Long-term neurocognitive outcomes of HIV-exposed uninfected children

每年有100多万感染艾滋病毒但未受感染的儿童在撒哈拉以南非洲出生，而这 随着抗逆转录病毒治疗(ART)可获得性的提高，人口将继续增加。长期的 宫内接触艾滋病毒和抗逆转录病毒药物对儿童健康和福祉的影响还不充分 具有特点的，特别是在资源有限的情况下。CHU感染传染病的风险较高，最近 研究表明，与没有感染艾滋病毒的孩子相比，他们的神经认知发育可能受到了损害 曝光。确定神经认知延迟的原因和危险因素对于发展神经认知延迟至关重要 有效的干预措施，改善CHU儿童的生活。这项提议利用了独特的 评估宫内HIV和ART暴露对儿童神经认知发育影响的机会 通过扩大我们正在马拉维进行的一项正在进行的临床研究的队列。我们正在放映 孕妇、招收婴儿及新生儿适应性免疫强化分析 三类婴儿：(1)首次产前检查时被诊断为艾滋病毒携带者所生的CHU，从而接触到 至少在怀孕一半的时间内出现不受控制的病毒血症；(2)怀孕前接受抗逆转录病毒治疗的妇女所生的CHU 病毒载量无法检测；以及(3)未感染艾滋病毒的母亲所生的婴儿。在这项提案中，我们将继续 加入我们的CHU和未接触艾滋病毒的儿童队列，以达到所需的样本量 对神经认知结果进行强有力的纵向分析。我们将适应标准化和本地化 经过验证的评估工具，以调查整体神经发展以及关键的神经认知领域。 在我们达到最初的里程碑后，我们建议在18、36和60岁时评估神经认知发展 几个月大的孩子。我们的跨学科研究团队由传染病专家、发育儿科医生、 心理学家和免疫学家将在资源有限的情况下领导对CHU的最全面的研究之一 设置以同时处理母亲和新生儿因素对神经认知发育的影响 在这群人身上。我们假设在子宫内暴露于艾滋病毒会损害小鼠的神经认知发育 生命的前五年和艾滋病毒感染母亲所生的孩子在开始时未经治疗的艾滋病毒感染 在整个过程中，怀孕将比母亲携带无法检测到的艾滋病毒病毒的孩子表现出更多的延迟 怀孕了。我们进一步假设出生时的免疫状态会导致神经认知受损。 并探讨基础母体病史或实验室检查是否有可能 找出风险最高的婴儿。这项研究的结果可以立即转化为干预措施 改善CHU的生活，特别是在资源匮乏的环境中。

Every year, over a million children HIV-exposed but uninfected (CHEU) are born in sub-Saharan Africa and this population will continue to increase with improving availability of antiretroviral therapy (ART). The long-term effects of in utero exposure to HIV and ART on child health and well-being have not been adequately characterized, especially in resource-limited settings. CHEU are at higher risk for infectious diseases and recent studies suggest they may have impaired neurocognitive development compared to their children without HIV exposure. Identifying the causes of and risk factors for neurocognitive delay is essential for the development of effective interventions to improve the lives of CHEU children. This proposal takes advantage of the unique opportunity to evaluate the impact of in utero HIV and ART exposure on neurocognitive development in children by extending the cohort enrolled in an ongoing clinical study we are conducting in Malawi. We are screening pregnant women, enrolling infants and conducting intensive analysis of neonatal adaptive immunity among infants in three categories: (1) CHEU born to women diagnosed with HIV at the first antenatal visit, thus exposed to uncontrolled viremia for at least half of gestation; (2) CHEU born to women initiated on ART prior to conception with undetectable viral loads; and (3) infants born to HIV uninfected mothers. In this proposal, we will continue enrollment into our cohort of CHEU and children without HIV exposure to reach the sample size required to conduct a robust longitudinal analysis of neurocognitive outcomes. We will adapt standardized and locally validated assessment tools to investigate overall neurodevelopment as well as key neurocognitive domains. After our initial milestones are achieved, we propose to evaluate neurocognitive development at 18, 36, and 60 months of age. Our interdisciplinary study team of infectious disease specialists, developmental pediatricians, psychologists and immunologists will lead one of the most comprehensive studies of CHEU in resource-limited settings to simultaneously address the impact of maternal and neonatal factors on neurocognitive development on this population. We hypothesize that in utero exposure to HIV will impair neurocognitive development in the first five years of life and children born to HIV-infected mothers with untreated HIV infection at the start of pregnancy will demonstrate more delay than children of mothers with undetectable HIV viral load throughout pregnancy. We further hypothesize that immunological status at birth will contribute to impaired neurocognitive development in HEU children and explore the possibility that basic maternal history or laboratory tests may identify the highest risk infants. The results of this study can immediately be translated into interventions to improve the lives of CHEU, especially in low-resource settings.