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

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

3. 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;346-355

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

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

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

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

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

9. Genotype 3 HCV Can we shorten therapy?

10. Screening Weeks 0 ------------------ 16 ---- 24 ----------------- 40 ----- 48 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 16 132 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

11. ACCELERATE: 24 weeks is more effective than 16 weeks in genotype 2/3 patients Standard analysis SVR (%) n=679n=630 65% 76% 0 20 40 60 80 100 10 30 50 70 90 16 weeks24 weeks PEGASYS 180  g/wk plus COPEGUS 800 mg/day Shiffman M, et al. N Engl J Med 2007; 357: 124

12. 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 ≤400 000 IU/mL400–800 000 IU/mL>800 000 IU/mL 90% 84% 78% 95% 92% 88% SVR (%) 0 20 40 60 80 100 Standard analysis Shiffman M, et al. 57th AASLD 2006; Abstract 340

13. 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?

14. 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

15. 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?

16. 03691215 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

17. Some G3 patients are more equal than others

19. 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)

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

21. 7977 and Genotype 3  Treatment-naïve, non-cirrhotic  Allowed concurrent methadone use PSI-7977+ RBV + Peg-IFN PSI-7977 + RBV PSI-7977 + RBV + Peg-IFN 84Wk 01224 PSI-7977 + RBV SVR12 n=10 Gane EJ, et al. Hepatology 2011;54(Suppl. S1): Abstract 34

22. 7977 and Genotype 3 Proportion of patients with undetectable HCV RNA (%) 1110910111091011109106554

23. 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