Transcript TREATMENT OF CHRONIC HCV PEGINTERFERON STUDIES
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 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
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.
ROLE OF RIBAVIRIN IN HCV TREATMENT
ENHANCES VIROLOGIC RESPONSE
100 80 60 40 20 0 24 50 59 69 Standard IFN PEGIFN 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: No Yes
ROLE OF RIBAVIRIN IN HCV TREATMENT
SPECTRUM OF RESPONSES
5 4 3 2 8 7 6 1 0 -6 0 Peginterferon/Ribavirin 2-log decline Limit of detection SVR 6 12 18 24 30 36 42 48 54 60 66 72 78 WEEKS
ROLE OF RIBAVIRIN IN HCV TREATMENT
ENHANCES COMPLETE EVR
50 40 38 30 20 18 18 17 10 11 10 0 4 12 24 Week First Became HCV RNA (-) P Ferrenci et al.
J Hepatology 2005; 43:453-471.
Ribavirin: No Yes
ROLE OF RIBAVIRIN IN HCV TREATMENT
REDUCES RELAPSE
80 60 40 20 0 45 22 51 19 Standard IFN PEGIFN 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: No Yes
TREATMENT OF CHRONIC HCV
EXTENDING RIBAVIRIN TREATMENT
Interferon alfa x 6 months Response then Relapse 100 80 15/20 Interferon alfa-2b 3 mU TIW Ribavirin 1000-1200 mg/day X 6 months 60 40 Stop Treatment Ribavirin 1000-1200 mg/day X 6 months ML Shiffman et al.
J Infect Dis 2001; 184:405-409.
20 0 13/26 Continue Stop Ribavirin
ROLE OF RIBAVIRIN IN HCV TREATMENT
IMPACT OF RIBAVIRIN DOSE
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 0 SJ Hadziyannis et al.
Ann Int Med 2004; 140:346-355.
24 Weeks 48 72
ROLE OF RIBAVIRIN IN HCV TREATMENT
HIGHER DOSES REDUCE RELAPSE
100 80 60 40 20 0 60 69 EOT SJ Hadziyannis et al.
Ann Int Med 2004; 140:346-355.
41 52 SVR 32 25 Relapse Ribavirin Dose: 800 1000/1200
HIGH DOSE RIBAVIRIN AND EPOETIN
STUDY DESIGN
0 Prospective randomized trial Treatment naïve HCV genotype 1 N=50 per group PEGIFN + Ribavirin ~13.3 mg/kg/d PEGIFN + Ribavirin ~13.3 mg/kg/d + EPO PEGIFN + Ribavirin ~15.2 mg/kg/d + EPO 12 24 Weeks 48 ML Shiffman et al.
Hepatology 2007; 46:371-379.
72
HIGH DOSE RIBAVIRIN AND EPOETIN
VIROLOGIC RESPONSE
80 60 40 20 34 36 0 PEGIFN WB-RBV ML Shiffman et al.
Hepatology 2007; 46:371-379.
22 40 PEGIFN WB-RBV EPO 49 8 PEGIFN HD-RBV EPO SVR Relapse
TREATMENT OF CHRONIC HCV
IMPACT OF STOPPING RIBAVIRIN
HCV RNA (-) Continue peginterferon Stop ribavirin Peginterferon alfa-2a and ribavirin Continue peginterferon and ribavirin 0 24 Weeks JP Bronowicki et al.
Gastroenterology 2006; 131:1040-1048.
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ROLE OF RIBAVIRIN IN HCV TREATMENT
IMPACT OF STOPPING RIBAVIRIN
50 40 30 20 10 0 Continue RBV Stop RBV 2 5 2 6 3 12 14 32 0 0 24 30 36 48 WEEKS 52 JP Bronowicki et al.
Gastroenterology 2006; 131:1040-1048.
26 60 42 29 72 42
ROLE OF RIBAVIRIN ON HCV TREATMENT
IMPACT OF DOSE REDUCTION
25 20 21 15 11 10 9 6 5 -2 0 4 12 24 Week First Became HCV RNA (-) ML Shiffman et al.
AASLD 2008; abstract 1423.
7 Time of dose reduction in relation to when first became HCV RNA negative Before After
TELAPREVIR – PROVE 2
STUDY DESIGN
0 PEGIFN+Telaprevir PEGIFN+R+Telaprevir PEGIFN+R+Telaprevir PEGIFN+R PEGIFN + Ribavirin 12 Weeks 24 GM Dusheiko et al.
EASL 2008 48
TELAPREVIR - PROVE 2
PHASE 2 FINAL RESULTS
100 80 60 40 20 69 62 36 0 PEG+TPV 12 Wks GM Dusheiko et al.
EASL 2008 80 79 52 51 73 68 12 Wks 24 Wks PEGINF+TPV+RVN Week 4 Week 12 SVR
TELAPREVIR - PROVE 3
NON-RESPONDER RETREATMENT
100 80 60 40 20 0 45 24 61 52 Week 4 SVR PEG+TPV PEG+TPV+RVN JM McHutchison et al.
AASLD 2008
ROLE OF RIBAVIRIN ON HCV TREATMENT
WHAT WILL THE FUTURE BE?
PEGIFN + Ribavirin (45%) PEGIFN + Ribavirin + Protease (~70%) PEGIFN + Ribavirin + Protease + Polymerase PEGIFN + Protease + Polymerase or Ribavirin + Protease + Polymerase
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.
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.