【摘要】 目的研究多种核苷类似物(NAs)序贯治疗产生交叉耐药的患者体内乙型肝炎病毒(HBV)RT区变异位点和变异类型。方法筛选6例临床上对两种或两种以上NAs产生交叉耐药的患者,并从患者血清中获取HBV交叉耐药株DNA,进行全基因克隆和测序,从而分析其变异特点和规律。结果经测序鉴定,6位患者体内HBV基因型均为C型,产生交叉耐药的相关性变异以rtM204V/I(YMDD)变异为主(50%),部分YMDD变异株伴有rtL180M变异(16.7%)、其他伴随变异包括rtV173L(16.7%),rtL80I(16.7%)。此外,还发现RT区次要变异伴随位点rtL269I(40%)、rtQ333K(56.7%)、rtH337N(56.7%)。结论RT区次要变异伴随位点rtL269I、rtQ333K、rtH337N的出现可能增强了HBV YMDD变异株在体内的复制能力,并对交叉耐药准种所占比例起到了放大的效果,从而导致本研究中6例患者出现对拉米夫定、恩替卡韦、阿德福韦和替比夫定产生多重耐药。更多还原

【Abstract】 Objective To study the sites and types of hepatitis B virus(HBV)variations at reverse transcriptase(RT)region in the patients with cross drug resistance generated by the nucleoside analogues(NAs)sequential treatment.Methods 6adult patients with cross-resistance to 2or above NAs were screened out.The DNA of cross resistant HBV strains was obtained from the serum of the patients and performed the whole-genome clone and sequencing for analyzing its variation characteristics and rule.Results The sequencing identification showed that HBV genotype in 6patients was the type C and the related variations generating the cross drug resistance were dominated by rtM204V/I(50%),rtL180M(16.7%),rtV173L(n=16.7%)and rtL80I(n=16.7%).In addition,some secondary variations accompanying sites at the RT region such as rtL269I(40%),rtQ333K(56.7%),rtH337N(56.7%)were found.Conclusion The secondary variations at RT region could enhance the replication capacity of HBV YMDD variant strains,and enlarge HBV quasispecies variant populations,which caused the emergence of multi-drug resistant mutant virus during sequential or combination therapy with lamivudine,entecavir,adefovir and telbivudine in 6patients of this study.更多还原