慢性HBV感染患者恩替卡韦基因型耐药突变特征分析  

Genotypic analysis of entecavir-resistant mutation of hepatitis B virus (HBV) in patients with chronic HBV infection

作　　者：刘妍[1,2] 李庆虹[2] 李乐[2] 施建飞[2] 纪冬[2] 白文林[2] 姚增涛[2] 戴久增[2] 徐东平[2] 

机构地区：[1]军事医学科学院,北京100850 [2]解放军302医院全军传染病研究所病毒性肝炎研究室

出　　处：《解放军医学杂志》2010年第6期621-624,628,共5页Medical Journal of Chinese People's Liberation Army

基　　金：国家“十一五”传染病重大专项子课题(2008ZX10002-011);国家重点基础研究发展计划课题(2007CB512803);北京市自然科学基金重点课题(7091006)

摘　　要：目的分析经核苷(酸)类似物治疗的慢性乙型肝炎病毒(HBV)感染患者反转录酶(RT)区恩替卡韦(ETV)基因型耐药突变特征及其临床意义。方法提取3800例慢性HBV感染患者血清中的HBV DNA,采用巢式PCR法扩增HBVRT基因,PCR产物直接测序检测RT突变,分析与ETV耐药相关突变的形式及其临床意义。结果 3800例慢性HBV感染患者中,128例(3.4%)检出38种ETV基因型耐药突变,以rtT184位点替换突变最常见(79/128,61.7%),包括7例rtT184/rtS202G位点同时突变。共有5种替代突变形式rtT184L/I/A/S/F,其中rtT184L(29/30)、rtT184A(7/7)和rtT184S(10/12)均伴随rtL180M+rtM204V突变,而rtT184I多伴随rtM204I突变(7/8)。rtS202位点突变33例(25.8%),全部为rtS202G,包括7例rtT184/rtS202G位点同时突变,多伴随rtL180M+rtM204V突变。rtM250位点突变23例(18.0%),其中rtM250L(15/17)常伴随rtM204I突变,而rtM250V均伴随rtL180M+rtM204V突变(5/5)。仅6例(4.7%)检出rtI169T突变并均伴有rtT184位点的突变。还检出同时含有ETV及阿德福韦(ADV)耐药位点的多药耐药突变3例。ETV耐药突变多出现在拉米夫定(LAM)和ETV经治的患者(96/128,75.0%),其中以LAM→ADV→ETV(42例)和LAM→ETV(28例)为主;还出现在LAM经治而未用过ETV治疗的患者(27/128,21.1%),其中以LAM单一治疗(10例)和LAM→ADV(9例)为主。结论慢性HBV感染患者抗病毒治疗中出现的ETV耐药突变多见于单药序贯治疗,突变形式以rtL180M+rtM204V+rtT184L或rtS202G为主,而rtI169T突变在ETV耐药中不起重要作用。Objective To analyze the genotypic features of entecavir-resistant （ETV-r） mutation and the clinical implications of reverse-transcriptase （RT） domain of hepatitis B virus （HBV） in patients with chronic hepatitis B （CHB） or HBV-related liver cirrhosis （HB-LC） who received nucleoside analogs （NA） treatment. Methods HBV DNA in serum was extracted from 3800 CHB and HB-LC patients and nested PCR was performed for RT gene amplification. Direct sequencing of PCR products was also carried out. The genotypic features of ETV-r mutation and their clinical implications in combination with clinical data of the patients were analyzed. Results Among the 3800 patients,128 cases showed ETV-r mutations with 38 kinds of different patterns. rtT184L or I or A or S or F substitutions were the most common ETV-r mutation （79/128,61.7%） including 7 cases with rtT184/rtS202G simultaneous mutations,among which 29/30 with rtT184L,7/7 with rtT184A and 10/12 with rtT184S generally emerged together with rtL180M＋rtM204V,while 7/8 with rtT184I was in concomitance with rtM204I mutation. rtS202 substitution were detected in 33/128（25.8%） cases,and rtS202G was the only detectable pattern,most of them were concomitant with rtL180M＋rtM204V. Among 23 cases with rtM250 substitutions,15/17 with rtM250L were concomitant with rtM204I mutation,while 5/5 with rtM250V were concomitant with rtL180M＋rtM204V. Only 6/128 （4.7%） cases with rtI169T mutation combining rtT184 substitutions were observed. In addition,3 patients harbored genotype of multi-drug-resistance to ADV and ETV mutations. Genotypic ETV-r mutations emerged mostly in LAM-and ETV-experienced patients （96/128）,with a majority of 42 in whom LAM was switched to ADV and then switched to ETV,and 28 in whom LAM was switched to ETV,or in LAM-experienced ETV-nave patients （27/128）,with a majority of LAM mono-therapy （10） and LAM treatment switched to ADV in 9. Conclusions Genotypic ETV-r mutations occur mostly in patients receiving sequential NA-m

关 键 词：肝炎病毒 乙型 恩替卡韦 基因型 突变 

分 类 号：R512.62[医药卫生—内科学]