Dynamics of hepatitis B virus resistance to lamivudine.
Lamivudine was the first approved inhibitor of hepatitis B virus (HBV) reverse transcriptase (RT). Lamivudine resistance develops in 53% to 76% of patients after 3 years of treatment. We extensively characterized the dynamics of HBV quasispecies variant populations in four HBV-infected patients who developed lamivudine resistance. Virological breakthrough was preceded by 2 to 4 months by the emergence of quasispecies variants bearing amino acid substitutions at RT position 204, i.e., within the YMDD catalytic motif (rtM204V/I). Three patients had a gradual switch from a YMDD variant population at baseline to a 100% lamivudine-resistant variant population, whereas the remaining patient had a fluctuating pattern of resistance variant dynamics. Careful analysis of amino acid substitutions located outside domain C of HBV RT, including those known to partially restore replication capacities in vitro, showed that the in vivo replication of HBV variants is driven by multiple forces, including intrinsic replicative advantages conferred by mutations accumulating outside domain C and the changing environment in which these variants replicate. Our findings also suggest that individual treatment optimization will require sensitive methods capable of detecting the emergence of viral resistance before the relevant variants acquire optimal replicative capacities.
Pallier
Coralie
C
Department of Bacteriology and Virology, Hôpital de Bicêtre, Université Paris XI, Le Kremlin-Bicêtre, France.
Castéra
Laurent
L
Soulier
Alexandre
A
Hézode
Christophe
C
Nordmann
Patrice
P
Dhumeaux
Daniel
D
Pawlotsky
Jean-Michel
JM
D000328:Adult; D000595:Amino Acid Sequence; D024882:Drug Resistance, Viral; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016415:Sequence Alignment; D013997:Time Factors; D014764:Viral Proteins / Q000235:genetics
D018894:Reverse Transcriptase Inhibitors; D014764:Viral Proteins; D019259:Lamivudine; D012194:RNA-Directed DNA Polymerase