Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial.
Impact of Next-generation Sequencing Defined Human Immunodeficiency Virus Pretreatment Drug Resistance on Virological Outcomes in the ANRS 12249 Treatment-as-Prevention Trial.
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DOI：
10.1093/cid/ciy881
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发表时间：
2019-07-02
期刊：
影响因子：
--
通讯作者：
Pillay D
中科院分区：
文献类型：
--
作者：
Derache A;Iwuji CC;Baisley K;Danaviah S;Marcelin AG;Calvez V;de Oliveira T;Dabis F;Porter K;Pillay D
以前对接受胸苷类似物骨架抗逆转录病毒治疗(ART)的人类免疫缺陷病毒(HIV)阳性患者进行的研究表明，在存在预处理耐药(PDR)的情况下，使用奈韦拉平或法韦伦进行抗逆转录病毒治疗(ART)的病毒学结果较差。我们在一项预防治疗试验中，评估了在夸祖鲁-纳塔尔农村地区，PDR对主要服用替诺福韦/恩曲他滨/依法韦伦的个体的病毒学抑制(VS；<；50拷贝/毫升)的影响。在1557名在进入研究时没有报告先前技术并提供血浆样本的艾滋病毒阳性患者中，1328名进入研究的病毒载量(VL)和1000拷贝/毫升的人使用MiSeq技术进行了艾滋病毒Poll基因的下一代测序(NGS)。结果获得了1148名个体，PDR的存在被评估为5%和20%的检测阈值。在920名ART发起者中，有837人在ART开始后至少有1次VL随访，用COX回归分析了病毒学结果。在20%和5%阈值下，PDR患病率分别为9.5%(109/1148)和12.8%(147/1148)。在接受固定剂量替诺福韦/恩曲他滨/伊法韦仑治疗的中位数为1.36年(四分位数范围，0.91-2.13)后，非核苷类逆转录酶抑制剂(NNRTI)/核苷类逆转录酶抑制剂PDR与无PDR的患者在5%的阈值下出现较长的VS时间(调整后的危险比[AHR]，0.32；95%可信区间[CI]，0.12-0.86)，而仅有NNRTI PDR与无PDR的患者(AHR，1.05；95%CI，0.82-1.34)在5%的阈值下没有差异。在20%的阈值下检测到的突变也有类似的差异，尽管没有统计学意义。NGS发现，在夸祖鲁-纳塔尔农村地区试验诊所登记的参与者中，PDR的患病率很高。以替诺福韦/恩曲他滨/依法韦仑为主的双类PDR方案与较差的VS相关。然而，NNRTI PDR本身并没有影响。NCT01509508；南非国家临床试验登记：DOH-27-0512-3974。我们记录了在夸祖鲁-纳塔尔农村地区试验诊所登记的参与者中高度流行的预处理耐药(PDR)。替诺福韦/恩曲他滨/依法韦仑一线方案的双类PDR与较差的病毒学抑制相关。然而，非核苷类逆转录酶抑制剂PDR单独作用不明显。
Previous studies in human immunodeficiency virus (HIV)-positive individuals on thymidine analogue backbone antiretroviral therapy (ART) with either nevirapine or efavirenz have suggested poorer virological outcomes in the presence of pretreatment drug resistance (PDR). We assessed the impact of PDR on virological suppression (VS; <50 copies/mL) in individuals prescribed primarily tenofovir/emtricitabine/efavirenz in rural KwaZulu-Natal within a treatment-as-prevention trial. Among 1557 HIV-positive individuals who reported no prior ART at study entry and provided plasma samples, 1328 individuals with entry viral load (VL) >1000 copies/mL had next-generation sequencing (NGS) of the HIV pol gene with MiSeq technology. Results were obtained for 1148 individuals, and the presence of PDR was assessed at 5% and 20% detection thresholds. Virological outcome was assessed using Cox regression in 837 of 920 ART initiators with at least 1 follow-up VL after ART initiation. PDR prevalence was 9.5% (109/1148) and 12.8% (147/1148) at 20% and 5% thresholds, respectively. After a median of 1.36 years (interquartile range, 0.91–2.13), mostly on fixed-dose combination tenofovir/emtricitabine/efavirenz, presence of both nonnucleoside reverse transcriptase inhibitor (NNRTI)/nucleoside reverse transcriptase inhibitor PDR vs no PDR was associated with longer time to VS (adjusted hazard ratio [aHR], 0.32; 95% confidence interval [CI], 0.12–0.86), while there was no difference between those with only NNRTI PDR vs no PDR (aHR, 1.05; 95% CI, 0.82–1.34) at the 5% threshold. Similar differences were observed for mutations detected at the 20% threshold, although without statistical significance. NGS uncovered a high prevalence of PDR among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a mainly tenofovir/emtricitabine/efavirenz regimen was associated with poorer VS. However, there was no impact of NNRTI PDR alone. NCT01509508; South African National Clinical Trials Register: DOH-27-0512-3974. We documented a high prevalence of pretreatment drug resistance (PDR) among participants enrolled in trial clinics in rural KwaZulu-Natal. Dual-class PDR to a first-line tenofovir/emtricitabine/efavirenz regimen was associated with poorer virological suppression. However, there was no impact of nonnucleoside reverse transcriptase inhibitor PDR alone.
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DOI：
10.1093/cid/cir1034
发表时间：
2012-03
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Tang MW;Kanki PJ;Shafer RW
通讯作者：
Shafer RW
影响因子：
4.9
作者：
Lapointe, H. R.;Dong, W.;Brumme, C. J.
通讯作者：
Brumme, C. J.
DOI：
10.2147/dddt.s84850
发表时间：
2015
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Kandel CE;Walmsley SL
通讯作者：
Walmsley SL
DOI：
10.1126/science.1228160
发表时间：
2013-02-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tanser F;Bärnighausen T;Grapsa E;Zaidi J;Newell ML
通讯作者：
Newell ML
影响因子：
3.7
作者：
Steegen, Kim;Carmona, Sergio;Stevens, Wendy S.
通讯作者：
Stevens, Wendy S.