核苷类似物干预后慢性乙型肝炎患者HBV多聚酶区基因突变模式与危险因素分析

Analysis in risk factors and gene mutation model of HBV polymerase region in patients with chronic hepatitis B after nucleoside analogues therapy

目的研究扬州市慢性乙型病毒性肝炎(CHB)患者用核苷类似物治疗过程中HBV多聚酶区(P区)发生基因变异的突变模式和危险因素。方法选取108例接受核苷类似物治疗后出现病毒学突破的慢乙肝患者作为研究对象,采用PCR产物直接测序法,分析HBV P区基因变异发生情况。结果 108例患者中,69例检测出基因型耐药,突变类型共计12种,其中rt M204I突变最多见(30.4%),其次为rt L180M/rt M204I联合突变(13.0%)。主要核苷类似物耐药所占比例最高为拉米夫定(62.3%),其次为阿德福韦酯(21.7%)及替比夫定(15.9%)。单个位点突变33例,2个位点突变29例,3个及以上位点突变7例,其中1例为单用拉米夫定,1例为单用恩替卡韦,其余5例为拉米夫定、阿德福韦酯、恩替卡韦不规则联合或序贯使用。结论 HBV P区基因耐药的氨基酸突变复杂多变,rt M204V/I突变最为常见,3个及以上位点突变与拉米夫定、阿德福韦酯、恩替卡韦不规则联合或序贯使用相关。

Objective To explore the variation in the gene mutation patterns and risk factors of HBV polymerase region（P） in chronic viral hepatitis（CHB） patients with nucleoside analogues therapy.Methods A total of 108 chronic hepatitis B patients with viral breakthrough after the treatment of nucleoside analogues were selected as the study subjects.The PCR product direct sequencing method was used to analyze the genetic variation of HBV P region.Results Among 108 cases,69 cases were detected by gene drug resistance,and the mutation type amount to 12,among which rt M204 I was the most common（30.4%）,and the second was rt L180M/rt M204 I combined mutation（13%）.The proportion of the major nucleoside analogues resistance highest proportion of lamivudine was 62.3%,followed by adefovir dipivoxil（21.7%） and telbivudine（15.9%）.There were 33 cases with a single site mutation,29 cases with two sites mutation and 7 cases with three and above sites mutation.In the 7 cases,1 case was treated with lamivudine,1 case with entecavir,and the remaining 5 cases with irregular combined or sequential use of lamivudine,adefovir dipivoxil and entecavir.Conclusion The amino acid of HBV P gene resistant mutation is complex and varied,and rt M204V/I mutation is the most common type.Three and above sites mutation is associated with irregular combined or sequential use of lamivudine,adefovir dipivoxil and entecavir.