Faculty Bibliography

Chronic hepatitis C virus (HCV) infection is a pressing medical problem worldwide. Current therapy with pegylated interferon plus ribavirin (Peg-IFN/RBV) is associated with a poor risk benefit profile, a long treatment duration (48 weeks) and inadequate success rate (approximately 40-50%) of SVR (sustained viral response) in patients infected with genotype 1 HCV. This review is focused on recent clinical trial results with specifically targeted antiviral therapy for HCV (STAT-C) protease and polymerase inhibitors. In the past decade, anti-HCV drug discovery has focused first on targeting host factors required for viral replication and second on multiple HCV antiviral agents. Owing to the large number of HCV inhibitors currently in pre-clinical and clinical development today, we have focused on the most advanced compounds in the HCV polymerase and HCV protease inhibitor classes. Within each class, compounds will be used to illustrate some of the properties associated with inhibitors that bind to the active site of HCV polymerase, the active site of HCV protease (macrocyclic and linear ketoamide inhibitors) and allosteric polymerase inhibitors.

Chronic hepatitis C affects 170 million people worldwide, including up to 4 million people in the United States. The current standard of care therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) while highly successful in patients with genotype 2 and 3 infection, allows for sustained virologic response in 42-46% of treatment-naive genotype 1 patients, comprising about 70% of cases of chronic hepatitis C in the USA. While awaiting approval of Specifically Targeted Antiviral Therapy for HCV (STAT-C) agents, which will require the completion of additional clinical trials, it is important to optimize the dose and duration of currently available treatment modalities, namely PEG-IFN and RBV, for treatment of CHC. Results of several recent trials evaluating optimal dosing of RBV and higher than standard dosing of PEG-IFN in treatment-naive genotype 1 patients, as well as data from retreatment trials with "induction" doses of PEG-IFN or high-dose RBV in prior non-responders to IFN-based therapy will be reviewed here. The possibility of shorter duration of therapy for genotype 2 and 3 patients based on recent publications and presentations will be discussed as well.