HBV Trials and Treatments


923

A phase III clinical trial with a therapeutic vaccine containing both HBsAg and HBcAg administered via both mucosal and parenteral routes in patients with chronic hepatitis B

Sheikh Mohammad Fazle Akbar1,4, Mamun A. Mahtab2, Salimur Rahman2, Julio Cesar Aguilar3, Yoichi Hiasa4, Shunji Mishiro1;

1Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan; 2Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh; 3Clinical Trials, Center for Genetic Engineering and Biotechnology, Havana, Cuba; 4Department of Gastroenetrology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan

Background and aims: Lack of information is prevailing about scope and limitation of a therapeutic vaccine for chronic hepatitis B (1) that utilized multiple antigens; both HBsAg and HBcAg, (2) applied via multiple routes of administration: both mucosal and parenteral, and (3) conducted as a phase III clinical trial in same run in which a different arm received an established and commercially-available antiviral drug. Methods: A total of 160 patients with clinical, biochemical, and virological evidences of chronic hepatitis B were enrolled in a phase III clinical trial (Clinical Trials.Gov identifier NCT01374308) after receiving written consent of the patients and written permission of institutional review board (Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh). The patients were randomly assigned to receive either a therapeutic vaccine (HBsAg/HBcAg-based vaccine) or pegylated interferon (Peg-IFN). Seventy-five CHB patients completed the therapeutic schedule of immunization with 1 00 microgram of both HBsAg and HBcAg (HBsAg/HBcAg) (Center for Genetic Engineering and Biotechnology, Havana, Cuba), once in every two weeks (5 vaccinations through only nasal route and followed by 5 additional vaccinations via both nasal and subcutaneous route). Seventy-six patients with CHB completed the treatment with Peg IFN (180 microgram, once weekly, subcutaneously for 48 consecutive weeks). Parameters of safety and therapeutic efficacy were checked during treatment period and also for 24 weeks after end of treatment (EOT). Results: Preliminary results evidenced the safety of HBsAg/HBcAg-based therapeutic immunization; no serious or severe adverse event was detected. Forty-six of 75 patients (61%) receiving HBsAg/HBcAg vaccine reduced the HBV DNA below 250 copies/ml (unde-tectable HBV DNA) at EOT and a similar proportion remain below 250 copies/mL at the end of 24 weeks of treatment-free follow up. Fifty-one of 76 patients (67%) receiving Peg-IFN reduced the HBV DNA level below 250 copies/mL at EOT, however, only 39% remain under the same level at 24 weeks after EOT during treatment-free follow up. ALT increases were not clinically symptomatic in patients receiving HBsAg/HBcAg vaccine and a generalized normalization of ALT values in the majority of patients at the EOT and 24 weeks of treatment-free follow up was recorded. Conclusions: A therapeutic vaccine therapy containing HBsAg/HBcAg represents a safe and efficacious therapeutic approach for CHB. This study inspired optimism that ongoing protocols of immune therapy against CHB may be improved by altering nature of antigens and route of administration.

Disclosures:

The following people have nothing to disclose: Sheikh Mohammad Fazle Akbar, Mamun A. Mahtab, Salimur Rahman, Julio Cesar Aguilar, Yoichi Hiasa, Shunji Mishiro

924

No association between IL28B genotype and response to peginterferon alfa-2a (40KD) in HBe antigen-positive and HBe antigen-negative patients with chronic hepati-tis B in three large randomized clinical studies

Lai Wei1, Heiner Wedemeyer2, Yun -Fan Liaw3, Henry Lik-Yuen Chan4, Teerha Piratvisuth5, Patrick Marcellin6, Jidong Jia7, Deming Tan8, Wan-Cheng Chow9, Maurizia R. Brunetto10, Moisés Diago11, Selim Gurel12, Viacheslav Morozov13, Hua He14, Yonghong Zhu15, Cynthia Wat14, Alexander J. Thompson16;

1Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China; 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 3Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; 4Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China; 5NKC Institute of Gastroenterology and Hepatology, Prince of Songkla University, Songklanagarind Hospital, Songkhla, Thailand; 6Service d'Hépatologie and INSERM CRB3/U773, Université Paris-Diderot, Clichy, France; 7Beijing Friendship Hospital, Capital Medical University, Beijing, China; 8Xiangya Hospital, Central South University, Hunan Province, China; 9Department of Gastroenterology & Hepatology, Singapore General Hospital, Singapore, Singapore; 10Hepatology Unit, University Hospital of Pisa, Pisa, Italy; 11Hospital General De Valencia, Valencia, Spain; 12Department of Gastroenterology, Medical Faculty, Uludag University, Bursa, Turkey; 13Hepatolog, Samara, Russian Federation; 14Roche Products Ltd, Welwyn, United Kingdom; 15Genentech, South San Francisco, CA; 16St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia

Background: It is yet to be firmly established whether host IL28B genotype influences the response to peginterferon alfa-2a (40KD) (PegIFN) in patients with chronic hepatitis B (CHB). Associations between markers of host IL28B genotype (rs8099917, rs12980275, rs12979860) and response to PegIFN were assessed using data from three large randomized studies. Methods: Patients with CHB (N=642) who had received 48 weeks' treatment with PegIFN 1 80 μg/week (with/without lamivudine) in three randomized international clinical studies were included. Treatment responses were determined 24 weeks after end of treatment and were defined as HBeAg seroconversion in HBeAg-positive patients and as HBV DNA <2000 IU/mL in HBeAg-negative patients. Three single nucleotide polymorphisms (SNPs) in the IL28B region were investigated (rs8099917, rs12980275, rs12979860) using stored serum. Results: The study population included a total of 419 HBeAg-positive patients (92% Oriental, 63% HBV genotype C, 29% genotype B), of whom 151 (36.0%) had a response, and 223 HBeAg-negative patients (83% Oriental, 51% HBV genotype C, 29% genotype B), of whom 108 (48.4%) had a response. The distribution of IL28B genotypes at the three SNPs in HBeAg-positive and HBeAg-negative patients was as follows: 1) rs8099917TT, 87% and 87%, respectively; 2) rs1 2980275 AA, 82% and 83%, respectively; 3) rs12979860 CC, 80% and 79%, respectively. Associations between treatment response and the number of copies of the rare allele were explored with additive models. In HBeAg-positive patients there were no associations between IL28B genotypes and response to PegIFN (p=0.393-0.956), including after adjusting for significant baseline variables (gender, HBV DNA level and ALT level). In HBeAg-negative patients, only rs1 2980275 was marginally associated with response (p=0.036), but the association was no longer apparent after adjusting for significant baseline variables (genotype C and race). Thus, the analyses did not detect a significant association at p<0.05 between response to PegIFN and any of the three SNPs after adjusting for baseline variables. Conclusions: This is the largest analysis of the association between IL28B genotype and response to PegIFN in patients with CHB. The data suggest that IL28B polymorphism is not a major determinant of the response to PegIFN in patients with CHB. F. Hoffman-La Roche Ltd-funded

Disclosures:

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

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

Yun -Fan Liaw - Advisory Committees or Review Panels: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis; Grant/Research Support: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis

Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Vertex, Bristol-Myers Squibb, Abbott, Novartis Pharmaceutical, Roche, MSD

Teerha Piratvisuth -Advisory Committees or Review Panels: Merck, Roche, Novartis; Grant/Research Support: Novartis, Roche, Bristol Myers Squibb, Fibrogen; Speaking and Teaching: Merck, Roche, Novartis, GlaxoSmithKline, Bristol Myers Squibb

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

Jidong Jia - Consulting: BMS, GSK, MSD, Novartis, Roche

Maurizia R. Brunetto - Speaking and Teaching: Roche, Gilead, Schering-Plough, Bristol-Myers Squibb, Abbott, Roche, Gilead, MSD, Novartis

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

Selim Gurel - Speaking and Teaching: Glead, BMS, Roche, MSD, Glead, BMS, Roche, MSD

Hua He - Employment: Roche

Yonghong Zhu - Employment: Genentech, A Member of the Roche Group

Cynthia Wat - Employment: Roche Products Ltd

Alexander J. Thompson - Advisory Committees or Review Panels: Merck, Inc, Roche, Janssen (Johnson & Johnson), BMS, GSK Australia, Novartis, GILEAD Sciences, Inc; Consulting: GILEAD Sciences, Inc; Grant/Research Support: Merck, Inc, Roche, GILEAD Sciences, Inc; Speaking and Teaching: Merck, Inc, Roche, BMS

The following people have nothing to disclose: Deming Tan, Wan-Cheng Chow, Viacheslav Morozov

925

Long-term nucleos(t)ide analog treatment reduces liver related mortality in chronic hepatitis B patients

Tetsuya Hosaka1, Fumitaka Suzuki1, Masahiro Kobayashi1, Tasuku Hara1, Taito Fukushima1, Yusuke Kawamura1, Hitomi Sezaki1, Norio Akuta1, Yoshiyuki Suzuki1, Satoshi Saitoh1, Yasuji Arase1, Kenji Ikeda1, Mariko Kobayashi2, Hiromitsu Kumada1;

1Hepatol-ogy, Toranomon Hospital, Tokyo, Japan; 2Research institute for hepatology, Toranomon Hospital, Tokyo, Japan

Background: Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma. Nucleos(t)ide analog (NA) such as lamivudine (LAM) and entecavir (ETV) are known to suppress viral loads and to lead to improve hepatic inflammation. We examined whether long-term NA treatment would reduce mortality in chronic HBV-infected patients when compared with NA-naïve patients. Methods: We conducted a retrospective cohort study of in 472 NA naïve patients who received ETV (ETV group), 791 patients who received LAM (LAM group), and 1141 untreated HBV patients (control group). The ETV group comprised patients who were recruited from 2004 to 2010, the LAM group patients from 1995 to 2006, and the control group patients from 1 973 to 1 999 and had been treated and followed in our institute. Patients in three groups were followed until death after the start of observation (primary outcome). We compared the survival outcomes in three groups. Results: Propensity score matching eliminated the baseline differences of the three cohorts, resulting in a matched sample size of 273 patients in each cohort. 81 patients (29.7%) in the ETV group had been diagnosed as cirrhosis at the beginning of follow-ups compared with 79 patients (28.9%) in the LAM group and 88 patients (32.2%) in the control group. 1 02 patients in the LAM group had received add-on adefovir rescue therapy due to the drug resistant mutations. During follow-ups of 4.1 years in the ETV group, 8.4 years in the LAM group and 9.4 years in the control group, two patients (0.7%) in the ETV group died (18/10,000 person-years) compared with eight patients (2.9%) in the LAM group (34/10,000 person-years) and 68 patients (24.9%) in the control group (265/10,000 person-years). The cumulative overall survival rates at 5-year were 99.1%, 97.6% and 92.2% for the ETV, LAM and control groups, respectively. The log-rank test revealed a statistically significant difference in overall survival rates between the ETV group and the control group (P = 0.001), or the LAM and the control group (P < 0.001) over time. Multivariate Cox regression analysis showed that patients in the ETV or LAM group were less likely to die than those in the control group (HR of ETV: 0.14, HR of LAM: 0.1 8). The prognostic advantages of the ETV and LAM group were greater in cirrhotic patients than those in non-cirrhotic patients. The overall survival rates in the LAM group without rescue therapy were marginally lower than those in the ETV group and LAM group with rescue therapy. Conclusion: Long-term NA treatment greatly reduced mortality in chronic hepatitis B patients. The treatment effect was greater in patients with cirrhosis.

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: Tetsuya Hosaka, Fumitaka Suzuki, Masahiro Kobayashi, Tasuku Hara, Taito Fukushima, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Mariko Kobayashi

926

Seven Years of Treatment with Tenofovir DF for Chronic Hepatitis B Virus Infection is Safe and Well Tolerated and Associated with Sustained Virological, Biochemical and Serological Responses with no Detectable Resistance

Patrick Marcellin1, Edward J. Gane2, NaokyTsai3, Robert Flisiak4, Joerg Petersen5, Selim Gurel6, Iskren A. Kotzev7, John F. Flaherty8, Phillip Dinh8, Anuj Gaggar8, Kathryn M. Kitrinos8, Mani Subra-manian8, John G. McHutchison8, Jacob George9, Maria Buti10;

1Hopital Beaujon, Clichy, France; 2Auckland City Hospital, Auckland, New Zealand; 3University of Hawaii at Manoa, Honolulu, HI; 4Medical University of Bialystok, Bialystok, Poland; 5Asklepios Klinik St. George, University of Hamburg, Hamburg, Germany; 6Uludag Universitesi Tip Fakultesi, Bursa, Turkey; 7University Hospital Sveta Marina, Varna, Bulgaria; 8Gilead Sciences, Foster City, CA; 9Storr Liver Unit, Westmead Hospital, Sydney, NSW, Australia; 10Hospital General Universitari Vall d'Hebron and Ciberehd,, Barcelona, Spain

Background: We previously reported that 5 years of tenofovir DF (TDF) therapy in treatment naïve patients results in sustained viral suppression with no development of resistance and was associated with either the halting or regression of fibrosis in 96%, and reversal of cirrhosis in 74% of previously cirrhotic patients. Here we present 7 year results from these two ongoing 8 year studies (Studies 102 and 103). Methods: After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, all patients undergoing liver biopsy were eligible to continue open-label TDF. Patients were assessed every 3 months for safety and efficacy with annual resistance surveillance. Annual assessments of bone mineral density (BMD) by DXA were added to both studies starting at year 4. Results: In a total 641 patients who were initially randomized and treated, 585 (93%) entered the TDF extension phase at Year 1, and at Year 7, 437 (68%) remain on study. Efficacy results at Year 7 are shown in the table. Overall (both studies combined), TDF was well tolerated over the 7 year evaluation period. Less than 2.5% of patients discontinued TDF due to an adverse event, and ≦ 1.7% experienced a confirmed renal event (>0.5 mg/dL increase in serum creatinine from baseline, or phosphorus <2 mg/dL, or CrCL <50 mL/min). BMD assessments (lumbar spine and hip T scores) were stable over 3 years of evaluation. No resistance to TDF has been detected through Year 7. Conclusions: In these two trials, TDF remains safe and effective over a 7 year treatment period with no detectable resistance to TDF; a relatively low rate of renal events and no evidence of clinically relevant bone loss were also observed.

 HBeAg- Patients (Study 102) N=375HBeAg+ Patients (Study 103) N=266
  1. aMissing-failure (LTE-TDF analysis set);bMissing=excluded (On treatment analysis set); cKaplan-Meier %; dOne patients experienced HBsAg loss and seroconversion at Week 240

HBV DNA <400 copies/mL (mITT)a77% (269/348)60% (149/247)
HBV DNA <400 copies/mLb99% (271/273)99% (159/160)
ALT Normalizationb84% (213/255)74% (115/155)
HBeAg lossb 54% (84/154)
HBeAg seroconversionb 40% (61/154)
HBsAg loss (KM%)C_d12% (n=26)
HBsAg seroconversion (KM%)C_d10% (n=2l)

Disclosures:

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

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

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

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

Selim Gurel - Speaking and Teaching: Glead, BMS, Roche, MSD, Glead, BMS, Roche, MSD

John F. Flaherty - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Phillip Dinh - Employment: Gilead Sciences Anuj Gaggar - Employment: Gilead Sciences

Kathryn M. Kitrinos - Employment: Gilead Sciences, Gilead Sciences; Stock Shareholder: Gilead Sciences, Gilead Sciences

Mani Subramanian - Employment: Gilead Sciences

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

Jacob George - Advisory Committees or Review Panels: Roche, BMS, MSD, Gilead, 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: NaokyTsai, Iskren A. Kotzev

927

Tenofovir monotherapy is effective for Adefovir experienced patients but requires careful monitoring of glomerular and tubular function and proactive dose reductions: a 4-year study in 320 patients

Pietro Lampertico1, Giampaolo Mangia1, Mauro Viganò2, Marta Borghi1, Roberta Soffredini1, Floriana Facchetti1, Federica Inv-ernizzi1, Massimo Colombo1;

11st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università di Milano, Milan, Italy; 2U.O. Epatologia, Ospedale San Giuseppe, Università degli Studi di Milano, Milano, Italy

Background and Aim. Tenofovir (TDF) has become a popular anti-HBV strategy for both naïve and experienced patients, but the 4-year effectiveness and safety in field practice patients previously exposed long-term to Adefovir (ADV) is poorly unknown. Methods. In a single center study, 320 NUC-experienced chronic hepatitis B patients with or without cirrhosis received Tenofovir (TDF) for 48 months (range 0-85) as a switch from ADV+Lamivudine (LAM) or as a rescue therapy of LAM, ADV or Entecavir (ETV) resistance or partial response. Virological response was undetectable HBV DNA by sensitive assays; safety analysis focused on dose adjustments, glomerular (eGFR) and tubular renal function. Baseline was defined as the start of TDF. Results. The baseline demographic and clinical features of the patients were as follows: mean age 59 (24-82), 85% HBeAg-negative, 62% with cirrhosis, 88% with normal ALT levels, 74% with undetectable HBV-DNA and 26% with a median viral load of 3.0 log IU/ml (1.1- >9.0). 86% of the patients were switched from ADV+LAM. TDF was started at 300 mg/24h in 71% of the patients, 300/48h in 25% and 300/72h or 96h in the remaining 4%. During 4 years of TDF treatment, virological response progressively increased to 1 00% at year 4 with most patients achieving normal ALT levels. Twelve patients (4%) cleared HBsAg and 9 successfully withdrew from antiviral treatment. Serum creatinine remained unchanged (1.01 to 1.07 mg/dl) as well as blood phosphate levels. The same was also true for the proportion of patients with serum creatinine >1.5 mg/dl (between 5% to 6% over time) and serum phosphate <2.3 mg (5-8%) and <2.0 mg/dl (3-2%). Because of eGFR decline, 72 patients (23%) had to reduce TDF dose to 300/48h (57 patients), to 300/72h (13 patients) and to 300/96h (2 patients). 19 additional patients (6%), who had to stop TDF because of drug-related side effects, were successfully switched to ETV. Overall, 91 patients (28%) either required a dose reduction or withdrew from TDF for side effects. Of note, none of the patients developed acute renal failure, Fanconi syndrome or required hemodialysis and viral load did not rebound in any patient who required dose adjustment. HCC developed in 7 compensated cirrhotics with a yearly rate of 1.2%, whereas no case of clinical decompensation was recorded. Overall, 7 patients (2%) were transplanted (all for HCC) and 14 (4%) died (7 because of HCC, 5 because of non liver causes and 2 for unknown reasons). In conclusion, careful monitoring of glomerular and tubular function and proactive dose adjustment of TDF minimized the risk of renal toxicity in ADV exposed patient treated for 4 years with TDF monother-apy.

Disclosures:

Pietro Lampertico - Advisory Committees or Review Panels: Bayer, Bayer; Speaking and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead

Mauro Viganò - Consulting: Roche; Speaking and Teaching: Gilead Sciences, BMS

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: Giampaolo Mangia, Marta Borghi, Roberta Soffredini, Floriana Facchetti, Federica Invernizzi

928

Targeting the cccDNA by epigenetic drugs inhibits HBV transcription and replication

Gianna Aurora Palumbo1,3, Laura Belloni1,3, Sergio Valente4, Dante Rotili4, Natalia Pediconi1,2, Antonello Mai4, Massimo Lev-rero1,2;

1Dept. Internal Medicine (DMISM), Sapienza University Rome, Rome, Italy; 2Life Nanosciences Laboratory, Sapienza University Rome, Rome, Italy; 3EAL Inserm U785, Sapienza University Rome, Rome, Italy; 4Dip. di Chimica e Tecnologie del Farmaco, Sapienza University Rome, Rome, Italy

Background: The HBV cccDNA is organized into mini-chromosomes in the nucleus of infected cells by histone and non-histone proteins. By using a cccDNA-specific chromatin immunopre-cipitation (ChIP)-based assay, we showed that HBV replication is regulated, both in a cell replication system and in the liver of HBV chronically infected patients, by the acetylation status of cccDNA-bound H3/H4 histones. We have also shown that interferon-α (IFNα) inhibits HBV transcription and replication in vitro and in vivo by favoring the long term recruitment to the nuclear cccDNA mini-chromosome of the class III Histone Deacetylase (HDAC) hSirt1 and of the PRC2 repressive complex, including the transcriptional co-repressors HDAC1 and Ezh2. Aims: We sought to test the ability of small compounds active on different classes of chromatin modifying enzymes to modulate HBV transcription and replication and to assess whether the modulation of cccDNA-bound Ezh2 histone methyl-trasferase (HMT) activity may mimic the IFNα repressive activity. Methods: Capsid-associated HBV-DNA (TaqMan real-time PCR), cccDNA (TaqMan real-time PCR) and pgRNA levels (quantitative real-time PCR with specific primers), were assessed in HepG2 cells transfected with full length HBV genomes or the inducible HepAD38 stable HBV cell line, left untreated and or treated with a) p300 and PCAF histone acetyltransferases (HAT) inhibitors; b) hSirt1/2 activators and c) JMJD3 histone demethy-lase inhibitors. Recruitment of transcriptional cofactors and cccDNA bound histones modifications were assessed using the cccDNA ChIP assay. Results: The combined inhibition of p300 and PCAF HATs (compound EML-264) or stimulation of hSirt1/2 HDAC activity (compound MC2791) resulted in an evident reduction of HBV replication that mirrored the decrease of pgRNA transcription. Potentiation of Ezh2 activity through the inhibition of JMJD3 histone demethylase with compound MC311 9 resulted in a >50% reduction of pgRNA transcription and a sharp increase in cccDNA bound H3 trimethylation at lysine 27 (H3K27me3). Conclusions: Altogether these results represent a proof of concept that small molecules / drugs that affect cccDNA bound chromatin modifying enzymes can modulate HBV transcription and replication. Activation of hSirt1/2 and Ezh2 by small molecules can induce an "active epigenetic suppression" of HBV cccDNA minichromosome similar to that observed with IFNα and provide the rationale to explore sequential treatments as a model for IFN sparing regimens in cellular or chimeric mice HBV replication systems.

Disclosures:

Massimo Levrero - Advisory Committees or Review Panels: BMS, Jansen, Gilead; Speaking and Teaching: MSD, Roche

The following people have nothing to disclose: Gianna Aurora Palumbo, Laura Belloni, Sergio Valente, Dante Rotili, Natalia Pediconi, Antonello Mai

929

Interim analysis of hepatitis B reactivation in patients with prior HBV exposure undergoing hematopoietic stem cell transplant: a prospective study

Wai-Kay Seto1, Thomas Sau Yan Chan1, Yu-Yan Hwang1, Olivia Choi1, Danny Wong1,2, James Fung1,2, Albert Kwok-Wai Lie1, Ching-Lung Lai1,2, Yok-Lam Kwong1, Man-Fung Yuen1,2;

1Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong; 2State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, Hong Kong

Background: Patterns of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative, antibody to the hepatitis B core antigen (anti-HBc)-positive individuals undergoing hematopoietic stem cell transplantation (HSCT) have not been well described. Methods: From October 201 1 onwards, we recruited HBsAg-negative, anti-HBc-positive Chinese patients with baseline undetectable serum HBV DNA (<10 IU/mL), undergoing either allogenic or autologous HSCT. For allogenic HSCT, only recipients whose donors were HBsAg negative were recruited. Liver biochemistry, serum HBV DNA (Abbott RealTime HBV), HBsAg and antibody to HBsAg (anti-HBs) (Abbott Laboratories) were prospectively monitored every 4 weeks after HSCT up to 2 years from recruitment. Following guidelines from the European Association for the Study of the Liver, entecavir was started when detectable HBV DNA (≧10 IU/mL) was encountered. Results: At the time of writing, among 197 patients undergoing HSCT, 51 (25.9%) were HBsAg-neg-ative, anti-HBc-positive. After excluding allogenic HSCT recipients with HBsAg-positive donors (n=6) and patients with baseline detectable HBV DNA (n=2), 43 (48.9% male) patients were recruited. The median age and duration of follow-up were 46.5 (range 1 9.9-66.7) years and 47.6 (range 4-76) weeks respectively. 41 (95.4%) had detectable anti-HBs (range 11->1000 mIU/mL). 6 patients (14.0%) had detectable HBV DNA after a median follow-up period of 38 (range 16-68) weeks. The median HBV DNA level at reactivation was 24.5 (range 14-428) IU/mL. 5 patients (83.3%) remained HBsAg-negative at reactivation. The 48- and 72-week cumulative reactivation rate, calculated using the Kaplan-Meier method, was 13.3% and 24.2% respectively. All patients with reactivation achieved undetectable HBV DNA when entecavir was started. Age and baseline anti-HBs levels were not associated with HBV reactivation (p=0.733 and 0.839 respectively). Conclusion: Among HBsAg-negative, anti-HBc-positive individuals undergoing HSCT, HBV reactivation could occur over a long time period, up to 66 weeks after HSCT. Baseline factors had no association with HBV reactivation. Serum HBsAg remained negative during early phase reactivation for majority of cases and the earliest surrogate marker to diagnose reactivation was HBV DNA level. Entecavir treatment controlled HBV reactivation in all cases. (ClinicalTrials.gov identifier NCT01481649)

Disclosures:

Wai-Kay Seto - Advisory Committees or Review Panels: Gilead Science; Speaking and Teaching: Gilead Science

James Fung - Speaking and Teaching: Bristol Myers Squibb

Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead Sciences Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc; Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, 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

The following people have nothing to disclose: Thomas Sau Yan Chan, Yu-Yan Hwang, Olivia Choi, Danny Wong, Albert Kwok-Wai Lie, Yok-Lam Kwong

930

Anti-HDV-IgM levels as a marker of disease activity and response to pegylated Interferon-α based therapy in hepatitis delta

Anika Wranke1, Cihan Yurdaydin2, Benjamin Heidrich1, Stefanie Ernst3, Armin Koch2, Beatriz Calle Serrano1, Florin A. Caruntu4, Manuela G. Curescu5, Kendal Yalcin6, Selim Gurel7, Stefan Zeuzem8, Andreas Erhardt9, Stefan Lüth10, George V. Pap-atheodoridis11, Birgit Bremer1, Judith Stift12, Janina Kirschner1, Ker-stin Port1, Markus Cornberg1, Hans P. Dienes13, Svenja Hardtke13, Michael P. Manns1,13, Heiner Wedemeyer1,13;

1Department of Gastroenterology, Hepatology and Endocrinology, Hannover medical school, Hannover, Germany; 2Ankara University Medical Faculty, Ankara, Turkey; 3Institute for Biometry, Hannover medical school, Hannover, Germany; 4Institutul de Boli Infectioase, Bucharest, Romania; 5Spitalul Clinic de Boli Infectioase si, Timisoara, Romania; 6Dicle University Medical Faculty, Diyarbakir, Turkey; 7Uluda University Medical Faculty, Bursa, Turkey; 8Johann Wolfgang Goethe University Medical Center, Frankfurt/Main, Germany; 9Heinrich Heine University, Düsseldorf, Germany; 10Univer-sity Medical Centre Hamburg-Eppendorf, Hamburg, Germany; 11Athens University School of Medicine, Athen, Greece; 12Medical University of Vienna, Vienna, Austria; 13HepNet Study-House, Hannover, Germany

INTRODUCTION Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. Given the limited treatment options with only 20-30% of patients responding to (PEG-)interferon (IFN)-α-based therapies and the numerous and burdensome side effects, therapy should be carefully chosen. Therefore there is a need for biomarkers to determine disease activity and response to therapy. We aimed to investigated if anti-HDV-IgM levels correlate with disease activity and response to PEG-IFNa-based therapy in HDV infection METHODS We investigated baseline samples of 120 HDV-infected patients recruited in the HIDIT-2 trial that enrolled patients in Germany, Greece, Turkey and Romania (Yurdaydin et al., AASLD 2012). Evaluation of liver biopsies was performed by a central pathologist. HDV-RNA, HBsAg and HBV-DNA levels were determined in one laboratory. Anti-HDV-IgM-testing was performed using the ETI-DELTA-IGMK-2 assay (Diasorin). Out of these 120 patients we selected a subgroup of 22 patients who were treated with PEG-IFNa-based therapy for repeated anti-HDV-IgM testing. Out of this 1 1 patients tested negative for HDV-RNA after 48 weeks of treatment (responder). The other 1 1 patients did not show any significant virological HDV-RNA decline at week 48 (nonresponder). RESULTS Anti-HDV-IgM correlated with histological inflammatory (p< 0.01) as well as with biochemical disease activity (ALT and AST p<0.01) and is associated with the stage of liver disease (p< 0.01). Before therapy, anti-HDV-IgM levels did not differ between patients responding to therapy and nonresponder patients. However, anti-HDV-IgM levels significantly declined from baseline to week 96 of therapy in virological responder patients whereas anti-HDV-IgM OD values remains unchanged or even increased in most of the nonresponders. Antibody declines became evident already during week 24 of therapy in responding patients (responder vs. nonresponder W24 p=0.05; W48 p<0.01; W96 p=0.02). At week 24 ten out of 1 1 virological responders had an anti-HDV-IgM decline while this was only the case in five out of 1 1 nonresponders patients. CONCLUSIONS Anti-HDV-IgM testing is a cheap and reliable marker providing valuable additional information on disease activity in hepatitis delta. Moreover, anti-HDV-IgM testing could be used as an on-treatment marker for response to individualize treatment and to avoid unnecessary exposure to PEG-IFNa. The value of this marker needs to be validated in larger studies.

Disclosures:

Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche, Merck, Gilead

Selim Gurel - Speaking and Teaching: Glead, BMS, Roche, MSD, Glead, BMS, Roche, MSD

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

George V. Papatheodoridis - Advisory Committees or Review Panels: Janssen, Abbott, Boehringer, Novartis, BMS, Gilead, Roche; Consulting: Roche; Grant/Research Support: BMS, Gilead, Roche; Speaking and Teaching: Janssen, Novartis, BMS, Gilead, Roche, MSD

Kerstin Port - Speaking and Teaching: Roche

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: Anika Wranke, Benjamin Heidrich, Stefanie Ernst, Armin Koch, Beatriz Calle Serrano, Florin A. Caruntu, Manuela G. Curescu, Kendal Yalcin, Andreas Erhardt, Stefan Lüth, Birgit Bremer, Judith Stift, Janina Kirschner, Hans P. Dienes, Svenja Hardtke

931

Hepatocyte HBcAg and HBsAg expressions as markers for predicting response to entecavir treatment in chronic hepatitis B infection

Sun Young Yim, Soon Ho Um, Yeon Seok Seo, Yoon TaeJeen, Bora Keum, Hong Sik Lee, Hoon Jai Chun, Hyung Joon Yim, Ji Hoon Kim, Chang Duck Kim, Seok Bae Yoon, Tae Jung Yun, Ho Sang Ryu;

Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea

Background/Aim: Expression of HBcAg in hepatocyte is known to be correlated with viral replication but studies regarding the role of histologic expression of HBsAg are lacking. The aim of this study was to determine the association between the histologic expression of HBsAg, HBcAg and entecavir treatment response. Methods: The study included 94 patients (sixty HBeAg-positive, 34 HBeAg-negative) with biopsy proven CHB who were treated with entecavir. Histologic expressions of HBcAg were classified into nuclear, cytoplasmic and mixed patterns. Histologic expressions of HBsAg were classified according to the distribution patterns (discrete and cluster) and staining patterns within the hepatocyte (membranous and non-membranous). Virological response (VR) was defined as undetectable serum HBV DNA by real-time PCR. Results: Forty three patients (46%) showed histologic expression of HBcAg while expression of HBsAg was observed in all patients. Mean age was 46±1.2 years while median serum HBV DNA level and serum ALT level were 7.04 log10 IU/mL (range 3.8-9.2 log10 IU/mL) and 103 IU/L (range 29-2273 IU/L), respectively. Positive intrahepatic expression of HBcAg was associated with higher rate of positive serum HBeAg (90.7% vs 41.2%, p<0.001), serum HBV DNA levels (7.9 log 10 IU/mL vs 6.3 log 10 IU/mL, p<0.001) and lower histologic necroinflammatory activity compared to negative intrahepatic HBcAg (grade 012 vs grade 34, 47.9% vs 14.3%, p<0.01). Non-membranous expression of HBsAg was correlated with increased histologic necroinflammatory activity and presence of precore mutation compared to membranous HBsAg (p=0.002 and p<0.001, respectively). In HBeAg-positive group, VR at 6, 9 and 12 months were significantly higher in patients with negative intrahepatic HBcAg (all, p<0.01) and non-membranous HBsAg (p<0.05) compared to those with positive intrahepatic HBcAg and membranous HBsAg. Multivariate analysis revealed negative intrahepatic HBcAg as the only determinant of VR. During the follow up period of 70 months, cumulative incidence of serum HBeAg loss was significantly higher in patients with non-membranous HBsAg compared to those with membranous HBsAg (p=0.028) while HBeAg seroconversion was significantly higher in patients with negative intrahepatic HBcAg compared to those with positive intrahepatic HBcAg (p=0.027). Conclusion: This is the first study revealing that intrahepatic HBcAg and HBsAg expression pattern can be used as markers in predicting entecavir treatment response, especially in HBeAg-positive patients.

Disclosures:

Hyung Joon Yim - Grant/Research Support: GSK Korea, Handok Pharm, Gilead Korea; Speaking and Teaching: BMS Korea

The following people have nothing to disclose: Sun Young Yim, Soon Ho Um, Yeon Seok Seo, Yoon Tae Jeen, Bora Keum, Hong Sik Lee, Hoon Jai Chun, Ji Hoon Kim, Chang Duck Kim, Seok Bae Yoon, Tae Jung Yun, Ho Sang Ryu

932

Rituximab-associated HBV Reactivation in Lymphoma Patients with Resolved Hepatitis B: Kinetics of Anti-HBs Titers with or without Entecavir Prophylaxis

Yi-Hsiang Huang1,2, I-Cheng Lee1,2, Liang-Tsai Hsiao3, Han-Chieh Lin1, Shou-Dong Lee4;

1Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan; 2Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; 3Division of Hematology and Oncology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Cheng Hsin General Hospital, Taipei, Taiwan

Background: Based on our recent randomized controlled trial, entecavir prophylaxis can prevent rituximab-associated HBV reactivation in CD20+ lymphoma patients with resolved hepatitis B (RHB). The presence of anti-HBs at baseline is borderline associated with HBsAg reverse seroconversion. However, the role of the kinetics of anti-HBs titers on HBV reactivation is unclear. Methods: Eighty CD20-positive lymphoma patients with RHB were randomized to receive either prophylactic entecavir (ETV) prior to chemotherapy to 3 months after completing chemotherapy (ETV prophylactic group, n=41) or therapeutic ETV at the time of HBV reactivation and HBsAg reverse seroconversion since chemotherapy (control group, n=39). Among them, 58 were positive for anti-HBs by qualitative assay. Serial anti-HBs titers during rituximab treatment were determined for those cases. Results: Patients in the ETV group received mean 7.2 cycles of rituximab-based chemotherapy, while patients in the control group received mean 6.5 cycles. During a mean 1 8 months of follow-up, 1 (2.4%) patient in the ETV prophylactic group and 7 (1 7.9%) in the control group developed HBV reactivation (P=0.027). The control group had a higher incidence of HBsAg reverse seroconversion (1 0.3% vs 0%). Among patients positive for anti-HBs, the anti-HBs titers significantly declined after rituximab treatment both in ETV group and control group (p<0.05). In patient with HBV reactivation, the degree of anti-HBs decline did not greater than those without HBV reactivation. Conclusion: Rituximab has impact on the anti-HBs titer both in patients with or without entecavir prophylaxis. The kinetics of anti-HBs titers could not predict HBV reactivation in lymphoma patients with RHB.

Disclosures:

The following people have nothing to disclose: Yi-Hsiang Huang, I-Cheng Lee, Liang-Tsai Hsiao, Han-Chieh Lin, Shou-Dong Lee

933

Four years of tenofovir monotherapy for NUC naïve field practice European patients suppresses HBV replication in most patients with a favorable renal safety profile but does not prevent HCC in patients with or without cirrhosis

Pietro Lampertico1, Roberta Soffredini1, Cihan Yurdaydin2, Ramazan Idilman2, George V. Papatheodoridis3, Ekaterini Mar-gariti3, Maria Buti4, Rafael Esteban4, Serena Zaltron5, Andrea Vavassori5, Francesco Castelli5, Mauro Viganò6, Maria G. Rumi6, Maria Vinci7, Luca S Belli7, Giuliana Cologni8, Marco Rizzi8, Maria Milanese9, Mario Strazzabosco9, Eliseo Minola10, Alessia M. Giorgini11, Massimo Zuin11, Andrea Salmi12, Silvia Colombo13, Osvaldo Fracassetti13, Paolo Del Poggio14, Savino Bruno15, Stefano Fagiuoli16, Marco Andreoletti17, Agostino Colli17, Alberto Eraldo Colombo18, Giorgio A. Bellati18, Carlo F. Magni19, Elena Angeli19, Guido A. Gubertini19, Massimo Fasano20, Teresa A. Santantonio21, Natalia M. Terreni22, Giampaolo Mangia1, Massimo Colombo1;

11st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università di Milano, Milan, Italy; 2Gastroenterology, University of Ankara Medical School, Ankara, Turkey; 32nd Dept of Internal Medicine, Hip-pokration Hospital, Athens, Greece; 4Internal Medicine and Liver Unit, Hospital General Universitario Valle Hberon and Ciberehd, Barcelona, Spain; 5II Divisione Malattie Infettive, Azienda Ospedaliera Spedali Civili, Brescia, Italy; 6U.O Epatologia, Ospedale San Giuseppe, Università degli Studi di Milano, Milano, Italy; 7SC Epatologia e Gastroenterologia, Ospedale Niguarda Cà Granda, Milano, Italy; 8Div Malattie Infettive, Ospedali Riuniti di Bergamo, Bergamo, Italy; 9Liver Center, Clinica Medica, Azienda Ospedaliera San Gerardo, Università Milano Bicocca, Monza, Italy; 10Servizio Malattie Epatiche e Infettive, Humanitas Gavazzeni, Bergamo, Italy; 11Division of Internal Medicine and Liver Unit, Ospedale San Paolo, Milano, Italy; 12U.O. Gastroenterologia, Fondazione Poliambulanza, Ospedale S. Orsola, Brescia, Italy; 13U.O. Epatologia, Ospedale di Treviglio, Treviglio, Italy; 14U.O. Gastroenterologia, Policlinico S. Marco, Zingonia, Italy; 15U.O. Medicina Interna ed Epatologia, A.O. Fatebenefratelli e Oftalmico, Milano, Italy; 16Gastroenterology Unit, Liver and Lung Transplantation Center, Ospedali Riuniti di Bergamo, Bergamo, Italy; 17S.C. Medicina Generale, Ospedale A. Manzoni, Lecco, Italy; 18Unità Operativa di Medicina, Servizio di Epatologia, Ospedale Sant'Anna, Como, Italy; 19I and II Division Infectious Diseases, Ospedale Luigi Sacco, Milano, Italy; 20Clinic of Infectious Diseases, Università di Bari, Bari, Italy; 21Clinic of Infectious Diseases, Università di Foggia, Foggia, Italy; 22U.O. Gastroenterologia, Ospedale Valduce, Como, Italy

While Tenofovir (TDF) has become a popular anti-HBV strategy for naïve patients worldwide, the 4 year effectiveness and safety in field practice is unknown. Methods: 374 naïve patients (55 years, 73% males, HBV-DNA 6.0 log IU/ml, 80% HBeAg-negative, 35% with cirrhosis, 47% with concomitant disease/medications) with chronic hepatitis B with or without cirrhosis were treated with TDF monotherapy and enrolled in a retrospective/prospective cohort study from 21 European centers. Median follow-up was 39 months (range 0-72). Virological response was undetectable HBV DNA; safety analysis focused on glomerular and tubular renal function. Results. Virological response rates increased over time reaching 97% at year 4, independently of HBeAg status. 22 (30%) patients serocon-verted to anti-HBe with a 4-year cumulative probability of 37%, 16 (17%) patients cleared HBsAg (1 1 HBeAg-positive patients), of whom 6 successfully stopped TDF. Partial virological response rates progressively declined from 14% at month 12 [residual viremia: 44 IU/ml (10-264.000)], to 5% at month18 [65 IU/ml (12-23.000)], 4% at month 24 [160 IU/ml (17-7.400)] and 3% at month 30 [27 IU/ml (12-1.040)]. Transient virological breakthroughs were observed in few patients only, no resistance to TDF was observed. Serum creatinine and phosphorus blood levels remained unchanged over time (0.90 mg/dl; 3.3 mg/dl) while eGFR declined from 84 to 80 ml/min. The proportion of patients with eGFR<50 and <60 ml/min (MDRD) increased from 2% to 3% (year 4) and from 7% to 1 1 % (year 4), respectively. The proportion of patients with blood phosphate below 2.3 mg/dl increased from 2%(baseline) to 5.1%(year 4), while 1% of the patients had phosphate <2.0 throughout the study period. Due to renal events, TDF dose was adjusted in 19 (5%) patients (eGFR decline in 17; low phosphate in 2) and discontinued in additional 7 (2%) patients who were switched to ETV (Overall, renal events in 26 patients,7%). Nine additional patients withdrew from TDF and switched to ETV because of nonrenal related side effects. HCC developed in 1 0 compensated cirrhotics (4-year cumulative probability: 1 7%, 4.2%/year) and in 6 non cirrhotics (4-year cumulative probability: 4%, 1 %/year) while no cirrhotics clinically decom-pensated. Overall, 3.7% of patients died (7 for HCC, 1 liver failure, 4 extrahepatic, 2 unknown) and 1.6% underwent liver transplantation (4 with HCC, 2 with baseline decompensated disease). In conclusion, 4 years of TDF suppressed HBV replication in most treatment-naïve field practice European patients with CHB without any major renal safety signal but failed to prevent HCC independently of liver disease severity

Disclosures:

Pietro Lampertico - Advisory Committees or Review Panels: Bayer, Bayer; Speaking and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead

Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche, Merck, Gilead

George V. Papatheodoridis - Advisory Committees or Review Panels: Janssen, Abbott, Boehringer, Novartis, BMS, Gilead, Roche; Consulting: Roche; Grant/Research Support: BMS, Gilead, Roche; Speaking and Teaching: Janssen, Novartis, BMS, Gilead, Roche, MSD

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

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

Serena Zaltron - Speaking and Teaching: BMS, MSD

Mauro Viganò - Consulting: Roche; Speaking and Teaching: Gilead Sciences, BMS

Maria G. Rumi - Advisory Committees or Review Panels: Roche, Vertex, Roche, Vertex, Roche, Vertex, Roche, Vertex; Speaking and Teaching: Roche, Roche, Roche, 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

The following people have nothing to disclose: Roberta Soffredini, Ramazan Idilman, Ekaterini Margariti, Andrea Vavassori, Francesco Castelli, Maria Vinci, Luca S Belli, Giuliana Cologni, Marco Rizzi, Maria Milanese, Mario Strazzabosco, Eliseo Minola, Alessia M. Giorgini, Massimo Zuin, Andrea Salmi, Silvia Colombo, Osvaldo Fracassetti, Paolo Del Poggio, Savino Bruno, Stefano Fagiuoli, Marco Andreoletti, Agostino Colli, Alberto Eraldo Colombo, Giorgio A. Bellati, Carlo F. Magni, Elena Angeli, Guido A. Gubertini, Massimo Fasano, Teresa A. Santantonio, Natalia M. Terreni, Giampaolo Mangia

934

Reappraisal of the Concept of Primary Virologic Response Defined by the Current Guidelines for the Management of Chronic Hepatitis B

Young Joo Yang1, Ju Hyun Shim2, Kang Mo Kim2, Young-Suk Lim2, Han Chu Lee2, Dong Jin Suh2,3;

1Internal Medicine, Asan medical center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Gastroenterology, Asan medical center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Internal Medicine, Vievis Namuh Hospital, Seoul, Republic of Korea

Background & Aims Given the substantial evidence that early hepatitis B virus (HBV) DNA response after oral antiviral therapy can strongly predict prolonged virologic outcomes, treatment adaptation at an early phase is strongly recommended for chronic hepatitis B (CHB) patients with primary non-response during treatment. The purpose of this study is to assess whether the definition of primary virologic response to guide the CHB treatment algorithm suggested by the AASLD guidelines was optimal for treatment with entecavir, a newer and more potent antiviral agent. Methods This retrospective study included 1,262 treatment-naïve CHB patients receiving entecavir (0.5mg/day) monotherapy for over six months: median age 47 years, 63 % Male, 55% HBeAg-positive, and 42% cirrhosis. All patients had an HBV DNA level of at least 2,000 IU/mL at the start of their entecavir treatment. "Primary non-response" was defined as <2 log decrease in the serum HBV DNA level from the baseline after at least six months of therapy, according to the AASLD guidelines. The primary endpoint of this study was the virologic response, evidenced by achieving the serum HBV DNA to an undetectable level (<15 IU/mL) during the study period. The cumulative probability of a virologic response was evaluated and compared between the groups using Kaplan-Meier analysis and the log-rank test. Results In our study, the median duration of entecavir therapy was 31 months (range, 6 to 72 months). A total of 19 (1.5%) patients were categorized as primary non-responders. The cumulative rates for achieving a virologic response over time were 68.3%, 88%, 95%, and 95.7%, respectively, at 12, 24, 36, and 48 months, and which were significantly greater than the 29.4%, 64%, 88%, and 88%, respectively, seen in the primary non-responders (P=0.002). At 48 months, the proportion of virologic respon-ders (95.6% vs 100%) and the mean reduction in the serum HBV DNA levels (-5.08 vs. -6.79 log 10 IU/mL) were not associated with the presence of a primary response (P=NS for both). Entecavir resistance mutation emerged in 1 3 of the 36 patients who showed a virologic breakthrough during follow-up, and all of whom were classified as primary responders. Conclusions Our data indicate that long-term entecavir therapy leads to the ultimate virologic response in the vast majority of CHB patients, although the time required to achieve a virologic response was later in patients who did not show a primary response at six months. The current concept of primary non-response for early treatment adaptation should be refined on a drug-related basis in this current era of potent antivirals

Disclosures:

Han Chu Lee - Grant/Research Support: Medigen Biotechnology Co., Novartis, Roche, Bayer HealthCare, Bristol-Myers Squibb, INC research, Boehringer Ingel-heim, Taiho Pharmaceutical Co., Yuhan Co.

The following people have nothing to disclose: Young Joo Yang, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Dong Jin Suh

935

Long-term safety and efficacy of infants born to telbivu-dine treated highly viremic mothers with HBeAg positive chronic hepatitis B (CHB) during 2nd or 3rd trimester

Guo Rong Han1, Hong Xiu Jiang1, Cui-min Wang1, Yi Ding2, Xin Yue1, Gen-ju Wang1, Yong-Feng Yang3;

1Department of Gynecol-ogy and Obstetrics, The Second Affiliated Hospital of the Southeast University, Nanjing, China; 2Department of Gynecology and Obstetrics, School of Medicine, Southeast University, Nanjing, China; 3Department of Infectious Diseases, The Second Affiliated Hospital of the Southeast University, Nanjing, China

Background: Despite the use of standard immunoprophylaxis, HBV perinatal transmission (PT) occurs in 10-30% of infants born to highly viremic mothers with HBeAg positive CHB. Tel-bivudine has shown reduction in HBV PT with no safety concerns in infants up to 1 y, but the long-term safety data of infants born to telbivudine-treated pregnant women has not been reported. Methods: A total of 200 pregnant women treated with telbivudine at the 20-32 wk of gestation period enrolled in this study (NCT00939068). The efficacy and safety data of 202 infants aged 1 or above during Feb 2008-Mar 2012 were collected. The HBV markers and HBV DNA of infants at 7 and 12 mo were used to determine PT rates; and were continuously followed at 1 y, 2 y, 3 y and 4 y of age. The infants' head circumference, height, weight, congenital abnormality rate and hospitalization rate were evaluated at each age. 1 00 infants were randomly selected by the hospital and were tested with Denver Developmental Screening Test (DDST). Results: None of the 202 infants were infected with HBV. The blocking of HBV PT rate was 1 00%. All infants had effective HBsAb and the serum levels (Mean±SD) by each age group were 552.12±394.89, 340.30±336.37, 390.86±393.98, 184.12±155.00 IU/L. Based on the WHO and the Chinese standard values of children's growth curve, there were no differences in mean values of the height, weight and head circumference in these 202 infants in all age groups born to telbivudine-treated mothers. There were no birth defects among the 202 babies born. During the long-term follow up, 1 infant (0.5%) was diagnosed with congenital megacolon at 1.5 y and underwent operation treatment; 1 infant (0.5%) had patent ductus arteriosus at 2 y without treatment. In the overall long-term follow up, congenital abnormality rate was 0.99% (2/202). SAE occurred in 18 infants (8.91%) and required hospitalization; of which 4 had inguinal hernia. Other SAEs includes pneumonia (8), tonsillitis (1), asthma (1), acute gastroenteritis (1), diarrhea (2) and herpetic angina (1). None of the 1 8 SAEs were related to telbivudine exposure during their mothers' pregnancy period. Of 100 infants selected for DDST, 92 infants' parents had agreed to test their infants with DDST and the qualified rate of DDST was found to be 97.82%, which was comparable to the rate of 92% in normal Chinese children. Conclusion: In highly viremic HBeAg positive mothers with CHB, telbivudine treatment at the 2nd or 3rd trimester of pregnancy safely blocks perinatal transmission. Infants born to telbivudine-treated mothers presented a normal growth and development during the long-term follow-up up to 4 y.

