Natural Polymorphisms Conferring Resistance to HCV Protease and Polymerase Inhibitors in Treatment-Naïve HIV/HCV Co-Infected Patients in China

BackgroundThe advent of direct-acting agents (DAAs) has improved treatment of HCV in HIV co-infection, but may be limited by primary drug resistance. This study reports the prevalence of natural polymorphisms conferring resistance to NS3/4A protease inhibitors and NS5B polymerase inhibitors in treatment-naïve HIV/HCV co-infected individuals in China.MethodsPopulation based NS3/4A sequencing was completed for 778 treatment-naïve HIV/HCV co-infected patients from twelve provinces. NS3 sequences were amplified by nested PCR using in-house primers for genotypes 1–6. NS5B sequencing was completed for genotyping in 350 sequences. Resistance-associated variants (RAVs) were identified in positions associated with HCV resistance.ResultsOverall, 72.8% (566/778) of all HCV sequences had at least one RAV associated with HCV NS3/4A protease inhibitor resistance. Variants were found in 3.6% (7/193) of genotype 1, 100% (23/23) of genotype 2, 100% (237/237) of genotype 3 and 92% (299/325) of genotype 6 sequences. The Q80K variant was present in 98.4% of genotype 6a sequences. High-level RAVs were rare, occurring in only 0.8% of patients. 93% (64/69) patients with genotype 1b also carried the C316N variant associated with NS5B low-level resistance.ConclusionsThe low frequency of high-level RAVs associated with primary HCV DAA resistance among all genotypes in HIV/HCV co-infected patients is encouraging. Further phenotypic studies and clinical research are needed.

研究背景 直接作用抗病毒药物（direct-acting agents, DAAs）的出现改善了人类免疫缺陷病毒（human immunodeficiency virus, HIV）/丙型肝炎病毒（hepatitis C virus, HCV）共感染患者的HCV治疗方案，但原发耐药性可能限制其临床应用价值。本研究针对中国境内初治的HIV/HCV共感染人群，报道了对NS3/4A蛋白酶抑制剂（NS3/4A protease inhibitor）及NS5B聚合酶抑制剂（NS5B polymerase inhibitor）具有耐药性的天然多态性分布特征。
研究方法 本研究纳入来自12个省份的778名初治HIV/HCV共感染患者，完成了基于人群的NS3/4A测序。针对基因型1至6型，采用实验室自主设计的引物通过巢式聚合酶链式反应（nested PCR）扩增NS3序列；对350份样本完成NS5B测序以进行基因分型。在与HCV耐药相关的位点上，鉴定出耐药相关变异体（resistance-associated variants, RAVs）。
研究结果 总体而言，72.8%（566/778）的HCV序列携带至少1种与NS3/4A蛋白酶抑制剂耐药相关的RAVs。不同基因型的变异检出率如下：基因型1型为3.6%（7/193），基因型2型为100%（23/23），基因型3型为100%（237/237），基因型6型为92%（299/325）。在基因型6a型序列中，98.4%携带Q80K变异体。高水平RAVs较为罕见，仅在0.8%的患者中检出。在基因型1b型患者中，93%（64/69）同时携带与NS5B低水平耐药相关的C316N变异体。
研究结论 在HIV/HCV共感染患者的所有基因型中，与原发HCV直接作用抗病毒药物耐药相关的高水平RAVs检出率较低，这一结果令人鼓舞。未来仍需开展更多表型研究及临床相关研究。