1. WHAT FUTURE FOR RIBAVIRIN? Mitchell L Shiffman, MD Chief, Hepatology Section Medical Director, Liver Transplant Program Virginia Commonwealth University Medical Center Richmond, VA

2. ROLE OF RIBAVIRIN IN HCV TREATMENT MECHANISM OF ACTION Guanosine analog Inhibits inosine 5’ monophosphate dehydrogenase Reduces intracellular guanosine stores Reduces RNA replication Modulates immune response by altering cytokine synthesis and cytotoxic T cell response Incorporated into viral RNA leading to extensive mutagenesis

3. TREATMENT OF CHRONIC HCV OPTIMIZING SVR  The ability to achieve SVR is the result of three independent steps: 1. Achieving a virologic response 2. Maintaining the virologic response 3. Not relapsing  Ribavirin plays a role in all 3 of these steps.  Side effects lead to dose reduction and/or discontinuation of treatment in 10-40% of patients.

4. ROLE OF RIBAVIRIN IN HCV TREATMENT ENHANCES VIROLOGIC RESPONSE JG McHutchison et al. N Eng J Med 1998; 339:1485-1492. MW Fried et al. N Eng J Med 2002; 347:975-982. Ribavirin:

5. ROLE OF RIBAVIRIN IN HCV TREATMENT SPECTRUM OF RESPONSES SVR 2-log decline Peginterferon/Ribavirin Limit of detection

6. ROLE OF RIBAVIRIN IN HCV TREATMENT ENHANCES COMPLETE EVR Ribavirin: P Ferrenci et al. J Hepatology 2005; 43:453-471.

7. ROLE OF RIBAVIRIN IN HCV TREATMENT REDUCES RELAPSE JG McHutchison et al. N Eng J Med 1998; 339:1485-1492. MW Fried et al. N Eng J Med 2002; 347:975-982. Ribavirin:

8. TREATMENT OF CHRONIC HCV EXTENDING RIBAVIRIN TREATMENT Interferon alfa x 6 months Response then Relapse Interferon alfa-2b 3 mU TIW Ribavirin 1000-1200 mg/day X 6 months Ribavirin 1000-1200 mg/day X 6 months Stop Treatment ML Shiffman et al. J Infect Dis 2001; 184:405-409. 13/26 15/20

9. ROLE OF RIBAVIRIN IN HCV TREATMENT IMPACT OF RIBAVIRIN DOSE 04824 Weeks PEGIFN-2a 180 mcg/wk + Ribavirin 800 mg/day Peginterferon alfa-2a 180 mcg/wk + Ribavirin 800 mg/day PEGIFN-2a 180 mcg/wk + Ribavirin 1000 –1200 mg/day PEGIFN-2a 180 mcg/wk + Ribavirin 1000-1200 mg/day SJ Hadziyannis et al. Ann Int Med 2004; 140:346-355. 72

10. Ribavirin Dose: ROLE OF RIBAVIRIN IN HCV TREATMENT HIGHER DOSES REDUCE RELAPSE SJ Hadziyannis et al. Ann Int Med 2004; 140:346-355.

11. HIGH DOSE RIBAVIRIN AND EPOETIN STUDY DESIGN 2448 Weeks 0 PEGIFN + Ribavirin ~13.3 mg/kg/d + EPO PEGIFN + Ribavirin ~15.2 mg/kg/d + EPO PEGIFN + Ribavirin ~13.3 mg/kg/d 7212 ML Shiffman et al. Hepatology 2007; 46:371-379.  Prospective randomized trial  Treatment naïve HCV genotype 1  N=50 per group

12. HIGH DOSE RIBAVIRIN AND EPOETIN VIROLOGIC RESPONSE WB-RBV EPO HD-RBV EPO WB-RBV ML Shiffman et al. Hepatology 2007; 46:371-379.

13. TREATMENT OF CHRONIC HCV IMPACT OF STOPPING RIBAVIRIN Continue peginterferon Stop ribavirin 0 48 24 Weeks HCV RNA (-) Continue peginterferon and ribavirin Peginterferon alfa-2a and ribavirin JP Bronowicki et al. Gastroenterology 2006; 131:1040-1048.

14. ROLE OF RIBAVIRIN IN HCV TREATMENT IMPACT OF STOPPING RIBAVIRIN JP Bronowicki et al. Gastroenterology 2006; 131:1040-1048.

15. ROLE OF RIBAVIRIN ON HCV TREATMENT IMPACT OF DOSE REDUCTION Time of dose reduction in relation to when first became HCV RNA negative ML Shiffman et al. AASLD 2008; abstract 1423.

16. PEGIFN+R+Telaprevir TELAPREVIR – PROVE 2 STUDY DESIGN 12 4824 Weeks 0 PEGIFN+R+Telaprevir PEGIFN + Ribavirin PEGIFN+R GM Dusheiko et al. EASL 2008 PEGIFN+Telaprevir

17. TELAPREVIR - PROVE 2 PHASE 2 FINAL RESULTS GM Dusheiko et al. EASL 2008 12 Wks

18. TELAPREVIR - PROVE 3 NON-RESPONDER RETREATMENT JM McHutchison et al. AASLD 2008

19. ROLE OF RIBAVIRIN ON HCV TREATMENT WHAT WILL THE FUTURE BE? PEGIFN + Ribavirin + Protease + Polymerase PEGIFN + Protease + Polymerase or Ribavirin + Protease + Polymerase PEGIFN + Ribavirin (45%) PEGIFN + Ribavirin + Protease (~70%)

20. ROLE OF RIBAVIRIN IN HCV TREATMENT SUMMARY  Ribavirin is an essential component of HCV treatment:  Enhances response  Prevents breakthrough  Reduces relapse  Higher starting doses of ribavirin are associated with lower relapse and higher SVR rates  Stopping ribavirin prematurely is associated with breakthrough and a higher relapse rate.  Reducing the dose of ribavirin has particularly after the patient has become HCV RNA undetectable has minimal impact on SVR.

21. RIBAVIRIN AND HCV TREATMENT WHAT IS THE FUTURE  Replacing ribavirin even with a potent protease inhibitor appear to:  Reduce virologic response  Increases relapse  Additional studies to remove ribavirin from the HCV treatment paradigm will be explored when several protease and/or polymerase inhibitors are available.  It may be more realistic to remove peginterferon as opposed to ribavirin in the future.