Disclosures:

The following people have nothing to disclose: Guo Rong Han, Hong Xiu Jiang, Cui-min Wang, Yi Ding, Xin Yue, Gen-ju Wang, Yong-Feng Yang

936

Multiscale mathematical modeling of HBV kinetics in humanized chimeric mice during treatment with lamivu-dine and/or pegylated interferon-alpha-2a

Tje Lin Chung1,2, Yuji Ishida3, Kazuaki Chayama3, Michio Ima-mura3, Nobuhiko Hiraga3, Susan L. Uprichard1, Alan S. Perelson4, Harel Dahari1,4;

1Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL; 2Institute for Bio-statistics and Mathematical Modeling, Department of Medicine, Goethe University Frankfurt, Frankfurt, Germany; 3Institute of Bio-medical & Health Sciences, Department of Gastroenterology and Metabolism, Applied Life Sciences, Hiroshima University, Hiroshima, Japan; 4Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM

Background: SCID chimeric mice with humanized livers are a useful tool for studying HBV infection and treatment response. Aim: To understand viral-host-drug dynamics in the serum and within infected hepatocytes a multiscale mathematical model was developed. Methods: Twenty-eight mice reached stable human serum albumin (hAlb) levels of 7.9±0.7 log10 mg/mL (corresponding to a replacement index of ~90%) and high steady-state levels of serum HBV (9.3±0.3 log10IU/mL). Total pretreatment intracellular HBV-DNA (vDNA) of 154±25 cps/cell was measured in representative mice. Thereafter, mice were treated with lamivudine (LAM), pegylated interferon-α-2a (pIFN) or LAM+pIFN for 14 days. Serum HBV and hAlb kinetics were measured at days 3,7, 10, and 14. A previous study showed that the majority of human hepatocytes are HBV-infected before treatment and we assumed that hAlb kinetics serve as a marker for the death of infected cells. Results: A biphasic decline in serum HBV was observed in all mice, consisting of a rapid 1st phase (0.41 ±0.02 log10/day) until day 3 followed by a 2nd slower phase with slopes 0.08±0.01, 0.05±0.02 and 0.16±0.02 log10/day for LAM, pIFN and pIFN+LAM, respectively (p=0.01). vDNA of 8.33 ± 3.56, 1 0.14 ± 2.43 and 1.72 ±1.18 cps/cell was measured at day 14 in representative mice treated with LAM, pIFN and pIFN+LAM, respectively. Sensitivity analyses of the model indicate that the vDNA degradation rate, μ, and the serum HBV clearance rate, c, cannot be estimated with confidence without early frequent data samples. However, assuming a vDNA half-life of ~17 h (Wieland et al.PNAS2005:1 02,9913-991 7) suggests the serum HBV half-life is less than 8h. All treatments had high effectiveness in blocking vDNA production ε=92±1% which appeared unaffected by changes in μ or c. Under LAM monotherapy, hAlb levels remained at baseline levels. In order to account for the 2nd phase HBV decline in the absence of (or limited) death of infected cells, an additional inhibitory effect on vDNA production during treatment (parameter g) was added to the model and was estimated as 0.06±0.01, 0.1 3±0.01, 0.32±0.02 /day with pIFN, LAM and pIFN+LAM, respectively (p<0.05). Conclusions: The biphasic serum HBV kinetics observed here is reminiscent of the biphasic HBV kinetics seen in HBeAg+ patients treated with LAM and/or pIFN. This may suggest that the 2nd phase decline observed in HBeAg+ patients mainly reflects intracellular loss of vDNA rather than previously presumed death/loss of infected cells. Further detailed modeling of intrahepatic and serum kinetics will shed light on the modes of action of HBV antivirals and help to design more efficient drug cocktails.

Disclosures:

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

Alan S. Perelson - Consulting: Achillion Pharmaceuticals, Merck, Roche, Santaris Pharma, Gilead; Grant/Research Support: Roche, Novartis; Stock Shareholder: Pfizer, Merck, Glaxo

Harel Dahari - Consulting: Roche TCRC, Inc

The following people have nothing to disclose: Tje Lin Chung, Yuji Ishida, Michio Imamura, Nobuhiko Hiraga, Susan L. Uprichard

937

The role of hepatitis B surface antigen quantification predict HBV reactivation after discontinuation of ente-cavir treatment

Chien-Hung Chen, Chuan-Mo Lee, Chao-Hung Hung, JIng-Houng Wang, Sheng-Nan Lu, Tsung-Hui Hu;

Chang Gung Memorial Hos-pital-Kaohsiung Medical Center, Kaohsiung, Taiwan

Background and Aims: It remains unclear the incidence of HBV reactivation and role of quantification of HBsAg (qHBsAg) in HBV reactivation after stopping entecavir treatment. This study investigated the incidence of HBV reactivation and the role qHBsAg level in HBV reactivation after stopping entecavir treatment. Patients and Methods: From 2008 to 201 1, a total of 126 chronic hepatitis B patients (40 HBeAg-positive, 86 HBeAg-negative at baseline) received entecavir treatment (treatment duration: median: 156 weeks, range: 78-274 weeks) and have stopped the treatment at least 12 months were recruited. The criteria of stopping entecavir therapy met the recommendations of APASL 2012. qHBsAg levels were determined at baseline, month 12 of treatment and at the end of treatment. HBV DNA levels were determined at baseline, every 6 month during treatment and after stopping treatment. Results: Of the 86 HBeAg-negative patients, the cumulative incidence of viro-logical relapse (HBV DNA>2000 IU/mL) at month 6, 12, 18 and 24 was 12.8%, 46.5%, 57.2%, and 57.2% respectively, and clinical relapse (ALT>80 U/L and HBV DNA>2000 IU/mL) was 6.8%, 31%, 46.4%, and 46.4% respectively, after stopping entecavir treatment. Cox regression analysis showed that older age [increased per one year; hazard ratio (HR):1.03, 95% confidence interval (CI): 1.006-1.061], qHBsAg level at the end of treatment (increased per one log IU/ml; HR: 2.02, 95% CI: 1.30-3.15) and prior adefovir experience (HR: 2.78, 95% CI: 1.15-6.71) were independent factors for virological relapse. Older age (HR: 1.05, 95% CI: 1.02-1.09), male (HR: 7.56, 95% CI: 1.52-37.53), prior adefovir experience (HR: 8.28, 95% CI: 2.73-25.15) and qHBsAg level at the end of treatment (HR: 2.92, 95% CI: 1.59-5.38) were independent factors for clinical relapse. qHBsAg level of 250 IU/ml was a best value for virological relapse. Four of 86 HBeAg-negative patients experienced HBsAg loss during follow-up period. Of the 40 HBeAg-positive patients, the cumulative incidence of virological relapse at month 6, 12, 18 and 24 was 12.5%, 36.3%, 41.7%, and 53.3% respectively, and clinical relapse was 12.5%, 31.1%, 36.4%, and 49.1% respectively, after stopping entecavir treatment. Cox regression analysis showed that older age (increased per one year; HR: 1.05, 95% CI: 1.007-1.1 0) and qHBsAg level at baseline (increased per one log IU/ml; HR: 2.94, 95% CI: 1.31-6.60) were independent factors for virological relapse, and only qHBsAg level at baseline (HR: 2.76, 95% CI: 1.1 0-6.96) was an independent factor for clinical relapse. Conclusions: Serum qHBsAg level is a useful predictor for HBV relapse after stopping entecavir treatment.

Disclosures:

The following people have nothing to disclose: Chien-Hung Chen, Chuan-Mo Lee, Chao-Hung Hung, JIng-Houng Wang, Sheng-Nan Lu, Tsung-Hui Hu

938

Safety, Tolerability and Immunogenicity of GS-4774, an HBV-specific Therapeutic Vaccine, in Healthy Volunteers

Anuj Gaggar1, Claire Coeshott2, Mani Subramanian1, John G. McHutchison1, David Apelian2;

1Gilead Sciences, Foster City CA, CA; 2Globeimmune, Louisville, CO

Background: Chronic HBV (CHB) infection is in part characterized by diminished T cell responses to viral antigens. A therapeutic vaccine enhancing the adaptive immune response to HBV may provide a strategy to improve the rate of HBsAg loss and seroconversion in CHB patients compared to nucleos(t)ide HBV polymerase inhibitors alone. GS-4774 is a yeast-based vaccine (Tarmogen) expressing a chimeric protein comprising of 60 amino acids of HBV X protein, the full 399 amino acids of HBV surface protein, and 1 82 amino acids of the HBV core protein.. The aim of this study was to evaluate the safety and immunogenicity of GS-4774 in healthy volunteers. Methods: A Phase 1 study was conducted in healthy volunteers (n=60) to determine the safety and immunogenicity of GS-4774 using different doses and schedules. Doses of 10 yeast units (YU), 40 YU or 80 YU/dose were evaluated as either a) weekly dosing for 5 doses then a single monthly dose, or b) monthly doses for 3 consecutive months. The immune response to GS-4774 was assessed on Days 15, 29, 36, 57 and 85 by lymphocyte proliferation assays (LPA), IFN-γ ELISpot assays, and antibody response to specific HBV antigens. Results: GS-4774 was well tolerated with no serious adverse events, no grade 3 or 4 adverse events, and no laboratory abnormalities observed in the study. Adverse events were more frequent with weekly dosing compared with monthly dosing and at the 80YU dose compared to the 1 0YU and 40YU group. There was one treatment discontinuation due to adverse event (skin reaction) in the 80 YU cohort. Available immunogenicity data until day 36 are summarized in the table. The majority of subjects demonstrated evidence of an HBV-specific immune response as assessed by LPA. No dose response in HBV-specific immunogenicity of GS-4774 was observed by LPA, and monthly dosing was similar to weekly dosing. An early HBV-specific T-cell response by IFN-γ ELISpot was observed in a greater number of subjects receiving the 10YU dose. As expected given the cellular immune targeting characteristics of the platform, no antibody response to core and surface antigens was observed at the early time points. Complete immunological and safety results of the study will be presented. Conclusions: GS-4774 was well tolerated, and elicits HBV specific immune activation at the lowest monthly dose of 1 0 YU. Further evaluation of GS-4774 in patients with chronic hepatitis B is warranted.

 10 YU40 YU
 WeeklyMonthlyWeeklyMonthly
LPA Response, n/N (%)5/7(71)3/4(75)7/9 (78)9/9(100)
ELISpot Response, n/N (%)5/10(50)8/10(80)3/10(30)1/10(10)

Disclosures:

Anuj Gaggar- Employment: Gilead Sciences Claire Coeshott - Employment: GlobeImmune Inc. Mani Subramanian - Employment: Gilead Sciences

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

David Apelian - Management Position: GlobeImmune; Stock Shareholder: GlobeImmune

939

Outcome of treatment with peginterferon alfa-2a (40KD) in HBeAg-positive and HBeAg-negative patients with chronic hepatitis B (CHB) in the real-world: interim analysis of data from the large European S-Collate cohort

Patrick Marcellin1, Manuela G. Curescu2, Anna Piekarska3, Wlodzimierz W. Mazur4, Christophe Hezode5, Dominique Guyader6, Christoph Jochum7, Graham R. Foster8, Denis Ouzan9, Markus Cornberg10, Manfred Bogdan11, Diethelm Messinger12, Veronique Cartier13, Joerg Petersen14;

1Service d'Hépatologie and INSERM CRB3/U773, Université Paris-Diderot, Clichy, France; 2Department of Infectious Diseases, University of Medicine and Pharmacy, Timisoara, Romania; 3Department of Infectious Diseases and Hepatology, Medical University of Lodz, Lodz, Poland; 4Department of Gastroenterology and Hepatology, Medical University of Silesia, Katowice, Poland; 5Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France; 6Clinique des Maladies du Foie and INSERM U 49, CHRU Pontchaillou, Rennes, France; 7Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany; 8The Liver Unit, Queen Mary, University of London, London, United Kingdom; 9Institut Arnault Tzanck, Saint-Laurent-du-Var, France; 10Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; 11Roche Pharma AG, Grenzach, Germany; 12IST GmbH, Mannheim, Germany; 13Roche S.A.S, Boulogne-Billan-court, France; 14Liver Unit IFI Institute, Asklepiosklinik Hamburg, Hamburg, Germany

Background:Results of randomized trials have shown that PegIFNα-2a is effective in patients (pts) with HBeAg-pos and -neg CHB, that serological responses are sustained in many pts after end of treatment, and that the rate of HBsAg loss increases during follow-up. The aim of S-Collate is to evaluate long-term outcomes with PegIFNα-2a in routine clinical practice. This interim analysis is focused on pts enrolled in European sites. Methods:S-Collate is a multinational, prospective, observational cohort study in which pts are treated with PegIFNα-2a 1 80μg/week (wk) according to the local label and are followed for up to 3 years post-treatment to assess response. This analysis reports outcomes in the subset of HBeAg-pos or HBeAg-neg pts who have completed 6 and 12 months of follow-up; percentages of pts with responses at a given timepoint are calculated based on the number of pts with available measurements. Results:Baseline characteristics of the 1 82 HBeAg-pos and 430 HBeAg-neg pts included in the analysis are shown in the Table. Among HBeAg-pos pts, HBeAg seroconversion rates at treatment Wk 48 and after 6 and 12 months of follow-up were 19% (14/72), 27% (24/88) and 26% (21/80), respectively. Among HBeAg-neg pts the proportion of pts with HBV DNA <2000 IU/mL at treatment Wk 48 and after 6 and 12 months of follow-up were 91% (290/318), 65% (212/328), and 70% (177/254), respectively. The percentages of pts with HBsAg clearance at treatment Wk 48 and at 6 and 12 months post-treatment were 4% (4/101), 5% (6/113), and 9% (8/86), respectively, among HBeAg-pos pts and 6% (18/303), 7% (20/274), and 8% (19/228) among HBeAg-neg patients. Treatment was well tolerated. Influenza-like illness and depression were reported by 12% and 6% of pts overall, and 7% of pts reported serious adverse events. Con-clusions:This interim analysis in European study sites demonstrates that outcomes with PegIFNα-2a in the large "real-world" S-Collate study are consistent with randomized controlled studies. In particular, HBsAg clearance rates increase during the first year of follow-up. Analysis of baseline and on treatment predictive factors of response is ongoing. F. Hoffmann-La Roche Ltd-funded

 HBeAg-pos (N=182)HBeAg-neg (N=430)
Male sex, n (%)125(69)306(71)
Caucasian/White race, n/N* (%)80/132(61)249/289 (86)
Mean age ± SD31.3 ±10.536.3 ±11.4
Mean ALT ratio ± SD2.6 ± 2.31.8 ±1.9
Cirrhosis/bridging fibrosis, n/N (%)21/151 (14)39/384(10)
Mean HBV DNA, log10 IU/mL ± SD6.75 ± 2.064.14± 1.77
Mean HBsAg, log10 IU/mL ± SD3.96 ± 0.843.49 ±0.89
Previous nucleos(t)ide analog, n (%)39(21)66(15)
* Patients from France do not hae race recorded due to loci1 regulations

Disclosures:

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

Wlodzimierz W. Mazur - Advisory Committees or Review Panels: Bristol-Myers-Squibb company; Speaking and Teaching: Gilead, MSD, Roche, Abvee

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

Dominique Guyader - Advisory Committees or Review Panels: Roche, Gilead, IRIS; Board Membership: Merck; Grant/Research Support: Janssen; Speaking and Teaching: BMS

Christoph Jochum - Advisory Committees or Review Panels: Gilead, Roche, Norgine, Janssen-Cilag; Speaking and Teaching: BMS, Roche, Janssen-Cilag, Gilead

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

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

Manfred Bogdan - Management Position: Roche Pharma, Germany Diethelm Messinger - Consulting: Roche, Roche Veronique Cartier - Employment: ROCHE

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

The following people have nothing to disclose: Manuela G. Curescu, Anna Piekarska, Denis Ouzan

940

Adequate virological response in chronic hepatitis B patients during entecavir therapy despite frequent sub-optimal adherence: a prospective multicenter study with electronic adherence monitoring

Lotte G. van Vlerken1, Pauline Arends2, Faydra I. Lieveld1, Joop Arends3, Willem Pieter Brouwer2, Peter D. Siersema1, Harry L. Janssen2,4, Karel J. van Erpecum1;

1Gastroenterology and Hepa-tology, University Medical Center Utrecht, Utrecht, Netherlands; 2Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 3Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, Netherlands; 4Liver Clinic, Toronto Western and General Hospital, Toronto, ON, Canada

Introduction. Treatment failure to nucleos(t)ide analogues (NUC) in chronic hepatitis B (CHB) patients could occur due to limited antiviral potency, viral resistance or patient non-adherence. However, real-life prospective data on treatment adherence in CHB patients are scarce. We aimed to study adherence rates during entecavir (ETV) treatment using real-time medication monitoring and to relate adherence to HBV DNA levels. Methods. We provided 100 consecutive CHB patients in 2 academic hospitals with a medication dispenser that monitors ETV intake in real time (Sensemedic, Evalan, Amsterdam, the Netherlands). During 16 weeks of treatment, adherence data were directly transferred to a central server. Poor adherence was defined as <80% pill intake during the study period. At both baseline and 16-week follow-up visits, quantitative serum HBV DNA (Cobas Taqman, Roche, Almere, the Netherlands: lower limit of detection 20 IU/mL) was performed. Results. At start of the study, 64% of patients were HBe-negative, 67% were treated > 1 year with ETV and 76% were HBV DNA unde-tectable. 29% was (PEG-)interferon-experienced, and 27% NUC-experienced. Adherence over 16 weeks averaged 85±17%. Percentages of patients with ≧70%, ≧80%, ≧90% and ≧95% adherence were 81 %, 70%, 52% and 43%, respectively. The longest interruption between two consecutive ETV doses was a median of 3 days (range 1-53). Patients with poor adherence were significantly younger (40 vs. 47 years, p=0.01), while no other predictors of poor adherence were identified. 82 patients had HBV DNA <20 IU/mL after 16 weeks, whereas in 18 patients HBV DNA levels >20 IU/mL were measured. No virological breakthrough occurred. Patients with HBV DNA >20 IU/mL were younger (37 vs. 47 years, p=0.001), more frequently treated <1 year (75% vs. 28%, p<0.001), more frequently HBeAg positive (72% vs. 28%, p=0.002), NUC-naive (89 vs. 69%, p=0.11), and had lower mean adherence (83% vs. 91% (p=0.19). In multivariate analysis, duration of ETV treatment (adjusted OR 18.8 (4.1-87.0, p<0.001) and negative HBe-status (adjusted OR 11.9 (2.6-53.6), p=0.001) predicted HBV DNA negativity, whereas adherence was not a significant predictor (adjusted OR 1.02 (0.98-1.07), p=0.34). Adherence tended to be lower in the 7 patients with HBV DNA >200 IU/mL compared to the 1 1 patients with HBV DNA 20-200 IU/mL (71 vs. 95%, p=0.1 0). Conclusions: Overall 70% of our CHB patients exhibited good adherence to ETV therapy, with younger patients being more prone to poor adherence. Even in case of poor adherence, virological responses seem to be generally excellent and poor adherence was not an independent predictor of virological response.

Disclosures:

Joop Arends - Advisory Committees or Review Panels: MSD, BMS

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

Karel J. van Erpecum - Grant/Research Support: Bristol Meyers Squibb, MSD

The following people have nothing to disclose: Lotte G. van Vlerken, Pauline Arends, Faydra I. Lieveld, Willem Pieter Brouwer, Peter D. Siersema

941

A European multicentre analysis of long term tenofovir (TDF) monotherapy for chronic hepatitis B in real life setting: efficacy, safety and HCC incidence

Florian van Boemmel1, Robert A. de Man2, Karoline Rutter3, Katja Deterding4, Christoph Sarrazin5, Viola Weich5, Marc Bourlière6, Christoph P. Berg7, Heiner Wedemeyer4, Michael Waizmann8, Bernd Moeller9, Michael Biermer1,9, Dietrich Hueppe10, Eckart Schott11, Christoph Eisenbach12, Stefan Mauss13, Ulrich Spen-gler14, Johannes Wiegand1, Karin C. Van Nieuwkerk15, Kerstin Stein16, Anna Schweinberger1, Marcus Schuchmann17, Peter Fer-enci3, Andreas Erhardt18, Pauline Arends2, Christoph R. Werner7, Renate Heyne9, Thomas Berg1;

1University Hospital Leipzig, Leipzig, Germany; 21 Department of Gastroenterology and Hepa-tology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands; 3Medical university of Vienna, Vienna, Austria; 4Department of Gastroenterology, Hepatology, and Endocrinology, Medical, Hannover, Germany; 5Johann Wolfgang Goethe University Hospital Frankfurt, Frankfurt a.M., Germany; 6Service d Hepato Gastroenterologie, Hopital Saint Joseph,, Marseille, France; 7Medicine I, University of Tuebingen, Tübingen, Germany; 8Schwerpunktpraxis Infektiologie und Hepatologie, Leipzig, Germany; 9Praxiszentrum am Checkpoint, Berlin, Germany; 10Gas-troenterologische Schwerpunktpraxis Herne, Herne, Germany; 11Charité University Hospital Berlin, Berlin, Germany; 12University Hospital Heidelberg, Heidelberg, Germany; 13Center for HIV and Hepatogastroenterology, Duesseldorf, Germany; 14University Hospital Bonn, Bonn, Germany; 15Dept. of Gastroenterology and Hepatology, VU Medisch Centrum, Amsterdam, Netherlands; 16University Hospital Magdeburg, Magdeburg, Germany; 17University Hospital Mainz, Mainz, Germany; 18Petrus Hospital Wup-pertal, Wuppertal, Germany

Background: Monotherapy with TDF is safe and effective in suppressing HBV replication in treatment-naïve patients. However, long term treatment with TDF as second or third line treatment has not been studied in many patients. We have investigated efficacy, safety, the influence of prior treatments and the incidence of hepatocellular carcinoma (HCC) in a European real life cohort of patients treated with TDF. Methods: 798 patients (565 male, mean age 47±19[range, 18-78] years) receiving TDF monotherapy for a duration > 6 months were included in 28 centres and evaluated over a mean period of 54±24 [6-141]months. At the start of treatment 369 patients (46%) were HBeAg positive, 404 (51%) had previously received lamivudine, 308 (39%) adefovirand 13 (1.6%) ente-cavir for mean durations of 15±21 [3-120], 21 ±28[5-1 74] and 26±15[3-54] months, respectively, 345 (43%) were treatment-naïve. 44 patients (5.5%) had liver cirrhosis and 42 patients (5.3%) had impaired kidney function. HBV DNA was expressed in IU/mL (lower detection limit 68 IU/mL). Glomerular filtration rate was estimated by MDRD formula. Results: Mean HBV DNA levels decreased from baseline to months 6, 12, 24, 36, 48 and 60 from 7.7±9[3.1-1 0] to 3.1 ±3[1.8-4.8], 1.9±1[1.8-2.2], 1.9±1 [1.8-2.1], 1.8±1 [1.8-2.1], 1.8±2[1.8-2] and 1.8±2[1.8-2] log 10 copies/mL. Detectable HBV DNA beyond month 12 was associated with prior use of adefovir (p=0.04) or baseline HBV DNA levels >7 log10 copies/mL (p=0.01). 26 patients received add-on treatment due to persistent viremia with entecavir (n=12), lamivudine (n=13) or telbivudine (n=1). Re-increases in HBV DNA levels were found in 16 patients; however HBV DNA levels also spontaneously decreased. HBeAg loss and seroconversion occurred in 148 (40%) and 136 patients (36%). HBsAg loss was observed in 21 HBeAg positive patients (6%). TDF treatment was stopped due to suspected association with tiredness (n=5), muscle pain (n=1), dry skin (n=1), joint pain (n=1), decreased kidney function (n=1) or

maldigestion (n=3). Glomerular filtration rates (GFR) changed from normal to pathologic values in 3 patients. There was no significant decrease in GFR in patients with pre-existing kidney dysfunction. HCC was detected in 8 patients (1 %) after a mean treatment period of 32±31 [3-68] months. Factors associated with HCC were age >55 years. Pre-treatment with other antivi-rals was not associated with frequency of adverse events, with changes in GFR rate or with HCC incidence. Conclusion: Long term second and third line monotherapy with TDF was comparably safe and effective as in treatment-naïve patients.

Disclosures:

Florian van Boemmel - Advisory Committees or Review Panels: Roche Pharma; Board Membership: Gilead Sciences; Grant/Research Support: Gilead Sciences, Roche Pharma, BMS; Speaking and Teaching: Gilead Sciences, Roche Pharma, BMS, MSD, Janssen-Cilag, Siemens

Robert A. de Man - Advisory Committees or Review Panels: crucell; Grant/Research Support: biotest, gilead

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, Novar-tis, 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

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

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 Biermer - Consulting: Janssen, Roche; Speaking and Teaching: Janssen, Roche, BMS, Gilead

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

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

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

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

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

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

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

The following people have nothing to disclose: Karoline Rutter, Katja Deterding, Viola Weich, Christoph P. Berg, Michael Waizmann, Bernd Moeller, Ulrich Spen-gler, Johannes Wiegand, Karin C. Van Nieuwkerk, Kerstin Stein, Anna Schweinberger, Andreas Erhardt, Pauline Arends, Christoph R. Werner, Renate Heyne

942

A novel baseline prediction model based on HBsAg levels predicts the probability of response to peginterferon alfa in HBeAg-positive chronic hepatitis B

Milan J. Sonneveld1, Henry Lik-Yuen Chan2, Vincent W. Wong2, Teerha Piratvisuth3, Jidong Jia4, Stefan Zeuzem5, Edward J. Gane6, Yun -Fan Liaw7, Qing Xie8, Harry L. Janssen1,9, Bettina E. Hansen1;

1Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands; 2Department of Medicine and Therapeutics and Institute of Digestive Disease, the Chinese University of Hong Kong, Hong Kong SAR, China; 3NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand; 4Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China; 5Medical Clinic 1, Johann Wolfgang Goethe University Medical Center, Frankfurt, Germany; 6Liver Unit, Auckland City Hospital, Auckland, New Zealand; 7Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; 8Department of Infectious Diseases, Ruijin Hospital, Shanghai, China; 9Division of Gastroenterology, University Health Network, Toronto, ON, Canada

Background & Aims. A limited number of HBeAg-positive patients responds to peginterferon alfa (PEG-IFN). Methods. A total of 822 HBeAg-positive patients treated with PEG-IFN ± lamivudine for one year in 3 global randomized trials (Pegasys Phase 3, Neptune, and HBV 99-01) were enrolled. Response was defined as HBeAg loss with HBV DNA <2,000 IU/mL at 6 months post-treatment, and predictors considered were: HBV genotype, HBsAg levels, baseline ALT and HBV DNA levels, patient age and sex, and previous IFN exposure. Results. Patients were infected with HBV genotype A/B/C/D in 14/25/48/14%, and were male in 76%. Response was achieved in 186 (22.6%) of patients. In univariate analysis, female sex, higher age, lower HBV DNA and HBsAg levels and HBV genotype were associated with response (all p<0.01). In multivariate analysis, only HBsAg (OR: 0.61, 95% CI: 0.44 -0.84, p=0.003), ALT (OR 1.39, 95% CI: 1.08 - 1.79, p=0.01), HBV genotype (P<0.001) and female sex (OR 1.96, 95% CI: 1.33 - 2.88, p=0.001) remained associated with response. Both the full model based on all analysed variables and a reduced model based solely on HBV genotype, HBsAg levels, ALT and patient sex accurately predicted probability of response to PEG-IFN therapy (table). Using these models, 47% of patients could be classified as subtoptimal candidates for PEG-IFN therapy, defined as a low predicted probability of response (<20%). This group comprised 10% of all patients with HBV genotype A, 29% of all genotype B patients and 52% and 1 00% of all patients with HBV genotypes C and D, respectively. Conversely, a subset of 26% was identified with excellent probabilities of response (~40%), comprising 65/34/1 8/0% of all patients with HBV genotypes A/B/C/D, respectively. Conclusions. A prediction-model based on readily available baseline factors can predict an individual patient's probability of response to PEG-IFN alfa therapy. The model can help identify patients with very low and very high chances of response and is a powerful tool for patient counselling.

Predicted and observed probability of response

  Full Model  Simple Model 
Predicted<20%20-30%>30%<20%20-30%>30%
Observed10%30%38%12%25%39%
No of patients385 (47%)223 (27%)211 (26%)385 (47%)226 (28%)209 (26%)

Full model: HBV genotype, patient age and sex, baseline ALT, HBV DNA, HBsAg, previous IFN exposure. Simple model: HBV genotype, patient sex, baseline HBsAg level, baseline ALT.

Disclosures:

Milan J. Sonneveld - Speaking and Teaching: Roche

Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Vertex, Bristol-Myers Squibb, Abbott, Novartis Pharmaceutical, Roche, MSD

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

Teerha Piratvisuth -Advisory Committees or Review Panels: Merck, Roche, Novartis; Grant/Research Support: Novartis, Roche, Bristol Myers Squibb, Fibrogen; Speaking and Teaching: Merck, Roche, Novartis, GlaxoSmithKline, Bristol Myers Squibb

Jidong Jia - Consulting: BMS, GSK, MSD, Novartis, Roche

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

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

Yun -Fan Liaw - Advisory Committees or Review Panels: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis; Grant/Research Support: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis

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

The following people have nothing to disclose: Qing Xie, Bettina E. Hansen

943

From add-on dual therapy back to mono-therapy in treatment experienced CHB patients with viral resistance or partial responses: results from an international multicenter cohort study

Joerg Petersen1, Stefan Unger1, Maria Buti2, Marc Lutgehetmann3, Pietro Lampertico4, Christoph Sarrazin5, Peter Buggisch1;

1Askle-piosklinik St. Georg, Liver Center Hamburg IFI Institute, Hamburg, Germany; 2Hepatology, Hospital Vall de Hebron, Barcelona, Spain; 3Microbiology and Medicine, University Hospital Hamburg Eppendorf, Hamburg, Germany; 4Division of Gastroenterology, Fondazione IRCCS Cà Granda Maggiore Hospital, Milan, Italy; 5Medicine, University of Frankfurt, Frankfurt, Germany

Background and aim: Long-term complete viral suppression is a major goal to prevent disease progression in patients with HBV. Aim of this ongoing cohort study is to investigate the safety and efficacy of mono-therapy with entecavir (ETV) ortenofovir (TDF) following a long-term rescue combination-therapy with ETV plus TDF in 22 chronic hepatitis B (CHB) patients who were only partial responders or multidrug resistant. Methods: Open label cohort study, investigator initiated, from 5 European centres. Patients were only included with suppressed viremia (LLoD < 69 IU/ml) for >12 months during ETV plus TDF rescue combination treatment. ALT,HBV-DNA, qHBsAg were measured at baseline and every 3 months and resistance tests determined. Results: 22 patients (15 HBeAg+), median age 48 years, 17 males, previously treated with a median of 5 lines of antiviral therapy (range 4-8), 8/22 (36%) with advanced liver disease, were included. Reason for switch from combination-therapy to mono-therapy was simplification in 21 cases and desire to have children in one case. Median ALT at baseline was 0.7 ULN (range 0.36-1.24). Median ETV plus TDF treatment duration was 31 months, median treatment duration of subsequent TDF mono-therapy (n=1 9) was 29, for ETV (n=3) 1 7 months, respectively. HBV-DNA remained suppressed during mono-therapy in 19 patients, in three patients there was a low level viremia

detectable (maximum 325 IU/ml). One patient was on ETV with lamivudine experience, two cirrhotic patients on TDF, all with negative resistance testing. ALT levels remained stable in all patients, no hepatic flares occurred. The probability for a continuous HBV DNA suppression was not reduced in patients with adefovir or lamivudine resistance or in patients with advanced liver disease. One patient lost HBeAg after 10 months on TDF mono-therapy, one cirrhotic patient developed an HCC. Quantitative HBsAg levels were not significantly different from end of combination therapy and end of observation mono-therapy. Conclusions: Mono-therapy with ETV or TDF after successful rescue combination therapy with ETV plus TDF in CHB patients harboring viral resistance patterns or showing only partial virologic responses to previous therapies was efficient, safe, and well tolerated in patients with or without advanved liver disease.

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

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

Pietro Lampertico - Advisory Committees or Review Panels: Bayer, Bayer; Speaking and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead

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

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: Stefan Unger, Marc Lutgehetmann

944

Tenofovir or Entecavir Monotherapy improves survival compared to Lamivudine in patients with Decompen-sated Liver Disease due to Chronic Hepatitis B

Spilios Manolakopoulos1, Melanie Deutsch1, Christos K. Triantos2, Nikoletta Mathou3, Maria Mela4, Athanasia Striki1, Maria Kalafateli2, Georgios Kontos1, Hariklia Kranidioti1, Emanuel K. Manesis5, George V. Papatheodoridis1;

12nd Academic Department of Internal Medicine, Hippokration General Hospital, Athens, Greece; 2Gastroenterology Department,, University of Patras;, Patras, Greece; 3Department of Gastroenterology, "Konstan-topoulio" General Hospital of Athens, Athens, Greece; 4Department of Gastroenterology, Polyclinic General Hospital of Athens, Athens, Greece; 5Department of Internal Medicine, Athens University School of Medicine, Athens, Greece

Background/Aim: The aim of our study was to assess the efficacy and safety of tenofovir (TDF) or entecavir (ENT) monotherapy in patients with decompensated chronic hepatitis B (dCHB) and to compare the survival rate with a group of patients treated with lamivudine (LAM). Patients/Methods: 33 patients (M/F=1 8/15, mean age=60.7±1 1.2y) with dCHB who started antiviral treatment with TDF (n=25) or ENT (n=8) were included. All patients were nucleos(t)ide analogue-naïve with a Child-Pugh-Turcotte (CPT) score >7 and serum creatinine <1.5mg/dl. Patients with evidence of HCC, co-infections, surgical or transjugular porto-systemic shunt, liver transplantation or active alcohol consumption were excluded. Survival was

compared with an historical group of 30 patients with dCHB matched for age and CPT scores who had received LAM monotherapy. Results: The median follow up period was 27.5 months (range 6-120). At treatment initiation, median serum HBV DNA concentrations were 1.25x105 IU/mL (range 120-9.55x108). At month 12 and 24, HBV DNA was undetectable in 77.8% and 100% of patients respectively, while transami-nases were within normal range in 55.6% and 83.3% of patients respectively. A significant reduction in CPT score was observed from 8.84±1.7 at baseline to 7.66±2.24, 6.67±1.68 and 6.50±1.38 at 6, 12 and 24 months, respectively (P=0.003). CPT was >1 0 in 36.4% of the patients at baseline, 21.8% at 6 months, 5.5% at 12 months, and in no patients thereafter. Similarly Modification for End-stage Liver Disease (MELD) score was reduced from 14.22±4.15 at baseline to 13.44±4.45 and 12.06±3.78, at 6 and 12 months, respectively (p=0.018). The mean serum creatinine changed from 0.90±0.20 at baseline to 1.00+0.20, 1.07+0.23, 1.10+0.30 and 1.10+0.23 mg/dl at 12, 24, 26 and 48 months respectively (P=0.81). None of the patients discontinued treatment due to SAEs while in 2 patients the TDF dose was reduced. Three patients died at 2 and 4 months of follow up because of liver failure and sepsis. All had severe disease (CPT and MELD scores 10.67±1.15 and 17.33±4.04, respectively). Treatment with TDF or ENT offered a significantly better survival rate compared to LAM monotherapy (log-rank test, P=0.02). Conclusions: In patients with decompensated liver disease due to CHB, long term TDF and ENT monotherapy is well tolerated and associated with an improvement in biochemical, virological and clinical parameters. In these severely ill patients, TDF or ENT monotherapy improves survival when compared to lamivudine monotherapy. However deaths may occur soon after TDF/ETV initiation in patients with severe liver disease.

Disclosures:

Spilios Manolakopoulos - Advisory Committees or Review Panels: NOVARTIS, ROCHE, MSD, BMS, GILEAD; Consulting: ROCHE, GILEAD, BMS; Speaking and Teaching: MSD, GILEAD, BMS

Melanie Deutsch - Consulting: MSD

George V. Papatheodoridis - Advisory Committees or Review Panels: Janssen, Abbott, Boehringer, Novartis, BMS, Gilead, Roche; Consulting: Roche; Grant/Research Support: BMS, Gilead, Roche; Speaking and Teaching: Janssen, Novartis, BMS, Gilead, Roche, MSD

The following people have nothing to disclose: Christos K. Triantos, Nikoletta Mathou, Maria Mela, Athanasia Striki, Maria Kalafateli, Georgios Kontos, Hariklia Kranidioti, Emanuel K. Manesis

945

Effective Prevention of perinatal transmission of hepatitis B virus infection using telbivudine in high viral load patients: a retrospective study

Quanxin Wu1, Xiaowen Sun1, Meimin Pan1, Shun Tan1, Yi Zeng2, Li Li2, Guohong Deng1, Hongfei Huang1, Zehui Yan1, Dengming He1, Yuming Wang1, JunNan Li2;

1Institute for Infectious Diseases,Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China, Chongqing, China; 2Department of Gynecology and Obstetrics, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China,, Chongqing, China

Objectives: To evaluate the efficacy and safety of telbivudine in preventing mother-to-child transmission (MTCT) of hepatitis B virus (HBV) in HBeAg-positive pregnant women with high viral load. Methods: We investigated the effect of telbivudine in preventing MTCT of HBV in an open-label study since 2008. A total of 232 HBeAg-positive pregnant women with HBV DNA levels≧106 IU/mL received telbivudine 600 mg daily from 24 to 33 weeks of gestation, and 153 pregnant women with the

same situation who were unwilling to take antiviral drugs were served as untreated controls. Each infant of both groups was vaccinated with recombinant HBV vaccine and injected with hepatitis B immune globulin (HBIG) according to standard routine methods. MTCT rate was determined by the results of HBsAg and HBV DNA of infants at week 26. Results: Baseline demographics and clinical characteristics of the mothers and the infants were comparable. The incidence of undetectable HBV DNA levels was significantly higher in infants born to tel-bivudine-treated mothers than in the controls (P=8.433x1 0-1 8). The serum anti-HBs positive rate in infants delivered from telbivudine-treated mothers over 3 months was significantly higher than in the controls (P<0.001). As for the serum HBsAg positive rate in infants over 6 months, the difference was strikingly significant between the two groups (P<0.001). Telbivudine-treated mothers displayed a marked decline in HBV DNA levels from the beginning to the end of the treatment. Twenty-five (20%) of 125 telbivudine-treated mothers had undetectable HBV DNA, as compared to 0% in the controls. No severe adverse events or complications were observed in telbivudine-treated mothers or infants. The rate of spontaneous delivery in untreated mothers and in telbivudine-treated mothers was similar (48.5% vs. 41.1%, P=0.1 70). Conclusion: Telbivudine was effective and well-tolerated in HBeAg-positive pregnant women and their infants, and it was associated with significant reduction of vertical transmission of HBV. [Key words] Hepatitis B virus, Telbivudine, Mother-to-child transmission, Prevention

Disclosures:

The following people have nothing to disclose: Quanxin Wu, Xiaowen Sun, Meimin Pan, Shun Tan, Yi Zeng, Li Li, Guohong Deng, Hongfei Huang, Zehui Yan, Dengming He, Yuming Wang, JunNan Li

946

Safety and Pharmacodynamics of Oral TLR-7 agonist GS-9620 in patients with Chronic Hepatitis B

Edward J. Gane1, Eric Sicard2, Stuart C. Gordon3, Daniel Gruener4, Stuart K. Roberts5, Suzanne Kim6, Wendy Cheng7, Carla S. Coffin8, Richard Fedorak9, Paul Y. Kwo10, Barbara A. Leggett11, Daryl Lau12, Young-Suk Lim13, Stefan Pflanz14, Benedetta Massetto14, Mani Subramanian14, John G. McHutchison14, Bradley Freilich15, Kumar Visvanathan16;

1Auckland Clinical Studies, Auckland, New Zealand; 2Algorithme Pharma, Inc, Montreal, QC, Canada; 3Henry Ford Health Systems, Detroit, MI; 4CRI Worldwide, LLC, Philadelphia, PA; 5Alfred Hospital, Melbourne, VIC, Australia; 6West Coast Clinical Trials, LLC, Costa Mesa, CA; 7Royal Perth Hospital, Perth, WA, Australia; 8Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada; 9University of Alberta, Alberta, AB, Canada; 10Indiana University, Indianapolis, IN; 11Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; 12Beth Israel Deaconess Medical Center, Boston, MA; 13Asan Medical Center, Seoul, Republic of Korea; 14Gilead Sciences, Inc, Foster City, CA; 15Kansas City Research Institute, Kansas City, MO; 16Southern Health, Monash University and St.Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia

Background and Aims: GS-9620 is an orally available specific agonist of TLR-7, a highly conserved innate immune receptor. GS-9620 has demonstrated a rapid and sustained reduction in viral load and surface antigen levels in animal models of viral hepatitis (woodchuck [Stephan Menne et al, J Hepatol 201 1; 54: S441] and chimpanzees [Robert E. Lanford et al, Gastroenterology 201 3; 144(7): 1508-1517]). In healthy volunteers and in patients with chronic hepatitis C, low doses (0.3 mg-4 mg) of GS-9620 demonstrated ISG15 and CCL8 mRNA

induction without systemic IFNα related adverse events. We assessed the safety, tolerability and pharmacodynamics (PD) of GS-9620 in patients with chronic hepatitis B (CHB). Methods: A dose escalation (0.3 mg, 1 mg, 2 mg, 4 mg) placebo controlled study of a single dose or 2 doses one week apart, one in treatment naïve CHB patients and one in virologically suppressed CHB patients, is ongoing. Serum levels of IFNα and IP1 0 are being assessed by Cyraplex assay, and whole blood mRNA expression of ISG15 and CCL8 genes are being determined by qRT-PCR. Results: Patients demographics are summarized in the table. GS-9620 was well tolerated in both single (SAD) and multiple (MAD) dose cohorts, in both CHB patient populations. None of the patients experienced treatment related grade 2-4 AEs or hematologic reductions. In both CHB patient populations, induced expression of interferon stimulated gene ISG15 and CCL8 was observed in the majority of patients in all dose cohorts (table). Peak mean induction was observed by Day 3 (48 hours) with return to baseline values by Day 8. No increase in serum IFNα was observed. No clinically significant changes in HBsAg levels or HBV DNA were observed. Conclusions: Oral administration of GS-9620 stimulates a pre-systemic immune response without clinical significant systemic adverse events associated with IFNα in chronic hepatitis B patients.

Baseline characteristics
 Treatment naϊve N=25 SAD 0.3 mg (N=6) 1 mg (N=6), 2 mg (N=6) MAD 0.3 (N=6), 1 mg (N=1)Virologically suppressed N=22 SAD 0.3 (N=6), 1 (N=6), 2 mg (N=4) MAD 0.3 (N=6)
Age, mean years40  44
Male, %68  96
HBeAg positive, %16  36
IL28B genotype, CC %44  59
HBsAg, mean IU/mL7169  5768
HBV DNA, mean log10 IU/mL4.15  <1.46
ISGl5and CCL8 mRNA inductioi> 2 fold changefrom baselinen of patients
 ISG15CCL8ISG15CCL8
SAD 0.3 mg [min, max induction]3/5 [2-12]5/5 [2-10]2/5 [3-18]3/5 [2-610]
SAD 1 mg [min, ma, Inc,Mont3/5 [3-36]4/5 [3-9]3/5 [2-9]4/5 [2-17]
SAD 2 mg [min, max induction]2/5 [2-16]5/5 [2-164]1/3 [3-13]1/3 [3-186]
Placebo [min, max induction]0/31/3 [2]0/31/3 [2]

Disclosures:

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

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.

Stuart K. Roberts - Board Membership: Jannsen, Roche, Gilead, BMS Carla S. Coffin - Grant/Research Support: BMS, Gilead Sciences, Roche

Paul Y. Kwo - Advisory Committees or Review Panels: Abbott, Anadys, Novartis, Merck, Gilead, BMS, Janssen; Consulting: Vertex; Grant/Research Support: Roche, Vertex, GlaxoSmithKline, Merck, BMS, Abbott, Idenix, Vital Therapeutics, Gilead, Vertex, Merck, Idenix; Speaking and Teaching: Merck, Merck

Barbara A. Leggett - Advisory Committees or Review Panels: MSD, MSD, MSD, MSD; Speaking and Teaching: Roche, Roche, Roche, Roche, Gilead

Daryl Lau - Advisory Committees or Review Panels: Gilead, BMS; Consulting: Roche; Grant/Research Support: Gilead, Merck

Stefan Pflanz- Employment: Gileadn Sciences

Benedetta Massetto - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sciences, Inc

Mani Subramanian - Employment: Gilead Sciences

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

Bradley Freilich - Grant/Research Support: schering plough, vertex, roche, abbott, pharmaset, anadys, abbott, schering plough, vertex, roche, abbott, phar-maset, anadys, abbott, schering plough, vertex, roche, abbott, pharmaset, anadys, abbott, schering plough, vertex, roche, abbott, pharmaset, anadys, abbott; Speaking and Teaching: onyx, onyx, onyx, onyx

Kumar Visvanathan - Grant/Research Support: Gilead, Gilead, Gilead, Gilead

The following people have nothing to disclose: Eric Sicard, Daniel Gruener, Suzanne Kim, Wendy Cheng, Richard Fedorak, Young-Suk Lim

947

Overview of Telbivudine Treatment in Pregnant Women with Chronic Hepatitis B Virus Infection

Guo Rong Han1, Charles Koehne2, Serguei Titaevski3, Yuhong Dong3, Aldo Trylesinski3;

1Department of Gynecology and Obstetrics, The Second Affiliated Hospital of the Southeast University, Nanjing, China; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ; 3Novartis Pharma AG, Basel, Switzerland

Background: Mother-to-child transmission (MTCT) of hepatitis B virus (HBV) during perinatal period accounts for about 50% of all new HBV infections. Immunoprophylaxis against HBV fails and MTCT occurs in 10-15% of infants. Telbivudine (LDT) has been classified as pregnancy category B (FDA) and has been recommended by EASL and APASL guidelines for preventing HBV infection during pregnancy. Methods: We performed a systemic review on all pregnancy cases with LDT exposure from 3 databases: Literatures, Periodic Safety Update Report (PSUR) (a Novartis data collecting system with adverse events collecting purpose) and antiretroviral pregnancy registry (APR). Reports were analyzed and overlapping cases were excluded through clarification with the responsible authors. Results: In total, 1695 LDT-treated pregnancies were reported from the 3 databases with the outcome of 1426 living babies. Of 26 publications identified, 16/26 publications were non-overlapping with 1260 pregnancy cases. 137/1260 cases were exposed during the first trimester. Of the 1260 pregnancy cases, 1 196 infants were born (2 with and 1 194 without congenital anomaly). The total prevalence rate of live birth defects in LDT-treated pregnancies was 2.5/1000 compared to 3.4/1000 in the non-antiviral control. The perinatal transmission rates reported with LDT was 4.2/1000 vs. 103/1000 in non-antiviral control (P<0.0001). The prevalence rate of spontaneous abortion in LDT-treated pregnancies was 4.73/1000 vs. 16/1000 in the overall population. From the PSUR, 405 pregnancy cases with exposure to LDT have been reported and out of 405 pregnancy cases, 207 infants were reported to be born (7 with and 200 without congenital anomaly). Of 30 pregnancy cases reported in APR, 1 6 cases were exposed in first trimester. Birth outcomes were reported in 23/30 cases and there were no birth defects reported with LDT exposure. Conclusions: Telbivudine treatment during pregnancy had a favorable safety outcome for mothers and infants with no increase in live birth defects or spontaneous abortion. Telbivudine could effectively prevent MTCT of HBV infection without increasing risks of birth defects in babies.

