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The ultimate goal of antiviral therapies for chronic HCV is to prevent progression of liver fibrosis progression, cirrhosis, complications of endstage liver disease (decompensation; HCC), need for liver transplantation, and deaths due to HCV. However, the best indicator of treatment efficacy is the sustained virological response (SVR), defined as an undetectable serum HCV RNA at the end of treatment that persists long-term after treatment is discontinued (for ~ 6 months). Patients who achieve a SVR have a> 95 % probability of maintaining undetectable serum HCV, improvement in liver biopsy hepatitis activity features, and decreased rates of hepatic fibrosis compared to non-SVR. Several major advances in antiviral therapy for chronic HCV have occurred since 1990 when interferon alfa (IFNa)-2b (3 million units 3 times per week for 6 months) became the first FDA-licensed treatment for chronic HCV in the USA. However, less than 10 % of treated subjects experienced a SVR. The efficacy of IFNa monotherapy was increased considerably by increasing the duration of therapy to 12 months. Still, the SVR was then 20 % overall. In 1998, combination therapy with IFN alpha-2b 3 times weekly with oral ribavirin for 48 weeks was licensed by the FDA based on superior efficacy compared to IFN alfa monotherapy (1). The SVR in patients treated with combination therapy was 38 % compared to 13 % in patients receiving IFNa monotherapy. Treatment for 48 weeks was superior to 24 weeks in patients infected with HCV genotype 1 (29 % vs. 17%). The SVR in HCV genotype 2 and 3 patients was the same regardless of the 24-week or 48 week treatment duration (65-66%). Subsequent studies found conjugating IFNa-2a to either a 40-Kd polyethylen