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

摘要

Abstract Background Tenofovir disoproxil fumarate (TDF) imposes a high genetic barrier to drug resistance and potently inhibits replication of multidrug‐resistant hepatitis B virus. Few clinical cases with confirmed TDF‐resistance have been reported to date. Methods and Results Here, we report viral rebound in a patient with chronic hepatitis B who underwent TDF monotherapy and harboured a quadruple mutant consisting of classic entecavir (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. Conclusion An rtL180M/T184L/A200V/M204V mutant with moderate resistance to TDF monotherapy was selected during sequential nucleoside analogue (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‐na?ve patients as well as patients with TDF resistance.