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 Faltered linear growth and pubertal delay, which are both common in children with HIV in sub-Saharan Africa, might affect adolescent bone accrual and future fragility fracture risk. We investigated the association of HIV with bone density adjusted for skeletal size in peripubertal children in Zimbabwe. MethodsWe did a cross-sectional study of baseline data from the IMVASK cohort, which enrolled children aged 8-16 years with HIV who had been taking antiretroviral therapy (ART) for at least 2 years, and children of the same age without HIV. Children with HIV were recruited from public sector HIV clinics at Parirenyatwa General Hospital and Harare Central Hospital (Harare, Zimbabwe), and children without HIV were recruited from six schools in the same suburbs that the hospitals serve. Sociodemographic, clinical, and anthropometric data were collected. Dual-energy X-ray absorptiometry (DXA) was used to measure the bone outcomes of total-body less-head bone mineral content for lean mass adjusted for height (TBLH-BMC LBM ), and lumbar spine bone mineral apparent density (LS-BMAD), and we assessed the prevalence of low TBLH-BMC LBM and low LS-BMAD (defined by Z-scores of less than -2•0). Size adjustment techniques were used to overcome the size dependence of DXA measurement. We used linear regression models, with multiple imputation for missing data, to assess relationships between risk factors and TBLH-BMC LBM and LS-BMAD Z-scores in children with and without HIV. Findings We recruited 303 children with HIV (mean age 12•4 years [SD 2•5]; 151 [50%] girls) and 306 children without HIV (mean age 12•5 years [SD 2•5]; 155 [51%] girls). In children with HIV, median age of HIV diagnosis was 3•0 years (IQR 1•2-5•8), and median ART duration was 8•1 years (6•2-9•5); for 102 (34%) children, ART included tenofovir disoproxil fumarate (TDF). Children with HIV had a higher prevalence of low TBLH-BMC LBM Z-score than children without HIV (29 [10%] of 279 children with available data vs 18 [6%] of 292 with available data; p=0•066) and a higher prevalence of low LS-BMAD Z-score (40 [14%] of 279 vs 17 [6%] of 293 with available data; p=0•0007). HIV and male sex were associated with earlier pubertal (Tanner) stage. The negative associations between HIV and Z-scores for TBLH-BMC LBM and LS-BMAD were more pronounced with pubertal maturation, particularly in girls. Among children with HIV, TDF exposure and orphanhood were associated with lower TBLH-BMC LBM Z-score in confounder-adjusted analysis. Current TDF use (vs non-TDF-based ART) was associated with a reduction in TBLH-BMC LBM Z-score of 0•41 (95% CI 0•08-0•74; p=0•015) and in LS-BMAD Z-score of 0•31 (0•08-0•69; p=0•12). Interpretation Despite ART, HIV is associated with substantial skeletal deficits towards the end of puberty. The extent of bone deficits associated with TDF and its widespread use in children in sub-Saharan Africa are a concern for future adult fracture risk. Funding Wellcome Trust.

Persistently lower bone mass and bone turnover among South African children living with well controlled HIV

“…To our knowledge, this is the first longitudinal study conducted among CLHIV in sub-Saharan Africa to include comprehensive evaluation of bone mass, as well as of bone turnover and inflammation. In addition to factors specific to chronic HIV infection, the higher prevalence of malnutrition and the distinct patterns of childhood infectious diseases found among children living in South Africa may be expected to adversely affect skeletal health [32][33][34][35][36]. This study, which had well matched uninfected controls and high retention and assessed bone mass adjusted for potential confounders with over 2 years of observation, found that South African CLHIV on a stable ART regimen had persistently lower bone mass with lower bone formation and resorption than controls.…”

A focus on disability is necessary to achieve HIV epidemic control

“…ototoxic drugs causing hearing loss 18 ) and potentially from long-term use of ART (e.g. lower bone mineral content for TDF-based ART, 19 mixed evidence for cognitive impairments and ART use 12 ). HIV-related disability is often described as being "episodic", as described in the Episodic Disability Framework, characterized by fluctuating periods of wellness and impairment over time, and influenced by contextual factors and life events.…”

Growth improvement following antiretroviral therapy initiation in children with perinatally-acquired HIV diagnosed in older childhood in Zimbabwe: a prospective cohort study

“…The results are consistent with a higher prevalence of subclinical delayed onset of pubertal growth spurt. Another study in Zimbabwe found that 8/127 (6%) of adolescents aged 14–16 with HIV and on ART had pubertal delay versus 0/132 of the same age without HIV who were recruited in schools [ 22 ]. The fact that late ART initiation is associated with poorer growth outcomes and delayed puberty [ 17 ] indicates that HIV infection may itself retard puberty, with ART reversing the effect.…”