HBV treatment


31

96 weeks of pegylated-Interferon-alpha-2a plus tenofovir or placebo for the treatment of hepatitis delta: the HIDIT-2 study

Heiner Wedemeyer1,14, Cihan Yurdaydin2, Stefanie Ernst3, Florin A. Caruntu4, Manuela G. Curescu5, Kendal Yalcin6, Ulus S. Akarca7, Selim Gurel8, Stefan Zeuzem9, Andreas Erhardt10, Stefan Luth11, George V. Papatheodoridis12, Onur Keskin2, Kerstin Port1, Mustafa K. Celen6, Judith Stift13, Benjamin Heidrich14, 1, Ingmar Mederacke14, Svenja Hardtke14, 1, Armin Koch3, Hans P Dienes13,14; Michael P. Manns1,14

1Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 2Medical Faculty, gastroenterology, Ankara University, Ankara, Turkey; 3Biometry, Hannover Medical School, Hannover, Germany; 4Infectious disease, Matei Bals Infectious Diseases Institute, Bucharest, Romania; 5Clinic of Infectious Diseases, University of Medicine and Pharmacy Timisoara, Timisoara, Romania; 6Gastroenterology, Dicle University School of Medicine, Diyarbakir, Turkey; 7Gastroenterology, Ege University Medical School, Izmir, Turkey; 8Gastroenterology, Uludag University, Bursa, Turkey; 9Department of Internal Medicine I, J. W. Goethe University Hospital, Frankfurt, Germany; 10Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf, Germany; 11Dept. of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 122nd Department of Internal Medicine, Athens University Medical School, Athen, Greece; 13University of Vienna, Vienna, Austria; 14German Liver Foundation, HepNet Study-House, Hannover, Germany

Hepatitis delta is the most severe form of chronic viral hepatitis. 48-72 weeks of pegylated interferon alfa therapy was effective in previous studies in 25-30% of patients. Combination of PEGIFNa with HBV polymerase inhibitors has been suggested to increase HBsAg decline which would be of particular importance in HDV infection. The aim of the investigator-initiated HepNet- International Delta Hepatitis Intervention-Trial (HIDIT)−2 was to investigate the efficacy of 96 weeks of PEG-IFNa-2a therapy plus tenofovir or placebo in patients with hepatitis delta. We report the primary efficacy analysis after 96w of treatment. Methods: 120 HDV-RNA-positive patients were recruited from 14 centers in 4 countries (Turkey n = 50, Germany n = 46, Romania n = 19, Greece n = 5). Patients were randomized to receive either 180 μg PEG-IFNa-2a weekly plus tenofovir disoproxil fumarate (300mg once daily; TDFarm A, n = 59) or 1 80 μg PEG-IFNa-2a weekly plus placebo (PBO arm B; n = 61). Predefined efficacy endpoints were HDV-RNA negativity, HBsAg loss, an HBsAg decline of at least 0.5log IU/ml and ALT normalization. Results: The majority of patients were male 79/120 (%) with an overall mean age of 40 ± 11 years at randomization. patients (45%) had liver cirrhosis. 15 patients (9 TDFarm, PBO arm) discontinued treatment prematurely. Serious adverse events affected a similar number of patients in both arms (TDF 18 vs. PBO14) including one death in each group. Overall, 846 adverse events were documented (440 TDF and 456 PBO). Mean HDV RNA levels declined until week 96 by 2.79 log copies/ml in TDF-treated patients ([2.24; 3.34]; p < 0.001) and by 2.31 log copies/ml in the PBOarm ([1.87; 2.76]; p < 0.001). After 96 weeks HDV RNA was negative in 28 patients (48%) receiving combination therapy and in 20 patients (33%) receiving PEG-IFNa-2a and placebo (ITT analysis). Logistic regression adjusted for country, gender and previous IFN therapy revealed an odds ratio for the treatment effect PBO vs. TDF of 0.54 [0.26; 1.16] (ITT, p = 0.115). HBsAg became negative in 3 patients in the TDFarm and in 5 patients receiving PBO. An HBsAg decline of >0.5 log IU/ml was observed in 19 patients in each arm (32% vs. 31%). ALT levels normalized until week 96 in 28 (48%) and 22 (36%) of TDF-and PBO-treated patients (p = 0.203). Conclusions: This is the largest prospective and randomized treatment trial in hepatitis delta, demonstrating that prolonged administration of PEG-IFNa2a and TDF for 96 weeks is safe in HDV-infected patients. Combination therapy and PEG-IFNa-2a alone showed similar efficacy concerning HDV RNA suppression, HBsAg reduction and ALT normalisation. Patients will be followed for 5 years after the end of therapy.

