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。几乎所有的婴儿艾滋病毒感染都归因于母婴传播（MTCT），这可能发生在怀孕、分娩或母乳喂养期间。在没有治疗的情况下，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，使用高效抗逆转录病毒疗法（HAART）治疗已将传播率降至2%以下；然而，确定最佳的检测时间和提供早期、及时的治疗仍然是值得关注的领域。诊断婴儿感染艾滋病毒的“金标准”测试是HIV-1 DNA和RNA分析。先前的研究表明，在受感染的婴儿中，检测出感染阳性的时间差别很大。目前的知识是基于主要在美国/欧洲进行的小型研究，以及在最多暴露于单一治疗方案的人群中进行的研究。以前关于MTCT时机的工作受到一些限制，包括有限的样本量和使用临时策略。我们建议在对几个HIV暴露婴儿队列数据进行综合分析的基础上，对检测婴儿HIV感染的检测方法进行特征化，并调查MTCT的时机。我们的建议的核心是组成一个跨学科合作的研究人员，他们来自几个队列，包括大约5800名艾滋病毒阳性母亲所生的配方喂养和母乳喂养的婴儿，这些婴儿代表了美国、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评估DNA/RNA测定在不同环境下的性能，包括暴露于HAART的人群和非b亚型感染占主导地位的环境。我们将应用新的统计模型来估计MTCT的时间，克服了以前采用的临时策略所固有的缺点。具体而言，我们的建议解决以下问题：目标1 - HIV-1感染的非母乳喂养婴儿中HIV-1 DNA和RNA检测阳性信号的时间分布的表征和比较；目的2a -估计艾滋病毒感染的非母乳喂养婴儿的艾滋病毒母婴传播时间和Aim 2b -估计艾滋病毒感染的母乳喂养婴儿进行艾滋病毒母婴传播的时间。在每个目标中，将特别强调评价孕产妇/婴儿因素，包括孕产妇/婴儿抗逆转录病毒治疗的类型、艾滋病毒亚型和分娩方式；母亲年龄、HIV-1病毒载量和CD4细胞计数；婴儿乳糜泻百分比和出生体重从Aim 2b中收集的结果将作为在母乳喂养为常态的人群中进行更大规模的艾滋病毒母婴传播风险和因素荟萃分析的基础。影响：更好地了解诊断检测的特点和MTCT的时机将指导在不同人群中优化婴儿艾滋病毒诊断检测的策略，并将为安排预防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. PUBLIC HEALTH RELEVANCE: Prevention of mother-to-child transmission of HIV is a fundamental component of the global effort to stem the HIV epidemic. Critical challenges in this endeavor include knowledge of the accuracy of commonly used HIV diagnostic tests in infants and insight into the mechanism and timing of mother-to-child transmission of HIV. This proposal utilizes in-depth statistical analyses to address these issues based on combined data from several large cohorts of HIV-positive mothers and their infants in the U.S., Europe, Africa, and Asia.