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

PEG-IFN & Ribavirin 48 weeks 0% 20% 40% 60% 80% IFN 24 weeks IFN 48 weeks 2002 IFN & Ribavirin 48 weeks PEG-IFN 48 weeks Sustained response (%) Future therapies ? Therapy of chronic hepatitis C

The PEG Molecule IFN-  conjugated to a 40kD (PEG-  2a) or 12kD (PEG-  2b) polyethylenglycol polymer

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

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

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

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

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

Conclusion Optimum ribavirin Dosing with PEG-IFN alfa2b 1.5 µg/kg <65 kg800 mg/day kg1000 mg/day >85 kg1200 mg/day Patient Weight ribavirin Dose Prospective analyses are needed

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

HCV- Genotype 1/4 HCV- Genotype 2/3 HCV-RNA < 0.8 x 10 6 IE/ml HCV-RNA > 0.8 x 10 6 IE/ml 24 weeks48 weeks24 weeks EASL Consensus 1999

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

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

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

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

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 Patient Categories  80/80/80 Group > 80% interferon > 80% ribavirin > 80% expected duration therapy  80 Group < 80% interferon and/or < 80% ribavirin and/or > 80% expected duration therapy Early discontinuations excluded

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

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  Ribavirin  Amantadine  Rimantadine  NSAIDs  N-acetyl-cysteine  Vitamin E  Antibiotics  Corticosteroid priming  Ursodeoxycholic acid  Pentoxifylline  Thymosin alpha  Phlebotomy  Extra-corporeal photophoresis  Mycophenolate  Maxamine

Italian nonresponder pilot study: IFN & Ribavirin & amantadine: Brillanti et al., Hepatology 2000 patients (%) 5 MU IFN tiw mg Riba 200mg Amantadine 5 MU IFN tiw mg Riba n=40 n=20 10% 5% HCV-RNA negative ALT normal 57% 48%

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

Optimize treatment algorithm Optimum duration to determine treatment response

PEG-IFN  -2a in Combination Therapy: Predictability / Compliance Analysis n = 390 (86%) n = 63 (14%) 2 log 10 drop or neg HCV RNA Yes No Week 12 (N = 453) n = 253 (65%) SVR n = 137 (35%) No SVR n = 2 (3%) SVR n = 61 (97%) No SVR Fried MW et al. DDW 2001

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

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

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

NEJM November 15, 2001; 345: 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

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

44 Patienten in 24 Behandlungszentren Patients

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

Wedemeyer et al., 1998 Summary of 23 publications 34,5% 7,4% ETRSR Sustained Response (%) Re-therapy in IFN - nonresponder patients with IFN/Ribavirin

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

Hannover-Study: SCHEDULE Follow-up 24 weeks 0 weeks8 weeks24 weeks48 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

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

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

Nishiguchi, Lancet 1995, 2001 Incidence of HCC in patients with chronic hepatitis C: Relevance of IFN Follow up [years] Cumulative Incidence of HCC [%] Interferon alpha Control

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

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

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

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 Prevention of Progression of Fibrosis

Liver transplantation 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 Problems of the combination therapy

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

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

Summary Naive patients with elevated ALT and fibrosis HCV-Genotype-1 HCV-Genotype-2/3 PEG-IFN 48 weeks and high ribavirin (>10,6mg ribavirin/kg) PEG-IFN 24 weeks and (800mg) ribavirin Acute Hepatitis C5MU 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 transplantationMulticenter trials