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Background: Children who initiate antiretroviral therapy (ART) before age 5 years can recover height and weight compared to uninfected peers, but growth outcomes are unknown for children initiating ART at older ages. We investigated factors associated with growth failure at ART initiation and modelled growth by age on ART., Methods: We conducted secondary analysis of cohort of children aged 6-15 years late-diagnosed with HIV in Harare, Zimbabwe, with entry at ART initiation in 2013-2015. Factors associated with height-for-age (HAZ), weight-for-age (WAZ) and BMI-for-age (BAZ) z-scores <- 2 (stunting, underweight and wasting respectively) at ART initiation were assessed using multivariable logistic regression. These outcomes were compared at ART initiation and 12 month follow-up using paired t-tests. HAZ and BAZ were modelled using restricted cubic splines., Results: Participants (N = 302; 51.6% female; median age 11 years) were followed for a median of 16.6 months (IQR 11.0-19.8). At ART initiation 34.8% were stunted, 34.5% underweight and 15.1% wasted. Stunting was associated with age ≥ 12 years, CD4 count < 200 cells/μl, tuberculosis (TB) history and history of hospitalisation. Underweight was associated with older age, male sex and TB history, and wasting was associated with older age, TB history and hospitalisation. One year post-initiation, t-tests showed increased WAZ (p = 0.007) and BAZ (p = 0.004), but no evidence of changed HAZ (p = 0.85). Modelling showed that HAZ and BAZ decreased in early adolescence for boys on ART, but not girls., Conclusion: Stunting and underweight were prevalent at ART initiation among late-diagnosed children, and HAZ did not improve after 1 year. Adolescent boys with perinatally acquired HIV and late diagnosis are particularly at risk of growth failure in puberty., (© 2022. The Author(s).)

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., Methods: We 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., Competing Interests: Declaration of interests RR (grant number 206764/Z/17/Z) and RAF (grant number 206316/Z/17/Z) are funded by the Wellcome Trust. CM-K is funded by a National Institute of Health 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 European and Developing Countries Clinical Trials Partnership 2 programme supported by the EU (grant number MR/R010161/1). All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Human immunodeficiency virus (HIV) infection causes impairment of the gastrointestinal barrier, with substantial depletion of CD4+ T cells in the gut. Antiretroviral therapy (ART) restores CD4+ counts and may have beneficial effects on gut microbiota in adults. Little is known about effect of long-term ART on gut microbiome in HIV-infected children. We investigated composition of gut microbiota in HIV-infected and -uninfected children and assessed associations between gut microbiota and patient characteristics., Methods: In a cross-sectional study, rectal swabs were collected from 177 HIV-infected and 103 HIV-uninfected controls. Gut microbial composition was explored using 16S ribosomal ribonucleic acid sequencing., Results: Human immunodeficiency virus-infected children had significantly lower alpha-diversity and higher beta-diversity compared to HIV-uninfected. No association was observed between microbiome diversity and CD4+ T-cell count, HIV viral load, or HIV-associated chronic lung disease. We found enriched levels of Corynebacterium (P < .01), Finegoldia (P < .01), and Anaerococcus (P < .01) in HIV-infected participants and enrichment of Enterobacteriaceae (P = .02) in participants with low CD4+ counts (<400 cells/mm3). Prolonged ART-treatment (≥10 years) was significantly associated with a richer gut microbiota by alpha diversity., Conclusions: Human immunodeficiency virus-infected children have altered gut microbiota. Prolonged ART may restore the richness of the microbiota closer to that of HIV-uninfected children., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Perinatally-acquired HIV infection commonly causes stunting in children; how this affects bone and muscle development is unclear. We investigated differences in bone and muscle mass and muscle function between children with HIV (CWH) and uninfected children., Setting: Cross-sectional study of CWH (6-16 years) receiving antiretroviral therapy (ART) for >6 months and similar aged children testing HIV-negative at primary health clinics in Zimbabwe., Methods: From Dual-energy X-ray Absorptiometry (DXA) we calculated total-body less-head (TBLH) Bone Mineral Content (BMC) for lean mass adjusted-for-height (TBLH-BMC LBM ) Z-scores, and lumbar spine (LS) Bone Mineral Apparent Density (BMAD) Z-scores., Results: The 97 CWH were older (mean age 12.7 vs. 10.0 years) and taller (mean height 142 cm vs. 134 cm) than 77 uninfected. However, stunting (height-for-age Z-score ≤ -2) was more prevalent in CWH (35% vs. 5%, p < 0.001). Among CWH, 15% had low LS-BMAD (Z-score ≤ -2) and 13% low TBLH-BMC LBM , vs. 1% and 3% respectively in those uninfected (both p ≤ 0.02). After age, sex, height and puberty adjustment, LS-BMAD was 0.33 SDs (95%CI -0.01, 0.67; p = 0.06) lower in CWH, with no differences by HIV status in TBLH-BMC LBM , lean mass (0.11 [-0.03, 0.24], p = 0.11) or grip strength (0.05 [-0.16, 0.27], p = 0.62). However, age at ART initiation was correlated with both LS-BMAD Z-score (r = -0.33, p = 0.001) and TBLH-BMC LBM Z-score (r = -0.23, p = 0.027); for each year ART initiation was delayed a 0.13 SD reduction in LS-BMAD was seen., Conclusion: Size-adjusted low bone density is common in CWH. Delay in initiating ART adversely affects bone density. Findings support immediate ART initiation at HIV diagnosis., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Chronic respiratory disease is a common cause of morbidity in children with HIV infection. We investigated longitudinal lung function trends among HIV-infected children, to describe the evolution of lung disease and assess the effect of anti-retroviral therapy (ART)., Methods: Prospective follow-up of two cohorts of HIV-infected children, aged 6 to 16 years, in Harare, Zimbabwe; one group were ART-naïve at enrolment, the other established on ART for a median of 4.7-years. Standardised spirometric assessments were repeated over a 2-year follow-up period. Forced expiratory volume (FEV1) and forced vital capacity (FVC) were expressed as Global Lung Initiative defined z-scores (FEV1z and FVCz). Linear mixed-effects regression modelling of lung function was performed, with co-variate parameters evaluated by likelihood ratio comparison., Results: We included 271 ART-naïve and 197 ART-established children (median age 11 years in both groups) incorporating 1144 spirometric assessments. Changes in FEV1 and FVC were associated with age at ART initiation and body mass index for both cohorts. Our models estimate that ART initiation earlier in life could prevent a deterioration of 0.04 FVCz/year. In the ART-naïve cohort, likelihood ratio comparison suggested an improvement in 0.09 FVCz/year during the two years following treatment initiation, but no evidence for this among participants established on ART., Conclusion: Early ART initiation and improved nutrition are positively associated with lung function and are important modifiable factors. An initial improvement in lung growth was seen in the first 2-years following ART initiation, although this did not appear to be sustained beyond this timeframe., Competing Interests: The authors have declared that no competing interests exist.

