1. Overview: Treatment of HCV Infection Jürgen Rockstroh Department of Medicine I, University of Bonn, Germany ICVH Baltimore 20114/22/2011

2. Discovery of Hepatitis C 4/22/2011ICVH Baltimore 2011

3. Treatment of HCV Epidemiology Natural history Staging of liver disease and indications for therapy Predictors of treatment success Treatment recommendations Shift in treatment paradigms ICVH Baltimore 20114/22/2011

4. Source: WHO 2002 4/22/2011ICVH Baltimore 2011 Estimated 180 Million individuals infected with HCV worldwide www.who.int/immunization/topics/hepatitis_c/en/.

5. Worldwide Distribution of HCV Genotypes Zein N. Clin Microbiol Rev. 2000;13:223-235. Reproduced with permission. http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999. http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999 1a 1b 2 3 4 5 6 7-8-9 Others

6. Natural History of HCV Liver Disease ~55-85% 25-30 yrs 2 - 4% / yr Liver failure (2 – 5% / yr)

7. Virus Viral load? HCV genotype? Environment Alcohol or drugs HBV co-infection HIV co-infection Steatosis Iron NASH Factors That May Influence the Progression of HCV Infection Host Sex Age Race Genetics Immune response Duration of infection Alberti A, et al. J Hepatol. 1999;31(suppl 1):17-24.

8. HIV-HCV Alcohol HBV Haemochromatosis HCV Steatosis BMI>25 2PBC 0.00 0.17 0.33 0.50 0.67 0.83 1.00 020406080 Hazard function 4682 patients Poynard, T. et al., (2003) A comparison of fibrosis progression in chronic liver disease. Journal of Hepatology 38:257-265 Age in years Progression to cirrhosis

9. Utility of the Liver Biopsy and Noninvasive Tests of Fibrosis There are three primary reasons for performing a liver biopsy: 1.it provides helpful information on the current status of the liver injury, 2.it identifies features useful in the decision to embark on therapy, 3.and it may reveal advanced fibrosis or cirrhosis that necessitates surveillance for hepatocellular carcinoma (HCC) and/or screening for varices. 4/22/2011ICVH Baltimore 2011

10. DefinitionNo Fibrosis Fibrous Portal ExpansionFew Bridges or Septa Numerous Bridges or SeptaCirrhosis IASLNo Fibrosis Mild Fibrosis Moderate Fibrosis Severe FibrosisCirrhosis MetavirF0F1F2F3F4 Staging of fibrosis in chronic viral hepatitis Goodman Z et al. J Hepatol 2007;47:598-607

11. Non-invasive tests Painless Frequent sampling possible Accurate at separating mild fibrosis from cirrhosis ?enough degree of separation to show progressive changes Fibrosis stage assessment is more important than which test or technique you use ………..

12. Who to treat ? 4/22/2011ICVH Baltimore 2011 Ghany MG et al. AASLD Practice guidelines; Hepatology 2009

13. Lindsay KL. Hepatology. 2002;36(suppl 1):S114-S120. Goals of HCV Therapy Primary goal of treatment is to eradicate the virus Additional goals Slow disease progression Minimize risk of liver cancer Improve liver damage Enhance quality of life Prevent transmission of virus Reduce extra-hepatic manifestations

14. Chronic Hepatitis C: Improvement by trial and error 0% 20% 40% 60% 80% 19881990199219941996 IFN 24 weeks IFN 48 weeks Sustained virological response Optimization of dose and duration

15. IFN & Ribavirin 48 weeks 0% 20% 40% 60% 80% 19881990199219941996 1998 IFN 24 weeks IFN 48 weeks Sustained virological response One unspecific drug plus another unspecific drug = highly effective therapy O N OH HO HO N N H 2 N O Chronic Hepatitis C: Improvement by trial and error

