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

儿童和年轻人的维生素 D 状况和 HIV 相关并发症

• 批准号: 8774918
• 负责人: Allison Ross Eckard
• 金额: $ 4.47万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-02 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774918
• 关键词: 25-hydroxycholecalciferol-24-hydroxylase; 25-hydroxyvitamin D; Address; Adolescent; Adult; Adverse effects; Affect; African American; Age; Anti-Retroviral Agents; Biological Markers; Blood; C-reactive protein; CAP18 lipopolysaccharide-binding protein; CD4 Lymphocyte Count; Cardiovascular Diseases; Cardiovascular system; Cell Adhesion; Cell Adhesion Molecules; Child; Childhood; Cholecalciferol; Chronic; Clinical Nutrition; Clinical Research; Communicable Diseases; Comorbidity; Data; Development; Disease; Disease Progression; Dose; Double-Blind Method; Enzymes; Etiology; Future; General Population; HIV; HIV Infections; Health; Health Status; High Prevalence; Immune; Immune System Diseases; Individual; Inflammation; Inflammatory; Institute of Medicine (U.S.); Interleukin-6; Learning; Life; Malignant Neoplasms; Mentors; Metabolic; Metabolism; Methods; Myocardial; Oral; Osteoporosis; Overweight; Participant; Patients; Pharmaceutical Preparations; Physicians; Physiologic pulse; Physiological; Plasma; Play; Population; Population Group; Primary Prevention; Process; Public Health; Randomized Controlled Clinical Trials; Randomized Controlled Trials; Recruitment Activity; Regimen; Reporting; Research; Research Methodology; Research Personnel; Risk; Risk Assessment; Role; Scientist; Serum; Specialist; Supplementation; Surrogate Markers; TNFR-Fc fusion protein; Testing; Time; Training; Vascular Cell Adhesion Molecule-1; Vascular Smooth Muscle; Vitamin D; Vitamin D Deficiency; Vitamins; antimicrobial; antiretroviral therapy; arm; arterial stiffness; cardiovascular disorder risk; cardiovascular health; cost effective; cytokine; disorder prevention; efficacy testing; endothelial dysfunction; experience; high risk; immune function; improved; intercellular cell adhesion molecule; intimal medial thickening; multidisciplinary; patient population; response; restoration; young adult

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.

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至关重要，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 (CVD) 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 缺乏会在多大程度上增加 CVD 等并发症的风险，影响免疫功能和疾病进展，或干扰 HIV 人群的最佳治疗。 HIV 人群中维生素 D 缺乏的影响可能会进一步加剧，因为 CVD 等 HIV 相关并发症的病因被认为部分与慢性 HIV 感染相关的炎症和有害内皮效应有关，与维生素 D 缺乏的机制相似。数据表明，最佳的维生素 D 状态可能有助于预防这些 HIV 相关并发症，并且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提高 HIV 相关并发症的风险，甚至可能改善接受抗逆转录病毒治疗的个体的免疫功能。制定适当的补充策略对于最大限度地提高健康状况至关重要，尤其是感染艾滋病毒的儿童和年轻人，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，并且数据表明一些抗逆转录病毒药物会干扰维生素 D 代谢。因此，我们假设 (1) 将维生素 D 状态优化至当前医学研究所 (IOM) 建议的 e20 ng/mL 25-羟基维生素 D (25(OH)D) 浓度可改善 HIV 感染者的 CVD 风险、炎症和 CD4 细胞计数，(2) 将 25(OH)D 浓度提高至 >30 ng/mL 可将 CVD 风险和炎症改善至 比增加 eto 20 ng/mL（一些专家认为对心血管健康最理想的浓度）的程度更大，并且 (3) 需要“高剂量”口服维生素 D 才能实现 25(OH)D 浓度 >30 ng/mL。这些假设将通过在一项双盲、随机对照试验中确定 HIV 感染儿童和年轻人血清 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来解决，该试验对 HIV 感染儿童和年轻人给予超过 24 个月的三种不同维生素 D 给药方案 （10-25 岁）维生素 D 缺乏症 (25(OH)D <20 ng/mL)。我们还将评估补充 6、12 和 24 个月后每只手臂的 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 疗法价格低廉且几乎没有不良副作用。 PI 是一位杰出的候选人，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拥有经过验证的研究重点。她受到一支忠诚的、多学科的高级研究人员团队的指导，他们在指导和与本提案相关的研究方法方面拥有丰富的经验。未来计划在临床研究、心血管疾病风险评估和临床营养等各个方面进行培训，以促进 PI 发展成为一名成功的独立医师科学家。