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

摘要 由于抗逆转录病毒疗法（ART）的广泛应用，垂直感染艾滋病毒的儿童可以 生存，甚至蓬勃发展，但仍然存在对长期使用ART的潜在影响的担忧 特别是在预期终生治疗的儿童中开始时。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、高血糖和低血糖水平升高， 高密度脂蛋白胆固醇是公认的。PI是否在儿童中同样诱导这种情况，以及 是否会导致神经血管损伤尚不清楚。在成人中，血管功能不全是 焦虑和抑郁神经精神不良事件（NP-AE），如焦虑和抑郁， 通常归因于PI的使用，但在研究中，这种效应可能被依法韦仑的NP-AE所掩盖 用于同一人群。如果PI相关的代谢变化导致脑血管功能不全， 可能进一步损害儿童中由最初的HIV CNS介导的既存内皮损伤 在尸检中，肿瘤浸润并局限于基底神经节和尾状核区域。甚至是炎症性中枢神经系统环境 如果是短暂的，可能会进一步增加血管病变的风险。我们提出了一个模型，其中PI诱导 代谢变化导致CNS血管病变，这有助于精神共病的负担， 垂直感染艾滋病毒的儿童以及增加他们过早脑血管疾病的长期风险 疾病为了评估我们的模型，我们将在赞比亚的一个子集内进行一项确定性对照研究。 目前正在进行的HIV相关神经认知障碍研究中的儿童。孩子们去 包括PI的联合抗逆转录病毒治疗（cART）方案将与接受以下治疗的儿童年龄匹配： 不包括PI的cART方案，将对代谢特征进行比较，无创 神经血管成像和NP-AE，包括焦虑、抑郁和行为障碍。

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.