1. Alessio Aghemo First Division of Gastroenterology Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Università degli Studi di Milano 5 th Paris Hepatitis C Conference Paris, 30 January 2012 Luncheon: How to optimize treatment of G2 and G3 patients

2. HCV infection (genotype 2a/c) known since 1998 No risk factors for HCV ALT values 2 x ULN since 1998 Comorbidities: overweight (BMI 28) September 2008: Fibroscan 10.2 KPa, SR 96%, IQR 1.1 Enlarged liver at US, no splenomegaly Refuses PegIFN plus Rbv Continues Follow-up visits at our center S.G. 57 yr Housewife

3. ALT IU/L 61 HCV-RNA 10 5 /IU/mL 2.68 Total Bilirubin mg/dL 1.2 Albumin g/dL 4.1 Prothrombin ratio 1.12 Platelets 10 3 /mmc 195 Fibroscan KPa 10.2 112 5.62 1.0 3.9 1.11 196 9.8 78 3.62 1.0 4.0 1.16 184 11.4 Sep 2008Sep 2010Sep 2009 Liver Function Tests Liver Function Liver biopsy: 24 mm specimen Chronic hepatitis with septae (Ishak G7, S4)

4. ALT IU/L 78 HCV-RNA 10 5 /IU/mL 3.68 Total Bilirubin mg/dL 1.0 Albumin g/dL 4.1 Prothrombin ratio 1.12 Platelets 10 3 /mmc 195 Hb 14 WBC 5500 Neutrophils 2900 33 <12 1.0 3.9 1.11 127 12.5 4130 1630 39 ND 0.9 3.9 1.16 118 11.8 3500 1450 BaselineWeek 4Week 2 Liver Function Tests During PegIFNalfa2a 180 mcg + Rbv 800 mg/day Liver Function What is the optimal treatment duration?

5. HCV RNA Kinetics During PegIFN + Rbv to Predict Treatment Outcome and Individualize Treatment Duration HCV-2/3 Patients Weeks 012-16 24 PegIFNalfa + RBV 800/dayPegIFNalfa + RBV 800 mg/day

6. DesignNo.RegimenDurationRVR (LOD) Allocation by RVR Dalgard 2004122 Peg  2b + Rbv wbd 14 w78% (50 IU) Mangia 2005283 Peg  2b 1.0 + Rbv wbd 12 w63% (50 IU) Randomization by RVR von Wagner 2005153 Peg  2a + Rbv wbd 16 w 93% (600 IU) Dalgard 2008428 Peg  2b + Rbv wbd 14 w71% (50 IU) Baseline Randomization Shiffman 20071469 Peg  2a + Rbv 800 mg 16 w65% (50 IU) Lagging 2008382Peg  2a + Rbv 800 mg12 w60% (15 IU) SVR Rates Following Abbreviated Therapy in HCV-2 and HCV-3 RVR (+)RVR (-) 50% 67% - 75% RVR (+) Standard (24 weeks)Abbreviated (12-16 weeks) 91% 87% 95% 93% - 89% 95% 97% HCV-2 only

7. The ACCELERATE Study: SVR Rates by Genotype SVR (%) Standard population; VR = HCV RNA < 50 IU/mL N=346N=303N=333N=327 P= <.0001P= 0.1565 60% 70% 77% 86% 60% 70% 66% 76% White lines represent 95% confidence intervals Shiffman ML et al NEJM 2007 Jul 12;357(2):124-34.

8. The ACCELERATE Study: sub-analysis of SVR in Patients with RVR N=215 SVR p=0.0012 p=0.1046 92% 90% 81% 84% 0%20%40%60%80%100% Genotype 3 Genotype 2 16 weeks Pegasys 180 ug + Copegus 800 mg 24 weeks Pegasys 180 ug + Copegus 800 mg N=243 N=212 N=193 Shiffman ML et al NEJM 2007 Jul 12;357(2):124-34.

9. Identifying HCV-2/3 Patients Who Can Receive a 16-wk Abbreviated Course of PegIFNalfa2a and Ribavirin Similar SVR rates 87% vs 88% in patients with at least 2 positive predictors LVL, <40 yrs, <65 Kg and absence of cirrhosis Diago M et al, Hepatology 2010 ; 51(6):1897-903

10. Efficacy of PegIFNalfa2a plus Rbv in 818 HCV-2 & HCV-3 Patients with Advanced Fibrosis and Cirrhosis EOTSVRRel 100 80 60 40 20 0 89 86 84 61 76 57 15 28 32 Response rates (%) Without advanced fibrosis Bridging fibrosis (no cirrhosis) Cirrhosis Bruno S et al, Hepatology 2010, 51(2):388-97

11. High Rates of Post-treatment Relapse in HCV-2 and 3 Patients with Advanced Fibrosis PegIFNalfa2a + Rbv 800 mgPegIFNalfa2b + Rbv 800-1200 mg Prati GM et al, J Hepatology 2012, 56:341-347

12. High Rates of Post-treatment Relapse in HCV-2 and 3 Patients with Advanced Fibrosis Prati GM et al, J Hepatology 2012, 56:341-347

13. ALT IU/L 39 HCV-RNA 10 5 /IU/mL ND Total Bilirubin mg/dL 0.9 Albumin g/dL 3.9 Prothrombin ratio 1.16 Platelets 10 3 /mmc 118 Hb 11.8 WBC 3500 Neutrophils 1450 55 ND 1.0 3.9 1.11 147 11.5 4130 1630 57 3.62 0.9 3.9 1.16 198 13.8 5500 2450 Week 4Week 4 fupWeek 24 (EOT) Liver Function Tests During PegIFNalfa2a 180 mcg + Rbv 800 mg/day anf Follow-up Liver Function

14. What Now???  Retreat with PegIFN plus Rbv?  Retreat using high dose Rbv? (Off Label)  Retreat using Telaprevir?(Off Label)  Wait for new drugs? (2014-2015)

15. Telaprevir Alone or in Combination With PegIFN/Rbv For HCV-2 Patients Foster GR et al, Gastroenterology 2011, 141:881-889 Phase II study on 23 HCV-2 and 26 HCV-3 patients