C virus (HCV) infection achieve great benefit in clearing HCV with antiviral treatment. However, advanced fibrosis impairs efficacy, reduces tolerability, and increases risk for serious adverse events, particularly infection, during inter-feron-based antiviral treatment. Herein we compare the efficacy, safety and tolerability of triple therapy (TT; peginterferon/ribavirin plus either telaprevir or boceprevir) between patients with minimal (F0-F2) versus advanced fibrosis (F3/F4). Methods: We retrospectively studied all patients with chronic HCV genotype 1 treated with TT at a university medical center outpatient hepatology clinic from May 1, 2011 - May 31, 2013. Information collected included demographic, clinical, virologic and outcomes data. A designation of advanced fibrosis was based on biopsy (F3/F4) or, in the case of cirrhosis, the diagnosis in 12 cases was based on clinical signs or imaging. A diagnosis of minimal fibrosis was based on biopsy (F0-F2). Results: 110 patients (54% with advanced fibrosis/cir-rhosis) were treated with triple therapy (94 telaprevir, 16 boceprevir). The majority were male (60%), older than 50 (71%), Caucasian (88%), and treatment-experienced (55%). Most demographic and baseline clinical characteristics were not statistically significant between minimal fibrosis and advanced fibrosis/cirrhosis cohorts; only males (69%) and previous null-responders (29%) were over-represented in the advanced fibrosis/cirrhosis group, and the proportion of patients naïve to treatment (57%) was significantly larger in the minimal fibrosis group (p<0.05). Sustained viral response (SVR) was 57% in patients with minimal fibrosis and 36% in patients with advanced fibrosis/cirrhosis (p<0.05). Early discontinuation of therapy was more common in the advanced fibrosis/cirrhosis cohort than in the minimal fibrosis cohort (58% vs. 33%; p<0.05). The proportion of patients who discontinued therapy early due to safety/tolerability did not vary between the groups (22% vs. 22%; p=0.95), however advanced fibrosis/cirrhosis patients discontinued therapy early because of viral breakthrough more often than those with minimal fibrosis (19% vs. 2%; p<0.01). Conclusion: Our results suggest that the impaired rate of SVR in patients with advanced fibrosis/cirrhosis is not due to side effects or intolerability, but rather viral breakthrough during antiviral therapy. This relationship may help inform reasons for decreased SVR in patients with advanced liver disease and warrants further investigation.

Disclosures:

James R. Burton - Grant/Research Support: Vertex pharaceuticals, Abbvie phar-maceuticals, Gilead pharmaceuticals

GregoryT. Everson - Advisory Committees or Review Panels: Roche/Genentech, Merck, HepC Connection, Roche/Genentech, Merck, HepC Connection; Board Membership: HepQuant LLC, PSC Partners, HepQuant LLC, PSC Partners; Consulting: Roche/Genentech, BMS, Gilead, Roche/Genentech, Bristol-Myers Squibb, Abbott; Grant/Research Support: Roche/Genentech, Pharmassett, Vertex, GSK, Schering-Plough, Bristol-Myers Squibb, Tibotec, GlobeImmune, Pfizer, Abbott, Conatus, Zymogenetics, PSC Partners, Roche/Genentech, Pharmassett, Vertex, GSK, Schering-Plough, Tibotec, GlobeImmune, Pfizer, Gilead, Conatus, Zymogenetics, PSC Partners, Abbott; Management Position: HepQuant LLC, HepQuant LLC; Patent Held/Filed: Univ of Colorado, Univ of Colorado

The following people have nothing to disclose: Lauren E. Ayres, Jacob Langness, Sarah Tise

1975

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Use of ribavirin monitoring to predict significant anaemia in patients being treated for Hepatitis C

Ashley Barnabas, Bo Wang, Halina Michur, Sarah Knighton, Suman Verma, Phillip Morgan, Abid Suddle, Ivana Carey, J Michael Tredger, Kosh Agarwal;
Institute for Liver Studies, Kings College London School of Medicine at Kings' College Hospital, London, United Kingdom

