Journée scientifique de l'arl Yverdon, 24 mars 2011 Darius Moradpour Service de Gastroentérologie et d'hépatologie Centre Hospitalier Universitaire Vaudois Université de Lausanne Significance of Hepatitis C 120-180 million chronically infected individuals worldwide 1% of the population in Northern Europe Most common cause of chronic, liver cirrhosis and HCC in the West Most common indication to liver transplantation Evolving treatment options Peak of disease burden expected ~2020 The Bad News... Chronic C is frequent, and the peak of disease burden is yet to be reached The Good News... Chronic C can be cured, even without IFN-α The Evolving Burden of Hepatitis C Prevalence Infections per 100,000 140 120 100 80 60 40 20 0 2.0% 1.5% 1.0% 0.5% Incidence Overall prevalence 0.0% 1960 1970 1980 1990 2000 2010 2020 2030 Infected > 20 years Adapted from Armstrong GL et al. Hepatology 2000;31:777-728. Chronic Hepatitis C Can be Cured n = 344 patients with SVR 1 median f/u 3.3 years SVR durable in 100% n = 1343 patients with SVR 2 mean f/u 3.9 years SVR durable in > 99% Davis GL et al. Gastroenterology 2010;138:513-521. 1 Maylin S et al. Gastroenterology 2008;135:821-829. 2 Swain MG et al. Gastroenterology 2010;139:1593-1601. 1
Natural History of Hepatitis C Acute Chronic Cirrhosis HCC EASL ILC. Berlin, March 30-April 3, 2011 Gut 2011, in press. 50-80% 2-20% 1-6% / yr Based on NIH Consensus Statement. Hepatology 2002;36 (Suppl 1):S2-S20, AASLD Practice Guideline. Hepatology 2009;49:1335-1374, and EASL Clinical Practice Guideline. J Hepatol 2011, in press. Cofactors of Disease Progression Acute Chronic Co-infections Alcohol Cirrhosis NAFLD HCC Smoking Gender Immunosuppression Age 50-80% 2-20% 1-6% / yr Chronic Hepatitis C Role of Liver Biopsy Grading Staging Recognition or exclusion of cofactors Molecular profiling Reviewed in Missiha SB et al. Gastroenterology 2008;134:1699-1714. Bihl F et al. Rev Med Suisse 2010;6:174-179. Chronic Hepatitis C Current Standard Therapy Chronic Hepatitis C Response-Guided Therapy Genotype 1 PEG-IFN-α 1 + RBV 1000-1200 2 mg/d for 48 wks Early virological response (EVR): 2 log drop of viremia at week 12 Genotypes 2 and 3 PEG-IFN-α 1 + RBV 800 2 mg/d for 24 wks 1 PEG-IFN-α2a 180 µg/wk PEG-IFN-α2b 1.5 µg/kg/wk 2 800-1200 mg/d in combination with PEG-IFN-α2b Marcellin P et al. J Hepatol 2007;47:580-587. 2
Monitoring of Antiviral Therapy in CHC Rapid virological response (RVR) HCV RNA negative at wk 4 Early virological response (EVR) HCV RNA negative at wk 12 Delayed virological response (DVR) > 2 log drop at wk 12 and negative at wk 24 Null response (NR) < 2 log drop at wk 12 Partial response (PR) > 2 log drop at wk 12 but detectable at wk 24 Breakthrough (BT) Reapparance of HCV RNA after virol. response EASL Clinical Practice Guideline. J Hepatol 2011, in press. Monitoring of Antiviral Therapy in CHC Based on EASL Clinical Practice Guideline. J Hepatol 2011, in press. wk 4 HCV Genotype 1 Response-Guided Therapy neg pos wk 12 baseline < 6 x 10 5 IU/ml baseline 6 x 10 5 IU/ml < 2 log drop stop neg 48 wks > 2 log drop wk 24 pos neg 24 wks 48 wks stop 72 wks IL28B EASL Clinical Practice Guideline. J Hepatol 2011, in press. Genetic Polymorphisms Near IL28B Determine Response to PEG-IFN-α and RBV Ge D et al. Nature 2009;461:399-401. Suppiah V et al. Nat Genet 2009;41:1100-1104. Tanaka Y et al. Nat Genet 2009;41:1105-1109. Rauch A et al. Gastroenterology 2010;138:1338-1345. Ge D et al. Nature 2009;461:399-401. 3
