Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory of Emerging infectious Diseases, Beijing, China.
Liver Int. 2020 Jan;40(1):83-91. doi: 10.1111/liv.14241. Epub 2019 Oct 21.
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.
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.
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-naïve patients as well as patients with TDF resistance.
富马酸替诺福韦二吡呋酯（TDF）对耐药性具有很高的遗传屏障，能强力抑制多种耐药性乙型肝炎病毒的复制。迄今为止，已报告了少数经确认存在 TDF 耐药的临床病例。
在这里，我们报告了一名慢性乙型肝炎患者在接受 TDF 单药治疗后出现病毒反弹的情况，该患者携带四重突变体，包括经典的恩替卡韦（ETV）耐药突变（rtL180M/T184L/M204V）以及逆转录酶基因中的 rtA200V 突变。测序分析表明，这种四重突变体成为主要病毒种群。体外表型分析表明，rtL180M/T184L/A200V/M204V 突变体对 TDF 治疗具有中度耐药性，其半数最大有效浓度比野生型病毒高 4.52 倍。重要的是，该 TDF 耐药患者在 TDF/ETV 联合挽救治疗后实现了病毒学抑制。
在逐步进行的连续核苷类似物（NA）治疗中，rtL180M/T184L/A200V/M204V 突变体对 TDF 单药治疗具有中度耐药性。ETV/TDF 联合治疗有效地抑制了这种 TDF 耐药突变体的复制。我们的研究为 NA 初治患者以及 TDF 耐药患者的治疗提供了新的见解。
