Antiviral Resistance and Correlates of Virologic Failure in the first Cohort of HIV-Infected Children Gaining Access to Structured Antiretroviral Therapy in Lima, Peru: A Cross-Sectional Analysis
Antiviral Resistance and Correlates of Virologic Failure in the first Cohort of HIV-Infected Children Gaining Access to Structured Antiretroviral Therapy in Lima, Peru: A Cross-Sectional Analysis
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DOI：
10.1186/1471-2334-13-1
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发表时间：
2013-01-02
影响因子：
3.7
通讯作者：
Oberhelman, Richard A.
中科院分区：
文献类型：
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作者：
Rath, Barbara A.;von Kleist, Max;Oberhelman, Richard A.
背景：在发展中国家广泛使用抗逆转录病毒药物的影响是巨大的。需要彻底了解促成抗逆转录病毒治疗成功的所有因素。本研究旨在探讨利用DNA和RNA寡核苷酸连接试验（OLA）进行横断面耐药监测在低资源环境下治疗队列中的价值。这项研究是在秘鲁第一批获得有组织的抗逆转录病毒治疗的儿童中进行的。方法：在2002- 2005年期间，46名符合条件的儿童开始AZT， 3TC和NFV的标准方案，患者的中位年龄为5.6岁（范围：0.7-14岁），中位病毒载量为1.7.10(5)RNA/ml(范围：2.1.10(3)- 1.2.10(6))，中位cd4计数为232细胞/ μ L（范围：1-1591）。其中20例为CDC临床C类，31/46例为CDC免疫3类。在2005年的横断面分析中，进行了依从性问卷调查。从冷冻的PBMC和血浆中进行DNA OLAs和RNA OLAs，从干燥的血斑进行RNA基因分型。结果：在抗逆转录病毒治疗的第一年，44%的儿童经历了病毒学失败，另外9%的儿童在第二年结束时失败。在横断面分析中，病毒学失败与DNA-OLA检测到的耐药突变数量显著相关（p < 0.001），但也与基线时低免疫cdc评分相关（p < 0.001）。DNA-OLA检测显示，在开始结构化抗逆转录病毒治疗前接受过无监督短期抗逆转录病毒治疗的儿童耐药突变数量显著增加（p = 0.01）。RNA-OLA和DNA-OLA检测M184V （3TC耐药）鉴定病毒学失败的敏感性分别为0.93和0.86，特异性分别为0.67和0.7。DNA-OLA检测到的RT突变N88D和L90M （NFV耐药）与病毒学失败相关，而RT位置215的突变（AZT耐药）与病毒学失败无关。结论：基线时的晚期免疫抑制和以前接受无监督的短周期抗逆转录病毒治疗，在该队列中最终引入结构化抗逆转录病毒治疗时，显著损害了治疗结果。母亲短暂接触AZT +/- NVP以预防母婴传播并不影响该组儿童的治疗结果。冷冻PBMC的DNA-OLA为检测存档的耐药性提供了一种高度特异性的工具。来自干血斑的RNA一致性基因分型和来自血浆的RNA- ola一致检测到耐药突变，但仅与病毒学失败相关。
Background: The impact of extended use of ART in developing countries has been enormous. A thorough understanding of all factors contributing to the success of antiretroviral therapy is required. The current study aims to investigate the value of cross-sectional drug resistance monitoring using DNA and RNA oligonucleotide ligation assays (OLA) in treatment cohorts in low-resource settings. The study was conducted in the first cohort of children gaining access to structured ART in Peru.Methods: Between 2002-5, 46 eligible children started the standard regimen of AZT, 3TC and NFV Patients had a median age of 5.6 years (range: 0.7-14y), a median viral load of 1.7.10(5) RNA/ml (range: 2.1.10(3) - 1.2.10(6)), and a median CD4-count of 232 cells/mu L (range: 1-1591). Of these, 20 patients were classified as CDC clinical category C and 31/46 as CDC immune category 3. At the time of cross-sectional analysis in 2005, adherence questionnaires were administered. DNA OLAs and RNA OLAs were performed from frozen PBMC and plasma, RNA genotyping from dried blood spots.Results: During the first year of ART, 44% of children experienced virologic failure, with an additional 9% failing by the end of the second year. Virologic failure was significantly associated with the number of resistance mutations detected by DNA-OLA (p < 0.001) during cross-sectional analysis, but also with low immunologic CDC-scores at baseline (p < 0.001). Children who had been exposed to unsupervised short-term antiretrovirals before starting structured ART showed significantly higher numbers of resistance mutations by DNA-OLA (p = 0.01). Detection of M184V (3TC resistance) by RNA-OLA and DNA-OLA demonstrated a sensitivity of 0.93 and 0.86 and specificity of 0.67 and 0.7, respectively, for the identification of virologic failure. The RT mutations N88D and L90M (NFV resistance) detected by DNA-OLA correlated with virologic failure, whereas mutations at RT position 215 (AZT resistance) were not associated with virologic failure.Conclusions: Advanced immunosuppression at baseline and previous exposures to unsupervised brief cycles of ART significantly impaired treatment outcomes at a time when structured ART was finally introduced in his cohort. Brief maternal exposures to with AZT +/- NVP for the prevention of mother-to-child transmission did not affect treatment outcomes in this group of children. DNA-OLA from frozen PBMC provided a highly specific tool to detect archived drug resistance. RNA consensus genotyping from dried blood spots and RNA-OLA from plasma consistently detected drug resistance mutations, but merely in association with virologic failure.