简短通讯：东西方交汇：乌干达和尼日利亚PEPFAR诊所一线治疗失败患者的HIV-1耐药突变模式描述

Short communication: east meets west: a description of HIV-1 drug resistance mutation patterns of patients failing first line therapy in PEPFAR clinics from Uganda and Nigeria.

作者信息

Crawford Keith W, Wakabi Salim, Kibuuka Hannah, Magala Fred, Keshinro Babajide, Okoye Ifeanyi, Akintunde Ezekiel, Hamm Tiffany E

机构信息

1 Global Health Programs, U.S. Military HIV Research Program (MHRP)/Walter Reed Army Institute of Research (WRAIR) , Bethesda, Maryland.

出版信息

AIDS Res Hum Retroviruses. 2014 Aug;30(8):796-9. doi: 10.1089/AID.2013.0294. Epub 2014 Jun 6.

DOI:10.1089/AID.2013.0294

PMID:24798614

Abstract

HIV-1 viral load (VL) monitoring is recommended but seldom performed in resource-constrained countries. An evaluation of patients receiving first-line antiretroviral therapy in a multicountry PEPFAR program (RV288) was performed to determine the rates and predictors of virologic suppression. Resistance data from treatment failures are available from Uganda and Nigeria. Each country enrolled 325 subjects into this cross-sectional study. Subjects on first-line therapy were randomly selected for HIV RNA testing (viral load). Regimens included efavirenz or nevirapine with zidovudine/lamivudine or tenofovir/lamivudine. VL was determined from plasma using the Roche COBAS TaqMan HIV-1 Test, High Pure System v1.0 (47 copies/ml). Genotypic resistance testing was performed on samples with VL>1,000 copies/ml. From Uganda, 85% of subjects were undetectable while 7% (23/325) had VL>1,000 copies/ml. The HIV-1 subtype distribution was as follows: A=47.6%, C=14.3%, and D=38.1%. No resistance mutations were found in 14% of subjects. All subjects with resistance had the M184V mutation. Of subjects failing a zidovudine regimen less than 1 year, 88% (7/8) had no thymidine analogue mutations (TAMs), compared to 50% (4/8) failing greater than 1 year. Four subjects (25%) had more than two mutations from the TAM-1 pathway (41L, 210W, 215Y). In Nigeria, 82% were undetectable while 14% (45/325) had VL>1,000 copies/ml. HIV-1 subtype distribution was as follows: 62.8%=CRF02_AG, 34%=pure G, and 2.8%=A. Of the 35 genotyped subjects, 14% (5/35) had no resistance mutations. Of the remainder, 10% (3/30) had no nucleoside analogue mutations while 33% (10/30) had only M184V along with nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations. Forty percent (10/25) of subjects on zidovudine failed without TAMs. Another 25% (5/25) of subjects failing on zidovudine had more than two TAM-1 mutations. Individuals failing first-line antiretroviral therapy (ART) may retain sensitivity to one or more nucleoside analogues from the regimen. Knowledge of drug resistance patterns allow for selection of drugs that can be recycled in future regimens. Accumulation of resistance mutations may compromise future treatment options.

摘要

建议进行HIV-1病毒载量（VL）监测，但在资源有限的国家很少开展。在一项多国总统紧急救援计划（PEPFAR）项目（RV288）中，对接受一线抗逆转录病毒治疗的患者进行了评估，以确定病毒学抑制率及其预测因素。乌干达和尼日利亚提供了治疗失败患者的耐药数据。每个国家招募了325名受试者参与这项横断面研究。随机选择接受一线治疗的受试者进行HIV RNA检测（病毒载量）。治疗方案包括依非韦伦或奈韦拉平联合齐多夫定/拉米夫定或替诺福韦/拉米夫定。使用罗氏COBAS TaqMan HIV-1检测试剂盒（高纯系统v1.0）从血浆中测定病毒载量（检测下限为47拷贝/ml）。对病毒载量>1000拷贝/ml的样本进行基因耐药性检测。在乌干达，85%的受试者病毒载量不可检测，而7%（23/325）的受试者病毒载量>1000拷贝/ml。HIV-1亚型分布如下：A = 47.6%，C = 14.3%，D = 38.1%。14%的受试者未发现耐药突变。所有有耐药性的受试者都有M184V突变。在接受齐多夫定治疗方案不到1年失败的受试者中，88%（7/8）没有胸苷类似物突变（TAM），而接受治疗超过1年失败的受试者中这一比例为50%（4/8）。4名受试者（25%）有超过两个来自TAM-1途径的突变（41L、210W、215Y）。在尼日利亚，82%的受试者病毒载量不可检测，而14%（45/325）的受试者病毒载量>1000拷贝/ml。HIV-1亚型分布如下：62.8%为CRF02_AG，34%为纯G型，2.8%为A型。在35名进行基因分型的受试者中，14%（5/35）没有耐药突变。其余受试者中，10%（3/30）没有核苷类似物突变，而33%（10/30）只有M184V突变以及非核苷类逆转录酶抑制剂（NNRTI）突变。接受齐多夫定治疗的受试者中有40%（10/25）在没有TAM的情况下治疗失败。另外25%（5/25）接受齐多夫定治疗失败的受试者有超过两个TAM-1突变。一线抗逆转录病毒治疗（ART）失败的个体可能对治疗方案中的一种或多种核苷类似物仍保持敏感性。了解耐药模式有助于选择可在未来治疗方案中再次使用的药物。耐药突变的积累可能会影响未来的治疗选择。