Resistance surveillance in chronic hepatitis B patients treated with adefovir dipivoxil for up to 60 weeks.
Current therapies for chronic hepatitis B virus (HBV) infection do not provide adequate long-term control of viral replication in the majority of patients. Monotherapy with nucleoside analogs, such as lamivudine and famciclovir, is effective for short periods but results in the emergence of drug-resistant HBV in a substantial number of patients within 1 year of therapy. Adefovir dipivoxil (ADV) has demonstrated clinical activity against wild-type and lamivudine-resistant HBV, but it is unclear whether resistance mutations will emerge after long-term therapy with this drug. To determine whether extended treatment with ADV led to the emergence of drug-resistant populations of HBV, we analyzed virus isolated from patients currently enrolled in a long-term open-label study. The reverse transcriptase domain of HBV polymerase was amplified and sequenced from patients that had received a cumulative exposure of up to 60 weeks of ADV. During our analyses, several previously unreported amino acid substitutions were observed in the reverse transcriptase domain of HBV. Importantly, none of the observed mutations occurred in more than 1 patient, nor were they associated with an adefovir-resistant phenotype in vitro. Furthermore, none of the patients from whom these mutant viruses were isolated had evidence of virologic rebound. In conclusion, these results, although based on a limited number of patients, suggest that treatment with ADV does not lead to the emergence of resistant virus after up to 60 weeks of therapy.
Yang
Huiling
H
Gilead Sciences Inc., Foster City, CA 94404, USA.
Westland
Christopher E
CE
Delaney
William E
WE
Heathcote
Elizabeth J
EJ
Ho
Victoria
V
Fry
John
J
Brosgart
Carol
C
Gibbs
Craig S
CS
Miller
Michael D
MD
Xiong
Shelly
S
D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular; D017124:Conserved Sequence; D004279:DNA, Viral / Q000032:analysis; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D005500:Follow-Up Studies; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D016296:Mutagenesis; D063065:Organophosphonates; D010641:Phenotype; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D004259:DNA-Directed DNA Polymerase; D000225:Adenine; C106812:adefovir dipivoxil