title: Different mechanism of selection of adefovir-resistant mutant viruses during adefovir monotherapy in patients with lamivudine-resistant chronic hepatitis B.
abstract: BACKGROUND
  Adefovir (ADV) resistance is more frequent in lamivudine (LMV)-resistant chronic hepatitis B (CHB) patients than in nucleos(t)ide analogue-naïve patients. The majority of LMV-resistant mutants harbor the rtM204V/I mutation, while a minor fraction harbor the rtA181V/T mutation. We aimed to elucidate the mechanism of the high rate of ADV resistance in LMV-resistant patients during ADV therapy.
  
  
  METHODS
  We performed a clonal analysis of HBV reverse transcriptase in treatment-naïve (n = 3) and LMV-resistant patients before ADV therapy (n = 14). Dynamic changes in the viral population (n = 9) during ADV therapy were also analyzed.
  
  
  RESULTS
  Before ADV therapy, rtA181V/T was observed in 30 of 680 clones (4.4%) from 7 patients with LMV resistance under dominant rt204V/I mutation and in one of 150 clones in treatment-naïve patients. The rtA181V/T mutation was more frequently found in clones from LMV-resistant patients than in treatment-naïve patients (p = 0.029). The rtN236T mutation was not observed in any clone. During ADV therapy, most rtM204V/I mutants were replaced by wild type in all 3 patients without the rtA181V/T mutation and in one patient with the rtA181V/T mutation. Subsequently, wild type was replaced by the rtN236T and/or rtA181V/T mutant. In patients with the rtA181V/T mutation (n = 6), the rtA181V/T mutant overtook the rtM204V/I mutant in 3 of 4 patients with ADV resistance. In 2 patients without ADV resistance, most of the viral population was replaced by wild type by the last follow-up.
  
  
  CONCLUSIONS
  The high rate of ADV resistance in patients with LMV-resistance might be attributable to preexisting rtA181V/T mutant virus.
authors.affiliation: Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Yoo-Kyung
authors.initials: YK
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Xiu-Ji
authors.initials: XJ
authors.lastname: Cui
authors.affiliation: Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea.
authors.forename: Seung Uk
authors.initials: SU
authors.lastname: Jeong
authors.affiliation: Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea. Electronic address: drsong@jejunu.ac.kr.
authors.forename: Byung-Cheol
authors.initials: BC
authors.lastname: Song
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D006509:Hepatitis B / Q000201:enzymology / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D059645:Mutation Rate; D020125:Mutation, Missense; D063065:Organophosphonates / Q000494:pharmacology* / Q000627:therapeutic use*; D017354:Point Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D012189:Retrospective Studies; D012641:Selection, Genetic; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D019259:Lamivudine; C053001:adefovir; D012194:RNA-Directed DNA Polymerase; D000225:Adenine
keywords: Adefovir; Chronic hepatitis B; Lamivudine resistance