云南省HIV/AIDS病人原发性整合酶基因耐药突变情况
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摘要
目的分析云南省原发性整合酶基因突变及相关耐药情况,为治疗提供参考依据。方法采集2015—2016年云南省14个地州(市)未接受过含整合酶抑制剂(INIs)抗病毒治疗的531例HIV-1感染者外周静脉血,分离血浆,-80℃冻存备用。所有感染者均进行个案流行病学调查并签署知情同意书。采用反转录/巢式聚合酶链式反应扩增病毒pol基因区并进行序列测定,分析IN区耐药突变位点及其耐药程度。结果 531例未经INIs抗病毒治疗的病人血浆扩增成功513例,5.7%(29/513)存在原发IN基因突变,其中9例病人表现出对INIs原发性耐药。全部INIs耐药毒株均属于交叉耐药,包括5例部分交叉耐药和4例完全交叉耐药。共检出10个IN区主要突变位点,其中T66A、E92A/G、G118R、 E138A/K、 G140A、Y143S、 P145S和Q148H等8种主要突变类型引起INIs不同程度耐药;共检出8个IN次要突变位点,A128T出现频率最高,引起INIs耐药的次要突变位点是S153F和G163R。结论云南省存在原发性INIs基因突变且变异位点具有多样性和特异性,应加强IN区耐药监测,合理调整INIs的用药方案。
Objective To investigate the mutations of primary integrase gene and related drug resistance in Yunnan province, and provide reference for the treatment. Methods Peripheral venous blood was collected from 531 HIV-1 infected individuals without initiation of antiviral therapy including INIs from 14 prefectures(cities) in Yunnan during 2015-2016, and plasma was separated and stored at-80℃ for later use. All patients underwent a case epidemiological survey and signed informed consent. The pol gene region was amplified by reverse transcription/nested polymerase chain reaction and sequenced. The resistance mutation sites and resistance levels in the IN region were analyzed. Results Out of 531 patients without INIs antiviral treatment, 513 patients had been successfully amplified, and 5.7%(29/513) had primary IN gene mutations, of which 9 patients showed primary resistance to INIs. All INIs resistant strains were cross-resistant, including 5 cases of partial cross-resistance and 4 cases of full cross-resistance. A total of 10 major mutation sites were detected in the IN region, of which 8 major mutations such as T66 A, E92 A/G, G118 R, E138 A/K, G140 A, Y143 S, P145 S and Q148 H caused different degrees of resistance to INIs. A total of 8 IN minor mutation sites were detected, and the frequency of A128 T was the highest. The secondary mutations that caused INIs resistance were S153 F and G163 R. Conclusion In Yunnan province, there are mutations of primary INIs gene with the sites diverse and specific. It is necessary to strengthen the monitoring of drug resistance in IN area and rationally adjust the regimen of INIs.
Objective To investigate the mutations of primary integrase gene and related drug resistance in Yunnan province, and provide reference for the treatment. Methods Peripheral venous blood was collected from 531 HIV-1 infected individuals without initiation of antiviral therapy including INIs from 14 prefectures(cities) in Yunnan during 2015-2016, and plasma was separated and stored at-80℃ for later use. All patients underwent a case epidemiological survey and signed informed consent. The pol gene region was amplified by reverse transcription/nested polymerase chain reaction and sequenced. The resistance mutation sites and resistance levels in the IN region were analyzed. Results Out of 531 patients without INIs antiviral treatment, 513 patients had been successfully amplified, and 5.7%(29/513) had primary IN gene mutations, of which 9 patients showed primary resistance to INIs. All INIs resistant strains were cross-resistant, including 5 cases of partial cross-resistance and 4 cases of full cross-resistance. A total of 10 major mutation sites were detected in the IN region, of which 8 major mutations such as T66 A, E92 A/G, G118 R, E138 A/K, G140 A, Y143 S, P145 S and Q148 H caused different degrees of resistance to INIs. A total of 8 IN minor mutation sites were detected, and the frequency of A128 T was the highest. The secondary mutations that caused INIs resistance were S153 F and G163 R. Conclusion In Yunnan province, there are mutations of primary INIs gene with the sites diverse and specific. It is necessary to strengthen the monitoring of drug resistance in IN area and rationally adjust the regimen of INIs.
