Viral hepatitis


211

All-oral Combination of Daclatasvir Plus Asunaprevir in Interferon Ineligible Naive/Intolerant and Nonresponder Japanese Patients Chronically Infected with HCV Genotype 1b: Results from a Phase 3 Trial

Kazuaki Chayama1, Yoshiyuki Suzuki2, Kenji Ikedo2, Joji Toyota3, Yoshiyasu Karino3, Yoshiiku Kawakami1, Akio Ido4, Kazuhide Yamamoto5, Koichi Takaguchi6, Namiki Izumi7, Kazuhiko Koike8, Tetsuo Takehara9, Norifumi Kawada10, Michio Sata11, Hidetaka Miyagoshi12, Timothy Eley13, Fiona McPhee13, Wenhuo Hu13, Hiroki Ishikawa12' Eric A. Hughes13, Hiromitsu Kumodo2

1Hiroshima University' Hiroshima, Japan; 2Toranomon Hospital, Tokyo, Japan; 3Sapporo-Kausei General Hospital, Sapporo, Japan; 4Kagoshima University, Kagoshima, Japan; University, Okayama, Japan; 6Kagawa prefectural Hospital, Kagawa, Japan; 7Musashino Red Cross Hospital, Tokyo, Japan; 8University of Tokyo, Tokyo, Japan; 9Osoko University, Osako, Japan; 10Osako City University, Osako, Japan; 11 Kurume University, Fukuoka, Japan; 12Bristol-Myers KK, Tokyo, Japan; 13Bristol-Myers Squibb, Princeton, NJ

Background: Rates of sustained virologic response (SVR) in Japanese nonresponder (NR) patients receiving peginterferon/ribavirin (P/R) combined with telaprevir are lower (34%) compared with rates in treatment-naīve patients (73%) infected with genotype 1. We evaluated the safety and efficacy of P/Rfree, dual oral therapy with daclatasvir (DCV) and asunaprevir (ASV) in interferon ineligible naive/intolerant (IN/I) and NR Japanese patients infected with HCV genotype 1b. Methods: In this open-label, parallel group, phase 3 study, IN/I (n=135) and NR (n=87) patients received DCV 60 mg once daily plus ASV 100 mg twice daily for 24 weeks. The primary endpoint was the percentage of patients with SVR at 24 weeks after the end of treatment (SVR24). Interim results at post-treatment followup Week 12 are described; complete SVR24 results will be presented. Results: The median age of patients was 62. 5 years, 65% were female, and 10% were cirrhotic Mean baseline HCV RNA was 6. 6 log10 IU/mL. IN/I patients were primarily CC IL28B genotype (7010%), 82% of NR patients were non-CC IL28B genotype (rs12979860). By Week 2, the mean decrease in HCV RNA was >5 log10 U/mL in both groups. Overall rates of SVR12 were 85. 6% (see Table). Baseline factors including gender, age, baseline HCV RNA, IL28B status, or cirrhosis did not appear to impact response rates. No deaths occurred. 14 patients in each group (13%) discontinued dual therapy mainly due to adverse events (AEs; 9-IN/I, 2-NR) and lack of efficacy (4-IN/I, 11-NR). 9 NR patients were administered additional treatment with P/R at the discretion of the investigator. The most common AE leading to discontinuation was ALT/AST elevation (10/11; 91%); despite early discontinuation 80% of these patients achieved SVR. 1 patient discontinued due to myasthenia gravis. The rate of serious AEs was low (6%) and varied among patients. The most common AEs were nasopharyngitis (30%), increased ALT (16%) and AST (13%), headache (15%), diarrhea (10%), and pyrexia (10%). Conclusions: Interim results at 12 weeks post-treatment demonstrate a high response rate to dual therapy with DCV and ASV in both IN/I and NR patients. Treatment with DCV plus ASV was well tolerated with no unexpected safety findings. Results at 24 weeks post-treatment (SVR24) will be presented.

