29th Viral Hepatitis Prevention Board Meeting

29th Viral Hepatitis Prevention Board Meeting Madrid, November 2006 Treatment of chronic hepatitis C José M. Sánchez-Tapias Liver Unit Hospital Clínic University of Barcelona Spain

CHRONIC HEPATITIS C Extremely common Variable outcome Most frequent cause of chronic liver disease including chronic hepatitis, hepatic cirrhosis and hepatocellular carcinoma Leading reason for liver transplantation.

ADVANCES IN THE TREATMENT OF CHRONIC HEPATITIS C Rate of sustained virological response (SVR) according to the therapeutic regime 100 90 80 70 SVR (%) 60 50 40 30 20 10 0 IFN 24 w IFN 48 w IFN + RIBA 24 w IFN + RIBA 48 w PEGIFN + RIBA 1990 1996 2001

SUSTAINED VIROLOGIC RESPONSE TO INTERFERON-ALPHA-2b +/- RIBAVIRIN THERAPY AT 6 MONTHS RELIABLY PREDICTS LONG- TERM CLEARANCE OF HCV AT 5-YEAR FOLLOW-UP 1 Probability of sustained virological response 0,9 n= 492 Relapse was observed in 5 patients (1%) 0,8 1 2 3 4 5 Follow-up (years) McHutchinson et al., EASL 2006

TREATMENT OF CHRONIC HEPATITIS C Recommended therapy: Peginterferón + Ribavirin Duration according to HCV genotype Sustained virological response: 45% in genotype 1 or 4 Problems: Relatively low efficacy Frequent side effects High cost 80% in genotype 2 or 3. Perspectives: More rationale use of PEGIFN RIBA New therapies

TREATMENT OF CHRONIC HEPATITIS C Factors related to response HCV genotype HCV viremia Severity of liver fibrosis Race, sex Body weight Insulin resistance Viral kinetics during therapy

TREATMENT OF CHRONIC HEPATITIS C Factors related to response HCV genotype HCV viremia Severity of liver fibrosis Race, sex Body weight Insulin resistance Viral kinetics during therapy

Schematic representation of the types of virological response to therapy of patients with genotype 1 chronic hepatitis C HVC-RNA WEEKS ON THERAPY Detection limit 0 4 12 24 48 72 Rapid response Slow response No response

Could standard therapy be modified according to the initial virological response?

PEG (40 KD)- IFN (α-2a) IN COMBINATION WITH RIBAVIRIN AS A THERAPY FOR CHRONIC HEPATITIS C Evaluation of treatment duration and ribavirin dose 100 90 Sustained virological response (%) 80 70 60 50 40 30 20 10 0 RIBA dose 29% 101 GENOTYPE 1 42% 118 0.8 1-1.2 24 weeks 41% 250 52% 271 0.8 1-1.2 48 weeks Hadzyannis et al., Ann Intern Med 2004

Early identification of HCV Genotype 1 patients responding to 24 weeks Peginterferon α-2a (40kd)/Ribavirin therapy Identification of factors associated to sustained virological response in 740 genotype 1 patients from a previous randomized study (Hadziyannis et al., Ann Intern Med 2004) Factor OR IC 95% p Baseline HCV-RNA <200x10 3 vs >600x10 3 2.7 1.1-6.3.026 Virological response at week 4 Yes vs No 23.7 9.1 61.7 <.0001 Sustainesd response (%) 100 80 60 40 20 0 89% 88% 73% 91% 18 33 40 55 Patients with undetectable HCV-RNA at week 4 16% 23% 35% 24 w., low RIB dose 24 w., high RIB dose 48 w., low RIB dose 48 w., high RIB dose 44% 81 84 208 210 Patients with detectable HCV-RNA at week 4 Jensen et al., Hepatology 2006

Efficacy of 24 weeks of treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia 235 patients with baseline viremia 600.000 IU/mL Therapy: Peg-IFN α-2b (1.5 µg/kg) + RBV (800-1400 mg), 24 weeks Historic control: Cohort of comparable patients treated for 48 weeks in a previous study (Manns et al., Lancet 2001) 100 SVR (%) 75 50 50% 71% 25 0 235 38 24 weeks 48 weeks Treatment duration Zeuzem et al. J Hepatology 2006

