Evolution of adefovir-resistant HBV polymerase gene variants after switching to tenofovir disoproxil fumarate monotherapy.
BACKGROUND
Tenofovir disoproxil fumarate (TDF), an acyclic nucleotide analogue was shown to be effective in many HBV-infected patients with resistance to adefovir dipivoxil (ADV). This observation is intriguing because in vitro studies show that HBV mutations selected by ADV confer cross-resistance to TDF. To assess the clinical relevance of this cross-resistance, we studied the evolution of HBV polymerase gene variants in patients with genotypic resistance against ADV (rtN236T and/or rtA181V/T) during TDF treatment.


METHODS
In 10 HBV-monoinfected patients (9 male, mean age 47 ±11 [range 27-67] years, 6 hepatitis B e antigen-positive) with virological breakthrough during ADV treatment associated with the mutations rtN236T and/or rtA181T/V, HBV polymerase gene variants were studied during up to 24 months of consecutive monotherapy with TDF by population sequencing, line probe assay and clonal analysis.


RESULTS
In all patients, switching to TDF resulted in a continuous reduction of HBV DNA from a median of 7.6 (4.6-9.4) log(10) copies/ml to 3.3 (2-5) log(10) copies/ml, remaining in 7 patients >400 copies/ml at 12 months. ADV-resistance mutations remained detectable throughout the whole observation period in most patients. Apart from an M204Q mutation in one sample, no new HBV polymerase gene mutations were found. In two patients with low level viraemia after 72 weeks of TDF, adding lamivudine led to a complete response within a few weeks.


CONCLUSIONS
ADV-resistant HBV variants may further become selected during TDF treatment, however they cause only a mild decrease in TDF susceptibility.
Department of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany. florian.vanboemmel@medizin.uni-leipzig.de
Florian
F
van Bömmel
Jörg
J
Trojan
Katja
K
Deterding
Heiner
H
Wedemeyer
Hermann E
HE
Wasmuth
Dietrich
D
Hüppe
Bernd
B
Möller
Friederike J
FJ
Bock
Heinz-Hubert
HH
Feucht
Thomas
T
Berg
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology*; D003001:Cloning, Molecular; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral; D057915:Drug Substitution; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D005260:Female; D005500:Follow-Up Studies; D015684:Gene Products, pol / Q000235:genetics* / Q000378:metabolism; D006509:Hepatitis B / Q000188:drug therapy* / Q000378:metabolism / Q000821:virology; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics / Q000472:pathogenicity; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology*; D000068698:Tenofovir; D014766:Viremia / Q000188:drug therapy / Q000378:metabolism / Q000821:virology
D000998:Antiviral Agents; D004279:DNA, Viral; D015684:Gene Products, pol; D006513:Hepatitis B e Antigens; D063065:Organophosphonates; C066027:P protein, Hepatitis B virus; D019259:Lamivudine; D000068698:Tenofovir; D000225:Adenine; C106812:adefovir dipivoxil