Dynamics of hepatitis B virus resistance to Lamivudine

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J Virol. 2006 Jan;80(2):643-53.

Dynamics of hepatitis B virus resistance to Lamivudine.

Pallier C, Castera L, Soulier A, Hezode C, Nordmann P, Dhumeaux D, Pawlotsky

JM.

Department of Virology, Hopital Henri Mondor, 51 avenue du Marechal de

Lattre de Tassigny, 94010 Creteil, France.

jean-michel.pawlotsky@....

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.

PMID: 16378967 [PubMed - in process]

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