Disclosures:

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

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

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

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

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

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

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

The following people have nothing to disclose: Stefanie Ernst, Florin A. Caruntu, Manuela G. Curescu, Kendal Yalcin, Andreas Erhardt, Stefan Luth, Onur Keskin, Mustafa K. Celen, Judith Stift, Benjamin Heidrich, Ingmar Mederacke, Svenja Hardtke, Armin Koch, Hans P. Dienes

32

Comparative Effectiveness of Entecavir and Lamivudine on Survival of Patients with Chronic Hepatitis B Virus Infection

Young-Suk Lim1, Nae-Yun Heo2, Seungbong Han3, Jithyun An1, Gi Ae Kim1, Dong Jin Suh1

1Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea; 3Department of Biostatistics and Clinical Epidemiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

Background/Aim: The beneficial effect of oral antiviral drugs in reducing mortality has been demonstrated in patients with chronic hepatitis B virus (HBV) infection and cirrhosis compared with no-treatment control patients. However, it has not been proven whether the current two first-line agents (entecavir and tenofovir), which have greater potency and minimal resistance rates, can further reduce the risk of death compared with earlier generation drugs. Methods: Data of 5374 consecutive patients with chronic HBV infection who commenced their first treatment with lamivudine (n=3374) or entecavir (0.5 mg/day, n = 2000) between 1999 and 2011 were analyzed. All patients had HBsAg and serum HBV DNA (>10[4] copies/mL) detectable for more than 6 months before treatment. Patients were excluded from the study if they met any of the following criteria: younger than 20 or older than 80, treatment with interferon or any other antiviral drugs within 5 years, duration of the treatment for less than 6 months, organ transplantation or death before or within 6 month after starting the treatment, diagnosis of hepatocellular carcinoma before or within 1 year after starting the treatment, or evidence of co-infection with other hepatotrophic virus. Overall transplant-free patient survival was compared with the use of propensity score matching and inverseprobability-weighting adjustment to reduce treatment-selection bias. Results: In the 1824 pairs of matched cohort, the risk of death or liver transplantation was significantly lower in the entecavir group (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.51-0.86) compared with the lamivudine group during median follow-up period of 5 years (inter-quartile range, 3-8 years). In subgroup analysis, the beneficial effect of entecavir in reducing mortality was demonstrated only in patients with cirrhosis at baseline (HR, 0.58; 95% CI, 0.44-0.78), but not in patients without cirrhosis (HR, 1.17; 95% CI, 0.54-2.53). Conclusion: Patients with chronic HBV infection and cirrhosis who start treatment with entecavir were associated with significantly lower risk of death or liver transplantation compared with those who start treatment with lamivudine.

