Stefan ZEUZEM

Stefan Zeuzem J.W. Goethe University Hospital Frankfurt, Germany What is the optimal treatment of naive patients with chronic hepatitis C ? 2nd Paris Hepatitis Conference Palais des Congrès, Paris, 22-23 January 2007 Stefan Zeuzem J.W. Goethe University Hospital Frankfurt, Germany

Sustained virologic response (%) Peginterferon alfa-2a/2b + Ribavirin for treatment of chronic hepatitis C Sustained virologic response (%) Fried et al., N Engl J Med 2002; 347:975-982 Manns et al., Lancet 2001; 358:958-965

PEG-IFN alfa-2a + RBV (LD vs SD) for treatment of chronic hepatitis C RBV 800 mg/d RBV 1000-1200 mg/d Sustained virologic response (%) HCV-1 HCV-2,3 Hadziyannis et al., Ann Intern Med 2004;40:346-355

HCV genotyping stop treatment or continue with PEG-IFN alone HCV RNA quant. HCV-2,3 Combination treatment 1000-1200 mg Ribavirin Combination treatment 800 mg Ribavirin for 24 weeks HCV RNA quant. at week 12 < 2log decline  2log decline HCV RNA +  2log decline HCV RNA - stop treatment or continue with PEG-IFN alone for inhibition of fibrosis progression continue tx until week 24 if HCV RNA - continue tx until week 48 continue tx until week 48

Individualisation according to HCV genotype: Shorter treatment in HCV-1?

Time to first negative HCV RNA PEG-IFN a-2b + RBV Virologic response in patients with HCV-1 and HCV RNA < 600,000 IU/mL 89% 80% 75% Patients (%) 50% 37% 25% 17% 8% (47%) (26%) (10%) Time to first negative HCV RNA PEG-IFN a-2b + RBV Zeuzem et al., J Hepatol 2006

Patients with HCV-1 and HCV RNA < 600,000 IU/mL Investigator HCV-1 patients HCV-1 & LVL Quantification assay Data source Manns et al. 1034 290 (28.1%) qPCR (NGI) Lancet 2001 Jacobson et al. 2710 989 (36.5%) SP TaqMan SPRI data base Fried et al. 725 253 (34.9%) Cobas Amplicor HCV Monitor 2.0 NEJM 2002 Hadziyannis et al. 740 267 (36.1%) Ann Intern Med 2004 Total 5209 1799 (34.5%) Zeuzem, J Hepatol 2006

Sustained virologic response (%) Early identification of HCV 1 patients responding to 24 wks PEG-IFN alfa-2a/RBV Sustained virologic response (%) 18 33 40 55 81 84 208 210 Jensen et al., Hepatology 2006;43:954-60

GAM analysis Effect of pre-treatment HCV RNA on SVR 5.6 log10 IU/mL 0.998 0.98 Probability of SVR* 0.88 0.5 3 4 5 6 7 *Logit scale 5.6 log10 IU/mL ~400 x103 IU/mL Baseline HCV RNA (log10 IU/ml)

Individualisation according to HCV genotype: Longer treatment in HCV-1 ?

Sustained virologic response rate (%) Extended treatment duration for HCV 1: 48 vs 72 weeks of PEG-IFN alfa-2a + RBV P=0.040 Sustained virologic response rate (%) 104/130 90/119 17/100 31/106 Berg, et al. Gastroenterology 2006;130:1086-1097

Virologic relapse rates in patients with rapid virologic response 3/46 5/32 19/123 12/101 Week 4 Week 12 Berg, et al. Gastroenterology 2006;130:1086-1097

Virologic relapse rates in patients with slow virologic response 46/124 28/122 30/47 21/52 Week 4 Week 12 Berg, et al. Gastroenterology 2006;130:1086-1097

Sustained virologic response rate (%) Peginterferon alfa-2a plus ribavirin for 48 vs. 72 weeks in patients with detectable HCV RNA at week 4 of treatment 51% 44% Sustained virologic response rate (%) 37% 28% 27% 28% P=0.003 P=0.002 P=0.35 Sanchez-Tapias et al., Gastroenterology 2006;131:451-460

Virologic relapse rate (%) Peginterferon alfa-2a plus ribavirin for 48 vs. 72 weeks in patients with detectable HCV RNA at week 4 of treatment 55% 53% 50% Virologic relapse rate (%) 27% 23% 17% P=0.002 P=0.007 P=0.15 Sanchez-Tapias et al., Gastroenterology 2006;131:451-460

Individualisation according to HCV genotype: Shorter treatment in HCV-2 and HCV-3 ?