Objective: To investigate CD4 cell count recovery following ART initiation in perinatally HIV-infected children diagnosed in later childhood., Design: Observational prospective cohort study of newly diagnosed children aged 6-15 in Harare, Zimbabwe., Methods: Participants were enrolled into a cohort at seven primary healthcare clinics between January 2013 and January 2015. ART was initiated according to national guidelines and CD4 cell counts were performed 6-monthly over 18 months. The relationship between CD4 cell count and time on ART was investigated using regression analysis with fixed (population) and random (individual) effects, and age at ART initiation as a covariate., Results: Of the 307 participants who initiated ART, the median age at initiation was 11.7 years (interquartile range 9.6-13.8). The addition of an individual intercept and slope as random effects significantly improved the model fit compared with a fixed effects-only model. CD4 response (using a square-root transformation) was best modelled using a two-knot linear spline, with significant effects of time on ART and age at ART initiation. Younger children had a higher CD4 cell count at ART initiation (-17.9 cells/μl per year of age), an accelerated increase during the first 3 months on ART (-38.9 cells/μl per year of age at day 84), and a sustained higher CD4 cell count., Conclusion: Earlier ART initiation in older children is associated with accelerated CD4 cell count recovery and lasting immune reconstitution. Our findings support WHO guidance recommending ART initiation in all children, irrespective of disease stage and CD4 cell count.

Objective: Respiratory disease is a major cause of morbidity and mortality in HIV-infected children. Despite antiretroviral therapy (ART), children suffer chronic symptoms. We investigated symptom prevalence, lung function and exercise capacity among older children established on ART and an age-matched HIV-uninfected group., Design: A cross-sectional study in Zimbabwe of HIV-infected children aged 6-16 years receiving ART for over 6 months and HIV-uninfected children attending primary health clinics from the same area., Methods: Standardized questionnaire, spirometry, incremental shuttle walk testing, CD4 cell count, HIV viral load and sputum culture for tuberculosis were performed., Results: A total of 202 HIV-infected and 150 uninfected participants (median age 11.1 years in each group) were recruited. Median age at HIV diagnosis and ART initiation was 5.5 (interquartile range 2.8-7.5) and 6.1 (interquartile range 3.6-8.4) years, respectively. Median CD4 cell count was 726 cells/μl, and 79% had HIV viral load less than 400 copies/ml. Chronic respiratory symptoms were rare in HIV-uninfected children [n = 1 (0.7%)], but common in HIV-infected participants [51 (25%)], especially cough [30 (15%)] and dyspnoea [30 (15%)]. HIV-infected participants were more commonly previously treated for tuberculosis [76 (38%) vs 1 (0.7%), P < 0.001], had lower exercise capacity (mean incremental shuttle walk testing distance 771 vs 889 m, respectively, P < 0.001) and more frequently abnormal spirometry [43 (24.3%) vs 15 (11.5%), P = 0.003] compared with HIV-uninfected participants. HIV diagnosis at an older age was associated with lung function abnormality (P = 0.025). No participant tested positive for Mycobacterium tuberculosis., Conclusion: In children, despite ART, HIV is associated with significant respiratory symptoms and functional impairment. Understanding pathogenesis is key, as new treatment strategies are urgently required.