Background Despite therapeutic advances in Hepatitis C (HCV) treatment, on-treatment anaemia commonly leads to suboptimal antiviral agent doses, particularly in difficult to treat populations, and is a common cause of treatment discontinuation . Ribavirin is a highly significant cause of anaemia in HCV treatment. Due to its long half-life, peak ribavirin concentrations are usually only reached after 4–8 weeks of treatment. Therapeutic ribavirin levels of 2.0 - 3.0 mg/L have been recommended, but evidence for this is limited. Ribavirin dose reduction can be effective in the management of anaemia, without compromising therapeutic efficacy . Thus if early ribavirin levels reliably predict anaemia, patients could be considered for early ribavirin dose reduction and closer follow-up. An appropriate range of target ribavirin concentrations in newer DAA regimens has not yet been identified. We hypothesised that ribavirin monitoring within the first 12 weeks of treatment would allow us to identify patients at risk of early on treatment anaemia, in both DAA and non-DAA regimens. Methods Between June 2011 and May 2013, plasma ribavirin concentrations were measured in 51 patients with HCV genotypes 1–4 during the first 12 weeks of HCV treatment. Whole blood samples were processed within 90 minutes of collection, to minimise diffusion of intra-erythro-cytic ribavirin. Plasma ribavirin levels concentrations were determined using HILIC-tandem mass spectrotometry. Results 34 patients (66%) had genotype 1/4 and 17 patients (33%) had genotype 2/3 HCV infection. 32 patients (64%) had cirrhosis. 14 patients had undergone liver transplantation.22 patients (43%) were treated with a DAA regimen (telprevir = 9, boceprevir = 13). 17 patients overall (33%) achieved a sustained virological response to HCV treatment. Ribavirin concentrations >3mg/L. were noted in 29 patients (56%). Of 32 patients (63%) who experienced a haemoglobin decline of at least 3 g/dl at treatment week 12, 23 had achieved a ribavirin concentration of 3 mg/L. A ribavirin concentration >3 mg/L had a sensitivity of 72.0% (95% CI, 53.3 - 86.2 %), a specificity of 81.0% (62.5 - 92.5%), a positive predictive value of 79% ( 60.3 - 92.0% ) and a negative predictive value of 73.0% ( 55.6 - 87.1%). Specificity and sensitivity were similar in patients treated with DAA regimens (68.8 % (41.4–88.9%) and 85.7% (42.2–97.6%) and non-DAA regimens (75% (47.6%-92.6%) and 79.2% (57.8–92.8%) Conclusions In a diverse cohort of predominantly difficult to treat patients, a ribavirin concentration > 3mg/L identified most patients at risk of anaemia. This threshold remains useful in patients treated with DAA regimens.

Disclosures:

Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and Teaching: BMS

Kosh Agarwal - Advisory Committees or Review Panels: Gilead, BMS, Novartis, Janssen, Abbott, Gilead, BMS, Novartis, Janssen, Abbott, Gilead, BMS, Novartis, Janssen, Abbott, Gilead, BMS, Novartis, Janssen, Abbott; Grant/Research Support: Roche, MSD, Roche, MSD, Roche, MSD, Roche, MSD; Speaking and Teaching: Astellas, Astellas, Astellas, Astellas

The following people have nothing to disclose: Ashley Barnabas, Bo Wang, Halina Michur, Sarah Knighton, Suman Verma, Phillip Morgan, Abid Suddle, J Michael Tredger

1976

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Hepatitis C Genotype 1 Treatment Response And Outcomes Utilizing Combination Therapy With Telaprevir, Pegylated Interferon Alfa 2a And Ribavirin In Liver Transplant Recipients With Recurrent Cirrhosis

Kalyan R. Bhamidimarri1, Adam Peyton1, Lydia Aye1, Violet Copado2, Omer Junaidi2, Cynthia Levy1, Paul Martin1, Madhavi Rudraraju2;
1 Hepatology, University of Miami-Miller School of Medicine, Miami, FL; 2Hepatology, Methodist Specialty and Transplant Hospital, San Antonio, TX

