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Michael P. Manns Markus Cornberg Medizinische Hochschule Hannover Dept. of Gastroenterology, Hepatology and Endocrinolog

PUBLIC HEALTH CHALLENGES FOR CONTROLLING HCV INFECTION. Hepatitis C: Therapeutic options. Michael P. Manns Markus Cornberg Medizinische Hochschule Hannover Dept. of Gastroenterology, Hepatology and Endocrinology Germany. VHPB Meeting, Ferney Voltaire, France May 13 - 14, 2002.

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Michael P. Manns Markus Cornberg Medizinische Hochschule Hannover Dept. of Gastroenterology, Hepatology and Endocrinolog

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  1. PUBLIC HEALTH CHALLENGES FOR CONTROLLING HCV INFECTION Hepatitis C: Therapeutic options Michael P. Manns Markus Cornberg Medizinische Hochschule Hannover Dept. of Gastroenterology, Hepatology and Endocrinology Germany VHPB Meeting, Ferney Voltaire, France May 13 - 14, 2002

  2. Therapy of chronic hepatitis C Future therapies ? 80% 60% PEG-IFN & Ribavirin 48 weeks IFN & Ribavirin 48 weeks 40% Sustained response (%) PEG-IFN 48 weeks IFN 48 weeks 20% IFN 24 weeks 0% 1988 1990 1992 1994 1996 1998 2002

  3. The PEG Molecule IFN- conjugated to a40kD (PEG-2a) or12kD (PEG-2b)polyethylenglycol polymer

  4. HCVRNA HCVRNA IFN  PEG-IFN  Mo. Di. Mi. Do. Fr. Sa. So. Mo. Di. Mi. Do. Fr. Sa. So. Comparison of Pharmacokinetic Profiles:PEG-IFN alfa vs. IFN alfa

  5. Sustained Response PEG-IFN alfa-2b/RBV Manns et al., Lancet 2001 n = 511 n = 505 n = 514 1/1.2 g RBV 0.8 g RBV Sustained Response PEG-IFN alfa-2a/RBV Fried et al., DDW 2001 n = 444 n = 224 n = 453

  6. Sustained Response PEG-IFN alfa-2b/RBV Genotype 1 + 9% Manns et al., Lancet 2001 Sustained Response PEG-IFN alfa-2a/RBV Genotype 1 + 9% Fried et al., DDW 2001

  7. Optimizing Response Rates • Body weight adjusted dosing • Treatment duration • 80/80/80 • New adjuncts (amantadine)

  8. Sustained Virologic ResponseOptimal ribavirin Dosing (retrospective) Optimal ribavirin >10.6 mg/kg IFN alfa-2b 3MU Peg IFN alfa-2b 1.5 Overall 47% 61% Genotype 1 34% 48% Genotype 2/3 80% 88% Manns et al., Lancet 2001

  9. ConclusionOptimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kg ribavirin Dose Patient Weight <65 kg 800 mg/day 65-85 kg 1000 mg/day >85 kg 1200 mg/day Prospective analyses are needed

  10. Optimizing Response Rates • Body weight adjusted dosing • Treatment duration • 80/80/80 • New adjuncts (amantadine)

  11. HCV- Genotype 1/4 HCV- Genotype 2/3 HCV-RNA < 0.8 x 106 IE/ml HCV-RNA > 0.8 x 106 IE/ml HCV-RNA < 0.8 x 106 IE/ml HCV-RNA > 0.8 x 106 IE/ml 24 weeks 48 weeks 24 weeks 24 weeks EASL Consensus 1999

  12. PEG-IFN alfa-2a and Ribavirin (n=1284) Hadziyannis et al., EASL 2002 180 µg PEG-IFN alfa-2a + 800 mg RBV 24 weeks N=207 180 µg PEG-IFN alfa-2a + 1000/1200 mg RBV N=280 24 weeks 180 µg PEG-IFN alfa-2a + 800 mg RBV N=361 48 weeks 180 µg PEG-IFN alfa-2a + 1000/1200 mg RBV 48 weeks N=436

  13. PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype 1 Hadziyannis et al., EASL 2002 48 weeks 24 weeks PEG+0,8RBV PEG+1/1,2RBV PEG+0,8RBV PEG+1/1,2RBV

  14. PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype 1 and low viral load Hadziyannis et al., EASL 2002 48 weeks 24 weeks PEG+0,8RBV PEG+1/1,2RBV PEG+0,8RBV PEG+1/1,2RBV