引文
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[7] Wills T,Vega V.Elvitegravir:a once-daily inhibitor of HIV-1 integrase[J].Expert Opin Investig Drugs,2012,21(3):395-401.
[8] Rathbun RC,Lockhart SM,Miller MM,et al.Dolutegravir,a second-generation integrase inhibitor for the treatment of HIV-1 infection[J].Ann Pharmacother,2014,48(3):395-403.
[9] Phuphuakrat A,Pasomsub E,Kiertiburanakul S,et al.HIV type 1 integrase polymorphisms in treatment-naive and treatment-experienced HIV type 1-infected patients in Thailand where HIV type 1 subtype A/E predominates[J].AIDS Res Hum Retroviruses,2012,28(8):937-943.
[10] Huang W,Frantzell A,Fransen S,et al.Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir[J].Antimicrob Agents Chemother,2013,57(9):4105-4113.
[11] DeAnda F,Hightower KE,Nolte RT,et al.Dolutegravir Interactions with HIV-1 Integrase-DNA:Structural Rationale for Drug Resistance and Dissociation Kinetics[J].PLoS One,2013,8(10):e77448.
[12] Brenner BG,Lowe M,Moisi D,et al.Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors[J].J Med Virol,2011,83(5):751-759.
[2] 杨绍敏,钟敏,杨壁珲,等.云南省2008—2012年HIV-1耐药基因型检测情况[J].中国艾滋病性病,2014,20(1):9-12.
[3] Quashie PK,Mesplède T,Wainberg MA,et al.HIV drug resistance against strand transfer integrase inhibitors[J].Curr Infect Dis Rep,2013,15(1):85-100.
[4] D'Costa J,Gooey M,Richards N,et al.Analysis of transmitted HIV drug resistance from 2005 to 2015 in Victoria,Australia:a comparison of the old and the new[J].Sex Health,2017,14(6):558-565.
[5] Parczewski M,Bander D,Urbańska A,et al.HIV-1 integrase resistance among antiretroviral treatment naive and experienced patients from Northwestern Poland[J].BMC Infect Dis,2012(12):368.
[6] Llibre JM,Clotet B.Resistance profile and genetic barrier of dolutegravir[J].Enferm Infecc Microbiol Clin,2015,33 (1):20-25.
[7] Wills T,Vega V.Elvitegravir:a once-daily inhibitor of HIV-1 integrase[J].Expert Opin Investig Drugs,2012,21(3):395-401.
[8] Rathbun RC,Lockhart SM,Miller MM,et al.Dolutegravir,a second-generation integrase inhibitor for the treatment of HIV-1 infection[J].Ann Pharmacother,2014,48(3):395-403.
[9] Phuphuakrat A,Pasomsub E,Kiertiburanakul S,et al.HIV type 1 integrase polymorphisms in treatment-naive and treatment-experienced HIV type 1-infected patients in Thailand where HIV type 1 subtype A/E predominates[J].AIDS Res Hum Retroviruses,2012,28(8):937-943.
[10] Huang W,Frantzell A,Fransen S,et al.Multiple Genetic Pathways Involving Amino Acid Position 143 of HIV-1 Integrase Are Preferentially Associated with Specific Secondary Amino Acid Substitutions and Confer Resistance to Raltegravir and Cross-Resistance to Elvitegravir[J].Antimicrob Agents Chemother,2013,57(9):4105-4113.
[11] DeAnda F,Hightower KE,Nolte RT,et al.Dolutegravir Interactions with HIV-1 Integrase-DNA:Structural Rationale for Drug Resistance and Dissociation Kinetics[J].PLoS One,2013,8(10):e77448.
[12] Brenner BG,Lowe M,Moisi D,et al.Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors[J].J Med Virol,2011,83(5):751-759.