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

服用抗逆转录病毒药物的围产期感染艾滋病毒的南非儿童的骨骼健康

• 批准号: 8686912
• 负责人: Stephen M Arpadi
• 金额: $ 66.49万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8686912
• 关键词: 15 year old; 2 year old; Adolescence; Adolescent; Adult; Affect; African; Age; Archives; Blood specimen; Bone Density; Bone Mineral Contents; Bone remodeling; Child; Childhood; Chronic; Cohort Studies; Country; Data; Developed Countries; Development; Dual-Energy X-Ray Absorptiometry; Enrollment; Environment; Exposure to; Fracture; Future; Genetic; Goals; Growth; HIV; HIV Infections; Hormonal; Immune; Individual; Infection; Inflammatory; Intervention; Intervention Studies; Ionizing radiation; Life; Lopinavir/Ritonavir; Measurement; Measures; Mediating; Methods; Minerals; Modality; Monitor; Nutritional; Observational Study; Osteoblasts; Osteoclasts; Outcome; Pathogenesis; Pathway interactions; Perinatal; Physical activity; Postmenopause; Protein-Energy Malnutrition; Puberty; Publishing; Randomized Controlled Trials; Regimen; Reporting; Research; Research Infrastructure; Research Priority; Resources; Risk; Risk Factors; Sexual Maturation; South Africa; Specimen; Time; Tuberculosis; Up-Regulation; Viral; Virus; Vitamin D; Woman; Youth; antiretroviral therapy; base; bone; bone health; bone mass; bone metabolism; bone quality; bone turnover; cytokine; early adolescence; efavirenz; immune activation; improved; innovation; mathematical model; men; microbial; micronutrient deficiency; modifiable risk; non-nucleoside reverse transcriptase inhibitors; nutrition; older men; osteoclastogenesis; osteoporosis with pathological fracture; prospective; quantitative ultrasound; repository; sex; skeletal; skeletal abnormality

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.

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）降低，在高度发达国家的艾滋病毒感染儿童和青少年中得到了很好的描述，但在资源有限的环境（RCS）中没有进行过研究，其中>90%的艾滋病毒感染青年现在生活在RCS中。最近对成年艾滋病毒阳性感染者的研究表明，绝经后和老年男性的骨折率较高，年轻的艾滋病毒阳性男性和女性的骨折率也可能较高。多个因素似乎参与，包括潜在的直接影响的病毒对成骨细胞和破骨细胞的分化和功能，间接影响的炎性细胞因子对破骨细胞的吸收和抗逆转录病毒治疗（ART）对破骨细胞和成骨细胞活性的影响。围产期艾滋病毒感染者一生中最容易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疗法有关的影响。在220万名生活在RCS的艾滋病毒感染儿童中，包括356 000多名接受抗逆转录病毒疗法的儿童，其他因素包括蛋白质和能量营养不良，微量营养素缺乏，和儿童感染，已知其对骨量增加有不利影响，并且非常普遍，可能对骨获得造成额外的威胁。成年期骨折的风险与青春期后期达到的“峰值骨量”密切相关。因此，在儿童晚期和青春期，如HIV感染者中报告的那样，骨积累减少可能会增加以后生活中骨质疏松性骨折的风险。在所提出的研究中，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累积的贡献;和3）比较基于洛匹那韦/利托那韦的方案与基于依法韦仑的方案对维生素D水平，骨转换，南非2岁之前开始抗逆转录病毒治疗的青春期前围产期HIV感染儿童的骨获得。这项为期5年的2国合作项目计划进行一项为期2年的纵向观察性研究，该研究将是一项针对8-10岁HIV阳性儿童的扩展研究，这些儿童参加了目前正在进行的一项随机对照试验，该试验比较了继续使用基于PI的ART与改用基于NNRTI的ART（NEVEREST 3）。我们提出的研究将利用研究基础设施，以及研究质量的前期数据和标本中获得的NEVEREST。这将极大地扩展骨结局评估的时间范围和变量。为了进行比较，还将招募年龄合适的未感染HIV的儿童。我们的目标是确定潜在的可改变的因素，为穷人的骨积累，并制定一个框架，为未来的研究，包括干预研究适合艾滋病毒感染的儿童在RCS。