Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro

Hepatology. 1998 Dec;28(6):1669-73. doi: 10.1002/hep.510280629.


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.

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Amino Acid Sequence
  • Anti-HIV Agents / pharmacology*
  • Baculoviridae
  • DNA-Directed DNA Polymerase / genetics*
  • Drug Resistance / physiology
  • Hepatitis B virus / genetics*
  • Humans
  • Lamivudine / pharmacology*
  • Molecular Sequence Data
  • Mutation / physiology*
  • Organophosphonates*
  • Recombinant Proteins


  • Anti-HIV Agents
  • Organophosphonates
  • Recombinant Proteins
  • Lamivudine
  • adefovir
  • DNA-Directed DNA Polymerase
  • Adenine