Introduction: Limited data exists regarding the outcomes of treating recurrent hepatitis c (HCV) in liver transplant recipients (LTR) with recurrent cirrhosis. Aim: To assess safety and outcomes of telaprevir based treatment in LTR with HCV and recurrent cirrhosis. Methods: We studied 7 patients from two centers with HCV genotype 1 of which 6 had cirrhosis and 1 had fibrosing cholestatic variant who received HCV treatment with telaprevir after a median period of 42 months from LT. Immunosuppres-sion was switched to cyclosporine in 5 patients. Tacrolimus and cyclosporine doses were lowered to one tenth and one fifth of their total doses respectively while the patients received telaprevir. All patients received pegylated interferon alpha 2a (P), ribavirin (R) and telaprevir (T) 750mg thrice daily or 1125 mg twice daily as per response guided therapy without a lead-in. Results: Baseline characteristics of the cohort include 71% males, mean age of 56 years, 85% caucasian, 71% genotype 1a and an average MELD of 11. All patients had baseline cytopenias with mean WBC of 2.5k, hemoglobin of 10.7 gm/dl, platelets of 108k and 85% of the patients needed growth factors within the first month. Five patients (71%) achieved RVR and eRVR and 3/7 patients achieved SVR. One patient is still undergoing treatment and is aviremic at week 32 and 2/7 experienced virologic breakthroughs. Drug discontinuations occurred in 3/7 patients due to SAE. A total of 3 patients developed hepatic decompensation of which one underwent re-transplantation on week 20 of treatment and interestingly remained aviremic upto 36 weeks post transplant. There were no on-treatment deaths. Conclusions: Telaprevir treatment in this difficult to treat population with recurrent cirrhosis is feasible despite frequent side effects, virologic breakthroughs and hepatic decompensation. Careful selection of patients is paramount and may be beneficial especially to those who can be retransplanted.

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Disclosures:

Cynthia Levy - Advisory Committees or Review Panels: Johnson & Johnson, Novartis; Consulting: Lumena; Speaking and Teaching: Bayer, Vertex

Paul Martin - Consulting: Roche, BMS, Gilead, Vertex, Roche, BMS, Gilead, Vertex, Roche, BMS, Gilead, Vertex, Roche, BMS, Gilead, Vertex; Speaking and Teaching: Roche, BMS, Roche, BMS, Roche, BMS, Roche, BMS

The following people have nothing to disclose: Kalyan R. Bhamidimarri, Adam Peyton, Lydia Aye, Violet Copado, Omer Junaidi, Madhavi Rudraraju

1977

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Predictive value of low level on-treatment viremia during boceprevir-based re-treatment in a prospective study on difficult to treat previous treatment failure chronic hepatitis C patients

Bela Hunyady1,2, Michael Makara3, Attila Haragh1, Eszter Újhe-lyi4, Simone Susser5, Christoph Sarrazin5;
1Department of Gas-troenterology, Somogy County Kaposi Mor Teaching Hospital, Kaposvar, Hungary; 2First Deptartment of Medicine, University of Pecs, Pecs, Hungary; 3Central Outpatient Clinic, Saint Laszlo Hospital, Budapest, Hungary; 4Department of Molecular Biology, Saint Laszlo Hospital, Budapest, Hungary; 5Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany

Background. Protease inhibitor based therapies provide high chances of cure for many patients with chronic hepatitis C (HCV). However, costs as well as significant side-effects of treatments warrant appropriate futility rules, and accurate PCR methods to select patients who are unlikely to benefit from continuation of therapy based on on-treatment viral response. Aim. Concordance of the HCV viral load results measured by two different commercially available assays has been prospec-tively analyzed in a difficult to treat chronic hepatitis C patient population during re-treatment with boceprevir-based triple therapies. Methods. Parallel on-treatment week 12 (n=88) and week 24 (n=76) HCV RNA tests have been performed in previous pegylated interferon+ribavirin failure CHC patient with bridging fibrosis (F3) or cirrhosis (F4) based on histology and/or transient elastography who received boceprevir based triple therapy with 1) Roche Ampliprep/Cobas Taqman 2.0 system, lower limit of quantification (LLQ) and lower limit of detection (LOD): 15 IU/ml, and 2) Abbott realtime HCV test, lower limit of quantification (LLQ) and lower limit of detection (LOD): 12 IU/ml. Results. In samples with quantifiable viral load HCV RNA concentrations were an average 2.8 fold higher with the Roche versus the Abbott assay. Concordance of the two assays for stopping rule of HCV RNA>100 IU/ml (i.e., number of patient who had to stop plus who could continue by both of the tests) at week 12 and week 24 were 80/88 (91%) and 74/76 (97%), respectively. Concordance of the two assays for RNA target not detected and for RNA<LLQ at week 12 or week 24 were 30/42 (71%) and 42/69 (61%), or 50/57 (88%) and 63/63 (100%), respectively. Of 10 patients with RNA levels between LLQ and 100 IU/ml by either method at week 12, 5 broke through, 1 relapsed, and 1 achieved SVR so far (3 outcomes are still pending). Of 12 patients with detectable, but <LLQ HCV RNA by either method at week 24, 5 broke through, 1 relapsed, and 2 achieved SVR so far (4 outcomes are still pending). Conclusions. We found an >90% concordance of the two PCR methods for futility rules of current triple-therapy at weeks 12 and 24 with no specific clinical advantage of one method over the other. However, low level viremia by both assays at week 12 and at week 24 was associated with higher rate of non-SVR. Further analysis and testing are required to achieve optimal stopping rules in difficult to treat patient population.