16. IFN & Ribavirin 48 weeks 0% 20% 40% 60% 80% 19881990199219941996 1998 IFN 24 weeks IFN 48 weeks Sustained virological response >50% cure of chronic Hepatitis C 2001 PEGIFN & Ribavirin PEG-IFN 48 weeks 40kDaPEG- - IFN alfa-2a 12kDaPEG-IFN alfa- - 2b

17. More than 50% of patients with chronic hepatitis C can be cured

18. PegIFN/RBV SVR RVR cEVR Virologic Responses Slow virologic response 0 1 2 3 4 5 6 7 8 EVR 2 log 10 decline Limit of detection Weeks 0412182430364248546066728 78 HCV RNA (log 10 IU/mL)

19. Null response Suboptimal Virologic Responses Relapse Breakthrough PegIFN/RBV Partial response 2 log 10 decline Limit of detection Weeks 0412182430364248546066728 78 HCV RNA (log 10 IU/mL) 0 1 2 3 4 5 6 7 8

20. Treatment start HCV-RNA-level Standard therapy in HCV genotyp 1/4 Week 4 HCV-RNA-determination Week 12 HCV-RNA-determination Treatment discontinuatio n HCV-RNA < 12-15 IU/ml HCV-RNA < 12-15 IU/ml HCV RNA > 2 log or > 3x10 4 IU/ml Initial HCV-RNA * < 6-8x 10 5 IU/ml + 24 weeks of therapy 48 weeks of therapy RVR cEV R * 6x10 5 IU/ml pegIFN 2b 8x10 5 IU/ml pegIFN 2a No shortened duration for F3/F4 Metabolic syndrome No data fror normal transaminases Week 24 HCV-RNA-determination Z Gastroenterol 2010; 48:289–351

21. Treatment start HCV-RNA-level Standard therapy in HCV genotyp 1/4 Week 4 HCV-RNA-determination Week 12 HCV-RNA-determination Week 24 HCV-RNA-determination Treatment discontinuatio n HCV-RNA < 12-15 IU/ml HCV-RNA < 12-15 IU/ml HCV-RNA < 12-15 IU/ml HCV RNA > 2 log or > 3x10 4 IU/ml HCV RNA pos Initial HCV-RNA * < 6-8x 10 5 IU/ml + 24 weeks of therapy 48 weeks of therapy 72 weeks of therapy RVR cEV R Slow Responder * 6x10 5 IU/ml pegIFN 2b 8x10 5 IU/ml pegIFN 2a No shortened duration for F3/F4 Metabolic Syndrom No data for normal transaminases Consensus: 98% Z Gastroenterol 2010; 48:289–351

22. Treatment start HCV-RNA-level Standard therapy in HCV genotyp 2/3 Week 4 HCV-RNA-determination Week 12 HCV-RNA-determination Treatment discontinuatio n HCV-RNA < 12-15 IU/ml HCV-RNA < 12-15 IU/ml HCV-RNA > 12-15 IU/ml HCV RNA* < 2 log Initial HCV-RNA < 8x 10 5 IU/ml + 16 weeks of therapy 24 weeks of therapy 48 weeks of therapy Consensus: 100% No shortened duration for F3/F4 Metabolic Syndrom No data for n ormal transaminases *extended therapy in case of slow response is currently studied Z Gastroenterol 2010; 48:289–351

23. Ge D et al. Nature 2009; 461(7262):399-401

24. IL-28B Polymorphism is the Strongest Baseline Predictor of SVR Using Peginterferon/Ribavirin Covariates - rs12979860 (2-level), ethnicity (4-level), age ( 40), gender, BMI ( 0%]), fibrosis (METAVIR F012), RBV (>13 mg/kg/d) Thompson AJ, et al Gastroenterology 2010 (139) p120-129 P <0.0001 P= 0.004