Disclosures:

The following people have nothing to disclose: Young-Suk Lim, Nae-Yun Heo, Seungbong Han, Jihyun An, Gi Ae Kim, Dong Jin Suh

33

TG1050, a viral-vector based immunotherapeutic designed to treat chronic hepatitis B induces immune responses with properties similar to those displayed by HBV resolving patients and has an early antiviral effect in a HBV tolerant model

Perrine Martin1, Clarisse Dubois1, Emilie Jacquier1, Alexei Evlachev1, Houda Boukhebza1, Sarah Dion3,4, Maryline ManciniBourgine3,4, Ophélie Godon3,4, Annie Findeli2, Yasmin Schlesinger2, Renée Brandely2, Jean-Baptiste Marchand2, Thierry Menguy2, Nathalie Silvestre2, Marie-Louise Michel3,4, Genevieve Inchauspe1

1Infectious Diseases, Transgene, Lyon, France; 2Molecular Immunology, Transgene, Strasbourg, France; 3U845, INSERM, Paris, France; 4Virology, Institut Pasteur, Paris, France

Currently used small molecules aiming at treating chronic hepatitis B infection (CHB) rarely achieve cure. They do not recruit the immune system yet a strong inverse correlation is widely described between HBV-specific functional T cells and eradication of viremia in cohort studies. Thus, T cell driven immunotherapies represent an attractive novel treatment approach to CHB offering the likelihood of increasing cure rate. We developed an immunotherapeutic, called TG1050, based on a nonreplicative adenovirus serotype 5 vector encoding a unique fusion protein composed of a truncated Core, a modified Polymerase and HBsAg domains. TG1050 capacities to induce robust, multispecific, polyfunctional and long-lasting T cells were assessed in 3 naϊve mouse models (HLA-A2 mice, BALB/c and C57BL/6J mice) following single or multiple subcutaneous injections. Induced immune responses were evaluated in blood, spleens and livers through IFNg ELISPOT, Intracellular Cytokine Staining, in vivo CTL assays, pentamers and memory markers staining. TG1050 ability to induce functional T cells in spleens and livers and its impact on viral parameters were assessed in a HBV tolerant mouse model based on a AAV (Adenovirus-Associated Virus) expressing the full length HBV genome. In naīve mice, TG1050 induces high levels of T cells targeting Core, Polymerase and HBsAg domains. High frequencies of IFNg and/or TNFa producing T cells and vigorous in vivo cytolytic functions are detected in spleens and/or livers of immunized mice. Induced HBV-specific T cells are detected up to 10 months post-immunization in blood of mice injected once. These cells display an effector memory phenotype (CD44+/CD62L-) and markers of good recall potential (CD27+/CD43-). In the AAV-HBV tolerant mouse model, a single injection of TG1050 induces functional and long-lasting T cells producing IFNg, TNFa and IL2 both detected in spleens and livers in absence of ALT elevation. Interestingly, following a single injection of TG1050, a transient control of HBV viremia and HBsAg level was observed in blood within 2 weeks postimmunisation. Experiments are ongoing to analyse immunological and virological effects of multiple injections of TG1050 as well as longer follow-ups. Overall, TG1050 is a unique targeted immunotherapeutic capable of inducing polyfunctional, multispecific, robust and long-lasting T cells targeting multiple epitopes from three major viral proteins. In a surrogate HBV tolerant model, it was possible to show an impact of TG1050 administration on a key virological parameter i. e. the level of circulating HBsAg. TG1050 has moved to GMP production.

Disclosures:

Marie-Louise Michel - Consulting: Transgene, Wittycell, ITS

The following people have nothing to disclose: Perrine Martin, Clarisse Dubois, Emilie Jacquier, Alexei Evlachev, Houda Boukhebza, Sarah Dion, Maryline Mancini-Bourgine, Ophelie Godon, Annie Findeli, Yasmin Schlesinger, Renee Brandely, Jean-Baptiste Marchand, Thierry Men guy, Nathalie Silvestre, Genevieve Inchauspe

34

Interim analysis of hepatitis B reactivation in patients with prior HBV exposure undergoing rituximab-containing chemotherapy: a prospective study