Disclosures:

Michael Makara - Advisory Committees or Review Panels: MSD, BMS; Consulting: MSD, Roche, Janssen; Grant/Research Support: Janssen, Idera, Novartis, Boehringer Ingelheim

Christoph Sarrazin - Advisory Committees or Review Panels: Boehringer Ingelheim, Vertex, Janssen, Merck/MSD, Gilead, Roche, Boehringer Ingelheim, Achillion, Janssen, Merck/MSD, Gilead, Roche; Consulting: Merck/MSD, Novartis, Merck/MSD, Novartis; Grant/Research Support: Abbott, Intermune, Roche, Merck/MSD, Gilead, Janssen, Abbott, Roche, Merck/MSD, Vertex, Gilead, Janssen; Speaking and Teaching: Bristol-Myers Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Falk, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead, Novartis, Abbott, Roche, Merck/MSD, Janssen, Siemens, Falk, Boehringer-Ingelheim

The following people have nothing to disclose: Bela Hunyady, Attila Haragh, Eszter Újhelyi, Simone Susser

1978

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Long term clinical impacts of interferon-free direct antiviral agent therapy for chronic hepatitis C genotype 1 infection in the Veterans Health Administration

Mai-Ngan Lai, Kee Chan, Erik J. Groessl, Samuel B. Ho;
VA San Diego Healthcare System, San Diego, CA

Background: Current estimates indicate there are 102,851 treatment naïve HCV genotype 1 patients in the Veterans Health Administration (VHA). The majority of patients with hepatitis C are unable or unwilling to use interferon (IFN)-based treatment. The advent of IFN-free DAA regimens of high efficacy and low adverse event (AE) profiles should allow for an expanded uptake of treatment. Our objective was to estimate the long term clinical outcomes with and without IFN-free DAA regimens compared with IFN-based DAA for HCV-1 patients in VHA. Methods: A Markov model was developed to simulate the lifetime progression of HCV and the clinical impacts of DAA in genotype 1 treatment naïve patients. We compared four treatment strategies: (1) No treatment, (2) NS3/4A inhibitor+pegy-lated intergeron/ribavirin (P/R) (3) Nuc NS5B inhibitor+P/R, and (4) IFN-free regimens. Adherence, AE and SVR rates were derived from phase II and phase III trial data. Sensitivity analyses examined the impact of varied treatment rates and SVR rates on clinical outcomes. Results: With 25% treatment rates of interferon-containing therapies, the long term reduction in liver related death from treatment NS3/4a+PR, NucNS5B+PR, and IFN-free regimens compared to no treatment, are 15%, 20%, and 20%, respectively. Increasing treatment rates to 50% results in long term reduction in liver-related deaths of 30%, 30% and 40%, respectively. Increasing treatment rates to 90% of patients with IFN-free regimens results in a 71% reduction in liver-related deaths. Incremental cost effectiveness ratio (ICER) of IFN-free regimens or NucNS5B+PR compared to IFN-based DAA range from “cost saving” to $107,000/QALY based on a range of potential costs from $50k -100k per course of treatment. Conclusions: In the near future, IFN-DAA regimens are expected to be highly effective, but maximal uptake will be limited. In contrast, IFN-free regimens may have a much higher treatment uptake, resulting in a potential for40%-71% reduction in liver deaths, respectively. These projections enable cost-effectiveness projections based on a range of possible medication costs. These data illustrate the implications of markedly increasing antiviral treatment rates using IFN-free regimens in the VHA system.

