Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.
BACKGROUND
Tenofovir (TDF) is an adenosine nucleotide analogue that has been approved for the treatment of HIV-1 infection. It also shows activity against hepatitis B virus (HBV) in patients with or without lamivudine (LAM)-associated mutations. Development of clinical or virological HBV breakthrough during TDF therapy has not been reported so far. The aim of this study was to analyse the HBV polymerase (pol) from HIV/HBV-coinfected patients with detectable serum levels of HBV DNA during treatment with TDF for longer than 6 months.


METHODS
The HBV pol was sequenced from 43 patient's serum before and during TDF therapy. Phenotypic analyses were performed using HBV replication-competent plasmids carrying unique mutations selected under TDF therapy.


RESULTS
Mean exposure to LAM was 35.3 +/- 27.5 months and to TDF 11.2 +/- 6.7 months. Genotypic analyses from 21 of the patients revealed LAM-associated mutations, and a further two patients developed a novel mutation, rtA194T, along with LAM-resistance-associated mutations. Phenotypic analyses revealed that constructs harbouring rtA194T combined with rtL180M and rtM204V displayed an over 10-fold increase in the IC50 for TDF compared with the wild type.


CONCLUSIONS
The selection of HBV mutations in HBV/HIV-coinfected patients failing TDF therapy is an unlikely event within the first 12 months of treatment. However, HBV from two of the 43 patients treated with TDF for more than 12 months was found to contain one novel mutation located distal to the catalytic site of the HBV pol. In vitro, rtA194T conferred a reduced susceptibility to TDF in the presence of LAM-associated mutations.
Sheldon
Julie
J
Hospital Carlos ill, Madrid, Spain.
Camino
Nuria
N
Rodés
Berta
B
Bartholomeusz
Angeline
A
Kuiper
Michael
M
Tacke
Frank
F
Núñez
Marina
M
Mauss
Stefan
S
Lutz
Thomas
T
Klausen
Gerd
G
Locarnini
Stephen
S
Soriano
Vincent
V
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004279:DNA, Viral / Q000097:blood; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006509:Hepatitis B / Q000150:complications / Q000188:drug therapy* / Q000821:virology; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D012641:Selection, Genetic; D000068698:Tenofovir
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D004259:DNA-Directed DNA Polymerase; D000225:Adenine