Outline. Outline. Natural History of Hepatitis C. Significance of Hepatitis C. Hepatitis C at a crossroads

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1 79 ème Assemblée Annuelle de la SSMI Lausanne, mai 2011 Outline Darius Moradpour Service de Gastroentérologie et d'hépatologie Centre Hospitalier Universitaire Vaudois Université de Lausanne Outline Significance of Hepatitis C million chronically infected individuals worldwide 1% of the population in Switzerland Most common cause of chronic hepatitis, liver cirrhosis and HCC in the West Most common indication to liver transplantation Evolving treatment options Peak of disease burden expected ~2020 Acute hepatitis Natural History of Hepatitis C Chronic hepatitis Cirrhosis 50-80% 2-20% 1-6% / yr HCC Based on NIH Consensus Statement. Hepatology 2002;36 (Suppl 1):S2-S20, AASLD Practice Guideline. Hepatology 2009;49: , and EASL Clinical Practice Guideline. J Hepatol 2011, in press ( 1

2 Cofactors of Disease Progression Acute Chronic hepatitis Co-infections hepatitis Alcohol Cirrhosis NAFLD HCC Smoking Gender Immunosuppression Age 50-80% 2-20% 1-6% / yr Chronic Hepatitis C Current Standard Therapy Genotype 1 PEG-IFN-α 1 + RBV mg/d for 48 wks Stopping rule: < 2 log drop of HCV RNA at week 12 Genotypes 2 and 3 PEG-IFN-α 1 + RBV mg/d for 24 wks Reviewed in Missiha SB et al. Gastroenterology 2008;134: Bihl F et al. Rev Med Suisse 2010;6: PEG-IFN-α2a 180 µg/wk PEG-IFN-α2b 1.5 µg/kg/wk mg/d in combination with PEG-IFN-α2b HCV Genotype 1 Response-Guided Therapy Monitoring of Antiviral Therapy in CHC wk 4 neg pos baseline < 6 x 10 5 IU/ml 24 wks baseline 6 x 10 5 IU/ml 48 wks wk 12 < 2 log drop stop neg 48 wks > 2 log drop pos stop wk 24 neg 72 wks EASL Clinical Practice Guideline. J Hepatol 2011, in press ( EASL Clinical Practice Guideline. J Hepatol 2011, in press ( 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 Partial response (PR) > 2 log drop at wk 12 but detectable at wk 24 Null response (NR) < 2 log drop at wk 12 Breakthrough (BT) Reapparance of HCV RNA after virol. response 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: Suppiah V et al. Nat Genet 2009;41: Tanaka Y et al. Nat Genet 2009;41: Rauch A et al. Gastroenterology 2010;138:

3 Potential Clinical Uses of IL28B Genotyping Patient stratification in clinical trials Recommend early treatment in patients with acute hepatitis C and unfavorable genotype? Treat now vs. await DAAs in CHC gt 1? Retreat with triple therapy vs. await quadruple therapy or IFN-sparing regimens in NR? Treat before or after LT in advanced cirrhosis? Organ allocation in LT? Ge D et al. Nature 2009;461: Abandon liver biopsy in CHC gt 1 with favorable genotype? Chronic Hepatitis C Current Standard Therapy Nonstructural Protein 3-4A: The Swiss Army Knife of Hepatitis C Virus 50% cured by current therapy 50% resistant to current therapy Response-guided therapy New antiviral strategies Morikawa K et al. J Viral Hepat 2011;18: NS3-4A Protease Inhibitors Placebo VX mg q8h VX mg q8h VX mg q12h Median HCV RNA (Log 10 IU/mL) Mean 4.4 log decline 4/8 HCV RNA <30 IU/ml Study time (in days) Reesink HW et al. Gastroenterology 2006;131: Hézode C et al. N Engl J Med 2009;360:

4 Telaprevir Phase III Trials Boceprevir Phase III Trials ADVANCE REALIZE Cohort 1 (non-black) SPRINT-2 Cohort 2 (Black) RESPOND-2 n = 1088 tx-naïve (21% F3/F4) n = 662 tx-experienced Jacobson IM et al. AASLD Hepatology 2010;52 Suppl:427A. Zeuzem S et al. EASL J Hepatol 2011;54 Suppl 1:S3. n = tx-naïve (9% F3/F4) n = 403 tx-experienced (only Rel and PR) Poordad F et al. N Engl J Med 2011;364: Bacon BR et al. N Engl J Med 2011;364: Treatment of CHC in 2012 (gt 1) Telaprevir-based PEG-IFN-α2a 180 µg/wk + RBV mg/d + 12 wks TVR 750 mg q8h + 12 (ervr*) or 36 (no ervr) wks of PR Boceprevir-based PEG-IFN-α2b 1.5 µg/kg/wk + RBV mg/d + 24 wks BOC 800 mg tid + PR + 20 wks PR if no RVR8 4 wks *ervr = extended RVR = neg. HCV RNA at wks 4 and 12 Key Points Consider the natural history of hepatitis 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 70% with shortened treatment duration in ~½ Advances will come at the expense of new adverse effects and increased cost Moradpour D and Hadengue A. Rev Med Suisse 2011, in press. Key Points Antiviral therapy will become much more complex (patient selection, adherence, treatment milestones, adverse effect management, resistance issues,...) IL28B genotyping and subtyping for genotype 1 likely to become No data in patients with high unmet need (coinfections, decompensated cirrhosis, post-olt recurrence,...) Moradpour D and Hadengue A. Rev Med Suisse 2011, in press. Combinations Albuferon Caspase inh. Taribavirin Nitazoxanide PEG-IFN-λ Alisporivir Others Mericitabine BMS GS9190 BI GS9256 Danoprevir BMS HCV Pipeline BI Mericitabine PSI7977 Preclinical Phase I Phase II Phase III Filed BI Filibuvir GS9190 NS5B Polymerase Inhibitors NS3-4A Protease Inhibitors GS9256 Vaniprevir MK5172 Danoprevir ABT450 TMC435 ACH1625 BI Telaprevir Boceprevir BMS BMS AZ07259 BMS NS5A Inhibitors 4

