Vitamin D status and HIV-related complications in children and young adults

描述(由申请人提供)：维生素D在许多生理和病理生理过程中都是至关重要的，包括炎症状态、免疫功能和心血管健康。维生素D缺乏症在感染艾滋病毒的成人和儿童中普遍存在。这尤其令人担忧，因为与普通人群相比，骨质疏松症、非艾滋病定义的恶性肿瘤和心血管疾病等并发症的风险更高--所有这些疾病都与维生素D缺乏有关。目前尚不清楚维生素D缺乏在多大程度上会增加心血管疾病等并发症的风险，影响免疫功能和疾病进展，或干扰艾滋病毒人群的最佳治疗。维生素D缺乏对艾滋病毒人群的影响可能会进一步加剧，因为CVD等艾滋病毒相关并发症的病原学被认为在一定程度上与炎症和与慢性艾滋病毒感染相关的有害内皮效应有关--与维生素D缺乏相似的拟议机制。数据表明，最佳的维生素D状态可能对这些HIV相关并发症具有保护作用，通过口服补充剂优化HIV感染者的维生素D状态可能会通过减少炎症和/或改善内皮功能障碍来改善HIV相关并发症的风险，甚至可能提高免疫功能，即使在接受抗逆转录病毒治疗的患者中也是如此。制定适当的补给战略对于最大限度地提高健康状况至关重要，特别是在感染艾滋病毒的儿童和年轻人中，因为他们有机会预防疾病。然而，补充维生素D的最佳方法尚不清楚，数据表明，一些抗逆转录病毒药物会干扰维生素D的新陈代谢。因此，我们假设(1)优化维生素D状态到当前医学研究所(IOM)建议的25-羟基维生素D(25(OH)D)浓度e20 ng/mL可改善HIV感染者的心血管风险、炎症和CD4细胞计数，(2)将25(OH)D浓度增加到30 ng/mL可更大程度地改善心血管疾病风险和炎症，而不是增加eto 20 ng/mL(一些专家认为对心血管健康最理想的浓度)，以及(3)“高剂量”口服维生素D是达到25(OH)D浓度和GT所必需的；30 ng/m L。这些假说将通过一项双盲随机对照试验确定HIV感染儿童和年轻人中血清25(OH)D浓度、颈动脉内膜中层厚度、脉搏波速度、促炎生物标志物和CD4细胞计数之间的纵向关系，这三种不同的维生素D剂量方案在HIV感染儿童和年轻人(年龄10-25岁)维生素D缺乏(25(OH)D&lt；20 ng/mL)的24个月内给予。我们还将在补充6个月、12个月和24个月后评估每个ARM的25(OH)D浓度，以确定剂量-反应关系。这些发现可能会对这一人群的健康产生相当大的影响，因为维生素D治疗成本低廉，而且几乎没有不良副作用。PI是一位特殊的候选人，他是一名儿科传染病专家，在艾滋病毒的代谢和心血管并发症方面具有公认的研究重点。她得到了一支忠诚的、多学科的高级调查人员团队的指导，他们在指导和与这项提案相关的研究方法方面都拥有丰富的经验。未来计划在临床研究、心血管疾病风险评估和临床营养的各个方面进行培训，以促进PI发展成为一名成功的独立内科科学家。 公共卫生相关性：在大多数研究中，艾滋病毒感染者与未感染者相比，维生素D缺乏症的患病率更高。缺乏维生素D可能会导致艾滋病毒感染的一些长期并发症，如心血管疾病和炎症增加。这项建议将增进我们对纠正维生素D缺乏是否会影响这些艾滋病毒相关并发症的风险和/或改善CD4细胞计数的理解。

DESCRIPTION (provided by applicant): Vitamin D is critical in many physiologic and pathophysiologic processes including inflammatory status, immune function, and cardiovascular health. Vitamin D deficiency is widespread among HIV-infected adults and children. This is particularly alarming since there is a higher risk than the general population for complications like osteoporosis, non-AIDS-defining malignancies, and cardiovascular disease (CVD) - all diseases associated with vitamin D deficiency. It is not known how much vitamin D deficiency heightens the risk of complications like CVD, affects immune function and disease progression, or interferes with optimal treatment in the HIV population. The impact of vitamin D deficiency in the HIV population may be compounded even further since the etiology of HIV-related complications like CVD is thought to be related in part to inflammation and detrimental endothelial effects associated with chronic HIV infection-similar proposed mechanisms as vitamin D deficiency. Data suggest that optimal vitamin D status may be protective against these HIV-related complications, and optimizing vitamin D status with oral supplementation in HIV-infected individuals may improve the risk of HIV-related complications by decreasing inflammation and/or improving endothelial dysfunction, and may improve immune function even in individuals on antiretroviral therapy. Developing suitable repletion strategies is crucial to maximizing health status, particularly in HIV-infected children and young adults, where an opportunity exists for disease prevention. However, the best method of vitamin D repletion is not known, and data suggest that some antiretroviral medications interfere with vitamin D metabolism. Thus, we hypothesize that (1) optimizing vitamin D status to the current Institute of Medicine's (IOM) suggested 25-hydroxyvitamin D (25(OH)D) concentration of e20 ng/mL improves CVD risk, inflammation, and CD4 cell counts in HIV-infected individuals, (2) increasing 25(OH)D concentrations to >30 ng/mL improves CVD risk and inflammation to a greater degree than increasing eto 20 ng/mL (the concentration some experts consider optimal for cardiovascular health), and (3) a "high dose" of oral vitamin D is necessary to achieve 25(OH)D concentrations >30 ng/mL. These hypotheses will be addressed by determining the longitudinal relationships between serum 25(OH)D concentrations, carotid intima-media thickness, pulse wave velocity, pro-inflammatory biomarkers, and CD4 cell counts in HIV-infected children and young adults in a double-blinded, randomized-controlled trial of three different vitamin D dosing regimens given over 24 months in HIV-infected children and young adults (ages 10-25 years) with vitamin D deficiency (25(OH)D <20 ng/mL). We will also evaluate the 25(OH)D concentrations from each arm after 6, 12, and 24 months of supplementation, in order to determine a dose-response relationship. These findings could have a sizable impact on health in this population, since vitamin D therapy is inexpensive and associated with few adverse side effects. The PI is an exceptional candidate who is a pediatric infectious diseases specialist with a proven research focus in the metabolic and cardiovascular complications of HIV. She is mentored by a committed, multidisciplinary team of senior investigators with extensive experience in both mentoring and in the research methodologies relevant to this proposal. Future training in all aspects of clinical research, cardiovascular disease risk assessment, and clinical nutrition is planned to facilitate the PI's development into a successful independent physician scientist. PUBLIC HEALTH RELEVANCE: In most studies, HIV-infected individuals have a higher prevalence of vitamin D deficiency compared to uninfected individuals. Vitamin D deficiency may contribute to some of the long-term complications of HIV infection, such as cardiovascular disease and increased inflammation. This proposal will advance our understanding of whether correction of vitamin D deficiency affects the risk of these HIV-related complications and/or improves CD4 cell counts.