Variation in Neurocognitive Impairment of HIV Ugandan Children by HIV Subtype

描述（由申请人提供）：撒哈拉以南非洲越来越多的艾滋病毒感染儿童现在受益于抗逆转录病毒治疗，但目前世卫组织和国家抗逆转录病毒（ARV）启动指南强调免疫功能受损（CD4%和机会性感染的发生）作为开始治疗的指征。关于撒哈拉以南非洲地区艾滋病毒导致的神经发育迟缓的程度，存在相互矛盾的数据。尚不确定的是，撒哈拉以南非洲地区高频率的合并症以及不同的艾滋病毒亚型流行如何影响病程。值得注意的是，众所周知，疟疾等并发症会影响儿童发育，除非加以说明，否则可能会扭曲艾滋病毒与神经认知障碍之间的联系。对于因CD4%高而推迟治疗的HIV感染儿童，尚不清楚什么可以预测显著的神经发育并发症，或者一旦出现，这种损害是否可以通过ARV治疗完全逆转。本申请利用乌干达坎帕拉的Makerere大学/UCSF联合疟疾研究项目的现有儿科队列和基础设施以及乌干达和美国的神经医学、行为和实验室专业知识来研究在并发疟疾的背景下延迟ARV治疗的神经发育后果。我们将在病毒基因特异性水平上评估HIV亚型组成和HIV DNA病毒载量（均由干血斑（DBS）确定），并估计过去的疟疾暴露作为HIV相关神经发育迟缓的新预测因子。此外，据我们所知，这将是第一次尝试在一项研究中使用统一的工具来分析和对比艾滋病毒和疟疾相关的神经认知功能障碍。当这些研究完成后，我们将更好地了解艾滋病毒神经认知障碍的决定因素，无论是治疗初治患者还是治疗患者。此外，我们将拥有必要的初步数据和工具，以进行明确的前瞻性研究，包括关于疟疾合并感染、病毒亚型和其他生物标志物的信息，以规划干预性研究，解决艾滋病毒感染非洲儿童的神经发育迟缓问题。这些研究是相关的，因为它们有可能改变发展中国家的儿科艾滋病毒治疗模式，并减轻个人和社会神经发育障碍的负担。艾滋病毒感染会影响成人和儿童的大脑功能。在这项研究中，我们将试图确定乌干达的艾滋病毒能在多大程度上改变儿童的大脑发育，什么可以用来预测哪个孩子会有这种并发症，以及抗艾滋病毒治疗是否可以预防这种情况。

DESCRIPTION (provided by applicant): Increasing numbers of HIV infected children in Sub-Saharan Africa now benefit from treatment with antiretroviral therapy but current WHO and national guidelines for antiretroviral (ARV) initiation stress impairment of immune function (CD4% and the occurrence of opportunistic infections) as indications for starting treatment. There are conflicting data on the magnitude of the neuro-developmental delay due to HIV in sub- Saharan Africa. Uncertainty exists on how the high frequency of co-morbidities and how different HIV subtypes prevalent in sub-Saharan Africa might impact disease course. Of note co-morbidities such as malaria are well known to impact child development and unless accounted for, may distort associations between HIV and neurocognitive impairment. For HIV infected children deferring therapy because of high CD4%, it is not known what might predict significant neuro-developmental complications or whether, once manifest, whether such impairment is fully reversible with ARV therapy. The current application utilizes existing pediatric cohorts and infrastructure at the Makerere University/UCSF Joint Malaria Study project in Kampala, Uganda and neuro- medical, behavioral and laboratory expertise in Uganda and in the U.S. to study the neuro-developmental consequences of deferred ARV therapy in the background of co- incident malaria. We will assess HIV subtype composition at the viral gene specific level and HIV DNA viral load, (both determined from dried blood spots (dbs)) and estimates of past malaria exposure as novel predictors of HIV related neuro-developmental delay. Additionally, this will be, to our knowledge, the first attempt to analyze and contrast HIV and malaria related neurocognitive dysfunction using uniform tools under one study. When these studies are complete we will have an improved understanding of the determinants of HIV neurocognitive impairment in both treatment na¿ve and on treatment patients. Furthermore, we will have the necessary preliminary data and tools to pursue definitive, prospective studies that include information on malaria co-infection, viral subtype and other biomarkers in planning interventional studies that address neuro- developmental delay in HIV infected African children. These studies are relevant because they have the potential to alter pediatric HIV treatment paradigms in the developing world and to ameliorate the burden of individual and societal neuro- developmental disability. HIV infection can affect the brain function of adults and children. In this study, we will try to determine how much HIV in Uganda can alter the brain development in children what can be used to predict which child will have this complication and whether anti-HIV treatment prevents this.