5 Outline The Physician's Dilemma IBS IBD Abdominal pain, bloating, altered bowel habits,... Courtesy of Dr. Alain Schoepfer Fecal Calprotectin Calprotectin is a complex of 2 calcium-binding proteins (S100A8 and A100A9) Produced by neutrophils, monocytes and macrophages Very stable at ambient temperature Can be measured in small stool samples Correlates well with leukocyte scintigraphy Biomarker for colonic inflammation Van Rheenen PF et al. BMJ 2010;341:c3369. Fecal Calprotectin: A Biomarker for Clinical Practice Outline Integrate fecal CP early in diagnostic algorithm > 50 µg/g organic cause likely < 20 µg/g and absence of 'red flags' or any other pathology organic cause unlikely Does not replace CRC screening Does not allow to rule out celiac disease Beglinger C et al. Hausarzt Praxis 2011;5:4-6. 5

6 Chronic Hepatitis B Therapy 2011 PEG-IFN-α Pro: Defined duration Durable response Nucleos(t)ide analogs Pro: Tolerability Expanded use Con: Adverse effects Contraindications Con: Undefined duration Resistance Seitz S et al. EMBO J 2007;26: Zoulim F and Perrillo RP. J Hepatol 2008;48 (Suppl 1):S2-S19. Doerig C et al. Rev Med Suisse 2010;6: Chronic Hepatitis B Therapy 2011 HBV Antiviral Resistance Testing Status CH 05/2011 PEG-IFN-α2a Pegasys licensed 1 st line Lamivudine LAM Zeffix licensed 1 st line Adefovir ADV Hepsera licensed 2 nd line Telbivudine LdT Sebivo licensed 1 st line Entecavir ETV Baraclude licensed 1 st line Tenofovir TDF Viread licensed 1 st line Emtricitabine FTC + TDF = Truvada licensed for HIV To be determined Doerig C et al. Rev Med Suisse 2009;5: Supported by unrestricted grants from Gilead, Roche, MSD and Novartis The HBV 'Antivirogram' LAM LdT ETV ADV TDF Wild-type S S S S S M204I R R I S S L180M+M204V R R I S S A181T/V I S S R S N236T S S S R I L180M+M204V/I ± I169T ± V173L ± M250V R R R S S L180M+M204V/I ± T184G ± S202I/G R R R S S Prevention of Antiviral Resistance in Chronic Hepatitis B Correct treatment indication and compliance are crucial (avoid unnecessary treatment) Avoid resistance by preemptive add-on Consider de novo combination therapy in patients with decompensated cirrhosis and very high baseline viremia Detect resistance early (HBV DNA q 3 mo) Manage resistance adequately EASL Clinical Practice Guideline. J Hepatol 2009;50:

7 Outline Eosinophilic Esophagitis Chronic esophagitis characterized by eosinophilic infiltration ( 15 per HPF) Prevalence 15-45:100'000 Peak age years, : = 4:1 Clinical manifestations: Dysphagia for solids, food impaction, chest pain Recommended treatments: Dietary elimination, topical corticosteroids (fluticasone, budesonide), PPI, endoscopic dilation of strictures Liacouras CA et al. J Allergy Clin Immunol 2011, in press. n = 38 adolescent or adult patients with EoE Topical budesonide 2 x 1 mg/d vs. placebo for 15 d Straumann A et al. Gastroenterology 2010;139: n = 28 patients with EoE in remission Topical budesonide 2 x 0.25 mg/d vs. placebo for 50 wks Straumann A et al. Gastroenterology 2010;139: Straumann A et al. Clin Gastroenterol Hepatol 2011, in press. 7

8 Outline Hepatitis E Virus Cryo-EM of VLP Crystal structure of VLP Guu TSY et al. Proc Natl Acad Sci USA 2009;106: Hepatitis E HEV genotypes: 1 and 2 strictly human, 3 and 4 human and swine, 5 avian Endemic in Asia, the Middle East, North Africa and Central America Travel-related or autochthonous cases (genotype 3) in industrialized countries Chronic hepatitis in immunosuppressed patients Diagnosis: anti-hev; HEV RNA Purcell RH and Emerson SU. J Hepatol 2008;48: Pavio N and Mansuy JM. Curr Opin Infect Dis 2010;23: The Raw Facts about Hepatitis E Colson P et al. J Infect Dis 2010;202: Summary 8