  15. PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype NON-1 Hadziyannis et al., EASL 2002 48 weeks 24 weeks PEG+0,8RBV PEG+1/1,2RBV PEG+0,8RBV PEG+1/1,2RBV

  16. Conclusion (Ribavirin dosing / Treatment duration) • Patients with HCV-Genotype-1:48 weeks therapy with optimal (high) ribavirin dosing independent of viral load • Patients with HCV-Genotype-2/3:24 weeks therapyhigh ribavirin dosing seems not to be necessary

  17. What is the impact of adherence to therapy on SVR?

  18. Patient Categories • 80/80/80 Group • > 80% interferon • > 80% ribavirin • > 80% expected duration therapy • < 80 ± < 80 + > 80 Group • < 80% interferon and/or • < 80% ribavirin and/or • > 80% expected duration therapy • Early discontinuations excluded

  19. p = 0.04 63% 54% 52% N=305 N=118 N=511 All Patients - PEG IFN 1.5 µg/kg + ribavirin Manns et al., Lancet 2001 McHutchison et al, EASL 2001 Sustained virologic response (%)

  20. Conclusions 80/80/80 • Patients who can be maintained on > 80% of PEG interferon and ribavirin for the proposed duration of therapy may have an enhanced sustained response rate • Every effort should be made to continue the maximum tolerable doses of therapy for the duration of treatment

  21. Optimizing Response Rates • Body weight adjusted dosing • Treatment duration • 80/80/80 • New adjuncts (amantadine)

  22. Other Combination Adjuncts • Corticosteroid priming • Ursodeoxycholic acid • Pentoxifylline • Thymosin alpha • Phlebotomy • Extra-corporeal photophoresis • Mycophenolate • Maxamine • Ribavirin • Amantadine • Rimantadine • NSAIDs • N-acetyl-cysteine • Vitamin E • Antibiotics

  23. 60 ALT normal HCV-RNA negative 40 20 0 Italian nonresponder pilot study: IFN & Ribavirin & amantadine: 57% 48% n=20 patients (%) n=40 10% 5% 5 MU IFN tiw800-1000mg Riba200mg Amantadine 5 MU IFN tiw800-1000mg Riba Brillanti et al., Hepatology 2000

  24. 60% 52% P=0,055 43% 40% Sustained Response 20% N=200 N=200 0% IFN, RBV, Amantadine IFN, RBV, Placebo German multicenter study (400 naive patients) 9 MU IFN alfa-2a qd 2 weeks 6 MU IFN alfa-2a qd 6 weeks 6 MU IFN alfa-2a tiw 16 weeks 3 MU IFN alfa-2a tiw 24 weeks 1000/1200 mg Ribavirin 200 mg Amantadine / Placebo Berg et al., AASLD 2001, GASL 2002, EASL 2002

  25. Optimize treatment algorithm • Optimum duration to determine treatment response

  26. n = 390 (86%) n = 63(14%) PEG-IFN -2a in Combination Therapy: Predictability / Compliance Analysis Week 12 (N = 453) SVR n = 253(65%) Yes No SVR n = 137 (35%) 2 log10 dropor neg HCV RNA SVR n = 2(3%) No SVR No n = 61 (97%) Fried MW et al. DDW 2001

  27. 24wks Assess fibrosis F2/F3/F4: consider maintenance • RNA (+) < 2 log drop • discontinue • n=31 SVR = 90% 108/120 12 wks • RNA (-) Continue for 48 wks • n=120 • n=188* SVR = 0% 0/17 • PCR (+) • RNA (+)  2 log drop • PCR (-) • n=23 Loss of SVR =26% SVR =100% 6/6 Continue to 48 wks Proposed treatment algorithm PEG-IFN alfa-2b study Week *12 HCVRNA not available in 14 patients McHutchison et al, EASL, 2002

  28. Other patient groups • Patients with acute HCV Infection • Nonresponder patients • Patients after liver transplantation

  29. Is a prevention of the chronic course possible ? Acute HCV-Infection 10-50% 50-90% Recovery Chronic infection (PEG)-Interferon alfa Ribavirin

  30. Treatment of Acute Hepatitis C with Interferon Alfa-2b Elmar Jaeckel, M.D., Markus Cornberg, M.D., Heiner Wedemeyer, M.D., Teresa Santantonio, M.D., Julika Mayer, M.D., Myrga Zankel, D.V.M., Giuseppe Pastore, M.D., Manfred Dietrich, M.D., Christian Trautwein, M.D., Michael P. Manns, M.D., and the German Acute Hepatitis C Therapy Group NEJM November 15, 2001; 345: 1452-1457

