Mutations in Hepatitis B Dna Polymerase Associated With Resistance to Lamivudine Do Not Confer Resistance to Adefovir In Vitro

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Abstract
To determine whether adefovir is active against lamivudine–resistant hepatitis B virus (HBV), the inhibition constants of adefovir diphosphate and lamivudine triphosphate for wild–type and mutant human HBV DNA polymerases, which contain amino acid substitutions associated with lamivudine resistance, were compared. Recombinant wild–type and mutant human HBV DNA polymerases were expressed and substantially purified using a baculovirus expression system and immunoaffinity chromatography. HBV DNA polymerase mutants M552I, M552V, and L528M/M552V showed resistance to lamivudine triphosphate with inhibition constants (Ki ) increased by 8.0–fold, 19.6–fold, and 25.2–fold compared with that of wild–type HBV DNA polymerase. However, these mutants remained sensitive to adefovir diphosphate with the inhibition constants increasing by 1.3–fold and 2.2–fold or decreasing by 0.79–fold. The L528M single mutation, identified in patients with increasing HBV DNA levels during therapy with famciclovir, also remained sensitive to adefovir diphosphate with the inhibition constant increased by only 2.3–fold.