Table. Cumulative VHA lifetime outcomes

 eo treatmentNS3/4A inhibitor+P/R Nuc NS5B inhibitor+P/R IFN-free regimens  
SVR0%70% 90% 90%  
Treatment rate0%25%50% (max expected)25%50% (max expected)25%50%90% (max expected)
Decompensated cirrhosis29,13524,03618,93722,57916,02422,57916,0245,536
HCC15,36813,43611,50312,88410,39912,88410,3996,425
Liver transplant3,0362,5101,9832,3601,6842,3601,684600
         
Liver related death30,82826,09821,36824,74618,66524,74618,6658,935

Disclosures:

Erik J. Groessl - Stock Shareholder: Gilead, Bristol Myers Squibb

Samuel B. Ho - Grant/Research Support: Roche, Genentech, Vital Therapies, Aspire Bariatrics

The following people have nothing to disclose: Mai-Ngan Lai, Kee Chan

1979

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Normalization of ALT at 8th week predicts viral response during peginterferon-ribavirin treatment in genotype 1 CHC patients

Umit B. Dogan, Mustafa S. Akin, Serkan Yalaki;
Gastroenterology, Adana Numune Training and Research Hospital, Adana, Turkey

Background: Rapid virological response (RVR) is a powerful on-treatment predictor of sustained virological response (SVR) during treatment of chronic hepatitis C (CHC). But RVR rates are relatively low and there is need for a new predictor such as ala-nine aminotransferase (ALT) for patients especially without RVR. We aimed to investigate the relationship between on-treatment ALT changes and SVR in CHC patients during peginterferon-ribavirin treatment. Methods: 151 genotype 1 CHC patients were retrospectively divided into two groups as having RVR (group-1, n=52) and not (group-2, n=99). We also subdivided each group into two groups according to the initial ALT level being high (group-1 h and group-2h) or normal (group-1 n and group-2n). ALT levels were obtained at baseline; weeks 4, 8, 12, 24, and 48 of treatment; and follow-up week 24. Patients with high and normal ALT levels were compared for each interval in terms of SVR. Results: The SVR rates were 83% vs. 40%, p=0.000, 82% vs. 84%, p=0.830, and 37% vs. 44%, p=0.466 when comparing group 1 with 2, 1 h with 1 n and 2h with 2n, respectively. In group 2h, SVR rates were 34% vs. 40%, p=0.701, 11% vs. 52%, p=0.004, 12% vs. 50%, p=0.007, 7% vs. 50%, p=0.003, 6% vs. 53%, p=0.001, and 0% vs. 64%, p=0.000 when comparing patients with high and normalized ALT levels at weeks 4, 8, 12, 24, 48, and 72, respectively (Figure). Multiple logistic regression analysis revealed that RVR (OR=7.05, 95% CI=3.1–16.05, P=0.000), cEVR (OR=17.55, 95% CI=6.32–48.76, P=0.000), normalization of ALT at week 8 (OR=3.04, 95% CI= 1.31–7.06, P=0.008), and at week 12 (OR=4.21, 95% CI=1 .65–10.76, P=0.002) were identified as independent significant predictive factors for SVR. Conclusion: In conclusion, normalization of ALT at 8th week may predict viral response during peginterferon-ribavirin treatment in genotype 1 CHC patients especially without RVR.

Sustained virological response (SVR) rates in the patients without rapid virological response (RVR) in terms of ALT normalization.

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Disclosures:

The following people have nothing to disclose: Umit B. Dogan, Mustafa S. Akin, Serkan Yalaki

1980

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Utility of acoustic radiation force impulse (ARFI) to assess liver fibrosis in chronic hepatitis C patients receiving triple therapy with NS3/4 protease inhibitors

Ryoko Yamada1, Naoki Hiramatsu1, Naoki Morishita1, Naoki Harada1, Hayato Hikita1, Tsugiko Oze1, Masanori Miyazaki1, Takayuki Yakushijin1, Yoshihiro Kamada1, Takuya Miyagi1, Yuichi Yoshida1, Tomohide Tatsumi1, Tatsuya Kanto2, Akinori Kasahara1, Norio Hayashi3, Tetsuo Takehara1;
1 Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan; 2The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Tokyo, Japan; 3Kansai Rousai Hospital, Amagasaki, Japan