Disclosures:

Charles Koehne - Employment: Novartis Pharmaceuticals

Yuhong Dong - Employment: novartis

Aldo Trylesinski - Employment: Novartis

The following people have nothing to disclose: Guo Rong Han, Serguei Titaevski

948

Predictors of Serum HBsAg Decline in Chronic Hepatitis B Patients Undergoing Entecavir Therapy

Hsueh-Chou Lai1,2, Cheng-Yuan Peng1,4, Wen-Pang Su1, Chia-Hsin Lin1, Po-Heng Chuang1, Jon-Ta Kao1,4, Sheng-Hung Chen1,3;

1Division of Hepato-gastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan; 2School of Chinese Medicine and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 3Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan; 4School of Medicine, China Medical University, Taichung, Taiwan

Background: The decline in quantitative serum hepatitis B surface antigen (qHBsAg) level and its predictors in chronic hepatitis B (CHB) patients undergoing long-term entecavir (ETV) therapy remain unclear. Patients and Methods: Three hundred and sixty-one treatment-naïve (321 compensated and 40 acutely decompensated) CHB patients had been treated with ETV for at least 1 year. Serum HBsAg and HBV DNA levels were measured with the Abbott Architect HBsAg QT assay and the Cobas Amplicor HBV Monitor Test throughout treatment, respectively. Results: The baseline features were: median age: 49 years, 75.3% men, 37.9% HBeAg-positive (N = 137), 59.2% genotype B infection, median ALT: 87 IU/L, HBV DNA: 6.56 log1 0copies/mL, and qHBsAg: 3.3 log10IU/mL. Among them, 249, 1 86 and 94 patients had received ETV therapy for ≧3, 4 and 5 years, respectively (mean duration: 46.5±14.6 months (M)). At 3 and 12M of therapy, 25.6% (HBeAg-positive: 38.4% vs -negative: 17.7%) and 30.8% (HBeAg-posi-tive:40.8% vs -negative: 24.9%) of patients had qHBsAg decline from baseline of ≧50%, respectively. For HBeAg-positive patients, there were significant declines in qHBsAg level between baseline and 3M, 12 and 24M (P=0.0281), and 36 and 48M (P=0.01 1 6). For HBeAg-negative patients, there were significant declines in qHBsAg level between baseline and 3M, 6 and 12M,12 and 24M, 24 and 36M, and 36 and 48M (all P<0.05). Patients were categorized in three subgroups according to the pattern of qHBsAg decline from baseline:≧50% at 3M, ≧50% at 12M, and <50% at 12M. For HBeAg-positive patients, the subgroup with qHBsAg decline from baseline of ≧50% at 3M of therapy had significantly lower qHBsAg levels than the other two subgroups up to 3 years of treatment. Multi-variate logistic regression analyses identified genotype B (OR=2.572, P=0.0460), ALT ≧120 IU/L (OR=9.295, P<0.0001) and baseline qHBsAg ≧5000 IU/mL (OR=3.795, P=0.0045) as predictors of qHBsAg decline from baseline of ≧50% at 3M of therapy. For HBeAg-negative patients, the qHB-sAg levels between the subgroups with qHBsAg decline from baseline of ≧50% at 3 or 12M of therapy were similar but was significantly lower than the subgroup with qHBsAg decline from baseline of <50% at 12M of therapy. Multivariate logistic regression analyses identified ALT ≧120 IU/L (OR=8.255, P<0.0001) and baseline qHBsAg ≧5000 log10 IU/mL (OR=6.31 1, P<0.0001) as predictors of qHBsAg decline from baseline of ≧50% at 12M of therapy. Conclusion: Higher base-line serum qHBsAg and ALT levels are predictors of qHBsAg decline from baseline of ≧50% for both HBeAg-positive and -negative patients undergoing ETV therapy.

Disclosures:

The following people have nothing to disclose: Hsueh-Chou Lai, Cheng-Yuan Peng, Wen-Pang Su, Chia-Hsin Lin, Po-Heng Chuang, Jon-Ta Kao, Sheng-Hung Chen

949

Prediction of Hepatocellular Carcinoma in Entecavir treated Patients: Results from 744 Chronic Hepatitis B patients in a European Multicenter Study (VIRGIL)

Pauline Arends1, Roeland Zoutendijk1, Ivana Carey2, Ashley S. Brown3, Massimo Fasano4, David J. Mutimer5, Katja Deterding6, Jurrien G. Reijnders1, Ye H. Oo5, Joerg Petersen7, Florian van Boemmel8, Robert J. de Knegt1, Thomas Berg8, Tania M. Welzel9, Teresa Santantonio4, Bettina E. Hansen1,10, Heiner Wedemeyer6, Maria Buti11, Pierre Pradat12, Fabien Zoulim12, Harry L. Janssen13,1;

1Gastroenterology and Hepatology, Erasmus MC university medical center, Rotterdam, Netherlands; 2Institute of Liver Studies and Transplantation, King's College London school of Medicine, London, London, United Kingdom; 3Hepatology and Gastroenterology, Imperial College London, London, United Kingdom; 4Clinic of Infectious Diseases, University of Foggia, Foggia, Italy; 5NIHR Biomedical Research Unit and Centre for Liver Research, Queen Elizabeth Hospital, Birmingham, United Kingdom; 6Gas-troenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany; 7Liver Unit, IFI Institute, Asklepios Klinik St. Georg, Hamburg, Germany; 8Hepatology, University Clinic Leipzig, Leipzig, Germany; 9Medizinische Klinik 1, Klinikum derJohann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; 10Public Health, Erasmus MC university medical center, Rotterdam, Netherlands; 11Hepatology, Hospital Vall de Hebron, Barcelona, Spain; 12Hepatology, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France; 13Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada

BACKGROUND The goal of HBV treatment is to reduce disease progression to (decompensated) cirrhosis, HCC and death. Entecavir (ETV) inhibits HBV replication and reduces HCC. Recently, CU-HCC, GAG-HCC, and REACH-B HCC-risk scores showed to predict HCC in Asian ETV treated patients. The aim of this study was to investigate risk factors for development of HCC under ETV treatment. METHODS We studied all HBV monoinfected patients treated with ETV monotherapy from 1 1 European referral centers within the Virgil Network. Patients with HCC at baseline or within the first 3 months of FU were excluded. RESULTS A total of 744 patients treated with ETV were included (mean age 44±14 years; 77%male; 42%Cau-casian/29%Asian/20%Black; 31%HBeAg+; HBV DNA 5.3±2.2log IU/ml; ALT 2.9xULN; 77%NA naive and 82%IFN naive; 164 patients (22%) had cirrhosis (by ultrasound or histology) at baseline. During a median FU of 167 (IQR 82-213) weeks, 14 patients were diagnosed with HCC of whom 9 (64%) had cirrhosis at baseline. Median time to development of HCC was 125 (IQR 59-1 88) weeks. The 5-year cumulative incidence rate of HCC was 4.4% (95% CI 1.7%-7.1%). Cumulative probability of HCC was higher in cirrhotic (p<0.001), older patients (p<0.001) and patients with lower platelet counts (p=0.02). Occurrence of HCC was not influenced by sex, HBeAg status, previous NA or IFN, baseline ALT, HBV DNA, or MELD score (p>0.1 1). All but one patient who developed HCC achieved virological response (VR) within 1 8 months of therapy. Early VR appeared protective for HCC development (HR0.63, 95%CI 0.15-2.63, p=0.52). At baseline, higher CU-HCC and GAG-HCC, but not REACH-B scores were associated with HCC. GAG-score was best in predicting HCC development. Cut-off values of 5 for the CU-HCC score and 1 01 for the GAG-HCC score were predictive for HCC development.(table) Hazard ratios of GAG-HCC score for development of HCC were less discriminative in Caucasians compared to Asians and Black (c-stat=0.72, 0.89 & 0.95 respectively). CONCLUSION Cumulative incidence of HCC in ETV treated patients is low and early VR may be protective for HCC. Baseline CU-HCC and

GAG-HCC, but not REACH-B scores predicted HCC in our population. Risk-scores were less discriminative in Caucasians, thus new risk-scores for this population are warranted.

 IR95%CIp-valuec-statistic
CU-HCC continuous1.071.03-1.110.00070.78
GAG-HCC continuous1.051.02-1.07<0.00l0.83
REACH-B continuous1.0030.90-1.110.9550.66
CU-HCC > 54.861.31-17.980.0180.71
GAG-HCC > 1014.451.54-12.870.0060.71
REACH-B > 81.350.30-6.120.6970.56

Disclosures:

Roeland Zoutendijk -Grant/Research Support: Gilead Sciences, BMS; Speaking and Teaching: BMS, Abott

Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and Teaching: BMS

Ashley S. Brown - Advisory Committees or Review Panels: MSD, Roche, Bristol-Myers-Squibb, Gilead, Novartis, Janssen, Abbvie, Achillion; Speaking and Teaching: MSD, Roche, Bristol-Myers Squibb, Gilead, Janssen, Abbvie

David J. Mutimer - Advisory Committees or Review Panels: BMS, Janssen, MSD, Gilead

Jurrien G. Reijnders - Speaking and Teaching: Bristol Myers-Squibb, Gilead

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

Florian van Boemmel - Advisory Committees or Review Panels: Roche Pharma; Board Membership: Gilead Sciences; Grant/Research Support: Gilead Sciences, Roche Pharma, BMS; Speaking and Teaching: Gilead Sciences, Roche Pharma, BMS, MSD, Janssen-Cilag, Siemens

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

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

Tania M. Welzel - Advisory Committees or Review Panels: 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

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

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

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

The following people have nothing to disclose: Pauline Arends, Massimo Fasano, Katja Deterding, Ye H. Oo, Teresa Santantonio, Bettina E. Hansen, Pierre Pradat

950

WITHDRAWN

951

Early application of telbivudine to block pregnant mother with high viral load of chronic HBV to child transmission

Yingxia Liu1, Miao Wang2, Jianhua Zhou2;

1department of infed-tious diseases, Shenzhen Third People's Hospital, shenzhen, China; 2Department of gynecology and obstetrics, Shenzhen Third People's Hospital, shenzhen, China

Abstract Objective To investigate the efficacy and safety of the early use of telbivudine to block mother-to-child transmission from pregnant women with high viral load of chronic hepatitis B virus (HBV). Method 1 78 cases of pregnant woman carrying HBV were included in this study. The number of pregnant women with high viral load (HBV-DNA > 107 IU/ml) was 80. 60 women with high viral load were treated with telbivudine (600 mg, qd, oral). Among that 32 cases which started antiviral therapy before 28 gestational weeks (4 cases of 12 weeks before pregnancy, 8 cases of between 4 to 14 gestational weeks, 20 cases of between 14 to 28 gestational weeks). 28 cases which started treatment after 28 to 32 gestational weeks. 20 cases of control group were not applied for antiviral therapy during pregnancy. The double immune measurements were performed for the neonates of by vaccinating yeast recombinant hepatitis B vaccine and hepatitis B immunoglobulin. Analyzed HBV-DNA overcast rate of all pregnant women before delivery and HBsAg, HBV-DNA positive rate of neonates which were new born and follow-up 1 year to explicit the situation of mother-to-child transmission. Results 178 newborn have given birth from 178 pregnant women. The positive rates of HBsAg, HBeAg and HBV-DNA of newborns from pregnant women with HBV-DNA high viral loads was significantly higher than that of the pregnant women with HBV-DNA low viral loads (HBV-DNA < 107 IU/ml) (25%, 25%, 5% vs. 1%, 1%, 0%, respectively). The HBV-DNA viral loads of telbivudine treatment group was significantly decreased before delivery when compared with the untreated group (P < 0.05), in which the HBsAg and HBeAg positive rate of early antiviral therapy were significantly lower than that of late antiviral therapy (3.57%) and control (25%). Early administration of telbivudine also significantly reduced the positive rate of HBV-DNA. All neonates have no birth defects. All women in two groups had no difference in the pregnant complications and neonatal complications during delivery. Conclusion The risk of mother-to-child transmission in pregnant women with HBV-DNA high viral loads was higher than that of the pregnant women with HBV-DNA low viral loads. The risk of mother-to-child transmission of hepatitis B virus can be reduced significantly by the early application of telbivudine to pregnant women with high viral load of chronic HBV. Key Word Chronic HBsAg carrier; Telbivudine;Early trimester of pregnancy; High HBV viral load; Mother-to-child transmission

Disclosures:

The following people have nothing to disclose: Yingxia Liu, Miao Wang, Jianhua Zhou

952

Efficacy and Safety Results of Tenofovir DF (TDF) Treatment from the First Trimester in HBV Pregnant Women in Real-Life Clinical Practice

Nathalie Ganne-Carrie1, Xavier Causse2, Jean-Pierre H. Zarski3, Ghassan Riachi4, Bruno Roche5, Fabien Zoulim6, Hervé Desmorat7, Thierry Constant8, Isabelle Fouchard-Hubert9, Jean françois D. Cadranel10, Denis Ouzan11, Olivier P. Libert12, Marie Terrier12, Christiane Stern12, Patrick Marcellin13;

1Hôpital Jean Verdier, Bondy, France; 2Hôpital La Source, Orléans, France; 3CHU Grenoble, Grenoble, France; 4CHU Rouen, Rouen, France; 5Hôpital Paul Brousse, Villejuif, France; 6Hôpital La Croix Rousse, Lyon, France; 7Clinique du Parc, Toulouse, France; 8CH Toulon, Toulon, France; 9CHU Angers, Angers, France; 10CH Laennec, Creil, France; 11InstitutA. Tzanck, Saint-Laurent-du-Var, France; 12Gilead Sciences, Boulogne-Billancourt, France; 13Hôpital Beaujon, Clichy, France

Background/Aims: Mother to child transmission (MTCT) is one of the main routes of HBV transmission, especially if the pregnant woman has HBV-DNA >6-7logIU/mL at delivery. Antiviral therapy given during the last trimester of pregnancy, in association with serovaccination, can reduce the risk of MTCT. Nonetheless, TDF use from the first trimester has not been well documented in HBV mono-infected patients. The aim of this study was to analyze the efficacy and safety of TDF during pregnancy. Methods: Among 441 HBV patients treated with TDF included in a French real-life cohort (VIREAL study), 14 cases of pregnancy were reported. Virologic data were collected at the beginning of pregnancy and at delivery. TDF treatment initiation and interruption were recorded. Serovaccination according to French guidelines (HBIg 1 00μg at birth plus 3 doses of HBV vaccine at 0, 1 and 6 months) was recommended for all babies. Safety data were analyzed during pregnancy, labor and follow-up. MTCT was evaluated by HBsAg status in infants after 9 months. Results: Baseline characteristics (n=14) were: mean age 29 years, 43% African origin and 57% HBeAg-positive. Among patients with prior fibrosis evaluation (n=1 0), 40% had METAVIR stage F0-F1 and 60% had F2. Eight patients were already receiving TDF treatment at the beginning of pregnancy with undetectable HBV-DNA. The other 6 patients had a median HBV-DNA of 8 logIU/mL. Regarding TDF exposure, twelve, one and one patient(s) received TDF from the first, second and third trimester, respectively. The median duration of TDF exposure during pregnancy was 35 weeks (range: 5-39 weeks). HBV-DNA was assessed at delivery in 12 patients. Among these, 10 patients (83%) had HBV-DNA < 6 logIU/mL at delivery. Two cases of high HBV-DNA were associated with non-compliance and TDF discontinuation at week 9 of pregnancy. The median gestational age at delivery was 39 weeks (range: 34-40 weeks). No adverse events related to TDF and no cases of birth defects were observed. Five patients reported breastfeeding, and 3 of them breastfed while receiving TDF treatment without any consequence on the babies up to 1 year. No cases of positive HBsAg were observed in infants. Additionally, among 5 infants with anti-HBs testing, all were anti-HBs positive (84-308mIU/mL). Conclusions: In a HBV real-life cohort, TDF treatment from the first trimester of pregnancy was well tolerated. No cases of MTCT were observed. Moreover, no safety issues were reported for breastfeeding while on TDF up to 1 year.

Disclosures:

Nathalie Ganne-Carrie - Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: BMS, Gilead

Xavier Causse - Board Membership: Gilead, BMS, MSD, Janssen-Cilag; Speaking and Teaching: Roche, Gilead, BMS, Janssen-Cilag

Jean-Pierre H. Zarski - Advisory Committees or Review Panels: BMS, Gilead, Janssen Cilag, BMS, Gilead, Janssen Cilag; Consulting: Roche, Scherring Plough, Novartis, Roche, Scherring Plough, Novartis; Speaking and Teaching: Siemens

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

Isabelle Fouchard-Hubert - Speaking and Teaching: JANSSEN Olivier P. Libert - Employment: Gilead Sciences Marie Terrier- Management Position: Gilead Sciences Christiane Stern - Employment: Gilead Sciences

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

The following people have nothing to disclose: Ghassan Riachi, Bruno Roche, Hervé Desmorat, Thierry Constant, Jean françois D. Cadranel, Denis Ouzan

953

Comparison of liver histology and liver stiffness measurement (LSM) in the assessment of pre-treatment liver fibrosis in chronic hepatitis B patients receiving oral antiviral therapy and the place of LSM in long-term monitoring; 5-year real life data

Iftihar Koksal, Gurdal Yilmaz, Selcuk Kaya;

Infectious Diseases, Black Sea Technical University Faculty of Medicine, Trabzon, Turkey

Background and aim; Non-invasive methods are therefore becoming increasingly important in the assessment of liver histopathology in CHB patients. One of such techniques is LSM performed with transient elastography (TE). In this study we compared pre-treatment liver histology and liver LSM results of CHB patients, and we evaluated the five-year prognostic value of LSM in CHB patients. Methods; Five hundred and eighty-seven CHB patients monitored since 2008 and in whom TE and LSM measurement was performed were enrolled. Patients' demographic characteristics, base-line liver biochemistry and HBV serological markers were recorded. Liver biopsy was performed simultaneously with LSM. All patients started on treatment had high ALT, serum HBV DNA>2,000 IU/ml and compensated liver disease. ALT was monitored every 3 months and HBV DNA every 6 months. LSM was repeated annually. Results; Two hundred and forty of the 587 patients were started on antiviral treatment, 347 were observed without treatment. Male to female ratios in treated and untreated patients were 97/143 and 140/207, respectively. Mean ages were 35.8±13.0 and 38.1±11.9 (p=0.029). Eighty (33.3%) patients in the treatment group and 55 (15.9%) in the non-treatment group were HBe Ag positive. Mean baseline HBV DNA in the treatment group was 5.5±2.3 log 1 0IU, and ALT was 117±189. Baseline liver histology in the 123 patients (51.3%) undergoing LB revealed F4 fibrosis in 27 (22.0%) patients, F3 in 28 (22.8%), F2 in 33 (26.8%) and F0-1 in 35 (28.5%). Initial LSM results in patients receiving treatment and those observed without treatment were 8.3±4.6 and 6.6±3.2, respectively (p<0.001). Comparison of LB and LSM results revealed a positive correlation between fibrosis scores (r=0.291; p<0.001). A total of 48.3% (n=1 16) of patients received teno-fovir, 26.7% entecavir (n=64), 12.5% telbivudin (n=30) and 12.5% lamivudin (n=30). There was no significant difference between pre-treatment LB and LSM results among antiviral drugs (p>0.05). Mean duration of monitoring was 2.8±1.3 in patients receiving antiviral treatment and 2.3±1.2 in patients not receiving treatment. At the end of monitoring, improvement was seen at LSM in patients receiving antiviral treatment (7.4±3.9) (p<0.001), but no difference was observed in the

untreated group (7.0±4.3) (p=0.561). There was no difference among the antiviral drugs in terms of fibrosis improvement (p>0.05). Conclusion; Since LSM is correlated with liver biopsy and is non-invasive and reproducible, it can be used in the diagnosis and long-term monitoring of CHB patients. It is a non-invasive test that also contributes to patients' compliance with treatment.

Disclosures:

Iftihar Koksal - Advisory Committees or Review Panels: MSD, Johnson; Speaking and Teaching: Gilead Sciences, Roche, BMS, MSD, Johnson

The following people have nothing to disclose: Gurdal Yilmaz, Selcuk Kaya

954

Sustained immune control in HBeAg-positive chronic hepatitis B patients who switched from long-term entecavir therapy to peginterferon alfa-2a (40KD): 1-year follow-up of the OSST study

Meifang Han1, Jia-ji Jiang2, Jinlin Hou3, Deming Tan4, Yongtao Sun5, Mianzhi Zhao6, Qin Ning1;

1Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 2The First Hospital, Fujian Medical University, Fuzhou, China; 3Nanfang Hospital, Nanfang Medical University, Guangzhou, China; 4Xiangya Hospital, Central South University, Changsha, China; 5Tangdu Hospital, The Fourth Military Medical University, Xi'an, China; 6Shanghai Roche Pharmaceutical Co., Ltd, Shanghai, China

Background Chronic hepatitis B (CHB) patients on nucleos(t)ide analog therapy can achieve maintained hepatitis B virus (HBV) DNA suppression, but over 75% do not achieve sustained immune control (hepatitis B e antigen [HBeAg] seroconversion post-treatment) and potentially require lifelong therapy. In the OSST study, HBeAg-positive patients who switched from long-term entecavir (ETV) therapy (0.5 mg QD for 9-36 months) to 48 weeks of peginterferon alfa-2a (40KD) (PegIFN alfa-2a) achieved higher rates of response (HBeAg seroconversion and hepatitis B surface antigen [HBsAg] loss) than those who continued ETV therapy. This 1-year follow-up study aimed to evaluate the sustainability of response in patients who switch from long-term ETV therapy to finite PegIFN alfa-2a therapy. Methods Sixty-two patients from the PegIFN alfa-2a arm of the OSST study (five centers) who completed 48 weeks of treatment were followed up for an additional 48 weeks. Primary endpoints were HBeAg seroconversion and maintenance of HBeAg seroconversion at 48 weeks post-treatment. Secondary endpoints included HBsAg loss, HBV DNA <1000 copies/mL and alanine aminotransferase (ALT) normalization (<1 x upper limit of normal [ULN]). Results HBeAg seroconversion rate increased from 1 7.7% (1 1/62) at the end of treatment to 38.7% (24/62) 48 weeks after discontinuation of PegIFN alfa-2a therapy. 63.6% (7/1 1) of patients who seroconverted at the end of treatment sustained response 48 weeks post-treatment, while 33.3% (17/51) of those who did not respond at end of treatment achieved delayed seroconversion. Almost all patients (6/7) with HBsAg loss at the end of treatment achieved sustained response 48 weeks post-treatment. HBV DNA suppression maintained at <1000 copies/mL was achieved in 60% (27/45) of patients (Table). Conclusion In patients who do not achieve HBeAg seroconversion despite virological suppression on long-term ETV therapy, switching to a finite course of PegIFN alfa-2a resulted in an increased rate of HBeAg seroconversion (1 7.7% at end of treatment to 38.7% 48 weeks post-treatment), and sustained HBeAg seroconversion (63.6%) and HBsAg loss (85.7%) 1 year after discontinuation of PegIFN alfa-2a therapy.

Response at end of treatment and 48 weeks post-treatment

Response variable, % (n)End of treatment (N=62)48 weeks post-treatment (N=62)Sustained response
  1. *Two patients with missing data are excluded.

HBeAg loss71.0(44)67.7 (42)72.7 (32/44)
HBeAg seroconversion17.7(11)38.7 (24)63.6(7/11)
HBsAg loss11.3(7)9.7 (6)85.7 (6/7)
HBsAg seroconversion6.5 (4)4.8 (3)75.0 (3/4)
HBVDNA<1000 copies/mL72.6 (45)53.3 (32/60)*60 (27/45)
ALT normalization (< 1 x ULN)61.3(38)65.0(39/60)*75.0 (27/36)*

Disclosures:

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

Mianzhi Zhao - Employment: Shanghai Roche Pharmaceuticals Ltd

Qin Ning - Advisory Committees or Review Panels: ROCHE, NOVARTIS, BMS, MSD, GSK; Consulting: ROCHE, NOVARTIS, BMS, MSD, GSK; Grant/Research Support: ROCHE, NOVARTIS, BMS; Speaking and Teaching: ROCHE, NOVARTIS, BMS, MSD, GSK

The following people have nothing to disclose: Meifang Han, Jia-ji Jiang, Deming Tan, Yongtao Sun

955

Viral response in long-term therapy with nucleos(t)ide analogues in chronic hepatitis B cirrhosis prevents decompensation

Ivana Carey, Sarah Knighton, Deepak Joshi, Ashley Barnabas, Suman Verma, Phillip M. Harrison, Abid Suddle, Kosh Agarwal;

Institute of Liver Studies, Kings College School of Medicine at King's College Hospital, London, United Kingdom

Long-term therapy with nucleos(t)ide analogues (NA) in chronic hepatitis B (CHB) reduces risk of liver disease progression, improves fibrosis and prevent liver disease related complications. Viral response (VR=HBV DNA<20IU/ml) in patients with liver cirrhosis prevents complication events. Only few studies have evaluated variable aspects of long-term NA therapy in CHB cirrhosis. Aims: To investigate the role of viral response on the improvement of synthetic function tested by MELD and UKELD scores, parameters of portal hypertension [platelets (PLT) counts, size of spleen] and preventing cirrhosis complications in patients with CHB cirrhosis during long-term NA therapy Patients: 190 monoinfected CHB cirrhotic patients (85%histo-logical confirmation) (median age 45y, 78%males, 43%HBeAg+) were treated in single centre with entecavir 0.5mg/day (n=78) or tenofovir 245 mg/d (n=62) or lamivu-dine 1 00mg/d +adefovir 1 0mg/d (n=50) for at least 2 years (median duration 5 years) and based on VR response after 1 year on therapy were divided into 2 groups: complete respon-ders (CR) (n=130) and partial responders (PR) (n=40). Patients achieving initial CR with viral breakthrough up to levels<100IU/ml (blips) were investigated separately (n=30). Methods: HBV DNA [log10IU/ml], haematological and biochemical markers of liver synthetic function and HCC surveillance abdominal ultrasound including size of spleen [cm] were analysed at baseline and every 6 months during therapy and MELD & UKELD scores were calculated. 32 patients had varices present at baseline. Results: Baseline median MELD & UKELD scores were 14 and 45 and were higher in PR than CR (14 vs 12,p=0.04; 45 vs 43,p=0.04). PLT counts and size of spleen were similar between PR and CR (145 vs 159,p=0.3 & 1 1.7 vs 10.9,p=0.2). Baseline HBV DNA was higher in PR than CR (7.33 vs 5.27,p<0.01). Yearly virological response had 77%, 84% 90%, 96% and 98% patients; 35% patients achieved

HBeAg seroconversion and 5% had HBsAg loss after 5 years NA therapy. MELD & UKELD scores improved during therapy in all patients, year 5 median MELD and UKELD scores were 12 (12 vs. 13) and 42 (42 vs 43), but PLT counts improved only in CR (year 5: 194 vs. 154,p=0.03). 18 (9%) patients developed HCC and 14 (7%) had decompensation while on therapy. HCC occurred equally in CR and PR or blips patients, but decompensation was present only in patients with PR or blips. Conclusions: Long-term antiviral therapy with NA in CHB patients with cirrhosis improved liver synthetic function in all patients. Viral response prevented decompensation and disease progression. HCC prevalence (2%patients/year) was similar viral responders and partial responders.

Disclosures:

Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and Teaching: BMS

Kosh Agarwal - Advisory Committees or Review Panels: Gilead, Novartis, Abbott; Grant/Research Support: Roche, MSD; Speaking and Teaching: BMS, Astellas, Janssen

The following people have nothing to disclose: Sarah Knighton, Deepak Joshi, Ashley Barnabas, Suman Verma, Phillip M. Harrison, Abid Suddle

956

Single-Nucleotide Polymorphisms of the HLA-DP Gene Are Associated With Virologic Response to Peginter-feron in Caucasian Patients with Chronic Hepatitis B

Willem Pieter Brouwer1, Milan J. Sonneveld1, Pauline Arends1, Vincent Rijckborst1, Andre Boonstra1, Robert J. de Knegt1, Bettina E. Hansen1,2, Harry L. Janssen3,1;

1Gastroenterology & Hepatology, Erasmus Medical Center Rotterdam, Rotterdam, Netherlands; 2Pub-lic Health, Erasmus Medical Center, Rotterdam, Netherlands; 3Gas-troenterology & Hepatology, University Health Network, Toronto Western Hospital, Toronto, ON, Canada

Background & Aims. Approximately 25% of chronic hepatitis B (CHB) patients benefit from peginterferon (PEG-IFN) treatment. Polymorphisms of HLA-DP on chromosome 6 are associated with spontaneous viral clearance in Asian hepatitis B patients. Our aim was to investigate the association of HLA-DP polymorphisms with response to PEG-IFN in Caucasian CHB patients. Methods. We studied 262 Caucasian CHB patients treated with PEG-IFN alfa for one year in two randomized controlled trials (HBV 99-01 and PARC study). Response at 6 months post-treatment was defined as an undetectable HBV DNA (<80 IU/ml). Polymorphism variants of HLA-DPA1 rs3077, HLA-DPB1 rs9277535 and IL28B rs1 2980275 were determined using competitive allele-specific PCR. Results. Of the 262 patients, 58% was HBeAg(+) and HBV genotype A and D were found in 33 and 67% respectively. Twenty-one patients achieved a virologic response (8%) and 16 lost HBsAg (6%). HLA-DPA1 genotypes TT/CT/CC and HLA-DPB1 genotypes AA/AG/GG were present in 63/26/6% and 62/26/6%, respectively. The HLA polymorphisms were in linkage disequilibrium for 31%. In uni-variate analysis, HLA-DPB1 GG was significantly associated with virologic response (OR GG vs AA/AG 9.4, 95%CI:2.9-29.8;p<0.001) and predisposed for HBsAg loss (OR GG vs AA/AG 3.8, 95%CI:1.0-15.2;p=0.055). HLA-DPA1 showed a trend (OR CC vs TT/CT 3.3, 95%CI:0.9-1 3.2;p=0.080) while IL28B was not associated with virologic response (OR AA vs AG/GG 0.9, 95%CI:0.4-2.5;p=0.899). In multivariate analysis taking into account the HBeAg status, adjusting for combination treatment and known response predictors (sex, age, previous (PEG-)IFN use, HBV genotype and baseline ALT, IP-10, HBV DNA load, HBsAg levels, precore/basal core promoter mutations) and using a stepwise logistic regression approach to avoid model overfitting, HLA-DPB1 GG (OR=8.7, 95%CI:2.4-30.7;p=0.001) and absence of precore/basal

core promoter mutations (OR=7.4, 95%CI:2.0-27.9;p=0.005) were significantly associated with virologic response. There was no interaction between HLA-DPB1 GG and HBV genotype or HBeAg status (all p-values>0.150). Using the same multi-variate analysis approach, patients with HLA-DPB1 GG had a predisposition for HBsAg loss (OR=3.2, 95%CI:0.3-12.0;p=0.168). Conclusion. HLA-DPB1 GG genotype is associated with virologic response to PEG-IFN 6 months post-treatment in Caucasian CHB patients infected with HBV genotype A or D.

Disclosures:

Milan J. Sonneveld - Speaking and Teaching: Roche

Vincent Rijckborst - Speaking and Teaching: Roche

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

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

The following people have nothing to disclose: Willem Pieter Brouwer, Pauline Arends, Bettina E. Hansen

957

Risk Factors for Late Genotypic Resistance to Entecavir after Achieving a Virologic Response: results from 617 Lamivudine Naïve Chronic Hepatitis B Patients

Pauline Arends1, Suzan D. Pas2, Roeland Zoutendijk1, Ashley S. Brown3, Ivana Carey4, Massimo Fasano5, David J. Mutimer6, Joerg Petersen7, Thomas Berg8, Jurrien G. Reijnders1, Tania M. Welzel9, Heiner Wedemeyer10, Maria Buti11, Fabien Zoulim12, Charles A. Boucher2, Bettina E. Hansen1,13, Annemiek A. van der Eijk2, Stephen Locarnini14, Harry L. Janssen15,1;

1Gastroenterology and Hepatology, Erasmus MC, Rotterdam, Netherlands; 2Virology, Erasmus MC, Rotterdam, Netherlands; 3Hepatology and Gastroenterology, Imperial College London, London, United Kingdom; 4Institute of Liver Studies and Transplantation, King's College London School of Medicine, London, United Kingdom; 5Clinic of Infectious Diseases, University of Foggia, Foggia, Italy; 6NIHR Biomedical Research Unit and Centre for Liver Research, Queen Elizabeth Hospital, Birmingham, United Kingdom; 7IFI Institute, Asklepios Klinik St. Georg, Hamburg, Germany; 8Hepatology, University Clinic Leipzig, Leipzig, Germany; 9Medizinische Klinik 1, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany; 10Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany; 11Hepatology, Hospital Vall de Hebron, Barcelona, Spain; 12Hepatology, Hospices Civils de Lyon, Lyon, France; 13Public Health, Erasmus MC, Rotterdam, Netherlands; 14Victorian Infectious Diseases Reference Laboratory, North Melbourne, VIC, Australia; 15Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada

BACKGROUND The risk of Entecavir resistance in Lamivudine naïve patients is low, especially after achieving undetectable HBV DNA. Guidelines thus suggest decreasing frequency of HBV DNA monitoring after confirming efficacy. METHODS We studied all HBV patients treated with ETV from 1 1 European centers within the Virgil Network. Patients were 3-6 monthly monitored for HBV DNA and ALT. Resistance testing was performed when viral breakthrough (VB) occurred (>1 log increase in HBV DNA from nadir). Resistance analysis was performed by InnoLiPA HBV-DR v2+v3 and/or Sanger sequencing of HBV RT gene. RESULTS Six of 617 LAM-naïve patients developed ETV resistance. Five year cumulative incidence of ETV resistance was 2.8%(95%CI 0.5-5.1%). At baseline HBeAg positivity

(p=0.004), higher HBV DNA (p=0.001) and HBsAg levels (p=0.02) were associated with ETV resistance. Occurrence of ETV resistance was not influenced by sex, previous NA or ALT (p>0.5). Only one patient who developed ETV resistance achieved VR within 2 years (p<0.001). At baseline, all 6 patients had wildtype and HBV DNA>7.5 log IU/mL. Five were HBeAg+ (genotypes A=3/B=2); 1 was pretreated with ADV (no resistance; treated with 1 mg ETV). One was HBeAg-, with genotype D. VB was accompanied by ALT flare (>5xULN) in patient 5. At VB, all were compliant and had genotypic resistance to ETV. The combination of rtL1 80M, rtM204V&rtS202G was seen in 3 patients; in 1 rtI169T, rtL180M, rtT1 84A&rtM204V; in 1 rtL80V, rtL180M, rtM204V&rt250L; and in 1 rtM204I&rtM250T. In all patients TDF±FTC was added to ETV with good response. CONCLUSION Baseline HBV DNA and slow response were related with ETV resistance in LAM-naïve patients. Infrequent monitoring of HBV DNA after achieving VR should be re-evaluated in these patients. Further studies are needed to assess initial combination therapy in order to prevent late viral resistance in this group.

image

Disclosures:

Suzan D. Pas - Grant/Research Support: the Virgo consortium, funded by the Dutch government (FES0908), the Netherlands Genomics Initiative (NGI) project number 050-060-452, the European Community Seventh Framework Programme (FP7/2007-201 3) under project EMPERIE (grant agreement no. 223498)

Roeland Zoutendijk - Grant/Research Support: Gilead Sciences, BMS; Speaking and Teaching: BMS, Abott

Ashley S. Brown - Advisory Committees or Review Panels: MSD, Roche, Bristol-Myers-Squibb, Gilead, Novartis, Janssen, Abbvie, Achillion; Speaking and Teaching: MSD, Roche, Bristol-Myers Squibb, Gilead, Janssen, Abbvie

Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and Teaching: BMS

David J. Mutimer - Advisory Committees or Review Panels: BMS, Janssen, MSD, Gilead

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

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

Jurrien G. Reijnders - Speaking and Teaching: Bristol Myers-Squibb, Gilead Tania M. Welzel - Advisory Committees or Review Panels: 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

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

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

Stephen Locarnini - Consulting: Gilead, Bristol-Myers Squibb, Merck Sharpe and Dohme; Employment: Melbourne Health

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

The following people have nothing to disclose: Pauline Arends, Massimo Fasano, Charles A. Boucher, Bettina E. Hansen, Annemiek A. van der Eijk

958

Week 24 HBeAg and HBsAg are better predictors of sustained response for Chinese HBeAg positive chronic hepatitis B patients receiving 48 weeks Peginterferon α-2b therapy

Song Yang1, Huichun Xing1, Qixin Wang2, Daozhen Xu1, Jun Cheng1;

1center of hepatology, Beijing Ditan Hospital, Beijing, China; 2Merck & Co., Inc, Beijing, China

Background: Studies have shown that HBeAg/HBsAg quantifications are predictors of sustained response to PEG-IFN. Little was known about the predictive values of HBeAg/HBsAg levels in Chinese CHB patients receiving PEG-IFN α-2b therapy. Previously we conducted a trial to evaluate PEG-IFN α-2b efficacy for Chinese HBeAg positive CHB patients (NCT 00536263). Totally 220 Chinese patients were enrolled to receive PEG-IFN α-2b 1.5μg/kg/week for 48 weeks. The aim of this study was to evaluate HBeAg/HBsAg for the prediction of sustained response to 48 weeks Peginterferon α-2b therapy in Chinese HBeAg-positive patients.Methods: Sustained response was defined as HBeAg seroconversion, HBV DNA<2,000 IU/mL and ALT normalization 24 weeks post-treatment. HBsAg and HBeAg levels were analyzed from samples collected at baseline, week 12, week 24, week 48 and follow-up 24 weeks. HBsAg/HBeAg levels were quantified using the Roche Elecsys assays. Week 12 and week 24 HBsAg/HBeAg decline were calculated. Receiver operating characteristic (ROC) curves and area under curves (AUC) were used to assess predictive values of variables. The optimal cut-off values of the predictors were determined and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for each predictor.Results: Samples of 181 Chinese patients were available for analysis, among which 30 patients had a sustained response (1 6.6%) AUC and best cut-off value of possible predictors were listed in the table. Week 24 HBeAg level, week 24 HBeAg decline and week 24 HBsAg level provided better predictions of sustained response. At week 24, the HBeAg cutoff value of 1.1000 PEIU/ml had sensitivity and NPV of 76.67% and 94.53%; HBeAg decline cut-off value of 11.3083 PEIU/ml had sensitivity and NPV of 93.33% and 97.75% and HBsAg cut-off value of 5925 IU/ml had sensitivity and NPV of 86.67% and 94.87%.Conclusions: For Chinese HBeAg positive CHB patients, Week 24 HBeAg and HBsAg levels and week 24 HBeAg decline are strong predictors of sustained response for 48 weeks Peginterferon α-2b therapy.

Predictors (log 10 IU/mL)AUCCut_offSensitivitySpecitivityPPVNPV
Baseline HBsAg0.67404.37660.80000.53640.25530.9310
Week 12 HBsAg0.68693.99540.90000.48320.25960.9600
Week 24 HBsAg0.70533.77270.86670.49330.25490.9487
Weekl2 HBsAg change0.6029-0.51700.53330.69130.25810.8803
Week 24 HBsAg change0.6304-0.37150.80000.44670.22430.9178
Baseline HBeAg0.59162.51320.56670.64900.24290.8829
Week 12 HBeAg0.68870.57980.56670.78000.34000.9000
Week 24 HBeAg0.81740.04140.76670.80130.43400.9453
Week 12 HBeAg change0.6971-0.52490.83330.54670.26880.9425
Week24 HBeAg change0.7969-1.05340.93330.57620.30430.9775

Disclosures:

Song Yang - Grant/Research Support: Merck & Co., Inc

Qixin Wang - Employment: Merck & Co., Inc.

Daozhen Xu - Grant/Research Support: Novartis

The following people have nothing to disclose: Huichun Xing, Jun Cheng

959

Monitoring serum HBV RNA is useful for predicting rebound of hepatitis after the discontinuation of nucleotide analogue therapy in chronic hepatitis B patients

Masataka Tsuge1,3, Eisuke Murakami1,2, Michio Imamura1,2, Hiromi Abe1,2, Daiki Miki1,2, Nobuhiko Hiraga1,2, Hidenori Ochi1,2, C. Nelson Hayes1,2, Hiroyuki Ginba4, Kazuhiro Mat-suyama4, Hiroiku Kawakami5, Kazuaki Chayama1,2;

1Department of Gastroenterology and Metabolism, Hiroshima university, Hiroshima, Japan; 2Liver Research Project Center, Hiroshima university, Hiroshima, Japan; 3Natural Science Center for Basic Research and Development, Hiroshima university, Hiroshima, Japan; 4Virology/Microbiology Group, Molecular Diagnostics Marketing Department, Roche Diagnostics K.K., Tokyo, Japan; 5Kawakami Clinic, Hiroshima, Japan

Background: Treatment for chronic hepatitis B has improved drastically since nucleot(s)ide analogues (NAs) became available. However, NA therapy fails to completely eliminate the virus from infected hepatocytes as hepatitis B virus (HBV) genomes remain in hepatocyte nucleus as minichromosomes. Rebound of HBV DNA and flare up of hepatitis after cessation of NA therapies is frequently observed. We previously showed that serum HBV RNA levels increase during NA therapy in sera of chronic hepatitis B patients. In the present study, we analyzed whether HBV RNA titers predict reactivation of hepatitis after discontinuation of NA therapy. Methods: Thirty-six patients who discontinued NA therapy were enrolled. Twenty-six of 36 patients underwent sequential interferon therapy, which included 6 months of conventional interferon therapy from one month prior to discontinuation until 5 months after discontinuation of NA therapy. Serum HBV DNA or DNA plus RNA levels were measured by reverse transcription real time PCR. The relationship between these levels and occurrence of HBV DNA rebound and flare up of hepatitis was analyzed. Results: Twenty-four weeks after discontinuation of NA therapy, HBV DNA rebound occurred in 19 of 36 patients (52.8%), and ALT rebounded in 12 of 36 patients (33.3%). Multivariate analysis identified a significant association between HBV DNA plus RNA titer after 3 months of NA treatment and HBV DNA rebound (P=0.043, OR=9.474). Presence of HBeAg at the end of treatment was significantly associated with ALT rebound (P=0.003, OR=13.500). Among 16 HBeAg positive patients, the cumulative ALT rebound rate during 24 weeks follow up was significantly lower in six patients where HBV DNA plus RNA titer after 3 months of treatment was less than 5.0 Log copies/ml than in remaining 10 patients (P=0.008). We also performed analysis in 26 of 36 patients who received sequential therapy. Higher serum HBV DNA plus RNA titer following 3 months of NA treatment was significantly associated with HBV DNA rebound (P=0.035, OR=3.064) and the following factors, higher levels of serum HBV DNA plus RNA (more than 4.8 Log copies/ml) following 3 months of treatment and the existence of HBeAg at the end of NA therapy, were significantly associated with ALT rebound (P=0.042; OR=1 8214, P=0.035; OR=15.370, respectively). Conclusions: HBV markers were closely associated with rebound of HBV DNA and ALT after discontinuation of NA therapy. Measurement of serum HBV DNA

plus RNA levels might be useful for predicting re-activation of chronic hepatitis B after discontinuation of NA therapy.

Disclosures:

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: Masataka Tsuge, Eisuke Murakami, Michio Imamura, Hiromi Abe, Daiki Miki, Nobuhiko Hiraga, Hidenori Ochi, C. Nelson Hayes, Hiroyuki Ginba, Kazuhiro Matsuyama, Hiroiku Kawakami

960

Entecavir Improve Liver Function and Fibrosis in Patients with Hepatitis B Virus-associated Liver Cirrhosis: 2 Years Study

Hyeonsu Park, Oh Sang Kwon, Jong Joon Lee, Young Kul Jung, Duck Joo Choi, Yun Soo Kim, Ju Hyun Kim;

Internal Medicine, Gachon University Gil Medical Center, Inchon, Republic of Korea

Background and aims: Entecavir (ETV) induces biochemical and histologic improvement of the liver in patients with chronic hepatitis B. This study aimed to verify whether ETV improves liver function and fibrosis in patients with hepatitis B virus (HBV)-associated liver cirrhosis (LC) during 2 years treatment. Methods: A total 145 naïve patients with HBV associated LC was treated by ETV for at least 2 years, between March 2007 and December 2012. All patients had HBV DNA level over than 4 log10 copies/mL and ALT level over than 40 IU/mL, because of regulation of Korea national health insurance. Exclusion criteria were the patients who 1) skipped the ETV more than 3 months and 2) developed hepatocelullar carcinoma within 2 years after ETV treatment. For the evaluation of liver function, laboratory findings, model for end stage liver disease (MELD) score, Child-Pugh (CP) score and class were compared between the baseline and 2 years after ETV treatment. For the evaluation of fibrosis, AST platelet ratio index (APRI) score, FIB-4 index, and fibrosis index (FI) were compared between the baseline and 2 years after ETV treatment. Results: The final 1 1 1 patients were enrolled. The mean age was 53±9 years old and 62.2% of patients was male. The baseline mean AST and ALT were 110±83 IU/L and 110±87 IU/L, respectively. The mean HBV DNA level was 6.8±1.2 log10 copies/mL. At 2 years after ETV treatment, the rate of ALT normalization was 77.8%, HBeAg loss in HBeAg positive-patients (n=58) was 43.1% and the undetectable rate of HBV DNA (by real-time polymerase chain reaction) was 90.1%. The changes of total bilirubin, albumin, platelet count, MELD score, and CP score between the two time points were from 2.1 ±3.2 to 1.3±1.0 mg/dL (p=0.014), from 3.6±0.6 to 4.1±0.5 g/dL (p<0.001), from 102±44 to 110±48xl000>/mm3 (p=0.013), from 9.2±5.2 to 6.7±5.2 (p<0.001), and from 6.4±1.8 to 5.5±1.0 (p<0.001), respectively. The distribution of CP class at baseline was 66.7% in A, 26.1% in B, and 7.2% in C. The distribution of CP class at 2 year after ETV treatment was 88.3% in A, 10.8% in B, and 0.9% in C. The improvement of CP class between the two time points was significant (p<0.001). The changes of APRI score, FIB-4 index, and FI between the two time points were from 3.2±2.4 to 1.1±0.9 (p<0.001), from 6.8±4.1 to 4.3±3.0 (p<0.001), and from 3.4±0.9 to 2.9±0.9 (p<0.001), respectively. Conclusions: Entecavir improves not only liver function but also fibrosis in patients with HBV-associated LC for long-term treatment.

