Risk factors for early morbidity and mortality of HIV-exposed uninfected infants

说明（由申请人提供）：感染艾滋病毒的妇女每年生下200多万名儿童。随着获得抗逆转录病毒治疗和预防母婴传播战略的进展，婴儿感染在博茨瓦纳等环境中已变得不常见。然而，这些接触艾滋病毒但未感染的婴儿的死亡风险仍然比未接触艾滋病毒的相应儿童高2至4倍，占博茨瓦纳5岁前所有死亡人数的一半以上。尽管其具有重大的公共卫生重要性，但这种死亡率差距的病因尚不清楚，并且以前没有研究过减轻艾滋病毒暴露的未感染（HIV-EU）婴儿的这种超额死亡率的策略。晚期产妇艾滋病毒疾病与保护性抗体转移减少和婴儿预后不良有关。经最近修订的世卫组织指南认可，通过扩大使用孕产妇高活性抗逆转录病毒疗法（HAART）预防母婴传播来治疗孕产妇艾滋病毒，也可改善未感染婴儿的健康结果。然而，产妇HAART与早产、低出生体重和严重婴儿贫血的风险增加有关，这些都是死亡率增加的重要预测因素。利用博茨瓦纳哈佛艾滋病研究所伙伴关系提供的独特临床数据和具有良好特征的队列标本，该项目将审查产妇HAART治疗和其他因素对艾滋病毒感染者婴儿整体健康的影响这一关键问题。该项目有两个具体目标：1)通过汇总来自4个大型队列的数据，确定与博茨瓦纳2621名HIV-EU婴儿死亡或住院（包括HAART）相关的因素；2)确定婴儿对常见病原体的抗体水平降低是否与母体缺乏HAART以及HIV-EU婴儿的死亡或住院有关。这些研究的结果可能会影响产妇HAART、疫苗接种策略和其他干预措施的使用，以改善越来越多的暴露于艾滋病毒的未感染婴儿的结果。此外，这些指导项目是详细的职业发展计划的一部分，将为候选人提供成功过渡到独立调查员的知识，技能和经验。

DESCRIPTION (provided by applicant): Over two million children are born to HIV-infected women annually. With advances in access to antiretroviral therapy and strategies to prevent mother-to-child transmission (MTCT), infant infection has become uncommon in settings like Botswana. However, these HIV-exposed but uninfected infants remain at 2 to 4-fold greater risk of dying than matched HIV-unexposed children, accounting for more than half of all deaths before age 5 in Botswana. Despite its great public health importance, the etiology of this mortality gap is unknown and strategies to mitigate this excess mortality in HIV-exposed uninfected (HIV-EU) infants have not been previously studied. Advanced maternal HIV disease is associated with decreased transfer of protective antibodies and poor infant outcomes. Treatment of maternal HIV, through expanded use of maternal highly- active antiretroviral therapy (HAART) for prevention of MTCT, as endorsed by recently revised WHO guidelines, may also improve health outcomes of uninfected infants. However, maternal HAART is associated with increased risk of prematurity, low birth weight, and severe infant anemia- all important predictors of increased mortality. Utilizing unique clinical data and specimens from well-characterized cohorts at the Botswana Harvard AIDS Institute Partnership, the project will examine the critical question of the effect of maternal HAART and other factors on the overall health of HIV-EU infants. The project as two specific aims: 1) determine factors associated with death or hospitalization (including HAART) among 2621 HIV-EU infants in Botswana by pooling data from 4 large cohorts, and 2) determine if reduced infant antibody levels to common pathogens are associated with lack of maternal HAART, and with death or hospitalization in HIV-EU infants. The results of these studies could impact the use of maternal HAART, vaccination strategy, and other interventions to improve outcomes for the rising number of HIV-exposed, uninfected infants. In addition, these mentored projects are part of a detailed Career Development Plan that will provide the Candidate with the knowledge, skills, and experience to successfully transition to an independent investigator. Public Health Relevance Statement (provided by the applicant): Worldwide two million children are born to women with HIV. Most of these infants will not get HIV, but they are still 2-4 times more likely to die by 2 years of age than infants born to mothers without HIV. This project aims to study reasons why this happens with a goal of developing strategies to prevent these deaths.