Evolution of hepatitis B virus polymerase gene sequence during famciclovir therapy for chronic hepatitis B

J Infect Dis. 2000 Apr;181(4):1221-33. doi: 10.1086/315368. Epub 2000 Apr 13.


Prolonged administration of nucleoside analogues for chronic hepatitis B may result in the emergence of hepatitis B viral polymerase mutants. To gain insight into the mechanism involved in the virus's resistance to famciclovir, the amino acid sequences of the terminal protein and reverse-transcriptase (RT) domains of the viral polymerase were determined during therapy among 28 patients. The antiviral response was independent of viral genotypes, and nonresponse to famciclovir was associated with a complex variability of the RT domain. No mutation in the YMDD motif was observed, whereas an L528M mutation was clearly selected by famciclovir treatment in 2 patients, as well as 14 novel mutations in 7 patients. Clone sequence analysis of the RT domains of patients undergoing retreatment with famciclovir and/or lamivudine showed the selection of a preexisting drug-resistant mutant in one case and indicated that sequential antiviral therapy may allow the rapid selection of resistant strains.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Aminopurine / analogs & derivatives*
  • 2-Aminopurine / therapeutic use
  • Adult
  • Amino Acid Sequence
  • Antiviral Agents / therapeutic use*
  • Cloning, Molecular
  • Drug Resistance, Microbial / genetics
  • Evolution, Molecular*
  • Famciclovir
  • Female
  • Gene Products, pol / chemistry
  • Gene Products, pol / genetics*
  • Hepatitis B e Antigens / analysis
  • Hepatitis B virus / enzymology*
  • Hepatitis B, Chronic / drug therapy
  • Hepatitis B, Chronic / enzymology*
  • Hepatitis B, Chronic / genetics
  • Humans
  • Longitudinal Studies
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • RNA-Directed DNA Polymerase / chemistry
  • RNA-Directed DNA Polymerase / genetics*
  • Sequence Alignment


  • Antiviral Agents
  • Gene Products, pol
  • Hepatitis B e Antigens
  • P protein, Hepatitis B virus
  • 2-Aminopurine
  • RNA-Directed DNA Polymerase
  • Famciclovir