title: Evolution of viral load and changes of polymerase and precore/core promoter sequences in lamivudine-resistant hepatitis B virus during adefovir therapy.
abstract: Adefovir dipivoxil (ADV) has demonstrated clinical activity against both wild-type and lamivudine-resistant hepatitis B virus (HBV). We analyzed the evolution of viral load and the changes of polymerase and precore/core promoter sequences in lamivudine-resistant virus during ADV therapy. The authors studied 14 patients who had breakthrough hepatitis after lamivudine therapy. Serial sera were obtained prior to adefovir administration and at 3, 6 and 12 months after ADV therapy. Nucleotide sequences of polymerase and the precore/core promoter from the hepatitis B virus were analyzed. The median serum HBV DNA decrease with adefovir treatment was 4.35 log(10) copies/mL at 12 months. Tyrosine-methionine-aspartate-aspartate (YMDD) mutants were found in 12 patients among the 14 patients with lamivudine resistance. The YMDD mutant viruses reversed to the wild-type in 6 patients out of the 12 patients after 3-6 months of ADV after discontinuing lamivudine therapy. In the analysis of the nucleotide sequences of the precore/core promoter gene, core promoter mutants in 12 patients were replaced by wild-type virus in three patients (25%), while precore mutants in four patients were replaced by the wild-type in three patients (75%). The results demonstrate the patterns of polymerase and precore/core promoter mutations in lamivudine-resistant hepatitis B viruses and the reversion from the mutant to the wild-type in some patients. In addition, despite several mutations in the polymerase during ADV therapy, ADV effectively suppressed HBV replication without the emergence of resistant viral mutants.
authors.affiliation: Department of Internal Medicine and WHO Collaborating Center on Viral Hepatitis, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: U Im
authors.initials: UI
authors.lastname: Chang
authors.forename: Young Chun
authors.initials: YC
authors.lastname: Lee
authors.forename: Seong Heon
authors.initials: SH
authors.lastname: Wie
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Jang
authors.forename: Si Hyun
authors.initials: SH
authors.lastname: Bae
authors.forename: Jong Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Jin Mo
authors.initials: JM
authors.lastname: Yang
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
authors.forename: Hee Sik
authors.initials: HS
authors.lastname: Sun
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004279:DNA, Viral / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D015684:Gene Products, pol / Q000235:genetics; D005814:Genes, Viral; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000627:therapeutic use*; D011401:Promoter Regions, Genetic; D014758:Viral Core Proteins / Q000235:genetics; D014766:Viremia / Q000188:drug therapy / Q000821:virology
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; D004279:DNA, Viral; D015684:Gene Products, pol; D063065:Organophosphonates; C066027:P protein, Hepatitis B virus; D014758:Viral Core Proteins; D019259:Lamivudine; D000225:Adenine; C106812:adefovir dipivoxil