Collaborative HIV Investigations of Antiretroviral Neuropsychiatric Toxicities in Zambia (CHANTZ): Protease Inhibitor Impact on Pediatric Cerebrovasculature and Mood

赞比亚抗逆转录病毒神经精神毒性合作艾滋病毒调查 (CHANTZ)：蛋白酶抑制剂对儿童脑血管和情绪的影响

• 批准号: 9925503
• 负责人: GRETCHEN L. BIRBECK
• 金额: $ 23.28万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-04 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925503
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; Adult; Adverse effects; Adverse event; Age; Alternative Therapies; Angiography; Anti-Retroviral Agents; Anxiety; Anxiety Disorders; Area; Autopsy; Basal Ganglia; Behavior Disorders; Behavioral; Blinded; Blood Vessels; Brain; CD4 Lymphocyte Count; Cerebrovascular Disorders; Cerebrovascular Insufficiency; Cerebrovascular system; Characteristics; Child; Childhood; Childhood Injury; Cholesterol; Disease; Dyslipidemias; Endothelium; Enrollment; Evaluation; Family; Goals; HIV; HIV-associated neurocognitive disorder; High Prevalence; Hypertriglyceridemia; Image; Impaired cognition; Inflammatory; Injury; Insulin Resistance; Investigation; LDL Cholesterol Lipoproteins; Magnetic Resonance Imaging; Mediating; Mental Depression; Mental disorders; Metabolic; Microvascular Dysfunction; Modeling; Moods; Neurocognitive; Outcome; Pathogenesis; Pathological anxiety; Pathology; Pharmaceutical Preparations; Play; Population; Prospective cohort study; Protease Inhibitor; Regimen; Research; Risk; Risk Factors; Role; Severities; Structural defect; Testing; Time; Toxic effect; Treatment-related toxicity; Triglycerides; Vascular Diseases; Vertebral column; Youth; Zambia; antiretroviral therapy; cardiovascular risk factor; cohort; common treatment; comorbidity; comparison group; efavirenz; improved; metabolic profile; neuropsychiatric disorder; neuropsychiatric symptom; neuropsychiatry; neurovascular; next generation; non-invasive imaging; pediatric human immunodeficiency virus; premature; radiologist; side effect

ABSTRACT Thanks to the widespread availability of antiretroviral therapies (ART), children with vertically acquired HIV can survive and even thrive, but there remain concerns about the potential effects of long-standing ART usage particularly when initiated in children in whom a lifetime of treatment is anticipated. Among adults, metabolic side effects of protease inhibitors (PIs) including insulin resistance, hypertriglyceridemia and elevations in low density lipoprotein cholesterol are well-established. Whether PIs similarly induce this in children and whether there is resulting neurovascular compromise is unknown. In adults, vascular insufficiency is a risk factor for anxiety and depression. Neuropsychiatric adverse events (NP-AEs) such as anxiety and depression are not typically attributed to PI usage but such effects might be overshadowed in studies by the NP-AEs of efavirenz used in the same population. If PI-associated metabolic changes result in cerebrovascular insufficiency, this may be further compromising pre-existing endothelial injury in children mediated by the initial HIV CNS invasion and localized at autopsy to the basal ganglia and caudate regions. An inflammatory CNS milieu, even if transient, could further increase the risk of vascular pathology. We propose a model in which PI-induced metabolic changes result in CNS vasculopathy which contributes to the burden of psychiatric comorbidity in children with vertically acquired HIV as well as increasing their long-term risk of premature cerebrovascular disease. To evaluate our model, we will conduct an exposure-control study within a sub-set of Zambian children presently enrolled in an ongoing study of HIV-associated neurocognitive disorders. Children on a combined antiretroviral therapy (cART) regimen that includes a PI will be age-matched to children treated with a cART regimen that does not include a PI and comparisons will be made on metabolic profiles, noninvasive neurovascular imaging and NP-AEs including anxiety, depression and behavioral disorders.

抽象的 得益于抗逆转录病毒疗法的广泛可用性（ART），患有垂直获得的艾滋病毒的儿童可以 生存甚至蓬勃发展，但仍然担心长期使用艺术的潜在影响 特别是在预计一生治疗的儿童中发起。在成年人中，代谢 蛋白酶抑制剂（PI）的副作用，包括胰岛素抵抗，高甘油三酯血症和低升高 密度脂蛋白胆固醇已建立良好。 PI是否同样在儿童中引起这一点 导致的神经血管妥协尚不清楚。在成年人中，血管功能不全是一个危险因素 焦虑和沮丧。神经精神上的不良事件（NP-AES），例如焦虑和抑郁症 通常归因于PI使用，但这种效果可能在Efavirenz的NP-AES研究中掩盖了 用于同一人群。如果PI相关的代谢变化会导致脑血管功能不全，那么 可能进一步损害了最初的HIV CNS介导的儿童预先存在的内皮损伤 入侵并在尸检中局部到基底神经节和尾状区域。炎症的CNS环境，甚至 如果瞬时，可以进一步增加血管病理的风险。我们提出了一个模型，其中PI诱导 代谢变化会导致CNS血管病变导致精神病合并症的负担 患有垂直艾滋病毒的儿童，并增加了早产脑血管的长期风险 疾病。为了评估我们的模型，我们将在赞比亚的子集中进行暴露控制研究 目前，儿童正在进行一项正在进行的HIV相关神经认知障碍的研究。儿童 包括PI在内的抗逆转录病毒疗法（CART）方案将与接受治疗的儿童相匹配 不包括PI和比较的购物车方案将在代谢概况上进行无创的 神经血管成像和NP-AE，包括焦虑，抑郁和行为障碍。