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: 8386355
• 负责人: Stephen M Arpadi
• 金额: $ 81.55万
• 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/8386355
• 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. PUBLIC HEALTH RELEVANCE: While skeletal abnormalities including reduced bone density and bone mineral content have been recognized in HIV-infected children, adolescents and adults for over 10 years, there are no published pediatric studies from resource constrained settings (RCS), where >90% of HIV-infected children live. With a goal of identifying modifiable risks for future intervention studies to improve bone health in HIV-infected children and adolescents living in RCS, we propose to use both innovative and standard bone measurement methods in a prospective observational study of the determinants of bone metabolism, bone quality and bone mass acquisition in pre- adolescent perinatally HIV-infected children in South Africa who initiated ART prior to age 2 years.

描述（由申请人提供）：虽然骨骼异常，包括骨矿物质含量降低（BMC）和骨矿物质密度（BMD），在高度发达国家的HIV感染儿童和青少年中得到了很好的描述，在资源约束的设置（RCS）中没有进行研究，而HIV感染了90％的HIV感染的年轻人现有实时。对成年艾滋病毒+感染个体的最新研究表明，绝经后和老年男性的骨折率更高，在年轻的艾滋病毒+男性和女性中也可能更高。似乎涉及多个因素，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，炎症细胞因子对骨细胞吸收的间接影响以及抗超代病毒疗法（ART）对骨质现代生成的影响以及骨质生成的影响。围产期HIV感染的个体对HIV感染的直接和间接作用以及与ART相关的人的直接和间接作用均具有最大的累积寿命暴露。在居住在RC中的220万名HIV感染的儿童中，包括超过356,000名艺术，包括蛋白质和能量营养不良，微量营养素缺陷以及儿童感染，这些因素对不利影响骨质量应计并高度流行的儿童感染可能对骨获得造成额外的威胁。成年后骨折的风险与青春期后期达到的“峰值骨质量”密切相关。因此，据报道，在儿童晚期和青春期，骨骼应计的减少可能会增加骨质疏松性骨折的风险。在拟议的研究中，我们将1）评估骨转换标记，骨密度和质量以及骨骼获取率； 2）评估促炎细胞因子，营养和体育活动对骨骼更新和应计的上调的贡献； 3）比较基于lopinavir/ritonavir与基于efavirenz的方案对维生素D水平，骨骼更新和骨获得的疗法在2岁之前启动ART的南非植物前艾滋病毒感染儿童中的维生素D水平，骨骼更新和骨骼获取。这个2个国家合作5年项目建议进行一项为期2年的纵向观察性研究，这将是一项针对8-10岁的艾滋病毒+儿童的扩展研究，他们参加了目前正在进行的基于PI的随机对照试验与基于NNRTI的ART（NERTEST3）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。这将大大扩大有关骨骼结局的时间表和变量。为了进行比较，还将招募适合年龄的艾滋病毒未感染的儿童。我们的目标是确定较差的BON应计的潜在可修改因素，并为将来的研究开发一个框架，包括适合RC中的HIV感染儿童的干预研究。 公共卫生相关性：尽管骨骼异常（包括骨密度降低和骨矿物质含量）已在10多年的时间内认识到HIV感染的儿童，青少年和成年人，但没有资源约束设置（RCS）出版的儿科研究，其中> 90％的HIV感染儿童居住在其中。 With a goal of identifying modifiable risks for future intervention studies to improve bone health in HIV-infected children and adolescents living in RCS, we propose to use both innovative and standard bone measurement methods in a prospective observational study of the determinants of bone metabolism, bone quality and bone mass acquisition in pre- adolescent perinatally HIV-infected children in South Africa who initiated ART prior to age 2 years.