Antiviral activity of clevudine [L-FMAU, (1-(2-fluoro-5-methyl-beta, 1-arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks (Marmota monax)

L-FMAU [1-(2-fluoro-5-methyl-beta ,L-arabinofuranosyl) uracil] has been sho wn to be an effective inhibitor of hepatitis B virus (HBV) and duck hepatit is B virus replication in cell culture and duck hepatitis B virus replicati on in acutely infected Peking ducks. The woodchuck hepatitis virus (WHV) an d its natural host, the Eastern woodchuck (Marmota monax), have been establ ished as a predictive model for the evaluation of antiviral therapies again st chronic HBV infection. In this report, the antiviral activity of L-FMAU against WHV replication in chronically infected woodchucks is described. Fo ur weeks of once-daily oral administration of L-FMAU significantly reduced viremia, antigenemia, intrahepatic WHV replication, and intrahepatic expres sion of woodchuck hepatitis virus core antigen (WHcAg) in a dose-dependent manner. At the highest dose administered (10 mg/kg/d), significant reductio ns of intrahepatic WHV RNA and covalently closed circular (ccc)WHV-DNA leve ls also were observed. The reduction in viremia was remarkably rapid at the higher doses of L-FMAU, with greater than 1,000-fold reductions in WHV-DNA serum levels observed after as little as 2 to 3 days of therapy. Following the withdrawal of therapy, a dose-related delay in viremia rebound was obs erved. At the highest doses used, viremia remained significantly suppressed in at least one half of the treated animals for 10 to 12 weeks' posttreatm ent. No evidence of drug-related toxicity was observed in the treated anima ls. L-FMAU is an exceptionally potent antihepadnaviral agent in vitro and i n vivo, and is a suitable candidate for antiviral therapy of chronic HBV in fection.