HCV RNA < LLOQ, n (%)Ineligible naive/Intolerant (IN/I) Patients n =135 a Nonresponder (NR) Patients n = 87b Total N = 222
  1. 3 Ineligible naive: n=100; Intolerant: n=35 bNull responders: n=48; Partial responders: n=36; Undetermined: n=3, す target not detected; + target detected or target not detected RVR: rapid viral response; cEVR: complete early viral response; SVR 4: sustained virologic response at follow-up Week 4; SVR 12: sustained virologic response at follow-up Week 12

RVR, Week 4114(84. 4)53 (60.9)167 (75. 2)
cEVR, f Week 12125 (92. 6)77 (88. 5)202(91. 0)
svr 4 * 126(93. 3)71(81. 6)197 (88. 7)
SVR 12 $ 120(88. 9)70 (80.5)190 (85. 6)

Disclosures:

Kazuaki Chayama - Consulting: Abbvie; Grant/Research Support: Dainippon Sumitomo, Chugai, Mitsubishi īanabe, DAIICHI SANKYO, Toray, BMS, MSD; Speaking and Teaching: Chugai, Mitsubishi īanabe, DAIICHI SANKYO, KYORIN, Nihon Medi-Physics, BMS, Dainippon Sumitomo, MSD, ASKA, Astellas, AstraZeneca, Eisai, Olympus, GlaxoSmithKline, ZERIA, Bayer, Minophagen,

Shinyaku, Takeda, AJINOMOTO, Meiji Seika, Toray

Kenji Ikeda - Speaking and Teaching: Dainippon Sumitomo Pharmaceutical Company

Joji Toyota - Speaking and Teaching: MSD

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

Namiki Izumi - Speaking and Teaching: MSD Co., Chugai Co., Daiichi Sankyo Co., Bayer Co., Bristol Meyers Co.

Kazuhiko Koike - Speaking and Teaching: Bristol-Myers Squibb

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

Michio Sata - Speaking and Teaching: MSD K. K., Chugai Pharmaceutical Co.,

Hidetaka Miyagoshi - Employment: Bristol-Myers KK

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

Fiona McPhee - Employment: Bristol-Myers Squibb Wenhua Hu - Employment: Bristol-Myers Squibb

Hiroki Ishikawa - Employment: Bristol-Myers Squibb, Bristol-Myers Squibb Eric A. Hughes - Employment: Bristol-Myers Squibb

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

The following people have nothing to disclose: Yoshiyuki Suzuki, Yoshiyasu Karino, Yoshiiku Kawakami, Akio Ido, Koichi Takaguchi, Norifumi Kawada

212

All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1,2, and 3 Infection in Patients Co-infected With HIV (PHOTON-1)

Mark S. Sulkowski1, Maribel Rodriguez-Torres2, Jacob P. Lalezari3, W. Jeffrey Fessel4, Karam Mounzer5, Magaret C. Shuhort6, Anne Luetkemeyer7, David M. Asmuth8, Anuj Gaggar9, William T Symonds9, John G. McHutchison9, Susanna Naggie10, Douglas T Dieterich11

1Johns Hopkins Medical Center, Baltimore, MD; 2Fundacion De Investigacion, San Juan; 3Quest Clinical Research, San Francisco, CA; 4Kaiser Permanente, San Francisco, CA; 5Philadelphia FIGHT, Philadelphia, PA; 6Harborview Medical Center, Seaftle, WA; 7San Francisco General Hospital, San Francisco, CA; 8University of California Davis Medical Center, Sacramento, CA; 9Gilead Sciences, Inc., Foster City, CA; 10Duke Clinical Research Institute, Durham, NC; 11Mount Sinai School of Medicine, New York, NY

