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bioRxiv · 10.1101/632984

Entecavir resistance mutations rtL180M/T184L/M204V combined with rtA200V lead to tenofovir resistance

Jiang, D.·Wang, J.·Zhao, X.·Li, Y.·Zhang, Q.·Song, C.·Zeng, H.·Wang, X.
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Abstract

Background & AimsTenofovir disoproxil fumarate (TDF) imposes a high genetic barrier to drug resistance and potently inhibits replication of multidrug-resistant hepatitis B virus (MDR HBV) and few clinical cases with confirmed TDF-resistance have been reported to date. We reported a quadruple mutant which showed moderate resistant to TDF.\n\nMethods and resultsViral rebound was reported in a patient with chronic hepatitis B who underwent TDF monotherapy and harbored a quadruple mutant consisting of classic ETV-resistance mutations (rtL180M/T184L/M204V) together with an rtA200V mutation in the reverse transcriptase gene. Sequencing analysis revealed that this quadruple mutant emerged as a major viral population. In vitro phenotyping demonstrated that the rtL180M/T184L/A200V/M204V mutant had moderate resistance to TDF treatment, with a 4.52-fold higher half maximal effective concentration than that of wild-type virus. Importantly, this patient with TDF resistance achieved virological suppression after TDF/ETV combination rescue therapy.\n\nConclusionAn rtL180M/T184L/A200V/M204V mutant with moderate resistance to TDF monotherapy was selected during sequential NA treatment in a stepwise manner. ETV/TDF combination therapy effectively suppressed replication of this TDF resistant mutant. Our studies provide novel insights into the treatment of NA-naive patients as well as patients with TDF resistance.

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Jiang, D., Wang, J., Zhao, X., Li, Y., Zhang, Q., Song, C., Zeng, H., Wang, X.. 2019-05-13. Entecavir resistance mutations rtL180M/T184L/M204V combined with rtA200V lead to tenofovir resistance. https://doi.org/10.1101/632984

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