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

Tshilo Dikotla 研究：博茨瓦纳未感染 HIV/ARV 的儿童的代谢结果

基本信息

批准号：
9925218
负责人：
Jennifer Jao
金额：
$ 57.81万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-22 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9925218
关键词：
3 year old Acquired Immunodeficiency Syndrome Adverse effects Affect Africa Africa South of the Sahara Amino Acids Anti-Retroviral Agents Birth Botswana Branched-Chain Amino Acids Child Childhood Country Development Diabetes Mellitus Energy Metabolism Environment Exhibits Exposure to Fasting Fetus Future Genus Hippocampus Gestational Age Glucose HIV HIV Infections HIV antiretroviral HIV-exposed uninfected infant Health High Prevalence Infant Institutes Insulin Insulin Resistance Life Link Mediating Metabolic Metabolism Mitochondria Modeling Mother-to-child HIV transmission Neonatal Nevirapine Outcome Participant Perinatal Pharmaceutical Preparations Phenotype Population Pregnant Women Prevalence Prevention Prevention strategy Prevention therapy Prophylactic treatment Prospective cohort study Public Health Randomized Regimen Reporting Research Research Infrastructure Risk Role Small for Gestational Age Infant Technology Time Translating Vertical Disease Transmission Vulnerable Populations Woman Work Zidovudine acylcarnitine antiretroviral therapy comparison group fetal in utero insulin sensitivity metabolic abnormality assessment metabolomics mitochondrial dysfunction neonatal exposure postnatal prenatal primary outcome public health relevance screening success transmission process treatment strategy trend

项目摘要

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.

描述（由申请人提供）：扩大使用联合抗逆转录病毒疗法（cART）预防艾滋病毒母婴传播（PMTCT）已将垂直传播率大幅降低至<2%。预防母婴传播的巨大成功一方面导致出生时感染围产期艾滋病毒的儿童人数减少，另一方面导致未感染艾滋病毒的儿童人数增加。目前，在撒哈拉以南非洲出生的所有婴儿中，估计有20%或更多的婴儿出生时就患有高浓缩铀。已知子宫内艾滋病毒/抗逆转录病毒治疗和产后抗逆转录病毒治疗会扰乱能量代谢，并可能对高浓缩铀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。接触抗逆转录病毒药物的高浓缩铀儿童的线粒体功能和中间代谢的早期适应不良变化可能通过胎儿代谢程序的变化在宫内环境中介导，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，在子宫内和新生儿暴露于特定的抗逆转录病毒药物可能会影响胰岛素敏感性和燃料底物的利用比其他抗逆转录病毒药物在高浓缩铀婴儿的生命早期。然而，在这一人群中，特别是在撒哈拉以南非洲，长期和机械的证据很少。这项研究调查了宫内和产后接触艾滋病毒/抗逆转录病毒药物对高浓缩铀婴儿/儿童代谢健康的影响。首先，我们将评估子宫内和新生儿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相关，使用HIV未暴露的未感染（HUU）婴儿作为对照组。此外，我们将评估特定的新生儿抗逆转录病毒预防方案是否对高浓缩铀儿童的代谢影响不同。其次，我们将使用靶向代谢组学来评估特定的中间代谢物（短链酰基肉碱和支链氨基酸）是否反映或有助于HEU和HUU儿童胰岛素敏感性的变化。第三，我们将探讨线粒体在高血压和高尿酸儿童胰岛素敏感性和中间代谢中的作用，以了解潜在的机制和未来研究的目标。在我们以前的工作与高浓缩铀和HUU婴儿在非洲的基础上，我们提出了一个新的前瞻性队列研究，在博茨瓦纳艾滋病毒感染和未感染的妇女/儿童二人组的嵌套随机组成部分。如果发现子宫内和出生后的艾滋病毒/抗逆转录病毒药物暴露有助于中间代谢紊乱，例如胰岛素敏感性在生命早期改变，高浓缩铀儿童在以后的生命中胰岛素抵抗的风险增加，这将影响这一脆弱人群的糖尿病筛查和预防战略，并主张进一步研究以确定具有上级预防母婴传播功效的出生前和出生后抗逆转录病毒药物治疗方案，但对暴露的胎儿或婴儿具有最小的不利代谢后果。