title: Lamivudine resistance in patients with chronic hepatitis B: role of clinical and virological factors.
abstract: BACKGROUND
  Lamivudine resistance is associated with long-term monotherapy for chronic hepatitis B and can lead to potentially serious clinical consequences. Scant information exists regarding the influence of hepatitis B virus variants in the development of resistance. The present study was designed to identify factors predictive of lamivudine resistance, with a particular focus on the role of precore and basal core promoter variants in the setting of hepatitis B e antigen-negative disease.
  
  
  METHODS
  Eighty-five patients, representing four major genotypes, were followed prospectively on lamivudine therapy. Resistance was defined as an increase in viral load, with polymerase gene sequencing confirming a lamivudine resistance mutation. Median follow up was 19 months (6-54 months). The Cox proportional hazards model was used to determine variables independently predicting for the early onset of lamivudine resistance.
  
  
  RESULTS
  The rate of lamivudine resistance was 6%, 31% and 51% at 12, 24 and 48 months, respectively. Multivariate analysis identified the precore variant, high baseline alanine aminotransferase (ALT), and persistent viremia (at 6 months) as independent predictors of the early development of lamivudine resistance, with rate ratios of 4.93 (95% confidence interval [CI]: 1.32-18.5), 1.22 (95%CI: 1.08-1.49), and 4.73 (95%CI: 1.49-15.0), respectively (P < 0.05). Female sex predicted early resistance (rate ratio 5.27 [95%CI: 1.23-22.5, P < 0.05]) although numbers were small (n = 12). Genotype did not influence treatment response nor time to onset of resistance.
  
  
  CONCLUSIONS
  Patients with precore variant hepatitis B virus are likely to develop lamivudine resistance early and should be considered for alternate first-line monotherapy. In the future, combination antiviral therapy may limit the development of resistance.
authors.affiliation: St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Alexander J V
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Anna
authors.initials: A
authors.lastname: Ayres
authors.forename: Lilly
authors.initials: L
authors.lastname: Yuen
authors.forename: Angeline
authors.initials: A
authors.lastname: Bartholomeusz
authors.forename: D Scott
authors.initials: DS
authors.lastname: Bowden
authors.forename: David M
authors.initials: DM
authors.lastname: Iser
authors.forename: Robert Y M
authors.initials: RY
authors.lastname: Chen
authors.forename: Barbara
authors.initials: B
authors.lastname: Demediuk
authors.forename: Gideon
authors.initials: G
authors.lastname: Shaw
authors.forename: Sally J
authors.initials: SJ
authors.lastname: Bell
authors.forename: Katrina J R
authors.initials: KJ
authors.lastname: Watson
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Locarnini
authors.forename: Paul V
authors.initials: PV
authors.lastname: Desmond
mesh_terms: D000328:Adult; D024882:Drug Resistance, Viral; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine