Hepatitis C Genotype 3 Paris 2012 Graham R Foster Professor of Hepatology Queen Marys School of Medicine Barts and The London

Hepatitis C – Genotype 3 Classically ‘easy to treat’ Common in Indian Sub-continent Increasing prevalence in Europe

Treating HCV overall Genotype non 1 – 40 KD PEG IFNα2a + Ribavirin SVR (%) 24 weeks48 weeks 78% 73% 77% n=106n=162n=111n=165 PEG IFN RBV 800 PEG IFN RBV 1000/1200 PEG IFN RBV 800 PEG IFN RBV 1000/1200 Hadziyannis et al Ann Intern Med 2004:140;

Hepatitis C – Genotype 3 Are these non-genotype 1 studies representative of real world response rates?

Genotype 3 HCV Response to Peg+Riba Shoeb et al E J Gastro Hep 2011

Genotype 3 Audit of 639 patients treated with Peg+Riba Shoeb et al E J Gastro Hep 2011

Genotype 3 Audit of 639 patients treated with Peg+Riba Shoeb et al E J Gastro Hep 2011

Genotype 3 and cirrhosis Relapse is the commonest mode of treatment failure

Genotype 3 HCV Can we shorten therapy?

Screening Weeks PEGASYS 180  g/week plus COPEGUS 800 mg/day Follow-up PEGASYS 180  g/week plus COPEGUS 800 mg/day Follow-up Treatment duration blinded until week centers; n=1469 Shortening treatment duration in genotype 2/3 patients: ACCELERATE Randomization to 16 or 24 weeks’ treatment Shiffman M, et al. N Engl J Med 2007; 357: 124

ACCELERATE: 24 weeks is more effective than 16 weeks in genotype 2/3 patients Standard analysis SVR (%) n=679n=630 65% 76% weeks24 weeks PEGASYS 180  g/wk plus COPEGUS 800 mg/day Shiffman M, et al. N Engl J Med 2007; 357: 124

Very high SVR rates with shorter duration in G2/3 patients with an RVR and LVL 16 weeks PEGASYS plus COPEGUS 24 weeks PEGASYS plus COPEGUS n=123n=101 n=295n=260 n=49n=43 ≤ IU/mL400– IU/mL> IU/mL 90% 84% 78% 95% 92% 88% SVR (%) Standard analysis Shiffman M, et al. 57th AASLD 2006; Abstract 340

Optimizing outcomes in genotype 3 Most patients need 24 weeks A few patients may only need 16 weeks People with cirrhosis respond poorly, should we extend therapy in such patients?

STEPS Randomised controlled trial comparing 24 to 48 weeks therapy in patients with Genotype 3 HCV and advanced fibrosis Fully recruited (140 patients) Results expected EASL 2013

Genotype 3 HCV What about the future? New drugs are transforming therapy for chronic HCV Cirrhotics with G3 who have failed to respond to Peg + Riba are queuing up for therapy What can we offer them?

Telaprevir in Genotype 3 Mean HCV RNA decline from baseline Mean (SE) change in log10 HCV RNA 0 –1 –2 –3 –4 –5 –6 Time (days) –0.5 T mono (n=8) –4.5 PR (n=9) –4.7 T/PR (n=9) Foster et al Gastro 2011

Some G3 patients are more equal than others

Genotype 3 HCV What about the future? Current protease inhibitors will not work for most patients with G3 Other drug classes may be more useful (NS5A, Cyclophilin, nucleosides)

Alisporivir + PegIFN may cure patients after 4 weeks Four similar patients presented at AASLD (Heathcote et al)

7977 and Genotype 3  Treatment-naïve, non-cirrhotic  Allowed concurrent methadone use PSI RBV + Peg-IFN PSI RBV PSI RBV + Peg-IFN 84Wk PSI RBV SVR12 n=10 Gane EJ, et al. Hepatology 2011;54(Suppl. S1): Abstract 34

7977 and Genotype 3 Proportion of patients with undetectable HCV RNA (%)

Hepatitis C – Genotype 3 Easy to treat – provided your patient is young with no fibrosis Tough to treat if your patient has cirrhosis Optimal duration of therapy remains controversial New drugs are desperately needed