Michalak TI, Zhang H, Churchill ND, Larsson T, Johansson NG, Oberg B
Profound antiviral effect of oral administration of MIV-210 on chronic hepadnaviral infection in the woodchuck model of hepatitis B. [JOURNAL ARTICLE]
Antimicrob Agents Chemother 2009 Jun 29.
MIV-210 is a prodrug of 3'-fluoro-2', 3'-dideoxyguanosine (FLG) with high oral bioavailability in humans and a potent activity against hepatitis B virus (HBV). Woodchucks infected with woodchuck hepatitis virus (WHV) represent an accurate model of HBV infection which is utilized for evaluation of efficacy and safety of novel anti-HBV agents. Oral administration of MIV-210 at 20 and 60 mg/kg/day induced a rapid virologic response in chronically infected woodchucks reducing in 2 weeks serum WHV DNA by 4.75-log10 and 5.72-log10, respectively. A progressive decline of WHV viremia occurred throughout the 10-week therapy, giving finally 7.23-log10 and 7.68-log10 reduction in the 20 and 60 mg/kg/day groups, respectively. Further, a daily dose of 10 mg/kg decreased by 400-fold serum WHV load after 4 weeks of treatment and a dose of 5 mg/kg/day was sufficient to maintain this antiviral effect during a following 6-week period. MIV-210 at 20 and 60 mg/kg/day reduced liver WHV DNA load by 200 to 2500-fold as compared to the pre-treatment levels and, importantly, a 2.0-log10 drop in the hepatic content of WHV covalently closed circular DNA. The treatment with 60 mg/kg/day was well tolerated. Liver biopsies obtained after the 10-week treatment with 20 or 60 mg/kg/day and the 10-week follow-up showed hepatocyte and mitochondrial ultrastructure comparable to that in the placebo-treated group. It was concluded that MIV-210 was highly effective against chronic WHV infection. These findings, together with the previously demonstrated MIV-210 inhibitory activity against lamivudine, adefovir and entecavir resistant HBV variants, makes MIV-210 a highly valuable candidate for further testing as an agent against chronic hepatitis B.
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