1. Terapia dell’Epatite cronica HCV correlata: Peg-IFN/ribavirina e che altro? L’infettivologia del terzo millennio: non solo AIDS Paestum 18-20 maggio 2006 T. Santantonio Malattie Infettive Università degli Studi di Bari

2. Milestones in Therapy of Chronic Hepatitis C Strader et al Hepatology 2004 6 16 34 42 39 54-56 1986199820012002 IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m PEG 12m PEG/RBV 12m Sustained Virologic Response

3. Sustained Virologica Response according to genotype 42% 82% 46% 76% Manns et al Lancet 2001, Fried et al NEJM 2002 Genotype 1Genotypes 2/3 % SVR

4. Virological determinants of treatment outcome Sustained Virologic Response Difficult to treat Easy to treat HCV-2 HCV-1 High viremia HCV-3 High viremia HCV-4 HCV-1 Low viremia HCV-3 Low viremia 30% 50% 60% 70% 80% 90%

5. Therapy of HCV - 2006 Whom to treat  All patients are potential candidates  Priority should be for: Progressive/advanced disease Highly motivated patients Young patients Easy-to-treat  Exclusions are: Major contraindications Decompensated liver disease

6. Therapy of HCV - 2006 How to treat  HCV-2/3  Peg-IFN/RBV 800-1000 mg x 6 mo  HCV-1/4  Peg-IFN/RBV 1000-1200 mg x 12 mo  Stopping rule for HCV-1 at 12-24 weeks  80/80/80 adherence rule important (particularly for HCV-1)

7. Attempts to optimize therapy Some patients might be OVERTREATED Some patients might be UNDERTREATED  Better Tailoring the Current Therapy  Development of New Therapies DIFFICULT-TO-TREAT SUBGROUPS

8. Genotype 2 & 3 Shorter duration ? increase tolerability lower costs Better Tailoring the Current Therapy

9. SVR in Patients HCV-2/3, 14 vs. 24 Weeks PEG-IFN  -2b 1.5  g/kg QW + ribavirin 800-1,400 mg/day, N=122 Dalgard O. et al. Hepatology 2004;40:1260 –1265. 78% of Patients were PCR Negative at Week 4/8.

10. SVR in HCV-2/3 Patients PCR neg at week 4/8 14 Week Tx. PEG-IFN  -2b 1.5  g/kg QW + ribavirin 800-1,400 mg/day * * p=0.019, G3a LVL vs HVL. Dalgard O. et al. Hepatology 2004;40:1260 –1265.

11. PEG-IFN  2b 1.0  g/Kg/week + RIBA 1000-1200 mg/day STANDARD REGIMEN (70 pts) VARIABLE REGIMEN (213 pts) Week 4 HCV-RNA (Amplicor) neg pos 12 wks 24 wks week 4 neg 89% 87% HCV-2 76% week 4 pos 50% 72% week 4 neg 100% 77% HCV-3 76% week 4 pos 43% 41% 24 wks Mangia et al. NEJM 2005 S V R

12. Relapse Rates *P=0.19, In patients PCR negative at week 4, 12 vs. 24 weeks Tx. Mangia A. N Engl J Med 2005;352:2609-17. Standard durationVariable duration

13. PEG-IFN  2a 180  g + RIBA 800-1200 mg/day (n=153) Week 4 HCV-RNA (Monitor) < 600 IU/mL (n=142) 16 wks (71)24 wks (71) > 600 IU/mL (n=11) randomized HCV-2All 95% 95% HVL 93% 93% 1/1100% LVL100%100% HCV-3All 76% 75% HVL 54% 67% 3/9 33% LVL 93% 84% 24 wks S V R Von Wagner et al, Gastroenterology 2005

14. - 20% - 10% - 7%- 5% - 12%- 9% (12 vs 24 wks)(16 vs 24 wks) AE requiring dose reduction Withdrawal Mangia 2005 (PEG-IFN  2b) Von Wagner 2005 (PEG-IFN  2a) Overall Safety / Tolerability

15. ACCELERATE: study design PEG-IFN  -2a 180  g/wk plus RBV 800 mg/day Follow-up Study week 032168244048 n=1469 PEG-IFN  -2a 180  g/wk plus RBV 800 mg/day Follow-up Randomisation. Treatment duration blinded until week 16 Shiffman M, et al. 41st EASL 2006; Abstract 734 732 731

16. THE ACCELERATE TRIAL MAIN CONCLUSIONS PEG-IFN Alfa-2a plus 800 mg Ribavirin 24 wks better than 16 wks for HCV-2 and HCV-3 due to higher relapse rates with shorter therapy Shiffman et al EASL 2006

17. New Schedule of Treatment for Rapid Responders HCV-2 Week 4 – HCV-RNA NegPos Treat for 12-16 wksTreat for 24 wks Solid with full WBD ribavirin Same for HCV-3 ? Same for advanced disease ?

