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

Background & Aims Tenofovir 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. Methods and results Viral 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. Conclusion An 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-naïve patients as well as patients with TDF resistance.