Sources of Hepatitis C Infection (U.S.) Previously Acquired (<1990s) Transfusion 10% Sexual 18% Other 1%* Unknown 9% Injection Drug Use 68% Unknown 10% Other 1%* Sexual 15% Injection Drug Use 60% 60% * Other includes nosocomial, iatrogenic, perinatal Occupational 4% Occupational 4% Newly Acquired ( ) Sources: Based on Sentinel Counties, NHANES III

Differences in Risk Behaviors for HCV Acquisition in IDUers Evans J, J Urban Health, 2003 % N=584 males N=260 females Young IDUers(< 30 yrs) in San Francisco

Predictors of Unsafe Syringe Sharing in Women IDUers PredictorOR(95% CI)*P Value Shared needles/syringes with partner previously (2.2, 154) Injection partner was primary male partner 5.05 (1.2, 21.0) 0.03 Felt they were not in control of injecting safely 2.56 (0.94, 8.33) 0.06 Felt “very close” to their injection partners 3.53 (0.89, 14.1) 0.08 Tortu S, AIDS and Behavior, 2003 * Adjusted odds ratios

Risk of HCV Transmission Between Sex Partners STD Patients Partner Status Total N N (%) Anti-HCV Positive ORP Value Female Male partner HCV+ Male partner HCV (10) 7 (3) Male Female partner HCV+ Female partner HCV (7) 18 (8) 0.9NS Thomas D, JID, 1995

Natural History of HCV Infection Liver Disease Progression Exposure (Acute Phase) Resolved Chronic Cirrhosis Stable HCC 5%-25% over 20 years 15-45% 55-85% 3% per year 75-95% Alter MJ. Semin Liver Dis Freeman, Hepatology % per year Decompensation Liver Failure

Rate of Spontaneous Clearance of HCV Following Exposure  704 Irish women infected with HCV by contaminated anti-D immune globulin were tested for HCV 17 years after exposure --> 55% HCV RNA+  Liver biopsies performed in 363 patients Kenny-Walsh et al, N Engl J Med 1999 %

Chronic HCV Infection with Persistently Normal ALT Levels  Accounts for ~30% of persons with chronic HCV infection  Histological disease tends to be mild  Cirrhosis present in 2.5% (X-sectional studies)  Rate of disease progression is slower than patients with abnormal ALT levels  Same genotype distribution and viral load as abnormal ALT  Female gender predominates -> 61-90% of the normal ALT population

 Persistently elevated ALT levels  Longer duration of infection  Alcohol excess (>50 gm/day)  Age >40 years at time of infection  HIV or HBV coinfection  High BMI  Male gender Risk Factors for Progressive Fibrosis and Cirrhosis Poynard T, Lancet : Mathurin P, Hepatology : Benhamou J, Hepatology :1054-8

Rate of Fibrosis Progression By Gender Duration of Infection (yrs) Males Females Poynard, Lancet, 1997 Cirrhosis Bridging Fibrosis Portal Fibrosis + Septae Portal Fibrosis No Fibrosis

Fibrosis and Alcohol Consumption Duration of Infection (Years) Fibrosis Stage Age of Biopsy (Years) Fibrosis Stage 0-49 g alcohol/day ≥50 g alcohol/day 0-49 g alcohol/day ≥50 g alcohol/day Poynard T et al, Lancet 1997

> 175 gms Lifetime Daily Alcohol Intake Corrao and Arico, Hepatology 1998;27:917. Risk of Cirrhosis in Alcohol and HCV 12 gms = 1 drink HCV negative HCV positive

With ingestion of equivalent amounts of alcohol, females are at higher risk of alcohol-related liver injury than males Women with HCV who drink alcohol may be at higher risk of progressive liver disease than male who drink Alcohol is an important cofactor in HCV disease progression

Becker U, et al. Hepatology beverage = 12 g/alcohol Alcoholic Cirrhosis Estimated relative risk Beverages per week Alcoholic Liver Disease Women Men Women Men Estimated relative risk Beverages per week 70

Alcohol Consumption and Risk of Chronic Liver Disease Odds of developing CLD and cirrhosis are increased in women consuming 1 or more drinks per day (≥13 g/day) –Dose-response is present --> More alcohol means higher risk of developing cirrhosis In setting of chronic HCV infection, the “safe” level of alcohol is unknown but predicted to be less than that for alcoholic liver disease –Risk of cirrhosis increased significantly by ingestion of >50/gm day alcohol (but gender specific data lacking)

Chronic HCV Infection and Hepatocellular Carcinoma (HCC)  Age-adjusted incidence of HCC increasing in the U.S.  Doubling in past 2 decades ( )  3.0/100,000 persons in  Incidence is expected to risk further as number of prevalent HCV cases with cirrhosis and other complications of long-standing disease increases  Ethnic, geographic and gender differences are evident  In all ethnic groups, men have twice the rate of HCC as females

Reproductive Status and HCC Risk in Women with CVH Reproductive FactorHCC OR (95%CI) P Value # full-term pregnancies (≥4 vs ≤1) 0.45 (0.24,0.84) Older age of natural menopause (≥50, 45-49, <45 yrs respectively) 1.46 (0.52,4.08) 2.14 (0.80,5.73) 4.27 (1.01,18.07) Bilateral Oophorectomy < age 50 yrs 2.57 (1.42,4.63) women HCC (majority infected with HBV or HCV), 719 controls Yu MW, Hepatology, 2003

Gender Differences in the Natural History of HCV Disease  Rate of spontaneous clearance of virus following exposure is high in (young) women  Among persons with chronic HCV infection and persistently normal liver enzymes, the majority are women  Severity of disease is less and rate of disease progression slower in women than men  Alcohol use by women with HCV is likely to have more pronounced effects on the liver than men  Rates of HCC are lower in women than men and reproductive factors may influence HCC risk. Summary

Summary of Advances in Antiviral Therapy 13-19% 55-56% 38-45% 0% 20% 40% 60% % Patients IFN  -2b + RBV IFN  48 wks PEG-IFN + RBV McHutchison JG. Semin Liver Dis. 1999; Manns M, Lancet 2001; Fried M, N Engl J Med 2002

Host Factors Viral Factors  Genotype  Viral Load Predictors of Virologic Response Treatment Factors  Target RBV dose  Treatment Duration  Adherence to full dose therapy  Age  Cirrhosis  Race  Gender  Weight

Factors Influencing Response to Interferon Plus Ribavirin Weight > 75 kg Weight  75 kg Advanced fibrosis Minimal fibrosis Male Female Age > 40 Age  40 High HCV RNA Low HCV RNA Genotype 1 Increasing usefulness in predicting viral clearance with Rx Sustained Virologic Response (%) Genotype 2 or 3 Adapted from McHutchison JG et al. Semin Liver Dis. 1999;19(suppl 1):63.

Baseline Factors Independently Associated with SVR FDA Antiviral Drugs Advisory Committee Proceedings Peginterferon alfa-2a. November 14, Genotype (1 vs non-1) Pretreatment Viral Load Age ALT Quotient Histology Race Weight 800 vs 1000/1200 mg RBV 24 vs 48 Wks Tx US vs Non US Gender Wald Chi-Square N= 1737 PEG IFN Alfa-2a + RBV