1. History of Alpha Interferon Therapy of Chronic Hepatitis C Paris Hepatitis Conference: 2012 Jay H. Hoofnagle, M.D. Director, Liver Disease Research Branch National Institutes of Health Bethesda, Maryland, USA

2. Hepatitis C 1980s A disease with no name: non-A, non-B hepatitis Virus was unknown and no serological markers Diagnosis based on serum ALT levels, liver biopsy and compatible history (risk factors) Despite this, trials of therapy were done Corticosteroids: 1980-82: harmful (ISVHLD 1983) Acyclovir: 1982-84: no effect (J Med Virol 1985) Recombinant interferon alfa developed and evaluated as cancer chemotherapy Paris: January 2012

3. Rationale for Alpha Interferon Therapy of Chronic Hepatitis C Broad spectrum of antiviral activity Activity in vitro against almost all viruses, both DNA and RNA Activity in humans against both HBV and HDV 4 month course induced remissions in disease in 30-40% of patients with chronic hepatitis B Side effects, effective dose and duration of therapy reasonably established in hepatitis B

4. Pilot Trial of interferon alfa-2b in Chronic Non-A, Non-B Hepatitis IRB approved protocol to treat 10 patients: 1982 Well defined non-A, non-B hepatitis with Clear risk factors for infection ALT levels persistently > 200 U/L Liver biopsy showing chronic hepatitis Planned Regimen: 5 MU daily for 4 months End points: Change in ALT levels, liver histology Sought industry sponsorship from 3 companies receiving approval from Schering-Plough: 1984

5. Time After Starting Therapy Interferon 5 → 1 MU/day Normal Interferon alfa for Chronic Non-A, Non-B Hepatitis Months Interferon 5 MU/d HAI/Fibrosis Pre = 10/1 Yr 1 = 3/0

6. Interferon for Hepatitis C First use of interferon alfa in chronic non-A, non-B hepatitis: 1984-86 Ten patients with clear epidemiological evidence for non-A, non-B hepatitis All had stable and persistent elevations in serum ALT for 6 months or more ALT levels fell to normal in 8 and remained normal after therapy in 5.

7. Two Randomized Controlled Trials of Alpha Interferon for Chronic Non-A, Non-B Hepatitis 48% n = 166 n = 51 46% 28% 10% 8% 3 MU 1 MU 2 MU PlaceboControl 1 to 3 mu three times weekly for 6 months New England Journal of Medicine 1989

8. Hepatitis C Virus Discovered! 1989 Identification of a small viral RNA sequence in serum of chimpanzee with experimental non-A, non-B hepatitis (Houghton et al 1989) Allowed for development of tests for anti-HCV Rapidly introduced into blood donor screening Allowed for accurate diagnosis Led to elucidation of the structure of HCV Tests for viral RNA in serum (PCR) A landmark medical advance of 20 th century

9. HCV RNA Time After Starting Therapy Interferon-α ++----- Normal Interferon alfa for Chronic Non-A, Non-B Hepatitis Months - Interferon-α HAI/Fibrosis Pre = 10/1 Yr 1 = 3/0 Genotype 1a - Shindo et al 1991

10. Interferon-alfa 2b Approved for use in the United States: 1991 Based upon results of two registration trials in the United States: 3 parts to response Biochemical: normalization ALT Histological: improvement in HAI Virological: loss of HCV RNA Sustained (for how long and in how many?)

11. Interferon Therapy of Chronic Hepatitis C: Long-term Outcome In long-term follow up, most patients with a sustained virological response demonstrate resolution of disease and gradual improvement in liver histology Underlying liver disease does not progress Fibrosis resolves in a proportion of patients HCC can occur, but is rare “Cure” of the infection and chronic liver disease

12. 1985, Pre: HAI = 11 1996, Post: HAI = 3

13. 1985, Pre: Fibrosis = 3+1996, Post: Fibrosis = 0

14. HCV RNA Time After Starting Therapy Interferon ++----- Normal Interferon alfa for Chronic Non-A, Non-B Hepatitis MonthsYears - Interferon HAI/Fibrosis Pre = 10/1 Yr 1 = 3/0 Yr 10 = 3/0 Genotype 1a --

15. Long Term Outcome after SVR  Of the first 103 patients who achieved an SVR at the Clinical Center, NIH:  All except three remained HCV RNA negative  No patient died of end-stage liver disease  One patient (with cirrhosis) developed HCC  Patients had no symptoms/signs of liver disease  Laboratory results improved: [baseline vs last]  ALT: 152 vs 27 U/L  AST: 86 vs 24 U/L  Platelets: 208,000 vs 239,000 /μL  APRI: 1.31 vs 0.33 Koh et al: 2010

16. Life Table of Relapse At 7.2 years, the relapse free rate was 96% 103 81 44 9 7 3

17. Outcomes of Therapy of Hepatitis C Sustained Virological Response (SVR) Absence of HCV RNA from serum 24 weeks after stopping therapy End-of-Treatment Virological Response with Relapse (Relapse) Virological Non-Response (NR) NIH Consensus Conference: 1997

18. Speakers: NIH Consensus Conference on Hepatitis C: 1997

19. Sustained Virological Response Rates Induced by Alpha Interferon Alone (3 MU thrice weekly) Were Quite Poor 24% 6% 13% n = 231n = 225 29% McHutchison et al 1998

