Michael P. Manns Markus Cornberg 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
Therapy of chronic hepatitis C PEG-IFN & Ribavirin 48 weeks Future therapies ? 80% 60% PEG-IFN & Ribavirin 48 weeks IFN & Ribavirin 48 weeks 40% Sustained response (%) PEG-IFN 48 weeks 20% IFN 48 weeks IFN 24 weeks 0% 1988 1990 1992 1994 1996 1998 2002
The PEG Molecule IFN- conjugated to a 40kD (PEG-2a) or 12kD (PEG-2b) polyethylenglycol polymer
Comparison of Pharmacokinetic Profiles: PEG-IFN alfa vs. IFN alfa HCV RNA IFN Mo. Di. Mi. Do. Fr. Sa. So. PEG-IFN
Sustained Response PEG-IFN alfa-2b/RBV Sustained Response Manns et al., Lancet 2001 n = 505 n = 514 n = 511 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
Sustained Response PEG-IFN alfa-2b/RBV Sustained Response Genotype 1 + 9% Manns et al., Lancet 2001 Sustained Response PEG-IFN alfa-2a/RBV Genotype 1 + 9% Fried et al., DDW 2001
Optimizing Response Rates Body weight adjusted dosing Treatment duration 80/80/80 New adjuncts (amantadine)
Sustained Virologic Response Optimal 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% Highlight the genotype 2/3 for the 1.5 Genotype 2/3 80% 88% Manns et al., Lancet 2001 19
Conclusion Optimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kg Patient Weight ribavirin Dose <65 kg 800 mg/day 65-85 kg 1000 mg/day >85 kg 1200 mg/day Note additions Prospective analyses are needed 18
Optimizing Response Rates Body weight adjusted dosing Treatment duration 80/80/80 New adjuncts (amantadine)
EASL Consensus 1999 HCV- Genotype 1/4 HCV- Genotype 2/3 24 weeks HCV-RNA < 0.8 x 106 IE/ml HCV-RNA > 0.8 x 106 IE/ml 24 weeks 48 weeks
PEG-IFN alfa-2a and Ribavirin (n=1284) Hadziyannis et al., EASL 2002 180 µg PEG-IFN alfa-2a + 800 mg RBV N=207 24 weeks 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 N=436 48 weeks
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
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
PEG-IFN alfa-2a and Ribavirin SVR Results HCV-Genotype NON-1 Hadziyannis et al., EASL 2002 24 weeks 48 weeks PEG +0,8RBV PEG +1/1,2RBV PEG +0,8RBV PEG +1/1,2RBV
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 therapy high ribavirin dosing seems not to be necessary
What is the impact of adherence to therapy on SVR?
Patient Categories 80/80/80 Group < 80 ± < 80 + > 80 Group > 80% interferon > 80% ribavirin > 80% expected duration therapy < 80 ± < 80 + > 80 Group < 80% interferon and/or < 80% ribavirin and/or Early discontinuations excluded
All Patients - PEG IFN 1.5 µg/kg + ribavirin 54% 63% 52% N=511 N=305 N=118 Manns et al., Lancet 2001 McHutchison et al, EASL 2001 Sustained virologic response (%)
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
Optimizing Response Rates Body weight adjusted dosing Treatment duration 80/80/80 New adjuncts (amantadine)
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
Italian nonresponder pilot study: IFN & Ribavirin & amantadine: 57% 20 40 60 HCV-RNA negative ALT normal 48% n=20 patients (%) n=40 10% 5% 5 MU IFN tiw 800-1000mg Riba 200mg Amantadine 5 MU IFN tiw 800-1000mg Riba Brillanti et al., Hepatology 2000
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 Sustained Response P=0,055 52% 43% 0% 20% 40% 60% IFN, RBV, Amantadine IFN, RBV, Placebo N=200 Berg et al., AASLD 2001, GASL 2002, EASL 2002
Optimize treatment algorithm Optimum duration to determine treatment response
