1. Hepatitis C Virus Infection Hepatitis C Virus Infection Burden of Disease in United States New infections (cases)/year 1985-89242,000 200520,000 Persons with chronic infection 3.2 million (2.7-3.9 million)* % Chronic liver disease = HCV-related 40% - 60% Deaths from chronic HCV/year (2004)12,000-41,000 (est./adj.) % Liver cancer due to HCV 1993-96 11% 1996-99 21% 200648%. Armstrong GL et al. Ann Intern Med 2006;144:705-714 Davila JA et al, Gastroenterology 2004;127:1372-80 Wise et al, Hepatology 2008;47:1128-35 http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/. Accessed May 8, 2008. * Minimum, likely underestimates due to exclusion of prisoners, homeless, etc from NHANES IV

2. 1960 1970* 1980 1990 2000 2010 2020 2030 Year 4.0% 3.0% 2.0% 1.0% 0.0% Prevalence of HCV Infection Predicted Future Prevalence of HCV in the United States Armstrong et al, Hepatology, 2000;31:777-782 Total Infected Infected >20 Years HCC Cirrhosis

3. Reducing the Burden of HCV- Related Liver Complications  Prevent new infections: primary prevention  No vaccine  Risk behaviors reduction  Preventing complications of liver disease in those with chronic infection = secondary and tertiary prevention  Identifying infected individuals  Identify and reverse/eliminate factors which accelerate rate of fibrosis progression  Therapies to stabilize or reverse liver injury and fibrosis

4. Potential Screening Criteria for HCV in the General Population Armstrong. Ann Intern Med, 2006;144:705. Screening Criteria Persons age 20-50 y Risk factor history IDU1.946.6 IDU or transfusion before 19927.353.1 IDU or transfusion before 1992 or ≥20 lifetime sex partners21.076.1 Any illicit drug use or transfusion before 1992 or ≥20 lifetime sex partners33.289.7 Risk factor history and ALT level Abnormal ALT level12.062.6 Abnormal ALT level or injection drug use13.382.8 Abnormal ALT level or injection drug use or transfusion before 199218.185.1 Abnormal ALT level or injection drug use or transfusion before 1992 or 30.093.5 ≥20 lifetime sex partners Abnormal ALT level or any illicit drug use or transfusion before 1992 or 40.798.6 ≥20 lifetime sex partners Persons age ≥60 y Risk factor history Transfusion before 199217.260.1 Risk factor history and ALT level Abnormal ALT level5.156.7 Abnormal ALT level or transfusion before 199221.187.4 GeneralHCV RNA–PositivePopulation Participants with Criteria, %

5. Established Risk Factors for Progression of Fibrosis and Cirrhosis Poynard T, Lancet 1997 349:825-32 Mathurin P, Hepatology 1998 27:868-72 Benhamou J, Hepatology 1999 30:1054-8  Male gender  Longer duration of infection  Age >40 years at time of infection  Alcohol excess  >50 gm/day - men  >30 gm/day - women  Persistently elevated ALT levels  HIV, HBV coinfections  Organ transplantation

6. Newly-Recognized Risk Factors for HCV Disease Progression  Menopausal status  Cannabis  Insulin resistance  Obesity, metabolic syndrome

7. Modifying Risk of Cirrhosis in Patients with HCV Summary  Alcohol  Moderate to heavy use clearly bad  Limited data on impact of “social” use of alcohol  Abstinence is generally recommended  Cannabis  Daily use accelerates fibrosis progression  Unclear if less frequent use is harmful  Insulin resistance and steatosis  Independent contributors to fibrosis progression  Weight loss reduces fibrosis progression  Menopausal status may be modifiable  HRT may reduce risk of fibrosis progression

8. Burden of HCV Disease Summary  Increasing number of persons with chronic HCV developing complications of cirrhosis and HCC  Fibrosis progression is not linear  Increase with age and post-menopausal status  Several “modifiable” factors recognized  Offers some opportunities to modify disease progression  Estimating risk of fibrosis progression and liver complications is important  Patients for whom treatment is deferred  Nonresponders

9. Early Data with Telaprevir: Important Principles Learned Kieffer. Hepatology. 2007;46:631. Copyright © 2007. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. -6 -5 -4 -3 -2 0 1 1234567891011121314 Study Time (days) HCV RNA Change from Baseline (Log 10 IU/mL) Telaprevir + PEG IFN alfa-2a N=8 Telaprevir N=8 PEG IFN alfa-2a + placebo N=4 Baseline Sequence analysis 15 Resistant mutations emerged within 4-7 days; subsequently suppressed by PEG IFN + RBV

