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Hepatitis B virus quasispecies susceptibility to entecavir confirms the relationship between genotypic resistance and patient virologic response.

Abstract：

BACKGROUND/AIMS:The efficacy of anti-viral therapy for chronic hepatitis B virus (HBV) is lost upon the emergence of resistant virus. Using >500 patient HBV isolates from several entecavir clinical trials, we show that phenotypic susceptibility correlates with genotypic resistance and patient virologic responses. METHODS:The full-length HBV or reverse transcriptase gene was amplified from patient sera, sequenced, and cloned into an HBV expression vector. Entecavir susceptibilities of individual virus clones and patient quasispecies populations were analyzed in conjunction with the sequenced resistance genotype and the patient's virologic response. RESULTS:Entecavir susceptibility decreased approximately 8-fold for isolates with various constellations of lamivudine resistance substitutions. The spectrum of additional substitutions that emerged during therapy at residues rtT184, rtS202, or rtM250 displayed varying levels of entecavir susceptibility according to the specific resistance substitutions and the proportion of resistant variants in the quasispecies. Phenotypic analyses of samples associated with virologic breakthrough confirmed the role of these residue changes in entecavir resistance. Additional longitudinal phenotypic analyses showed that decreased susceptibility correlated with both genotypic resistance and increased circulating HBV DNA. CONCLUSIONS:HBV phenotypic analysis provides additional insight as part of a resistance monitoring program that includes genotypic analysis and quantification of circulating virus.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Baldick CJ,Eggers BJ,Fang J,Levine SM,Pokornowski KA,Rose RE,Yu CF,Tenney DJ,Colonno RJ

doi

10.1016/j.jhep.2007.12.024

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

895-902

issue

6

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(08)00088-3

journal_volume

48

pub_type

杂志文章

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