Background and Aims: HIV/HCV co-infected patients are in need of effective interferon-free HCV therapy that can be given safely with antiretroviral therapy (ART). We evaluated the safetyand efficacy of the oral HCV NS5B inhibitor sofosbuvir (SOF) with ribavirin (RBV) in HIV-seropositive patients coinfected with HCV genotypes (GT) 1-3. Methods: HCV treatment-naīve patients with stable HIV disease received SOF 400 mg QD and RBV 1000-1200 mg/day; GT 1 patients received 24 weeks and GT 2/3 patients received 12 weeks of treatment. Multiple ART regimens were permitted as were patients with compensated cirrhosis. The primary efficacy endpoint was sustained virologic response 12 weeks after treatment, (SVR12); safety assessments included HIV RNA and CD4 cell levels. Results: The table shows baseline characteristics and virologic responses. Among patients with GT 2 and 3, SVR12 was achieved in 81% (21/26) and 67% (28/42), respectively. Among the 19 GT 2 or 3 patients without SVR12, viral relapse was confirmed in 12 and post-treatment week 12 data were missing for 6. HCV breakthrough was observed in 1 patient with documented non-adherence. Week 4 HCV RNA was <25 Iし/mL in 96% of GT 1 patients. Treatment discontinuations due to adverse events (AEs) have been uncommon (3%) and grade 3/4 AEs were reported in 17 (9%) patients. Two patients had HIV breakthrough: 1 in the setting of ART non-adherence, and regained HIV control without ART change. Conclusions: Treatment-naīve HCV GT 2/3 patients coinfected with HIV achieved high rates of SVR12 with 12 weeks of an interferon-free, oral regimen of S〇F+RBV. These preliminary data suggest that S〇F+RBV treatment was well-tolerated and safe with multiple ART regimens and may be equally safe and efficacious in patients with and without HIV coinfection.

GT1 (N=114)GT2 (N=26) <b/>GT3 (N=42)
Male, n (%) 93 (82) 21(81) 34 (81)
Black, n(%) 37 (33) 6(23) 2(5)
IL28B CC genotype, n (%) 30 (27) 10 (39) 15 (36)
Baseline Characteristics Cirrhosis, n (%) 5⑷ 1⑷ 6(14)
Log10 HCV RNA (IU/mL), mean (SD) 6. 6 (0.8) 6. 5 (0.6) 6. 2 (0.6)
CD4 T-cell count (cells/μL), mean (SD) 636 (251) 627 (278) 559 (224)
On ART, n(%) 112(98) 22 (85) 39 (93)
Efavirenz, n (%) 42 (37) 7(27) 13 (31)
ART Regimen: Tenofovir/Emtricitabine PLUS Atazanavir/ritonavir, n 24 (21) 4(15) 3(7)
Darunavir/ritonavir, n 15 (13) 6(23) 11(26)
Raltegravir, n (%) 21(18) 2(8) 6(14)
Other, n (%) 10(9) 3(12) 6(14)
Virologic Responses Week 4 HCV RNA <25 IU/mL, n/N (%) 109/113 (96) 25/26 (96) 41/41 (100)
SVR12, n/N (%) [To be presented] 21/26 (81) 28/42 (67)

Disclosures:

Mark S. Sulkowski - Advisory Committees or Review Panels: Pfizer; Consulting: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead, BMS, BMS; Grant/Research Sup port: Merck, AbbVie, BIPI, Vertex, Janssen, Gilead

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

Karam Mounzer - Advisory Committees or Review Panels: Gilead Sciences, BMS, J& J; Grant/Research Support: Boehrlingher Ingelheim, Gilead Sciences, Glaxo Smith Kline ViiV, Janssen and Janssen; Speaking and Teaching: Gilead Sciences,

Margaret C. Shuhart - Grant/Research Support: Gilead

Anne Luetkemeyer - Grant/Research Support: Gilead, Vertex, Pfizer, Bristol Myers Squibb

Anuj Gaggar - Employment: Gilead Sciences William ī. Symonds - Employment: Gilead

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

Susanna Naggie - Advisory Committees or Review Panels: Vertex Pharmaceuticals, Boehinger Ingelheim, Gilead, Abbott; Grant/Research Support: Vertex Pharmaceuticals, Anandys, Scynexis, Medtronic, Gilead, Abbott, BMS, Jenssen

Douglas T. Dieterich - Advisory Committees or Review Panels: Gilead, Genentech, Janssen, achillion, idenix, Merck, Tobira, Boehringer Ingelheim, Tibotec, Inhibitex, Roche, Vertex

The following people have nothing to disclose: Jacob P. Lalezari, W. Jeffrey Fessel, David M. Asmuth

