Properties of HIV-1 DNA/RNA Assays for Detecting HIV Infection in Infants

描述(由申请人提供)：联合国艾滋病规划署的统计数据估计，每年约有80万婴儿感染艾滋病毒，其中90%的感染发生在资源有限的环境中。几乎所有婴儿中的艾滋病毒感染都归因于母婴传播(MTCT)，这种传播可能发生在怀孕、分娩或哺乳期间。在缺乏治疗的情况下，艾滋病毒阳性母亲所生的婴儿中约有25%将感染艾滋病毒。在资源丰富的环境中，采用高效抗逆转录病毒疗法(HAART)的治疗已将传播率降至2%以下；然而，确定最佳检测时间并提供早期、及时的治疗仍然是令人关切的领域。诊断婴儿感染HIV的“金标准”检测是HIV-1DNA和RNA检测。先前的研究表明，不同感染婴儿的阳性检测时间有很大差异。目前的知识是基于主要在美国/欧洲和最多接触单一疗法的人群中进行的小规模研究。以前关于母婴传播时间的工作受到几个限制，包括样本数量有限和使用特别战略。我们建议，基于对几个HIV感染婴儿队列数据的联合分析，确定检测婴儿中HIV感染的方法，并调查母婴传播的时机。我们建议的核心是由来自几个队列的研究人员组成一个跨学科的合作，其中包括大约5800名艾滋病毒阳性的配方奶和母乳喂养的婴儿，这些婴儿的母亲是艾滋病毒阳性的，代表美国、欧洲、非洲和亚洲的人口。由此产生的大型数据库将使统计分析能够在不同的环境下评估DNA/RNA分析的性能，包括在暴露于HAART的人群中以及在非B亚型感染占主导地位的环境中。我们将应用新的统计模型来估计MTCT的时间，以克服以前采用的特别策略中固有的缺点。具体来说，我们的建议涉及以下内容：目标1--艾滋病毒-1感染非母乳喂养婴儿中艾滋病毒-1 DNA和RNA检测阳性信号的时间分布的表征和比较；目标2a--估计艾滋病毒感染非母乳喂养婴儿中艾滋病毒的母婴传播时间；以及目标2b--估计艾滋病毒感染的母乳喂养婴儿中艾滋病毒的母婴传播时间。在每个目标中，将特别强调评估母婴因素，包括母婴抗逆转录病毒治疗的类型、艾滋病毒亚型和分娩方式；母亲的年龄、艾滋病毒-1病毒载量和CD4细胞计数；以及婴儿的CD%和出生体重。从Aim 2b收集的结果将成为对母乳喂养为常态的人群中艾滋病毒母婴传播所涉及的风险和因素进行更大规模荟萃分析的基础。影响：更好地了解诊断化验的特点和母婴传播的时间将指导优化不同人群中婴儿艾滋病毒诊断检测的战略，并将为制定预防计划的最佳方法提供信息，特别是在资源有限的情况下。

DESCRIPTION (provided by applicant): UNAIDS statistics estimate that approximately 800,000 infants are infected with HIV annually, with 90% of infections occurring in resource-limited settings. Virtually all HIV infections in infants are attributed to mother-to-child transmission (MTCT), which can occur during the periods of pregnancy, birth, or breast- feeding. In the absence of treatment, approximately 25% of infants born to HIV-positive mothers will be infected with HIV. In resource-rich settings, treatment with highly-active anti-retroviral therapies (HAART) has reduced the transmission rate to under 2%; However, determining the optimal time to test and providing early, timely treatment remain areas of concern. The "gold standard" tests for diagnosis of HIV infection in infants are HIV-1 DNA and RNA assays. Previous work has shown that the time to positive detection of infection varies significantly among infected infants. Current knowledge is based on small studies conducted primarily in the U.S./Europe and in populations who are, at most, exposed to monotherapy regimens. Previous work on the timing of MTCT suffers from several limitations, including limited sample size and the use of ad hoc strategies. We propose to characterize assays to detect HIV infection in infants and to investigate the timing of MTCT, based on a combined analysis of data from several cohorts of HIV-exposed infants. Central to our proposal is the formation of an interdisciplinary collaboration of investigators from several cohorts including approximately 5,800 HIV-positive formula-fed and breastfed infants born to HIV-positive mothers representing populations in the U.S., Europe, Africa, and Asia. The resulting large database will enable statistical analyses to evaluate the performance of DNA/RNA assays in diverse settings, including in populations exposed to HAART and in settings where non-B subtype infections dominate. We will apply novel statistical models for the estimation of timing of MTCT that overcome disadvantages inherent in previously employed ad hoc strategies. Specifically, our proposal addresses the following: Aim 1 - Characterization and comparison of the distribution of time to positive signal of HIV-1 DNA and RNA assays in HIV-1 infected, non-breastfed infants; Aim 2a - Estimation of timing of MTCT of HIV in HIV-infected, non- breastfed infants; and Aim 2b - Estimation of the timing of MTCT of HIV in HIV-infected, breastfed infants. In each aim, special emphasis will be placed on evaluating maternal/infant factors, including type of maternal/infant antiretroviral treatment, HIV subtype, and mode of delivery; mother's age, HIV-1 viral load, and CD4 cell count; and infant's CD% and birth weight. The results gathered from Aim 2b, will serve as a foundation for a larger meta-analysis of risks and factors involved in MTCT of HIV in populations where breastfeeding is the norm. IMPACT: A better understanding of the characteristics of diagnostic assays and the timing of MTCT will guide strategies to optimize HIV diagnostic testing in infants in various populations, and will inform the best approaches for scheduling prophylaxis, particularly when resources are limited.