Changes in viral loads of lamivudine-resistant mutants and evolution of HBV sequences during adefovir dipivoxil therapy

J Med Virol. 2006 Aug;78(8):1025-34. doi: 10.1002/jmv.20658.


The addition of adefovir dipivoxil (ADV) to ongoing lamivudine therapy is effective against lamivudine-resistant virus in patients with hepatitis B virus (HBV) infection. We studied 39 patients who received ADV added to lamivudine for breakthrough hepatitis. We determined early viral changes (12 weeks) in YMDD mutants (rtM204I [YIDD sequence], rtM204V [YVDD]) and rtL180M in all 39 patients as well as amino acid changes in the polymerase reverse transcriptase (rt) region and precore/core promoter mutations in 15 patients who received long-term treatment (more than 1 year). Changes in rtM204I and rtL180M viral loads were greater than that of the rtM204V, albeit statistically insignificant. Moreover, the greatest change in viral load was seen for rtM204I without hepatitis B e antigen (HBeAg). The precore mutant was replaced with wild-type virus in three of eight patients after 1 year of added ADV therapy. Compared to baseline with lamivudine therapy only, new amino acid mutations were seen in the rt region at baseline with ADV in seven patients. At 1 year after ADV coadministration, the YMDD motif was replaced with wild-type (rt204M) in two patients, in whom mutations were fewer and of a different type. We conclude that the rtM204I may be more sensitive to ADV in vivo. ADV tended to select wild-type virus from precore mutants. Moreover, viruses that were wild-type in the rt region reappeared after 1 year of ADV coadministration in some patients.

Publication types

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

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Adenine / therapeutic use
  • Adult
  • Antiviral Agents / administration & dosage
  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • Drug Administration Schedule
  • Drug Resistance, Viral*
  • Evolution, Molecular*
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Viral
  • Hepatitis B / drug therapy
  • Hepatitis B / virology*
  • Hepatitis B virus / drug effects*
  • Hepatitis B virus / genetics*
  • Hepatitis B virus / growth & development
  • Humans
  • Interferons / therapeutic use
  • Lamivudine / pharmacology*
  • Male
  • Middle Aged
  • Mutation
  • Organophosphonates / administration & dosage
  • Organophosphonates / pharmacology*
  • Organophosphonates / therapeutic use
  • RNA-Directed DNA Polymerase / genetics
  • RNA-Directed DNA Polymerase / metabolism
  • Viral Load*


  • Antiviral Agents
  • Organophosphonates
  • Lamivudine
  • Interferons
  • RNA-Directed DNA Polymerase
  • Adenine
  • adefovir dipivoxil