Background & Aim: In chronic hepatitis C (CH-C) patients receiving dual therapy with peginterferon plus ribavirin, the degree of fibrosis is strongly associated with the anti-viral effect and improvement in the histological fibrosis score in SVR patients. As a non-invasive assessing liver fibrosis, acoustic radiation force impulse (ARFI) has been utilized for patients with chronic liver disease. In this study, we investigated the association between the sheer wave velocity (Vs) values measured by ARFI at baseline and the anti-viral response following triple therapy, as well as the change in Vs values after initiating therapy. Patients & Methods: A total of 44 CH-C patients receiving triple therapy were enrolled and examined using ARFI at baseline, at the end of therapy (EOT) and at the end of follow-up (EOF). Triple therapy consisted of telaprevir (n=17), simepre-vir (n=20) and vaniprevir (n=7). Liver biopsy was performed in 43 patients at baseline and graded using the METAVIR score. The enrolled patients showed the following characteristics: age, 58.6±9.6 y.o.; male/female, 21/23; genotype 1/2, 36/8; IL28B genotype TT/GT or GG, 32/11; activity A1/2/3, 39/4/0; and fibrosis F1/2/3/4, 31/2/8/2. Results: The Vs value at baseline was significantly correlated with the METAVIR fibrosis score (Pearson correlation coefficient, 0.761, p<0.001) and demonstrated better correlation than APRI (0.600, p<0.001) or FIB4 (0.562, p<0.001). In genotype 1 patients, 81% achieved RVR, 97% EVR and 92% SVR. Patients with above-average Vs values (>1.27 m/s) demonstrated equiva-lently high SVR rates as those with lower Vs values (<1.27) (100% (13/13) vs. 87% (20/23), p = 0.248). Among patients with higher Vs values, favorable SVR rates were observed for both the TT genotype and the GT or GG genotype (100% (8/8) vs. 100% (4/4)). In regards to the change in Vs values after the initiation of triple therapy, we divided the patients into SVR and non-SVR groups. In the SVR group, the mean Vs values were 1.28±0.33 at baseline, 1.23±0.26 at EOT and 1.18±0.26 at EOF; these values decreased significantly with time. In the non-SVR group, the Vs values at these time points were 1.15±0.10, 1.05±0.04 and 1.05±0.12, respectively, indicating no significant change after initiating therapy. Conclusions: For patients receiving triple therapy for CH-C, the Vs values measured using ARFI (reflecting the degree of liver fibrosis) did not serve as a predictive factor for treatment response. However, among patients achieving SVR, the Vs value decreased during treatment, indicating an improvement in liver fibrosis following triple therapy with NS3/4 protease inhibitors.

Disclosures:

Tetsuo Takehara - Grant/Research Support: Chugai Pharmaceutical Co., MSD K.K.

The following people have nothing to disclose: Ryoko Yamada, Naoki Hiramatsu, Naoki Morishita, Naoki Harada, Hayato Hikita, Tsugiko Oze, Masanori Miyazaki, Takayuki Yakushijin, Yoshihiro Kamada, Takuya Miyagi, Yuichi Yoshida, Tomohide Tatsumi, Tatsuya Kanto, Akinori Kasahara, Norio Hayashi

1981

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Virological response and tolerance of triple therapy including Telaprevir or Boceprevir in HIV-HCV co-infected cirrhotic patients: real-life early findings from the prospective ANRS CO13 HEPAVIH cohort

Patrick Miailhes2, Eric Rosenthal3, Stephanie Dominguez4, Philippe Morlat5, Michel Dupon6, Marc-Antoine Valantin7, Camille Gilbert1, Maria Winnock1, Dominique Salmon8, Philippe Sogni9;
1Centre Recherche INSERM U897, ISPED Université Bordeaux2, Bordeaux, France; 2Serv Maladies Infectieuses, Hôpital Croix Rousse, Lyon, France; 3Serv Médecine Interne, CHU Archet, Nice, France; 4Serv Immunologie Clinique, CHU Henri Mondor, Paris, France; 5Serv Médecine Interne, CHU Saint André, Bordeaux, France; 6Fédéra-tion Maladies Infectieuses et Tropicales, CHU Pellegrin, Bordeaux, France; 7Serv Maladies Infectieuses et Tropicales, Gpe Hospitalier Pitié Salpétrière, Paris, France; 8Serv Maladies Infectieuses et Tropicales, Hôpital Cochin, Paris, France; 9Serv Hépatogastroentérolo-gie, Hôpital Cochin, Paris, France