10. Pharmacokinetics of PEG IFN PEG IFN-2b PEG IFN-2a IFN 3 Hours 0 5 10 15 20 25 30 024487296120144168 Mean Concentration (ng/mL) After first dose 1 At steady state 2 Adapted from Glue. Clin Pharmacol Ther. 2000;68(5):556. 1. Algranati. Hepatology. 1999;30(suppl 1):190A. 2. Modi. Hepatology. 2000;32(suppl 2):394A. 3. Kozlowski. BioDrugs. 2001;15(7):419-429.

11. SVR in Genotype 1 Non-US vs US Patients in Major Registration Trials http://www.hivandhepatitis.com/2005icr/aasld/docs/111805_a.html. Accessed May 8, 2008.

12. IDEAL Study USA G1 N=3070 End point n=960 Screening n=960 48 Weeks24 Weeks PEG-IFN alfa-2b 1.0 mcg/kg/wk + ribavirin 800-1,400 mg/d PEG-IFN alfa-2b 1.5 mcg/kg/wk + ribavirin 800-1,400 mg/d PEG-IFN alfa-2a 180 mcg/wk + ribavirin 1,000-1,200 mg/d 0* 2 4 12 24 48 +4 +12 +24 Data on file Schering Corporation.*Time 0 = screening value Follow-up Sulkowski. EASL 2008

13. IDEAL Final Results USA G1 n=3070 Sulkowski. EASL 2008

14. SVR With Fixed-dose PEG IFN  -2a + Weight Adjusted RBV: All Genotypes 66% 36% Fried. NEJM. 2002;347:975.

15. PEG IFN/RBV for 48 vs 72 Weeks in Patients With Detectable HCV at Week 4 of Treatment: Study Design 510 HCV Patients PEG IFN  -2a 180  g/wk plus RBV 800 mg/day for 4 weeks 326 With Detectable HCV-RNA 184 With Undetectable HCV RNA Group A 48 Weeks Total Treatment n=165 Group B 72 Weeks Total Treatment n=161 Group C 24 Weeks Total Treatment n=148 Group D 48 Weeks Total Treatment n=36 Adapted from Sánchez-Tapias. Gastroenterology 2006;131:451.

16. Peg-IFN/RBV for 48 vs. 72 Weeks in Patients with Detectable HCV at Week 4 of Treatment: SVR Comparisons SVR (%) OverallGenotype 1 Baseline HCV RNA  800,000 IU/mL Baseline HCV RNA >800,000 IU/mL Adapted from Sánchez-Tapias. Gastroenterology 2006;131:451. 48 Weeks 72 Weeks P=0.014P=0.003 P=0.004 P=0.60 n= 165 n= 161 n= 149 n= 142 n= 96 n= 86 n= 69 n= 75

17. REPEAT Trial: cEVR Was Predictive of SVR With an Expected Relapse PEG-2a + RBV *P<0.0001 † P=0.003 ‡ P<0.0001 Marcellin. Presented at: AASLD 2005. Abstract 1174, LB04. 0 10 20 30 40 50 60 70 180 µg/wk n=469 360 µg/wk n=473 Patients (%) with HCV RNA (-) <600 IU/mL Patients (%) with HCV RNA (-) <50 IU/mL (%) 25% N=942 patients have reached Week 12 13% 42%* 20% † 1/3 relapse: expect 9% SVR and 15% with higher dose

18. REPEAT Final Results 360 mcg 180 mcg Jensen. AASLD 2007.

19. SVR (%) IFN 6 m IFN/RBV PEG/RBV 12 m IFN IFN/RBV 1991199920012008 Evolution of Therapy of HCV Genotype 1 The number to beat is 40% and the time to beat is 12 months

20. Early Data with Telaprevir: Important Principles Learned Kieffer. Hepatology. 2007;46:631. Copyright © 2007. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. -6 -5 -4 -3 -2 0 1 1234567891011121314 Study Time (days) HCV RNA Change from Baseline (Log 10 IU/mL) Telaprevir + PEG IFN alfa-2a N=8 Telaprevir N=8 PEG IFN alfa-2a + placebo N=4 Baseline Sequence analysis 15 Resistant mutations emerged within 4-7 days; subsequently suppressed by PEG IFN + RBV