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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. Terapia dell’Epatite cronica HCV correlata: Peg-IFN/ribavirina e che altro?. T. Santantonio. Malattie Infettive Università degli Studi di Bari. Milestones in Therapy of Chronic Hepatitis C. 1986. 1998.

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Terapia dell’Epatite cronica HCV correlata: Peg-IFN/ribavirina e che altro?

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

  2. Milestones in Therapy of Chronic Hepatitis C 1986 1998 2001 2002 54-56 42 39 34 Sustained Virologic Response 16 6 IFN 6m IFN 12m IFN/RBV 6m IFN/RBV 12m PEG 12m PEG/RBV 12m Strader et al Hepatology 2004

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

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

  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 • Better Tailoring the Current Therapy Some patients might be OVERTREATEDSome patients might be UNDERTREATED • Development of New Therapies DIFFICULT-TO-TREAT SUBGROUPS

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

  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 78% of Patients were PCR Negative at Week 4/8. Dalgard O. et al. Hepatology 2004;40:1260 –1265.

  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 Mangia et al. NEJM 2005 STANDARD REGIMEN (70 pts) VARIABLE REGIMEN (213 pts) Week 4 HCV-RNA (Amplicor) 24 wks neg pos 12 wks 24 wks week 4 neg89%87% HCV-2 76% week 4 pos50% 72% week 4 neg100% 77% HCV-3 76% week 4 pos43% 41% S V R

  12. Relapse Rates Standard duration Variable duration *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.

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

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

  15. ACCELERATE: study design PEG-IFN -2a 180 g/wk plus RBV 800 mg/day Follow-up 732 n=1469 PEG-IFN -2a 180 g/wk plus RBV 800 mg/day 731 Follow-up 0 8 16 24 32 40 48 Study week Randomisation. Treatment duration blinded until week 16 Shiffman M, et al. 41st EASL 2006; Abstract 734

  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 Neg Pos Treat for 12-16 wks Treat for 24 wks Solid with full WBD ribavirin Same for HCV-3 ? Same for advanced disease ?

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

  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 24 Weeks Tx.1, N=235 48 Weeks Historical Control2, N=38 • Zeuzem et al, J Hepatol 2006 • Manns et al, Lancet 2001

  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 Control2, N=38 • Zeuzem et al, J Hepatol 2006 • 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 • Zeuzem et al, J Hepatol 2006 • Manns et al, Lancet 2001

  22. PEG IFN  2a + RBV: comparison of SVRs in Genotype 1 patients with and without RVR(n=729) 100 91 24-LD 88 89 24-SD 80 73 48-LD 48-SD 60 SVR (%) 44 40 35 23 16 20 81 84 208 210 n= 18 33 40 55 0 Patients with an RVR at week 4 Patients without an RVR at week 4 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

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

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

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

  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. A prospective, randomised clinical trial in genotype 1 or 4 patients Week 4; RVR Week 12; EVR 0 24 48 72 96 No RVR AND EVR: Peg-iFN -2a 180 g/wk + RBV 1000-1200 mg/day Follow-up Randomisation No RVR AND EVR: Peg-IFN -2a 180 g/wk (48wks) then 135 g/wk (24wks) + RBV 1000-1200mg/day n=267 Follow-up Follow-up No RVR AND No EVR: Peg-IFN -2a 180 g/wk +RBV 1000-1200mg/day n=104 RVR: Peg-IFN -2a 180 g/wk +RBV1000-1200 Follow-up RVR = HCV RNA <50 IU/mL at week 4, EVR = HCV RNA <600 IU/ml or >2-log10 drop at week 12 Ferenci P, et al. EASL 2006

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

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

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

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

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

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

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