Susceptibility of lamivudine-resistant hepatitis B virus to other reverse transcriptase inhibitors

The emergence of resistant hepatitis B virus (HBV), with mutations in the Y MDD motif of the polymerase gene after treatment with lamivudine, is becomi ng an important clinical problem. In this study, susceptibility of wild-typ e and lamivudine-resistant HBV M552I, M552V, and L528M/M552V mutants to oth er reverse transcriptase inhibitors was investigated by transient transfect ion of full-length HBV DNA into human hepatoma cells. HBV DNA replication w as monitored by Southern blot hybridization, which showed the presence of a single-stranded band (representative of the HBV replicative intermediates) in the drug-free, wild-type HBV-transfected cells. This band was diminishe d in the samples of wild-type HBV DNA treated with either lamivudine, adefo vir, or lobucavir. The band intensities from the lamivudine-resistant mutan ts were not decreased by treatment with lamivudine, but were decreased by t he treatments with adefovir or lobucavir. In contrast, penciclovir and nevi rapine did not diminish the intensity of the single-stranded band of wild-t ype HBV or the lamivudine-resistant mutants. These results demonstrate that lamivudine-resistant HBV is susceptible to adefovir and lobucavir. Lamivud ine-resistant HBV should be treated with adefovir or lobucavir, and combina tion therapy with lamivudine and adefovir/lobucavir may prevent the emergen ce of lamivudine-resistant HBV.