The Tshilo Dikotla Study: Metabolic Outcomes of Children HIV/ARV-Exposed Uninfected in Botswana

 描述(由申请人提供)：扩大联合抗逆转录病毒疗法(CART)用于预防艾滋病毒母婴传播(PMTCT)的使用已大大降低垂直传播率至2%。防止母婴传播的压倒性成功一方面导致出生时感染艾滋病毒的儿童人数减少，另一方面导致感染艾滋病毒的未感染儿童人数增加。目前，在撒哈拉以南非洲出生的所有婴儿中，估计有20%或更多出生时患有HEU。众所周知，宫内艾滋病毒/抗逆转录病毒(ARV)和出生后ARV治疗会扰乱能量代谢，并可能对HEU婴儿未来的代谢健康产生永久性影响，包括胰岛素抵抗的发展。暴露于ARV的HEU儿童线粒体功能和中间代谢的早期不良适应改变可能是通过胎儿代谢程序的改变在宫内环境中调节的，因此可能影响这些儿童的代谢结果。通过我们的工作，我们已经证明，在HEU婴儿早期，暴露于特定的宫内和新生儿ARV可能比其他ARV对胰岛素敏感性和燃料底物利用的影响更大。然而，在这些人口中，特别是在撒哈拉以南非洲，长期和机械的证据很少。本研究探讨宫内和产后HIV/ARV暴露对HEU婴儿/儿童代谢健康的影响。首先，我们将评估宫内和新生儿HIV/ARV暴露是否与HEU儿童从出生到3岁的胰岛素敏感性变化有关，并将未暴露于HIV的未感染(HUU)婴儿作为对照组。此外，我们将评估特定的新生儿ARV预防方案是否会在HEU儿童中产生不同的代谢影响。其次，我们将使用靶向代谢组学来评估特定的中间代谢物(短链酰肉碱和支链氨基酸)是否反映或促成HEU和HUU儿童胰岛素敏感性的变化。第三，我们将探索线粒体在HEU和HUU儿童胰岛素敏感性和中间代谢中的作用，以努力了解潜在的机制和未来研究的目标。在我们之前对非洲HEU和HUU婴儿进行的工作的基础上，我们提出了一项新的前瞻性队列研究，在博茨瓦纳感染和未感染HIV的妇女/儿童二人组中包含嵌套随机成分。如果宫内和出生后的HIV/ARV暴露被发现导致中间代谢紊乱，导致胰岛素敏感性在生命早期改变，HEU儿童在以后的生活中胰岛素抵抗的风险增加，这将影响这一脆弱人群中糖尿病的筛查和预防策略，并主张进一步研究，以确定出生前和出生后ARV方案具有更好的预防母婴传播效果，但对暴露于该病毒的胎儿或婴儿的不良代谢影响最小。

 DESCRIPTION (provided by applicant): Expanding use of combination antiretroviral therapy (cART) for the prevention of mother-to-child transmission (PMTCT) of HIV has dramatically decreased vertical transmission rates to <2%. The overwhelming success of PMTCT has resulted in a diminishing population of children born with perinatally acquired HIV infection on the one hand, and a mounting number of HIV-exposed uninfected (HEU) children on the other hand. Currently an estimated 20% or more of all infants born in sub-Saharan Africa are born HEU. In utero HIV/antiretroviral (ARV) and postnatal ARV treatment are known to perturb energy metabolism and could have permanent effects on the future metabolic health of HEU infants, including the development of insulin resistance. Early maladaptive changes in mitochondrial function and intermediary metabolism in HEU children exposed to ARVs may be mediated in the intrauterine environment through changes in fetal metabolic programming, and thus, may impact metabolic outcomes in these children. Through our work, we have demonstrated that exposure to specific in utero and neonatal ARVs may affect insulin sensitivity and fuel substrate utilization more than other ARVs in HEU infants early in life. Long-term and mechanistic evidence is scarce, however, in this population, particularly in sub-Saharan Africa. This study investigates the impact of in utero and postnatal HIV/ARV exposure on the metabolic health of HEU infants/children. First, we will assess whether in utero and neonatal HIV/ARV exposure is associated with changes in insulin sensitivity in HEU children from birth to 3 years of life using HIV-unexposed uninfected (HUU) infants as a comparator group. In addition, we will evaluate whether specific neonatal ARV prophylaxis regimens differ in metabolic effects amongst HEU children. Second, we will use targeted metabolomics to evaluate whether specific intermediary metabolites (short chain acylcarnitines and branched-chain amino acids) reflect or contribute to changes in insulin sensitivity in HEU and HUU children. Third, we will explore the role of the mitochondria in insulin sensitivity and intermediary metabolism amongst HEU and HUU children in an effort to understand potential mechanisms and targets for future studies. Building on our previous work with HEU and HUU infants in Africa, we propose a new prospective cohort study with a nested randomized component in HIV-infected and -uninfected woman/child dyads in Botswana. If in utero and postnatal HIV/ARV exposures are found to contribute to derangements in intermediary metabolism such that insulin sensitivity is altered early in life and HEU children are at increased risk for insulin resistance later in life, this woud impact screening and prevention strategies for diabetes in this vulnerable population and argue for further research to identify pre- and postnatal ARV regimens with superior PMTCT efficacy, but with minimal adverse metabolic consequences to the exposed fetus or infant.