20. Ribavirin for Chronic Hepatitis C: Rationale A broad spectrum antiviral agent with activity against flaviviruses (RSV, Hantavirus) HCV was found to be a flavivirus Pilot studies of monotherapy were initiated Improved ALT levels in ~50% Had little effect on HCV RNA levels Possibility that the combination of ribavirin and interferon might be beneficial

21. Ribavirin Markedly Increases the Response Rate to Alpha Interferon in Chronic Hepatitis C 43% n = 912 n = 832 38% 31% 13% 35% IFN & Rbv 12 mo IFN 12 mo IFN & Rbv 12 mo IFN 12 mo NEJM 1998Lancet 1998 19% IFN & Rbv 6 mo IFN & Rbv 6 mo

22. Peginterferon Further Increases the Response Rate in Chronic Hepatitis C 54% n = 1121n = 1530 56% 44% 13% 47% Peg & Rbv 12 mo IFN & Rbv 12 mo Peg & Rbv 12 mo IFN & Rbv 12 mo NEJM 2002Lancet 2001 alfa-2aalfa-2b

23. 16% 55% 6% Progress in Therapy of Hepatitis C: 1991-2002 34% 42% 6 mo 12 mo 6 mo12 mo 1991 1995 1998 2002

24. 16% 55% 6% Lack of Progress in Therapy of Hepatitis C 2002-2010 34% 42% 6 mo 12 mo 6 mo12 mo 1991 1995 1998 2002 55% 2010 6-12 mo

25. Therapy of Hepatitis C Factors that Correlate with Non-Response Genotype 1 vs 2 and 3 African-American vs Caucasian race Higher Initial levels of HCV RNA Higher degrees of fibrosis Older age Other significant co-morbidities

26. Chronic Hepatitis C: Sustained Response Rates by Genotype 82% 46% 42% n = 453n = 511 76% Manns et al 2001 Fried et al 2002

27. Chronic Hepatitis C: Sustained Response Rates by Race Response Rate n = 196 205 40% 70% Virahep-C: Conjeevaram 2006 Genotype 1 only

28. HCV Advance of the Year: 2009 “Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance” Nature 2009; 461: 399-401. David Goldstein and 12 colaborators. GWAS on more than 1600 recipients of peginterferon/ ribavirin therapy of chronic hepatitis C, genotype 1. Polymorphism on chromosome 19 [rs12979860] was associated with SVR in all patient groups. Variants: C/C, C/T, T/T: Resides 3 kb upstream of IL28B gene [interferon λ-3] Ge et al: Nature 2009

29. IL28b Genome wide view of p values of SNPs associated with a sustained virological response to peginterferon and ribarivin treatment of chronic hepatitis C 1 2 3 4 5 6 7 8 9 10 11 12 13 14 16 18 20 X 15 17 19 21 Y -30 -15 0 Ge et al Nature 2009

30. SVR rates by rs12979860 genotype Response Rate Ge Nature: 2009 Thomas Nature : 2009 C allele: 68%C allele: 36%

31. What is IL28B? Interferon λ-3 Type III Interferons, discovered in 2003 Unclear significance Separate receptor on cells Has similar activity and induces similar genes as interferon α and β Slower, somewhat weaker but more prolonged effect What is its relationship to hepatitis C?

32. IL28 in Response to HCV Infection Thomas et al: Gastroenterology 2012, in press

33. HCV Advance of the Year: 2010 Development and licensure of first Direct Acting Agents (DAAs) with proven activity against hepatitis C HCV NS3/4 Protease Inhibitors  Boceprevir  Telaprevir Promise of other DAAs with activivity against other HCV specific targets HCV Polymerase inhibitors HCV NS5A inhibitors

34. Two HCV Protease Inhibitors Efficacy in Chronic Hepatitis C, genotype 1 75% n = 938 n = 1088 68%67% 40% 69% 44% T12 wk Peg & Rbv T8 wk Peg & Rbv Peg & Rbv 12 mo Boc Peg & Rbv Boc Peg & Rbv [TG] Peg & Rbv 12 mo Boceprevir NEJM 2011 Telaprevir NEJM 2011

35. 2012 and A Vision of the Future The combination of two Direct Acting Agents with peginterferon and ribavirin for 24 weeks In 10 patients with genotype 1 who had failed to respond to peginterferon and ribavirin alone 100% SVR rate The two DAAs alone yielded a 36% SVR rate in 9 similar patients with genotype 1 Demonstration of success of an interferon-free regimen Lok et al: NEJM 2012; 366: 216-24

36. 16% 55% 6% Progress in Therapy of Hepatitis C 42% 6 mo12 mo6-12 mo 3-6 mo 1991 1995 1998 2002 2011 2014 ? 6-12 mo 75% >95%

37. New Therapy for a Chronic Liver Disease Drug Histology Score Pre: 6 / 0 96 wks: 2 / 0 199 22 60 2426 59 27 140

38. Vitamin E for NASH: PIVENS Vitamin E (800 IU/day) Patient 6098 NAS Score Pre: 6 / 0 96 wks: 2 / 0 199 22 60 24 [3 wk] 26 59 27 140 1 kg weight loss Sanyal et al NEJM 2010

39. Lessons from the History of Interferon Therapy of Hepatitis C? Clinical observation in a small number of patients can lead to important advances The interplay between basic and clinical research ensures and speeds such advances Ultimately, most liver diseases will be treatable Some will be preventable Some curable Paris: January 2012

40. Liver Diseases Branch, NIH: 2011