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WHAT FUTURE FOR RIBAVIRIN?

WHAT FUTURE FOR RIBAVIRIN?. Mitchell L Shiffman, MD Chief, Hepatology Section Medical Director, Liver Transplant Program Virginia Commonwealth University Medical Center Richmond, VA. ROLE OF RIBAVIRIN IN HCV TREATMENT MECHANISM OF ACTION. Guanosine analog

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WHAT FUTURE FOR RIBAVIRIN?

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  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 TREATMENTMECHANISM 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 HCVOPTIMIZING SVR • The ability to achieve SVR is the result of three • independent steps: • 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 TREATMENTENHANCES VIROLOGIC RESPONSE Ribavirin: JG McHutchison et al. N Eng J Med 1998; 339:1485-1492. MW Fried et al. N Eng J Med 2002; 347:975-982.

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

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

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

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

  9. PEGIFN-2a 180 mcg/wk + Ribavirin 1000-1200 mg/day PEGIFN-2a 180 mcg/wk + Ribavirin 800 mg/day PEGIFN-2a 180 mcg/wk + Ribavirin 1000 –1200 mg/day Peginterferon alfa-2a 180 mcg/wk + Ribavirin 800 mg/day ROLE OF RIBAVIRIN IN HCV TREATMENTIMPACT OF RIBAVIRIN DOSE 72 0 24 48 Weeks SJ Hadziyannis et al. Ann Int Med 2004; 140:346-355.

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

  11. PEGIFN + Ribavirin ~13.3 mg/kg/d PEGIFN + Ribavirin ~13.3 mg/kg/d + EPO PEGIFN + Ribavirin ~15.2 mg/kg/d + EPO 0 12 24 48 72 Weeks HIGH DOSE RIBAVIRIN AND EPOETINSTUDY DESIGN • Prospective randomized trial • Treatment naïve HCV genotype 1 • N=50 per group ML Shiffman et al. Hepatology 2007; 46:371-379.

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

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

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

  15. ROLE OF RIBAVIRIN ON HCV TREATMENTIMPACT 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. TELAPREVIR – PROVE 2STUDY DESIGN PEGIFN+Telaprevir PEGIFN+R+Telaprevir PEGIFN+R+Telaprevir PEGIFN+R PEGIFN + Ribavirin 24 48 0 12 Weeks GM Dusheiko et al. EASL 2008

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

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

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

  20. ROLE OF RIBAVIRIN IN HCV TREATMENTSUMMARY • 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 TREATMENTWHAT 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.

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