慢性丙型肝炎患者NS5B聚合酶抑制剂预存耐药的特点研究  

Naturally occurring NS5B variants resistant to non-nucleoside or nucleoside polymerase inhibitors among treatment-naive hepatitis C patients in south China

作　　者：李展翼[1] 刘莹[1] 蔡庆贤[1] 邵晓琼[1] 严颖[1] 赵志新[1] 

机构地区：[1]中山大学附属第三医院感染科,广州510630

出　　处：《中华肝脏病杂志》2015年第9期653-657,共5页Chinese Journal of Hepatology

基　　金：国家“十二五”规划项目（2012ZX10002003）,中山大学临床医学研究5010计划资助（2010011）,广东省自然科学基金（S2012010009155）,广东省医学科研基金（B2012195）

摘　　要：目的 对我国华南地区184例未行抗病毒治疗的慢性丙型肝炎患者进行NS5B聚合酶抑制剂相关耐药位点检测并分析其特点. 方法 根据NS5B区变异位点的特点,将其分成3段扩增.NS5B聚合酶抑制剂相关的耐药位点分析采用自行设计型别特异性引物行巢式PCR,PCR产物纯化后直接测序鉴定,同时对患者的临床资料进行分析.定量资料如人口学指标、生物化学指标、血液学指标、病毒学等指标,参数比较用Student＆#39;s t检验或ANOVA方差分析,两组间非参数比较用Mann Whitney U检验;分类资料用x 2检验. 结果 对核苷类聚合酶抑制剂耐药的变异位点A15G,S96T,S282T主要在HCV 6a型中发生（20/88,22.73％）,在HCV 1b型中未发现变异位点;对非核苷类聚合酶抑制剂耐药的变异位点C316N,S365A主要见于HCV 1b型,I482L、V499A主要见于HCV 6a型及HCV 2a型;本研究发现一些新的变异位点如A15S,S365F,S365P,S368A,S368L,这些变异位点能否导致耐药尚待研究. 结论 我国慢性丙型肝炎患者对NS5B聚合酶抑制剂存在预存耐药,变异率因HCV基因型而异.不同的基因型可预存不同的耐药,提示使用直接抗病毒药前应常规进行基因检测.Objective To determine the prevalence of mutations in the non-structural protein 5B （NS5B） of the hepatitis C virus （HCV）,which are associated with natural resistance to non-nucleoside and nucleoside polymerase inhibitors （PIs）,in treatment-naive hepatitis C patients in south China.Methods A nested PCR protocol that amplified three different regions of NS5B was used to detect the naturally occurring drag-resistant substitutions.Direct PCR sequencing was performed to analyze the sequences.Results NS5B mutations known to confer resistance to nucleoside PIs,such as A15G,S96T and S282T,were mainly detected in HCV genotype 6a （20/88,22.73%）.Of the NS5B mutations known to confer resistance to non-nucleoside PIs,C316N and S365A were detected in HCV genotype lb （60/60,100% and 2/60,3.33%,respectively） and I482L and V499A were mainly detected in HCV genotype 2a （9/9,100% and 4/4,100%,respectively） and HCV genotype 6a （9/9,100% and 4/4,100%,respectively）.Other NS5B mutations found in the study population included A1 5S,S365F,S365P,S368A and S368L;although none of these has been previously shown to confer resistance to PIs.Conclusion Naturally occurring dominant PI resistance mutations in NS5B exist in treatment-na（i）ve hepatitis C patients in south China and may be related to the virus genotype.

关 键 词：肝炎病毒 丙型 基因型 耐药变异 

分 类 号：R512.63[医药卫生—内科学]