213

Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation

Michael P Curry1, Xavier Forns2, Raymond T Chung3, Norah Terrault4, Robert S. Brown5, Jonathan M. Fenkel6, Fredric D. Gordon7, Jacqueline G. Oleary8' Alexander Kuo9, Thomas D. Schiano10, Gregory T. Everson11, Eugene R. Schiff12, Alex Befeler13, John G. McHutchison14, William T. Symonds14, Jill M. Denning14, Lindsay McNair14, Sarah arterburn14, Dilip Moonko15, Edward J. Gone16, Nezam H. Afdhal1

1Beth Israel Deaconess Medical Center, Boston, MA; 2The Liver Unit, Barcelona, Spain; 3Massachuset General Hospital, Boston, MA; 4University of California San Francisco, San Francisco, CA; 5Columbia University, New York, NY; 6Thomas Jefferson University Hospital, Philadelphia, PA; 7Lahey Clinic, Burlington, MA; 8Baylor University Medical Center, Dallas' TX; 9University of California San Diego' La Jolla, CA; 10Mount Sinai School of Medicine, New York, NY; 1 University of Colorado, Denver, CO; 12University of Miami, Miami, FL; 13St. Louis University, St Louis, MO; 14Gilead Sciences, Foster City, CA; 15Henry Ford Health Sysfem, Detroit, Ml; 16Auckland City Hospital, Auckland, New Zealand

Background: Recurrent HCV infection of the allograft is universal in patients with detectable HCV RNA at the time of liver transplantation (LT) and may result in accelerated progression to cirrhosis and graft loss. Interferon-based antiviral treatment before LT can prevent HCV recurrence, but this treatment is poorly tolerated and effective in only a minority of patients. Methods: In this phase 2 open-label study, patients with chronic HCV infection of any genotype (GT) listed for LT for hepatocellular carcinoma (HCC) received up to 48 weeks of sofosbuvir 400 mg/day and ribavirin 1000-1200 mg/day before LT. All patients had HCC within Milan criteria and well compensated cirrhosis (しhild-Pugh-Turcotte score of <7). The primary endpoint was virologic response (HCV RNA <25 Iし/mL)12 weeks after LT in patients who had HCV RNA <25 Iし/mL at their last measurement prior to LT (SVR12). Post-LT immunosuppressive regimen was tacrolimus plus prednisone with or without mycophenolate mofetil. Results: A total of 61 patients (24 GT 1a, 21 GT 1b, 8 GT 2, 7 GT 3, and 1 GT 4) were enrolled and received study drug (mean age 59 years, 80% male, 10% black, 20% Hispanic, 75% previously treated, with a mean baseline HCV RNA of 6. 14 log10 IU/mL [range 4. 06-7. 23 log10 IU/mL]). To date, 40 patients have undergone LT. Of these, 37 were <25 IU/mL and 3 were >25 IU/mL at last HCV RNA measurement prior to LT. Of the 3 patients with HCV RNA >25 IU/mL, 1 had on-treatment virologic failure and 2 had post-treatment relapse (after 24 weeks of treatment). One of the 37 patients received an HCV-infected allograft and was excluded from the efficacy analysis. The remaining 36 patients included in efficacy analysis received a mean of 17. 1 (range to 33. 7) weeks of treatment prior to LT. At the time of writing, 26 patients have reached at least 12 weeks post-transplant, of whom 18 (69%, 90% CI 51% to 84%) achievedSVR12. Seven patients (27%) had recurrence, and one (4%) died of primary graft non-function after retransplantation. The rate of recurrence was not associated with the duration of pretransplantation treatment nor with HCV genotype. The most frequently reported adverse events were fatigue, anemia, and rash. Two patients discontinued treatment due to AEs of acute renal failure and pneumonitis, neither was attributed to study drug. One SAE, anemia, was considered related to study drug. Conclusions: Sofosbuvir and RBV was safe and effective in patients with well compensated cirrhosis, and prevented posttransplant HCV recurrence in 69% of patients who had HCV RNA <25 Iし/mL prior to transplant.

