Department of Gastroenterology & Hepatology, National University Health System, Singapore.
Liver Int. 2013 Apr;33(4):642-6. doi: 10.1111/liv.12104. Epub 2013 Jan 24.
Few cases of primary entecavir resistance in chronic hepatitis B patients have been reported to date. The serial profiling of the HBV polymerase gene mutations from a treatment-naive patient who developed drug resistance after 32 months of entecavir therapy is presented here.
Serum samples were collected at multiple time points from before the start of therapy to virological and biochemical breakthrough. The evolution of the hepatitis B virus polymerase gene mutations was analysed with commercial line probe assay and pyrosequencing.
Drug resistance mutation analysis by pyrosequencing revealed a two-step process in the selection of drug resistance. The patient had a good initial response to entecavir 0.5 mg/day. A partially resistant HBV strain first emerged as the predominant species from as early as 2 weeks. After a period of non-compliance to therapy, there was virological breakthrough, which resolved on restarting entecavir. Shortly after, there was secondary failure of entecavir therapy, caused by a new resistant strain carrying all three mutations required.
In this patient, pre-existence of minor population of partially resistant viral strains and treatment non-compliance probably contributed to his development of primary entecavir resistance.
迄今为止，仅报道了少数慢性乙型肝炎患者发生原发性恩替卡韦耐药的病例。本文介绍了一例在接受恩替卡韦治疗 32 个月后发生耐药的初治患者，其乙型肝炎病毒聚合酶基因的耐药突变情况。
在治疗开始前、病毒学和生化突破时，从多个时间点采集血清样本。采用商业线性探针分析和焦磷酸测序分析乙型肝炎病毒聚合酶基因突变的演变情况。
焦磷酸测序耐药突变分析显示，耐药的选择经历了一个两步过程。该患者对恩替卡韦 0.5mg/天有良好的初始应答。早在 2 周时，就出现了一种部分耐药的 HBV 株作为主要种系。在一段时间不遵医嘱治疗后，发生了病毒学突破，重新开始恩替卡韦治疗后得到解决。此后不久，由于携带所有三种必需突变的新耐药株的出现，导致恩替卡韦治疗的继发性失败。
在该患者中，预先存在的部分耐药病毒株的低病毒载量和治疗不依从可能导致了其原发性恩替卡韦耐药的发生。
