History of Alpha Interferon Therapy of Chronic Hepatitis C Paris Hepatitis Conference: 2012

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

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 1 to 3 mu three times weekly for 6 months 46% 48% 3 MU 28% 2 MU 1 MU 10% 8% Control Placebo n = 51 n = 166 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 20th century

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

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

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

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 29% 24% 13% 6% n = 231 n = 225 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 NEJM 1998 Lancet 1998 43% 38% 35% 31% IFN & Rbv 12 mo IFN & Rbv 12 mo IFN & Rbv 6 mo IFN & Rbv 6 mo 19% 13% IFN 12 mo IFN 12 mo n = 832 n = 912

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

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

24. Lack of Progress in Therapy of Hepatitis C2002-2010 2002 2010 55% 55% 1998 42% 34% 1995 1991 16% 6% 12 mo 6 mo 6 mo 12 mo 12 mo 6-12 mo

25. Therapy of Hepatitis CFactors 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% 76% 46% 42% Fried et al 2002 Manns et al 2001 n = 453 n = 511

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

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 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 Genome wide view of p values of SNPs associated with a sustained virological response to peginterferon and ribarivin treatment of chronic hepatitis C 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 Boceprevir NEJM 2011 Telaprevir NEJM 2011 75% 68% 67% 69% T12 wk Peg & Rbv Boc Peg & Rbv T8 wk Peg & Rbv Boc Peg & Rbv [TG] 44% 40% Peg & Rbv 12 mo Peg & Rbv 12 mo n = 1088 n = 938

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

37. Drug New Therapy for a Chronic Liver Disease 199 140 60 59 27 22 26 24 Histology Score Pre: 6 / 0 96 wks: 2 / 0

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