Disclosures:

The following people have nothing to disclose: Hyeonsu Park, Oh Sang Kwon, Jong Joon Lee, Young Kul Jung, Duck Joo Choi, Yun Soo Kim, Ju Hyun Kim

961

HBeAg seroconversion is lower in Asian versus non-Asian patients during treatment of chronic hepatitis B with tenofovir (TDF) or entecavir (ETV)

Kahee Jo1,2, Jennifer L. Dodge3,4, Adrian Wadley1,2, Adil E. Wakil1,2, Jody L. Baron3,5, Stewart Cooper1,2;

1Division of Hepa-tology and Center for Liver Disease, California Pacific Medical Center, San Francisco, CA; 2The El Hefni Liver Biorepository, California Pacific Medical Center, San Francisco, CA; 3The Liver Center, University of California San Francisco, San Francisco, CA; 4Department of Surgery, University of California San Francisco, San Francisco, CA; 5Division of Gastroenterology, University of California San Francisco, San Francisco, CA

BACKGROUND/AIM Hepatitis B early antigen (HBeAg) seroconversion (SC) is the principal treatment endpoint in HBeAg-positive patients and the main therapeutic objective after viral suppression. Uncertain SC rates (SCR) in Asian patients treated with modern nucleos(t)ide analogs hamper prediction of treatment duration causing patient trepidation. We conducted a single-center study to evaluate SCR and virologic response (VR) among Asians and non-Asians treated with ETV or TDF. METHODS In HBeAg-positive patients treated with ETV or TDF monotherapy we estimated the cumulative probability of SC (HBeAb synthesis and HBeAg loss) in 1 87 patients (83% Asian) and VR (serum HBV DNA <1000IU/mL) in 145 patients (78% Asian). Cumulative probability of SC and VR were calculated by ethnicity and compared using the log-rank test. Cox regression modeled the risk of SC and VR; covariates included gender, age, LAM exposure, HBV genotype and baseline ALT. RESULTS The respective cumulative probabilities of SC on ETV or TDF at year 1, 2, 3, 4 and 5 were 5%, 10%, 16%, 25% and 35% in Asians, and 14%, 39%, 39%, 55% and 55% in non-Asians; differing significantly after year 1 (p<0.002). After adjusting for covariates the probability of SC remained significantly lower in Asians versus non-Asians (HR 0.33, 95%Cl p=0.004). In non-Asians, 2 and 3 year SCR were similar to rates reported in clinical trials. The cumulative probabilities of VR on ETV or TDF at year 1, 2, 3 and 4 were 59%, 77%, 84% and 92% in Asians, and 84%, 88% and 100% in non-Asians, which differed significantly (p<0.05) only in the univariate analysis. VR was greater at 2 years for Asians treated with TDF vs ETV (100% and 67%, p<0.001). CONCLUSION The likelihood of SC is lower in Asians versus non-Asians treated with ETV or TDF despite no overall difference in VR. The SCR in Asians is lower than reported by clinical trials in ethnically mixed populations. This is important information for Asian patients and supports that factors other than VR impact Asian SCR.

image

Disclosures:

The following people have nothing to disclose: Kahee Jo, Jennifer L. Dodge, Adrian Wadley, Adil E. Wakil, Jody L. Baron, Stewart Cooper

962

Dexamethasone Can Not Improve Outcome of Patients with HBV Related Acute-on-chronic Liver Failure (ACLF)

Shaoquan Zhang, ZiYing Lei, Junfeng Chen, Bingliang Lin;

The third affliated hospital of Sun Yat-sen University, Guangzhou, China

Objective Acute-on-chronic liver failure (ACLF) caused by hepatitis B virus (HBV) is a severe disease with high mortality. Immune injury plays an important role during the early stage of the disease. Our research aimed to investigate the safety and efficacy of dexamethasone therapy for patients with HBV related ACLF. Methods A total of 1 38 inpatients with the diagnosis for HBV induced ACLF were enrolled from January 2009 to December 2012. All the patients received the standard medicine treatment, among whom 35 cases underwent additional dexamethasone injection for 3 times (DMT Group). A total of 35 patients (SMT Group) matched for baseline characters served as controls. Both the groups were followed up for 12 weeks. The survival rates, liver functions and complications were recorded. Results The 12-week cumulative survival rates were 45.7%(16/35)and 54.3% (19/35) for SMT Group and DMT Group respectively, and no significant differences were found (P=0.654). There were no dramatic differences in the levels of alanine aminotransferase (ALT), albumin (ALB), total biliru-bin (TBil), international normalized ratio (INR), and Model for End-Stage Liver Disease score (MELD score) at 1, 2, 4, 8 and 12 weeks after enrollment between two groups. There were no significant differences in the incidence of complications (i.e., infection, gastrointestinal bleeding, encephalopathy, hepatore-nal syndrome, electrolyte disturbance and ascites) from 1-12 weeks between Group SMT and Group DMT. More than 40 ages, MELD score more than 28 and encephalopathy were independent risk factors for the mortality of patients. Conclusion Dexamethasone can not improve liver functions and 12-week survival rates of patients with HBV related ACLF. Age, MELD score and encephalopathy are independent risk factors. Key Words dexamethasone; acute-on-chronic; liver failure; hepatitis B; outcome

Disclosures:

The following people have nothing to disclose: Shaoquan Zhang, ZiYing Lei, Junfeng Chen, Bingliang Lin

963

Clinical outcomes and risk factors of hepatitis B virus recurrence in patients who received prophylaxis with entecavir and hepatitis B immunoglobulin following liver transplantation

Young-Kyu Kim, Seong Hoon Kim, Seung Duk Lee;

Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea

Although entecavir (ETV) and hepatitis B immunoglobulin (HBIG) have widely been used for prophylaxis of hepatitis B virus (HBV) recurrence following liver transplantation (LT), there have been few studies about clinical outcomes and risk factors of HBV recurrence. This study assessed clinical outcomes and identified risk factors of posttransplant HBV recurrence in patients who received prophylaxis with both ETV and HBIG after LT. We retrospectively analyzed the outcomes and risk factors of posttransplant HBV recurrence in the 155 patients who received prophylaxis with a combination of ETV and HBIG. The median follow-up duration was 28.0 months (range, 1.0-57.8 months). Posttransplant HBV recurrence occurred in 6 patients (3.9%) without any ETV-resistant mutants. The overall rates of HBV recurrence at 1, 3 and 5 years were 1.3%, 4.7% and 6.8%, respectively. We found that recurrent HCC was an independent risk factor of HBV recurrence (hazard ratio = 13.5, 95% confidence interval, 2.4-74.4; p = 0.003). Prophylaxis with a combination of ETV and HBIG resulted in a low HBV recurrence rate following LT without any emergence of ETV-resistant mutants. Recurrent HCC was an independent risk factor of HBV recurrence in patients who received prophylaxis with both ETV and HBIG for prophylaxis following LT.

Disclosures:

The following people have nothing to disclose: Young-Kyu Kim, Seong Hoon Kim, Seung Duk Lee

964

Predictive Value of Baseline and On-Treatment Quantitative Serum HBsAg Levels in Therapeutic Outcome to Entecavir in Patients with Chronic Hepatitis B

Cheng-Yuan Peng, Hsueh-Chou Lai, Wen- Pang Su, Chia-Hsin Lin, Po-Heng Chuang, Sheng-Hung Chen;

Division of Hepatogastroen-terology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

Background: The predictive value of baseline and on-treatment quantitative serum hepatitis B surface antigen (qHBsAg) levels in the therapeutic outcome to entecavir (ETV) in chronic hepatitis B (CHB) patients remains unclear. Patients and Methods: Between June 2006 and May 201 3, 321 treatment-naïve compensated CHB patients had been treated with ETV for at least 1 year. Serum HBsAg and HBV DNA levels were quantified using the Abbott Architect HBsAg QT assay and the Cobas Amplicor HBV Monitor Test during therapy, respectively. Results: The baseline features were: median age: 49 years, 75.1% men, 37.4% HBeAg-positive (N=120), 59.1% genotype B infection, median ALT: 79 IU/L, HBV DNA: 6.56 log10copies/mL, and qHBsAg: 3.29 log10IU/mL. Among them, 218, 163 and 81 patients have received ETV therapy for ≧3, 4 and 5 years, respectively, with the mean treatment duration of 45.8 ± 1 8.3 months. The cumulative rates for virological response (VR, HBV DNA <312 copies/mL) were 90.3%, 97.8% and 99.4% at 1, 2 and 3 years, respectively. The cumulative HBeAg loss rates were 12.5%, 32.9%, 50%, 59% and 77.4% at 1, 2, 3, 4 and 5 years, respectively. Multivariate logistic regression analyses identified baseline HBV DNA <8 log10 copies/mL(OR=5.746, P=0.0044) and qHBsAg decline from baseline ≧50% at 3 months of therapy (OR=4.202, P=0.0207) as predictors of VR

at one year for the HBeAg-positive subgroup. Multivariate Cox regression analyses identified ALT ≧120 IU/L (HR= 1.881, P=0.0369) and baseline qHBsAg level between 5000 to 16000 IU/mL (HR=4.421, P=0.0008) as predictors of HBeAg loss during treatment. The cumulative HBeAg loss rates after 5 years of therapy in patients with baseline qHBsAg ≧16000, 5000-16000, and <5000 IU/mL were 50%, 100%, and 77.8%, respectively (P=0.005). Multivariate Cox regression analyses showed that baseline qHBsAg level <3.5 log10 IU/mL (HR=4.784, P=0.021) and qHBsAg decline from baseline ≧50% at 3 months of therapy (HR=4.115, P=0.0368) were predictors of achieving qHBsAg level ≧2 log10IU/mL during treatment in HBeAg-positive patients, and that baseline qHBsAg level <2.5 log10 IU/mL (HR=3.965, P=0.0059) and qHBsAg decline from baseline ≧50% at 12 months of therapy (HR=22.355, P<0.0001) were predictors of achieving qHB-sAg level ≧2 log 10IU/mL during treatment in HBeAg-negative patients. Conclusion: Baseline qHBsAg and ALT levels are predictors of HBeAg loss during ETV therapy in HBeAg-positive patients. Baseline qHBsAg levels and on-treatment qHBsAg decline from baseline are predictors of achieving qHBsAg level ≧2 log10IU/mL during ETV therapy in both HBeAg-positive and -negative patients.

Disclosures:

The following people have nothing to disclose: Cheng-Yuan Peng, Hsueh-Chou Lai, Wen- Pang Su, Chia-Hsin Lin, Po-Heng Chuang, Sheng-Hung Chen

965

Nucleoside analogue treatment can not reduce the incidence of hepatocellular carcinoma in patients with chronic hepatitis B

Tetsuya Yasunaka, Fusao Ikeda, Nozomu Wada, Yuuki Morimoto, Kenji Kuwaki, Akinobu Takaki, Kazuhide Yamamoto;

Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine and Dentistry,and Pharmaceutical Science, Okayama-shi, Japan

Background & Aims: Chronic hepatitis B virus (HBV) infection leads to cirrhosis and hepatocellular carcinoma (HCC). Antiviral agents are thought to reduce the risk of hepatic failure and HCC development. Methods: We compared the incidence of HCC in 332 nucleoside analogue (NA) treated patients (NA group) and 494 non-treated HBV patients (control group). In the NA group, patients were initially prescribed LAM or entecavir (ETV). The drug mutation resistance was treated with LAM and adefovir (ADV) or ETV and ADV. Patient characteristics of the NA group and the control group differed significantly in age, gender, genotype, baseline HBV DNA level. Propensity score matching was used to eliminate the baseline above, resulting in a sample size of 137 patients per cohort. Results: The cumulative incidence rates of HCC in the NA groups were 1.6% at year 2, 3.5% at year 3, 4.5% at year 5, and 1 0.5% at year 10, while 0.7%, 2.3%, 3.2%, and 7.4%, respectively in the matched control group. Cox proportional hazard regression analysis showed that the NA group had similar risks of HCC development as the control group (hazard ratio 1.42, P = 0.54). In the patients treated with NA, serum HBV DNA decreased from 6.9 log IU/mL to 2.6 log IU/mL, albumin increased from 4.0 g/dL to 4.3 g/dL and ALT decreased from 82 IU/L to 23 IU/L, after 48 weeks treatment (p<0.001, <0.001, and <0.001, respectively). Conclusions: Even with long-term NA treatment, the incidence of HCC development was not reduced significantly in HBV-infected patients. Though long-term NA treatment can bring back hepatic reserve effectively, careful observation with periodical HCC screening is recommended.

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: Tetsuya Yasunaka, Fusao Ikeda, Nozomu Wada, Yuuki Morimoto, Kenji Kuwaki, Akinobu Takaki

966

Renal impairment in patients treated with adefovir and analysis of blood adefovir concentrations

Itaru Ozeki, Tomoaki Nakajima, Shuhei Hige, Yoshiyasu Karino, Joji Toyota;

Sapporo Kosei General Hospital, Sapporo, Japan

Background: It has already been reported that adefovir dip-ivoxil (ADV) causes renal impairment at a certain frequency but few studies have analyzed serum ADV concentrations. Methods: The study subjects were 89 lamivudine (LAM)-resistant patients who were co-administered ADV in our hospital. LAM and ADV doses were 100 mg/day and 10 mg/day, respectively. Baseline characteristics of these patients were as follows: median age, 59 years; 63 men (71%); 43 patients with hepatic cirrhosis (48%); median serum creatinine, 0.8 mg/dL; median estimated glomerular filtration rate (eGFR), 81.5 mL/min/1.73m2; median duration of ADV administration, 78 months. 1) Serum ADV concentrations at 3 years after starting ADV were measured to identify factors impacting serum ADV concentrations (factors studied: age at 3 years after starting ADV, serum creatinine, eGFR, sex, and liver disease at start of ADV). 2) Pre-treatment characteristics (age, sex, liver disease, serum creatinine, and eGFR at start of ADV) and serum ADV concentrations at 3 years after starting ADV were compared by dividing the patients according to eGFR level at 3 years after starting ADV into two groups: 24 patients (27%) with eGFR <60 mL/min/1.73m2 and 65 patients (73%) with eGFR >60 mL/min/1.73m2. In addition, a multivariate analysis was performed on factors contributing to an eGFR <60 mL/min/1.73m2 at 3 years after starting ADV. Serum ADV concentrations were measured employing LC-MS/MS. Results:1 )The median serum ADV concentration at 3 years after starting ADV was 15.7 (2.5-54.5) ng/mL and showed a negative correlation with eGFR at the same time point (r = -0.287, p = 0.006). The serum ADV concentration showed no significant correlation with age or sex. The median serum ADV concentrations in patients with chronic hepatitis and in those with hepatic cirrhosis were 17.5 ng/mL and 14.9 ng/mL, respectively (p = 0.098). 2) A univariate analysis showed significant differences in baseline serum creatinine and eGFR and in serum ADV concentrations at 3 years after starting ADV. The multivariate analysis identified the following 2 factors: serum ADV concentration at 3 years after starting ADV (odds ratio [OR], 3.574 for ≧16 ng/mL relative to <16 ng/mL; 95% confidence interval [CI], 1.152-1 1.082; p = 0.027) and baseline eGFR (OR, 10.1 for <80 mL/min/1.73m2 relative to >80 mL/min/1.73m2; 95% CI, 3.023-33.744; p < 0.001 ).Conclusion: The serum ADV concentration at 3 years after starting ADV correlated negatively with eGFR at the same time point, and was identified, together with baseline eGFR, as a factor contributing to an eGFR below 60 mL/min/1.73m2 at 3 years after starting administration.

Disclosures:

Joji Toyota - Speaking and Teaching: MSD

The following people have nothing to disclose: Itaru Ozeki, Tomoaki Nakajima, Shuhei Hige, Yoshiyasu Karino

967

Long-Term Effects of Antiviral Administration on Esophageal Varice Dimensions in Cirrhotic Cases

Murat Aladag1, Murat Harputluoglu1, Hulya Aladag2, Yuksel Seckin1;

1Gastroenterology, Inonu University Medical Faculty, Malatya, Turkey; 2Gynaecology & Obstetrics, Inonu University Medical Faculty, Malatya, Turkey

Introduction: Progression of cirrhosis leads to portal hypertension, which can result in esophageal varices and other complications. The onset of esophageal varices is a crucial cornerstone in the outcome of cirrhosis. The objective of our trial is to evaluate long-term clinical findings and impact of treatment on esophageal varices among cirrhotic cases secondary to chronic HBV. Patients enrolled to study were transplantation candidates and treated with oral antiviral treatments Method: Our study evaluated 71 transplant candidates treated with antiviral agents, between 2002 and May 2013. Lamivudine was initiated in 1 8 cases, Entecavir in 26 patients and Teno-fovir Disoproxil Fumarate in 27 cases. Endoscopic follow-up was carried out, both during the preoperative period and during the treatment period, and the status of esophageal varices were assessed. Clinical, laboratory and virologic load parameters were evaluated during control visits. Ten of Lamivudine treated patients, 24 of Entecavir treated patients and 25 of Tenofovir treated patients had control endoscopies. 16/18 Lamivudine treated patients, 24/24 Entecavir treated patients and 25/25 Tenofovir treated patients had negative HBV-DNA at fourth year. Esophageal varices disappeared in five of ten on Lamivudine treatment, in eleven of twentyfour on Entecavir treatment and in eleven of twentyfive on Tenofovir treatment. Regression of esophageal varices was observed in 5 (from grade 3 to grade 2 and 1), 13 (from grade 3 to grade 2 and 1) and 14 (from grade 3 to grade 1) patients, respectively. Discussion and Conclusion: In cirrhotic cases, liver transplantation should be appropriate after suppression of HBV-DNA to negative or minimal levels. In terms of both patient and graft survival, supression of HBV-DNA minimizes the rate of relapse in the post-operative period. Oral antiviral treatment in cirrhotic cases provides a high rate of viral suppression; in addition, it was previously reported to provide significant histological improvement, leading to delays of operations and even to delisting from transplant schedules. In several trials conducted in cases of viral eradication, patient's clinical status was reported to have improved, accompanied by histological improvement and regression in endoscopic cirrhotic parameters. In our trial, the long-term administration of all three antiviral agents provided clinical improvement and reduction in terms of the dimensions of esophageal varices, numerically more with Entecavir and Tenofovir leading to the disappearance of varices in some patients.

Disclosures:

The following people have nothing to disclose: Murat Aladag, Murat Harputluoglu, Hulya Aladag, Yuksel Seckin

968

Efficacy and Safety of Entecavir Treatment of Chronic Hepatitis B Patients in Real-world clinical Practice

Tawesak Tanwandee, Phunchai Charatcharoenwitthaya, Siwaporn Chainuvati, Watcharasak Chotiyaputta, Supot Nimanong;

Gastroenterology, Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

Background and Aim: Effective and sustained suppression of hepatitis B virus (HBV) replication results in regression of liver fibrosis. Entecavir (ETV) is a potent inhibitor of HBV replication and can be used as an effective therapy in naïve to

nucleos(t)ides analogue (NUC), interferon failure, NUC experienced chronic hepatitis B (CHB) patients. Aim of this study was to assess biochemical, virological response, long term outcome, and safety of ETV in patients who have been receiving ETV continuously for at least one year in several different clinical settings in single center. Methods: This is a retrospective chart review of adult CHB patients who have received ETV more than one year at Siriraj hospital. Co-infection with HCV, HDV, or HIV was excluded as well as those who were pregnant, underlying malignancy or receiving immunosuppressive agents. Patients were divided into 4 groups (G) as follow: G 1 for NUC naïve, G 2 for NUC switching (exposure to other NUCs without evidence of virological breakthrough or virological resistance), G 3 for lamivudine failure (exposure to lamivudine with evidence suggesting virological breakthrough), and G 4 for pegylated-interferon (Peg-INF) failure. Entecavir 0.5 mg daily was prescribed except in G 3 where 1.0 mg was used. Liver biochemistries, creatinine, HBV serology, and HBV DNA were monitored every 3-6 months. Hepatocellular carcinoma surveillance with ultrasound was done every 6 months. Adverse events were captures. Results: There were 709 patients, male 63.2%, mean age of 50.8±1 0.5 years with mean follow up of 61.5±37.2 months, and median of follow up of 63 months (12-108 months). Mean baseline HBV DNA was 5.1 log10 IU/mL and 34.8% HBeAg positive. Patients in G 1, 2, 3, 4 were 535, 123, 17, and 34 patients, respectively. During 5 years of follow up, viral load was undetectable 97.3% in G 1, 97.6% in G 2, 94.1% in G 3, and 95.5% in G 4. Normalization of ALT was observed more than 90% in every G. HBeAg seroconver-sion was found 33.3%, 20.3%, 29.4%, and 30.1% in G 1, 2, 3, and 4, respectively. Eleven patients had HBsAg loss. Virological breakthrough was found in 6 patients (4, 1, and 1 in G 1, 2 and 3, respectively). However, no virologic resistance was detected. No significant adverse event was observed. Conclusions: This is one of the largest real-world study in a single center which has shown that ETV can effectively and continuously suppress HBV DNA from 94.1 to 97.6% in NUC-naïve, NUC experienced, lamivudine or Peg-IFN failure CHB patients for the average of more than 5 years. Rate of virological breakthrough was low and the treatment is safe without significant side effects.

Disclosures:

Tawesak Tanwandee - Grant/Research Support: Bristol-Myers Squibb, Biotron, MSD, Roche

The following people have nothing to disclose: Phunchai Charatcharoenwitthaya, Siwaporn Chainuvati, Watcharasak Chotiyaputta, Supot Nimanong

HEPATOLOGY, VOLUME 58, NUMBER 4 (SUPPL) AASLD A

969

Tenofovir Treatment in Chronic Hepatitis B Patients with Older Age and Comorbidities is Effective and Well Tolerated

Fabien Zoulim1, Christophe Hezode2, Georges-Philippe Pageaux3, Xavier Causse4, Dominique G. Larrey3, Denis Ouzan5, Regine Truchi6, Jérôme Dumortier7, Marc Bourlière8, Thierry Fontanges1, Jean Didier Grange9, Veronique Loustaud-Ratti10, Stanislas Pol11, Jean françois D. Cadranel12, Jean-Pierre Zarski13, Valerie Tilliet14, Olivier P. Libert14, Christiane Stern14, Patrick Marcellin15;

1Hôpital de la Croix-Rousse, Lyon, France; 2Hôpital Henri Mondor, Créteil, France; 3CHU Saint-Eloi, Montpellier, France; 4Hôpital La Source, Orléans, France; 5Institut A. Tzanck, Saint-Laurent-du-Var, France; 6CHU Nice, Nice, France; 7Hôpital Édouard Herriot, Lyon, France; 8Hôpital Saint-Joseph, Marseille, France; 9Hôpital Tenon, Paris, France; 10CHU Limoges, Limoges, France; '11Hôpital Cochin, Paris, France; 12CH Laennec, Creil, France; 13CHU Grenoble, Grenoble, France; 14Gilead Sciences, Boulogne-Billancourt, France; 15Hôpital Beaujon, Clichy, France

Background/Aims: Long-term treatment of chronic hepatitis B patients with tenofovir DF (TDF) is associated with high sustained virologic response (VR) and favorable safety profile up to 6 years. Patients with older age and severe comorbidities are usually excluded from clinical trials. Thus, data from real-life cohorts are needed. The aim of this study was to analyze the 2-year data on the efficacy and tolerance of TDF treatment in a real-life cohort, especially in elderly patients. Methods: 441 HBV patients treated with TDF were included from June 2009 to April 201 0 in a French real-life, multicentre, prospective cohort (VIREAL study). Clinical, serologic and virologic data were collected at baseline and every 6 months. Preliminary analyses after 2 years of treatment were performed in the overall population and a subgroup of elderly patients (>65 years). VR was defined as HBV-DNA < 69 IU/mL. Results: The 441 patients had the following baseline characteristics: mean age 45±14 years, 71% male, 44% abnormal ALT, 74% HBeAg-negative and 33% advanced fibrosis (METAVIR F3-F4). 59% of patients were treatment-experienced. Overall VR was 94% at 2 years. Naïve patients had similar VR to treatment-experienced patients after 2 years (96% vs 93%, p=NS). To date, HBsAg-loss was observed in 1 1 patients at 2 years. The rate of adverse events (AE) was 14%. No major safety issues were reported. Liver-related complications were observed in 3 patients (2 cases of hepatocellular carcinoma, 1 episode of spontaneous bacterial peritonitis). Forty-nine elderly patients were subsequently analyzed: mean age 71 ±6 years, 73% male, 35% hypertension, 1 8% diabetes, 87% HBeAg-negative, 58% advanced fibrosis and 80% treatment-experienced. VR did not differ between elderly and younger patients (92% vs 94%, p=NS) at 2 years. AE rate in elderly was 14%. The most common AE was nausea (n=3). Although 82% of elderly had prior estimated glomerular filtration rate < 90mL/min (eGFR estimated by CKD-EPI formula), the mean eGFR remained stable: 72, 69 and 70 mL/min at baseline, 1 and 2 years. In addition, elderly patients with hypertension had stable mean eGFR: 62, 60 and 66 mL/min at baseline, 1 and 2 years. Similar results were observed in elderly patients with diabetes where the mean eGFR was 72, 74 and 80 mL/min at baseline, 1 and 2 years. Conclusions: TDF treatment in clinical practice was associated with a high virologic response, in accordance with phase III studies. In older patients with comorbidities, such as hypertension and diabetes, TDF treatment presented a favorable safety profile.

Disclosures:

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

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

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

Xavier Causse - Board Membership: Gilead, BMS, MSD, Janssen-Cilag; Speaking and Teaching: Roche, Gilead, BMS, Janssen-Cilag

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

Regine Truchi - Independent Contractor: Gilead

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

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

Veronique Loustaud-Ratti - Board Membership: Gilead; Speaking and Teaching: Roche, Schering Plough MSD, Schering Plough MSD, Janssen, Bristol meyers squibb, gilead

Stanislas Pol - Board Membership: Sanofi, Bristol-Myers-Squibb, Boehringer Ingel-heim, 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

Jean-Pierre Zarski - Advisory Committees or Review Panels: Janssen Cilag, Janssen Cilag; Board Membership: BMS, Gilead, BMS, Gilead; Consulting: Roche, Scher-ring Plough, Novartis, Roche, Scherring Plough, Novartis; Speaking and Teaching: Siemens

Valerie Tilliet - Employment: Gilead Sciences Olivier P. Libert - Employment: Gilead Sciences Christiane Stern - Employment: Gilead Sciences

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

The following people have nothing to disclose: Denis Ouzan, Thierry Fontanges, Jean Didier Grange, Jean françois D. Cadranel

970

Dynamics of liver stiffness values assessed using transient elastography in patients with chronic hepatitis B receiving entecavir: 3-year follow-up study

Mi Na Kim1,2, Seung Up Kim1,2, Beom Kyung Kim1,2, Jun Yong Park1,2, Do Young Kim1,2, Sang Hoon Ahn1,2, Kwang-Hyub Han1,2;

Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea

Background/Aims: Liver stiffness (LS) values using transient elastography provides accurate assessment of liver fibrosis in patients with chronic liver disease. The influence of antiviral treatment using entecavir (ETV) on LS values was assessed in patients with chronic hepatitis B (CHB). Methods: One hundred and twenty-one NUC-naïve patients with CHB who completed 3-year ETV treatment at the end of follow-up (April 201 3) were evaluated. LS was measured at the start and completion of the 3-year ETV treatment. The aim of this study was to evaluate the change in LS value under ETV therapy, and the presence of a decrease in LS value >1 kPa from the baseline. Results: The mean baseline LS value of the patients was 1 8.0 kPa. During the 3-year ETV treatment, the mean LS values decreased significantly from 18.0 to 9.3 kPa (P<0.001). In univariate analyses, the absence of diabetes mellitus, higher HBV DNA level, normalization of alanine aminotransferase (ALT) during the study period, and higher baseline LS values were associated with a LS decrease in LS values >1 kPa (all P<0.05). Together with ALT normalization, multivariate analysis identified higher baseline

LS values as an independent predictor of a decrease of LS values >1 kPa (P<0.001; hazard ratio [HR], 1.235; 95% confidence interval [CI], 1.104-1.382). Using the optimal cutoff baseline LS value of 10 kPa (area under receiver operating characteristic curve=0.835; 95% CI, 0.732-0.937, P<0.001; sensitivity 76.5%; specificity, 73.9%), patients with baseline LS values 1 0> kPa had a greater chance of experiencing a decrease in LS values >1 kPa than those with baseline LS values <10kPa(P<0.001;HR, 8.914; 95% CI, 3.231-24.597). Conclusions: A significant decrease in LS values after 3-year ETV treatment was observed in CHB patients. The baseline LS values and ALT normalization were independent predictors of a decrease in LS value >1 kPa.

Disclosures:

The following people have nothing to disclose: Mi Na Kim, Seung Up Kim, Beom Kyung Kim, Jun Yong Park, Do Young Kim, Sang Hoon Ahn, Kwang-Hyub Han

971

HBsAg quantification in HBeAg negative cirrhosis on nucleoside/nucleotide analogue (NA) and risk of development of HCC

Fabrizio Bronte1, Donatella Ferraro2, Vincenza Calvaruso1, Giulia Pecoraro1, Sandro Sferrazza1, Matteo Augugliaro1, Natalia Li destri3, Antonio Craxi1, Vito Di Marco1;

1Sezione di Gastroen-terologia Di.Bi.Mi.S, Università degli Studi di Palermo, Palermo, Italy; 2Sezione di Virologia Dip.PRO.SA.M.I., Università degli Studi di Palermo, Palermo, Italy; 3Laboratorio di Microbiologia e, A.R.N.A.S. Civico, Palermo, Italy

Background and Aims: Long term suppression with NA of HBV-DNA in patients with HBV cirrhosis does not entirely cancel the risk of hepatocellular carcinoma (HCC). The amount of circulating HBsAg after HBV DNA suppression by NA reflects the number of HBV cccDNA copies in the liver, which in turn could affect the residual risk of HCC after viral suppression. We quantified serum HBsAg at baseline and at last observation in a cohort of patients with HBeAg negative cirrhosis on long term NA in order to assess its value as a risk marker for development of HCC. Methods: 97 patients (82.5% males; mean age 53, range 24 - 80 years) with HBeAg negative, genotype D, compensated cirrhosis were treated with different schedules of NAs (lamivudine + adefovir; entecaviur; tenofovir). During profound and stable viral suppression (serum HBV-DNA < 20 UI/ml) we evaluated serum levels of HBsAg by Abbott's ARCHITECT® (analytical sensitivity 0.01 7 to 0.022 IU/mL) until the last observation or the diagnosis of HCC. Results: During follow-up (mean time 52 months; range 8-154 months) 16 out of 97 patients (1 6.5 %) developed HCC The mean time of diagnosis of HCC was 38.7 months (range 8-82 months) since obtaining HBV-DNA suppression. Patients who did not developing HCC had a more significant reduction of HBsAg levels between the time of onset of HBV-DNA suppression and the last observation (2,715 UI/ml vs 1,376 UI/ml; p<0.001 by t Student) when compared with patients who developed HCC ( 2,249 UI/ml vs 1,712 UI/ml (p=0.184) (Fig.1). Conclusion: Subjects with HBeAg negative cirrhosis and durable HBV DNA suppression on NA therapy have a higher risk of developing HCC if HBsAg levels do not decline sharply during treatment.

image

Disclosures:

The following people have nothing to disclose: Fabrizio Bronte, Donatella Ferraro, Vincenza Calvaruso, Giulia Pecoraro, Sandro Sferrazza, Matteo Augugliaro, Natalia Li destri, Antonio Craxi, Vito Di Marco

972

Association between HLA-DP genes polymorphisms and hepatitis B surface antigen kinetics and seroclearance during long-term nucleot(s)ide analog treatment in hepatitis B e antigen-positive chronic hepatitis B patients

Tetsuya Hosaka1, Fumitaka Suzuki1, Masahiro Kobayashi1, Tasuku Hara1, Taito Fukushima1, Yusuke Kawamura1, Hitomi Sezaki1, Norio Akuta1, Yoshiyuki Suzuki1, Satoshi Saitoh1, Yasuji Arase1, Kenji Ikeda1, Mariko Kobayashi2, Hiromitsu Kumada1;

1Hepatol-ogy, Toranomon Hospital, Tokyo, Japan; 2Research institute for hepatology, Toranomon Hospital, Tokyo, Japan

Background: Genome-wide association studies (GWAS) recently reported that the human leukocyte antigen (HLA) -DP genes polymorphisms were associated with risk of persistent hepatitis B virus (HBV) infection and clearance of HBV. However, it is unclear whether HLA-DP genes polymorphisms are associated with the effect of antiviral therapy. We investigated whether HLA-DP genes polymorphisms were associated with HBsAg declines and seroclearance in chronic hepatitis B patients who received long-term lamivudine (LAM) treatment and achieved favorable virological responses (VR). Method: The study included 202 Japanese patients with baseline hepatitis B e antigen-positive who received LAM and could undergo HLA-DP genotyping (HLA-DPA1 rs3077 and HLA-DPB1 rs9277535). Analyses were performed after separating two cohorts; the achievement of virological responses without rescue therapy cohort (cohort 1, n = 98) and with an add-on rescue therapy cohort (cohort 2, n = 104). Results: Eighteen of 202 patients successfully cleared HBsAg. Of these, 1 1 consisted of cohort 1, and 7 of cohort 2. The minor allele frequencies (MAF) of rs3077 and rs9277535 were 0.220 and 0.245 (minor allele = A). Among patients with number of 'A' allele> 2 of rs3077 and rs9277535, the median HBsAg change from baseline was -0.36 log IU/mL at 3 years, -0.49 at 5 years, -0.60 at 7 years, and -0.73 at 9 years. Among patients with < 2, the median changes were -0.06 log IU/mL at 3 years, -0.15 at 5 years, -0.23 at 7 years, and -0.38 at 9 years. HLA-DP polymorphisms had a significant effect on the slopes between data collection points at 3 years to 9 years (P < 0.05). The percentages of ≧0.5 logIU/mL HBsAg declines from baseline in cohort 1 patients with number of 'A' allele> 2 were higher than those with < 2 (71.8% (28/39) vs. 38.9% (23/59); P = 0.004). However, there was no significant difference in cumulative HBsAg seroclearance rates between number of 'A' allele> 2 and < 2 in cohort 1. In cohort 2, among patients with number of 'A' allele> 2, the median HBsAg change from VR with rescue therapy was -0.15 log IU/mL at 1 years, -0.31 at 3

years, and -0.53 at 5 years. Among patients with < 2, the median changes were -0.08 log IU/mL at 1 years, -0.21 at 3 years, and -0.37 at 5 years. HLA-DP polymorphisms had a significant effect on the slopes from VR (P < 0.05). HBsAg sero-clearance rates were significantly higher in patients with number of 'A' allele> 2 than in those with < 2 in cohort 2 (P = 0.003). Conclusion: HLA-DP polymorphism might influence HBsAg declines and seroclearance among baseline HBeAg-positive patients who received LAM and achieved VR.

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: Tetsuya Hosaka, Fumitaka Suzuki, Masahiro Kobayashi, Tasuku Hara, Taito Fukushima, Yusuke Kawamura, Hitomi Sezaki, Yoshiyuki Suzuki, Satoshi Saitoh, Yasuji Arase, Mariko Kobayashi

973

Twenty Eight Day Safety and Efficacy of Tenofovir Alafenamide (TAF) Fumarate in Chronic Hepatitis B (CHB) Patients

Kosh Agarwal1, Scott K. Fung2, Tuan T. Nguyen3, Wendy Cheng4, Eric Sicard5, Stephen D. Ryder6, John F. Flaherty7, Eileen Lawson7, Sally Zhao7, Mani Subramanian7, John G. McHutchison7, Edward J. Gane8, Graham R. Foster9;

1Institute of Liver Studies, Kings College Hospital, London, United Kingdom; 2Toronto General Hospital, Toronto, ON, Canada; 3T Nguyen Research and Education, San Diego, CA; 4Royal Perth Hospital, Perth, WA, Australia; 5Algo-rithme Pharma, Montreal, QC, Canada; 6Nottingham University Hospitals NHS Trust and Biomedical Research Unit, Nottingham, United Kingdom; 7Gilead Sciences, Foster City, CA; 8Auckland Clinical Studies, Auckland, New Zealand; 9Queen Mary's University of London, Barts Health, London, United Kingdom

Background: TAF, an alternate prodrug of tenofovir (TFV), is stable in plasma and more efficiently delivers TFV into lymphoid cells and hepatocytes at lower systemic TFV exposures than tenofovir DF (TDF). In ongoing Phase 2 studies in HIV infection when combined with other antiretrovirals, TAF demonstrated similar efficacy to TDF with less impact on renal function and bone mineral density. Methods: Prospective, randomized (1:1:1:1:1), open-label, Phase 1b study. CHB subjects with HBV DNA >2 x 1 03 IU/mL and ALT ≦10 x ULN received treatment with TAF at doses of 8, 25, 40, and 120 mg, or TDF 300 mg for 28 days with 4 weeks off-treatment follow-up. Intensive pharmacokinetics (PK) were performed on Day 1. Results: 51 subjects were enrolled and completed 28 days of dosing. Groups were well matched at baseline (table) and subjects were mostly male and either Asian or Black; 53% were HBeAg-negative. No subject experienced a serious adverse event (SAE), grade 3/4 AE, or discontinued for AE. No subject experienced a renal event (>0.5 mg/dL increase in creatinine from baseline, phosphorus <2 mg/dL, or CrCL <50 mL/min). The kinetics of reduction in serum HBV DNA were similar across all TAF dose groups and comparable to TDF. PK analysis suggested mean reductions in TFV exposures (AUCinf) of 97%, 93%, 81 %, and 32% at TAF doses of 8, 25, 40, and 120 mg, respectively, relative to the mean TFV exposure with TDF. Conclusions: Over 28 days, TAF was safe and well tolerated. Declines in HBV DNA with TAF did not differ by dose and were similar to TDF. Additionally, TAF may have less impact on renal function (CrCL) compared to TDF. Further clinical trials with TAF are warranted in CHB patients.

 TAF 8 mg (N=10)TAF 25 mg (N=10)TAF 40 ng (N=ll)TAF 120 mg (N=10)TDF 300 mg (N=10)
  1. Results are median (IQR) unless otherwise stated.

Male sex4 (40%)8 (80%)8 (73%)8 (80%)6 (60%)
Age, yr34 (24, 40)34 (28, 36)40 (30, 47)42 (34,49)34(29,41)
Asian Black White Pacific Islander4 (40%) 4 (40%) 2 (20%) 07 (70%) 1 (10%) 1 (10%) 1 (10%)8 (73%) 3 (27%) 0 05 (50%) 2 (20%) 3 (30%) 05 (50%) 5 (50%) 0 0
HBeAg-negative5 (50%)4 (40%)8 (73%)5 (50%)5 (50%)
Baseline ALT, U/L41 (25,65)52.5 (44. 62)50 (24, 85)43 (29, 78)27.5(20,51)
Baseline HBV DNA (log10 IU/mL), median (IQR)6.26(5.01, 8.50)6.35(4.10, 7.68)5.37 (3.42, 7.78)5.98 (4.34, 8.83)4,78(4.11, 6.86)
A Day 29 HBV DNA (log 10 IU/mL), median (IQR)-2.76 (-3.17, -2.48)-2.67 (-3.23, -2.12)-1.98 (-2.65, -1.82)-2.70 (-2.92, -2.56)-2.60 (-2.99, -2.52)
Baseline CrCL (mL/min)107.1 (91.9, 118.5)121.7(97.0, 152.6)117.9 (88.4, 148.3)107.6 (92.1, 121.9)127.1 (106.6,140.7)
A Day 29 CrCL (mL/min)-1.96 (-5.39, 0.24)-1.99 (-9.96, 3.65)-3.79 (-24.29, -1.15)0.00 (-7.96, 11,61)-10.35 (-18.81, 0.94)

Disclosures:

Kosh Agarwal - Advisory Committees or Review Panels: Gilead, Novartis, Abbott; Grant/Research Support: Roche, MSD; Speaking and Teaching: BMS, Astellas, Janssen

Scott K. Fung - Advisory Committees or Review Panels: BMS, Vertex, Gilead Sciences; Grant/Research Support: Gilead Sciences, Hoffman La Roche, Merck; Speaking and Teaching: Gilead Sciences, Hoffman La Roche, Merck, BMS

Tuan T. Nguyen - Grant/Research Support: Bristol Myers Squibb, Gilead Sciences, Idenix Pharmaceuticals Incorporation, Globeimmune Pharmaceuticals, Vertex Pharmaceuticals

John F. Flaherty - Employment: Gilead Sciences; Stock Shareholder: Gilead Sciences

Eileen Lawson - Employment: Gilead Sciences, Inc.; Stock Shareholder: Gilead Sciences, Inc.

Mani Subramanian - Employment: Gilead Sciences

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

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

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

The following people have nothing to disclose: Wendy Cheng, Eric Sicard, Stephen D. Ryder, Sally Zhao

974

Altered underlying tubular function in HBV monoin-fected patients receiving nucleos(t)ide analogs in a real-world setting: preliminary findings of MENTE study

Sonia Rodriguez Novoa1, Javier García-Samaniego2, José L. Calleja3, Martin Prieto4, Maria Buti5, Juan Manuel Pascasio6, Javier Crespo7, Manuel Praga8, Javier del Pino9, Manuel B. Del-gado10, Angeles Castro10, Ricard Sola11, Lucía Bonet12, Olga Fernández1, Elena Alvarez1, Miriam Romero2, Joaquin Cabezas7;

1Molecular Biology Laboratory, Hospital Carlos III, Madrid, Spain; 2Depatment of Hepatology, Hospital Carlos III, Madrid, Spain; 3Department of Hepatology, Hosp. Puerta de Hierro-Majada-honda, Madrid, Spain; 4Hepatogastroenterology Service, Hosp. Univ. La Fe, Valencia, Spain; 5Department of Hepatology, Hosp. Vall d Hebrón, Barcelona, Spain; 6Digestive Diseases, Virgen del Rocio, Sevilla, Spain; 7Department of Hepatology, Hosp. Univ Marqués de Valdecilla, Santander, Spain; 8Department of Nephrology, Hosp. 12 Octubre, Madrid, Spain; 9Department of Rheumatology, Hosp. Univ Salamanca, Salamanca, Spain; 10Hepatology and Internal Medicine, Hosp. Univ. La Coruña, La Coruña, Spain; 11Liver section, Hosp. del Mar, Barcelona, Spain; 12Department of Digestive Diseases, Hosp. Son Espases, Palma de Mallorca, Spain

Introduction Entecavir (ETV) and tenofovir (TDF) are second-generation nucleos(t)ide analogues used as first line therapies for treatment of chronic hepatitis B (CHB). In clinical trials, TDF and ETV have shown a good safety renal profile. However, several cases of tubular dysfunction have been reported in HIV-infected patients receiving TDF. Little is known about the impact on renal tubular function in CHB patients under long-term use of ETV and TDF. The aim of this study is to evaluate markers of renal tubular function and bone turnover in CHB patients treated with ETV or TDF for at least two years. Patients and Methods A multicenter, cross-sectional study was conducted in CHB patients (MENTE study). Analysis of renal parameters and markers of bone turnover were performed on patients with compensated liver disease, on first line therapy with ETV or TDF for at least two years or without treatment (control group). Tubular function was assessed by: ratio retinol binding protein/creati-nine (RBP/Cr), urinary neutrophil gelatinase-associated lipocalin (NGAL), renal tubular phosphate reabsorption (RTF), tubular maximal reabsorption of phosphate to glomerular filtration rate (TmPO4/GFR). Glomerular filtrate was assessed using CKD-EPI, MDRD4, Cockroft-Gault formulas and creatinine clearance in 24h urine. Markers of bone turnover were also assessed by: collagen type 1 C-telopeptide (CTx), Procollagen type I N-terminal propeptide (PINP). Other parameters evaluated: Vitamin D and parathormone (PTH). Results A total of 139 CHB patients (TDF- 34, ETV- 51 and control group- 54) were included. The median exposure to TDF or ETV was 39 months (IQR,31-48). Patients on the ETV-group were older with a higher rate of hypertension and a higher proportion of males. Altered excretion of RBP was more frequent in the TDF group (24% vs 6% and 4%, p<0.004). No differences were found in NGAL excretion. Glomerular filtrate measured as CG, CKD-EPI and MDRD4 was comparable across three groups. No statistically differences were found among groups in total excretion of phosphate, RTF and TmPO4. CTX and PINP did not show any differences among groups. More than 80% of patients in all groups were deficient in Vit D. PTH abnormal levels were more frequent in TDF group. Conclusions Though still preliminary, these findings in patients taking TDF in the long-term have a significant higher frequency of underlying tubular dysfunction compared with ETV and control groups. These differences in tubular function were not associated with concomitant glomerular filtrate reduction. Results are also in alignment with previous data in HIV patients taking TDF-based treatment.

Disclosures:

Sonia Rodriguez Novoa - Grant/Research Support: Bristol Myers-Squibb

Javier García-Samaniego - Consulting: Boehringer-Ingelheim

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

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

The following people have nothing to disclose: José L. Calleja, Martin Prieto, Juan Manuel Pascasio, Manuel Praga, Javier del Pino, Manuel B. Delgado, Angeles Castro, Lucía Bonet, Olga Fernández, Elena Alvarez, Miriam Romero, Joaquin Cabezas

975

Risk Factors Associated with Development of Hepatocel-lular Carcinoma during Nucleotide Analogs Therapy for Patients with Chronic Hepatitis B Virus Infection

Etsuro Orito1, Chitomi Hasebe2, Masayuki Kurosaki3, Atsunori Kusakabe1, Yukio Osaki4, Namiki Izumi3;

1Gastroenterology, Nagoya Daini Red Cross Hospital, Nagoya, Japan; 2Gastroen-terology, Asahikawa Red Cross Hospital, Asahikawa, Japan; 3Gas-troenterology, Musashino Red Cross Hospital, Musashino, Japan; 4Gastroenterology, Osaka Red Cross Hospital, Osaka, Japan

[Background and Aims] In most of patients receiving nucleotide analogs (NAs), HBV DNA levels often decrease very much. However, some patients develop hepatocellular carcinoma (HCC) during NAs therapy even if serum HBV DNA levels sufficiently fall down. So, the aim of this study is to identify the risk factors associated with development of HCC during NAs therapy for patients with chronic HBV infection. [Patients and Methods] Three hundred and eleven patients were recruited from the Japan Red Cross Hospitals Liver Study Group. All patients were receiving NAs for more than 1 year. The patients who developed HCC before or within 1 year during NAs therapy were excluded in this study. In all patients, HBsAg levels were determined quantitatively. The median (range) age was 51(21-79) years old, male:female=1 81:1 30, the median duration of therapy was 72 (1 3-1 86) months. The disease status was chronic hepatitis (CH):liver cirrhosis (LC)=259:52. The HBeAg status was positive:negative=140:168, and the HBV genotypes were A:B:C:others:NA=2:14:130:1:164. [Results] During NAs therapy, of 31 1 patients, the normalization of ALT, undetectable HBV DNA by the real-time PCR, HBeAg-seroconversion, HBsAg-seroclearance, and development of HCC were observed in 90.4%, 53.4%, 27.1 %, 1.9%, and 5.1 %, respectively. The significant factors associated with development of HCC were LC, shorter duration of therapy, and lower platelets count by the uni-variate analysis (p<0.01, 0.02, 0.03, respectively). By the mul-tivariate analysis, LC and shorter duration of therapy were significant (p=0.02, 0.045). The cumulative incidence of development of HCC in the patients with LC was significantly higher than in those with CH (p<0.01). The annual incidence of development of HCC was 2.15% in the LC patients, compared to 0.35% in the CH patients. In the CH patients, the incidences of HCC in the positive HBV DNA group was 4.2%, and the incidence in the undetectable HBV DNA with HBsAg=>1 00IU/L group was 2.6%, and the incidence in the undetectable HBV DNA with HBsAg< 1 00IU/L group was 0%. However, in the LC patients, the incidences of HCC in the positive HBV DNA group, in the undetectable HBV DNA with HBsAg =>1 00IU/L group or in the undetectable HBV DNA with HBsAg<1 00IU/L group were 33.3%, 10.0%, and 33.3%, respectively. [Conclusions] During NAs therapy, the incidence of development of HCC was low in the CH patients when HBV DNA and HBsAg

levels were suppressed. However, in the LC patients, there remained some risk of HCC even if HBV DNA and HBsAg levels were substantially decreased by NA therapy. Patients with LC should undergo regular HCC surveillance even during NAs therapy.

Disclosures:

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

The following people have nothing to disclose: Etsuro Orito, Chitomi Hasebe, Masayuki Kurosaki, Atsunori Kusakabe, Yukio Osaki

976

Risk of Abnormal Renal Phosphate Handling or Osteoporosis in Treated and Untreated Asian-American Chronic Hepatitis B Patients

Connie Tien1, Jason J. Xu1, Linda S. Chan2, Mimi Chang1, Hae-sung Kim1, Sue Lee1, Brian Huh1, Shuntaro Shinada2, Ho Bae1, Tse-Ling Fong1,2;

1Asian Pacific Liver Center, St. Vincent Medical Center, Los Angeles, CA; 2Univ Southern California, Los Angeles, CA

Background and Aims: Increased risk of renal proximal tubular injury resulting in decreased urinary phosphate reabsorption and osteoporosis has been reported in HIV patients treated with tenofovir (TDF). Goals of this study were to evaluate the prevalence of abnormal renal phosphate wasting and abnormal bone mineral density (BMD) in a cohort of chronic hepatitis B (CHB) patients taking TDF compared to CHB patients treated with entecavir (ETV) and untreated CHB patients. Patients and Methods: Cross-sectional study of 146 consecutive Asian-American CHB patients who were treatment naïve or treated with either TDF or ETV. Assignment of anti-viral agent was at the discretion of the physician. Testing included fasting blood and urinary levels of phosphate and creatinine to assess proximal tubular handling of phosphate by measuring maximal rate of tubular reabsorption of phosphate (TmPO4) over glomerular filtration rate (GFR) (TmPO4/GFR). Abnormal TmPO4/GFR) was defined as < 2.8-4.4 mg/dL. BMD of the lumbar spine (from L1-L4) and hip was measured using dual X-ray absorptiometry (DEXA). Results: TmPO4/GFR was similar among CHB patients treated with TDF (n=42) compared to untreated patients (n=60) and patients taking ETV (n=44). However, among patients treated with > 1 8 months of TDF or ETV, the prevalence of abnormal TmPO4/GFR was higher among patients treated with TDF compared to ETV patients (48.5% (16/33) vs. 12.5% (3/24), p=0.005). Overall prevalence of osteoporosis (T score < -2.5) in this cohort of CHB patients was 14%, with no significant difference between the 3 groups. Patients with osteoporosis were older, had lower BMIs and higher serum alkaline phosphatase levels. There was no association with treatment or type of treatment and the presence of osteoporosis. Renal phosphate handling did not correlate with osteoporosis in this CHB cohort. The proportion of patients who had suffered fractures was uniformly low (< 5%) in all three groups. Conclusions: CHB patients treated > 1 8 months of TDF experienced an increased risk of proximal tubular dysfunction assessed by TmPO4/GFR. No clinical effects of abnormal TmPO4/GFR were seen. TDF did not increase the risk of osteoporosis or impaired creatinine clearance. Larger, preferably long term longitudinal studies are needed to confirm these findings.