Disclosures:

Michael P. Curry - Grant/Research Support: Gilead Sciences, Mass Biologics, Merck, Ikaria; Stock Shareholder: Achilion, Idenix

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

Raymond ī. Chung - Advisory Committees or Review Panels: Idenix; Consulting: Enanta; Grant/Research Support: Gilead, Merck, Mass Biologic, Gilead

Norah Terrault - Advisory Committees or Review Panels: Eisai, Biotest; Consulting: BMS; Grant/Research Support: Eisai, Biotest, Vertex, Gilead, AbbVie, Novartis

Robert S. Brown - Consulting: Salix, Janssen, Vertex; Grant/Research Support: Gilead, Merck, Vertex, AbbVie, Salix, Janssen, BI; Speaking and Teaching: Genentech, Gilead, Merck

Jonathan M. Fenkel - Consulting: Vertex Pharmaceuticals, Idenix Pharmaceuticals, Janssen Therapeutics

Fredric D. Gordon - Advisory Committees or Review Panels: Vertex, Gilead; Grant/Research Support: Vertex, Gilead; Speaking and Teaching: Merck

Jacqueline G. O'Leary - Consulting: Vertex, Gilead

Alexander Kuo - Advisory Committees or Review Panels: Gilead, Novartis; Grant/Research Support: Gilead, Roche

Thomas D. Schiano - Advisory Committees or Review Panels: vertex, salix, merck, gilead, pfizer; Grant/Research Support: massbiologics, itherx

Gregory T. Everson - Advisory Committees or Review Panels: Roche/Genentech, Merck, HepC Connection, Roche/Genentech, Merck, HepC Connection; Board Membership: HepQuant LLC, PSし 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

Eugene R. Schiff - Advisory Committees or Review Panels: Bristol Myers Squibb, Gilead, Merck, Vertex, Globeimmune, Johnson and Johnson, Salix Pharmaceutical, Sanofi Aventis, Pfizer; Grant/Research Support: Bristol Myers Squibb, Abbott / AbbVee, Gilead, Anadys, Merck, Vertex, Globeimmune, Roche, Salix Pharmaceutical, Sanofi Aventis, Orasure Technologies, Discovery Life Sciences, Siemens

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

William ī. Symonds - Employment: Gilead

Jill M. Denning - Employment: Gilead Sciences, Inc.

Lindsay McNair - Independent Contractor: Gilead

Sarah Arterburn - Employment: Gilead Sciences Inc.; Stock Shareholder: Gilead Sciences Inc.

Dilip Moonka - Advisory Committees or Review Panels: Gilead; Grant/Research Support: Genentech; Speaking and Teaching: Merck, Genentech, Gilead, Novartis

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

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

The following people have nothing to disclose: Alex Befeler

214

Hepatitis A to E Virus Infections in Selected United States-bound Refugee Populations

Tonya Mixson-Hayden, Deborah Lee, Lilia Ganova-Raeva, Jan Drobeniuc, William Stauffer, Eyasu H. Teshale, Saleem Kamili

Division of Viral Hepatitis, CDC, Atlanta, GA

Purpose: Despite recommended post-arrival medical screening for refugees entering the United States, little information exists regarding the extent of current infections with hepatitis viruses in them; therefore we sought to determine the extent of current infections with hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis E virus (HEV) among USbound refugees. Methods: Serum samples maintained at the CDC's Division of Global Migration and Quarantine from 755 Bhutanese, 1076 Burmese, 1137 Iraqi and 1215 Hmong refugees, and 707 Bantu refugees from Somalia, which were collected during 2002-2007, were screened for viral genomes by NAT. All samples were first tested for anti-HAV IgM and antiHEV IgM to identify persons with incident HAV and HEV infections, and for anti-HBs to determine prior immunity against hepatitis B. Anti-HAV IgM or anti-HEV IgM positive samples were further tested for HAV RNA or HEV RNA, respectively. For identifying subjects with current HCV and HBV infections, all samples were tested for HCV RNA and HBV DNA (excepting those that tested anti-HBs positive). All NAT-positive samples were sequenced to determine the viral genotype. Results: Of 4, 890 specimens: 211(4. 3%) were anti-HAV IgM positive, of which HAV RNA was detected in 1(0.47%); and 122 (2. 3%) were anti-HEV IgM positive, of which HEV RNA was detected in 23 (18. 9%). 2127 samples (43. 4%) were positive for antiHBs. HBV DNA was detected in 331(10.7%) tested samples, mostly from Hmong (33. 2%) and Burmese (18. 9%) refugees; genotypes identified were A (2. 7%), B (49. 5%), し(41. 4%), D (0.3%), G (0.3%), and H (0.3%). HCV RNA was detected in 63 (1. 3%) tested samples, mostly (71%) from Hmong refugees; genotypes identified were 1(68. 3%), 3 (1. 6%) and 6 (9. 5%). Four tested samples (1%) were positive for HBV DNA and HCV RNA. Conclusion: Incident HAV or HEV infection was identified in a small but substantial proportion (<5%) of the refugees tested who potentially act as reservoirs of secondary transmission. Almost half have immunity against hepatitis B. Current HBV and HCV infections were particularly prevalent among the Hmongs, who could benefit from early identification of these infections with view to referring them to care.