Background: The prescription of triple therapy including Telaprevir or Boceprevir has been limited, so far, in HIV-HCV co-infected cirrhotic patients. Methods: We prospectively gathered data from the ANRS C013 HEPAVIH cohort of HIV-HCV co-infected patients with non decompensated cirrhosis and who initiated a triple therapy with Telaprevir (TPV) or Boceprevir (BOC) outside clinical trials. Data points were : triple therapy initiation, week (W) 2, W4, and every four weeks thereafter. Cirrhosis was defined as previously published in the cohort [1 ]. Rapid virological response (RVR4) and early virological response (EVR) were defined as undetectable HCV plasma RNA at W4 and at W12. Adverse events (rash, anemia) were prospectively documented. Results: 27 HIV-HCV cirrhotic patients (4 naïve, 22 non responders, 1 relapser after a previous HCV treatment course of Peg-IFN and Ribavirin) were included. Twenty-one received TPV and 6 BOC. Their median age was 49 years and 85% were male. All patients were on HAART, HIV RNA was undetectable at baseline in 92%, and median CD4 was 527/mm3 [IQR: 415–801 ] at HCV treatment initiation. HCV genotype 1a was identified in 20 (74%) patients and 1 b in 7 patients; median HCV RNA was 6.04 log 10 UI/ml at baseline. RVR4 was observed in 10/22 (45%) patients with available results (all of them were on TPV), and EVR in 13/17 (76%) patients (9/13 on TPV). EVR was achieved in 11/14 (79%) and in 2/3 of patients with HCV genotype 1 a and 1 b, respectively. After 12 weeks of triple therapy, half of the patients (2/6 on BOC and 7/12 on TVR) developed severe anemia (Hb <9 g/dl or an absolute drop >4.5 g/dl). EPO was prescribed in 3 patients, and a blood transfusion in 2 patients. Only one level-1 rash was observed, in the TVR-treated group. The Ribavirin dose was reduced in 7/27 patients during the course of triple therapy. Four patients discontinued the treatment during the first three months because of virological failure (3/4) or drug toxicity (1/4). No decompensation of cirrhosis was observed. Conclusion: In real-life, triple therapy leads to a high rate of EVR in cirrhotic HIV-HCV co-infected patients. EVR was observed at W12 on all of the naïve patients and on more than 2/3 of the nonresponders. However, severe anemia was frequent and led to intensive monitoring and prescription of EPO. [1] Loko et al. BMC Infectious Diseases 2010, 10:303

Disclosures:

Eric Rosenthal - Board Membership: gilead, msd

Michel Dupon - Consulting: janssen Cilag France

Marc-Antoine Valantin - Board Membership: Gilead, Bristol-Myers; Speaking and Teaching: Janssen-cilag

Philippe Sogni - Independent Contractor: Gilead, Roche, MSD, BMS, Janssen, Mayoli-Spindler

The following people have nothing to disclose: Patrick Miailhes, Stephanie Dominguez, Philippe Morlat, Camille Gilbert, Maria Winnock, Dominique Salmon

1982

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Symptoms of anxiety and depression are frequent in patients with acute hepatitis C and are not associated with disease severity

Katja Deterding1,2, Norbert Grüner1,3, Peter Buggisch1,5, Peter R. Galle1,6, UlrichSpengler1,7, Holger Hinrichsen1,8, Thomas Berg1,9, Andrej Potthoff1,2, Nisar P. Malek1,10, Anika Grosshennig1,11, Armin Koch1,11, Helmut M. Diepolder1,3, Stefan Lüth1,5, Sandra Feyerabend1, Maria-Christina Jung1,3, Magdalena Rogalska-Taranta1,12, Verena Schlaphoff1,12, Markus Cornberg1,2, Michael P. Manns1,2, Heiner Wedemeyer1,2, Johannes Wiegand1,4;
1Hep-Net: German Network of Competence on Viral Hepatitis, Hannover, Germany; 2Dep. of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 3Medical Department II and Institute for Immunology, Ludwig-Max-imilians-University, Munich, Germany; 4Department of Internal Medicine, Division of Gastroenterology and Rheumatology, University of Leipzig, Leipzig, Germany; 5I. Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 6I. Department of Internal Medicine, University Medical Center, Mainz, Germany; 7Department of Internal Medicine I, University of Bonn, Bonn, Germany; 8Department of Medicine, Christian-Albrechts-University, Kiel, Germany; 9Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany; 10Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany; 11Department of Biometry, Hannover Medical School, Hannover, Germany; 12Diagnostic Laboratory, Hannover Medical School, Hannover, Germany