Phosphate Handling, Renal Function and Osteoporosis By Treatment Group

ParameterTotal N=146No Treatment N=60ETV N=44TDF N=42p value
Phosphate threshold for renal tubular resorption Mean±SD % (n)<2.8 mg/dL3.0±0.5 32% (46)3.0+0.5 30% (18)3.1±0.5 23% (10)2.9±0..5 43% (18)0.31 0.13
GFR by Cockcroft Gault (mL/min) % (n)<60 ml/min2% (3)0% (0)4% (2)2%(1)0.27
Osteoporosis (any T-score <-2.5) %(n)14% (20)12% (7)17% (7)14% (6)0.82

None of the paired comparisons were statistically significant at p<0.05

Disclosures:

Ho Bae - Grant/Research Support: Gilead; Speaking and Teaching: Gilead, BMS, Genentech

Tse-Ling Fong - Grant/Research Support: Gilead Sciences; Speaking and Teaching: BMS, Vertex

The following people have nothing to disclose: Connie Tien, Jason J. Xu, Linda S. Chan, Mimi Chang, Haesung Kim, Sue Lee, Brian Huh, Shuntaro Shinada

977

Tenofovir Monotherapy in Asian Chronic Hepatitis B Patients with Genotypic Resistance or Partial Virologic Response to Multiple Previous Antiviral Therapies

Jihyun An, Gi Ae Kim, Hyung-Don Kim, Dong Jin Suh, Young-Suk Lim;

Department of Gastroenterology and Liver Center, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

Background: The efficacy of tenofovir monotherapy is controversial for Asian chronic hepatitis B (CHB) patients who have developed genotypic resistance or showed partial virologic response to multiple previous antiviral therapies. Methods: Patients who had developed antiviral resistance or showed partial virologic response to multiple previous therapies were included. All patients were treated with tenofovir monotherapy for at least 3 months. The lower limit of detection for serum HBV DNA was 15 IU/mL (60 copies/mL). Results: At least one antiviral drug resistance mutations were detected in 301 (88%) patients prior to tenofovir therapy; lamivudine mono-resistance, 226 (66.4%); dual resistance to lamivudine and entecavir, 40 (11.7%); dual resistance to lamivudine and adefovir, 34 (1 0.0%). At baseline, 221 (64.6%) patients were being treated with combination therapy (lamivudine+adefovir or ente-cavir+adefovir), and mean serum HBV DNA was 2.7 ± 2.0 log 10 IU/mL. At 3 months of tenofovir monotherapy, serum HBV DNA was undetectable in 240 (70.2%) patients. One hundred-two patients who had detectable HBV DNA at 3 months showed a significant reduction in their HBV DNA levels (4.59 ± 1.85 log10 IU/ml vs. 2.26 ± 0.98 log10 IU/ml, P<0.01). Four patients experienced increases in viral titer, and two of them were associated with poor adherence. The rate of HBV DNA undetectability was not statistically different by the degree of previous resistance or by the number of antiviral agents exposed previously (P>0.05). Five patient discontinued tenofovir because of gastrointestinal symptoms. Otherwise, no patient reported significant clinical or laboratory adverse events. Conclusions: With short-term tenofovir monotherapy, the virologic response was achieved in most Asian patients who had partial virologic response or genotypic resistance to multiple previous drugs. Tenofovir monotherapy may be an effective and safe rescue therapy regardless of the nature of previous antiviral drug resistance or the number of exposed drugs in Asian CHB patients with low viral load.

Disclosures:

The following people have nothing to disclose: Jihyun An, Gi Ae Kim, Hyung-Don Kim, Dong Jin Suh, Young-Suk Lim

978

Incidence and clinical consequences of reduced tubular phosphate reabsorption in naïve chronic hepatitis B patients either untreated or treated with tenofovir for 2 years in a field practice study

Mauro Viganò1, Pietro Lampertico2, Giampaolo Mangia2, Roberta Soffredini2, Floriana Facchetti2, Federica Invernizzi2, Massimo Colombo2;

1Liver Unit, Ospedale San Giuseppe, Università di Milano, Milan, Italy;21 st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università di Milano, Milan, Italy

Background and Aim: The ratio between the maximal tubular re-absorption of phosphate and glomerular filtration rate indicates the tubular capacity of phosphate re-absorption and has been suggested to be more accurate than phosphatemia to detect an early proximal tubular dysfunction. The prevalence and incidence of hypophosphatemia and hyperphosphaturia among untreated and tenofovir (TDF)-treated naïve CHB patients are unknown. Material and Methods: 156 consecutive NUC-naïve CHB patients (55 yr, 75% males, 33% cirrhotics, creatinine 0.87 mg/dL, GFR 86 mL/min, 32% with vitamin D deficiency) were assessed at baseline for phosphatemia and phosphaturia. Changes of these 2 markers of kidney tubular dysfunction were evaluated every 3 months in 106 of these 156 patients who received TDF therapy for at least 6 months. Hypophosphatemia was defined as grade 1 (<2.5 mg/dL), grade 2 (<2.3) and grade 3 (<2.0); whereas hyperphosphaturia was classified as grade 1 (<0.80) and grade 2 (<0.60). Results: Before treatment, 44 (28%) and 10 (6%) patients had grade 1 and grade 2 hyperphosphaturia, respectively, while 15 (1 0%), 5 (3%) and 1 (0.6%) patients had grade 1, grade 2 and grade 3 hypophosphatemia, respectively. All patients with grade 1-3 hypophosphatemia had grade 1 hyperphosphaturia. Male gender and phosphate levels were independently associated with baseline hyperphosphaturia. Over a median follow-up of 27 (6-48) months, grade 1 and grade 2 hyperphosphaturia occurred in 1 3 (1 9%) and 5 (7%) of the 70 patients without it at baseline, respectively. However, hyperphosphaturia was also associated to grade 1 hypophosphatemia in only 4 of these 1 8 patients. Among the 29 patients with baseline grade 1 hyperphosphaturia, this condition worsened in 4 (14%) remained stable in 21 (72%) and improved 4 (14%) patients whereas 1 of the 7 patients with baseline grade 2 hyperphosphaturia improved to grade 1 while the other 6 patients remained stable. Overall, phosphaturia remained unchanged in 79 (75%), improved in 5 (5%) but worsened in 22 (24%) patients. Median phosphaturia declined from 0.89 to 0.81 mmol/L (p=0.031) whereas phosphatemia remained unchanged (3.2 to 3.1 mg/dL, p=0.20). Overall, 6 (5%) patients had to reduce TDF after a median of 10 months (5 because of GFR decline and one for hypophosphatemia grade 3) whereas one additional patients, a kidney transplanted recipient, had to stop TDF after 38 months due to a significant GFR reduction. Conclusions. Hyperphosphaturia affects approximately 1/3 of untreated NUC-naïve CHB patients and worsens in 1/5 of the patients during the first 2 years of TDF treatment, yet causing significant hypophosphatemia in few patients, only.

Disclosures:

Mauro Viganò - Consulting: Roche; Speaking and Teaching: Gilead Sciences, BMS

Pietro Lampertico - Advisory Committees or Review Panels: Bayer, Bayer; Speaking and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead

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: Giampaolo Mangia, Roberta Soffredini, Floriana Facchetti, Federica Invernizzi

979

Tenofovir resistance associated with A194 mutation on reverse transcriptase domain in a naive chronic hepatitis B patient responded to entecavir combination

Senol Comoglu1, Ayten Kadanali1, Gul Karagoz1, Behiye Dede1, Murat Sayan2, Birol Tok3;

1Infectious Diseases, Umraniye Training and Research Hospital, Istanbul, Turkey; 2PCR Unit Clinical Laboratory, Kocaeli Universty Faculty of Medicine, Kocaeli, Turkey; 3Infectious Diseases, Babaeski State Hospital, Kirklareli, Turkey

Background Nucleotide analogues such as tenofovir (TDF) and entecavir (ETV) are active against hepatitis B virus (HBV). TDF (acyclic phosphonat) and ETV confers potent and durable HBV-DNA suppression. Primary drug resistance mutation to ETV is reported but for TDF is not yet reported. We experienced one case of genotypic TDF resistance with viral rebound during TDF treatment of nucleos(t)ide-naive patients with HBeAg negative chronic hepatitis B. Case presentation A 27-year-old male patient was admitted to our clinic for HBsAg positivity. The patient was HBeAg negative and treatment-naive. HBV-DNA viral load was 8.2+E6 IU/mL. The baseline serum ALT level was 94 IU/L. A liver biopsy revealed chronic hepatitis B with moderate inflammation and stage II fibrosis (Ishak). A treatment with TDF 245 mg daily was started. The level of HBV DNA declined to 4.8+E4 IU/mL at week 12 and then rebounded to 2.1+E7 IU/mL at week 20 and 1.7+E8 IU/mL at week 24. The serum ALT level declined to 59 IU/L at week 12 and increased to 1 00 IU/L at week 20 and 122 IU/L at week 24 and HBeAg became positive during TDF treatment. The sequence analysis was revealed TDF possible resistance-related substitution (A194S) and adefovir (acyclic phosphonat) resistance-related substitutions (233F, P236T). Adding ETV to failing TDF therapy at week 24 was well-tolerated and resulted in virological response (serum HBV-DNA 5.2+E4 and ALT: 42U/L at week 12 of combination therapy). The TDF resistance-releated substitution (A194S) was undetectable in following sequence analysis (Table-1). Conclusions The three substitutions associated with acyclic phosphonats determined in a nucleotide-naive CHB patient who developed a viral breakthrough. However, A194S mutation is a novel mutation pattern and may be associated with TDF resistance. It is suggested that acyclic phosphonat mutations should be searched when breaktrough develops during the TDF treatment for the management of the patient.

Sequence information during tenofovir treatment

 At week 24 of TDFAt week 12 of TDF anf ETV combination therapy
GenotypeDD
SubgenotypeDlDl
Mutations RT domainT172S, L182P, NI89H, AI94S S201F, F209C, I215V, A217T, L223F, F230S,V231F, I232V, C233F, P236TH124Y, Y135S, QI49K
Mutations SHB proteinC107L,T111N, P1 17L, P122H, K124E, P127L, L129P, Q131L, L201V, Y215F, V225LT127P, KI4IV, DI44C
Escape mutations SHB proteinP127L, L129PK141V, D144C

Disclosures:

The following people have nothing to disclose: Senol Comoglu, Ayten Kadanali, Gul Karagoz, Behiye Dede, Murat Sayan, Birol Tok

980

Is it possible to predict the delayed response of patients with a partial virological response to 48 weeks of ente-cavir treatment for chronic hepatitis B?

Jung Hyun Kwon1, Jeong Won Jang2;

1Internal Medicine, College of Medicine, Catholic University, Incheon, Republic of Korea;2Internal nal Medicine, College of Medicine, Catholic University, Seoul, Republic of Korea

Backgrounds Entecavir is a potent inhibitor of viral replication in chronic hepatitis B (CHB) patients. The aim of this study is whether to predict the delayed response in naive CHB patients, particularly in those with partial virological response (PVR). Methods In s single center cohort study, we investigated 425 patients treated with entecavir monotherapy. PVR was defined as the detectable HBV DNA after 48 weeks. Virological response (VR) was defined as HBV DNA <20 IU/mL. Quantitative serum levels of HBsAg, HBeAg and HBV DNA were serially assessed at baseline and 3-month intervals. Results Virological response was achieved in 91%, 95%, 93% and 93% of patients at weeks 48, 96, 144, and 192 respectively. One hundred one patients out of 291 patients (65.3%) who were treated over one year showed PVR to 48 weeks of entecavir treatment. The patients with PVR from baseline to weeks 12, 24, 36 and 48 had more HBeAg positivity and higher levels of HBsAg, HBeAg, and HBV DNA than those with VR (P < 0.005). During prolonged entecavir monotherpy in 101 patients with PVR, 32/71 (45.1%) and 31/50 (62%) and 15/21 (71.4%) achieved virological response at weeks 96, 144 and 192, and none of them developed entecavir resistance. In the patients with PVR at week 48 for the predicting VR at week 96, HBsAg <3.5 log IU/ml at week 48 showed 73.9% of sensitivity and 70.0% of specificity (AUROC 0.707, P = 0.008) and HBV DNA < 343 IU/ml at week 48 showed 64.1% of sensitivity and 90.6% of specificity (AUROC 0.811, P = 0.000). Conclusions The majority of patients with PVR to 48 weeks of entecavir therapy achieved VR during the prolonged monotherpy. The patients with PVR had the higher levels of HBsAg, HBeAg, and HBV DNA at baseline and on-treatment period for 48 weeks than those with VR. In addition, the patients who showed HBsAg <3.5 log IU/ml or HBV DNA < 343 IU/ml at week 48 were likely to achieve the VR at the short term, week 96.

Disclosures:

The following people have nothing to disclose: Jung Hyun Kwon, Jeong Won Jang

981

Renal function improvement with telbivudine but not lamivudine in patients with chronic hepatitis B (CHB) and severe fibrosis or cirrhosis

Edward J. Gane1, Yun -Fan Liaw2, Yuming Wang3, Ching-Lung Lai4, Stefan Zeuzem5, Henry Lik-Yuen Chan6, Hong Ren7, George V. Papatheodoridis8, Antonio Craxi9, Sophie Bosset10, Aldo Trylesinski10;

1Auckland City Hospital, Auckland, New Zealand; 2Chang Gung Memorial Hospital and Chang Gung University, Hong Kong, Hong Kong; 3Xi Nan Hospital, Chongqing, China; 4Queen Mary Hospital, Hong Kong, Hong Kong; 5J.W. Goethe University Hospital, Frankfurt/Main, Germany; 6The Chinese University of Hong Kong, Hong Kong, Hong Kong; 7The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; 8Hippokration Hospital, Athens, Greece; 9Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy; 10Novartis Pharma AG, Basel, Switzerland

Background: Nucleotide analogues have been implicated in decreasing the estimated glomerular filtration rate (eGFR). Observational data suggest that telbivudine (LdT) may improve eGFR in compensated CHB patients. This retrospective study evaluates the changes in eGFR during long-term telbivudine therapy in patients with advanced fibrosis and cirrhosis. Methods: eGFR was assessed in GLOBE study patients (CLDT600A2302) with an Ishak Fibrosis score of 3-6 (IF >3-6) at baseline, using MDRD formula, and evaluated as absolute changes and percentage changes from baseline to 1 04 weeks. Analyses of patients grouped by baseline eGFR values were performed. Response to LdT and lamivudine (LAM) was assessed by HBV DNA <300 cp/ml (undetectability) and by HBeAg loss or seroconversion at Week 104. A multivariate analysis was performed to assess if baseline characteristics and predictors of efficacy outcomes at Week 104 influence eGFR shifts. Results: At baseline, patients were evenly distributed for fibrosis score, HBeAg status (60% HBeAg positive), HBV DNA, ALT and eGFR levels by treatment group. Among IF >3 patients, at Week 104, HBV DNA was undetectable in 69.2% of LdT group vs 47.6% of LAM group (p<0.0001) and HBeAg loss was 41.7% of LdT vs 34.1% of LAM (p=0.232). In patients with moderate fibrosis to complete cirrhosis (IF>3-6), the LdT group exhibited a significantly greater improvement in eGFR compared to LAM group (+6.14 (+8.02%) in LdT group vs. -4.96 ml/min/1.73m2 (-4.62%) in LAM group; LS means, p<0.0001). In 80% of LdT-treated patients with baseline eGFR 60-90, eGFR improved to >90 by Week 104. LDT treatment was the major predictive determinant for eGFR shifts (For IF >3 patients odds ratio: 9.964, 95% CI: 4.309 to 23.049, p<0.001). Increasing age was also associated to likelihood of shifting from eGFR insufficiency to normal (odds ratio: 0.926, p<0.001).Virologic response was not associated with improvement in eGFR. Conclusions: In patients with CHB and severe fibrosis or cirrhosis, two years of LdT treatment, but not LAM, resulted in a significant improvement in eGFR over baseline. LdT treatment and age were the only independent predictors for eGFR improvement (IF >3-6).

Table: Renal Function Evolution in Patients with Baseline Ishak Fibrosis score ≧a3 and Baseline eGFR (MDRD formula) 60-90 mL/min/1.73 m2

 eGFR at Week (ml/min)104% of patients with eGFR improvement at Week 104
 <60(N)60-90(N)>90(N)% (n/N)
LdT (n = 69)0145580% (55/69)*
LAM (n = 94)4553537% (35/94)*

*p<0.001 from Fischer exact test comparing improvement between 2 treatment groups

Disclosures:

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

Yun -Fan Liaw - Advisory Committees or Review Panels: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis; Grant/Research Support: Bristol-Myers Squibb, Roche, Gilead Sciences, Novartis

Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead Sciences, Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc; Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, Inc, Novartis Pharmaceuticals (HK) Ltd

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

Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Vertex, Bristol-Myers Squibb, Abbott, Novartis Pharmaceutical, Roche, MSD

George V. Papatheodoridis - Advisory Committees or Review Panels: Janssen, Abbott, Boehringer, Novartis, BMS, Gilead, Roche; Consulting: Roche; Grant/Research Support: BMS, Gilead, Roche; Speaking and Teaching: Janssen, Novartis, BMS, Gilead, Roche, MSD

Sophie Bosset - Employment: Novartis Pharma AG Aldo Trylesinski - Employment: Novartis

The following people have nothing to disclose: Yuming Wang, Hong Ren, Antonio Craxi

982

Discontinuation of long-term Nucleos(t)ide analogue therapy before HBsAg loss in HBeAg negative CHB patients: follow-up of long-term responders

Joerg Petersen1, Bettina E. Hansen5,6, Peter Buggisch1, Holger Hin-richsen2, Thomas Berg3, Heiner Wedemeyer4, Albrecht Stoehr1, Henry Lik-Yuen Chan7, Pauline Arends5, Steffen B. Wiegand4, Maurizia R. Brunetto8, Markus Cornberg4, Harry L. Janssen9,5;

1Liver center IFI Institute, Asklepios Klinik St. Georg Hamburg, Hamburg, Germany; 2Gastroenterology, Gastroenterologische Schwer-punkt Praxis, Kiel, Germany; 3Gastroenterology and Hepatology, University of Leipzig, Leipzig, Germany; 4Gastroenterology and Hepatology, Hanover Medical School, Hanover, Germany; 5Gas-troenterology and Hepatology, Erasmus MC, Rotterdam, Netherlands; 6Public Health, Erasmus MC, Rotterdam, Netherlands; 7Medicine & Therapeutics, Chinese University of Hong Kong, Hong Kong SAR, China; 8Hepatology Unit, University of Pisa, Pisa, Italy; 9Gastroenterology and Hepatology, University Health Network Toronto Western Hospital, Toronto, QC, Canada

Background and aim: Long-term therapy with NUCs is highly effective but HBsAg loss is rare in HBeAg-neg. patients. Small pilot trials have challenged the question of sustained remission after discontinuation of long-term NUC-therapy in some patients. We recently reported on high relapse rates (72% and 79%) in two cohorts of patients after NUC discontinuation in 32 and 28 HBeAg-neg. patients (AASLD 2011/2012). The aim of this combined cohort is to report on the long-term outcome of

patients without HBV relapse after discontinuation of NUC therapy after 37-84 months. Methods: 14/60 patients without relapse were identified by retrospective data base search from eight centres. These patients were prospectively followed (median 46 months). Results: All patients were HBeAg-negative, 8 male, median age 43 years, mostly genotype A or D. Seven patients had received lamivudine, three adefovir (one in combo with Lam), one telbivudine, three entecavir. At discontinuation of treatment ALT range was 0.3-1.3ULN with 9/14 patients with ALT <ULN, 10/14 patients showed qHBsAg levels of < 1000 IU/ml, and all patients showed HBVDNA <300copies/ml. Seven patients lost HBsAg off therapy and three of these developed anti-HBs, one developed a hepatic flare that resolved spontaneously. No patient displayed apparent liver disease progression by regular fibroscans, whereas a trend towards improvement (albeit not significant) could be detected. Conclusion: Stopping long-term NUC therapy in HBeAg-negative CHB patients without advanced liver disease might be an option for patients with HBsAg titers < 500IU/ml since these selected patients develop a high rate of HBsAg loss off-therapy. Reconstitution of some degree of immunological control over HBV in these patients during and after NUC treatment needs to be studied in greater detail to identify predictive markers to stop long-term NUC-therapy in selected patients.

HBsAg over time

image

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

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

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

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

Albrecht Stoehr - Board Membership: MSD, B≧dhringer Ingelheim; Speaking and Teaching: Janssen, MSD, Gilead, Abbvie, Boehringer Ingelheim

Henry Lik-Yuen Chan - Advisory Committees or Review Panels: Gilead, Vertex, Bristol-Myers Squibb, Abbott, Novartis Pharmaceutical, Roche, MSD

Maurizia R. Brunetto - Speaking and Teaching: Roche, Gilead, Schering-Plough, Bristol-Myers Squibb, Abbott, Roche, Gilead, MSD, Novartis

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

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

The following people have nothing to disclose: Bettina E. Hansen, Pauline Arends, Steffen B. Wiegand

983

Telbivudine versus Entecavir in Patients with Chronic Hepatitis B: 2-Year Results of a Head-To-Head Trial

Jing Huang, Xiaoping Chen, Xuefu Chen, Re Chen, Wenli Chen, Xiaojun Ma, Xiaodan Luo;

Guangdong Academy of Medical Sci-ences,Guangdong General Hospital, Guangzhou, China

Purpose: To compare the efficacy of 1 04-week treatment of telbivudine and entecavir in Hepatitis B e Antigen (HBeAg)-posi-tive chronic hepatitis B (CHB) patients in a head-to-head trial. Methods: In this randomized, controlled study, we randomly assigned 1 80 HBeAg-positive CHB patients in a ratio of 1:1 to receive oral telbivudine 600 mg once daily (n=90) or oral entecavir 0.5 mg once daily (n=90) for 1 04 weeks. At 52 weeks, if virological rebound and HBV DNA>103 copies/mL were observed, adefovir dipivoxil 1 0 mg QD was added to ongoing therapy. At 1 04 weeks, we evaluated the efficacy of telbivudine and entecavir treatment, and analyzed the predicators of HBeAg seroconversion. Results: At 104 weeks, the HBV DNA undetectable rate was 96.25% in the entecavir group and 94% in the telbivudine group, the rate of ALT normalization was 97.5% with entecavir and 95.23% with telbivudine (P>0.05). The HBeAg loss rate in the telbivudine group was significantly higher than that in the entecavir group (47.62% vs. 27.5%), telbivudine also demonstrated a higher rate of HBeAg seroconversion rate than entecavir (45.24% vs. 22.5%) (P<0.01). The overall rate of virological rebound in the telbivudine and entecavir groups were 8.3% and 1.25%, respectively (P<0.05). After adjustment for ongoing treatment at week 52, the new virological breakthrough rate at week 104 was 3.75% in the telbivudine group versus 1.25% in the entecavir group (P>0.05). No correlation was found between HBeAg seroconversion rate at week 104 and HBV DNA levels at baseline (P>0.05). Stepwise multivariate Logistic regression analysis showed that HBeAg decline by>1 log at week 12 and baseline HBeAg level were independent factors predicting the HBeAg seroconversion at week 104 in the telbivudine group; while in the entecavir group, HBeAg decline by>1 log at week 12, ALT and HBeAg levels at baseline predicted HBeAg seroconversion at week 1 04. Conclusions: During 1 04 weeks of treatment, telbivudine demonstrates higher HBeAg seroconversion rate compared with entecavir, but entecavir shows lower virological rebound rate. However, after adjustment for ongoing treatment at week 52, the rate of new virological rebound induced by telbivudine tends to be similar with entecavir. HBeAg decline by>1 log at week 12 is an optimal factor predicting HBeAg seroconversion at week 1 04.

Disclosures:

The following people have nothing to disclose: Jing Huang, Xiaoping Chen, Xuefu Chen, Re Chen, Wenli Chen, Xiaojun Ma, Xiaodan Luo

984

Predictive value of qHBsAg for SVR and HBsAg loss in chronic hepatitis B patients receiving peginterferon with or whithout tenofovir

Patrick Marcellin1, Michelle Martinot-Peignoux1, Martine Lapalus1, Olivier Lada1, Ahmed El Ray2, Qian Zhang1, Marie-Pierre Ripault1, Feryel Mouri1, Tarik Asselah1, Nathalie Boyer1;

1INSERM U/CRB3 et service d'Hépatologie, Université Paris Diderot-Hopital Beaujon, Clichy, France; 2Theodor Bilaz Research Institut, Giza, Egypt

Background. The combination of pegylated interferon (PEG-IFN) with a potent analogue might accelerate HBsAg decline and clearance. Our aim was to assess the predictive value of baseline HBsAg titer and on treatment decline during PEG-IFN and combination of PEG-IFN plus tenofovir (TDF) therapy. Patients-Methods. 90 patients CHB patients received 48 weeks of PEG-IFN or PEG-IFN + TDF were included: 25 HBeAg positive (e+) and 65 HBeAg negative (e-). HBsAg (qHBsAg) and HBV-DNA levels were measured at baseline, week 12, week 24, end of therapy and 24 weeks after treatment cessation. Sustained virological response (SVR) was defined as HBV-DNA < 2000 IU/ml at the 24 weeks post-treatment follow-up. Results. Among the 25 e(+) patients 12 received PEG-IFN and 13 the combination or PEG-IFN + TDF. An end of treatment response was observed in 20/25 (80%), SVR observed in 6/25 (24%) and an HBsAg loss observed in 1/25 (4%). No further analysis was performed because of the small number of patients. Among the 65 e(-) patients, 34 received PEG-IFN and 31 the combination or PEG-IFN + TDF. An end of treatment (EOT) response was observed in 58/65 (89%), SVR was observed in 19/65 (29%), HBsAg loss was observed in 11/65 (17%). Patients receiving PEG-IFN and PEG-IFN+TDF demonstrated: an EOT response in 28/34 (82%) and 30/31 (97%), SVR in 10/34 (29%) and 9/31 (29%), HBsAg loss in 6/34 (17%) and 5/31 (16%), respectively. A week 24 HBsAg decrease <0.5 or > 0.5 log IU/ml showed for SVR a Positive Predictive Value (PPV) 57% and Negative Predictive Value (NPV) 84%, respectively and for HBsAg loss a PPV 38% and NPV 93%, respectively. A week 24 HBsAg decrease <1 or > 1 log IU/ml showed for SVR a Positive PPV 69% and NPV81 84%, respectively and for HBsAg loss a PPV 54% and NPV 92%, respectively. Conclusions. In patients receiving PEG-IFN or PEG-IFN + TDF, SVR (24 weeks post-treatment) was observed in 29% and HBsAg loss in 17%. In HBeAg (-) patients baseline HBsAg titer > 2000 IU/ml was highly predictive of absence of SVR (NPV 80%) and absence of HBsAg loss (NPV 95%). Lack of > 0.5 log IU/ml HBsAg decline at week 24 allows identifying with high NPV, non-responders (84%), and absence of HBsAg loss (93%). Our results strongly suggest that qHBsAg both at baseline and on treatment is a useful tool for selecting HBeAg (-) patients that will benefit from PEG-IFN with or without TDF therapy.

Prediction in e(-) of SVR and HBsAg loss according to baseline HBsAg titer

HBsAg (IU/ml)< 1500 n=22> 1500 n=43<2000 n=25>2000 n=40
SVRPPV45%NPV79%PPV44%NPV80%
HBsAg lossPPV27%NPV88%PPV36%NPV95%

Disclosures:

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

Olivier Lada - Speaking and Teaching: Gilead, Gilead, Gilead, Gilead

Tarik Asselah - Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen

Nathalie Boyer - Board Membership: MSD, JANSSEN; Speaking and Teaching: BMS

The following people have nothing to disclose: Michelle Martinot-Peignoux, Mar-tine Lapalus, Ahmed El Ray, Qian Zhang, Marie-Pierre Ripault, Feryel Mouri

985

Preemptive antiviral therapy can reduce acute deterioration of hepatic function following transarterial chemo-embolization

Sun Hong Yoo1, Jeong Won Jang2, Jung Hyun Kwon2, Kyu Won Chung2;

1Hepatology Center & Laboratory of Hepatocarcinogene-sis, Bundang Jesaeng General Hospital, Kyungki-do, Republic of Korea; 2The Catholic University of Korea, Seoul, Republic of Korea

BACKGROUND : Acute deterioration of hepatic function following transarterial chemo-embolization(TACE) is a potentially life threatening complication and interfere with persisting TACE occasionally in patients with hepatitis B virus(HBV)-related hepa-tocellular carcinoma(HCC). Apart from its role in preventing HBV reactivation, there are limited data on the benefit of preemptive antiviral therapy in deterioration of hepatic function related with TACE. This study aimed to evaluate the effect of preemptive antiviral therapy on deterioration of hepatic function following TACE. METHODS : This is a retrospective observational study of 100 prospectively enrolled patients with intermediate-stage HBV-related HCC undergoing TACE between January 2007 and June 2012. Overall and treatment related deterioration of hepatic function following TACE were evaluated. Acute deterioration of hepatic function was defined as newly developed encephalopathy, ascites, variceal bleeding, bilirubin level more than 2.5 times the upper normal limit, prolongation of prothrombin time by more than 3 seconds, or an elevation of the Child-Pugh score (>2) within 2weeks following TACE. RESULTS : Of the 100 patients, 25 (25.0%) received preemptive antiviral therapy. During the follow-up, 23 (23%) and 40 (40%) patients developed acute and overall deterioration of hepatic function. Acute deterioration of hepatic function following TACE was significantly lower in the preemptive antiviral group than the antiviral-untreated group (4.0% vs. 29.3%, p=0.008). In addition, antiviral-untreated group had more frequent events of overall deterioration of hepatic function when compared to the preemptive antiviral group (45.3% vs. 24.0%, p=0.01). In multivariate analysis, jaundice (>1.2mg/dl) (OR 5.849, 95% CI 1.885-18.148, p=0.002) and antiviral-untreat group (OR 18.770, 95% CI 2.147-164.127, p=0.008) were significantly associated with the acute deterioration of hepatic function. CONCLUSION : Our results showed that preemptive antiviral therapy can reduced the risk of acute and overall deterioration of hepatic function. In this regard, preemptive antiviral therapy should be administered during TACE. Prevent deterioration of hepatic function by preemptive antiviral therapy may facilitate continuing anti-cancer therapy and improve long term outcomes.

Disclosures:

The following people have nothing to disclose: Sun Hong Yoo, Jeong Won Jang, Jung Hyun Kwon, Kyu Won Chung

986

Tenofovir and Pegylated Interferon combination therapy for HBeAg positive chronic hepatitis B: a randomised, open label pilot study

Dilip Ratnam1,2, Paul O'Neill1, Hugh Harley3, Wendy Cheng4, Sally Bell5, William Sievert1,2, Anouk Dev1,2;

1Gastroenterology, Monash Medical Centre, Clayton, VIC, Australia; 2Medicine, Monash University, Clayton, VIC, Australia; 3Gastroenterology, Royal Adelaide Hospital, Adelaide, SA, Australia; 4Gastroenterol-ogy, Royal Perth Hospital, Perth, WA, Australia;5Gastroenterology, St Vincent's Hospital, Fitzroy, VIC, Australia

Introduction Current first line options for the treatment of chronic hepatitis B (CHB) involve the use of either Pegylated interferon-α(Peg-IFN) or nucleos(t)ide analogue therapy. There is increasing interest in the potential benefits of combining these two classes, particularly in relation to improving the rates of HBsAg clearance, a rare but highly desirable endpoint. The aim of this study was to examine the efficacy and safety of combining Peg-IFN with Tenofovir TDF in HBeAg positive CHB patients. Methods In this prospective multicenter study, HBeAg positive CHB patients were randomized in a 1:1:1 ratio to receive either Peg-IFN monotherapy 1 80mcg sc weekly (Peg-IFN) for 48 weeks, (2) Peg-IFN and TDF (300mg daily) combination ther-apy(PEG-TDF) for 48 weeks or (3) 'lead in' therapy with Peg-IFN for 24 weeks followed by combination therapy for 24 weeks and then another 24 weeks of TDF alone. Patients were then followed up for 24 weeks off treatment. Baseline data included patient demographics, liver histology and HBV genotype. On treatment data included HBV DNA viral load, quantitative HBsAg and HBeAg titres, routine biochemistry, serum calcium and phosphate and adverse events. The primary end-point was the loss of HBsAg, while secondary endpoints included HBV DNA <20 IUml, HBeAg seroconversion and normalization of ALT. Results Twenty seven patients have been enrolled to date with the baseline characteristics of all 3 treatment groups (Peg-IFN, Peg+TDF and lead-in) comparable in terms of mean age (3 1,29, 32 years), median ALT (1 07, 1 12, 86 U/L) and HBV DNA viral load (7.2, 7.7 and 7.7 log 10 IU/ml). 26 of 27 patients were of Asian ethnicity and one patient in each group had Metavir fibrosis >3. An interim analysis of the end of treatment outcomes of 15 patients who have completed a minimum of 48 weeks of therapy is presented here. No patient achieved the primary endpoint of HBsAg loss and no significant differences were noted in the on-treatment kinetics of HBsAg levels between the 3 groups. HBV DNA suppression <20 IU/ml was observed in 1, 4 and 2 patients in the Peg-IFN, Peg+TDF and lead-in groups respectively. HBeAg to anti-HBe seroconversion was achieved in 2,3 and 1 patient respectively. One patient in the Peg-IFN group developed symptomatic hyperthyroidism, while 2 patients in each of the Peg-IFN and Peg+TDF groups developed a transient mild hypophos-phatemia (Serum PO4 between 0.65 to 0.81 mmol/L). No other significant AEs were noted. Conclusion In a CHB cohort of predominantly Asian ethnicity, combination therapy with Peg-IFN and TDF is not associated with an early on-treatment loss of HBsAg, but appears safe and well tolerated.

Disclosures:

Hugh Harley - Advisory Committees or Review Panels: Roche, MSD, Janssen; Grant/Research Support: Gilead, Abbott, BMS

Sally Bell - Speaking and Teaching: MSD, Roche, BMS

William Sievert - Advisory Committees or Review Panels: Merck, Janssen, AbbVie, Gilead; Speaking and Teaching: Bristol-Myers Squibb, Merck

The following people have nothing to disclose: Dilip Ratnam, Paul O'Neill, Wendy Cheng, Anouk Dev

987

Clinical characteristics of patients with chronic hepatitis B who developed genotypic resistance to entecavir

Ki Bae Bang, Hong Joo Kim, Yong Kyun Cho, Byung Ik Kim;

Internal Medicine, Sungkyunkwan University Kangbuk Samsung Hospital, Seoul, Republic of Korea

<Background/aims> It has been reported that the development of entecavir resistance in nucleoside-naïve patients is very rare, even after 5 years of treatment. Most cases of entecavir resistance were reported in patients with prior use of lamivudine. For these reasons, recent treatment guidelines have recommended entecavir as the first-line nucleoside analogue for nucleoside-naïve chronic hepatitis B (CHB) patients. Here, the authors present the clinical characteristics of patients with CHB who developed genotypic resistance to entecavir compared to those who did not develop resistance. <Methods> One hundred twelve patients with CHB who underwent entecavir treatment at our institution from July 2007 to July 201 1 were included in the current study. We included the nucleoside-naïve patients (n=74, 66.1%) as well as those who had prior nucleoside treatment (total n=38, 33.9%; lamivudine n=33, 29.5%; clevudine n=4, 3,6%; telbivudine n=1, 0.9%) who had underwent hepatitis B virus (HBV) mutation test just before the switching to entecavir and at least once during the follow-up period (Drug resistance pyrosequencing assay). Patients were monitored at baseline and every 3 months thereafter during the dosing period. <Results> Eight (7.1%) patients developed genotypic resistance to entecavir during the follow-up period. The patterns of genotypic resistance to entecavir were as follows: L1 80M + M204V + S202G (n=3); M204I + V173M (n=1); I169V + V173M (n=1); L180M + M204V + V173L(n=1); L180M + M204V + V173L + M250V (n=1); M204I + V214A + P237H (n=1). Mean ± standard deviation(SD) time to develop genotypic resistance to entecavir was 27.1 ± 1 1.6 months. Prior nucleoside treatment and drug compliance were not significant contributors to the development of entecavir resistance. Older age, higher baseline log10HBV-DNA (copies/ml), non-complete responder (less than 300 copies/ml of HBV DNA at 24 weeks of entecvir treatment by real-time PCR), and nonresponder (less than 2log10 decrease of HBV-DNA at 24 weeks of entecvir treatment) were significant contributors to the development of genotypic resistance to entecavir. By Kaplan-Meier analysis with log rank comparison, negative conversion of HBeAg was significantly lower in patients with CHB who developed entecavir resistance (P=0.019). <Conclusions> Clinical characteristics of patients who developed genotypic resistance to entecavir were older age, higher baseline log1 0HBV-DNA, non-complete responder and nonresponder during the entecavir treatment. Adding potent another antiviral drug, such as teno-fovir may be needed for patients with CHB who have above-mentioned characteristics during the entecavir treatment.

Disclosures:

The following people have nothing to disclose: Ki Bae Bang, Hong Joo Kim, Yong Kyun Cho, Byung Ik Kim

988

Comparison of Entecavir Treatment in Chronic Hepatitis B, HBeAg positive Patients who have Failed Pegylated Interferon and Naïve Patients

Rattapon Thummanusarn, Phunchai Charatcharoenwitthaya, Siwa-porn Chainuvati, Watcharasak Chotiyaputta, Tawesak Tanwandee

Gastroenterology, Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

Background: Treatment of chronic hepatitis B (CHB), HBeAg positive patients includes pegylated interferon (PegIFN) or nucleos(t)ide analogues (NUC). However, the treatment outcome is not yet satisfactory, about two-thirds of patients treated with PegIFN do not achieve HBeAg seroconversion and may require subsequent treatment with NUC. There are few data about the outcomes of CHB patients who have failed PegIFN followed by NUC. The objective of this study was to investigate the outcome of CHB patients who have failed PegIFN followed by Entecavir (ETV) compared with patients treated with ETV alone in CHB, HBeAg positive. Methods: This is a retrospective chart review of patients who attended Hepatitis Clinic from January 2005 to July 2012. CHB, HBeAg positive patients who were treated with PegIFN alfa-2a 180 mcg weekly for 48 weeks but did not achieve HBeAg seroconversion and required treatment with Entecavir (ETV) (0.5 mg) daily within 1 year after stopping PegIFN (PegIFN/ETV group) compared with CHB, HBeAg positive patients treated with ETV (0.5 mg) alone during the same period (ETV group). HBeAg status and HBV DNA level at baseline and every 3-6 months after starting ETV treatment were collected and compared between 2 groups. Results: There were 46 patients in PegIFN/ETV group compared with 50 patients in ETV group. Baseline characteristics of both groups were not significantly difference except patients' age in PegIFN/ETV group which was younger (mean age 45.4 vs 52.3 years, p=0.004). Furthermore, the ETV treatment duration was shorter in PegIFN/ETV group (116.8 vs. 162.5 week, p=0.004). After 1 year of ETV treatment, there was no significantly difference in rate of HBeAg seroconversion, HBeAg loss and undetectable HBV DNA (less than 20 IU/mL) of both groups (10.9% vs 14.0%, p=0.64; 7.3% vs 4.6%, p=0.67 and 54.3% vs 64.0%, p=0.34; respectively). These outcomes were also not difference between two groups at year 2 and 3 after ETV treatment. There was no virological rebound and no significant side effects in both groups. Conclusions: In HBeAg-positive CHB patients, patients who have failed PegIFN alfa-2a, treatment with ETV (0.5 mg/day) could be as effective as naïve patients in term of HBeAg seroconversion, HBeAg loss and HBV DNA suppression. Previous PegIFN exposure did not affect the efficacy of ETV therapy.

Baseline characteristics and treatment outcome after ETV

  1. Data expressed in number (%) or median (range)

 PeglFN/ETV (n=46)ETV (n=50)p-value
Initial HBV DNA (loglO lU/mL)7.3(1.3-8.2)7.1 (2.3-8.3)0.696
HBV DNA suppression at year 333(93.1%)42 (90.7%)0.484
HBeAg seroconversion at year 38 (26.8%)15(35.5%)0.282

Disclosures:

Tawesak Tanwandee - Grant/Research Support: Bristol-Myers Squibb, Biotron, MSD, Roche

The following people have nothing to disclose: Rattapon Thummanusarn, Phunchai Charatcharoenwitthaya, Siwaporn Chainuvati, Watcharasak Chotiyaputta

989

Application of roadmap-concept on chronic hepatitis B patient with entecavir therapy previously exposed to lamivudine: A long term follow-up study

Sang Jun Suh1, Hyung Joon Yim1, Yeon Seok Seo2, Chang Wook Kim3, Chang Don Lee3, Sang Hoon Park4, Myung Seok Lee4, Choong Kee N. Park5, Hee Bok Chae6, Moon Young Kim7, Soon Koo Baik7, Yun Soo Kim8, Ju Hyun Kim8, Jung Il Lee9, Jin-Woo Lee9, Sun P. Hong10, Soon Ho Um2;

1Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea; 2Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea; 3Inter-nal Medicine, The Catholic University of Korea Uijeongbu St. Mary's Hospital, Uijeongbu, Republic of Korea; 4Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, Republic of Korea; 5Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea; 6Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; 7Internal Medicine, Yonsei University Wonju Christian Hospital, Wonju, Republic of Korea; 8Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea; 9Internal Medicine, Inha University Hospital, Incheon, Republic of Korea; 10GeneMarix Inc., Yongin, Republic of Korea

Background/Aim: A number of patients with lamivudine-resist-ant (LAM-R) chronic hepatitis B (CHB) had been treated by switching to entecavir (ETV) 1 .0mg. As the rate of genotypic resistance to ETV (ETV-R) is reported high currently, changing ETV to the other agent may be needed even in patients whose resistance to ETV was not identified. However, appropriate indication and time point have not been proposed yet. This study was aimed to stratify ETV therapy in LAM-R patients. Methods: One hundred and nine CHB patients who developed LMV-R and then received ETV 1.0mg up to 5 years were evaluated prospectively. Virologic response (VR, HBV DNA <20 IU/mL) and ETV-R during 5 years of treatment were evaluated as primary end points. We divided subjects into non-detection group (HBV DNA <20 IU/mL) and detection group (HBV DNA >20 IU/mL) at 6 months and 12 months of switching to ETV for prediction of long term response. Results: The mean age of the patients was 45±1 1 years, the proportion of male and HBeAg-positive patient was 72% (79/109) and 77% (84/109), respectively. VR rates were 0%, 20%, 24%, 32%, 37%, and 39% and the mean serum HBV DNA levels were 6.89±1.03, 3.26±1.81, 3.06±1.82, 2.49±1.53, 2.43±1.35 and 1.73±0.87 log 10 IU/ml at baseline, month 12, 24, 36, 48 and 60, respectively. Genotypic resistance to ETV occurred at 30±12 months (median 24 months, 12-66 months). Resistance rates were 4.6%, 19%, 32%, 36%, and 37% at baseline, month 12, 24, 36, 48 and 60, respectively. When we predicted long term responses according to delectability of HBV DNA at 6 months of treatment, VR (100% vs. 28%, p <0.001) was higher and ETV-R (0% vs. 45%, p = 0.001) was lower in non-detection group than in detection group. Likewise, at 12 months of treatment, VR (96% vs. 21%, p <0.001) was higher and ETV-R (12% vs. 49%, p = 0.001) was lower in non-detection group than detection group. Multivariate analysis showed non-detection of HBV DNA at 6 months as well as 12 months were independent factors associated with VR. To evaluate predictive value for VR, area under the receiver operating characteristic curve (AUROC) was used. AUROC (0.865; 95% confidence interval [CI], 0.789-0.940; P <0.001) of non-detection of HBV DNA at 12 months showed slightly better than that of 6 months (AUROC, 0.828; 95% confidence interval [CI], 0.742-0.914; P <0.001). Conclusion: Resistance rates were high in patients with detectable HBV DNA at 12 months of ETV therapy. Therefore, switching to or adding a potent nucleotide

analogue (e.g. tenofovir) is warranted in LAM-R CHB patients whose HBV DNA is detected after 12 months of ETV therapy.

Disclosures:

Hyung Joon Yim - Grant/Research Support: GSK Korea, Handok Pharm, Gilead Korea; Speaking and Teaching: BMS Korea

Chang Wook Kim - Consulting: Gilead; Grant/Research Support: BMS, Boehringer Ingelheim, Pharmicell; Speaking and Teaching: BMS, GSK, Dae-woong

Hee Bok Chae - Advisory Committees or Review Panels: Bristol-Meyers Squibb-Korea; Consulting: Gilead Science-Korea

The following people have nothing to disclose: Sang Jun Suh, Yeon Seok Seo, Chang Don Lee, Sang Hoon Park, Myung Seok Lee, Choong Kee N. Park, Moon Young Kim, Soon Koo Baik, Yun Soo Kim, Ju Hyun Kim, Jung Il Lee, Jin-Woo Lee, Sun P. Hong, Soon Ho Um

990

Virological Supression Does not Prevent the Development of Hepatocellular Carsinoma in Cirrhotic Patients with Genotype D Hepatitis B Infection

Suut Gokturk1, Rafet Basar2, Ali Riza Ucar2, Barbaros Hayrettin Basgoze2, Mustafa Altinkaynak2, Pinar Buyukballi2, Busra Alpaslan2, Bulent Baran1, Asli Cifcibasi Ormeci1, Ozlem Mutluay Soyer1, Sami Evirgen1, Baris Bakir3, Filiz Akyuz1, Cetin Karaca1, Kadir Demir1, Fatih Besisik1, Sabahattin Kaymakoglu1;

1Gastroen-terohepatology, Istanbul school of medicine, Istanbul, Turkey;2Internal Medicine, Istanbul school of medicine, Istanbul, Turkey; 3Radiology, Istanbul school of medicine, Istanbul, Turkey

INTRODUCTION:Chronic hepatitis B (CHB) infection is a common cause of hepatocellular carcinoma (HCC).Nucleos(t)ide analogues (NA) are effective in suppressing viral replication and decreasing the inflammatory response in the liver,but their effect on progression to HCC is unclear.This study examines the factors affecting development of HCC in patients receiving long-term NA therapy. METHODS:CHB patients,who received at least 12 months of NA therapy,were enrolled in the study.The patients who diagnosed with HCC before they have completed the first 12 months of treatment were excluded.Clinical and biochemical findings, stage of fibrosis and type of NA treatment were recorded .The patients were screened for HCC at every 6 months by USG and AFP. A drug with a higher genetic barrier against resistance was added or switched,if HBVDNA negativity could not be achieved or genotypic resistance/virological breakthrough developed during treatment. Lamivudine and adefovir were accepted to be low genetic barrier drugs,while entecavir and tenofovir were defined as high genetic barrier drugs. RESULTS:661 patients with genotype D CHB infection (71% male,mean age 50±12 years,71% HBeAg (-) ) were enrolled in the study.66% of patients were pre-cirrhotic, while 34% were cirrhotic.The median duration of NA treatment was 48 months (1 2 - 1 94 months). HCC developed in a total of 57 (8.6%) patients.The cumulative incidence of HCC was significantly higher in patients with cirrhosis than in those without (p<0.001).Also it tended to be higher in patients with decom-pensated cirrhosis compared to those with compensated cirrhosis.Cumulative HCC incidence in cirrhotic and CHB patients were 2.3% vs.0.2% at 1st year, 8.3% vs.0.5 % at 2nd year, 14.8% vs. 1.4% 3rd year and 22.9% vs.2.6% at 5th year, respectively (log-rank,p<0.001 ).The median time for HCC development during NA treatment was 36 months.In univariate Cox regression analyses,factors associated with HCC development were found to be male sex (p=0.002), cirrhosis (p<0.001),alcohol (p=0.02),HBeAg negativity (p=0.001),low genetic barrier drug regimen (p<0.001),resistance/virological breakthrough (p=0.002) and diabetes (p=0.03).In a multivariate analysis,cirrhotic liver (p<0.001), low genetic barrier drug regimens (p=0.02) and resistance-virological breakthrough

(p=0.04) were independent factors associated with HCC development. CONCLUSION:Development of resistance/virological breakthrough,treatment with low genetic barrier NAs and being in a cirrhotic stage increase the risk of developing HCC in CHB patients treated with NAs.The risk of HCC development is low in pre-cirrhotic patients, but remains high in patients with cirrhosis.