Disclosures:

The following people have nothing to disclose: Tonya Mixson-Hayden, Deborah Lee, Lilia Ganova-Raeva, Jan Drobeniuc, William Stauffer, Eyasu H. Teshale, Saleem Kamili

215

Once Daily Sofosbuvir/Ledipasvir Fixed Dose Combination with or without Ribavirin Resulted in ≥95% Sustained Virologic Response In Patients with HCV Genotype 1, Including Patients with Cirrhosis: the LONESTAR trial

Eric Lawitz1 , Fred Poordad1,Robert H. Hyland2, Xiao Ding2, Christy Hebner2, Phil S. Pang2, William T. Symonds2, John G. McHutchison2, Fernando E. Membreno1

1The Texas Liver Institute, University of Texas Health Science Center San Antonio, TX; 2Gilead Science, Inc, Foster City, CA

Background: In a prior phase 2 study, patients with HCV genotype 1 who received sofosbuvir (SOF), an HCV-specific uridine nucleotide analog, together with 丨edipasvir (LDV), an NS5A inhibitor, plus ribavirin (RBV) for 12 weeks, achieved a high rate of sustained virologic response (SVR), irrespective of whether the patients were treatment-naīve or prior null responders. We therefore assessed the safety and efficacy of 8 and 12-week regimens of a fixed-dose combination (FDC) of SOF and LDV with and without RBV in treatment-naīve and protease inhibitor-experienced patients with HCV genotype 1. Methods: non-cirrhotic treatment-naīve patients with HCV genotype 1 were randomized 1: 1: 1 to receive: 1)FDC for 8 weeks, 2) FDC + RBV for 8 weeks, or 3) FDC for 12 weeks. In parallel, 40 patients who had not achieved SVR after previous treatment with a protease inhibitor regimen (50% of whom also had compensated cirrhosis) were randomized to receive twelve weeks of: 1)FDC or 2) FDC + RBV. The primary end point was SVR 12 weeks after completion of treatment. Results: 100 patients were enrolled. The treatment-naīve group was 88% genotype 1a and 20% were IL28B CC. The protease-inhibitor experienced group was 85% genotype 1a and 7. 5% were IL28B CC. Biopsy-confirmed cirrhosis was present in 22/40 (55%) of the Pl-experienced subjects. Results are tabulated below. SOF/LDV FDC with or without RBV for 8 and 12 weeks was generally well tolerated; 1 patient discontinued treatment early. Adverse events were generally mild, and no SAEs attributed to treatment were reported. Grade 3/4 laboratory abnormalities were infrequent. Adverse events and laboratory abnormalities consistent with the safety profile of RBV were noted in groups receiving SOF/LDV FDC+RBV. SVR12 from all groups will be presented. Conclusions: SOF/LDV FDC elicited rapid declines in HCV RNA and high rates of SVR regardless of the presence of RBV in all treatment groups with no viral breakthrough observed. 97% of patients achieved SVR, two relapsed, and one was lost to follow up. Further evaluation of SOF/LDV FDC in treatmentnaīve and treatment-experienced patients in Phase 3 studies is in progress.