25. RVR is Stronger than All Baseline Predictors of SVR Using Peginterferon/Ribavirin P <.001 P =.0001 P = 0.0361 P <.001 Comparison of RVR vs no RVR + non-CC genotype Comparison of no-RVR + CC genotype vs no-RVR + non-CC genotype Co-variates : RVR vs no RVR + CC genotype vs no RVR + non-CC genotype (3-level), ethnicity (4-level), age ( 40), gender, BMI ( 0%]), fibrosis (METAVIR F012), RBV (>13 mg/kg/d) Thompson AJ, et al Gastroenterology 2010 (139) p120-129

26. First DAAs under review FDA Panel to Review Merck, Vertex Hepatitis Drugs in Late April NEW YORK - A U.S. Food and Drug Administration panel will review two hepatitis C drugs in development from Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. Inc. (MRK) in late April, as the companies race to compete against each other in a potentially lucrative market. The agency's Antiviral Drugs Advisory Committee will review boceprevir on April 27 and telaprevir on April 28. The widely expected reviews will have outside experts recommend whether the agency should allow the drugs on the market. Both drugs have shown success in increasing the cure rates of the liver disease when added to current treatments. They are expected to come to the market at similar times and be widely used, creating a market share battle. Merck said in early January that it was granted a six-month review; Vertex is getting a similar review and expects a decision by May 23. Both the Merck and Vertex drugs are known as protease inhibitors, which are designed to block an enzyme that helps the hepatitis C virus replicate. Standard treatment is a combination of the drug pegylated interferon and ribavirin, but adding the new drugs may improve cure rates and shorten the duration of treatment. ICVH Baltimore 20114/22/2011

27. TW 8-24 HCV-RNA Undetectable TW 8-24 HCV-RNA Detectable PR + PlaceboFollow-up BOC RGT (N=368) PR + Boceprevir PR lead-in BOC/ PR48 (N=366) PR + BoceprevirFollow-up PR lead-in SPRINT 2: Boceprevir in HCV Mono- infected Patients Week 4Week 48 PR + PlaceboFollow-up PR lead-in Week 28Week 72 Control 48 P/R (N=363) Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.

28. p < 0.0001 Non-Black Patients p = 0.044 p =0.004 Black Patients SVR SPRINT-2: Sustained Virologic Response and Relapse Rates (ITT) Relapse Rate Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.

29. SPRINT-2: Safety Profile Over Entire Course of Therapy Sulkowski M, et al. 18th CROI; Boston, MA; February 27-March 2, 2011. Abst. 115.

30. ADVANCE: Telaprevir in Combination with PegIFN/RBV in Genotype 1 HCV Treatment-Naïve Patients 2404872 Weeks 12836 Follow-up PR48 SVR Pbo + PRPR T12PR TVR + PR Follow-up SVR eRVR- PR eRVR + Follow-up SVR PR Follow-up SVR TVR + PR T8PR eRVR- PR Pbo + PR Follow-up SVR eRVR + PR 72 weeks assessme nt Follow-up Jacobson IM, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 211. Jacobson IM, et al. AASLD 2010: Abstract 211.

31. ADVANCE: Overall SVR rates Jacobson IM, et al. 61st AASLD; Boston, MA; October 29-November 2, 2010; Abst. 211. 75% 69% 44% Percent of Patients with SVR 0 10 20 30 40 50 60 70 80 90 100 T12P R T8P R PR T12PR and T8PR vs. PR: P<0.0001 Jacobson IM, et al. AASLD 2010: Abstract 211.

32. Tolerability Discontinuation rates higher in PI arms Telaprevir o Pruritus, nausea, rash, anemia, and diarrhea o Severe rash in 3-6% (1% PEG/RBV) o 5-7% stop TVR; 1% stop treatment o Hgb <10g/dl: 35-45% vs. 14% [ESA use not allowed] 4/22/2011ICVH Baltimore 2011

33. Remaining challenges Unclear how to use in special patient populations with highest risk of disease progression Need for defining stopping rules to prevent resistance emergence High compliance requirement Drug-drug interactions In whom to start and in whom to wait 4/22/2011ICVH Baltimore 2011

34. 4/22/2011ICVH Baltimore 2011 Thank you !!!!