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

描述（由申请人提供）：维生素D作为一种强大的免疫调节剂发挥作用，其不足最近已成为普通人群中心血管疾病（CVD）和胰岛素抵抗的风险因素。最近，维生素D不足和缺乏的患病率被认为在美国儿科人群中非常高，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，独立于肥胖或其他CVD风险因素。由于预计感染HIV的儿童可以活几十年，长期毒性问题，如CVD和糖尿病在HIV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/年轻人发生亚临床动脉粥样硬化和胰岛素抵抗的危险因素，并且该风险是由全身炎症的变化介导的。为了加强观察性研究的结果，我们将进行一项干预性研究，在这项研究中，我们假设给予维生素D水平低的HIV感染儿童/年轻人高剂量的维生素D将以低于匹配的健康HIV阴性对照组的程度增加25-羟基维生素D（25（OH）D）水平，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共病产生重大影响，特别是考虑到在临床实践中可以容易且廉价地实施干预措施。 公共卫生相关性：感染艾滋病毒的儿童可以活到成年;然而，他们患有艾滋病毒及其治疗的几种并发症，包括心脏病和糖尿病的风险增加。维生素D可以积极地改变炎症，这是心脏病和糖尿病的已知危险因素，因此已在一般人群中显示出改善心血管风险。这项研究将研究维生素D水平与心血管和代谢并发症之间的关系以及炎症的相互作用。我们还将研究补充维生素D对感染艾滋病毒的儿童/青少年心脏和代谢疾病的影响。最后，将对艾滋病毒治疗对维生素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.