Bone health in perinatally HIV-infected South African children on antiretrovirals

描述（由申请人提供）：虽然骨骼异常，包括骨矿物质含量（BMC）和骨矿物质密度（BMD）下降，在高度发达国家感染艾滋病毒的儿童和青少年中得到了很好的描述，但在资源受限的环境（RCS）中没有进行过研究，现在有bbb90 %的艾滋病毒感染青年生活在那里。最近对成年HIV+感染者的研究表明，绝经后和老年男性的骨折率更高，年轻的HIV+男性和女性也可能更高。可能涉及多种因素，包括病毒对成骨细胞和破骨细胞分化和功能的潜在直接影响，炎症细胞因子对破骨细胞吸收的间接影响以及抗逆转录病毒治疗（ART）对破骨细胞发生和成骨细胞活性的影响。围产期艾滋病毒感染者一生中受到艾滋病毒感染的直接和间接影响以及与抗逆转录病毒治疗有关的影响最大。在居住在RCS的220万感染艾滋病毒的儿童中，包括接受抗逆转录病毒治疗的356 000多名儿童，其他因素，包括蛋白质和能量营养不良、微量营养素缺乏以及已知对骨量累积产生不利影响且非常普遍的儿童感染，可能对骨骼形成构成额外威胁。成年期骨折的风险与青春期后期达到的“骨量峰值”密切相关。因此，在艾滋病毒感染者中，在儿童晚期和青春期骨质积累减少可能会增加生命后期骨质疏松性骨折的风险。在拟议的研究中，我们将1)评估骨转换标志物，骨密度和质量，以及骨获得率；2)评估促炎细胞因子、营养和体力活动的上调对骨转换和骨积累的贡献；3)比较以洛匹那韦/利托那韦为基础的方案与以依非韦伦为基础的方案对南非2岁前开始抗逆转录病毒治疗的青春期前围产期艾滋病毒感染儿童的维生素D水平、骨转换和骨获得的影响。这个两国合作的5年项目提议进行一项为期2年的纵向观察研究，这将是一项针对8-10岁艾滋病毒阳性儿童的扩展研究，这些儿童参加了目前正在进行的继续基于pi的抗逆转录病毒治疗与转向基于nnrti的抗逆转录病毒治疗（NEVEREST3）的随机对照试验。我们提出的研究将利用研究基础设施以及在NEVEREST中获得的研究质量的先行数据和标本。这将大大扩展时间框架和评估骨骼结果的变量。为了进行比较，还将纳入适龄未感染艾滋病毒的儿童。我们的目标是确定不良碳积累的潜在可改变因素，并为未来的研究制定一个框架，包括适合RCS中艾滋病毒感染儿童的干预研究。

DESCRIPTION (provided by applicant): While skeletal abnormalities, including decreased bone mineral content (BMC) and bone mineral density (BMD), are well described among HIV-infected children and adolescents in highly developed nations, no studies have been conducted in resource constrained settings (RCS), where >90% of HIV-infected youth now live. Recent studies of adult HIV+ infected individuals demonstrate that fracture rates are higher in postmenopausal and older men and possibly higher in younger HIV+ men and women as well. Multiple factors appear to be involved, including potential direct effects of virus on osteoblast and osteoclast differentiation and function, indirect effects of inflammatory cytokines on osteoclast resorption and effects of antiretroviral therapy (ART) on osteoclastogenesis and osteoblast activity. Perinatally HIV-infected individuals have the greatest cumulative life-time exposure to both the direct and indirect effects of HIV infection as well as to those associated with ART. Among 2.2 million HIV-infected children living in RCS, including over 356,000 on ART, additional factors including protein and energy malnutrition, micronutrient deficiencies, and childhood infections that are known to adversely affect bone mass accrual and are highly prevalent, may pose additional threats to bone acquisition. Risk of fracture in adulthood is strongly related to "peak bone mass" reached in late adolescence. Therefore, reduced bone accrual during late childhood and adolescence, as reported among those with HIV, may increase the risk of osteoporotic fractures later in life. In the proposed study we will 1) assess bone turnover markers, bone density and quality, and rate of bone acquisition; 2) evaluate the contribution of upregulation of pro-inflammatory cytokines, nutrition and physical activity on bone turnover and accrual; and 3) compare the effects of lopinavir/ritonavir-based versus efavirenz-based regimens on vitamin D levels, bone turnover, and bone acquisition in pre-pubertal perinatally HIV-infected children in South African who initiated ART prior to age 2 years. This 2 country collaborative 5 year project proposes to conduct a 2 year longitudinal observational study that will be an extension study for HIV+ children ages 8-10 years who participated in a randomized controlled trial of continued PI-based vs. switch to NNRTI-based ART (NEVEREST3) that is currently being conducted. Our proposed study will exploit the research infrastructure as well as the research-quality antecedent data and specimens obtained in NEVEREST. This will greatly expand both the timeframe and the variables that will be assessed with respect to bone outcomes. For comparisons, age appropriate HIV-uninfected children will also be enrolled. Our goal is to identify potentially modifiable factors for poor bon accrual and to develop a framework for future research, including intervention studies suitable for HIV-infected children in RCS.