Study VisitTreatment-naϊveProtease-inhibitor Experienced
SOF/LDV FDC 8 Weeks (n=20)SOF/LDV FDC+RBV8 Weeks (n=21)SOF/LDV FDC 12 Weeks (n=19)SOF/LDV FDC 12 Weeks (n=19)SOF/LDV FDC+RBV 12 Weeks (n=21)
  1. *One patient has not yet returned for post-treatment follow up.

RVR100%100%100% 95% 100%
EOTR100%100%100%100%100%
SVR4100%100%100%95%95%*
SVR 12 95% 100%PendingPendingPending

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

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, Pharmassett, Vertex, Salix, Tibotec/Janssen, Novartis

Robert H. Hyland - Employment: Gilead Sciences, Inc

Xiao Ding - Employment: Gilead Sciences

Christy Hebner - Employment: Gilead Sciences, Inc.

Phil S. Pang - Employment: Gilead Sciences

William ī. Symonds - Employment: Gilead

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

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

216

Sustained Virological Response After Protease Inhibitorbased Therapy For Hepatitis C Recurrence After Liver Transplantation: A Multicentric European Experience

Audrey Coilly1,2, Jerome Dumortier4, Danielle Botta-Fridlund5, Marianne Latournerie6, Vincent Leroy7, Georges-Philippe Pageaux8, Emiliano G. Giostra9, Christophe Moreno10, Bruno Roche1, 3, Pascol LebroY11, Sylvie Rodenne12, Anne-Cotnenne Soouli13, Yvon Calmus14, Laurent Alric15, Maryline Debette-Gratien16, Victor de Ledinghen17, Francois Durand18, Christophe Duvoux19, Didier Samuel1,2, Jean-Charles Duclos-Vallee1, 3

1Centre Hepato-Biliaire, AP-HP, Hopital Paul Brousse, Villejuif, France; 2Unit 785, Inserm, Villejuit, France; 3UMRS785, Univ paris-Sud, Villejuif, France; 4Depf Hepatogastro-enterologie, Hopital Edouard Herriot, Lyon, France; 5Hepato-gastro-enterologie, AP-HM Hopital de la Conception, Marseille, France; 6Maladies du foie et de l'appareil digestif' Centre Hospitalier Universitaire Pontchaillou, Rennes' France; 7Hepato-gastro-enterologie, Centre Hospitalier Universitaire de Grenoble, Grenoble, France; 8Hepato-gastro-enteroloqie et Transplantoation, CHU - Hopital Saint Eloi, Montpellier, France; 9Gastroenterologie et Hepatologie, Hopitaux Universitaire de Geneve, Geneve, Switzerland; 10Hepato-Gastro-Enterologie, Hopital Erasme - Cliniques Universitaires de Bruxelles' Bruxelles, Belgium; 11 Hepato-gastro-enterologie, AP-HP, Hopital pitié Salpétriére' Paris' France; 12Hepatogastro-enterologie, Hopital de la Croix Rousse, Lyon, France; 13Hepato-gastro-enterologie' CHRU de Strasbourg, Strasbourg, France; 14Chirurgie Digestive, AP-HP, Hopital Saint Antoine, Paris, France; 15Médecine Interne' CHU purpan, Toulouse, France; 16Hepato-gastro-enterologie, Centre Hospitalier Régional Universitaire Dupuytren, Limoges, France; 17Hepatogastroenterologie et Oncologie digestive, CHU de Bordeaux - Hopitol Haut Leveque, pessac, France; 18Hepato-Gastro-Enterologie, AP-HP, Hopital Beaujon, Clichy, France; 19Hepatogastro-enterologie' AP-HP, Hopital Henri Mondor, Creteil, France