Wai-Kay Seto1, Thomas Sau Yan Chan1, Yu-Yan Hwang1, Olivia Choi1, Danny Wong1, 2, James Fung 1, 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 receiving rituximab-containing chemotherapy have not been well described. Methods: From October 2011 onwards, we recruited HBsAg-negative, anti-HBc-positive Chinese patients with baseline undetectable serum HBV DNA (<10 IU/mL), diagnosed with hematological malignancies and receiving rituximab-containing chemotherapy. Liver biochemistry, serum HBV DNA (Abbott RealTime HBV), HBsAg and antibody to HBsAg (anti-HBs) (Abbott Laboratories) were prospectively monitored every 4 weeks after the first dose of rituximab 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 210 patients receiving rituximabcontaining chemotherapy, 56 (26.7%) were HBsAg-negative, anti-HBc-positive, of which 54 (42.6% male) patients with undetectable viremia at baseline were recruited. The median age and duration of follow-up were 71.7 (range 38.1-90.2) years and 37.5 (range 4-76) weeks respectively. 44 (81.5%) had baseline detectable anti-HBs (range 1 1-683 mIU/mL). 11 patients (20.4%) had detectable HBV DNA after a median follow-up period of 20 (range 4-36) weeks. The median HBV DNA level at reactivation was 41(range 16-920) IU/mL. 10 patients (90.9%) remained HBsAg-negative at reactivation. There were no cases of reactivation among patients after >1 year of follow-up (n=15). The 1-year cumulative rate of HBV reactivation, calculated using the Kaplan-Meier method, was 27.4%. Reactivation was significantly more common within the first 6 months of rituximab commencement when compared to the period of 6 months to 1 year (19.3% versus 6.2% respectively, p=0.024). Age and baseline anti-HBs levels were not associated with HBV reactivation (p=0.974 and 0.302 respectively). Conclusion: High rate of HBV reactivation was observed in HBsAg-negative, anti-HBc-positive individuals undergoing rituximab-containing chemotherapy within the first year of therapy commencement, with the majority occurring within the first 6 months. 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 NCT01502397)

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, Novartis Pharmaceuticals (HK) Ltd

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, BristolMyers 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

35

Low serum IL-10 and HBsAg concentrations are associated with long-term immune control in persistent HBVinfection

Jerzy Jaroszewicz, Anna Parfieniuk-Kowerda, Magdalena widerska, Magdalena Rogalska-Plonska, Tadeusz W. Lapinski, Robert Flisiak

Department of Infectious Diseases and Hepatology, Medical University of Bialystok, Bialystok, Poland

Introduction. HBeAg(-) chronic hepatitis B (CHB) is a progressive disease characterized by fluctuations of ALT and HBVDNA. Single measurement of HBV-DNA and ALT is not able to distinguish between active disease and low replicative HBsAg carriers (LR). LR-phase is associated with immune control of HBV and favorable outcomes but its immune correlates are unclear. Recently high IL-10 was connected with flares of CHB while its blocking restored functional CD8 responses. The aim of study was to assess the value of single L-10 and HBsAg measurement in predicting of long-term immune control in CHB. Patients and methods. 78 HBeAg(-) CHB patients (41 male, median age of 33) were included in the study. Sixty of them had persistently normal ALT activities, while 18 had elevated ALT and HBVDNA>2000 IU/mL. Serum levels of IL-10 were measured by HS ELISA (R&D Systems), HBsAg by CLIA (Architect, Abbot), and HBV-DNA by PCR (Amplicor, Roche). In 55 patients long-term data was available with median follow-up of 31 months. Results. Serum IL-10 and HBsAg showed highly significant association with phase of disease. The lowest IL-10 levels were observed in low replicative carriers (0.55±0.10), higher in patients with normal ALT but HBV-DNA>2000 IU/mL (0.75±0.12) and highest with elevated ALT activity (1.6±0.32 pg/mL, AN〇VA P=0.0002). Similarly, baseline serum HBsAg was the lowest in LR-patinets (3.38 log10 IU/mL), while higher in both groups of replicative patients (4.11 and 3.38 log10IU/mL). Importantly, serum IL-10 correlated with both baseline ALT activity (r=0.30,P=0.01) and HBV-DNA (r=0.39, P=0.001), while serum HBsAg showed weaker association HBV-DNA (r=0.27, P=0.02) but no with ALT. In the long term follow-up up to 3 years only 10/18 patients remained persistently low replicative (HBV-DNA<2000 IU/mL, normal ALT). Of importance, this group was characterized by lower baseline IL-10 (0.42 vs 0.74 pg/mL, P=0.01) and HBsAg (3.1 vs 4.2 log10 IU/mL, P=0.003) compared to patients with normal ALT but fluctuating HBV-DNA. Conclusions. Low serum IL-10 and HBsAg seem to be associated with long-term immune control of persistent HBV. Single measurement of IL-10 and HBsAg (<1000 IU/mL) may indicate stable low replicative carrier phase. On the other hand patients with high IL-10 (>0.9 pg/mL) and normal ALT will most likely reactivate HBV replication.

