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Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient.: Mechanism of entecavir resistance

Abstract : BACKGROUND/AIMS: Complex mutants may be selected under sequential anti-VHB pressures. We analyzed the genotypic and phenotypic evolution of the viral quasi-species of a patient who developed resistance to entecavir following lamivudine breakthrough. METHODS: The polymerase gene was amplified, cloned and sequenced at different time points. Hepatoma cell lines were transfected to compare the replication capacity of HBV mutants and their drug susceptibility. RESULTS: A mixture of lamivudine-resistant HBV strains coexisted following viral breakthrough to lamivudine, all harboring the rtM204V mutation. The rtV173L+L180M+M204V dominant mutant displayed strong lamivudine-resistance and the highest replication capacity. Following the switch to entecavir, the viral load dropped but the lamivudine-resistant strains continued to be selected. Three years later, the viral load rose again, and a complex mixture of entecavir-resistant strains, all harboring the lamivudine-resistance signature rtL180M+M204V and the rtS202G mutation were observed. Although the rtL180M+S202G+M204V variant, that prevailed at the end of entecavir therapy, did not show the highest viral genome replication capacity, it conferred one of the strongest resistance levels to entecavir. CONCLUSIONS: We report the selection of complex HBV mutants that escaped lamivudine and entecavir antiviral pressures. Genotypic and phenotypic analysis provided additional information to understand the process of HBV variant selection.
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https://www.hal.inserm.fr/inserm-00133115
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Submitted on : Friday, February 23, 2007 - 6:41:35 PM
Last modification on : Thursday, June 4, 2020 - 4:24:06 PM
Long-term archiving on: : Tuesday, April 6, 2010 - 10:51:50 PM

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Stéphanie Villet, Aurélie Ollivet, Christian Pichoud, Luc Barraud, Jean-Pierre Villeneuve, et al.. Stepwise process for the development of entecavir resistance in a chronic hepatitis B virus infected patient.: Mechanism of entecavir resistance. Journal of Hepatology, Elsevier, 2007, 46 (3), pp.531-8. ⟨10.1016/j.jhep.2006.11.016⟩. ⟨inserm-00133115⟩

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