Vitamin D, drug metabolism, and cardiovascular complications in pediatric HIV

描述(申请人提供)：维生素D是一种强大的免疫调节剂，它的不足最近在普通人群中成为心血管疾病(CVD)和胰岛素抵抗的风险因素。最近，维生素D缺乏和缺乏的患病率在美国儿童人群中被认为是非常高的，低血清维生素D被发现与高血压、高血糖和代谢综合征密切相关，与肥胖或其他心血管疾病危险因素无关。由于感染艾滋病毒的儿童预计可以活几十年，心血管疾病和糖尿病等长期毒性问题在艾滋病毒管理中变得越来越重要。我们提出的研究的中心假设是，维生素D缺乏是HIV感染儿童/年轻人发展为亚临床动脉粥样硬化和胰岛素抵抗的危险因素，并且这种风险是通过全身炎症的变化来调节的。为了加强观察性研究的结果，我们将进行一项干预性研究，在该研究中，我们假设，给低维生素D水平的艾滋病毒感染儿童/年轻人服用高剂量维生素D将比匹配的健康艾滋病毒阴性对照组增加25-羟基维生素D(25(OH)D)的程度更低，特别是在接受NNRTI治疗的患者中，并将减少炎症、胰岛素抵抗和血脂异常。还将确定维生素D途径的详细措施。维生素D的使用有可能对预防艾滋病毒、心血管和代谢合并症产生重大影响，特别是考虑到这种干预措施在临床实践中可以很容易和廉价地实施。 与公共卫生相关：感染艾滋病毒的儿童可以存活到成年；然而，他们正遭受艾滋病毒及其治疗的几种并发症，包括心脏病和糖尿病风险的增加。维生素D可以积极地改善炎症，炎症是心脏病和糖尿病的已知风险因素，因此在普通人群中已被证明可以改善心血管风险。这项研究将研究维生素D水平与心血管和代谢并发症的关系，以及炎症的相互作用。我们还将研究在感染艾滋病毒的儿童/青少年中补充维生素D对心脏和代谢疾病的影响。最后，将对艾滋病毒疗法对维生素D代谢的影响进行详细评估。

DESCRIPTION (provided by applicant): Vitamin D functions as a powerful immune modulator and its insufficiency has recently emerged as a risk factor for cardiovascular disease (CVD) and insulin resistance in the general population. Recently, the prevalence of vitamin D insufficiency and deficiency was recognized to be very high in the US pediatric population and low serum vitamin D were found to be strongly and independently associated with hypertension, hyperglycemia, and metabolic syndrome, independent of adiposity or other CVD risk factors. As HIV-infected children are expected to live several decades, issues of long- term toxicities, such as CVD and diabetes become increasingly important in the management of HIV. The central hypothesis of our proposed studies is that, vitamin D deficiency is a risk factor for the development of subclinical atherosclerosis and insulin resistance in HIV infected children/young adults, and that the risk is mediated by changes in systemic inflammation. To strengthen the findings from the observational study, we will conduct an interventional study, in which we hypothesize that high doses of vitamin D given to HIV-infected children/young adults with low vitamin D levels will increase 25-hydroxyvitamin D (25(OH)D) levels at a lower extent than in a matched healthy HIV-negative control group, specifically in patients treated with NNRTI, and will reduce inflammation, insulin resistance and dyslipidemias. Detailed measures of vitamin D pathways will also be determined. The use of vitamin D has the potential to have a significant impact on prevention of HIV cardiovascular and metabolic co-morbidities especially given that the intervention can be implemented easily and inexpensively in clinical practice. PUBLIC HEALTH RELEVANCE: Children living with HIV are surviving through adulthood; however they are suffering from several complications of HIV and its therapy, including increased risk of heart disease and diabetes. Vitamin D can positively modify inflammation, a known risk factor for heart disease and diabetes, and as such has been shown in the general population to improve cardiovascular risk. This study will examine the relationship between vitamin D levels and cardiovascular and metabolic complications and the interplay of inflammation. We will also study the effect of vitamin D supplementation in HIV infected children/youths on cardiac and metabolic morbidities. Lastly, a detailed assessment of the effect of HIV therapies on vitamin D metabolism will be undertaken.