河南省抗病毒治疗失败的艾滋病患者耐药特征

Characteristics of drug resistance in HIV/AIDS patients with antiretroviral treatment failure in Henan Province

目的对河南省艾滋病患者抗病毒治疗(ART)失败后的基因型耐药检测,分析ART失败的耐药特征。方法研究对象为2018年1月至2021年5月河南省18个城市接受ART时间≥6个月且病毒载量≥1000拷贝数/ml艾滋病患者,收集艾滋病患者血液样本、社会人口学特征和ART信息。采用In-house方法进行HIV-1基因型耐药检测,将基因序列提交到美国斯坦福HIV-1耐药数据库分析耐药突变位点和药物耐药情况。结果在887例ART失败的艾滋病患者中,样本成功扩增率为91.54%(812/887),总耐药率为83.25%(676/812),其中核苷类反转录酶抑制剂(NRTIs)、非核苷类反转录酶抑制剂(NNRTIs)、蛋白酶抑制剂(PIs)和整合酶抑制剂(INSTIs)的耐药率分别为73.40%(596/812)、80.54%(654/812)、5.54%(45/812)和2.56%(17/663),4类药物的耐药率差异有统计学意义(χ2=1686.34,P<0.001),对2类药物同时耐药率为66.38%(539/812),对3类药物同时耐药率为5.79%(47/812)。共检出9个HIV-1基因亚型,以B亚型为主(59.61%,484/812),其次是CRF01AE亚型(22.17%,180/812)和CRF07BC亚型(9.48%,77/812),不同基因亚型的耐药率差异有统计学意义(χ2=21.33,P=0.001)。NRTIs相关突变位点中,M184V/I突变率最高(63.42%,515/812),其次是K65R(27.46%,223/812);NNRTIs相关突变位点中,突变率位居前3位的是K103N/S(34.98%,284/812)、G190A/S(26.11%,212/812)和V106M/I(24.63%,200/812);PIs相关突变位点中,突变率位居前3位的是M46I(4.31%,35/812)、V82A/F(3.82%,31/812)和I54V/MV(3.69%,30/812);INSTIs相关突变位点中,E157Q/EQ突变率最高(3.47%,23/663),其次是R263K和G140A(均为0.75%,5/663)。在NRTIs中,拉米夫定和恩曲他滨以高度耐药为主(65.52%,532/812);在NNRTIs中,奈韦拉平(77.46%,629/812)和依非韦伦(71.18%,578/812)以高度耐药为主;在PIs中,洛匹那韦/利托那韦中/高度耐药占比仅为4.19%(34/812);在INSTIs中,艾维雷韦和拉替拉韦中、高度耐药分别占1.66%(11/663)和1.21%(8/663),未发现比克替拉韦和多替拉韦的高度耐药。结论河南省艾滋病患者ART失败的耐药率高,表现以NRTIs和NNRTIs耐药率高、耐药突变多样且复杂为特点。建议选择高耐药屏障药物,同时加强ART后病毒载量和耐药监测。

Objective To analyze the drug resistance characteristics of HIV/AIDS patients in Henan Province with antiretroviral treatment(ART)failure through the genotypic drug resistance detection.Methods Blood samples were collected from HIV/AIDS patients who received ART for more than 6 months with viral loads≥1000 copies/ml in 18 cities of Henan from January 2018 to May 2021.The genotypic drug resistance detection was conducted by using an In-house drug resistance detection method.The drug resistance mutation(DRM)and antiretroviral susceptibility were analyzed by submitting the determined sequences to the Stanford HIV-1 drug resistance database.The information about patients'demographic characteristics and antiviral treatment data were collected.Results A total of 887 HIV/AIDS patients with ART failure,812 sequences were successfully amplified with the success rate of 91.54%.In the 812 patients,676 were drug resistant(83.25%,676/812).The drug resistance ratesto nucleoside reverse transcriptase inhibitors(NRTIs),non-nucleoside reverse transcriptase inhibitors(NNRTIs),protease inhibitors(PIs),and integrase strand transfer inhibitors(INSTIs)were 73.40%(596/812),80.54%(654/812),5.54%(45/812),and 2.56%(17/663),respectively.There were significant differences in drug resistance rates among four types of drugs(χ²=1686.34,P<0.001).The drug resistance rate to two drugs was 66.38%(539/812),and the drug resistance rate to three drugs was 5.79%(47/812).A total of 9 subtypes of HIV-1were detected,in which subtype B accounted for 59.61%(484/812),followed by subtype CRF01_AE(22.17%,180/812)and subtype CRF07_BC(9.48%,77/812).There were significant differences in drug resistance rate among different subtypes(χ²=21.33,P=0.001).Among NRTIs related mutation sites,the DRM rate of M184V/I was highest(63.42%,515/812),followed by K65R(27.46%,223/812).The top three DRM rates were detected for K103N/S(34.98%,284/812),G190A/S(26.11%,212/812)and V106M/I(24.63%,200/812)among NNRTIs related mutation sites,and M46I(4.31%,35/812),V82A/F(3.82%,31/812),and I54V/MV(3.69%,30/812)among PIs related mutation sites.While among INSTIs related mutation sites,E157Q/EQ had the highest DRM rate(3.47%,23/663),followed by R263K(0.75%,5/663)and G140A(0.75%,5/663).The resistance to lamivudine and emtricitabine of NRTIs was at high-level(65.52%,532/812),and the resistance to nevirapine(77.46%,629/812)and efavirenz(71.18%,578/812)of NNRTIs was also at high-level.The medium/high-level resistance to lopinavir/ritonavir of PIs was only 4.19%(34/812),the medium/high-level resistance to elvitegravir and raltegravir of INSTIs was 1.66%(11/663)and 1.21%(8/663),respectively,and no high-level resistance to bictegravir or dolutegravir was found.Conclusions The drug resistance in HIV/AIDS patients with ART failure was high in Henan,characterized by high drug resistance rates to NRTIs and NNRTIs,and diverse and complex resistance mutations.So high resistance barrier ART-regimens were recommended,and the viral load monitoring and drug resistance testing after ART should be strengthened.