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Antiviral activity of clevudine [ L ‐FMAU, (1‐(2‐fluoro‐5‐methyl‐β, L ‐arabinofuranosyl) uracil)] against woodchuck hepatitis virus replication and gene expression in chronically infected woodchucks ( Marmota monax )
Author(s) -
Peek Simon F.,
Cote Paul J.,
Jacob James R.,
Toshkov Ilia A.,
Hornbuckle William E.,
Baldwin Betty H.,
Wells Frances V.,
Chu C. K.,
Gerin John L.,
Tennant Bud C.,
Korba Brent E.
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.20899
Subject(s) - woodchuck hepatitis virus , viremia , cccdna , virology , hepatitis b virus , hepadnaviridae , virus , duck hepatitis b virus , viral replication , orthohepadnavirus , biology , medicine , hbsag
L ‐FMAU [1‐(2‐fluoro‐5‐methyl‐β, L ‐arabinofuranosyl) uracil] has been shown to be an effective inhibitor of hepatitis B virus (HBV) and duck hepatitis B virus replication in cell culture and duck hepatitis B virus replication in acutely infected Peking ducks. The woodchuck hepatitis virus (WHV) and its natural host, the Eastern woodchuck ( Marmota monax ), have been established as a predictive model for the evaluation of antiviral therapies against chronic HBV infection. In this report, the antiviral activity of l‐FMAU against WHV replication in chronically infected woodchucks is described. Four weeks of once‐daily oral administration of L ‐FMAU significantly reduced viremia, antigenemia, intrahepatic WHV replication, and intrahepatic expression of woodchuck hepatitis virus core antigen (WHcAg) in a dose‐dependent manner. At the highest dose administered (10 mg/kg/d), significant reductions of intrahepatic WHV RNA and covalently closed circular (ccc)WHV‐DNA levels 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 observed. At the highest doses used, viremia remained significantly suppressed in at least one half of the treated animals for 10 to 12 weeks' posttreatment. No evidence of drug‐related toxicity was observed in the treated animals. L ‐FMAU is an exceptionally potent antihepadnaviral agent in vitro and in vivo , and is a suitable candidate for antiviral therapy of chronic HBV infection.