title: Variability of reverse transcriptase and overlapping S gene in hepatitis B virus isolates from untreated and lamivudine-resistant chronic hepatitis B patients.
abstract: BACKGROUND
  The high degree of diversity of the hepatitis B virus (HBV) quasispecies in chronically infected individuals raises the possibility that HBV genetic variants favouring resistance to nucleoside/nucleotide analogues (NAs) might pre-exist to treatment. The aim of this study was to investigate the genetic variability of the entire HBV reverse transcriptase (RT) domain and of the overlapping S gene in a large series of untreated hepatitis B surface antigen carriers and in lamivudine (3TC)-resistant patients.
  
  
  METHODS
  Sequencing analysis of the entire HBV RT domain of isolates from 100 untreated (treatment-naive group) and 59 3TC-resistant (3TC-resistant group) consecutive patients with chronic hepatitis B was performed.
  
  
  RESULTS
  In the treatment-naive group, primary mutations known to cause resistance to NAs were not detected, but variably combined secondary/compensatory mutations were found in 46 (46%) patients. Moreover, four patients carried mutations that modified the S protein antigenicity. In the 3TC-resistant group, besides the primary 3TC-resistant mutations, various combinations of primary and secondary mutations conferring resistance to other NAs were detected in 41/59 (69.5%) patients. Importantly, the RT mutations induced by 3TC provoked stop codons in the overlapping S gene in two patients and modified the S protein antigenicity in another nine.
  
  
  CONCLUSIONS
  This study shows that HBV mutants associated with resistance to NAs might already be present as the major infecting population in untreated patients, and that variants emerging under 3TC might also carry mutations favouring resistance to other NAs and/or potentially altering the S protein immunoreactivity.
authors.affiliation: Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy. tpollicino@unime.it
authors.forename: Teresa
authors.initials: T
authors.lastname: Pollicino
authors.forename: Graziella
authors.initials: G
authors.lastname: Isgrò
authors.forename: Rosa
authors.initials: R
authors.lastname: Di Stefano
authors.forename: Donatella
authors.initials: D
authors.lastname: Ferraro
authors.forename: Sergio
authors.initials: S
authors.lastname: Maimone
authors.forename: Santa
authors.initials: S
authors.lastname: Brancatelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Squadrito
authors.forename: Vito
authors.initials: V
authors.lastname: Di Marco
authors.forename: Antonio
authors.initials: A
authors.lastname: Craxì
authors.forename: Giovanni
authors.initials: G
authors.lastname: Raimondo
mesh_terms: D000328:Adult; D000368:Aged; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
chemical_list: D006514:Hepatitis B Surface Antigens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D012194:RNA-Directed DNA Polymerase