Background: Telaprevir (TVR) or boceprevir (B〇C) associated with peg-interferon/ribavirine improved sustained virological response (SVR) rate in hepatitis C (HCV) genotype 1 patients (pts), naive or previously treated. We describe in this large European cohort, the results of first generation protease inhibitors based regimen after liver transplantation (LT) for HCV recurrence. Patients and Methods: This cohort study enrolled 97 liver transplant pts (male: 86%, mean age 56±10years [3175]), with an active genotype 1 hepatitis C, in 17 centers between March 2011 and November 2012, treated with B〇C (n=41) or TVR (n=56) immediately or after a 4-weeks lead-in phase (n=21). The meantime between LT-PI was 61±63months [2-300]. Indication was HCV recurrence (> F1), including cirrhotic pts (n=21), and cholestatic hepatitis (n=10). Thirty-five (36%) pts were non-responders to a previous course of dual therapy post-LT; 95% of pts received cyclosporine (n=50) or tacrolimus (n=42). Results: The mean follow-up was 56±20 weeks (W) [21-115]. At baseline, HCV viral load, GGT and hemoglobin levels were 6. 48±0.95log10 Iし/mL [2. 66-8. 28], 269±349 Iし/L [22-2179], 13. 6±1. 8 g/dL [8. 8-17. 5], respectively. After 12W, a complete early virological response (EVR) was obtained in 34 (83%) B〇C pts and in 34 (61%) TVR pts (p=0.025). Among 20 B〇C and 16 TVR pts, 17 (85%) and 7 (44%) achieved an end of treatment response (EOT), respectively (p=0.014). Negative predictive factors of EOT were a null non-response to a previous course of pre-LT bitherapy (p=0.011), the absence of EVR achievement (p<0.0001) and the absence of anemia (<10g/dL) during triple therapy (p=0.010). Among 10 B〇C and 5 TVR pts, 6 and 1 achieved SVR12, respectively. Among 7 pts in the B〇C group, 3 achieved SVR24. In the TVR group, 28 pts discontinued therapy, after 13±10 W [1-44] (serious adverse events, n=13; virological breakthrough, n=6; non-response, n=8). In the B〇C group, 14 pts discontinued therapy, after 19±11 W [1-44] (serious adverse events, n=7; virological breakthrough, n=2; non-response, n=4; retransplantation, n=1). Two pts relapsed after BOC withdrawal. Four pts died in a context of infectious disorders: B〇C, n= 2 (W20/W24); TVR, n= 2 (W2/W9). The most common side effect was anemia in 85% of pts and 95% received erythropoietin alone or combined with ribavirin dose reduction. Conclusions: In liver transplanted pts, EOT rate was 85% and 44% with B〇C and TVR, respectively. Among the overall population, 43% of pts discontinued therapy because of treatment failure or occurrence of serious adverse events. SVR12 and SVR24 results will be presented.

Disclosures:

Audrey Coilly - Speaking and Teaching: Gilead, BMS, Janssen, MSD, Roche, Novartis, Astellas

Danielle Botta-Fridlund - Consulting: BMS, MSD, ROCHE, GILEAD, JANSSEN

Vincent Leroy - Board Membership: roche, merck, gilead, bms, roche, merck, gilead, bms, roche, merck, gilead, bms, roche, merck, gilead, bms; Consulting: jansen, jansen, jansen, jansen; Grant/Research Support: roche, gilead, bms, roche, gilead, bms, roche, gilead, bms, roche, gilead, bms; Speaking and īeaching: bms, merck, gilead, roche, bms, merck, gilead, roche, bms, merck, gilead, roche, bms, merck, gilead, roche

Georges-Philippe Pageaux - Advisory Committees or Review Panels: Roche, Roche, Roche, Roche; Board Membership: Astellas, Astellas, Astellas, Astellas

Pascal Lebray - Grant/Research Support: Schering-Plough, Schering-Plough, Schering-Plough, Schering-Plough; Speaking and Teaching: Gilead, Gilead, Gilead, 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

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

Christophe Duvoux - Advisory Committees or Review Panels: Novartis, Roche, Novartis, Roche, Novartis, Roche, Novartis, Roche; Speaking and Teaching: Astellas, Astellas, Astellas, Astellas

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

The following people have nothing to disclose: Jerome Dumortier, Marianne Latournerie, Emiliano G. Giostra, Christophe Moreno, Bruno Roche, Sylvie Radenne, Anne-Catherine Saouli, Yvon Calmus, Laurent Alric, Maryline DebetteGratien, Jean-Charles Duclos-Vallee

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