18. Genotype 1 & Rapid Virologic Response Shorter duration ? increase tolerability lower costs Better Tailoring the Current Therapy

19. Virologic Response Rates in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks PEG-IFN  -2b 1.5  g/kg QW + ribavirin 800-1400 mg/day 1.Zeuzem et al, J Hepatol 2006 2.Manns et al, Lancet 2001 24 Weeks Tx. 1, N=235 48 Weeks Historical Control 2, N=38

20. SVR Rates by First Time to PCR Negativity in HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx. PEG-IFN  -2b 1.5  g/kg QW + ribavirin 24 Weeks Tx. 1, N=235 48 Weeks Historical Control 2, N=38 1.Zeuzem et al, J Hepatol 2006 2.Manns et al, Lancet 2001

21. Discontinuation and Dose Reductions for Adverse Events HCV-1 (≤600,000 IU/mL), 24 vs. 48 Weeks Tx. PEG-IFN  -2b 1.5  g/kg QW + ribavirin 24 Weeks Tx., N=235 1 48 Weeks Historical control, N=38 2 Discontinuation3%25% Dose reductions14%49% 1.Zeuzem et al, J Hepatol 2006 2.Manns et al, Lancet 2001

22. 89 16 73 35 0 20 40 60 SVR (%) Patients with an RVR at week 4 88 91 80 23 44 100 Patients without an RVR at week 4 n= 18 33 40 55 81 84 208 210 24-LD 24-SD 48-LD 48-SD LD = RBV 800 mg/day; SD = RBV 1000–1200 mg/day; RVR = HCV RNA <50 IU/mL at week 4 Jensen D, et al. AASLD 2005 PEG IFN  2a + RBV: comparison of SVRs in Genotype 1 patients with and without RVR (n=729)

23. Week 4 - qualitative HCV-RNA Week 12 - quantitative HCV-RNA NegativePositive Treat for 24 wks > 2 log  Treat for 48 wks < 2 log  Stop (or shift to suppressive therapy) New Schedule for Rapid Responders HCV-1 Applicable only to patients with LVL and without cirrhosis

24. WHAT ABOUT SLOW RESPONDERS ? Time HCV RNA negative Level of detection End of Treatment Adapted from Bekkering F. et al, Hepatology, 2001, Buti M. et al, Hepatology, Vol. 35, No. 4, 2002 Time HCV RNA negative

25. Genotype 1 & Slow Virologic Response Longer duration ? increase response rate decreased tolerability higher costs Better Tailoring the Current Therapy

26. Extended treatment duration for HCV type 1: comparing 48 vs 72 weeks of PEG-IFN α-2a plus Ribavirin Berg et al Gastroenterology 2006

27. Extended treatment duration for HCV type 1: comparing 48 vs 72 weeks of PEG-IFN α-2a plus Ribavirin Berg et al Gastroenterology 2006

28. Follow-up A prospective, randomised clinical trial in genotype 1 or 4 patients Randomisation 072 Week 4; RVR 244896 No RVR AND EVR : Peg-iFN  -2a 180  g/wk + RBV 1000-1200 mg/day No RVR AND EVR: Peg-IFN  -2a 180  g/wk (48wks) then 135  g/wk (24wks) + RBV 1000-1200mg/day RVR: Peg-IFN  -2a 180  g/wk +RBV 1000-1200 Follow-up Week 12; EVR No RVR AND No EVR: Peg-IFN  -2a 180  g/wk +RBV 1000- 1200mg/day n=267 n=104 Ferenci P, et al. EASL 2006 RVR = HCV RNA 2-log 10 drop at week 12

29. Attempts to optimize therapy Some patients might be OVERTREATED Some patients might be UNDERTREATED  Better Tailoring the Current Therapy  Development of New Therapies DIFFICULT-TO-TREAT SUBGROUPS

30. Potential targets and approaches in the next 5 years Treatment of chronic hepatitis C New IFNs Albumin-linked IFN alfa Peg-Consensus IFN Gene-shuffled IFN “oral IFN inducers”

31. Potential targets and approaches in the next 5 years Potential antiviral targets and approaches New IFNs Ribavirin analogues Viramidine

32. Potential targets and approaches in the next 5 years Potential antiviral targets and approaches New IFNs Alternative “ribavirin-like” drugs Specific HCV Inhibitors NS3 Protease Inhibitors NS5B RNA Polymerase Inhibitors IRES inhibitors (antisense oligonucleotides, ribozymes, siRNAs) Other HCV inhibitors

33. Potential targets and approaches in the next 5 years Treatment of chronic hepatitis C New IFNs Immune Therapies Alternative “ribavirin-like” drugs Specific HCV Inhibitors Thymosin alfa-1 IL-10 Histamine HC Ig Therapeutic vaccine

34. Therapies in Development for HCV Levovirin Development Stage Phase II On Market Phase III Phase I Research Preclinical Thymosin HCV Vaccines Other IFNs Many others including Antisense Antifibrotics Immune stimulants Gene therapy Many others including Antisense Antifibrotics Immune stimulants Gene therapy Ribozymes E2 Vaccine Ribavirin Antisense HCV Immunotherapy Levovirin Viramidine Gamma IFN Histamine HCl IL 10 & IL 12 others IL 10 & IL 12 others IMPDH inhibitors Apoptosis Inhibitors Apoptosis Inhibitors siRNA IFN & PEG IFN Polymerase inhibitors Polymerase inhibitors Protease Inhibitors Protease Inhibitors