Patients with acute hepatitis C virus (HCV) infection can be treated with an interferon alpha based therapy if severe psychiatric diagnosis has been excluded. However, frequency and intensity of anxiety and depression in patients with acute hepatitis C have not been investigated yet. We applied the Hospital Anxiety and Depression Scale (HADS) within a prospective clinical trial in patients with acute hepatitis C. Methods: Data were analysed from the German Hep-Net-Acute HCV-III study which was designed as a prospective, randomized trial in patients with symptomatic acute hepatitis C comparing the efficacy and safety of immediate PEG-IFNa-2b monotherapy versus delayed treatment with PEG-IFNa-2b plus ribavirin starting 12 weeks after randomisation in patients who were still HCV-RNA positive (Lancet Infect Dis., Epub 2013 Mar 22). All asymptomatic patients were assigned to early PEG-IFNa-2b treatment. Patients with a confirmed diagnosis of psychiatric disorders (e.g. severe depression) and ongoing i.v. drug abuse were excluded. To identify symptoms of anxiety and depression we used the Hospital Anxiety and Depression Scale which is divided in an anxiety (HADS-A) and a depression subscale (HADS-D) both containing seven items. The maximum HADS score is 21 and more than 8 points in each subscale are considered clinically relevant. HADS data were prospectively collected at baseline, end of treatment and at the end of the study. Results: At baseline, HADS- A and HADS-D scores above 8 were observed in 23 (22%, mean 5; range 0–16) and 12 (12%; mean 4; range 0–19) of 103 patients. Antiviral therapy did not influence severity and intensity of anxiety as 24% of patients had HADS-A above 8 at the end of therapy. Of note, the depression subscale HADS-D did not increase during antiviral therapy and only 5 patients with a normal HADS-D before therapy showed a score above 8 after the end of treatment. Symptoms of anxiety and depression did not correlate with severity of disease as investigated by ALT and bilirubin levels. Similarily, gender and HCV-genotype were not associated with HADS scores. Sustained virological response did not influence HADS-A and HADS-D. HADS data from 8 of 21 patients (38%) who were lost to follow-up before the end of therapy were available, only one of these patients had an HADS-A and HADS-D above 8 at baseline. Conclusion: Symptoms of anxiety and depression are frequent in patients with symptomatic and asymptomatic acute HCV infection and are independent of the severity of disease. However, HADS does not seem to be associated with lost to follow-up both in immediate as well as in delayed treatment.

Disclosures:

Peter Buggisch - Advisory Committees or Review Panels: BMS; Speaking and Teaching: MSD Pharma, Roche Pharma AG, Gilead Sciences, Novartis AG, Janssen Pharma

Peter R. Galle - Advisory Committees or Review Panels: Bayer, BMS, Lilly, Daiichi, Jennerex; Consulting: Medimmune; Grant/Research Support: Roche, Lilly; Speaking and Teaching: Bayer, BMS

Holger Hinrichsen - Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: Janssen

Thomas Berg - Advisory Committees or Review Panels: Gilead, BMS, Roche, Tibotec, Vertex, Jannsen, Novartis, Abbott, Merck; Consulting: Gilead, BMS, Roche, Tibotec; Vertex, Janssen; Grant/Research Support: Gilead, BMS, Roche, Tibotec; Vertex, Jannssen, Schering Plough, Boehringer Ingelheim, Novartis; Speaking and Teaching: Gilead, BMS, Roche, Tibotec; Vertex, Janssen, Schering Plough, Novartis, Merck, Bayer

Markus Cornberg - Advisory Committees or Review Panels: Merck (MSD Ger-mamny), Roche, Gilead, Novartis; Grant/Research Support: Merck (MSD Ger-mamny), Roche; Speaking and Teaching: Merck (MSD Germamny), Roche, Gilead, BMS, Novartis, Falk

Michael P. Manns - Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis

Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD, Roche, Gilead, Abbott, BMS, Falk; Grant/Research Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS, MSD, Novartis, ITF

The following people have nothing to disclose: Katja Deterding, Norbert Grüner, Ulrich Spengler, Andrej Potthoff, Nisar P. Malek, Anika Grosshennig, Armin Koch, Helmut M. Diepolder, Stefan Lüth, Sandra Feyerabend, Maria-Christina Jung, Magdalena Rogalska-Taranta, Verena Schlaphoff, Johannes Wiegand