Disclosures:

The following people have nothing to disclose: Suut Gokturk, Rafet Basar, Ali Riza Ucar, Barbaros Hayrettin Basgoze, Mustafa Altinkaynak, Pinar Buyukballi, Busra Alpaslan, Bulent Baran, Asli Cifcibasi Ormeci, Ozlem Mutluay Soyer, Sami Evir-gen, Baris Bakir, Filiz Akyuz, Cetin Karaca, Kadir Demir, Fatih Besisik, Sabahat-tin Kaymakoglu

991

Entecavir Pharmacokinetics Among Nucleos/tide-Naïve Pediatric Subjects

Mei-Hwei Chang1, Deirdre A. Kelly2, Nanda Kerkar3, Maureen M. Jonas4, Philip Rosenthal5, Peter Ackerman6, Marc Bifano7;

1National Taiwan University Hospital, Taipei, Taiwan;2Birmingham Children's Hospital, Birmingham, United Kingdom; 3Children's Hospital of Los Angeles, Los Angeles, CA; 4Boston Children's Hospital, Boston, MA; 5University of California-San Francisco, San Francisco, CA; 6Research and Development, Bristol-Myers Squibb, Wallingford, CT; 7Bristol-Myers Squibb, Hopewell, NJ

Background/Aims: Entecavir (ETV) is approved for the treatment of adults with chronic hepatitis B (CHB). The purpose of Study AI463-028 was to support ETV dose selection in pediatric subjects. Safety and efficacy of ETV in pediatric CHB subjects is being evaluated in ongoing clinical trials. Methods: Adult dosing, scaled to body surface area (BSA), was extrapolated to determine ETV dosing in pediatric subjects (>2-l 8 years old [yo]) using a weight-based algorithm (0.015 mg/kg up to a maximum dose of 0.5 mg). Dose selection was designed to achieve a median exposure (AUC[TAU]) across each of three age groups (A: >2-<6 yo [n=7], B: >6-≦12 yo [n=9], and C: >12-≦18 yo [n=8]) within ±30% of the median exposure obtained in adults (1 8.7 ng.h/mL). Subjects in each of the three age cohorts had pharmacokinetics (PK) samples drawn at selected times. Individual subject PK parameters were derived by noncompartmental methods using a validated PK program. Results: Target median exposure (13.1-24.3 ng.h/mL) was achieved in all three age cohorts (17.0, 20.5, and 15.4 ng.h/mL, respectively). ETV clearance (CLT/F) increased as age increased, CLT/F normalized to body weight decreased with increasing age. ETV BSA-normalized CLT/F was independent of age. Conclusions: ETV dosing using a weight-based algorithm (0.015 mg/kg up to a maximum dose of 0.5 mg) provided comparable exposures in pediatric subjects compared with historical exposures in adults receiving 0.5 mg/day (AUC[TAU] geo.mean [CV] at day 14: 14.78 ng.h/mL1). 1. Yan JH, et al. J Clin Pharmacol. 2006 Nov;46(1 1): 1250-8.

Table 1. Summary Statistics for Entecavir Pharmacokinetic Parameters in Nucleos/tide-Naïve Subjects
Age cohortCMAX (ng/ML) geo.mean(CV)(ng/mL) geo.mean (CV)AUC(TAU| (ng.h/mL) medianAUC(TAU) (ng.h/mL) geo.mean (CV)CLT/F (L/h) mean (SD)CLT/F/kg (L/h/kg) mean (SD)CLT/F/m2 (L/h/m2) mean (SD)
A fn=7)8.07 (24)0.244 (32)17.018.7 (21)11.4 (2.564)0.814 (0.1436)I9.5 (3.51)
B(n=9)6.29 (25)0.320 (22)20.520.42 (20)22.7 (6.134)0.656 (0.1232)19.5 (3.22)
C (n=8)5.11 (27)0.271 (25)15.416.0 (22)31.9 (6.429)0.499 (0.1139)I8.8 (3.09)

Disclosures:

Deirdre A. Kelly - Consulting: Sanofi Pasteur; Grant/Research Support: BMS, Astellas, Acitllion, MSD, Roche

Nanda Kerkar - Advisory Committees or Review Panels: Gilead Inc.

Maureen M. Jonas - Advisory Committees or Review Panels: Gilead Sciences; Consulting: Novartis; Grant/Research Support: Bristol Myers Squibb, Roche, Merck Schering Plough

Philip Rosenthal - Advisory Committees or Review Panels: Ikaria, Gilead, Merck, General Electric; Consulting: Roche; Grant/Research Support: Roche, Bristol MyersSquibb, Gilead, Vertex

Peter Ackerman - Employment: Bristol-Myers, Squibb

Marc Bifano - Employment: Bristol-Myers Squibb

The following people have nothing to disclose: Mei-Hwei Chang

992

Tenofovir mono-rescue therapy in multi-drug resistant CHB: A prospective cohort study

Sangheun Lee, Jung Yoen Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Do Young Kim, Chae Yoon Chon, Kwang-Hyub Han, Sang Hoon Ahn

Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

Background/Aims: Tenofovir disoproxil fumarate (TDF) has high antiviral efficacy in treatment-naïve patients with chronic hepatitis B virus (HBV) infection. However, patients treated with a nucleoside/nucleotide analogue (NA) before TDF have rarely been studied. Here, we investigated the viral kinetics and response in CHB patients with lamivudine (LAM-R), adefovir (ADV-R), or entecavir (ETV-R) resistance. Methods: This retrospective study examined 1 64 patients who were treated with TDF monotherapy from December 2012 to March 2013, including patients with LAM-R (n=1 13) and multiple-drug resistance (MD-R) including LAM-R + ADV-R (n=21), LAM-R + ETV-R (n=42), and LAM-R + ADV-R + ETV-R (n=3). The mean reduction in serum HBV DNA levels and viral response defined as serum HBV DNA levels <60 IU/ml were analyzed according to LAM-R or MD-R. Results: At baseline, the patients' mean serum HBV DNA level was 5.2 (range 2.3-8.2) and 5.0 (range 2.2-8.2) log 10 IU/ml in the LAM-R and MD-R groups, respectively. At week 12, the mean reduction in serum HBV DNA levels from baseline was significantly greater in the LAM-R group than the MD-R group (-2.8 vs. -2.5 log1 0 IU/ml, respectively). The proportion of patients with a viral response did not differ significantly between LAM-R and MD-R (n = 18, 17.1% vs. n=6, 10.2%). Conclusion: LAM-R results in a superior reduction in HBV DNA at 12 weeks compared with MD-R in TDF monotherapy. However, the viral response at 12 weeks did not differ significantly between the two groups. Further study should evaluate the efficacy and safety of TDF monotherapy for CHB patients with MD-R.

Disclosures:

The following people have nothing to disclose: Sangheun Lee, Jung Yoen Lee, Beom Kyung Kim, Seung Up Kim, Jun Yong Park, Do Young Kim, Chae Yoon Chon, Kwang-Hyub Han, Sang Hoon Ahn

993

IL28B polymorphisms as predictors of response to peginterferon-alfa-2a in HBeAg-negative chronic hepatitis B

George V. Papatheodoridis1, Nikolaos Gatselis2, Ioannis Goulis3, Stylianos Karatapanis4, Melanie Deutsch1, Konstantinos Mimidis5, Christos Drakoulis6, Evangelos A. Akriviadis3, George N. Dalekos2;

12nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece; 2Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly School of Medicine, Larissa, Greece; 34th Department of Internal Medicine, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece; 41st Department of Internal Medicine, General Hospital of Rhodes, Rhodes, Greece; 51st Department of Internal Medicine, Democritus University of Thrace Medical School, Alexandroupolis, Greece; 62nd Department of Internal Medicine, General Hospital of Nikaia, Piraeus, Greece

Background/Aim: To date, there is no reliable baseline predictor of response to PegInterferon-alfa (PegIFNa) in HBeAg-negative chronic hepatitis B (CHB). The IL28B polymorphisms have been shown to strongly affect the probability of response to PegIFNa and ribavirin in chronic hepatitis C, but their significance in CHB remains rather controversial. We evaluated the role of IL28B polymorphisms as predictors of response to PegIFNa in HBeAg-negative CHB patients. Methods: Seventy patients (M/F: 52/1 8, mean age: 42±1 1 years) with predominantly genotype D HBeAg-negative CHB were included. They were all treated with PegIFNa-2a (1 80 μg/week) for 48 weeks and followed for 48 weeks post-treatment. End of therapy (EOT) virological response (VR) was based on serum HBV DNA levels at EOT, while sustained virological response (SVR) or sustained response (SR) were defined as HBV DNA <2,000 IU/mL only or combined with normal ALT at 48 weeks after the EOT. IL28B polymorphisms were retrospectively determined by an in-house real-time PCR method using genomic DNA extracted from frozen serum samples in conjunction with minor groove binder specific probes. Results: Mean baseline serum HBV DNA and HBsAg levels were 5.3±1.4 log 10 IU/ml and 3.5±0.6 log 10 IU/ml, respectively. Of the 70 patients, 55 (79%) and 37 (53%) had HBV DNA <2,000 (EOTVR-2000) and <80 IU/mL (EOTVR-80) at EOT. SVR and SR were achieved in 17 (24%) patients. IL28B polymorphisms were CC in 28 (40%), CT in 29 (41%) and TT in 13 (19%) patients. Patients with IL28B CC vs IL28B CT/TT did not differ significantly in age (42±12 vs 43±11), gender (M: 78% vs 71%), baseline mean ALT (93 vs 113 IU/L), HBV DNA (5.1 vs 5.5 log 10 IU/ml) or HBsAg levels (3.4 vs 3.6 log 10 IU/ml), EOTVR-2000 (82% vs 76%), EOTVR-80 (61%vs 48%) (P>0.30 for all comparisons). Similar findings were observed for comparisons between IL28B CC/CT vs TT or among IL28B CC vs CT vs TT patients. SVR/SR rates were numerically but not significantly higher in IL28B CC than CT and TT patients (9/28 or 32% vs 5/29 or 17% and 3/13 or 23%, P=0.371) or than CT/TT patients (32% vs 19%, P=0.333). Conclusions: In HBeAg-negative, predominantly genotype D, CHB patients, IL28B polymorphisms do not seem to be associated with the baseline patient and viral characteristics or to affect the probability of response to PegIFNa-2a. If there is any effect of the IL28B polymorphisms on the PegIFNa response in this setting, it should be limited and will require very large patient cohorts to be documented.

Disclosures:

George V. Papatheodoridis - Advisory Committees or Review Panels: Merck, Novartis, Abbvie, Boerhinger, Bristol-Meyer Squibb, Gilead, Roche, Janssen; Grant/Research Support: Roche, Gilead, Bristol-Meyer Squibb ; Speaking and Teaching: Merck, Bristol-Meyer Squibb, Gilead, Roche, Janssen

Ioannis Goulis - Consulting: MSD, Gilead Sciences, Novartis, Janssen-Cilag; Grant/Research Support: BMS, Roche; Speaking and Teaching: BMS, MSD, Gilead Sciences, Novartis, Janssen-Cilag, Roche

Melanie Deutsch - Consulting: MSD

Konstantinos Mimidis - Advisory Committees or Review Panels: ROCHE, MSD, NOVARTIS; Grant/Research Support: GILEAD

The following people have nothing to disclose: Nikolaos Gatselis, Stylianos Karatapanis, Christos Drakoulis, Evangelos A. Akriviadis, George N. Dalekos

994

Changes of serum HBsAg levels in HBeAg-negative chronic hepatitis B patients treated with tenofovir

George V. Papatheodoridis1, Christos K. Triantos2, Emilia Hadziyannis1, Konstantinos Zisimopoulos2, Anastasia Georgiou1, Katerina Margariti1, Melanie Deutsch1, Vasiliki Nikolopoulou1, Spilios Manolakopoulos1;

12nd Department of Internal Medicine, Hippokration General Hospital of Athens, Athens, Greece;2Department of Gastroenterology, University Hospital of Patras, Patras, Greece

Background/Aim: Serum HBsAg represents the only serological marker of chronic HBV infection in HBeAg-negative chronic hepatitis B (CHB) patients effectively treated with nucleos(t)ide analogue(s) [NA(s)] and therefore HBsAg decline may be an important predictor of on-therapy and most importantly off-treatment remission. We studied the changes of serum HBsAg levels in a cohort of patients with HBeAg-negative compensated CHB who had been treated with tenofovir disoproxil fumarate (TDF) for at least 12 months. Methods: Until April 2013, 1 37 patients (M/F: 102/35, mean age: 58±16 years) who started therapy with TDF 300mg daily between 2008 and 201 1 have been included. TDF has been given for a mean of 32±15 months. Of the 137 patients, 69 were naive to NAs (Group A), while 68 had been exposed to other NAs (lamivudine resistance: 59, tel-bivudine resistance: 6, other: 3) (Group B). TDF was given as monotherapy in group A and in combination with lamivudine, at least during the initial period, in group B patients. Stored serum samples taken before and at 6, 12, 24 and 36 months after TDF initiation were tested for serum HBsAg levels on the Architect analyzer (Abbott Labs). Results: Before TDF, Group A and B patients had median serum levels of ALT 78 and 49 IU/L (P<0.001), HBV DNA 5.8 and 3.3 log 10 IU/mL (p<0.001) and HBsAg 3.5 and 3.2 log 10 IU/mL (p=0.177), respectively. Virological remission rates (HBV DNA undetectable by PCR) were 93% at 1 2 months and 98% beyond 1 2 months, without any difference between Groups A and B. Compared to before TDF, levels of HBsAg decreased by a median of 0.06, 0.12, 030 and 0.37 log 10 IU/mL at 6, 12, 24 and 36 months, respectively (p<0.030 by paired non-parametric test for all changes). Median HBsAg decrease was numerically but not significantly higher in Group A than B patients at all time points (6 months: 0.10 vs 0.02, 12 months: 0.14 vs 0.11, 24 months: 0.32 vs 0.24, 36 months: 0.43 vs 0.26 log 10 IU/mL; p>0.350 for all comparisons). No decline of HBsAg levels was observed in 24%, 1 8% and 1 6% of patients at 12, 24 and 36 months of TDF therapy. Three patients cleared HBsAg, while the cumulative rates of HBsAg levels <500 IU/mL were 1 7%, 27% and 43% and of HBsAg levels <100 IU/mL 11%, 17% and 1 7% at 12, 24 and 36 months of TDF therapy. Conclusions: In both NA(s) naive and experienced patients with HBeAg-negative CHB, TDF therapy decreases significantly serum HBsAg levels, but the rate of HBsAg decline is slow with a median of <0.5 log 10 IU/mL at 36 months. However, a proportion of such patients could achieve relatively low HBsAg levels with approximately 4/1 0 and 1/6 of them reaching levels <500 and <1 00 IU/mL, respectively.

Disclosures:

George V. Papatheodoridis - Advisory Committees or Review Panels: Merck, Novartis, Abbvie, Boerhinger, Bristol-Meyer Squibb, Gilead, Roche, Janssen; Grant/Research Support: Roche, Gilead, Bristol-Meyer Squibb ; Speaking and Teaching: Merck, Bristol-Meyer Squibb, Gilead, Roche, Janssen

Melanie Deutsch - Consulting: MSD

Spilios Manolakopoulos - Advisory Committees or Review Panels: NOVARTIS, ROCHE, MSD, BMS, GILEAD; Consulting: ROCHE, GILEAD, BMS; Speaking and Teaching: MSD, GILEAD, BMS

The following people have nothing to disclose: Christos K. Triantos, Emilia Hadziyannis, Konstantinos Zisimopoulos, Anastasia Georgiou, Katerina Margar-iti, Vasiliki Nikolopoulou

995

ETV monotherapy improves renal function in lamivudine resistant patients developing renal side effects during long-term TDF exposure

Giampaolo Mangia1, Pietro Lampertico1, Mauro Viganò2, Flori-ana Facchetti1, Federica Invernizzi1, Roberta Soffredini1, Massimo Colombo1;

11st Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università di Milano, Milan, Italy; 2Liver Unit, Ospedale San Giuseppe, Università degli Studi di Milano, Milano, Italy

Background: Tenofovir (TDF) is a recommended first-line therapy for both naïve and experienced chronic hepatitis B patients because of its efficacy and favorable safety profile, though selected patients may have to stop treatment because of renal side effects. Aim: To assess the efficacy and safety of Entecavir (ETV) in patients switched from TDF for hypophosphatemia or hyperphosphaturia. Methods: 18 chronic hepatitis B patients (63 years, 94% males, 56% cirrhotics, 94% HBeAg-negative, 94% Adefovir+Lamivudine exposed, 100% with normal ALT and undetectable HBV DNA) who have been treated with TDF monotherapy for 39 months (range: 7-52), were switched to ETV monotherapy (1.0 mg or 0.5 mg according to eGFR by MDRD) due to renal side effects. HBV DNA, ALT, serum creati-nine, eGFR, serum phosphate levels and tubular phosphate re-absorption (TmPO4/eGFR) were assessed at baseline (start ETV) and every 3 months. Hypophosphatemia was defined as grade 1 (<2.5 mg/dL), grade 2 (<2.3), grade 3 (<2.0), whereas hyperphosfaturia (TmPO4/eGFR) was classified as grade 1 (<0.80), grade 2 (<0.60) and grade 3 (<0.40). Results: At baseline, 6 (33%), 7 (39%) and 5 (28%) patients had grade 1, 2 or 3 hypophosphatemia, whereas 12 (67%) and 6 (33%) patients had grade 2 or grade 3 hyperphosphaturia, respectively. During 6 months (range: 5-12) of ETV therapy (1.0 mg in 8 patients and 0.5 in 10 patients), median serum creatinine remained unchanged (1.20 vs 1.17 mg/dL), whereas eGFR (60 vs 62 mL/min, p=0.004), serum phosphate levels (2.2 vs 2.4 mg/dL, p=0.046) and TmPO4/eGFR (0.42 vs 0.57 mmol/L, p=0.004) significantly increased. After ETV switch, 7 (39%) patients achieved normal phosphatemia levels (>2.5 mg/dL) as well as either normal phosphaturia or grade 1 iperphosphaturia. As far virological responses are concerned, 13 (72%) patients maintained a virological response whereas 5 (28%) patients(3 treated with 0.5 mg/24h) had a mild virological breakthrough (HBV DNA: 10, 17, 20, 27, 79 IU/mL) without ALT increase, occurring between month 3 and 6. In one of the 2 patients in whom ETV dose was increased to 1 mg, HBV DNA was cleared from serum. In 2 patients who had a further increase of HBV DNA (from 27 to 244; from 79 to 109 IU/mL) ETV was topped and TDF restarted. Conclusions: Switching to ETV monotherapy patients who developed renal side effects during long-term TDF treatment, improved kidney tubular function with minimal risk of virological rebounds.

Disclosures:

Pietro Lampertico - Advisory Committees or Review Panels: Bayer, Bayer; Speaking and Teaching: Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead, Bristol-Myers Squibb, Roche, GlaxoSmithKline, Novartis, Gilead

Mauro Viganò - Consulting: Roche; Speaking and Teaching: Gilead Sciences, BMS

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: Giampaolo Mangia, Floriana Facchetti, Federica Invernizzi, Roberta Soffredini

996

Efficacy of telbivudine compared with entecavir in hepatitis B virus-related cirrhosis

Hyung Joon Yim, Hae Rim Kim, Seong Hee Kang, Eileen L. Yoon, Hyun Jung Lee, Sang Jun Suh, Ji Hoon Kim, Yeon Seok Seo, Jong Eun Yeon, Soon Ho Um, Kwan Soo Byun;

Internal medicine, Korea University Hospital, Seoul, Republic of Korea

Background & Aims: Telbivudine (TBV) is a potent antiviral agent for the treatment of chronic HBV (Hepatitis B virus) infection. However, there is little information on the effect of TBV in chronic hepatitis B (CHB) patients with cirrhosis. Entecavir (ETV) is known to be effective for the treatment of chronic HBV infection even in patients with underlying liver cirrhosis. This study is aimed to evaluate antiviral efficacy of TBV in patients with HBV-related cirrhosis and to compare with that of ETV. Methods: We consecutively enrolled 140 patients with HBV-related liver cirrhosis who started antiviral therapy with TBV (n=52, TBV group) or ETV (n=88, ETV group) between March 2010 and October 2011. Antiviral response was evaluated after 12 months of treatment. Virologic response (VR) was defined as an undetectable HBV DNA (< 20 IU/mL) during treatment. Improvement of liver function was assess by parameters associated with Child-Pugh score and model for end stage liver disease (MELD) in both groups. Results: After 12 months of treatment, 65.1% (28/43) patients in TBV group and 76.8% (63/82) patients in ETV group showed VR (serum HBV DNA level <20 IU/mL) (P=0.162). Mean reductions in serum HBV DNA levels from baseline to month 12 (3.54±2.10 vs. 4.89±1.42, respectively, P=0.001) was greater in ETV group than in TBV group. In the subgroup analysis, mean changes of serum HBV DNA level was greater in ETV group (3.67±2.53 vs. 5.29±1.28, respectively, P=0.025) compared with TBV group, in both HBeAg-pos-itive patients and HBeAg-negative patients (3.47±1.85 vs 4.48±1.44, respectively, P=0.014). Four patients were reported to have antiviral resistance in the TBV group, while no resistance was reported in the ETV group. (P=0.001) However, HBeAg seroconversion, HBeAg loss, and biochemical response rates between two groups at month 12 did not differ significantly. Serum albumin, Child-Pugh score, and MELD score was significantly improved compared to pretreatment state in patients of both groups. The change of liver function including serum albumin (0.18±0.79 vs 0.29±0.46, respectively, p=0.408), total bilirubin (-0.02±1.15 vs 0.36±1 .06, respectively, p=0.118), prothrombin time (-0.08±0.12 vs -0.10±0.18, respectively, p=0.584), and Child-Pugh score (-0.55±1 .75 vs -0.45±1 .10, respectively, p=0.745) were not different between the TBV and ETV groups. Conclusions: TBV therapy shows comparable effect on improvement in liver function with ETV therapy. However, degree of viral suppression during L-dT therapy is inferior to that in ETV therapy in HBV-related liver cirrhosis.

Disclosures:

Hyung Joon Yim - Grant/Research Support: GSK Korea, Handok Pharm, Gilead Korea; Speaking and Teaching: BMS Korea

The following people have nothing to disclose: Hae Rim Kim, Seong Hee Kang, Eileen L. Yoon, Hyun Jung Lee, Sang Jun Suh, Ji Hoon Kim, Yeon Seok Seo, Jong Eun Yeon, Soon Ho Um, Kwan Soo Byun

997

Management of hepatitis B virus (HBV) infection in immunosuppressed oncohematologic patients (OHPs): lamivudine (Lam) prophylaxis and rescue therapy of HBV infection reactivation

Aldo Marrone1, Mariarosaria Esposito2, Chiara D'Amore1, Isabella Siniscalchi1, Romina Salpini3, Marco Ciotti3, Massimo CIc-cozzi4, Carlo Federico Perno3, Lucia Mastrullo2;

1Internal Medicine and Hepatology, Second University of Naples, Napoli, Italy; 2Hematology Unit, San Gennaro Hospital, Naples, Italy; 3Depart-ment of Experimental Medicine and Biochemical Sciences, University of Rome, Tor Vergata, Rome, Italy; 4Department of Infectious, Parasitic and Immune Mediated Disease, Epidemiology Section, National Institute of Health of Italy, Rome, Italy

Overt and occult HBV infection reactivation in OHPs can lead to severe hepatitis and to liver acute failure even. Antiviral prophylaxis is recommended but the optimal length and monitoring are still uncertain. AIMS: To evaluate the efficacy and safety of: 1) Lam prophylaxis given for 18m after discontinuation of chemotherapy (chemoth.); 2) antiviral standard treatment in OHPs chronic HBV carriers; 3) antiviral rescue therapy of HBV reactivation. PATIENTS: 1) Forty-eight OHPs (M/F:33/15; median age yrs:65; range 29-82) were studied: 28 non Hodgkin lymphoma (NHL), 1 Hodgkin lymphoma (HL), 9 chronic lymphocytic leukemia (CLL), 10 multiple myeloma (MM). All were screened, before starting chemoth., for HBsAg, HBsAb, HBcAb, HCV-Ab, HAV-Ab and ALT values. HBsAg and ALT were monthly monitored and serum HBV-DNA was tested every 3 m after the start of chemoth. 2) Eleven pts. with HBV reactivation. RESULTS: Following serological screening pts. were distinguished in 2 groups. Group A including 9/48 (1 8%) pts. (M/F:7/2; median age: 67 yrs (34-71) which resulted HBsAg/HBV-DNA pos (2 HBeAg+, 7 HBeAg-). One of these was HCV-Ab/HCV-RNA pos and all were HAV-Ab (IgG) pos. Group B including 39/48 (82%) HBsAg neg pts. (M/F: 26/13; median age yrs:65; range 29-82). Nine of 39 (23%) presented isolated HBcAb positivity and 29/39 (74%) HBsAb/HBcAb positivity. Five of 39 (13%) were HCV-Ab pos and 38/39 (99%) HAV-Ab (IgG) pos. Group C: 12 pts. (M/F: 7/5; median age 68 yrs), 7 with severe clinical reactivation (jaundice and high ALT levels) and 5 with mild/moderate disease. 4 pts. were HBsAg neg/HBV-DNA pos. Standard therapy: Group A pts. (4 inactive and 5 active carriers) received antiviral therapy (5 entecavir (Ent) 0.5 mg/d, 3 Lam 100 mg/d, 1 Lam+adefovir); all cleared HBV-DNA (median time months:1 1; range 4-24), normalized ALT and completed chemoth. but are still HBsAg+. Lam prophylaxis: Group B pts. started Lam 1 00 mg/d for 1 8 m after the last chemoth. Twenty of 39 (51%) pts. completed 1 8 m of Lam prophylaxis and 14/20(70%) passed 12 m after discontinuation of Lam prophylaxis. Median time after discontinuation of chemoth. and Lam is 30m (1-58) and 19m (1-54) respectively. None case of HBV reactivation has been observed. Five pts. of Group B died because hematologic malignancy. Rescue therapy: Group C pts. received Ent (7) and Lam (5). Two died because liver failure, 3 because hematologic disease; 7/1 1 cleared HBV-DNA and 3 returned HBsAg neg, 4 are still under treatment CONCLUSIONS: HBV reactivation is life threatening condition and must be prevented. Prolonged 18 months Lam prophylaxis is

safe and effective in preventing HBV reactivation and in completing chemotherapy.

Disclosures:

The following people have nothing to disclose: Aldo Marrone, Mariarosaria Esposito, Chiara D'Amore, Isabella Siniscalchi, Romina Salpini, Marco Ciotti, Massimo CIccozzi, Carlo Federico Perno, Lucia Mastrullo

998

Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated inter-feron-alpha therapy via mathematical modeling

Jeremie Guedj1,2, Yaron Rotman3, Scott Cotler4, Peter Schmid5, Jeff Albrecht5, Vanessa Haynes-Williams3, T. Jake Liang3, Jay H. Hoof-nagle3, Theo Heller3, Harel Dahari1,4;

1Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM; 2INSERM UMR 738, F-75018, University Paris Diderot, Paris, France; 3Liver Diseases Branch, NIDDK, NIH, Bethesda, MD; 4Division of Hepatology, Department of Medicine, Loyola University Medical Center, Maywood, IL; 5National Genetics Institute, Los Alamos, CA

Background: Chronic hepatitis delta virus (HDV) infection results in an accelerated course of liver disease and the only proven effective treatments for HDV (standard and pegylated inter-feron-alpha [pIFN]) result in a limited rate (~23%) of sustained response (SR). There is little information on the kinetics of loss of HDV RNA, HBV DNA and HBsAg during IFN therapy. Aim: To assess kinetics of decrease in HBV and HDV during the first month of pIFN therapy and correlate these to ultimate response. Methods: HDV-RNA, HBV, and HBsAg levels were measured every 6h during the first day, at days 2, 3 and 7 and every 4 weeks until week 28 in 13 patients treated with pIFN-2a for up to 240 weeks. Mathematical modeling was applied to the changes in both virus and antigen. Results: After initiation of therapy, a median delay of 8.5 days (interquartile range [IR]: 5.3 to 14.7 days) was observed with no significant change in HDV levels. Thereafter, HDV declined in a biphasic manner, with a rapid 1st phase lasting for 25 days (IR:23;58) followed by a slower (or plateau) 2nd phase. We previously showed a strong association between the 2nd phase in HDV and HBsAg kinetics. A mathematical model was developed that explains the biphasic HDV kinetics and assumes that the production of HDV is from HBsAg-infected cells. The model predicted that the main effect of pIFN was to block HDV production and/or release with a median effectiveness of 96% (IR:[93;99.8]). Median HDV half-life (t1/2) was estimated to be 2.9 days (IR:[1.5;5.3]) with median pretreatment production and clearance of about 1 01 0 (IR:[ 1 07-1 01 0]) virions per day. HBsAg kinetics paralleled the 2nd phase in HDV, suggesting that HBsAg-productive infected cells were the source of HDV production and the median estimated loss/death rate of HDV-pro-ductive infected cells, delta=0.0051 /day (IR:[0.0015-0.035]), corresponding to a median t1/2=135 days. Three patients reached SR, defined as lack of detectable HDV RNA 6 months after completion of treatment, 2 of whom had a rapid second phase of viral decline (delta>0.04 /day), about 10 times greater than patients who did not achieve SR. Notably, no patient with a flat 2nd phase in HDV viremia (or delta~0.001 /day) reached SR. Conclusions: The new dual model of HDV and HBsAg suggests that IFN acts by blocking production/release of HDV i.e., allowing clearance of infected cells. The low estimated the loss/death of HDV-infected cells (delta) explains the modest SR rate with IFN therapy. The observation that a flat 2nd phase in HDV and HBsAg kinetics was associated with non-SR provides the basis to develop early stopping rules during pIFN treatment in HDV patients.

Disclosures:

Jeremie Guedj - Consulting: Gilead; Grant/Research Support: Novartis

Scott Cotler- Speaking and Teaching: Genentech, Vertex, Brystal Myers, Gilead

Harel Dahari - Consulting: Roche TCRC, Inc

The following people have nothing to disclose: Yaron Rotman, Peter Schmid, Jeff Albrecht, Vanessa Haynes-Williams, T. Jake Liang, Jay H. Hoofnagle, Theo Heller

999

2-years impact of entecavir (ETV) on liver fibrosis and activity as assessed by the non-invasive methods of FibroTest-ActiTest (FT-AT) and liver stiffnesse measurements (LSM) by Fibroscan in patients with chronic hepatitis B (CHB)

Fabien Zoulim1, Xavier Causse2, Vincent Leroy3, Denis Ouzan4, Nathalie Ganne-Carrie5, Valerie Bourcier5, Victor de Ledinghen6, Philippe Mathurin7, Marika Rudler8, Joseph Moussalli8, Dominique Thabut8, Luminita Bonyhay8, Vlad Ratziu8, Fabienne Drane9, Yen Ngo9, Mona Munteanu9, Thierry Poynard8;

1Hepato-Gastroen-terology, Hospices Civiles de Lyon, Lyon, France; 2Hepato-Gas-troenterology, CHR Orleans La Source, Orleans, France; 3Hepato-Gastroenterology, CHU Grenoble, Grenoble, France; 4Hepato-Gastroenterology, Institut Arnaud Tzanck, Saint Laurent du Var, France; 5Hepato-Gastroenterology, CH Jean Verdier, Bondy, France; 6Hepato-Gastroenterology, CH Haut Leveque, Bordeaux, France; 7Hepato-Gastroenterology, CHU Lille, Lille, France; 8Hepato-Gastroenterology, APHP UPMC Liver Center, Paris, France; 9Hepatology Research Unit, BioPredictive, Paris, France

Background.Fibrosis-regression rate in treated chronic hepatitis B (CHB) patients was similar using Fibrotest (Biopredictive) or liver biopsy, while for liver stiffness measurements (LSM) by Fibroscan(Echosens) there was a possible overestimation related to necroinflammatory activity (NIA)(AVT 201 0). Aim.To prospectively evaluate the histological impact of a strong inhibitor of HBV-replication, entecavir motherapy at 0.5mg per day, using non-invasive methods, i.e. FibroMax (including Fibrotest, Actitest, Steatotest for estimating fibrosis, activity and steatosis) and LSM. Methods. 133-CHB monoinfected, NUC-naive patients were pre-included in 19 centers in France. Data was recorded at baseline(M0), six, and 12-months(M6,M12): viral load, Fibromax [panel of scores (0-1)] and LSM(0-75kPa). Applicability(App) was defined as after exclusion of unreliable LSM and failures. Viral response (VR) was defined as unde-tectable HBVDNA. Statistics included repeated measures AVOVA (Bonferroni Multiple-Comparison Tests). Results. 1 16patients were included [5 lost of follow-up, 9 missing, 3 non-App Fibrotest (acute flare-up ALT>600IU/L)]. Characteristics were: age 44(1 9-82)yrs; 72%males; 70% anti-HBe(+); 46% Caucasian; 2.6% alcohol>20g/day; median viral load=4.6 logIU/ml; App-LSM 81%(55/68). 31%(N=36) had advanced fibrosis (AF, F2F3F4-METAVIR) and 11%(N=12) cirrhosis as per Fibrotest; 46%(N=53) significant NIA (A1 A2A3-METAVIR) as per Actitest; 26%(N=21) had M0 steatosis>1% as per Steatotest. 88 patients achieved M6, 61 M1 2 with 64% M6-VR and 84% M12-VR. Significant NIA as per ActiTest regressed from M0 0.58(0.03) to M6 0.27(0.03,P< 0.0001) and M1 2 0.27(0.03,P< 0.0001 vsM0). The same was true for AF as per FibroTest: M0 0.67(0.02) vs M6 0.56(0.02,P=0.0001) and M12 0.54(0.02,P=0.002 vsM0). Among AF-patients without M6 fibrosis-regression, 43% had baseline steatosis>5% as per Steatotest compared to 0% (p=0.04) in AF-patients that regressed fibrosis. As per AF App-LSM no regression was observed vs M0 at M6[8.5(1)vs10.1(1)kPa, P=0.28] but at M12 [6.3(0.4)kPa,P=0.009 vs M0)]. M6 regressions of significant NIA and AF as per Actitest and Fibrotest were observed regard-

less the VR (vs non-VR) 32% vs 48%(p=0.30) and 38% vs 50% (p=0.74), respectively. Conclusion. After six and twelve months of entecavir treatment, advanced fibrosis and activity as presumed by Fibrotest-Actitest were significantly reduced, regardless of the viral response. F Fibrosis regression as per liver stiffness measurement was observed only after twelve-month treatment. Patients without fibrosis-regression after 6-months treatment had more baseline steatosis.

Disclosures:

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

Xavier Causse - Board Membership: Gilead, BMS, MSD, Janssen-Cilag; Speaking and Teaching: Roche, Gilead, BMS, Janssen-Cilag

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 Teaching: bms, merck, gilead, roche, bms, merck, gilead, roche, bms, merck, gilead, roche, bms, merck, gilead, roche

Nathalie Ganne-Carrie - Advisory Committees or Review Panels: Roche, MSD; Speaking and Teaching: BMS, Gilead

Victor de Ledinghen - Advisory Committees or Review Panels: Merck, Gilead, Merck, Gilead; Grant/Research Support: Merck, Janssen, Gilead, Roche, Echo-sens, Merck, Janssen, Gilead, Roche, Echosens; Speaking and Teaching: Merck, Janssen, Bayer, Abbott, Roche, Merck, Janssen, Bayer, Abbott, Roche

Philippe Mathurin - Board Membership: Schering-Plough, Janssen-Cilag, BMS, Gilead; Consulting: Roche, Bayer, Boehringer

Marika Rudler - Speaking and Teaching: Gilead Sciences, BMS, Gore, Eumedica Joseph Moussalli - Consulting: merck, roche, gilead

Vlad Ratziu - Advisory Committees or Review Panels: GalMed, Abbott, Genfit, Enterome, Gilead; Consulting: Astellas, Axcan, Pfizer, Sanofi-Synthelabo, Genentech, Nycomed

Fabienne Drane - Employment: BIOPREDICTIVE Yen Ngo - Employment: BioPredictive Mona Munteanu - Employment: Biopredictive

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

The following people have nothing to disclose: Denis Ouzan, Valerie Bourcier, Dominique Thabut, Luminita Bonyhay

1000

Hepatitis B-associated Acute Liver Failure: Immediate Treatment with Entecavir/Tenofovir Safely Avoids Transplantation and does not Interfere with HBsAg Clearance

Felix Maischack1, Ali Canbay1, Joerg Timm2, Mechthild Beste1, Guido Gerken1, Christoph Jochum1;

1Clinic of Gastroenterology and Hepatology, Universitaetsklinikum Essen, Universitaet Duis-burg-Essen, Essen, Germany; 2Virology, Universitaetsklinikum Essen, Universitaet Duisburg-Essen, Essen, Germany

Background: Acute adult HBV infection is followed by high viral replication rates leading to hepatocyte death and in some cases to acute liver failure (ALF) necessitating liver transplantation. The objective of treating HBV-induced ALF is to eliminate or significantly suppress HBV replication in order to stop liver cell damage. Despite some evidence the use of nucleos(t)ide analogues in ALF remains controversial. Methods: In this retrospective study we analyzed the outcome of 24 patients with acute liver failure [10 female and 14 male, median age 38.5 years] admitted between 2009 and March 201 3 to the university hospital of Essen, Germany. 22 patients received nucles(t)ide analogues (Entecavir 16, Lamivudine 2 and Tenofovir 4 patients) beginning between day 1 and day 28 after admission (median 1.5 days). Two patients did not receive any HBV-specific treatment. HBV-DNA and HBsAg levels were detected. Treatment follow up was performed in regular time schedule until HBsAg loss or HBsAg seroconversion at our outpatient unit. Results: All

patients who received treatment survived and did not need liver transplantation. One of the two patients who did not receive HBV-treatment died before getting transplantation. In all treated patients pathological parameters rapidly decreased and returned to normal values within three months. 16 patients lost their HBsAg in the time between 1 month and a year after diagnosis (median 95 days). A seroconversion to anti-HBsAg was achieved in 9 out of the 1 6 patients between 59 and 1 68 days (median 123 days). Of the 6 patients who did receive treatment and did not showed HBsAg clearance 5 were lost to follow up between discharge from the hospital and 3 months thereafter. Only one patient did not show HBsAg loss until 1 year. 1 patient who survived without treatment was lost to follow up. Conclusion: This retrospective study of twenty four patients with acute fulminant hepatitis B reveals that immediate treatment of HBV-induced ALF with nucleos(t)ide analogues is well tolerated and avoids liver transplantation and does not negatively influence HBsAg clearance.

Disclosures:

Christoph Jochum - Advisory Committees or Review Panels: Gilead, Roche, Norgine, Janssen-Cilag; Speaking and Teaching: BMS, Roche, Janssen-Cilag, Gilead

The following people have nothing to disclose: Felix Maischack, Ali Canbay, Joerg Timm, Mechthild Beste, Guido Gerken

1001

Comparison of clinical outcomes in cirrhotic chronic hepatitis B patients treated with Entecavir or Lamivudine plus Adefovir dipivoxil for 144 weeks

Hong-Ying Pan1, Hong-Yi Pan2, Jun Yan4, Hong Liu3, Li Chen4, Cui-Rong Chen3, Jie Jin3, Jing Xu3, Zhen-Jiang Sun3, De-Rong Lu3;

1Department of Infectious Diseases, Zhejiang Provincial People's Hospital, Hangzhou, China; 2Department of Medicine, Pujiang People Hospital,, Jinhua, China; 3Department of Internal Medicine, Hangzhou XiXi hospital, Hangzhou, China; 4Zhejiang Chinese Medical University, Hangzhou, China

Background: Chronic hepatitis B (CHB) patients with cirrhosis are mandatory for long-term antiviral therapies. However, little is known about the clinical outcomes of these therapies. We comparatively evaluated the clinical outcomes of Entecavir (ENT) versus lamivudine (LAM) plus adefovir (ADV) in treating CHB patients with cirrhosis over 144 weeks. Methods: 160 nucleos(t)ide analogues-naive CHB patients with cirrhosis (1 15 compensated and 45 decompensated) enrolled from our medical centers (1/09-4/1 0) were randomized to group A (n=80), ENT 0.5 mg daily and group B (n=80), LAM 100 mg+ADV 10 mg daily, administered over 144 weeks. The periodic assessments of clinical outcomes include serum HBV DNA (quantitative PCR), HBV immunological markers, biochemistries, viral resistance (direct sequencing), and major complications. HBV DNA-negative was defined as serum HBV DNA <103copies/mL. Results: 3 cases in group A, 2 cases in group B did not complete the study. No significant difference in baseline characteristics was found between the two groups (HBeAg-positive: 58 in group A, 54 in group B). The rates of HBV DNA-negative at 1 2 and 24 weeks of antiviral treatment were higher in group A than in group B (87.0% and 89.6% vs. 61.5% and 69.2 %, respectively, P <0.05). Cumulative rates converged after 24 weeks, 98.7% in group A and 94.9% in group B, P >0.05) at 144 weeks. HBeAg seroconversion rate at 48 weeks was significantly lower in group A than in group B (17.2% vs. 48.2%, P <0.05). HBsAg loss occurred in one patient, group B, at 140 weeks, proven by liver histology. The proportion of ALT normalization was similar at each time point in the two groups; the cumulative rates were 89.1%, 96.6% (P

>0.05) at 144 weeks. No drug-resisted gene mutation was detected in group A; one was detected in group B (L1 80M, A1 81V, M204I). The cumulative incidence of ascites following the treatment was reduced significantly in both groups as compared with baseline, 60.9% (A: 14/23), 63.6% (B:14/22). The cumulative incidence of hepatocellular carcinoma (HCC) was 6.0 % (3/77) in group A, 2.0% (1/78) in group B in 144 weeks. No significant difference was observed in upper gastrointestinal bleeding and hepatic encephalopathy. No antiviral drug related safety issue was observed during the treatment. Conclusions: Both ENT monotherapy and LAM plus ADV combination therapy for long-term treatment of CHB with cirrhosis can result in higher viral suppression, low incidence of antiviral drug resistance, ascites, and HCC. ENT achieved an earlier viral suppression as compared to LAM plus ADV; but had lower HBeAg seroconversion. This clinical significance needs to be further investigated.

Disclosures:

The following people have nothing to disclose: Hong-Ying Pan, Hong-Yi Pan, Jun Yan, Hong Liu, Li Chen, Cui-Rong Chen, Jie Jin, Jing Xu, Zhen-Jiang Sun, De-Rong Lu

1002

A Clinical Trial on Anti-HBV-DC Vaccine Combined with Thymosin-α1 in the HBeAg Negative Chronic Hepatitis B Patients

Bang-Fu Wu1,2, Jiang-Ying Yang1;

1Gastroenterology and Hepatol-ogy Center, Southern Medical University Renkang Hospital, Dong-guan, China; 2Guangzhou Pubang Bio-Immunological Tech Research Institute, Guangzhou, China

Background/Aims: To observe the clinical efficacy of anti-HBV-DC vaccine, the dendritic cells originating from peripheral blood mononuclear cells(PBMC) sensitized by HBsAg, in combination with thymosin-α1, in the HBeAg negative chronic hepatitis B(CHB) patients. Methods: 25 patients were recruited in the trial including 18 with ALT<2ULN and 7 with ALT>2ULN. PBMCs obtained from 50ml of heparinized peripheral blood through density gradient centrifuge and adherence method were proliferated under the induction by GM-CSF and IL-4, and sensitized with the stock of hepatitis B vaccine containing 30μg HBsAg on day 5 and with hepatitis B vaccine commercially available containing 20μg HBsAg on day 6. anti-HBV-DC vaccine was harvested on day 7 and injected, half hypodermically and half intravenously, to the patient once every two weeks for 12 practices applications totally. Thymosin-α1 1.6mg was injected hypodermically twice a week. Quantitative HBVM(TRFIA) and HBVDNA and hepatic functions were evaluated at week 0, 4, 12, and 24. Results: Mean of HBsAg, ATL and TBIL decreased gradually along the time from week 4, 12 to 24, with significant difference compared with the values prior to treatment. At week 4, 12 and 24, HBsAg negative conversion rate were 8.00%(2/25), 12.00(3/25) and 20.00%(5/25) respectively, HBVDNA negative conversion rate were 63.64%(7/1 1), 72.73%(8/1 1) and 72.73%(8/1 1), ALT normalization rate were 48.00%(12/25), 64.00%(16/25) and 80.00%(20/25), and HBsAg negative conversion rate was 11.11%(2/18), 16.67%(3/18) and 22.22%(4/18) in patients with ALT<2ULN. But HBsAg negative conversion occurred only in one patient (14.29%, 1/7) those with ALT>2ULN at week 24. The rate of adverse effect was 2.67% observed in reinfusion of anti-HBV-DC vaccine. Conclusions: anti-HBV-DC vaccine in combination with thymosin-α1 can be considered as a safe approach with high efficacy for HBeAg negative CHB patients, which can effectively inhibit the viral

replication, decrease rapidly and eliminate the HBsAg and HBVDNA from body.

Disclosures:

The following people have nothing to disclose: Bang-Fu Wu, Jiang-Ying Yang

1003

Predictive Value of hepatitis B Virus Genotypes on the Responses to Long-term Nucleoside Analogue Therapy in Patients with Chronic Hepatitis B

Hisayoshi Watanabe1, Chikako Sato1, Kei Mizuno1, Tomohiro Kat-sumi1, Kyoko Tomita1, Kazuo Okumoto1, Yuko Nishise1, Takafumi Saito1, Sumio Kawata2, Yoshiyuki Ueno1;

1Department of Gas-troenterology, Yamagata University Faculty of Medicine, Yama-gata, Japan; 2Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan

Background/Aims: HBV genotype B and C are common in Japan, and they have been demonstrated as one of the important factors associated with the clinical outcomes. For treatment with nucleoside analogue (NUC) in chronic hepatitis B (CHB), discontinuation of NUC often results in hepatic flare. However, it has not been evaluated how to efficiently identify these patients at risk. To avoid risks resulting from discontinuation of NUC, the guideline using scoring matrix of viral antigen levels is recently summarized (Hepatol Res 2013). The aim of this study was to examine whether HBV genotype has a predictive value on the response to long-term NUC therapy in patients with CHB. Methods: We evaluated genotypes in 645 HBsAg-positive chronic HBV carriers who had a medical examination, 75 patients (genotype B: C = 47%: 53%) were administered NUC. Of 75 patients included, mean age was 53.7 years and follow-up period was 6.1 years. The clinical and virological characteristics, such as ALT value, HBsAg (CLIA), HBV DNA (PCR), HB core-related antigen (HBcrAg, CLEIA), reported marker reflecting cccDNA levels in hepatocytes, at the time of baseline and 24 weeks, 1, 2, 5 years after that since NUC treatment initiation, were compared between subjects with genotype B and those with genotype C. Both HBsAg and HBcrAg levels were scored according to the guideline by the following three groups based on the total score: low- (score 0), medium- (score 1-2), and high-risk (score 3-4). Cumulative incidence curve was estimated by the Kaplan-Meier method, the factors associated with the response to NUC therapy was evaluated by the Cox hazard model. Results: The prevalence of ALT normalization and undetectable HBcrAg of genotype B and C at 24 weeks were 72.5% and 42% (P < .05) and 50% and 21% (P < .05), respectively. There was no difference between both genotypes in HBV DNA seroclearance rate. Based on the scoring matrix system, the 5-year cumulative rate of archive low- and medium-risk groups (score 0-2) of genotype B and C was 29/35 (82.9%) and 12/40 (30.0%), respectively (P < .01). Multivariate analysis revealed that genotype B was the most predictive factor associated with archive score 0-2 (HR, 2.96; 95%CI, 1.14-7.70; P =.03), compared with age at the start of NUC treatment (HR, 1.04; 95%CI, 1.00-1.08; P =.04) and pretreatment ALT (HR, 1.0; 95%CI, 0.99-1.00). Conclusions: In Japanese CHB patients, genotype B shows a better virological response to NUC therapy than genotype C. This suggests that HBV genotype is a useful indicator to predict response to NUC therapy and to efficiently identify the patients at risk for relapsing of hepatitis resulting from discontinuation of NUC.

Disclosures;

The following people have nothing to disclose: Hisayoshi Watanabe, Chikako Sato, Kei Mizuno, Tomohiro Katsumi, Kyoko Tomita, Kazuo Okumoto, Yuko Nishise, Takafumi Saito, Sumio Kawata

1004

Retrospective Observational study to evaluate the efficacy of Entecavir in patients with chronic hepatitis B virus infection in Korea ; Real-Life Clinical Outcomes

Chung-Hwa Park1,2, Jin Mo Yang1,2, Hee Yeon Kim1,2, Do Seon Song1,2, Myeong Jun Song1,2, Jung Hyun Kwon1,2, Chan Ran You1,2, Jeong Won Jang1,2, U Im Chang1,2, Se Hyun Cho1,2, JinMo Yang1,2, Nam Ik Han1,2, Young Sok Lee1,2, Si Hyun Bae1,2, Jong Young Choi1,2, Seung Kew Yoon1,2;

1Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2The Catholic University Liver Research Center (CULRC), The Catholic University of Korea, Seoul, Republic of Korea

Background: Entecavir has demonstrated superior histologic, virologic, and biochemical benefits for chronic hepatitis B worldwide. Still, its long-term clinical outcome is not well established in Korean clinical area, and also in subjects who stopped the treatment . Methods: This is a multicenter, retrospective cohort observational study to evaluate the efficacy of Entecavir long-term treatment in CHB patients at hospitals affiliated to the Catholic University of Korea through analysis of the electronic medical record data from January 1, 2006 to December 31, 2012. Results: Among 2,440 patients who were prescribed with entecavir 0.5mg qd, 1,337 patients were treatment naïve. Excluding 533 patients with concomitant conditions, 578 patients were on-treatment and 226 patients stopped the treatment during the study period. At 6mo, year 1,2, 3,4 and 5, cumulative incidences of complete virologic response (HBVDNA <300 copies/mL) was 379, 530, 573, 577, 579 and 579, respectively. HBsAg loss rate was 9.86%, and among 440 HBeAg-positive patients, HBeAg loss rate and HBeAg loss with HBeAb positivity rate were 20.00% and 17.43%, respectively, at year 1. During the study period, 226 patients stopped entecavir, and at year 1 after cessation, cumulative virologic relapse (HBV-DNA>1 0A4 copies/mL) and biochemical relapse rate (ALT>40U/L) were 22.57% and 20.35%, respectively with mean days of 191.06±67.0 and 1 88.39±90.15. Prognostic factor for earlier CVR was HBV-DNA<1 0^7cpm at the initiation of entecavir treatment (p<0.005). Among those who stopped the medication, prognostic factor for virological relapse was HBV-DNA ≧10^7cpm at the initiation of entecavir treatment(p=0.022). Conclusions: Long term use of entecavir may achieve CVR in most patients, and patients with higher viral load should be considered for indefinite duration of treatment regardless of age, sex, biochemical markers or HBeAg status.

