Clearance of the original hepatitis B virus YMDD-motif mutants with emergence of distinct lamivudine-resistant mutants during prolonged lamivudine therapy

Hepatology. 2000 Jun;31(6):1318-26. doi: 10.1053/jhep.2000.7296.


Tyrosine-methionine-aspartate-aspartate (YMDD)-motif mutants may emerge and elicit immune clearance during prolonged lamivudine treatment. The aim of this study was to investigate the virological events following development of the original mutants. Twenty-three patients who developed YMDD-motif mutants during the Asian lamivudine trial were included. Serial serum samples from these patients were subjected to sequence analysis to identify new mutants. Site-directed mutagenesis experiments were performed to investigate whether the new mutations were responsible for lamivudine resistance. Of the 23 patients included, 13 harbored either one or a mixture of the two common YMDD-motif mutants (methionine 552-to-isoleucine [M552I] and leucine 528-to-methionine/methionine 552-to-valine [L528M/M552V]) throughout the course, whereas in the remaining 10 patients, distinct mutants became dominant over the original mutants to cause continuing chronic hepatitis. Of them, 3 developed an alanine 529-to-threonine (A529T) mutant, 6 developed a leucine 528-to-methionine/methionine 552-to-isoleucine (L528M/M552I) mutant, and 1 developed these two mutants sequentially. Site-directed mutagenesis experiments confirmed that the aforementioned mutations were responsible for the resistance to lamivudine in vitro. The nucleotide substitution in the A529T mutant concomitantly generated a stop codon at the surface gene, leading to impaired secretion of HBsAg. Strikingly, the replication of this mutant was lamivudine dependent. These results suggested that distinct lamivudine-resistant mutants could emerge and replace the original YMDD-motif mutants as the cause of continuing chronic hepatitis during prolonged lamivudine therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Motifs / genetics
  • Amino Acid Sequence / genetics
  • Clinical Trials as Topic
  • Drug Resistance, Microbial / genetics
  • Female
  • Follow-Up Studies
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / genetics*
  • Hepatitis B, Chronic / drug therapy
  • Hepatitis B, Chronic / virology
  • Humans
  • Lamivudine / therapeutic use*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Multicenter Studies as Topic
  • Mutagenesis, Site-Directed
  • Mutation / drug effects
  • Mutation / genetics*
  • Mutation / physiology
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Time Factors


  • Reverse Transcriptase Inhibitors
  • Lamivudine