  31. Jaeckel, et al., NEJM 2001 Therapy within 4 months after infection Induction Therapy Follow-up Week 1-4 Week 5-24 Week 25-48 5 MU daily Interferon alfa-2b 5 MU tiw Interferon alfa-2b Schedule

  32. Patients 44 Patienten in 24 Behandlungszentren

  33. Virological Response during therapy 100% 98% 80% therapy n=44 60% natural course n=40 HCV-RNA negative 40% 30% 20% Santantonio et al. (Bari, Italy) 0% 48=F24 0 4 8 12 16 20 24 weeks Jaeckel, Cornberg, Wedemeyer et al., NEJM 2001

  34. 50 Summary of 23 publications 40 34,5% 30 Sustained Response (%) 20 7,4% 10 0 ETR SR Re-therapy in IFN - nonresponder patients with IFN/Ribavirin Wedemeyer et al., 1998

  35. HCV therapies - new strategies • Daily dosing • Induction dosing • New adjuncts (amantadine) • New interferons (CIFN, PEG-IFN)

  36. 0 weeks 8 weeks 24 weeks 48 weeks A 9 µg Consensus Interferon (Inferax) daily 1. – 48. weeks 1.000/1.200 mg Ribavirin Meduna daily B 18 µg Inferax daily 1. – 8. wk 9 µg Inferax daily 9. – 48. weeks 1.000/1.200 mg Ribavirin weeks Hannover-Study: SCHEDULE Follow-up 24 weeks

  37. VIROLOGICAL response (intent to treat) 40 Nonreponder patients (>90% HCV-G-1) 80% Group A (n=21) 71,4% Group B (n=19) 57,9% 60% 40% 65% 20% 0% ETR SR

  38. Chronic Hepatitis C - Nonreponder Patients: Therapeutic goals • Viral clearance • Histological response • Prevention of HCC

  39. 50 Control 40 30 Cumulative Incidence of HCC [%] Interferon alpha 20 10 1 2 3 4 5 6 7 Follow up [years] Incidence of HCC in patients with chronic hepatitis C: Relevance of IFN Nishiguchi, Lancet 1995, 2001

  40. % Cumulative Incidence of HCC 882 patients with F3 / F4 NR (6 mo IFN) NR = Non Responders PR = Partial Responders (ALT < x 2.5 n.v.) SR = Sustained Response 15 Untreated 12 9 PR (12 mo IFN) 6 PR (24 mo IFN) 3 SR 0 1 2 3 4 5 Years after inclusion Alberti, 2000

  41. PEG-IFN 2a therapy: naive patients histological response (HAI-Score reduction >2) Peg-IFN 180µg 1x/week 48 week (n=228) 83% 79% IFN 3MU 3x/week 48 week (n=202) 80% p=0.001 57% 60% p=0.06 47% 44% 43% 41% Patients 40% 30% 20% 0% Patients with SR Partially Responder all Patients Nonresponder Heathcote et al., 2000

  42. PEG-IFN & Ribavirin in Nonresponder HALT-C-Study (NIH) AASLD 2001: Shiffman et al. 146 Nonresponder 20 weeks Peg-IFN alfa-2a + Ribavirin 8 drop outs 59/138 Response (ITT 40,1%) 79 Nonresponder PEG-IFN + RBV 48 Wochen PEG-IFN Mono (HALT-C)

  43. Prevention of Progression of Fibrosis • Anti-fibrotic effect of IFN alfa • Inhibition of collagen synthesis in cell culture and in vivo • Clinical Experience • Histological improvement with IFN-based therapy in responders and non responders • Fibrosis regression in subjects on maintenance IFN compared with subjects who stop IFN • Decrease in development of HCC and/or decrease in mortality rate in all studies

  44. Liver transplantation Problems of the combination therapy • Ribavirin leads to anemia and accumulation of iron • Significant side effects of IFN/RBV • Reported sustained response rates differ between different centers • No data on long-term benefit are available •  multicenter trials

  45. Therapy of HCV-Reinfection with Interferon with or without Ribavirin IFN IFN+Riba Patients n=43 n=21 Biochemical Response ca. 20% 100% Viral elimination (PCR-neg. ETR) 0% 48% Histological Response ca. 5% 100% Rejection episodes ca. 15% 0% Wright et al 1992, 1994, Feray et al 1995, Bizollon et al 1997

  46. Liver transplantation More important • Deciding the best immunosuppression regimen rejection Disease progression

  47. Summary

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