title: Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase.
abstract: OBJECTIVE
  Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment.
  
  
  METHODS
  HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient-derived HBV as well as specific mutations created by site-directed mutagenesis of a HBV/baculovirus recombinant.
  
  
  RESULTS
  Following the commencement of treatment with adefovir dipivoxil, the patient initially responded with a 2.4 log(10) decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near-pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to adefovir.
  
  
  CONCLUSIONS
  The development of this novel mutation in the HBV polymerase confers resistance to adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.
authors.affiliation: Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia. peter.angus@armc.org.au
authors.forename: Peter
authors.initials: P
authors.lastname: Angus
authors.forename: Rhys
authors.initials: R
authors.lastname: Vaughan
authors.forename: Shelly
authors.initials: S
authors.lastname: Xiong
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.forename: William
authors.initials: W
authors.lastname: Delaney
authors.forename: Craig
authors.initials: C
authors.lastname: Gibbs
authors.forename: Carol
authors.initials: C
authors.lastname: Brosgart
authors.forename: Danielle
authors.initials: D
authors.lastname: Colledge
authors.forename: Rosalind
authors.initials: R
authors.lastname: Edwards
authors.forename: Anna
authors.initials: A
authors.lastname: Ayres
authors.forename: Angeline
authors.initials: A
authors.lastname: Bartholomeusz
authors.forename: Stephen
authors.initials: S
authors.lastname: Locarnini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000627:therapeutic use*; D004279:DNA, Viral / Q000097:blood; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics*; D024882:Drug Resistance, Viral; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates; D014764:Viral Proteins / Q000235:genetics*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D014764:Viral Proteins; D000410:Alanine Transaminase; D004259:DNA-Directed DNA Polymerase; D000225:Adenine; C106812:adefovir dipivoxil