Type I and Type III IFNs Use a Similar Intracellular Signaling Pathway Chronic Hepatitis C Therapy 2011 Broad distribution Epithelial expression 50% cured by current therapy 50% resistant to current therapy Response-guided therapy New antiviral strategies O'Brien TR. Nat Genet 2009;41:1048-1050. Hepatitis C Virus Life Cycle Description of non-a, non-b Delineation of HCV genome organization and polyprotein processing First infectious clone of HCV constructed Replicon system established Production of recombinant infectious HCV in tissue culture 2009 Identification of HCV First three-dimensional structure of an HCV protein (NS3-4A serine protease) Interferon-α and ribavirin combination therapy Proof-of-concept clinical studies of an HCV protease inhibitor IL28B genetic polymorphisms determine treatment outcome Adapted from Moradpour D et al. Nat Rev Microbiol 2007;5:453-463. Moradpour D, Penin F and Rice CM. Nat Rev Microbiol 2007;5:453-463. Novel Antiviral Strategies Membrane Association of HCV Proteins Entry inhibitors RNA interference Antisense strategies Antagomirs IRES inhibitors Structural Nonstructural Immunotherapy Antifibrotic therapy Vaccines Protease inhibitors Helicase inhibitors Polymerase inhibitors NS5A inhibitors Assembly module Replication module Assembly inhibitors Host factors Moradpour D et al. In: Zakim and Boyer's HEPATOLOGY. 6 th ed. In press. 4
Nonstructural Protein 3-4A: The Swiss Army Knife of Hepatitis C Virus The HCV NS3-4A Complex Morikawa K et al. J Viral Hepat 2011, in press. Yao N et al. Structure 1999;7:1353-1363. Sensing of Viral RNA Membrane Association of the NS3-4A Complex TLR3 NS3 5'-ppp RIG-I TBK1 TRIF IKKε MAVS IRF-3 IFN-β Brass V et al. Proc Natl Acad Sci USA 2008;105:14545-14550. 5'-ppp IKKε IRF-3 Huh-7.5 Replicon Replicon Hepatitis C FL C RIG-I TBK1 Control TLR3 TRIF MAVS Cleavage in Patients with Hepatitis C Huh-7.5 Disruption of Innate Immune Responses by NS3-4A MAVS = Cardif = VISA = IPS-1 β-act MAVS IFN-β HCV NS3-4A Li K et al. PNAS 2005;102:2992. Meylan E et al. Nature 2005;437:1167. Bellecave P, Sarasin-Filipowicz M et al. Hepatology 2010;51:1127-1136. Pantxika Bellecave 5
NS3-4A Protease Inhibitors NS3-4A Protease Inhibitors Median HCV RNA (Log10 IU/mL) Macrocyclic Placebo VX-950 450 mg q8h VX-950 750 mg q8h 6 5 4 3 Linear VX-950 1250 mg q12h 7 Mean 4.4 log decline 4/8 HCV RNA <30 IU/ml 2 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study time (in days) Structures courtesy of Steve W. Ludmerer Reesink HW et al. Gastroenterology 2006;131:997-1002. NS3-4A Protease Inhibitors Sarrazin C et al. Gastroenterology 2007;132:1767-1777. Telaprevir Phase II Trials PROVE-2 PROVE-3 n = 323 tx-naïve n = 453 tx-experienced Hézode C et al. N Engl J Med 2009;360:1839-1850. McHutchison JG et al. N Engl J Med 2010;362:1292-1303. Hézode C et al. N Engl J Med 2009;360:1839-1850. HCV Nonstructural Protein 5A Penin F et al. J Biol Chem 2004:279:40835-40843. Penin F et al. J TL BioletChem 2004:279:40835-40843. Tellinghuisen al. Nature 2005;435:374-379. Moradpour D et 2005;42:732-735. Tellinghuisen TLal. ethepatology al. Nature 2005;435:374-379. 6
