1. Optimal therapy in genotype 1 patients 3 rd Paris Hepatitis Conference 19-20 January 2009 Stefan Zeuzem, MD J.W. Goethe University Hospital Frankfurt, Germany

2. Standard Treatment

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

4. Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL study) EASL 2008 (Late-Breaker Abstract) Sustained virologic response (%)

5. Virologic response in HCV genotype 1 or 4 infected patients 62,3 75,3 49,5 47,3 54,8 39,8 20,4 0 10 20 30 40 50 60 70 80 90 100 P<0.0003 P=0.04 Overall PEG IFN alfa-2aPEG IFN alfa-2b ETR SVR REL P=0.04 Percentage 15.1 9.7 Ascione et al., EASL 2008 62.3 47.3 75.3 54.8 20.4 49.5 39.8

6. Milan Safety Tolerability (MIST) Study Rumi, Colombo et al, AASLD 2008, A212 p = 0.02 p = 0.01p = 0.8 48% 96% 65% 54% 32% 82% 69% 66% 0% 20% 40% 60% 80% 100% Overall SVR SVR G1/4 SVR G2SVR G3 Sustained virologic response rates PEG alfa-2a PEG alfa-2b

7. Retrospective analysis of patients treated with either peginterferon alfa-2a or alfa-2b (PRACTICE study) Witthöft et al., EASL 2008 Sustained virologic relapse rate (%) 54.4% 59.1% 43.7% 76.8% 49.6% 78.3% P=0.05

8. Optimization of Standard Treatment

9. *Logit scale 5.6 log 10 IU/mL ~400 x10 3 IU/mL Effect of pre-tx HCV RNA on SVR Probability of SVR* Baseline HCV RNA (log 10 IU/ml) 34675 0.5 0.88 0.98 0.998 5.6 log 10 IU/mL

10. Relapse rate (%) Baseline viremia > 800.000 IU/mL All patients Baseline viremia 800.000 IU/mL Time to HCV RNA < 5.3 IU/mL by TMA in weeks Relation between the dynamics of virologic response and relapse prediction in patients receiving PEG-IFN / RBV x 48 weeks (n=225) Berg et al., AASLD 2007 (179A)

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

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

13. Early identification of HCV 1 patients responding to 24 wks PEG-IFN alfa-2a/RBV Jensen et al., Hepatology Jensen et al., Hepatology 2006;43:954-60 Sustained virologic response (%) 183340558184208210

14. Rates of relapse and SVR according to RVR and baseline viral load Yu et al., Hepatology 2008; 47:1884-1893 LVL and RVR HVL or non-RVR Response (%)

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

16. Extended treatment duration for HCV 1: 48 vs 72 weeks of PEG-IFN alfa-2a + RBV Sustained virologic response rate (%) Berg, et al. Gastroenterology 2006;130:1086-1097 104/130 90/119 17/10031/106 P=0.040

17. Virologic relapse rates in patients with slow virologic response Berg, et al. Gastroenterology 2006;130:1086-1097 Virologic relapse rate (%) Week 4 Week 12 30/47 21/52 46/124 28/122 P=0.016 P=0.021

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

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

20. Viral kinetics: tailoring of therapy in HCV genotype 1 infected patients 0123 1 2 3 4 5 6 7 7142128 detection limit a b c t (days) Serum HCV RNA (log 10 copies/mL) HCV-1 (LVL, RVR)24 weeks Zeuzem et al. 2004; Zeuzem et al. 2005; Jensen et al. 2006 HCV-1 (cEVR)48 weeks Manns et al. 2002; Hadziyannis et al. 2004; Kamal et al. 2005 HCV-1 (SPR)72 weeks Buti et al. 2003; Berg et al. 2006; Sanchez-Tapias et al. 2006

21. Treatment of Difficult-to-cure Patients

22. Virologic Response in G1, HVL, > 85 kg patients % Patients with VR VR = HCV RNA < 50 copies/mL Arm A (n=46) Arm B, C,& D (n=47) Fried et al., AASLD 2006 (n=66) (n=53)

23. SVR and anemia as functions of exposure AUC – HCV genotype 1 n = 242, Snoeck et al, Br J Clin Pharm 2006

24. Weight-based exposure of ribavirin and treatment response Yu et al., Hepatology 2008; 47:1884-1893 Treatment response (%) Relapse SVR

25. Case: HCV1, HVL, cirrhosis 5/06Standard therapy 8/06< 2 log decline (Hb 12.8) 9/06High dose (270 µg PEG-IFN alfa-2a + 1600 mg RBV) 12/06 > 2 log decline (RBV 2000 mg) 3/07HCV RNA negative 9/0818 months therapy with HD + EPO 1/09HCV RNA still negative (4 mo post-tx)

26. Conclusions Individualisation of treatment duration (24 – 72 weeks) Maintaining drug doses, subtle dose reductions when necessary Compliance and adherence very important Successful treatment also possible in difficult-to-treat populations Future options: small molecules (2011/12) which influence treatment indications today