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Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient.

Abstract : BACKGROUND & AIMS: Sequential anti-hepatitis B virus (HBV) therapy may lead to the selection of complex mutants. We analyzed the genetic and phenotypic evolution of the viral quasispecies of a patient who received successively lamivudine, add-on adefovir+lamivudine, followed by lamivudine+adefovir+hepatitis B immunoglobulins (HBIg) after orthotopic liver transplantation. METHODS: For genotypic analysis, a 1310-bp region of the polymerase gene was amplified, cloned, and sequenced. Huh-7 cells were transfected to compare the replication fitness of HBV mutants and their susceptibility to drugs. RESULTS: At baseline, all HBV genomes carried a wild-type (wt) RT gene but 22% harbored the sP120S and 55% the sC107stop mutations within the surface (S) gene associated with vaccine escape. Following viral breakthrough to lamivudine monotherapy, a complex mixture of lamivudine-resistant HBV strains prevailed. Interestingly, among these mutants emerged a population harboring only the rtL180M+A181V mutations, conferring lamivudine-resistance in vitro. After addition of adefovir to the ongoing treatment, viral load dropped, and the patient underwent an orthotopic liver transplantation and received HBIg. As viral load rose again, a single viral population was progressively selected, harboring the rtV173L+L180M+A181V+N236T and sP120S mutations. In vitro, this last mutant showed a level of replication reduced by only 30% compared to wt HBV and a strong resistance to both lamivudine (>1000-fold) and adefovir (>10-fold). It remained sensitive to tenofovir both in vitro and in vivo. CONCLUSIONS: We report the selection of a complex HBV mutant that escaped the antiviral pressure of lamivudine, adefovir, and HBIg, and provide insight on the process of selection via genotypic and phenotypic analysis.
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https://www.hal.inserm.fr/inserm-00133169
Contributor : Fabien Zoulim <>
Submitted on : Tuesday, February 27, 2007 - 10:41:32 AM
Last modification on : Wednesday, November 20, 2019 - 3:08:03 AM
Long-term archiving on: : Tuesday, April 6, 2010 - 9:17:35 PM

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Stéphanie Villet, Christian Pichoud, Jean-Pierre Villeneuve, Christian Trépo, Fabien Zoulim. Selection of a multiple drug-resistant hepatitis B virus strain in a liver-transplanted patient.. Gastroenterology, WB Saunders, 2006, 131 (4), pp.1253-61. ⟨10.1053/j.gastro.2006.08.013⟩. ⟨inserm-00133169⟩

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