摘要
目的 分析慢性乙型肝炎病毒（HBV）感染者核苷（酸）类药物（NAs）HBV逆转录酶区相关耐药突变位点的异质性,为规范抗病毒治疗和耐药管理提供参考价值.方法 收集2011年4月至2018年3月宁波市第二医院及宁波市第四医院慢性HBV感染者NAs治疗发生病毒学突破或应答不佳2765例的血液标本,采用实时荧光定量PCR方法对血清HBV多聚酶区进行扩增,对PCR产物进行直接测序并分析测序结果.根据用药情况分为拉米夫定（LAM）单药耐药组（n=603）、替比夫定（LdT）单药耐药组（n=147）、阿德福韦酯（ADV）单药耐药组（n=68）、恩替卡韦（ETV）单药耐药组（n=10）和NAs序贯或联合耐药组（n=365）,分析各组耐药突变位点及耐药模式（通路）.采用SPSS 19.0统计软件对数据进行分析.结果 在2765例慢性HBV感染者的血液标本中,检测出NAs相关HBV-RT区耐药突变1193例,总突变率为43.15％.LAM单药耐药组的突变率为62.62％（603/963）,共19种突变类型,以单位点突变rtM204I/V最多见（40.30％,243/603）.LdT单药耐药组的突变率为45.51％（147/323）,共3种突变类型,以单位点突变rtM204I/V最多见（59.86％,88/147）.ADV单药耐药组的突变率为17.80％（68/382）,主要为rtA181T单点突变（64.71％,44/68）.ETV单药耐药组的突变率为4.06％（10/246）,以rtT184A/G/S/I/L/F单点突变最多见（80.00％,8/10）.序贯或联合治疗耐药组的突变率为41.91％（365/871）,其中LAM/LdT应答不佳或耐药序贯ADV组突变率为63.39％（142/224）,以rtA181V/T最多见（35.21％,50/142）;LAM/LdT应答不佳或耐药联合ADV组突变率为42.19％（54/128）,以rtA181V/T最多见（46.30％,25/54）;LAM/LdT应答不佳或耐药后序贯ETV 1.0 mg组突变率为44.66％（117/262）,以rtL180M＋M204I/V＋S202G/I最多见（31.62％,37/117）;LAM/LdT应答不佳或耐药ETV联合ADV组突变率为7.14％（5/70）,均为多位点突变;ADV应答不佳或耐药序贯
Objective To analyze the heterogeneities of hepatitis B virus （ HBV ） reverse transcriptase domain （RT） gene mutations related to nucleos （t）ide analogues （NAs） resistance.Methods Blood samples from 2765 chronic hepatitis B patients with virological breakthrough or poor drug response treated in Ningbo No .2 Hospital and Ningbo Fourth Hospital from April 2011 to March 2018 were collected . According to the medication status , it was divided into LAM monotherapy group （ n =603 ） , LdT monotherapy group （n=147）, ADV monotherapy group （n=68）, ETV monotherapy group （n=10） and the sequential or combined drug resistance of NAs group （n=365）.The resistance mutation sites and drug resistance patterns （pathways） of each group were analyzed .The SPSS 19.0 software was used to analyze the data.Results Among 2765 serum samples, the NAs-related HBV-RT resistance mutations were detected in 1193 cases with an overall mutation rate of 43.15％.The mutation rate of LAM monoclonal resistance group was 62.62％ （603/963） with 19 mutation types, the most common single point mutation was rtM204I/V （40.30％, 243/603）.The mutation rate of LdT monoclonal resistance group was 45.51％（147/323）, and there were 3 mutation types, with the single point mutation rtM204I/V being the most common （59.86％, 88/147）.The mutation rate of the ADV monoclonal resistance group was 17.80％（68/382）, mainly rtA181T single point mutation （64.71％, 44/68）.The mutation rate of the ETV monoclonal resistance group was 4.06％（10/246）, and the single point mutation of rtT184A/G/S/I/L/F was the most common one （80.00％, 8/10）.The mutation rate of the sequential or combination therapy group was 41.91％ （365/871）, among which the mutation rate of the LAM/LdT poor response or the resistance with the sequential ADV group was 63.39％（142/224）, and the most single mutation point was rtA181V/T （ 35.21％, 50/142 ）;the mutation rate of LAM/LdT poor response or drug-resistant with c
作者
马军
胡爱荣
蒋素文
陆佳林
孟依娜
陈凯
胡耀仁
张增增
练祥
Ma Jun;Hu Airong;Jiang Suwen;Lu Jialin;Meng Yina;Chen Kai;Hu Yaoren;Zhang Zengzeng;Lian Xiang(Department of Infectious Diseases,Ningbo Fourth Hospital,Ningbo 315700,China;Ningbo Institute of Liver Diseases,Ningbo No.2 Hospital,Ningbo 315010,China;Section of Graduate Study,School of Medicine,Ningbo University,Ningbo 315211,China)
出处
《中华临床感染病杂志》
2018年第5期346-352,共7页
Chinese Journal of Clinical Infectious Diseases
基金
浙江省基础公益研究计划项目（LGF18H030012）
中国肝炎防治基金会--天晴肝病研究基金（TQGB20170009）
宁波市领军和拔尖人才培养工程择优资助科研项目（NBLJ201801034）
关键词
肝炎病毒
乙型
核苷(酸)类药物
耐药突变
逆转录酶区耐药突变
基因测序
Hepatitis B virus
Nucleos （t） ide analogues
Drug resistance mutation
Reverse transcriptase resistance mutation
Gene sequencing