PEG-IFN -2a in Combination Therapy: Predictability / Compliance Analysis Week 12 (N = 453) SVR n = 253 (65%) n = 390 (86%) Yes No SVR n = 137 (35%) 2 log10 drop or neg HCV RNA SVR n = 2 (3%) n = 63 (14%) No SVR No n = 61 (97%) Fried MW et al. DDW 2001
Proposed treatment algorithm PEG-IFN alfa-2b study RNA (+) 2 log drop n=23 Loss of SVR =26% 24wks discontinue RNA (+) < 2 log drop n=31 Assess fibrosis F2/F3/F4: consider maintenance RNA (-) n=120 Continue for 48 wks SVR = 90% 108/120 n=188* 12 wks PCR (+) SVR = 0% 0/17 PCR (-) Continue to 48 wks SVR =100% 6/6 Week *12 HCVRNA not available in 14 patients McHutchison et al, EASL, 2002
Patients with acute HCV Infection Other patient groups Patients with acute HCV Infection Nonresponder patients Patients after liver transplantation
Is a prevention of the chronic course possible ? Acute HCV-Infection 10-50% Is a prevention of the chronic course possible ? 50-90% Recovery Chronic infection (PEG)-Interferon alfa Ribavirin
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
5 MU tiw Interferon alfa-2b Therapy within 4 months after infection Schedule 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 Jaeckel, et al., NEJM 2001 Therapy within 4 months after infection
Patients 44 Patienten in 24 Behandlungszentren
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% 4 8 12 16 20 24 48 =F24 weeks Jaeckel, Cornberg, Wedemeyer et al., NEJM 2001
Re-therapy in IFN - nonresponder patients with IFN/Ribavirin Summary of 23 publications 34,5% 7,4% 10 20 30 40 50 ETR SR Sustained Response (%) Wedemeyer et al., 1998
HCV therapies - new strategies Daily dosing Induction dosing New adjuncts (amantadine) New interferons (CIFN, PEG-IFN)
Hannover-Study: SCHEDULE 0 weeks 8 weeks 24 weeks 48 weeks 18 µg Inferax daily 1. – 8. wk B A 9 µg Consensus Interferon (Inferax) daily 1. – 48. weeks 1.000/1.200 mg Ribavirin Meduna daily 9 µg Inferax daily 9. – 48. weeks 1.000/1.200 mg Ribavirin weeks Follow-up 24 weeks
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
Chronic Hepatitis C - Nonreponder Patients: Therapeutic goals Viral clearance Histological response Prevention of HCC
Cumulative Incidence of HCC [%] Incidence of HCC in patients with chronic hepatitis C: Relevance of IFN Follow up [years] Cumulative Incidence of HCC [%] 1 2 3 4 5 6 7 10 20 30 40 50 Interferon alpha Control Nishiguchi, Lancet 1995, 2001
% 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 1 2 3 4 5 Years after inclusion Alberti, 2000
PEG-IFN 2a therapy: naive patients histological response (HAI-Score reduction >2) Peg-IFN 180µg 1x/week 48 week (n=228) 83% 79% 80% IFN 3MU 3x/week 48 week (n=202) 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
PEG-IFN & Ribavirin in Nonresponder Peg-IFN alfa-2a + Ribavirin 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)
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
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
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 2
Liver transplantation More important Deciding the best immunosuppression regimen rejection Disease progression
Summary Naive patients with elevated ALT and fibrosis HCV-Genotype-1 PEG-IFN 48 weeks and high ribavirin (>10,6mg ribavirin/kg) PEG-IFN 24 weeks and (800mg) ribavirin Acute Hepatitis C 5MU IFN qd 4 wk, 5MU IFN tiw 20 wk or PEG-IFN oiw 24 wk (ongoing study) Nonresponder No fibrosis fibrosis advanced fibrosis/cirrhosis no treatment Studies (PEG-IFN, CIFN, etc.) Studies (long-term IFN) Liver transplantation Multicenter trials