Efficacy of 24 weeks of treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia 100 80 Relationship with time on therapy till clearance of HCV-RNA (Less than 29 IU/mL by real time PCR) Sustained response Relapse Response (%) 60 40 20 0 Week 4 Week12 Week 24 Zeuzem et al. J Hepatology 2006

24-week Peginterferon alfa-2a plus ribavirin regimen appears effective in patients with genotype 1 or 4 HCV who respond early to treatment week 4 week 12 week 24 week 48 week 72 week 96 N = 104 371 patients (90% geno 1) HCV-RNA <50 UI/mL N = 106 PEGIFN α-2a 180 µg/s. Riba 1-1.2 mg/d HCV-RNA 50-600 UI/mL N = 105 HCV-RNA >600 UI/mL N = 56 Ferenci et al., EASL 2006

24-week Peginterferon alfa-2a plus ribavirin regimen appears effective in patients with genotype 1 or 4 HCV who respond early to treatment Sustained virological response (SVR) in super-responders 1 Global Baseline viremia <600.000 UI/mL 600.000 UI/mL Fibrotic stage 0-2 3-4 SVR (%) 77 93 74 90 79 1: Defined by HCV-RNA <50 IU/mL at week 4 Ferenci et al., EASL 2006 Ferenci et al., EASL 2006

Peginterferon α-2a plus ribavirin for 48 versus 72 weeks in patients with detectable HVC-RNA at week 4th of treatment 517 patients PEG-IFN α-2a (180 µg/wk) Ribavirin 800 mg/d Negative 185 (36%) According to HCV genotype and baseline viremia Week 4 HCV-RNA (N = 512) Positive 327 (64%) Randomized 1:1 48 weeks 72 weeks S.Tapias et al., Gastroenterology 2006

Peginterferon α-2a plus ribavirin for 48 versus 72 weeks in patients with detectable HVC-RNA at week 4th of treatment End of treatment (EOT) response and sustained virological response (SVR) Response (%) 70 60 50 40 30 20 10 0 61,2 61 32,1 48 weeks (n=165) p = 0.014 Duration of treatment 45,3 72 weeks (n=161) ITT Analysis EOT SVR S.Tapias et al., Gastroenterology 2006

Who may benefit from extended duration therapy? Rate of sustained virological response according to viral kinetics during therapy in non-responders at week 4 Treatment duration All patients HCV-RNA-VHC at week 12 Negative Positive > 2 log drop 48 weeks 53/165 (32%) 30/58 (52%) 5/31 (16%) 72 weeks 73/161 (45%) 45/74 (61%) 11/25 (44%) Ribavirin: 800 mg S.Tapias et al., Gastroenterology 2006 48 sem. 54/99 (57%) 47/59 (80%) 7/19 (31%) 72 sem. 46/78 (59%) 36/44 (82%) 10/13 (77%) Ribavirin1.000 1200 mg Ferenci et al., AASLD 2006

Effects of shortening therapy duration in genotype 2 or 3 infected patients Sustained response Num. RVR RVR No RVR Dalgard et al., 2004 122 78% 90% (14) 56% (24) Mangia et al., 2005 213 63% 86% (12) 64% (24) Wagner et al., 2005 153 93% 82% (16) 36% (24) Shiffmann et al., 2006 1463 --- 82% (16) 27% (16) 90% (24) 49% (24) RVR: Rapid virological response (HCV-RNA undetectable at week 4) Red figures in brackets indicate treatment duration

Treatment of chronic hepatitis C Currently recommended Pegylated interferon plus ribavirin combination therapy is acceptably effective but not fully satisfactory as a treatment for chronic hepatitis C. Individualizing therapy duration according to HCV genotype, baseline viremia, liver fibrosis, and viral kinetics early during therapy is an attractive strategy. More effective, safer and cheaper therapies are urgently required.