慢性丙型肝炎患者NS3/4A蛋白酶抑制剂预存耐药的临床研究  

Characterization of Naturally Occurring Resistant Mutations to Hepatitis C Virus NS3/4A Protein Protease in Treatment-nave Patients in China

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

机构地区：[1]中山大学附属第三医院感染科,广东广州510630

出　　处：《中山大学学报（医学科学版）》2015年第3期437-441,448,共6页Journal of Sun Yat-Sen University:Medical Sciences

基　　金：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】了解我国华南地区从未接受任何抗病毒治疗的慢性丙型肝炎(慢丙肝)患者NS3/4A蛋白酶抑制剂相关耐药位点的流行情况、临床特点包括其对干扰素联合利巴韦林抗病毒治疗的影响。【方法】在接受抗病毒治疗前对183例慢丙肝患者的NS3/4A蛋白酶抑制剂相关的耐药位点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法鉴定,有变异的患者为变异组(125例),无变异的患者为野生组(37例),对两组患者的临床资料包括干扰素联合利巴韦林抗病毒治疗后的持续病毒应答率等进行分析。【结果】183例患者中162例患者样本的NS3区扩增成功,其中125例(77.16%)患者检出耐药相关的变异位点266个,其中HCV 1b型A156S变异率为18.33%(11/60),T54S为5.00%(3/60);HCV 2a型V36L变异率为100.00%(14/14),A156S为64.29%(9/14);HCV 6a型Q80K变异率为95.45%(84/88),V36L为4.55%(4/88),D168E为2.27%(2/88),变异组患者经干扰素联合利巴韦林抗病毒治疗后的持续病毒性应答率为81.60%(102/125),而野生组的为81.03%(30/37),两者比较无明显差异(P=0.943)。【结论】我国不同基因型的慢丙肝患者对NS3/4A蛋白酶抑制剂存在不同的预存耐药,耐药变异对慢丙肝患者疾病状态包括干扰素联合利巴韦林的疗效无影响。预存耐药的存在警示我们未来在使用此类药物时需分析病毒基因型及预存耐药变异情况,从而为患者提供最好的病毒学监测及最优的治疗方案。[Objective] To assess the prevalence of hepatitis C virus （HCV） NS3/4A protease inhibitor （PI） resistant mutations in different HCV genotypes among 183 NS3/4A protein protease treatment-na（i）ve patients in south China.[Methods] The dominant regions of HCV NS3/4A were determined in 183 HCV infected patients before pegylated interferon plus ribavirin （PEG-IFN/RBV） therapy,and investigated the patients＇ clinical characteristics as well as treatment responses including sustained virological response （SVR） rate.[Results] 162 cases were successfully amplified in 183 samples.A total of 266 amino acid substitutions were detected in 125 （77.16％） patients.In HCV genotype 1 b infected patients,we detected the resistant mutations of A 156S in 11 patients （18.33％,11/60） and we detected T54S in 3 patients （5.0％,3/60）.In HCV genotype 2a infected patients,we detected the resistant mutations of V36L in 14 patients （100％,14/14） and In HCV genotype 6a infected patients we detected Q80K variability in 84 patients （95.45％,84/88）,V36L in 4 patients（4.55％,4/88） and D168E in 2 patients（2.27％,2/88）.Responses to PEG-IFN/RBV therapy did not differ between patients with and without PI-resistance mutations （mutation group,SVR 81.60％;wild-type group,SVR 81.08％;x2 =0.005,P =0.943）.[Conclusions] Naturally occurring dominant resistance mutations to NS3/4A protein protease do pre-exist in treatment-na（i）ve patients with various genotypes in China.Resistant variants had no effect on the status of disease,including the response to PEG-interferon combined with ribavirin therapy in HCV-infected patients.While the use of PIs is established in HCV-infected patients,analyzing the evolution of the target region in the HCV genome is warranted in order to disclose the role of HCV drug resistance and provide the most convenient virological monitoring for patients who are candidates for treatment or are under treatment.

关 键 词：丙型肝炎病毒 NS3/4A蛋白酶抑制剂 预存耐药 基因型 

分 类 号：R512.63[医药卫生—内科学]