Disclosures:

The following people have nothing to disclose: Chung-Hwa Park, Jin Mo Yang, Hee Yeon Kim, Do Seon Song, Myeong Jun Song, Jung Hyun Kwon, Chan Ran You, Jeong Won Jang, U Im Chang, Se Hyun Cho, JinMo Yang, Nam Ik Han, Young Sok Lee, Si Hyun Bae, Jong Young Choi, Seung Kew Yoon

1005

Quantitative Hepatitis B Surface Antigen Kinetics In Entecavir Treated Patients

Ju Yeon Cho1, Yong Han Paik1, Won Sohn1, Seon Woo Kim2, Sook Young Woo2, Geum-Youn Gwak1, Moon Seok Choi1, Joon Hyeok Lee1, Kwang Cheol Koh1, Seung Woon Paik1, Byung Chul Yoo1;

1Medicine, Samsung Medical Center, Seoul, Republic of Korea; 2Biostatistics, Samsung Medical Center, Seoul, Republic of Korea

Background: Hepatitis B surface antigen (HBsAg) loss is associated with immunological control of the hepatitis B virus and durable suppression of viral replication. HBsAg levels reflect transcription of closed covalent circular DNA in patients with chronic hepatitis B (CHB). The aim of this study was to investigate the on-treatment kinetics of quantitative HBsAg during entecavir therapy to predict the treatment period needed to achieve HBsAg seroconversion. Methods: From a cohort of 1 006 CHB treatment-naïve patients who were started on entecavir, 425 patients with a quantitative HBsAg value after initiation of entecavir were selected. Among the patients, 321 patients (75.1%) had more than 2 serial samples. The kinetics of quantitative HBsAg decline was assessed using 1465 samples from 413 patients with normal distribution and homoscedasticity with mixed linear model to predict the time to clear HBsAg while on entecavir treatment. Results: Among the 413 patients, 213 patients (51.6%) were HBeAg positive and 200 patients (48.4%) were HBeAg negative. At baseline, the age of the HBeAg(-) group was significantly older (p < 0.001) and the level of HBV-DNA was significantly lower (p < 0.001) compared to the HBeAg (+) group. During a median follow up of 49.5 months, the quantitative HBsAg level showed a slow but consistent decrease in value regardless of the HBeAg status. The HBeAg-positive group had a mean slope of -0.0036 ± 0.0003 Log 10 IU/month (p<0.001) and the HBeAg-negative group had a mean slope of -0.0037 ± 0.0004 Log10 IU/month (p<0.001). The calculated time to clear quantitative HBsAg in HBeAg-positive and HBeAg-negative groups were 87 years and 73 years, respectively. Conclusions: Analysis of the kinetics for HBsAg level during entecavir therapy suggests the treatment period required to achieve quantitative HBsAg clearance during entecavir therapy is life-long, regardless of the HBeAg status of chronic hepatitis B patients.

image

Disclosures:

Kwang Cheol Koh - Grant/Research Support: Roche, Novartis, Roche, Novartis

The following people have nothing to disclose: Ju Yeon Cho, Yong Han Paik, Won Sohn, Seon Woo Kim, Sook Young Woo, Geum-Youn Gwak, Moon Seok Choi, Joon Hyeok Lee, Seung Woon Paik, Byung Chul Yoo

1006

Higher HBsAg clearance rate achieved in nucleos(t)ide analogues experienced CHB patients treated with pegy-lated-interferon α-2a

Yao Xie, Ming-hui Li, Yao Lu, Guo-hua Qiu, Lu Zhang, Li-wei Zhuang, Jun Cheng;

Ditan Hospital, Capital Medical University, Beijing, China

Aim:To investigate the efficacy of pegylated interferon α-2a treatment in nucleos(t)ide analogues(NA) experienced chronic hepatitis B(CHB)patients with satisfied or poor virological response. Method:In this observational study, inclusion criteri-ons were HBeAg positive CHB with prior NA exposure history for more than 3 months (3-82 months) and remaining on HBeAg positive status. Pegylated interferon α-2a was either added on or switched to at baseline. Follow-up periods varying from 12 to 108 weeks post-interferon treatment were recorded. Results:A total of 1 63 patients who were previously exposed to LAM, ADV, ETV or Ldt were included. Among them, 83 were defined as satisfied-responders (HBV DNA<1 000copies/ml) and 80 were poor-responders (HBV DNA>1 000copies/ml). Baseline characteristics, including age, gender, prior NA treatment duration and serum ALT level, were comparable between satisfied- and poor-responders. Statistically lower mean qHB-sAg level and qHBeAg level were observed in satisfied-responders than in poor-responders (4503.3IU/ml vs 9338.6IU/ml and 21.6PEIU/ml vs 126.4PEIU/ml, both P<0.05). The mean pegylated interferon α-2a treatment duration was similar between satisfied- and poor-responders (83 weeks vs 80 weeks). At end of treatment, a trend of higher rate of HBeAg clearance, HBsAg loss and obvious qHBsAg decline (qHBsAg declined to <10IU/ml) was observed in satisfied-responders than in poor-responders (38.6%, 1 3.3% and 26.5% vs 32.5%, 1 1.3% and 1 8.8%, respectively), though without significant difference (all P >0.05). The HBeAg clearance rate continued raising to 45% after the treatment was stopped. Baseline qHBsAg level was demonstrated to be associated with HBsAg loss and obvious qHBsAg decline at end of treatment. The HBsAg loss(27.6% vs 5.9%,P=0.0067) and obvious decline(51.7% vs 1 1.8%,P<0.001) rate were higher in the patients with baseline qHBsAg <1500IU/ml than those with baseline qHBsAg >1500IU/ml. In addition, baseline HBsAg<1 500IU/ml was identified by ROC analysis as the optimal prediction cutoff of HBsAg<1 0IU/ml at end of treatment (PPV71.4%, NPV 76.7%). Conclusion: Pegylated interferonα-2a induces high HBsAg loss rate in NA-experienced CHB patients with or without virological response, however, patients with virological response and low qHBsAg level (<1500IU/ml) achieves higher HBsAg loss.

Disclosures:

The following people have nothing to disclose: Yao Xie, Ming-hui Li, Yao Lu, Guo-hua Qiu, Lu Zhang, Li-wei Zhuang, Jun Cheng

1007

Hepatitis B Viral Load after One Year of Tenofovir is Predicted by Patient's Self-reported Adherence and Patient-doctor Relationship

Jean-Pierre H. Zarski1, Silla M. Consoli2, Fabien Zoulim3, Xavier Causse4, Christophe Hezode5, Dominique G. Larrey6, Georges-Philippe Pageaux6, Bruno Roche7, Regine Truchi8, Denis Ouzan9, Jean françois D. Cadranel10, Christiane Stern11, Valerie Tilliet11, Olivier P. Libert11, Patrick Marcellin12;

1Hepatogastroenterology, Hopital Michallon, Grenoble, France; 2Psychiatry, Hopital Europeen Georges Pompidou, Paris, France; 3Hepatogastroenterology, Hopital de la Croix Rousse, Lyon, France; 4Hepatogas-troenterology, Centre Hospitalier, Orléans, France; 5Hepatogastroenterology, Hopital Henri Mondor, Créteil, France; 6Hepatogastroenterology, Hopital Saint Eloi, Montpellier, France; 7Centre Hepatobilaire, Hopital Paul Brousse, Villejuif, France; 8Hepatogastroenterology, CHU Nice, Nice, France; 9Institut Arnault Tzanck, St Laurent du Var, France; 10Hepatogastroenterol-ogy, CH Creil, Creil, France; 11Medical Affairs, Gilead Sciences, Boulogne-billancourt, France; 12Hepatogastroenterology, Hopital Beaujon, Clichy, France

Background/Aims: Tenofovir DF (TDF) represents a very efficient and safe therapy option in patients with Chronic Hepatitis B, as shown in pivotal trials over 6 years. A correlation between HBV-DNA levels and long term clinical outcomes has been reported. However, the impact of therapeutic adherence on the viral load (VL) is still poorly documented in field practice. The aim of this study is to assess behavioral determinants of biological outcome within a cohort of HBV-patients treated with TDF (VIREAL Study) in real life from France. Methods: 441 CHB patients (mean age 45.3 (SD 14.3), 70.9% males, 59.1% treatment-experienced) were invited to fill in a short self-reported adherence questionnaire at 3, 6 and 12-month. Their practitioners were also invited on the same visits to answer a short questionnaire describing patients' knowledge about their disease, motivation, reluctance to be treated, mood, and therapeutic partnership with the practitioner. The questionnaire used three ratings to report treatment adherence: good adherence, minor problems related to adherence and poor adherence. VL was measured at baseline, 3, 6 and 12 month. Results: HBV-DNA was lower than 69IU/mL at week 48 in 91 % of patients. Overall, good adherence was observed in 56%, minor adherence problems in 39% and poor adherence in 5%. Similar to registration trials for TDF, VL significantly decreased from baseline to 12 months, with a final VL positively correlated with baseline VL. After adjusting for baseline VL, higher final VL was found in patients who reported having skipped their last medication at the 3-month visit (p=0.001) or at the 12-month visit (p=0.017), patients who reported having been out of drugs at the 12-month visit (p=0.001), patients considered by their practitioner as insufficiently informed about their disease at the 3-month (p=0.02) or 12-month visits (p=0.008) or reluctant to have treatment at the 12-month visit (p=0.003). Conclusions: A simple questionnaire to CHB patients and/or to their practitioners can provide useful information about risk factors for lower efficacy of antiviral treatment in CHB. These indicators could help practitioners to better motivate and manage these patients and prevent disappointing biological results, with their at risk long term consequences.

Disclosures:

Jean-Pierre H. Zarski - Advisory Committees or Review Panels: BMS, Gilead, Janssen Cilag, BMS, Gilead, Janssen Cilag; Consulting: Roche, Scherring Plough, Novartis, Roche, Scherring Plough, Novartis; Speaking and Teaching: Siemens

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

Xavier Causse - Board Membership: Gilead, BMS, MSD, Janssen-Cilag; Speaking and Teaching: Roche, Gilead, BMS, Janssen-Cilag

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

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

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

Regine Truchi - Independent Contractor: Gilead Christiane Stern - Employment: Gilead Sciences Valerie Tilliet - Employment: Gilead Sciences Olivier P. Libert - Employment: Gilead Sciences

Patrick Marcellin - Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott

The following people have nothing to disclose: Silla M. Consoli, Bruno Roche, Denis Ouzan, Jean françois D. Cadranel

1008

Week 96 Analysis of a Phase IIb Study of the Efficacy and Safety of Besifovir (LB80380) vs. Entecavir in Treat-ment-naïve Patients with Chronic Hepatitis B

Man-Fung Yuen1, Sang Hoon Ahn2, Kwan Sik Lee2, Soon Ho Um3, Mong Cho4, Seung Kew Yoon5, Jin-Woo Lee6, Neung Hwa Park7, Young Oh Kweon8, Joo Hyun Sohn9, Jiyoon Lee10, Jeong-Ae Kim10, Ching-Lung Lai1, Kwang-Hyub Han2;

1University of Hong Kong, Hong Kong, Hong Kong; 2Yonsei University, Seoul, Republic of Korea; 3Korea University, Seoul, Republic of Korea; 4Pusan National University, Pusan, Republic of Korea; 5The Catholic University of Korea, Seoul, Republic of Korea; 6Inha University, Incheon, Republic of Korea; 7Ulsan University, Ulsan, Republic of Korea; 8Kyungpook National University, Daegu, Republic of Korea; 9Hanyang University, Seoul, Republic of Korea; 10LG Life Sciences, Seoul, Republic of Korea

Background: Besifovir (formerly, LB80380), a novel nucleotide analogue, is effective and safe in chronic hepatitis B(CHB) patients with lamivudine-resistant mutations, with doses above 90 mg daily. Aim: To compare the efficacy and safety of besifovir with entecavir in treatment-naïve CHB patients up to week 96 of therapy. Methods: Total 1 15 CHB patients fulfilling the following criteria were recruited from Hong Kong and Korea: (1) HBsAg positive for >6 months, (2) HBeAg-positive with HBV DNA >20,000 IU/mL or HBeAg-negative with HBV DNA >2,000 IU/mL, (3) elevated ALT levels (1.2-10 X ULN), (4) treatment-naïve and (5) compensated liver disease. They were randomized in the ratio of 1:1:1 to receive either besifovir 90 mg, 150 mg or entecavir 0.5 mg daily orally for 96 weeks. 101 patients completed the 96 weeks of treatment with 92 patients who adhered to the protocol were analysed as per-protocol analysis set. Results: The data of the 92 patients up to week 96 of treatment are tabulated. Besifovir, 90 mg or 150 mg daily, showed comparable anti-viral activity with entecavir 0.5 mg daily after 96-week treatment. Carnitine supplement was given to the patients who developed low serum L-carnitine levels throughout the treatment period (26 patients (78.8%) in the 90 mg group and 35 (94.6%) in the 150 mg group). The levels became normal in all patients after the carnitine supplements. No drug-related serious or significant adverse events were reported. Full sequencing of the HBV polymerase region was performed at baseline, at week 48, at week 96 and whenever there was virologic breakthrough for samples with HBV DNA > 200 IU/ml. No resistant mutations were found in any of the 3

groups of patients by week 96. Conclusions: (1) At week 96, besifovir 90 mg or 150 mg daily, had comparable antiviral activity with entecavir 0.5 mg daily. (2) Low serum L-carnitine levels, though occurring in a significant proportion of patients, were normalized in all patients with carnitine supplement. (3) Other than lowering of serum L-carnitine levels, no besifovir-related serious or significant adverse events were not reported.

  1. NS: Not significant

 Besifovir 90mg (n=31)Besifovir 150mg (n=30)Entecavir 0.5mg (n=31)P
M : F19:1223:723:8NS
Age(yrs)±SD42.8±10.640.8 ± 10.842.4±11.8NS
HBeAg+: HBeAg-15: 1614: 1618: 13NS
Baseline HBV DNA(loglO IU/mL) ± SD6.75 ± 1.356.50 ±1.686.96± 1.43NS
Week 96 HBV DNA (loglO IU/mL) ± SD1.45 ±0.361.60 ± 1.141.43 ±0.32NS
LoglO HBV DNA decrease at week 96 ± SD-5.29 ±1.27-4.89 ±1.70-5.54 ±1.38NS
HBV DNA < 20 IU/mL at week 96 (%)80.780.080.7NS
HBeAg loss for HBeAg+ pts3/153/144/18NS

Disclosures:

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

Jiyoon Lee - Employment: LG Life Sciences, Ltd Jeong-Ae Kim - Employment: LG Life Sciences, Ltd.

Ching-Lung Lai - Advisory Committees or Review Panels: Bristol-Myers Squibb, Gilead Sciences Inc; Consulting: Bristol-Myers Squibb, Gilead Sciences, Inc; Speaking and Teaching: Bristol-Myers Squibb, Gilead Sciences, Inc

The following people have nothing to disclose: Sang Hoon Ahn, Kwan Sik Lee, Soon Ho Um, Mong Cho, Seung Kew Yoon, Jin-Woo Lee, Neung Hwa Park, Young Oh Kweon, Joo Hyun Sohn, Kwang-Hyub Han

1009

Better outcomes of switching to Peg IFN a-2a plus adefovir after childbirth in pregnant HBV carriers receiving nucleoside analogs for prevention of mother-to-child transmission

Junfeng Lu, Xinyue Chen, Yali Liu, Hongwei Zhang, Lina Ma, Hua Zhang;

BeiJing YouAn Hospital, Capital Medical University, BeiJing, China

Background The prevalence of Chronic hepatitis B virus(HBV) infection is high in China, where most of HBV infection are due to mother to child transmission (MTCT). It has been documented that high viral load (HBV DNA>1 06IU/ml) is one of the major reasons of failure in preventing MTCT and the risk of MTCT can be reduced by antiviral therapy. However, it is not clear how to choose therapeutic strategies after childbirth for pregnant HBV carriers receiving nucleoside analogs for prevention of mother-to-child transmission (PMTCT). Objectives We aimed to investigate the outcome of Peg IFN a-2a plus adefovir after childbirth in pregnant HBV carriers who received telbivudine for PMTCT. Methods Forty-four HBeAg-positive highly viremic(HBV DNA≧6loglOIU/ml) pregnant HBV carriers (with normal ALT) were treated with telbivudine from 24th to 28th week of gestation to prevent HBV perinatal transmission between 2010 and 2011. Biochemical, serological and virological parameters were measured after 1-2 month(s) of childbirth. If a patient had 2 or more of the following 3 conditions, including ALT>80U/L, titer decrease of HBeAg >80% and reduction of HBV DNA>3

logIU/ml compared with baseline values, telbivudine would be stopped and switched to Peg IFN a-2a plus adefovir. Otherwise, patients were suggested to cease antiviral therapy. Under informed consent, 1 8 cases switched to Peg IFN a-2a plus adefovir, 5 continued therapy with telbivudine, 1 1 refused to receive treatment and 10 followed the suggestion to stopped treatment. The durations of treatment are from 48 to 96 weeks. Results Among 1 8 cases switched to Peg IFN a-2a plus adefovir, 15(83.3%) achieved complete virological response (HBV DNA<20IU/ml), 9(50%) achieved HBeAg clearance or sero-conversion with HBV DNA<20IU/ml, 5(27.8%) achieved HBsAg clearance(HBsAg <0.05IU/ml) or seroconversion with HBeAg loss and HBV DNA<20IU/ml, 1 did not achieve virological response, and 2 lost to follow-up. 3 patients who achieved HBsAg seroconversion had stopped antiviral therapy with HBsAb titers greater than 300IU/L persistently. Conclusions Based on postpartum ALT elevation, decrease of HBeAg titer and reduction of HBV DNA, switching to IFN-based regimen may achieve high rates of response after childbirth in pregnant HBV carriers who received nucleoside analogs for PTMCT . The mechanism may be associated with recovery of immune function after childbirth and enhancement of immune function by antiviral therapy in the third trimester of pregnancy.

Disclosures:

The following people have nothing to disclose: Junfeng Lu, Xinyue Chen, Yali Liu, Hongwei Zhang, Lina Ma, Hua Zhang

1010

Tenofovir induced Inter- and Intra-switch of hepatitis B virus (HBV) genotypes among chronic hepatitis B patients on therapy

Ranjit Chauhan1, Avishek K. Singh2, Shiv K. Sarin 1,2;

1Advanced Center For Liver Diseases, ILBS, New Delhi, India; 2Research, ILBS, New Delhi, India

Switch in HBV genotypes is well known on interferon therapy. Whether prolonged Tenofovir therapy introduces genotype switches in patients (pts) during treatment is not known. Eighty-Eight chronic hepatitis B pts with raised ALT (>1.5 x ULN) and histologically proven chronic hepatitis, receiving tenofovir as per protocol were followed up every 6 months. HBV genotypes were studied if pts had at least two follow-ups (n=67) . Of these pts, 17 were treatment exposed (Lamivudine 12, Adefovir 3, Lamivudine + Adefovir 2). HBV Polymerase/surface region sequences from 67 pts were subjected to phylogenetic, recombination analysis and inter-genotype (change of genotype), intra-genotype (change of subgenotype), recombination were determined in follow-up samples and compared to baseline. Majority of pts were male (n 58). Median HBV DNA was 3.1x106 IU/ml. HBeAg was +ve in 38 (56.7%). At baseline, HBV genotypes were : A 14 (20.8%), D 52 (77.6%) and C 1 (1.5%) with predominance of sub-genotype A1, C1 and D1. Twenty-two of 67 (32.8%) pts experienced inter-genotype switches. Six pts experienced switch in genotype at 6 months and 7 at 1 year, 3 at 1.5 year, 4 at 2 year and 2 pts at 2.5 years. The trend of genotype switch was more often detected from A to D [13 (92.8%), baseline HBeAg +ve: 9; HBeAg -ve 4] as compared to genotype D to A [9 (17.3%) baseline HBeAg +ve: 2; HBeAg -ve: 7] (P <0.002). Of 22 pts, in 3 change in HBeAg coincided with genotype switch i.e. [HBeAg +ve, Genotype A converted to HBeAg -ve, genotype D in one ], [HBeAg -ve, genotype D reverted to HBeAg +ve, genotype A in 2 pts]. In one such patient, a recombination of genotype A and D was identified. Once changed, genotype switch was stable in 12/22 (54.5%) pts, whereas in 7/22 (32%) and 3/22 (13.6%) pts switches were detected at 2 and 3 time points respectively. Though in remaining 45 (67%) pts, HBV genotypes were stable, however a change to subgenotype was identified in 34/45 (74%) [D:29 and A: 5] pts, of which a few showed a new/quasi subgenotype of A and D. Among 17 treatment exposed pts, inter- and intra-genotype changes were identified in 1 3/1 7 (76.5%), and was comparable to the treatment naïve group, (P = 0.568). No switch of sub-genotype was detected in 1 1 pts during entire follow-up Conclusions: This novel report documents a high frequency of inter- and intra-genotype changes in tenofovir treated patients. Majority of switches were identified within one year of the treatment and genotype A was more susceptible compared to genotype D. Constant evolution of virus under drug pressures may select new or recombinant molecular forms and the later might transmit to treatment naïve population.

Disclosures:

The following people have nothing to disclose: Ranjit Chauhan, Avishek K. Singh, Shiv K. Sarin

1011

A Long-term Follow-up Study of Adefovir and Lamivu-dine Combination Therapy for Lamivudine Resistance: Time to Rescue the Rescue Therapy?

Hyung Joon Yim1, Hae Rim Kim1, SangJun Suh1, Yeon Seok Seo2, Chang Wook Kim3, Chang Don Lee3, Sang Hoon Park4, Myung Seok Lee4, Choong Kee N. Park5, Hee Bok Chae6, Moon Young Kim7, Soon Koo Baik7, Yun Soo Kim8, Ju Hyun Kim8, Jung Il Lee9, Jin-Woo Lee9, Sun P. Hong10, Soon Ho Um2;

1Department of Internal Medicine, Korea University Medical College, Seoul, Republic of Korea; 2Department of Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea; 3Department of Internal Medicine, The Catholic University of Korea Uijeongbu St. Mary's Hospital, Uijeongbu, Republic of Korea; 4Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, Republic of Korea; 5Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea; 6Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea; 7Deparment of Internal Medicine, Yonsei University Wonju Severance Christian Hospital, Wonju, Republic of Korea; 8Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea; 9Department of Internal Medicine, Inha University Hospital, Incheon, Republic of Korea; 10GeneMarix Inc, Yongin, Republic of Korea

Background: Lamivudine (LMV) resistance is still a challenging issue as it predisposes a multidrug resistance in the management of chronic hepatitis B (CHB). Combination of LMV and adefovir (ADV) has been suggested as a standard treatment for LMV resistance in the countries where tenofovir is not available. However long term efficacy of ADV+LMV is needed to be further evaluated especially in genotype C patients. The previous prospective study compared the efficacy of ADV and LMV combination with that of entecavir monotherapy for LMV resistant CHB after 2 years of treatment. After then patients were further followed-up up to 5 years. As ADV plus LMV therapy was shown to be better than ETV monotherapy in the previous study, this current study was planned to evaluate the long-term efficacy of ADV+LMV therapy. Methods: One hundred and ten CHB patients who had developed LMV resistance received ADV+LMV therapy up to 5 years. Virologic response (VR) which is defined as non-detectable HBV DNA (< 20 IU/mL) by real time PCR was evaluated as a primary end point. Result: The mean age was 44±1 2 years and 77% were male. The proportion of HBeAg-positive patient was 79% (87/110). All the patients had genotype C HBV. The mean serum HBV DNA lev-

els were 7.05±1.07, 2.57±1.54, 2.20±1.25, 2.27±1.05, 2.09±0.93 and 1.66±0.59 log10 IU/ml at baseline, month 12, 24, 36, 48 and 60 respectively. The cumulative rates of virologic response (HBV DNA <20 IU/ml) were 25%, 41%, 48%, 54%, and 55%, and genotypic resistance to adefovir were 6%, 8%, 8%, 9%, and 9% at month 12, 24, 36, 48, and 60, respectively. When we predicted long term responses according to detectability of HBV DNA at 12 months of treatment, VR was higher in patients with non-detectable HBV DNA than in patients with detectable HBV DNA (85% vs. 50%, p = 0.002). Likewise, at 24 months of treatment, VR was higher in patients with detectable HBV DNA (100% vs. 38%, p = 0.012). Multivariate analysis showed only HBV DNA unde-tectability at month 24 was the independent predictor for long term VR (p=0.002). When Area Under the Receiver Operating Curve (AUROC) was compared between HBV DNA unde-tectability at month 12 and month 24, AUROC value of month 24 (0.898; 95% confidence interval [CI], 0.829-0.968; P <0.001) was higher than that of month 12 (0.842; 95% confidence interval [CI], 0.752-0.932; P <0.001). Conclusion: Long term ADV and LMV combination therapy lead to VR in a significant number of LMV resistant CHB patients with genotype C. However the efficacy was not satisfactory during long term treatment. Alternative therapy is certainly needed in patients who have detectable HBV DNA after month 24.

Disclosures:

Hyung Joon Yim - Grant/Research Support: GSK Korea, Handok Pharm, Gilead Korea; Speaking and Teaching: BMS Korea

Chang Wook Kim - Consulting: Gilead; Grant/Research Support: BMS, Boehringer Ingelheim, Pharmicell; Speaking and Teaching: BMS, GSK, Dae-woong

Hee Bok Chae - Consulting: BMS-Korea, Gilead Science-Korea

The following people have nothing to disclose: Hae Rim Kim, Sang Jun Suh, Yeon Seok Seo, Chang Don Lee, Sang Hoon Park, Myung Seok Lee, Choong Kee N. Park, Moon Young Kim, Soon Koo Baik, Yun Soo Kim, Ju Hyun Kim, Jung Il Lee, Jin-Woo Lee, Sun P. Hong, Soon Ho Um

1012

The antiviral efficacy of entecavir is not influenced by prior treatment with nucleos(t)ide analogues in patients with chronic hepatitis B

Bulent Baran1, Ozlem Mutluay Soyer1, Asli Cifcibasi Ormeci1, Suut Gokturk1, Sami Evirgen1, Filiz Akyuz1, Cetin Karaca1, Kadir Demir1, Fatih Besisik1, Derya Onel2, Mine Gulluoglu3, Selim Badur2, Sabahattin Kaymakoglu1;

1Department of Gastroentero-hepatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey; 2Department of Microbiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey; 3Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey

Aim: In this study, we aimed to investigate the antiviral efficacy of entecavir (ETC) therapy in chronic hepatitis B (CHB) patients with previous nucleos(t)ide analogue (NA) experience. Methods: Study inclusion criteria were being NA-naïve or previous NA-experience in the absence of lamivudine (LAM) resistance and receiving ETC therapy for at least 6 months. Biochemical and virological tests were obtained at baseline and 3-month intervals in the first year and every 6 months thereafter. The primary outcome measure for efficacy was complete virological response (CVR), defined as HBV-DNA<20 IU/ml. Estimated cumulative response rates were calculated by Kaplan-Meier analysis. Results: 211 patients (148 male, mean age 43.8±12.8, 58 HBeAg+ CHB, and 61 cirrhosis) were included in the study. 1 81 patients were NA-naïve and 30 patients had prior exposure to NAs. Among NA-experienced patients there were 9 patients with previous adefovir (ADF) failure, and the

remaining had LAM experience without a history of virological breakthrough or LAM resistance. However, A1 81T/V mutation was detected in 4 patients with previous LAM experience, despite being naïve to ADF. LAM experienced patients received LAM at a median of 12 (6-48) months and patients with ADF failure were treated with ADF at a median of 24 (8-48) months. One patient with ADF failure received add-on combination therapy with ETC after a virological breakthrough and the remaining patients were switched to ETC due to suboptimal response. Four patients with ADF failure had mutations associated with ADF resistance (rtA1 81T and/or N236T). Median duration of ETC treatment was 38 months (6-66). Cumulative CVR rates in NA-naïve and experienced patients were 69% vs. 54% at 12th month and 84% vs. 68% at 24th month, 92% vs. 86% at 36th month, respectively (Fig.1, log-rank, p=0.32). 3 patients (10.3%) in NA-experienced group and 4 patients in NA-naïve group (2.2%) required a switch to tenofovir (TDF) due to sub-optimal response to ETC (p=0.061) and 1 NA-naïve patient developed ETC resistance (L180M, M204V, S202G). Multi-variate logistic regression analysis showed that HBeAg positiv-ity (OR: 6.3, 95% CI 1.16-34.3, p=0.033) and previous LAM experience (OR: 5.8, 95% CI 1.15-29.2, p=0.033) were independent predictors for a requirement to switch to TDF. Conclusion: ETC has a potent antiviral efficacy in patients with CHB. The antiviral efficacy of ETC is not influenced by prior treatment with NAs if LAM resistance is excluded at baseline. However, HBV-DNA kinetics should be carefully monitored in patients with HBeAg-positive CHB and previous LAM experience.

Disclosures:

The following people have nothing to disclose: Bulent Baran, Ozlem Mutluay Soyer, Asli Cifcibasi Ormeci, Suut Gokturk, Sami Evirgen, Filiz Akyuz, Cetin Karaca, Kadir Demir, Fatih Besisik, Derya Onel, Mine Gulluoglu, Selim Badur, Sabahattin Kaymakoglu

1013

Three-year outcomes of tenofovir disoproxil fumarate (TDF) treatment in Asian-American adults with chronic hepatitis B in real-life practice in the US: A prospective open label study

Calvin Pan1, ZhengZeng2, Ho Bae3, Huy N. Trinh4, Xiaoli Ma5, Li-Jun Mi6, Truong-Sinh Leduc9, Sing Chan7, Ke-Qin Hu8;

1Division of Gastroenterology and Hepatology, NYU Langone Medical Center, NYU School of Medicine, Flushing, NY; 2Department of Infectious Diseases, Peking University First Hospital, Beijing, China; 3Asian Pacific Liver Center, St. Vincent Medical Center, Los Angeles, CA; 4San Jose Gastroenterology, MC, San Jose, CA; 5Department of Medicine, Temple University Hospital, Philadelphia, PA; 6Depart-ment of Medicine, New York Downtown Hospital, New York, NY; 7Sing Chan Endoscopy, Flushing, NY; 8Department of Hepatology, UCI School of Medicine, Orange, CA; 9Leduc Medical Group, Fountain Valley, CA

Background: Chronic hepatitis B (CHB) disproportionately affects Asian-Americans in the US. TDF has been demonstrated potent antiviral in clinical trials, but real-life data in Asian-Americans are lacking. We prospectively followed patients on TDF for 144 weeks and assessed outcomes. Methods: Asian-American patients with CHB from multiple community-based practices were prospectively enrolled and treated with TDF (300 mg/day) in a single arm study for 48 weeks. After week 48, patients had the option to continue TDF up to week 144, or opt out of further observation. The primary efficacy endpoint was hepatitis B virus (HBV) DNA < 29 IU/mL at week 48 and 144. Secondary endpoints were safety and tolerability, serologic and biochemical responses, liver fibrosis by FibroTest at week 48, and the development of drug resistant mutations. Results: Ninety patients were enrolled with baseline values in Table 1.

At week 48, seventy four patients (82% overall; 70% HBeAg-positive and 100% HBeAg-negative) had HBV DNA <29 IU/mL. 12% (6/52) HBeAg+ patients achieved HBeAg loss/seroconversion. The percentage of patients with alanine aminotransferase (ALT) in the normal range increased from 26% at baseline to 66% at week 48. The percentage of patients with F0 fibrosis by FibroTest increased from 48% to 51%, and those with F4 fibrosis decreased from 4% to 1 %. At week 48, 31 /90 patients (19 HBeAg+) opted to continue on TDF with assessment at 12 week intervals up to week 144. Two patients with HBV viremia did not participate beyond week 48. At week 144, 84% (26/31) patients had HBV DNA <29 IU/mL; No viremic patient (n=5) had genotypic mutation on Sanger sequencing (2/5 TDF non-adherence); 67.3% ( 21/31) patients had normal ALT; cumulatively, 1 3% (7/52) had HBeAg loss/seroconversion; and 2% (1/52) of HBeAg (+) patients had HBsAg loss. Treatment was well tolerated. Most adverse events were mild in severity and considered unrelated to TDF. No subject had confirmed 0.5 mg/dL increase in serum creatinine, or creatinine clearance <50 mL/min. Conclusions: TDF is effective and well-tolerated in Asian-American CHB patients in a real-life setting, consistent with larger registration trials except HBsAg loss occurred in a small percentage of Asian-American patients. Improvement in liver fibrosis was seen in a proportion of patients at week 48. No genotypic resistance to antiviral drug was developed up to week 1 44.

Table 1. Baseline characteristics
  1. *At the baseline, 52 patients were HBeAg (+); one patient with indeterminate HBeAg result at baseline was HBeAg (+) at week 48. ‡ Normal range ALT: <34 U/L female; <43 U/L male

Characteristic Median age, (year with range) Male gender, n (%) Country of origin, n (%) Chinese Vietnamese Korean Cambodian Mean HBV DNA, loglO copies/ml (SD) HBeAg positive, n (%) ALT, n (%)‡ >ULN <ULN Prior treatment history, n (%) Lamivudine Adefovir Interferon Genotype, n (%) B C FibroTest score, % F0 F1-F2 F3F4n=90 37(18-62)47(52) 58(64) 19(21) 12(13) 1(1) 7.5(1.8)52(58)*67(74) 23(26) 3(3) 6(7) 5(6) 43(48) 47(52) 48 46 2 4

Disclosures:

Calvin Pan - Advisory Committees or Review Panels: BMS, Gilead; Consulting: BMS, Gilead; Grant/Research Support: BMS, Gilead, Genentech; Speaking and Teaching: BMS, Gilead, Genentech, Onyx, Vertex

Ho Bae - Grant/Research Support: Gilead; Speaking and Teaching: Gilead, BMS, Genentech

Huy N. Trinh - Advisory Committees or Review Panels: BMS, Gilead; Grant/Research Support: BMS, Gilead; Speaking and Teaching: BMS, Gilead, vertex; Stock Shareholder: Gilead

Xiaoli Ma - Consulting: Gilead Sciemces, Inc, Bristol-Myers Squibb, Inc

Truong-Sinh Leduc - Advisory Committees or Review Panels: Gilead, BMS; Grant/Research Support: Gilead; Speaking and Teaching: Gilead, BMS, Merck, Vertex

Ke-Qin Hu - Grant/Research Support: BMS, Gilead, Merck, Vertex, Genentech; Speaking and Teaching: BMS, Gilead, Merck, Vertex, Genentech

The following people have nothing to disclose: Zheng Zeng, Li-Jun Mi, Sing Chan

1014

Treatment outcomes are associated with HBeAg and HBsAg reduction after 24 weeks of treatment with tel-bivudine in the 2410 Roadmap study

Karsten Wursthorn1,4, Teerha Piratvisuth2, Heiner Wedemeyer1, Michael P. Manns1, Mechthild E. Jung3, Yuhong Dong3, BehrendJ. Zacher1, Aldo Trylesinski3;

1Hannover Medical School, Hannover, Germany; 2NKC Institute of Gastroenterology and Hepatology, Hat Yai, Thailand; 3Novartis Pharma AG, Basel, Switzerland; 4Liver Center Hamburg IFI Institute, Hamburg, Germany

Background: Serum HBsAg is a useful tool to describe the natural course and antiviral response in chronic hepatitis B (CHB)

patients especially when HBV DNA has become undetectable due to effective treatment. We assessed the predictive use of quantitative HBV serum markers in the LDT600A2410 Roadmap study with telbivudine (LDT) monotherapy and teno-fovir (TDF) add-on. Methods / Patients: mITT population was 100 HBeAg-positive CHB patients. Quantitative HBsAg/HBeAg from screening, W24, W52, W76 and W1 04/EoT was correlated with serological (HBe/sAg loss), combined (normal ALT, undetectable HBV-DNA) and complete (normal ALT, undetectable HBV-DNA, HBeAg loss) EoT response. Off treatment follow-up data up to two years was available from 6/7 patients with HBsAg loss. Results: W24 predictive factors for combined (n=82) and complete (n=45) W104/EoT response were W24 HBeAg <10 PEIU/L (n=54, positive predictive value, PPV 85% and 67%, negative predictive value, NPV 22% and 76%) and undetectable HBV DNA (PPV 87% and 64%, NPV 24% and 73%). HBeAg <10 PEIU/L showed a higher AUC (0.7908) and lower p-value (p<0.0001) for the prediction of complete response compared to undetectable HBV DNA at W24 (0.6979, p=0.0007). ROC curves for HBV DNA negativity and for HBeAg <10 PEIU/L did not differ significantly (p=0.095). The 7 HBsAg loss patients had significantly higher screening HBsAg (5.2 vs. 4.9 log10IU/l), HBV DNA (11.4 vs. 9.8 log10IU/ml) and ALT levels (90.7 vs. 83.6 U/L). HBsAg loss could be maintained off-treatment for up to two years in six patients with available data, two patients developed anti-HBs. A >0.5log10 reduction in HBsAg levels after 24 weeks was achieved in 6/7 (85.7%, sensitivity) patients with HBsAg loss compared to 23/93 without (24.7%) resulting in NPV of 98% (70/71), PPV of 21% (6/29) and specificity of 75% (70/93). A >1 log10 reduction in HBsAg levels after 52 weeks was seen in 7/7 (100%, sensitivity) patients with HBsAg loss compared to 13/92 without resulting in NPV of 100%, PPV of 35% (7/20) and specificity of 86% (79/92). 20/21 patients with w52 >1log10 HBsAg reduction had also w24 >0.5log10 HBsAg. The HBsAg slope up to week 24 is significantly associated with HBsAg loss (p=0.0315). Conclusions: In HBeAg-positive CHB, HBeAg <10 PEIU/L and undetectable HBV DNA after 24 weeks of antiviral treatment are equally predictive for W104/EoT outcomes. A >0.5log HBsAg reduction after 24 weeks of telbivudine is associated with a better on-treatment response as well as higher rate of sustained HBsAg loss after 2 years. Negative predictive values for HBsAg decrease by week 24 and 52 allow identifying patients who will not achieve HBsAg loss.

Disclosures:

Teerha Piratvisuth -Advisory Committees or Review Panels: Merck, Roche, Novar-tis; Grant/Research Support: Novartis, Roche, Bristol Myers Squibb, Fibrogen; Speaking and Teaching: Merck, Roche, Novartis, GlaxoSmithKline, Bristol Myers Squibb

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

Mechthild E. Jung - Employment: Novartis Pharma AG Yuhong Dong - Employment: novartis Aldo Trylesinski - Employment: Novartis

The following people have nothing to disclose: Karsten Wursthorn, Behrend J. Zacher

1015

On treatment prediction of post-treatment sustained response to Peginterferon alfa-2a for HBeAg-negative Chronic Hepatitis B (CHB) patients using HBsAg and HBV DNA levels at weeks 12 and 24: PERSEAS cohort final results

Ioannis Goulis1, Stylianos Karatapanis2, Evangelos A. Akriviadis1, Melanie Deutsch3, George N. Dalekos4, Maria Raptopoulou-Gigi5, Konstantinos Mimidis6, Georgios Germanidis7, Christos K. Triantos8, Christos Drakoulis9, Athina Chounta10, Irene Vafiadis11, Grigorios Hatzis12, Asterios Gagalis13, Jiannis Vlachogiannakos11, Elias Zintzaras14,15, Sokratis Koulouris16, George Bakalos14,16, George V. Papatheodoridis3;

14th Department of Internal Medicine, Hippokration General Hospital, Thessaloniki, Greece; 21st Department of Internal Medicine, Rhodes Hospital, Rhodes, Greece; 32nd Department of Internal Medicine, Hippokration General Hospital, Athens, Greece; 4Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly School of Medicine, Larissa, Greece; 52nd Department of Internal Medicine, Hippokration General Hospital, Thessaloniki, Greece; 61st Department of Internal Medicine, Democritus University of Thrace Medical School, Alexandroupoli, Greece; 71st Internal Medicine Clinic, AHEPA Hospital, Thessaloniki, Greece; 8Gas-troenterology Department, University of Patras Medical School, Patra, Greece; 92nd Department of Internal Medicine, Nikaia Hospital, Athens, Greece; 10Internal Medicine Department, University Hospital ATTIKON, Athens, Greece; 11Department of Internal Medicine - Propaedeutic, Laiko University General Hospital, Athens, Greece; 12Physiopathology Department, Laiko General Hospital, Athens, Greece; 13Gastroenterology Department, Papageorgiou General Hospital, Thessaloniki, Greece; 14Department of Biomath-ematics, University of Thessaly School of Medicine, Larissa, Greece; 15The Institute for Clinical Research and Health Policy Studies Tufts Medical Center, Tufts University School of Medicine, Boston, MA; 16Medical Affairs, Roche Hellas, Athens, Greece

Background/Aim: HBsAg quantification has been associated with response to peginterferon in HBeAg-negative CHB. The PERSEAS cohort study aimed to assess predictors of response in HBeAg-negative CHB patients treated with peginterferon-alfa-2a in routine clinical practice. Methods: PERSEAS, a prospective, multicenter, observational study in Greece enrolled 95 predominantly genotype D HBeAg-negative CHB patients who were treated with peginterferon-alfa-2a for 48 weeks. All patients were followed for 48 weeks post-treatment. Serum HBsAg and HBV DNA levels were measured centrally by Abbott Architect and COBAS TaqMan assay, respectively, at 0, 4, 8, 12, 16, 24 and 48 weeks of therapy and at 6 and 12 months post-therapy. Sustained off-therapy response (SR) was defined as HBV DNA <2,000 IU/mL combined with normal ALT at 12 months post-therapy. Results: Mean±SD age at baseline was 42±1 1 years and 75% of the patients were males. Mean baseline HBV DNA and HBsAg levels were 5.4±1.4 log10 IU/ml and 3.5±0.6 log10 IU/ml, respectively. Of the 95 patients, 22 (23%) achieved SR and 9 (9.5%) lost HBsAg. HBsAg decline was more profound in responders than in non-responders. HBsAg decline ≧10% from baseline to week 12 was not significantly associated with SR [OR:2.196 (0.740-6.519), p=0.169]. In contrast, HBsAg decline >10% from baseline to week 24 was found significantly more frequently in patients with than without SR [81% (17/21) vs 37% (21/57); OR:7.286 (2.162-24.552), p=0.001]. The predictability of the PARC rule based on HBsAg and HBV DNA levels at 12 weeks was evaluated in a subset of 47 patients with available data [SR: 13/47 (28%)]. Of them, 60% (28/47) did not have any HBsAg decline and 1 7% (8/47) did not have both any HBsAg decline and decline of HBV DNA >2 log 10. Of the latter 8 patients who fulfilled the PARC stopping rule, none achieved SR [Negative Predictive Value (NPV): 1 00%]. Of the 39 patients who did not fulfill the PARC stopping rule, 24 (62%) had HBsAg decline ≧10% at 24 weeks with 12/24 (50%) achieving SR, while 15 (38%) had HBsAg decline <10% at 24 weeks with only 1/15 (7%) achieved SR (NPV: 93%). Conclusions: In HBeAg-negative, predominantly genotype D, CHB patients treated with peg-interferon-alfa-2a, HBsAg decline >1 0% at 24 weeks is associated with significantly higher probability of SR at 12 months post-therapy. The combination of HBsAg and HBV DNA levels at week 12 with HBsAg decline at week 24 can identify patients with no or a very low chance of SR leading to early discontinuation of an unsuccessful regimen in almost 50% of patients or more importantly in almost 2/3 of patients without SR.

Disclosures:

Ioannis Goulis - Consulting: MSD, Gilead Sciences, Novartis, Janssen-Cilag; Grant/Research Support: BMS, Roche; Speaking and Teaching: BMS, MSD, Gilead Sciences, Novartis, Janssen-Cilag, Roche

Melanie Deutsch - Consulting: MSD

Konstantinos Mimidis - Advisory Committees or Review Panels: ROCHE, MSD, NOVARTIS; Grant/Research Support: GILEAD

Sokratis Koulouris - Employment: Roche Hellas George Bakalos - Employment: Roche Hellas SA

George V. Papatheodoridis - Advisory Committees or Review Panels: Janssen, Abbott, Boehringer, Novartis, BMS, Gilead, Roche; Consulting: Roche; Grant/Research Support: BMS, Gilead, Roche; Speaking and Teaching: Janssen, Novartis, BMS, Gilead, Roche, MSD

The following people have nothing to disclose: Stylianos Karatapanis, Evangelos A. Akriviadis, George N. Dalekos, Maria Raptopoulou-Gigi, Georgios Germani-dis, Christos K. Triantos, Christos Drakoulis, Athina Chounta, Irene Vafiadis, Grig-orios Hatzis, Asterios Gagalis, Jiannis Vlachogiannakos, Elias Zintzaras

1016

Safety of Tenofovir in Renal Transplanted and Hemodialysis Patients with Chronic Hepatitis B

Filiz Akyuz2,1, Suut Gokturk2,1, Bulent Baran2,1, Asli Ormeci2,1, Ozlem Mutluay Soyer2,1, Sami Evirgen2,1, Cetin Karaca2,1, Kadir Demir2,1, Fatih Besisik2,1, Sabahattin Kaymakoglu2,1;

1Gastroen-terology, Istanbul Medical Faculty, Istanbul, Turkey; 2Istanbul University, Istanbul, Turkey

Background and Aim: In this study, we aimed to evaluate the safety and efficacy of TDF in renal transplant recipients and hemodialysis patients with CHB during the long-term follow-up. Material and Methods: CHB patients undergoing hemodialysis (group 1), renal transplanted (group 2) and patients with normal renal function were included in the study. All patients were treated with TDF for at least 6 months. The groups were compared in regards to safety and efficacy. The symptoms which did not exist before treatment and were distinctly related with the start of the drug were recognized to be clinical drug side effects. TDF was initiated at a dosage of 245 mg once a week after dialysis in group 1 and 245 mg/day in group 3. TDF dosage was adjusted according to GFR in group 2. HBV-DNA levels were studied using Cobas-Taqman 96 system. Results: A total of 217 chronic hepatitis B patients (group 1; 8 patients, group 2; 9 patients, group 3; 200 patients) were enrolled in this study. Demographic and clinical features were similar across groups [Mean age (41 ±11 vs 43±6 vs 42±7 years), gender (75% vs 90% vs 70% male), HBeAg situation (75% vs 90% vs 63.5% HBeAg negative) and mean TDF usage periods (21±12 vs20±12 vs26±10 months) p>0.05]. Two patients in group 1 and group 2 (11%), 86 patients in group 3 (41.3%) were treatment-naive (p=0.000). The frequency of clinical side effects (myalgia, nausea, headache, skin rash, insomnia, stomachache, diarrhea) was significantly higher in group 1 and 2 compared to group 3 (37.5% vs. 11.1% vs. 0.5%, respectively p<0.001). However, there were no patients who discontinued the drug because of side effects. Serum creatinine levels were similar at baseline and at the end of the follow-up in Group 1 and 2 (6.5±1.8 mg/dl and 6.9 ±1.5 mg/dl; 1.3±0.2 and 1.4±0.4 mg/dl; respectively, p<0.05). Serum creatinine level changed significantly over the course of treatment from a mean of 0.9±0.2 mg/dl (range, 0.5-1.5) at baseline to 0.9 ± 0.2 mg/dl (range, 0.5-1.7) at the end of follow-up (p=0.001). HBV-DNA negativity rates were comparable at12th month and at the end of the follow-up (50%-83% for group 1, 60%-67% for group 2 and 70%-75% for group 3, respectively, p>0.05). Conclusion: Clinical side effects of TDF are more common in patients with CRF in comparison to patients without CRF. However, the occurrence of side effects does not necessitate discontinuation of the drug. TDF is safe and effective for this group of patients.

