title: Evolution of full-length HBV sequences in chronic hepatitis B patients with sequential lamivudine and adefovir dipivoxil resistance.
abstract: OBJECTIVE
  The aim of this study was to determine the evolution of full-length hepatitis B virus (HBV) sequences in chronic hepatitis B (CHB) patients with sequential lamivudine (LAM) and adefovir (ADV) resistance.
  
  
  METHODS
  The full-length genomes of HBV were sequenced from 11 CHB patients before LAM treatment and at the emergence of LAM- and ADV-resistant HBV.
  
  
  RESULTS
  Besides the known LAM-resistant polymerase gene mutations, 10 of 11 patients who had LAM-resistant HBV variants had additional amino acid changes in the reverse transcriptase (RT) domain, and ADV therapy reversed these additional changes to pre-LAM therapy status. Furthermore, new amino acid changes in the RT domain, distinct from the known ADV-resistant HBV variants, were selected at the emergence of ADV resistance in six of 11 patients. Seven patients had amino acid changes within the known T-cell or B-cell epitopes of HBV surface and core antigens at the emergence of LAM and/or ADV resistance. The frequency of pre-S deletions between nucleotide 3037-56 was higher at the emergence of ADV resistance compared with that at the emergence of LAM resistance (7/11 vs. 1/11; p=0.024). Combined LAM-ADV resistance was detected in one of 11 patients. This patient had resistant mutations to both drugs on the same viral genome by molecular cloning (5/24 polymerase gene clones).
  
  
  CONCLUSIONS
  In addition to the known LAM- and ADV-resistant mutations accompanying the emergence of LAM and ADV resistance, the changes of nucleotide or amino acid sequences occurred commonly in the HBV surface antigen or RT domain and were scattered along the full-length HBV genomes.
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Chen
authors.forename: Chuan-Mo
authors.initials: CM
authors.lastname: Lee
authors.forename: Wei-Chih
authors.initials: WC
authors.lastname: Tung
authors.forename: Jing-Houng
authors.initials: JH
authors.lastname: Wang
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Hung
authors.forename: Tsung-Hui
authors.initials: TH
authors.lastname: Hu
authors.forename: Jyh-Chwan
authors.initials: JC
authors.lastname: Wang
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Lu
authors.forename: Chi-Sin
authors.initials: CS
authors.lastname: Changchien
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use; D024882:Drug Resistance, Viral / Q000235:genetics*; D018985:Epitopes, B-Lymphocyte / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D015684:Gene Products, pol / Q000235:genetics; D016679:Genome, Viral / Q000235:genetics; D005838:Genotype; D006512:Hepatitis B Core Antigens / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006513:Hepatitis B e Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000627:therapeutic use*; D010802:Phylogeny; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D015684:Gene Products, pol; D006512:Hepatitis B Core Antigens; D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; C066027:P protein, Hepatitis B virus; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000225:Adenine; C106812:adefovir dipivoxil