中国肝脏病杂志(电子版)

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慢性乙型肝炎患者核苷（酸）类似物耐药位点
多变性分析

作者：张怡青常静霞王洁汪茂荣

单位：解放军第八一医院全军肝病中心南京 210002

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出版年,卷(期):页码：2015,7(3):70-73

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摘要：目的了解近年来核苷（酸）类似物治疗的慢性乙型肝炎患者耐药变异位点的变化新特点。方法对590例PCR产物测序结果为耐药变异位点阳性的慢性乙型肝炎患者HBV逆转录酶区与核苷（酸）类似物相关的耐药位点的突变情况进行分析。取患者血清200 μl，提取HBV模板。PCR扩增HBV逆转录酶区。PCR反应液5 μl以1.5%琼脂糖凝胶进行电泳，产物经纯化后直接用于测序，Sequence Scanner分析软件进行耐药位点分析。结果 590例患者血清中检出的1354个变异位点中出现频率较高的分别为L180M、M204I、M204V、A181T、L80I、N236T和A181V，分别占45.3%、42.7%、29.7%、26.6%、24.4%、17.3%和16.9%。耐药位点变异出现的形式以联合变异为主，其中2个及2个以上位点同时出现变异者占70.8%，单个位点变异仅占29.2%。涉及LAM、FTC、ETV、ADV、LdT、TDF耐药的例数分别为909、729、524、359、252、4例，分别占32.7%、26.3%、18.9%、12.9%、9.1%、0.1%。2种药物同时耐药的有283例，占47.9%，主要为LAM和LdT同时耐药以及LAM和ETV同时耐药，分别占37.6%和7.1%；涉及3种以上药物耐药的有33例，占5.6%，主要为LAM、LdT和ADV同时耐药。符合3个位点联合变异的ETV临床耐药意义的病例为50例，占8.5%。结论随着慢性乙型肝炎核苷（酸）类似物治疗的日益普及，耐药位点呈现更加复杂的变化，多位点变异和多药耐药的情况有增加趋势，在临床抗病毒治疗过程中，如何选用合适的核苷（酸）类药物，预防和控制耐药的问题应引起高度重视。

Abstract: Objective To explore the new characteristics of drug resistant mutations against nucleos(t)ide analogues in patients with chronic hepatitis B (CHB). Methods Total of 590 CHB patients conducted antiviral therapy with nucleos(t)ide analogues were included for analysis. The results of the PCR-product
direct sequencing for HBV drug resistance mutations were positive in all patients and 200 μl serum was taken to extract the DNA template and the RT genes of HBV were amplified by PCR technique. Electrophoresis for the purified products was conducted in 1.5% agarose gel and the DNA sequence was measured for HBV drug resistant mutations by the Sequence Scanner. Results It was demonstrated that the higher occured mutation sites in all detected 1354 mutations were L180M, M204I, M204V, A181T, L80I, N236T and A181V, with the frequency of 45.3%, 42.7%, 29.7%, 26.6%, 24.4%, 17.3% and 16.9%. The most common resistant pattern was multiple mutation sites, with the rate of 70.8% and only 29.2% of 590 patients had just one mutation site. The frequency rate concerning LAM, FTC, ETV, ADV, LdT and TDF were 32.7% (909), 26.3% (729), 18.9% (524), 12.9% (359), 9.1% (252) and 0.1% (4), respectively. There were 283 patients involved for two-drug resistant, accounting for 47.9%. The common forms of two-drug resistant were LAM plus LdT and LAM plus ETV, with the rates of 37.6% and 7.1%. There were 33 cases involved for three and more NAs drug resistant, taking the rate of 5.6%, and the most popular drug resistant pattern was the combination of LAM、LdTand ADV. There were 50 cases defined for ETV resistance, taking the rate of 8.5%. Conclusions The drug resistant mutations against NAs are more variable now after decades of administration clinical. The situations of multiple mutation sites and multiple drugs resistance are increasing. Investigation and comprehensive analysis for NAs resistant mutations, especially for multiple drug resistant is valuable for prevention and management of NAs resistance among during antiviral treatment.

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