Effect of HIV Infection on Growth and Bone Density in Peripubertal Children in the Era of Antiretroviral Therapy: A Cross-Sectional Study in Zimbabwe

Abstract

Background: Poor linear growth and pubertal delay, both common in children with HIV (CWH) in sub-Saharan Africa, may affect adolescent bone accrual and future fragility fracture risk. We investigated the association of HIV with size-adjusted bone density in peri-pubertal children in Zimbabwe. Methods: CWH aged 8-16 years taking ART for ≥2 years from public-sector HIV clinics in Harare, and HIV-uninfected children from schools in the same catchment area, were recruited into a cross-sectional study. Sociodemographic, clinical and anthropometric data were collected. Outcomes were dual-energy X-ray absorptiometry (DXA) measured total-body less-head bone mineral content-for-lean mass adjusted for height (TBLH-BMCLBM) and lumbar spine bone mineral apparent density (LS-BMAD). Linear regression models using multiple imputation for missing data, assessed relationships between risk factors and DXA measures by HIV status, and interaction by sex and pubertal (Tanner) stage. Findings: We recruited 303 CWH and 306 without HIV, mean (SD) age 12.5 (2.5) years and 50% female. Mean ART duration was 7.9 (2.6) years; for 34% ART included tenofovir disproxil fumarate (TDF). The prevalence of low TBLH-BMCLBM and LS-BMAD (Z-Score<-2) was higher in children with than without HIV (10.4% vs. 6.2%, p=0.066; 14.3% vs. 5.8%, p=0.001 respectively). HIV and male sex were associated with earlier Tanner stage. The negative effects of HIV on TBLH-BMCLBM and LS-BMAD were more pronounced with pubertal maturation, particularly in females. Among CWH, years of TDF exposure and orphanhood were strongly associated with lower TBLH-BMCLBM Z-Score in both unadjusted and adjusted analyses. Current TDF use was associated with 0.40 (95%CI 0.07, 0.73; p=0.018) and 0.31 (0.07, 0.69; p=0.110) lower TBLH-BMCLBM and LS-BMAD Z-Scores respectively. Interpretation: Despite ART, HIV is associated with substantial skeletal deficits by the end of puberty. The size of bone deficits associated with TDF and its widespread use in children in sub-Saharan Africa raise concern for future adult fracture risk. Funding Statement: Wellcome Trust. Declaration of Interests: RR (206764/Z/17/Z) RAF (206316/Z/17/Z) are funded by the Wellcome Trust. CK is funded by a National Institute of Health (NIH) Fogarty Trent Fellowship. AMR is partially supported by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement which is also part of the EDCTP2 programme supported by the European Union Grant Ref: MR/R010161/1. All other authors declare no competing interests. Ethics Approval Statement: Ethical and governance approvals were granted by the London School of Hygiene and Tropical Medicine Ethics Committee (Ref: 15333), the Institutional Review Board of the Biomedical Research and Training Institute in Harare (Ref: AP145/2018), the Joint Research Ethics Committee for University of Zimbabwe College of Health Sciences and the Parirenyatwa Group of Hospitals (Ref: 11/18), Harare Central Hospital Ethics Committee (Ref: 170118/04), the Medical Research Council of Zimbabwe (Ref: MRCZ/A/2297) and the Ministry of Primary and Secondary Education Zimbabwe (Ref: C/426/Harare). Guardians provided written informed consent and children provided written assent.