PEG-IFN-a2b + RBV for treatment of chronic HCV-2 and -3 infection (ITT) 90% 82% 56% Patients (%) 26% 19% 14% 10% 4% 0% Dalgard et al., Hepatology 2004;40:1260-65

Virologic response (%) End-of-treatment (ETR) and sustained virologic response (SVR) - HCV genotypes 2 and 3 combined - SVR B vs C: P = 0.003 94% 86% 82% 81% 69% Virologic response (%) 39% 67/71 58/71 59/69 56/69 9/13 5/13 (16 weeks) (24 weeks) (24 weeks) v. Wagner et al, Gastroenterology 2005

Sustained virologic response (SVR) according to HCV genotype Tx: PEG-IFN alfa-2b 1.0 µg/kg + RBV 1000-1200 mg 87% 77% 76% 76% 72% SVR (%) 41% 40/53 13/17 89/102 24/31 42/58 9/22 (24 weeks) (12 weeks) (24 weeks) Mangia et al, N Engl J Med 2005

Virologic response (%) Treatment of chronic HCV-2 infection with PEG-IFN alfa-2a + RBV for 16 vs. 24 weeks 94% 95% 86% 87% Virologic response (%) 43/50 87/100 47/50 95/100 M-L Yu et al, GUT 2006

PEG-IFN alfa-2a + RBV for 16 or 24 weeks in HCV-2 and -3 (ACCELERATE Study) Shiffman et al., Late-Breaker Abstract EASL 2006

PEG-IFN alfa-2a + RBV for 16 or 24 weeks in HCV-2 and -3 (ACCELERATE Study) 98% 94% 92% 90% 85% 72% 80% 77% 74% 67% 75% 70% 65% 60% 56% SVR (%) 52% tpcr05_p N=61 N=46 N=285 N=257 N=92 N=84 N=241 N=243 Genotype 2 Genotype 3 Standard population; VR = HCV RNA < 50 IU/mL Shiffman et al., Late-Breaker Abstract EASL 2006

ACCELERATE MANGIA VON WAGNER DALGARD PEG-IFN alfa-2a 180 µg qw Ribavirin 800 mg qd PEG-IFN α-2b 1.0 µg/kg qw Ribavirin 1000-1200 mg qd PEG-IFN α-2a 180 µg qw Ribavirin 800-1200 mg qd PEG-IFN α-2b 1.5 µg/kg qw Ribavirin 800-1400 mg qd Regimen 1469 (993 US) 273 153 122 Number Global Italy Germany Norway Region 50% 78% 25% 19% % GT 2 Treatment duration based on RVR? No Yes Yes Yes 5.6 x 106 ~1 x 106 ~0.6 x 106 50% <0.6 x 106 Mean baseline viral load IU/ml 46 46.6-49.7 38-42 37 (median) Mean Age (yrs) 81.5 69.5 74-80 76 (median) Mean body weight (kg)

Individualisation according to HCV genotype: Longer treatment in HCV-3 (HVL) ?

Relapse rate by HCV genotype and baseline viral load in patients treated for 24 weeks (Peg-IFN alfa-2b + RBV) 23% Relapse (%) 9% 8% 5% HCV-2 HCV-3 Zeuzem et al., J Hepatol 2004

Individualisation according to HCV genotype: Treatment duration for HCV-4 ?

sustained virologic response (%) PEG-IFN-a2a + ribavirin for treatment of patients with chronic HCV-4 infection 79% 67% 63% sustained virologic response (%) 0% M Diago et al., Ann Intern Med 2004;140:72-73

Sustained virologic response (SVR) in patients infected with HCV-4 Tx: PEG-IFN alfa-2b 1.5 µg/kg + RBV 1000-1200 mg SVR (%) 69% 66% 29% Kamal et al, GUT 2005

Sustained virologic response (SVR) in patients infected with HCV-4 (HVL) Tx: PEG-IFN alfa-2b 1.5 µg/kg + RBV 1000-1200 mg SVR (%) 65% 35% 0% Kamal et al, GUT 2005

Future individualization of therapy HCV-2, HCV-3 (LVL) 12-16 Wochen Delgaard et al. 2005; v. Wagner et al. 2005 Mangia et al. 2005, Shiffman et al. 2006 HCV-2 (HVL) 24 Weeks Shiffman et al. 2006 HCV-3 (HVL), HCV-4 (LVL) 36-48 (?) Wochen v. Wagner et al. 2005, Kamal et al. 2006 HCV-1 (LVL, RVR) 24 Wochen Zeuzem et al. 2004, Zeuzem et al. 2005 HCV-1, HCV-4 48 Wochen Manns et al. 2002, Hadziyannis et al. 2004 Kamal et al., 2005 HCV-1 (SPR) 72 Wochen Buti et al. 2003, Berg et al. 2006 7 NR (c < 0,2) 6 FPR (0.0  d < 0,05) 5 Serum HCV RNA (log) 4 SPR (0.05  d < 0.35) 3 RVR (d  0.35) 2 Limit of detection 1 1 2 3 7 14 21 28 days 7 a 6 b 5 copies/mL) c Serum HCV RNA 4 10 3 (log detection limit 2 1 1 2 3 7 14 21 28 t (days)

Conclusions (1) Virologic response rates are better in HCV-2 than HCV-3 infected patients Certain patients with HCV-2 or HCV-3 infection may be successfully treated with 12-16 weeks of combination therapy Patients infected with HCV-3 and high viral load may require longer than 24 weeks of combination therapy

Conclusions (2) Patients infected with HCV-1 and low baseline viral load who respond early (at week 4) may only require 24 weeks of combination therapy Slow viral responders infected with HCV-1 benefit from longer than 48 weeks of combination therapy Compliance and adherence important Future options: small molecules (HCV protease and polymerase inhibitors)