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Dynamics of Hepatitis B Virus Resistance to Lamivudine

Coralie Pallier,^1,2, Laurent Castéra,^2,3, Alexandre Soulier,² Christophe Hézode,⁴ Patrice Nordmann,¹ Daniel Dhumeaux,^2,4 and Jean-Michel Pawlotsky^2*

Department of Bacteriology and Virology, Hôpital de Bicêtre, Université Paris XI, Le Kremlin-Bicêtre,¹ Department of Virology, INSERM U635, Hôpital Henri Mondor, Université Paris XII, Créteil,² Department of Hepatology and Gastroenterology, Hôpital Haut-Lévêque, Université de Bordeaux, Bordeaux,³ Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, Université Paris XII, Créteil, France⁴

Received 1 April 2005/ Accepted 26 October 2005

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.

C.P. and L.C. contributed equally to this study.

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