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.
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.
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|Shiau, Stephanie; Strehlau, Renate; Shen, Jing et al. (2018) Biomarkers of Aging in HIV-Infected Children on Suppressive Antiretroviral Therapy. J Acquir Immune Defic Syndr 78:549-556|
|Shiau, Stephanie; Webber, Acadia; Strehlau, Renate et al. (2017) Dietary Inadequacies in HIV-infected and Uninfected School-aged Children in Johannesburg, South Africa. J Pediatr Gastroenterol Nutr 65:332-337|
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|Manavalan, John S; Arpadi, Stephen; Tharmarajah, Shenthuraan et al. (2016) Abnormal Bone Acquisition With Early-Life HIV Infection: Role of Immune Activation and Senescent Osteogenic Precursors. J Bone Miner Res 31:1988-1996|
|Arpadi, Stephen M; Shiau, Stephanie; Strehlau, Renate et al. (2016) Efavirenz is associated with higher bone mass in South African children with HIV. AIDS 30:2459-2467|
|Yin, Michael T; Shiau, Stephanie; Rimland, David et al. (2016) Fracture Prediction With Modified-FRAX in Older HIV-Infected and Uninfected Men. J Acquir Immune Defic Syndr 72:513-20|
|Wong, Marcia; Shiau, Stephanie; Yin, Michael T et al. (2016) Decreased Vigorous Physical Activity in School-Aged Children with Human Immunodeficiency Virus in Johannesburg, South Africa. J Pediatr 172:103-9|
|Arpadi, Stephen M; Shiau, Stephanie; Marx-Arpadi, Charlotte et al. (2014) Bone health in HIV-infected children, adolescents and young adults: a systematic review. J AIDS Clin Res 5:|
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