Disclosures:

Jerzy Jaroszewicz - Speaking and Teaching: Roche, Gilead, Abbott, MSD, BMS

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

The following people have nothing to disclose: Anna Parfieniuk-Kowerda, Magdalena widerska, Magdalena Rogalska-Plonska, Tadeusz W. Lapinski

36

Nucleoside Analogs Prevent Disease Progression in HBV-Related Acute-on-Chronic Liver Failure: Validation of the TPPM Model

Ke Ma, Junshuai Wang, Meifang Han, Wei Guo, Jiaquan Huang, Daofeng Yang, Xiping Zhao, Jianxin Song, Deying Tian, Junying Qi, Yuancheng Huang, Qin Ning

Institute and Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Background and aims: Hepatitis B related acute-on-chronic liver failure (HBV-ACLF) has a poor prognosis with very high mortality. Experience in nucleoside analogues treated patients with HBV-ACLF is limited. This study aimed to evaluate the efficacy and safety of Entecavir, Lamivudine and Telbivudine in treating patients with HBV-ACLF and to validate TPPM model in these patients. Methods: In this retrospective study, we enrolled 283 patients with HBV-ACLF (100 treated with Entecavir, 98 treated with Lamivudine and 85 treated with Telbivudine). There were no significant differences in baseline clinical and virological characteristics between patients treated with Entecavir, Telbivudine or Lamivudine. Results: There were no significant differences in the 4 and 12-week survival rates of Entecavir, Telbivudine and Lamivudine-treated patients (79.00%, 81.18%, and 86.73%, respectively at 4 weeks and 67.00%, 65.88%, and 73.47%, respectively at 12 weeks). Patients in all three groups achieved an improvement of MELD score. Using the Hosmor and Lemeshow test, the validation of TPPM for HBVACLF demonstrated a good degree of fit with disease prognosis. Based on this unique group of patients, the TPPM with an AUC of 0.787 was superior to MELD which had an AUC of 0.736 in the prediction of 12-weeks mortality. TPPM had an AUC of 0.733 and MELD had an AUC of 0.672 in the prediction of 4-weeks mortality. Using a cutoff of 0.22 for 12-weeks mortality prediction by TPPM, the positive predictive value was 49.66%, with a negative predictive value of 89.55%. Conclusion: Nucleotide analogs including Entecavir, Lamivudine and Telbivudine treatment prevented disease progression and increased the survival of patients with HBV-ACLF. Validation of the established TPPM scoring system in this study confirmed its superior predictive value for HBV-ACLF patients when compared with MELD.

Disclosures:

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: Ke Ma, Junshuai Wang, Meifang Han, Wei Guo, Jiaquan Huang, Daofeng Yang, Xiping Zhao, Jianxin Song, Deying Tian, Junying Qi, Yuancheng Huang

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