HCV Host Factor Interaction Network Cyclophilin A PI4KIIIα DGAT1... Gao M et al. Nature 2010;465:96-100. Li Q et al. Proc Natl Acad Sci USA 2009;106:16410-16415. Cyclophilin binding Cyclophilin Inhibitors CsA Alisporivir (Debio 025) Antiviral Effect of Alisporivir HCV RNA (log10 cp/ml) 8 7 6 5 4 3 2 1 Treatment (n=3) (n=16) Alisporivir Placebo Calcineurin binding Paeshuyse J et al. Hepatology 2006;43:761-770. Inoue K et al. Hepatology 2007;45:921-928. - 2 8 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 T i m e ( D a y s ) Flisiak R et al. Hepatology 2008;47:817-826. Flisiak R et al. Hepatology 2009;49:1460-1468. Combinations Mericitabine BMS650032 GS9190 Caspase inh. BI201127 GS9256 Danoprevir BMS790052 Albuferon Taribavirin BI201335 HCV Pipeline Preclinical Phase I Phase II Phase III Filed Telaprevir Boceprevir Vaniprevir GS9256 Danoprevir TMC435 NS3-4A Protease Inhibitors MK5172 BI201335 BMS650032 ABT450 ACH1625 BMS824393 Features of HCV DAA Efficacy Genotype independence Barrier to resistance NS3-4A PI +++ + + - ++ NS5A inhibitors +++ ++ ++ Nitazoxanide PEG-IFN-λ Alisporivir BMS790052 NS5B polymerase NI + - ++ +++ +++ Others Mericitabine BI201127 Filibuvir PSI7977 GS9190 AZ07259 NS5A Inhibitors NS5B polymerase NNI + - ++ + + NS5B Polymerase Inhibitors 7
Combination Therapy Telaprevir Phase III Trials ADVANCE REALIZE Ribavirin PEG-IFN-α PI N(N)I or NS5A-I n = 1088 tx-naïve (21% F3/F4) n = 662 tx-experienced Inspired by Stefan Zeuzem Jacobson IM et al. AASLD 2010 - Hepatology 2010;52 Suppl:427A. Zeuzem S et al. EASL 2011 - J Hepatol 2011;54 Suppl, in press. Boceprevir Phase II and III Trials SPRINT-1 n = 520 tx-naïve Cohort 1 (non-black) SPRINT-2 Cohort 2 (black) n = 938 + 159 tx-naïve (10% F3/F4) Kwo P et al. Lancet 2010;376:705-716. Poordad F et al. AASLD 2010 - Hepatology 2010;52 Suppl:107A. Key Points Consider the natural history of C Correct treatment indication crucial ("Treat the disease, not the infection!") Triple therapy will become standard for patients with genotype 1 in 2011/2012 TVR and BOC increase SVR rates to 75% with shortened treatment duration in ~½ Advances will come at the expense of new adverse effects and increased cost Key Points Antiviral therapy will become much more complex (patient selection, adherence, treatment milestones, adverse effect management, resistance issues,...) Acute Management of Hepatitis C Chronic Cirrhosis HCC IL28B genotyping and subtyping for genotype 1 likely to become clinical practice No data in patients with high unmet need (coinfections, decompensated cirrhosis, post-olt recurrence,...) Prevention Antiviral therapy LT HCC surveillance Cofactors 8