Hepatitis C Virus Infection Hepatitis C Virus Infection Burden of Disease in United States New infections (cases)/year , ,000 Persons with chronic infection 3.2 million ( 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 % % %. Armstrong GL et al. Ann Intern Med 2006;144: Davila JA et al, Gastroenterology 2004;127: Wise et al, Hepatology 2008;47: Accessed May 8, * Minimum, likely underestimates due to exclusion of prisoners, homeless, etc from NHANES IV

* 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: Total Infected Infected >20 Years HCC Cirrhosis

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

Potential Screening Criteria for HCV in the General Population Armstrong. Ann Intern Med, 2006;144:705. Screening Criteria Persons age y Risk factor history IDU IDU or transfusion before IDU or transfusion before 1992 or ≥20 lifetime sex partners Any illicit drug use or transfusion before 1992 or ≥20 lifetime sex partners Risk factor history and ALT level Abnormal ALT level Abnormal ALT level or injection drug use Abnormal ALT level or injection drug use or transfusion before Abnormal ALT level or injection drug use or transfusion before 1992 or ≥20 lifetime sex partners Abnormal ALT level or any illicit drug use or transfusion before 1992 or ≥20 lifetime sex partners Persons age ≥60 y Risk factor history Transfusion before Risk factor history and ALT level Abnormal ALT level Abnormal ALT level or transfusion before GeneralHCV RNA–PositivePopulation Participants with Criteria, %

Established Risk Factors for Progression of Fibrosis and Cirrhosis Poynard T, Lancet : Mathurin P, Hepatology : Benhamou J, Hepatology :  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

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

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

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

Early Data with Telaprevir: Important Principles Learned Kieffer. Hepatology. 2007;46:631. Copyright © Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc 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

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

SVR in Genotype 1 Non-US vs US Patients in Major Registration Trials Accessed May 8, 2008.

IDEAL Study USA G1 N=3070 End point n=960 Screening n= 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* Data on file Schering Corporation.*Time 0 = screening value Follow-up Sulkowski. EASL 2008

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

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

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.

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: 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

REPEAT Trial: cEVR Was Predictive of SVR With an Expected Relapse PEG-2a + RBV *P< † P=0.003 ‡ P< Marcellin. Presented at: AASLD Abstract 1174, LB µg/wk n= 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

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

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

Early Data with Telaprevir: Important Principles Learned Kieffer. Hepatology. 2007;46:631. Copyright © Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc 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