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: 8511767
• 负责人: Stephen M Arpadi
• 金额: $ 69.04万
• 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/8511767
• 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）：虽然高度发达国家的 HIV 感染儿童和青少年存在骨骼异常，包括骨矿物质含量 (BMC) 和骨矿物质密度 (BMD) 下降，但尚未在资源有限的环境 (RCS) 中进行研究，而目前超过 90% 的 HIV 感染青少年居住在资源有限环境中。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较高，年轻 HIV+ 男性和女性的骨折率也可能较高。似乎涉及多种因素，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）对破骨细胞生成和成骨细胞活性的影响。围产期 HIV 感染者一生中累积暴露于 HIV 感染以及 ART 相关影响的直接和间接影响最大。在居住在 RCS 的 220 万感染艾滋病毒的儿童中，其中包括超过 356,000 名接受抗逆转录病毒治疗的儿童，蛋白质和能量营养不良、微量营养素缺乏以及已知会对骨量增长产生不利影响且非常普遍的儿童感染等其他因素可能对骨获取构成额外威胁。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，正如艾滋病毒感染者所报告的那样，儿童晚期和青春期骨质增生减少可能会增加晚年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) 评估促炎细胞因子的上调、营养和体力活动对骨转换和增长的贡献； 3) 比较基于洛匹那韦/利托那韦的治疗方案与基于依非韦伦的治疗方案对 2 岁前开始 ART 的南非青春期前围产期 HIV 感染儿童的维生素 D 水平、骨转换和骨获取的影响。这个为期 5 年的两国合作项目提议开展一项为期 2 年的纵向观察研究，该研究将是一项针对 8-10 岁 HIV+ 儿童的延伸研究，这些儿童参加了一项目前正在进行的持续基于 PI 的 ART 与改用基于 NNRTI 的 ART (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 中获得的研究质量前期数据和样本。这将大大扩展骨骼结果评估的时间范围和变量。为了进行比较，年龄适当的未感染艾滋病毒的儿童也将被纳入。我们的目标是找出导致不良应计奖金的潜在可改变因素，并为未来的研究制定框架，包括适合 RCS 中艾滋病毒感染儿童的干预研究。