Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.

Objectives Intra-hepatic cholestasis of pregnancy (ICP) is uncommon, but has severe effects on pregnancy outcomes. ICP is characterized by elevated serum bile acids and liver enzymes and preferentially affects women with liver disorders. We compared bile acids and pregnancy outcomes of HIV-infected pregnant women, who commonly have elevated live enzymes, with uninfected controls. Methods Twenty-four HIV-infected, including 2 co-infected with hepatitis C virus (HCV), and 25 uninfected women were tested during early and late pregnancy and postpartum. Results After exclusion of the HCV-infected women, serum bile acids were similar in HIV-infected and uninfected participants. -glutamyl transpeptidase was elevated in HIV-infected compared with uninfected women during pregnancy and postpartum. Bilirubin and aspartate transaminase were higher in uninfected compared with HIV-infected women in early pregnancy, but subsequently similar. Bile acids in late pregnancy correlated with bile acids in the baby at birth. An HIV- and HCV-co-infected pregnant woman with active hepatitis developed ICP complicated by fetal distress. Another co-infected participant without active hepatitis had an uneventful pregnancy and delivery. Conclusion In the absence of HCV co-infection, bile acid metabolism appeared to be similar in HIV-infected and uninfected pregnant women. Both HIV-infected and uninfected pregnant women had mild liver enzyme elevations.