Disclosures:

The following people have nothing to disclose: Filiz Akyuz, Suut Gokturk, Bulent Baran, Asli Ormeci, Ozlem Mutluay Soyer, Sami Evirgen, Cetin Karaca, Kadir Demir, Fatih Besisik, Sabahattin Kaymakoglu

1017

Tenofovir disoproxil fumarate has a substantial efficacy against adefovir and multi-drug resistant strains of hepatitis B virus

Bulent Baran1, Ozlem Mutluay Soyer1, Asli Cifcibasi Ormeci1, Suut Gokturk1, Sami Evirgen1, Filiz Akyuz1, Cetin Karaca1, Kadir Demir1, Fatih Besisik1, Derya Onel2, Selim Badur2, Sabahattin Kaymakoglu1;

1Department of Gastroenterohepatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey; 2Department of Microbiology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey

Background/Aim: There is cumulative clinical and published evidence which indicates tenofovir disoproxil fumarate (TDF) has substantial antiviral efficacy against resistant strains of hepatitis B virus (HBV), especially in lamivudine (LAM) resistance. However antiviral efficacy of TDF in adefovir (ADF) and multi-drug resistance has not been completely elucidated yet. Methods: Patients with ADF failure who receive TDF therapy for at least 6 months were included in the study. Biochemical and viro-logical tests were obtained at baseline and 3-month intervals in the first year and every 6 months thereafter. The primary outcome measure for efficacy was complete virological response (CVR), defined as HBVDNA<20 IU/ml. CVR rates were calculated by Kaplan-Meier analysis and a multivariate Cox proportional hazard model was generated in order to find out predictive factors independently associated with time to CVR. Results: 60 patients (45 male, mean age 43±1 3) were included in the study. 24 (40%) patients had HBeAg+ chronic hepatitis B and 20 patients (33%) were cirrhotic. There were 32 patients with suboptimal response to ADF (ADF-S group) and 28 patients were infected by ADF resistant (ADF-R) strains of HBV. 49 patients had previous LAM experience and LAM resistance mutations were detected in 33 patients among them. Multidrug resistance patterns (combination of LAM and ADF resistance) were detected in 16 patients. Mean duration of TDF treatment was 30 (6-51) months. 50 patients (83%) were treated with LAM and TDF combination therapy, while the remaining received TDF monotherapy. The frequency of HBeAg+ patients (50% vs. 31%, p=0.14) and baseline HBVDNA level (median 5.29 vs. 4.58 log 10 IU/ml, p=0.13) were higher in ADF-R group compared to ADF-S group. Cumulative CVR rates in ADF-S and ADF-R groups were 50% vs. 36% at 6th month, 75% vs. 59% at 12th month and 88% vs. 79% at 24th month, respectively (log-rank, p=0.046). According to multivariate Cox regression model baseline HBVDNA level (>2x106 IU/ml) (HR: 0.41, 95% CI 0.18-0.94, p=0.034) and HBeAg positivity (HR: 0.50, 95% CI 0.27-0.94, p=0.032) had significant influence on time to CVR. ADF or multi-drug resistance patterns did not have any significant effect on time to CVR in multivariate analyses. Conclusion: Cumulative CVR rates during the follow-up shows that TDF has a slightly decreased, yet still potent in vivo efficacy against ADF-R strains of HBV whether there is multi-drug resistance or not.

Disclosures:

The following people have nothing to disclose: Bulent Baran, Ozlem Mutluay Soyer, Asli Cifcibasi Ormeci, Suut Gokturk, Sami Evirgen, Filiz Akyuz, Cetin Karaca, Kadir Demir, Fatih Besisik, Derya Onel, Selim Badur, Sabahattin Kay-makoglu

1018

Short Duration of Lamivudine for Prevention of HBV Transmission in Pregnancy: Lack of Potency and Selection of Resistance Mutations

Lilly Yuen1, Anna Ayres1, Kathy Jackson1, Julianne Bayliss1, Sutha-haran Manoharan2, Anne L. Glass2, Michael Maley2, Scott Bow-den1, Fabio Luciani3, Miriam Levy2, Stephen Locarnini1;

1Victorian Infectious Diseases, North Melbourne, VIC, Australia; 2Liverpool Hosptial, Sydney, NSW, Australia; 3University of New South Wales, Sydney, NSW, Australia

BACKGROUND: Antiviral therapy during late pregnancy has been shown to reduce the risk of perinatal hepatitis B virus (HBV) transmission in HBeAg-positive highly viremic pregnant women. AIM: This study sought to assess the antiviral efficacy of lamivudine (LMV) therapy administered during the third trimester to reduce maternal viremia and to identify any emergence of LMV-resistance. Of 26 mothers with high viral load (>107 IU/mL), serum samples from two time points were used to measure HBV-DNA levels and antiviral drug-resistance. Twenty-one women received LMV for an average of 53 days (range 22 - 88 days), and a median HBV-DNA reduction of 2.6-log10 IU/mL was achieved. Although end-of-treatment (EOT) HBV-DNA in four (1 8%) LMV-treated women remained at >107 IU/mL (±0.5 log IU/ml), no mother-to-baby transmission was observed. One baby from the untreated maternal group was HBsAg-positive at 9 months post-partum. Drug resistance testing compared population-based (20% quasispecies sensitivity) to ultra-deep pyrosequencing (UDPS) (< 1 % quasispecies sensitivity). UDPS revealed that LMV therapy resulted in increased viral quasispecies diversity and the positive selection of HBV-variants with reverse transcriptase amino acid substitutions at sites associated with primary LMV resistance (rtM204I/V and rtA1 81T) in four (19%) women. These viral variants were detected mostly at low frequencies (0.63% to 5.92%) at EOT, but one LMV-treated mother had an rtA1 81T-variant that increased from 2.2% pre-therapy to 25.59% at EOT. This mother was also infected with the vaccine-escape variant (sG145R) which was inhibited by LMV treatment. Conclusion: LMV-therapy during late pregnancy only reduced maternal viremia moderately, and drug-resistant viral variants emerged.

Disclosures:

Miriam Levy - Grant/Research Support: Gilead

Stephen Locarnini - Consulting: Gilead, Bristol-Myers Squibb, Merck Sharpe and Dohme; Employment: Melbourne Health

The following people have nothing to disclose: Lilly Yuen, Anna Ayres, Kathy Jackson, Julianne Bayliss, Suthaharan Manoharan, Anne L. Glass, Michael Maley, Scott Bowden, Fabio Luciani

1019

Th1 /2 ratio was associated with anti-viral effects of sequential therapy with lamivudine and interferon-α in HBe antigen-positive chronic hepatitis B patients

Nami Mori1, Masataka Tsuge2, Yoshiiku Kawakami2, Hiroiku Kawakami3, Kazuaki Chayama2;

1gastroenterology, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan; 2gastroenterology and metabolism, Hiroshima University, Hiroshima, Japan; 3gastroenterology, Clinic Kawakami, Hiroshima, Japan

Background and Aims: The effectiveness of interferon-α (IFN-α) to chronic hepatitis B has been demonstrated by many large clinical trials and meta-analyses. However, the effect of IFN-α therapy is unsatisfactory because HBV infection was considered to attenuate IFN responses in HBV-infected hepatocytes. To evaluate the improvement of the effectiveness of IFN therapy by prior treatment with nucleot(s)ide analogues, we measured the biological markers for Th1/2 immune response in patients who underwent the sequential therapy; lamivudine (LMV) alone for 20 weeks followed by the LMV and IFN-α combination for 4 weeks and lastly IFN-α alone for 20 weeks. Then the associations between Th 1 /2 ratio and therapeutic response were evaluated. Patients and Methods: Thirty HBe antigen (HBeAg)-positive chronic hepatitis B patients who underwent sequential therapy were enrolled. Twenty four weeks after the termination of IFN treatment, the effects of the therapy were assessed by ALT normalization, HBeAg negativity, and decrease of HBV-DNA to less than 3.7 LGE/ml. Fulfillment in all three of the criteria was defined as sustained virological response (SVR), and fulfillment in two of them, ALT normalization and HBeAg negativity, as partial response (PR). The number of IFN-γ positive cells and IL-4 positive cells in PBMC was calculated by three-color flow cytometric analysis and Th1/2 ratio (= IFN-γ positive cells / IL-4 positive cells) evaluated at respective commencements of LMV and IFN-α in 20 patients. Results: Rates of SVR and PR were 20 and 50%, respectively. In multivariate analysis, younger age (< 32 yr, p=0.04, OR=13.15) and lower HBV-DNA titer (< 7.9 LGE/ml, p=0.03, OR=17.98) were significantly associated with PR. To analyze the impacts of Th1/2 ratio for PR, Th1/2 ratios at the commencements of LMV and IFN-α were compared between partial and non-partial responders. The ratios were not different between two groups at the commencement of LMV, however the ratio of partial responder increased during LMV treatment and became significantly higher than those of non-responders (p=0.01). Conclusions: The present study indicated that HBV-DNA and age were predictive factors for the effectiveness of sequential therapy and an increase of Th1/2 ratio caused by HBV suppression with LMV might improve the effect of IFN-α in HBeAg-positive chronic hepatitis B patients.

Disclosures:

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: Nami Mori, Masataka Tsuge, Yoshiiku Kawakami, Hiroiku Kawakami

1020

Suboptimal virological response to adefovir rescue therapy was associated with occurrence of hepatocellular carcinoma in patients with lamivudine-resistant chronic hepatitis B

Jihyun Kim1, Sae Hwan Lee1, Jin Nyoung Kim2, Yun Nah Lee3, Soung Won Jeong2, Sang Gyune Kim3, Jae Young Jang2, Young Seok Kim3, Hong Soo Kim1, Boo Sung Kim3;

1Internal Medicine, Soonchunhyang University Cheonan hospital, Cheonan, Republic of Korea;2Internal Medicine, Soonchunhyang University Seoul hospital, Seoul, Republic of Korea; 3Internal Medicine, Soonchunhyang University Bucheon hospital, Bucheon, Republic of Korea

Background/Aim: Suboptimal virological response to adefovir rescue therapy is often experienced in patients with lamivudine (LAM)-resistant chronic hepatitis B. The aim of this study was to investigate association between efficacy of adefovir (ADV) rescue therapy and the occurrence of hepatocellular carcinoma (HCC). Methods: Electronic medical records of 221 patients with LAM-resistant chronic hepatitis B who received ADV more than 1 2 months with or without LAM from 3 referral centers of Soonchunhyang University, Korea were reviewed retrospectively from July 2007 to June 2012. Baseline characteristics, outcomes of antiviral therapy, and occurrence of HCC were investigated during ADV rescue therapy. Virological response was defined as undetectable serum HBV DNA levels (< 20 IU/mL). The risk factors for development of HCC were evaluated with Cox-proportional hazard model. Results: Study subjects were followed for median period of 51 (12-1 01) months. Sixty-nine percent (152/221) of patients were treated with ADV-LAM combination during follow-up periods and 26% (59/221) of the patients were assessed as cirrhosis at beginning of rescue therapy. Seventy-six percent of patients HBeAg positive and baseline HBV DNA levels was 5.95 (1.94-8.98) log 10 IU/mL. Cumulative virological response was 22%, 41% and 55% at 1, 3, and 5 years, respectively. ADV resistant mutations with virological breakthrough were confirmed in 7 patients during rescue therapy. HCC were diagnosed in 1 1 of 221 patients during follow-period and cumulative occurrence of HCC was 1.4%, 3.4%, and 6.5% at 1, 3, and 5 years, respectively. Age (P = 0.048) and underlying cirrhosis (P = 0.002) were associated with the occurrence of HCC, but baseline HBV DNA level (P = 0.567), ADV monotherapy (P = 0.1 16), emerging mutations to ADV (P = 0.338), and cumulative virological response (P = 0.126) were not correlated in univariate analysis. In multivariate analysis, underlying cirrhosis (P = 0.003) and cumulative virological response (P = 0.041) were independent risk factors for occurrence of HCC. Conclusion: Suboptimal response to long-term ADV rescue therapy in patients with lamivudine-resistant chronic hepatitis B is independent predisposing risk factor for the occurrence of HCC.

Disclosures:

The following people have nothing to disclose: Jihyun Kim, Sae Hwan Lee, Jin Nyoung Kim, Yun Nah Lee, Soung Won Jeong, Sang Gyune Kim, Jae Young Jang, Young Seok Kim, Hong Soo Kim, Boo Sung Kim

1021

Hepatitis B core antigen expression in liver predicts HBeAg seroconversion in HBeAg positive chronic hepatitis B with pegylated interferon α-2a therapy

Su LIN, Yue-Yong Zhu, Da-wu Zeng, Jia You, Jing Dong, Jing Chen, Jia-ji Jiang;

liver research center, the first affiliated hospital ofFujian Medical University, FUZHOU, China

Objective To evaluate the predictive role of HBcAg expression in liver for HBeAg seroconversion in HBeAg positive chronic

hepatitis B (CHB)with pegylated interferon α-2a (PEG-IFNα-2a)therapy. Methods Patients diagnosed HBeAg positive chronic hepatitis B(CHB) were given PEG-IFNα-2a (1 80μg/week, subcutaneously) for 48 weeks and follow-up for 24 weeks. Liver expression of HBcAg was immunohistochemi-cally determined before initiation of interferon therapy. Result A total of 54 patients were enrolled in this respectively study, with means age of (26.8±6.6) years and a male/female ratio of 43:1 1. HBcAg stained negatively in 21 (38.9%, HBcAg negative group) and positively in 33(61.1%, HBcAg positive group) patients, with 20(60.6%) located in cytoplasm, 5(15.2%) in nuclear and 8(24.2%) in both. The baseline ALT level, serum HBsAg level, serum HBeAg and HBV DNA level were not significantly different between two groups. In the end of 24-week follow-up, the normalization rate of alanine aminotransferase (ALT) were 47.7 %( 10/21) and 66.7 %( 22/33) in HBcAg negative group and HBcAg positive group, respectively. Virus response(< 3 log 10 copies/ml) rates were in 47.6%(10/21)and 63.6%(21/33). The seroconversion rate of HBeAg were 23.8%(5/21)and 54.5%(1 8/33). Three patients achieved HBsAg loss, including one with HBsAg seroconversion at the end of follow-up (Figure 1). The positive predictive value of HBcAg staining in predicting HBeAg seroconversion was 66.7%, negative predictive value was 52.4%, sensitivity was 68.8% and specificity was 50.0%. Conclusion Pretreat-ment HBcAg expression in liver can predict sustained HBeAg seroconversion in HBeAg positive CHB patients with PEG-IFNα-2a therapy.

image

Disclosures:

The following people have nothing to disclose: Su LIN, Yue-Yong Zhu, Da-wu Zeng, Jia You, Jing Dong, Jing Chen, Jia-ji Jiang

1022

A Clinical Trial on Anti-HBV-DC Vaccine Combined with Lamivudine and Thymosin-α1 in the HBeAg Positive Chronic Hepatitis B Virus Carriers

Bang-Fu Wu1,2, Jiang-Ying Yang2;

1 Gastroenterology and Hepatol-ogy Center, Southern Medical University Renkang Hospital, Dong-guan, China; 2Guangzhou Pubang Bio-Immunological Tech Research Institute, Guangzhou, China

Background/Aims: To observe the clinical efficacy of anti-HBV-DC vaccine, the dendritic cells originating from peripheral blood mononuclear cells(PBMC) sensitized by HBsAg, in combination with lamivudine and thymosin-α1, in HBeAg positive chronic hepatitis B virus(HBV) carriers. Methods: 19 HBeAg positive chronic HBV carriers were recruited in the trial including 15 males and 4 females aged 14-54 years. PBMCs obtained from 50ml of heparinized peripheral blood through density gradient centrifuge and adherence method were proliferated under the induction by GM-CSF and IL-4, and sensitized with the stock of hepatitis B vaccine containing 30μg HBsAg on day 5 and with hepatitis B vaccine commercially available containing 20μg HBsAg on day 6. anti-HBV-DC vaccine was harvested on day 7 and injected, half hypodermically and half intravenously, to the patient once every two weeks for 12 practices applications totally. Lamivudine was taken 1 00mg daily, and thymosin-α1 1.6mg was injected hypodermically twice a week. Quantitative HBVM(TRFIA) and HBVDNA and hepatic functions were evaluated at week 0, 4, 12, and 24. Results: Mean of HBsAg, HBeAg and HBVDNA decreased significantly, while mean of HBeAb increased after therapy of 4, 12 and 24 weeks. At week 4, 12 and 24, HBeAg negative conversion rate were 21.05%(4/1 9), 15.79(3/19) and 15.79%(3/19) respectively, HBeAb positive conversion rate were 10.53%(2/19), 21.05%(4/19) and 15.79%(3/19), HBeAg seroconversion rate were 1 0.53%(2/1 9), 15.79%(3/19) and 15.79%(3/19), HBVDNA negative conversion rate were 21.05%(4/19), 21.05%(4/19), and 36.84%(7/1 9), ALT abnormal increased rate were 5.26%(1/1 9), 1 0.53%(2/1 9) and 15.79%(3/19).The rate of adverse effect was 3.07% observed in re-infusion of anti-HBV-DC vaccine. Conclusions: anti-HBV-DC vaccine in combination with lamivudine and thymosin-α1 can be considered as a safe approach for HBeAg positive chronic HBV carriers, which may effectively inhibit the viral replication, lower HBsAg, HBeAg and HBVDNA, improve the production of HBeAb, and increase the HBeAg seroconversion rate.

Disclosures:

The following people have nothing to disclose: Bang-Fu Wu, Jiang-Ying Yang

1023

Baseline Quantitative Hepatitis B Core antibody is the Strongest Predictor for 2-year HBeAg seroconversion in HBeAg Positive CHB Patients Treatedwith Telbivudine Alone or Combined with Adefovir

Jian Sun1, Quan Yuan2, Qing Xie3, Rong Fan1, Deming Tan4, Qin Ning5, Junqi Niu6, Xuefan Bai7, Liuwei Song2, Shijun Chen8, Jun Cheng9, Yanyan Yu10, Hao Wang11, Min Xu12, Guangfeng Shi13, Mobin Wan14, Xin-Yue Chen15, Hong Tang16, Jifang Sheng17, Xiaoguang Dou18, Junping Shi19, Hong Ren20, Wang Maorong21, Hongfei Zhang22, Zhiliang Gao23, Chengwei Chen24, Hong Ma25, Jidong Jia25, Ningshao Xia2, Jinlin Hou1;

1Nanfang Hospital, Southern Medical University, Guangzhou, China; 2School of Public Health, Xiamen University, Xiamen, China; 3Ruijin Hospital, Shanghai, China; 4Xiangya Hospital, Central South University, Chang-sha, China; 5Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 6No. 1 Hospital affiliated to Jilin University, Changchun, China; 7Tangdu Hospital, Xi'an, China; 8Ji'nan Infectious Diseases Hospital, Ji'nan, China; 9Beijing Ditan Hospital, Beijing, China; 10First Hospital of Peking University, Beijing, China; 11 Peking University People's Hospital, Beijing, China; 128th People's Hospital, Guangzhou, China; 13Huashan Hospital, Fudan University, Shanghai, China; 14Chang-hai Hospital, Shanghai, China; 15Beijing Youan Hospital, Beijing, China; 16West China Hospital, Chengdu, China; 17Zhejiang University 1 st Affiliated Hospital, Hangzhou, China; 18Shengjing Hospital of China Medical University, Shenyang, China; 196th People's Hospital, Hangzhou, China; 20The second Affiliated Hospital, Chongqing Medical University, Chongqing, China; 2181st PLA Hospital, Nanjing, China; 22302nd PLA Hospital, Beijing, China; 23Sun Yat-Sen University 3rd Affiliated Hospital, Guangzhou, China; 2485th PLA Hospital, Shanghai, China; 25Beijing Friendship Hospital, Capital Medical University, Beijing, China

Background and Aims: A pilot study has shown that baseline quantitative hepatitis B core antibody (anti-HBc) level could pre-

dict the treatment response in both interferon-treated and nucleos(t)ide analogues-treated cohorts but with limited sample size. Here, we tried to explore the value of quantitative anti-HBc at baseline in predicting treatment outcome at year 2 in a randomized controlled study (EFFORT study, NCT00962533). Methods: 606 patients with HBV DNA ≧10,000 copies/ml, ALT 2-10xULN and compensated HBeAg-positive CHB were enrolled in the study, receiving telbivudine or combined with adefovir for 104 weeks. Serum quantitative anti-HBc levels were measured by using a newly developed double-sandwich anti-HBc immunoassay validated by the WHO anti-HBc standards from baseline to week 52. A post-hoc multivariate analysis was conducted to investigate predictors for treatment outcome at week 104. Results: 599 patients of ITT population were included in the analysis. The kinetics of quantitative anti-HBc levels from baseline to week 52 showed a steady decline. The regression analysis showed that baseline anti-HBc level was the strongest predictor for better outcomes at week 1 04, including virological response, HBeAg seroconversion and ALT normalization (P <0.001, P <0.001 and P =0.001, respectively); odds ratios for baseline anti-HBc level >4 vs. <4 log10 IU/mL were 4.047, 4.167 and 2.031, respectively. Patients with baseline HBV DNA <9 log1 0 copies/mL and anti-HBc >4 log 10 IU/mL together with early on-treatment response (24-week HBV DNA<300 copies/mL) (N = 1 36) could achieve high rates of virological response (95%) and HBeAg seroconversion (49%). Conclusions: Pre-treatment anti-HBc quantitation is the strongest predictor of 1 04-week treatment outcomes. This bio-marker might represent a new, inexpensive predictor of response to antiviral therapy in chronic hepatitis B patients.

image

Disclosures:

Qin Ning - Advisory Committees or Review Panels: Roche medical (china), BMS, GSK; Consulting: Roche medical (china), BMS, GSK; Grant/Research Support: Roche medical (china), BMS; Speaking and Teaching: BMS, GSK

Jidong Jia - Consulting: BMS, MSD, Novartis, Roche; Speaking and Teaching: GSK

Jinlin 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: Jian Sun, Quan Yuan, Qing Xie, Rong Fan, Deming Tan, Junqi Niu, Xuefan Bai, Liuwei Song, Shijun Chen, Jun Cheng, Yanyan Yu, Hao Wang, Min Xu, Guangfeng Shi, Mobin Wan, Xin-Yue Chen, Hong Tang, Jifang Sheng, Xiaoguang Dou, Junping Shi, Hong Ren, Wang Maorong, Hongfei Zhang, Zhiliang Gao, Chengwei Chen, Hong Ma, Ningshao Xia

1024

Long Term Results of Entecavir versus Tenofovir in Treatment-naive Patients with Chronic Hepatitis B. A Single Center, Daily Practice Data

Cenk E. Meral1, Fulya Gunsar1, Galip ERsoz1, Genco Gencdal1, Imre Altuglu2, Funda Yilmaz3, Deniz Nart3, Zeki Karasu1, Omer Ozutemiz1, Ulus S. Akarca1;

1 Gastroenterology Department, Ege University, Izmir, Turkey; 2Microbiology Department, Ege University, Izmir, Turkey; 3Pathology Department, Ege University, Izmir, Turkey

Entecavir (ETV) and tenofovir (TDF) are potent oral antiviral agents with high genetic barriers to drug resistance for the treatment of chronic hepatitis B (CHB). In this study, we aimed to evaluate and compare the antiviral efficacy, side effects and discontinuation rate of ETV and TDF in patients with treatment-naïve CHB, as there is no comparative study for these agents after one year. Methods: We retrospectively analyzed the data of the naïve patients with CHB or B cirrhosis who were treated with ETV or TDF for at least 6 months. The parameters indicating efficacy and side effects were collected and compared at baseline and during the treatment. Follow-up occurred at months 3, 6, and 12, and then every 6 months. Results: 140 ETV patients (age 50±12.7; M/F:88/52 and 49 TDF patients (age 47±14.4, M/F:30/19) were enrolled. There were 43 (31%) and 10 (20%) cirrhotics and 37 (26%) and 15 (36%) HBeAg(+) patients in ETV and TDF groups, respectively. Baseline HBV DNA levels, stage and grade of liver biopsies and duration of the treatments (median 30 month) were similar in 2 groups. There remained 42 patients in ETV and 13 patients in TDF groups at 42nd month of the treatments. The rate of ALT normalization (F<19, M<30 IU/L) at 6th, 12th, 24th, and 36th months were 61 and 39% (p=0.019), 65 and 44% (p=0.024), 75 and 47% (p=0.006), 75 and 43% (p=0.015) in ETV and TDF groups, respectively. However, the difference was not significant at 42nd month and later. The rate of HBV DNA negativity (<20 IU/ml) was higher at 1 8th and 24th month in ETV patients comparing to TDF-treated patients (86.2 vs. 96.7% at month 24, p=0.036). It was similar at the other time points. The differences in ALT normalization and HBV DNA negativity between the groups showed the same pattern in HBeAg positive and negative patients. Both drugs had similar rates of side effects and serum creatinine course. Conclusions: Although both drugs have similar high potency in long-term, ETV seems to achieve an earlier ALT normalization and HBV DNA negativity comparing to TDF that could be important for particularly the patients with severe disease in CHB.

Disclosures:

Ulus S. Akarca - Advisory Committees or Review Panels: GILEAD, BMS, MSD

The following people have nothing to disclose: Cenk E. Meral, Fulya Gunsar, Galip ERsoz, Genco Gencdal, Imre Altuglu, Funda Yilmaz, Deniz Nart, Zeki Karasu, Omer Ozutemiz

1025

The Efficacy of Adefovir-based Combination Regimens for Chronic Hepatitis B Patients with Entecavir Resistance: A Multicenter Retrospective Study

Hyoung Su Kim1, Hyung Joon Yim2, Myoung KukJang1, Sang Jun Suh2, Yeon Seok Seo2, Sun Young Yim2, Soon Ho Um2, Ji Hoon Kim2, Bo Hyun Kim3, Sang Jong Park3, Sae Hwan Lee4, Sang Gyune Kim4, Young Seok Kim4, Jung Il Lee5, Jin-Woo Lee5, In Hee Kim6, Tae Yeob Kim7, Jin Wook Kim8, Sook-Hyang Jeong8, Young Kul Jung9, Hana Park10, Seong Gyu Hwang10;

1Department of Internal Medicine, Hallym University College of Medicine, Seoul, Republic of Korea; 2Department of Internal Medicine, Korea University Medical College, Seoul, Republic of Korea; 3Department of Internal Medicine, Bundang Jesaeng Hospital, Seongnam, Republic of Korea; 4Department of Internal Medicine, Soon Chun Hyang University College of Medicine, Seoul, Republic of Korea;5 Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea; 6Department of Internal Medicine, Jeonbuk National University Medical College, Jeonju, Republic of Korea; 7Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea; 8Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; 9Department of Internal Medicine, Gachon University School of Medicine, Incheon, Republic of Korea; 10Department of Internal Medicine, CHA Medical College, Seongnam, Republic of Korea

Background/Aims: Little is known about efficacy of rescue therapy for ETV resistance. This study was aimed to evaluate the efficacy of adefovir (ADV)-based combination regimens for CHB patients with ETV resistance. Methods: A total of 48 CHB patients with ETV genotypic resistance and without ADV exposure, who received rescue therapy with ADV-based combination regimens for at least 12 months, were enrolled and analysed in this multicenter retrospective study. Initial virologic response at 3 months (IVR-3) and virologic response (VR) were defined as HBV DNA <3.3 log1 0 IU/mL after 3 months of treatment and HBV DNA was undetectable by PCR assay during the treatment. Results: Thirty five (72.9%) patients were men, and their median age was 46.5 (22-74) years. Twelve patients (25.0%) had liver cirrhosis and 45 patients (93.8%) were HBeAg. All patients but one had a history of exposure to prior nucleoside analogue. Mean HBV DNA levels were 5.50 (±1.24) log1 0 IU/mL, and the median duration of ETV therapy was 24 (13-58) months. ADV+lamivudine (LAM) (n=28) and ADV+ETV (n=20) were used as rescue therapies. VR was observed in 17 patients (35.4%) and HBeAg seroconversion occurred in 6 patients (13.3%). Seven patients (14.6%) were primary non responders. ADV+ETV was superior to ADV+LAM in HBV DNA reduction (HBV DNA levels at baseline, 3, 6 and 12 months; 5.24, 2.65, 2.40 and 2.1 8 vs. 5.69, 3.86, 3.55 and 3.20 log10 IU/mL, P=0.006). In multivariate analysis, baseline HBV DNA levels (<5.2 log 10 IU/mL) and IVR-3 were independent predictive factors for VR. Patients with low baseline HBV DNA and IVR-3 achieved VR in 81.3% (13/16). Conclusions: Although ADV combination therapy showed limited efficacy for CHB patients with ETV resistance, ADV+ETV combination could be considered in patients who have low HBV DNA titer and be continued in the presence of IVR-3.

Disclosures:

Hyung Joon Yim - Grant/Research Support: GSK Korea, Handok Pharm, Gilead Korea; Speaking and Teaching: BMS Korea

The following people have nothing to disclose: Hyoung Su Kim, Myoung Kuk Jang, Sang Jun Suh, Yeon Seok Seo, Sun Young Yim, Soon Ho Um, Ji Hoon Kim, Bo Hyun Kim, Sang Jong Park, Sae Hwan Lee, Sang Gyune Kim, Young Seok Kim, Jung Il Lee, Jin-Woo Lee, In Hee Kim, Tae Yeob Kim, Jin Wook Kim, Sook-Hyang Jeong, Young Kul Jung, Hana Park, Seong Gyu Hwang

1026

HBsAg pre-treatment levels and therapy kinetics -marker of HBV viral control in HBV/HIV co-infected patients treated with tenofovir

Mary Horner1, Matthew J. Bruce1, Kate E. Childs1,2, Chris Taylor2, Deepak Joshi1, Kosh Agarwal1, Ivana Carey1;

1 Institute of Liver Studies, Kings College School of Medicine at King's College Hospital, London, United Kingdom; 2Department of Sexual Helath, King's College Hospital, London, United Kingdom

Complete virololgical suppression of HIV RNA and HBV DNA is the therapeutic goal of nucelos(t)ide analogue containing combination antiretroviral therapy (cART) in co-infected patients. Lamivudine/emtricitabine (3TC/FTC) and tenofovir (TDF) target reverse transcriptase of both viruses. Adding TDF improves viral response with pre-existing HBV 3TC/FTC resistance. Despite full HIV RNA suppression, indicating optimal cART adherence, some patients have a slow HBV viral response. Serological (HBeAg status and HBsAg levels), viro-logical (HBV DNA, mutation profile) and immunological (plasma IP 1 0 levels) markers and their change during therapy may explain differences between HBV viral responders (VR) and slow responders (SR) after add-on/switch to TDF and were investigated in this study. Patients: 46 HIV/HBV co-infected patients (37 males, median age 42y, 67%HBeAg+, 1 3%cir-rhosis) were treated for HIV infection for median 5 years and TDF containing cART for a median 48 months. They were divided into 2 groups according to HBV viral response (HBV DNA<20IU/ml) after 1-year post adding/starting TDF: 23 responders (VR) and 23 slow responders (SR) Methods: HBsAg plasma levels were measured by Abbott ARCHITECT® assay [log10IU/ml], HBV DNA by real-time PCR [log10IU/ml] and IP-1 0 levels by ELISA [pg/ml] at baseline, year (Y) 1, 2, 3, 4 and 5 of therapy. Drug resistance mutations were assessed at TDF baseline using direct sequencing. Results: 19 patients were exposed to 3TC/FTC therapy (7VR vs 12SR,p=0.13) and 10 had YMDD mutation (4VR vs 6SR,p=0.3); 7 achieved HBeAg seroconversion (5VR vs 2SR,p=0.01). Baseline median HBV DNA and HBsAg were significantly higher in SR than VR (HBV DNA: 5.91 vs 4.63,p=0.02; HBsAg: 4.75 vs 3.74,p<0.01), but IP1 0 levels were similar (IP1 0: 200 vs 232,p=0.6). The proportion with HBV DNA>106IU/ml was similar in both groups (9VRvs 10SR). HBV DNA was higher in SR than VR at year 1-3 on therapy and similar at 4-5, but HBV DNA reduction from baseline was similar in both groups at all time-points. HBsAg was higher in SR than VR only at year 1 and from then on was similar between VR and SR. HBsAg decline from baseline was more rapid in SR than VR at all treatment years (Y1 :-0.5 vs.-0.1; Y2:-0.8 vs.-0.1; Y3:-0.9 vs.-0.1; Y4:-1.1 vs-0.1 andY5:-1.17 vs.-0.2,all p<0.05). IP10 was similar in VR and SR at all therapy time-points. Conclusion: HBV/HIV co-infected patients with HIV RNA suppression, but slow HBV virological response after adding TDF have higher baseline HBV DNA and HBsAg, but similar HBV DNA reduction and sharper HBsAg decline. Further studies investigating the relationship between HBsAg and liver cccDNA according to response are needed.

Disclosures:

Kosh Agarwal -Advisory Committees or Review Panels: Gilead, Novartis, Abbott; Grant/Research Support: Roche, MSD; Speaking and Teaching: BMS, Astellas, Janssen

Ivana Carey - Grant/Research Support: Gilead, BMS, Roche; Speaking and Teaching: BMS

The following people have nothing to disclose: Mary Horner, Matthew J. Bruce, Kate E. Childs, Chris Taylor, Deepak Joshi

1027

Comparison of the efficacy and drug resistance of de novo combination of lamivudine and adefovir dipivoxil versus entecavir monotherapy for treatment-naive patients with chronic hepatitis B:a systematic review and meta-analysis

Fen Liu1, Fang Wei1, Xiwei Wang1,2, Huaidong Hu1,2, Peng Hu1,2, Dazhi Zhang1,2, Hong Ren1,2;

1 Department of Infectious Diseases, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China; 2Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing, China

Background: The aim of this study was to evaluate the effectiveness and drug resistant of de novo combination of lamivudine (LAM) and adefovir dipivoxil(ADV) compared to entecavir(ETV) monotherapy for nucleos(t)ide -naive patients with CHB. Methods:Publications on the effectiveness and drug-resistant of LAM plus ADV versus ETV monotherapy for nucleos(t)ide-naive patients with CHB were identified by a search of PubMed, Embase, the Cochrane Library, OVID and CBM until May1 ,201 3.Biochemical response, hepatitis B antigen seroconversion and virological response were extracted and combined to obtain an integrated result. Viral breakthrough, drug-resistance mutants and safety were reviewed. Results: Five eligible studies (328 patients in total) were included in the analysis, of whom 161 were included in the combination of LAM and ADV groups and 1 67 were included in ETV monotherapy groups.There were no statistical differences in virologic response and ALT normalization in either group at 12 and 24 weeks post treatment. LAM plus ADV combi- nation therapy produced more rapid and significant HBV DNA reduction rates at 12 weeks, compared to ETV monotherapy. At the end of 48-week therapy LAM in combination with ADV group was superior to ETV at virologic response( RR = 1.14, 95 %CI (1.03, 1.26), P =0.01 ].While there was no significant difference in the ALT normalization,HBeAg seroconversion. At week 96, LAM+ADV was more effective than ETV at the ALT normalization[ RR = 1. 11, 95 %CI (1.02, 1.21), P =0.01] and HBeAg seroconversion[ RR = 2.00, 95 %CI (1.26, 3.18, P =0.003], but no significant difference was found in the virologic response[ RR = 1. 93, 95 %C I (0.93, 1.38), P =0.23].No virologic breakthrough occured in combination therapy during the period of treatment,Six patients in monotherapy group were found with virologic breakthrough and five cases among were confirmed to be of variants associated with ETV resistance. There was no severe adverse reaction in both groups. Conclusion: De novo combination of LAM and ADV therapy was not superior to the ETV monotherapy in short duration therapies; however, the combination therapy had a great advantage over monotherapy in both biochemical response and HBeAg seroconversion when the therapy duration was prolonged up to 96 weeks. The rate of emergence of viral drug resistance in de novo combination group is less than that in ETV monotherapy. Acknowledgements: This research was supported by the National Natural Science Foundation of China (81171560, 30930082, 81171561, 30972584),the National Science and Technology Major Project of China (2012ZX1002007001, 2011ZX09302005).

Disclosures:

The following people have nothing to disclose: Fen Liu, Fang Wei, Xiwei Wang, Huaidong Hu, Peng Hu, Dazhi Zhang, Hong Ren

1028

Entecavir Plus Tenofovir Combination Therapy in Patients with Multi-drug Resistant Chronic Hepatitis B: A multicenter, Prospective Study - Early Experience

Jun Yong Park1, Chang Wook Kim2, Si Hyun Bae2, Sang Hoon Ahn1;

1 Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 2Department of Internal Medicine, The Catholic University College of Medicine, Seoul, Republic of Korea

Background: It has been one of unsolved issues and unmet needs in chronic hepatitis B (CHB) treatment to manage multi-drug resistant (MDR) hepatitis B virus. The aim of this study was to elucidate the antiviral efficacy and safety of entecavir plus tenofovir combination therapy in patients with MDR CHB. Methods: In this prospective ongoing multicenter study, patients with MDR CHB defined as detectable HBV DNA (> 60 IU/mL) while on any rescue treatment regimen for at least 24 weeks and prior experience of genotypic resistance to both nucleoside analogue(s) and nucleotide analogue are treated with entecavir and tenofovir combination therapy. The primary endpoint is the proportion of patients with HBV DNA < 60 IU/ml at Week 48. We present here the first 12 week interim analysis. Results: 61 patients were enrolled at the time interim analysis and 42 of these reached week 12. At baseline, mean age was 47.4 years, 83% were male, 86% were HBeAg(+), mean HBV DNA was 4.55 (±1.23) log 10IU/ml, and mean ALT was 41.3 IU/ml; 4 patients (9.5%) had documented resistance mutations to lamivudine (LAM) only, 3 (7.1%) to LAM and adefovir (ADF), 14 (33.3%) to ADF, 4 (9.5%) to LAM and entecavir, and 8 (19.0%) to all. By week 4, 9 (21.4%) patients achieved HBV DNA < 60 IU/ml and the mean reductions in HBV DNA was 1.39 ± 0.77 log 10IU/ml. By week 12, 24 (57.1%) patients achieved HBV DNA < 60 IU/ml and the mean reductions in HBV DNA was 2.11 ± 0.77 log 10IU/ml. On-treatment ALT flare was reported in 1 patient during the first 12 week. There was no serious adverse event. Conclusions: In the first 12 week interim analysis in patients with MDR CHB, entecavir plus tenofovir combination therapy early suppressed HBV replication to undetectable HBV DNA levels in the majority (57.1%) of patients.

Disclosures:

Chang Wook Kim - Consulting: Gilead; Grant/Research Support: BMS, Boehringer Ingelheim, Pharmicell; Speaking and Teaching: BMS, GSK, Dae-woong

The following people have nothing to disclose: Jun Yong Park, Si Hyun Bae, Sang Hoon Ahn

1029

Tenofovir (TDF) Monotherapy Rescue Therapy is Comparable to Tenofovir and Entecavir (ETV) Combination Rescue Therapy in ETV Partial Responders

Louis Lu1, Vincent G. Nguyen1,2, Huy N. Trinh2,3, Jiayi Li4, Mindie H. Nguyen1;

1 Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA; 2Pacific Health Foundation, San Jose, CA; 3San Jose Gastroenterology, San Jose, CA; 4Palo Alto Medical Foundation, Mountain View, CA

Background: ETV is one of the most effective antiviral drugs for the treatment of chronic hepatitis B (CHB). Some patients, however, will have suboptimal response to ETV; and there are limited data in how to proceed with alternative treatment. Methods: This is a retrospective cohort study of 51 consecutive adult patients with CHB who, as ETV partial responders (detectable HBV DNA levels >60 IU/mL after ≧12 months of ETV), were switched to either TDF monotherapy or TDF+ETV combination therapy at four U.S. liver/gastroenterology clinics.

Patients were identified via ICD-9 query for CHB and were individually reviewed. Cumulative rates of complete viral suppression (HBV DNA PCR < 60 IU/mL) were analyzed using Kaplan-Meier methods and log-rank test. Results: Of the two rescue therapy groups, 1 0 patients received TDF and 41 patients received TDF+ETV. Patients in the two groups were similar with respect to mean age (46.7 vs. 46.6, p=0.97), sex (males: 60% vs. 63%, p=0.84), body mass index (24.1 vs. 23.4, p=0.46), and prior treatment history (40% vs. 24%, p=0.32). Importantly, both groups had similar HBV DNA levels prior to ETV (6.61 log10IU/mLvs. 7.45 log10 IU/mL, p=0.26) and at the start of rescue therapy (3.00 log 10 IU/mL vs. 3.54 log 10 IU/mL, p=0.09). Kaplan Meier analysis of complete viral suppression rates in Figure 1 (p=0.37) showed no statistically significant difference between the two rescue therapies, and complete viral suppression rates after 12 months of rescue therapy were also similar: 89% with TDF and 83% with TDF+ETV (p=0.66). Conclusion: TDF monotherapy and TDF+ETV combination therapy appeared comparable in achieving complete viral suppression in patients with suboptimal response to ETV. Further studies with more patients receiving TDF are needed. TDF would be more convenient and cost-effective than TDF+ETV in this patient population.

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Disclosures:

Huy N. Trinh - Advisory Committees or Review Panels: BMS, Gilead; Grant/Research Support: BMS, Gilead; Speaking and Teaching: BMS, Gilead, vertex; Stock Shareholder: Gilead

Mindie H. Nguyen - Consulting: Gilead Sciences, Inc., Bristol-Myers Squibb, Bayer AG; Grant/Research Support: Gilead Sciences, Inc., Bristol-Myers Squibb, Novartis Pharmaceuticals, Roche Pharma AG

The following people have nothing to disclose: Louis Lu, Vincent G. Nguyen, Jiayi Li

1030

Effectiveness and safety of entecavir and tenofovir in chronic hepatitis b patients: A multicenter Turkish study in clinical practice

Ramazan Idilman1, Fulya Gunsar2, Onur Keskin1, Cenk E. Meral2, Mehmet Koruk3, Murat T. Gulsen3, Atilla Halil Elhan4, A Mithat Bozdayi1, Ulus S. Akarca2, Cihan Yurdaydin1;

1Gastroenterology, Ankara University School of Medicine, Ankara, Turkey; 2Gastroenterology, Ege University, Izmir, Turkey; 3Gastroenterology, Gaziantep University, Gaziantep, Turkey; 4Biostatistics, Ankara University, Ankara, Turkey

Background and Aims: The aims of the study were to determine 2-year effectiveness and safety of potent antiviral agents, entecavir (ETV) and tenofovir disoproxil fumarate (TDF) in real life. Methods: A total of 51 1 patients with chronic hepatitis B (CHB) (M/F: 353/158) were enrolled into study from 3 tertiary centers. The diagnosis of CHB infection was made on the basis of biochemical, serological and histological data, when available. Seventy and six percent of the patients were nucleos(t)ide naïve. Virological response was defined as undetectable serum HBV DNA level (<200 copy/ml) by COBAS Taqman (Roche Diagnostics, Mannheim, Germany). Safety issue was analyzed based on renal function. Results: Median age was 47.0 years. At baseline, 32% of the patients were HBeAg positive, 38% had cirrhosis, 201 patients were treated with ETV and 310 were treated with TDF based on the discretion of investigators. There were no significant differences in terms of the baseline characteristics observed between two treatment groups except initial higher serum AST (p=0.001), GGT (p=0.007) and HBV DNA levels (p=0.001) in ETV treatment group. Overall virological response rates in ETV and TDF treatment groups were 60% vs 58% (p>0.05), 81% vs 70% (p=0.017), 84% vs 77% (p>0.05) and 86% vs 84% (p>0.05) at 24, 48, 72 and 96 weeks, respectively. In NUC-naïve group, response rates were 59% vs 59% (p>0.05), 81% vs 72% (p=0.042), 84% vs 78% (p>0.05) and 86% vs 85% (p>0.05) at 24, 48, 72 and 96 weeks, respectively. With logistic regression analysis, after adjusted age and gender, ETV treatment (p=0.039, OR: 1.72) and HBeAg negativity (p=<0.001, OR: 3.69) were predictive factors for undetectable HBV DNA at week 48. Primary non response (< 1 log 1 0 decrease) at week 24 was observed in 2% (2 ETV, 7 TDF) and partial virological response at week 48 in 25% of the patients (19% ETV vs 29% TDF, p=0.011). HBeAg loss was achieved in 23 of HBeAg positive patients. The cumulative probability of HBeAg loss was 10.9% and 20.4% at weeks 48 and 96, respectively. HBsAg loss was achieved in 2 patients. Hepatocellular carcinoma developed in 10 cirrhotic patients. Both treatments were well tolerated, no serious adverse event was observed. From baseline to the end of the 96 weeks, no significant difference in terms of the serum crea-tinine levels was observed between two treatment groups (median 0.87 mg/dL vs 0.87 mg/dL in ETV group and 0.82 mg/dL vs 0.84 mg/dL in TDF group (p>0.05). Conclusions: This study confirms that ETV and TDF suppressed HBV viral replication in CHB patients with/without cirrhosis in clinical practice. Both drugs are safe and tolerable in such patients.

Disclosures:

Ulus S. Akarca - Advisory Committees or Review Panels: GILEAD, BMS, MSD

Cihan Yurdaydin - Advisory Committees or Review Panels: Janssen, Roche, Merck, Gilead

The following people have nothing to disclose: Ramazan Idilman, Fulya Gunsar, Onur Keskin, Cenk E. Meral, Mehmet Koruk, Murat T. Gulsen, Atilla Halil Elhan, A Mithat Bozdayi

1031

Identification of New Amino Acid Changes in Drug Resistance Sites in Hepatitis B Virus (HBV) Genotype H

David A. Fernandez-Galindo1, Juan F. Sanchez-Avila2, Pedro Gómez-Quiróz3, Héctor R. Pérez-Gómez5,3, Jaime Andrade-Vil-lanueva5,3, Miguel A. Jimenez Luevano3, Arturo Rodríguez-Toledo4, Miriam R. Bueno-Topete1, Juan Armendáriz-Borunda1, Laura V. Sánchez-Orozco1;

1Biología Molecular y Genómica, Universidad de Guadalajara, Guadalajara, Mexico; 2Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, Mexico; 3OPD Hospital Civil de Guadalajara, Guadalajara, Mexico; 4Hospital General de Occidente, Guadalajara, Mexico; 5Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico

Background and aim: Approved HBV therapies include immune modulators and nucleos(t)ide analogues (NA). The ultimate therapeutic goal when treating chronic HBV infection is to prevent

development of liver cirrhosis or hepatocellular carcinoma by producing sustained suppression of HBV replication or eliminating it. Drug resistance has been associated with the emergence of polymerase gene mutations that are localized within the reverse transcriptase (RT) domain. Current evidence indicates that drug-related mutation does occur naturally and can be found in naïve-treated HBV carriers. Aim: To determine the presence of mutations in the RT domain of viral polymerase in Mexican patients with HBV infection. Material and methods: We analyzed DNA-HBV positive blood samples from patients with chronic hepatitis B from the center and western Mexico. RT region of viral polymerase was amplified using PCR, the amplified products were directly sequenced by terminal labeling technique and the amino acid sequence was deduced from the nucleotide sequence. Results: Samples from 1 7 patients were sequenced. Eleven mono-infected patients were carriers of HBV genotype H. Meanwhile, six patients co-infected with HIV were infected with HBV genotype H (67%) and G (33%). Drug mutations were present in 4/17 (23.5%) samples. In a patient infected with HBV genotype H treated previously with lamivu-dine (LAM) during two years, rtI169M mutation was identified instead of rtI169T, which was previously reported as primary resistance site to entecavir (ETV) and secondary resistance site to LAM. In 3 naïve-treatment patients, drug mutations were found: one HIV co-infected patient infected with HBV genotype G was affected by rtM204V and rtL1 80M mutations characteristics of primary and compensatory resistance to LAM. In two patients infected with HBV genotype H, the changes identified were rtQ215E instead of rtQ215S, site that was previously reported as a secondary resistance site to LAM and ADV. Conclusions: New amino acid changes were identified in the HBV genotype H in sites of antiviral resistance in naïve-treated and previously treated patients; also, classical mutations of LAM resistance were identified in a naïve-treated patient infected with HBV genotype G. In vitro studies are needed to examine the effect of these mutations in order to elucidate their influence in antiviral resistance. Drug mutations are present in naïve-treated patients placing them in a risk group for empirical treatment failure.

Disclosures:

The following people have nothing to disclose: David A. Fernandez-Galindo, Juan F. Sanchez-Avila, Pedro Gómez-Quiróz, Héctor R. Pérez-Gómez, Jaime Andrade-Villanueva, Miguel A. Jimenez Luevano, Arturo Rodríguez-Toledo, Miriam R. Bueno-Topete, Juan Armendáriz-Borunda, Laura V. Sánchez-Orozco

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