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An estimated 25% of South African women live with human immunodeficiency virus (HIV). Antiretroviral therapy roll-out has improved life expectancy, so many more women now reach menopause. We aimed to quantify changes in bone mineral density (BMD) during the menopausal transition in urban-dwelling South African women with and without HIV and determine whether HIV infection modified the effect of menopause on BMD changes. A 5-year population-based longitudinal study recruited women aged 40-60 years residing in Soweto and collected demographic and clinical data, including HIV status, anthropometry, and BMD, at baseline and at 5-year follow-up. All women were staged as pre-, peri-, or postmenopausal at both time points. Multivariable linear regression assessed relationships and interactions between HIV infection, menopause, and change in BMD. At baseline, 450 women had mean age 49.5 (SD 5.7) years, 65 (14.4%) had HIV, and 140 (31.1%), 119 (26.4%), and 191 (42.4%) were pre-, peri-, and postmenopausal, respectively; 34/205 (13.6%) women ≥50 years had a total hip (TH) or lumbar spine (LS) T-score ≤ -2.5. At follow-up 38 (8.4%), 84 (18.7%), and 328 (72.9%) were pre-, peri-, and postmenopausal. Those with HIV at baseline lost more total body (TB) BMD (mean difference -0.013 [95% confidence interval -0.026, -0.001] g/cm2 , p = 0.040) and gained more weight 1.96 [0.32, 3.60] kg; p = 0.019 than HIV-uninfected women. After adjusting for age, baseline weight, weight change, and follow-up time, the transition from pre- to postmenopause was associated with greater TB BMD losses in women with HIV (-0.092 [-0.042, -0.142] g/cm2 ; p = 0.001) than without HIV (-0.038 [-0.016, -0.060] g/cm2 , p = 0.001; interaction p = 0.034). Similarly, in women who were postmenopausal at both time points, those with HIV lost more TB BMD (-0.070 [-0.031, -0.108], p = 0.001) than women without HIV (-0.036 [-0.015, -0.057], p = 0.001, interaction p = 0.049). Findings were consistent but weaker at the LS and TH. Menopause-related bone loss is greater in women with HIV, suggesting women with HIV may be at greater risk of osteoporotic fractures. HIV services should consider routine bone health assessment in midlife women as part of long-term HIV care delivery. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

BackgroundDue to the complexity of human diets, it is difficult to relate single foods to health outcomes. We aimed to identify the dietary patterns and associated factors and to assess the association of dietary patterns with prediabetes/diabetes among adults living with and without HIV in Tanzania.MethodsDiet data were collected by a food frequency questionnaire (FFQ) and dietary patterns were derived by principal component analysis (PCA) and reduced rank regression (RRR). The associations between dietary patterns and associated factors as well as with prediabetes/diabetes were assessed using multinomial logistic regression and presented by marginal plots.ResultsOf 572 recruited, 63% were people living with HIV. The mean (±SD) age was 42.6 (±11.7) years and 60% were females. The PCA identified two major dietary patterns, i.e., vegetable-rich pattern (VRP) and vegetable-poor pattern (VPP) whereas RRR identified one dietary pattern, i.e., carbohydrate-dense pattern (CDP). In comparison to females, males had higher adherence to VPP and CDP, but less to VRP. Higher socioeconomic status was associated with higher adherence to VRP and VPP but low adherence to CDP. Compared to HIV-negative participants, people living with HIV had higher adherence to VRP but less adherence to CDP. Compared to younger people, older people had lower adherence to VPP. High adherence to CDP or VRP was positively associated with prediabetes. Higher adherence to VRP was associated with a borderline decrease in diabetes. No association was observed between VPP with either prediabetes or diabetes.ConclusionOur findings suggest that dietary patterns may impact the risk of prediabetes and diabetes differently. Awareness of the health benefits of VRP should be encouraged in the community, especially for men who seem to consume fewer vegetables. Longitudinal studies are needed to explore the contribution of dietary patterns to prediabetes/diabetes development in sub-Saharan Africa.

The rollout of antiretroviral therapy globally has increased life expectancy across Southern Africa, where 20.6 million people now live with human immunodeficiency virus (HIV). We aimed to determine the prevalence of age-related osteoporosis and sarcopenia, and investigate the association between HIV, bone mineral density (BMD), muscle strength and lean mass, and gait speed. A cross-sectional community-based study of individuals aged 20-80 years in rural South Africa collected demographic and clinical data, including HIV status, grip strength, gait speed, body composition, and BMD. Sarcopenia was defined by the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) guidelines, and osteoporosis as BMD T-score ≤ -2.5 (if age ≥50 years). The mean ± standard deviation (SD) age of 805 black South African participants was 44.6 ± 14.8 years, 547 (68.2%) were female; 34 (13.2%) were men, and 129 (23.6%) women had HIV, with 88% overall taking anti-retroviral therapy. A femoral neck T-score ≤ -2.5, seen in four of 95 (4.2%) men and 39 of 201 (19.4%) women age ≥50 years, was more common in women with than without HIV (13/35 [37.1%] versus 26/166 [15.7%]; p = 0.003). Although no participant had confirmed sarcopenia, probable sarcopenia affected more men than women (30/258 [11.6%] versus 24/547 [4.4%]; p = .001]. Although appendicular lean mass (ALM)/height2 index was lower in both men and women with HIV, there were no differences in grip strength, gait speed, or probable sarcopenia by HIV status. Older age, female sex, lower ALM/height2 index, slower gait speed, and HIV infection were all independently associated with lower femoral neck BMD. In conclusion, osteoporosis rather than sarcopenia is the common musculoskeletal disease of aging in rural South Africa; older women with HIV may experience greater bone losses than women without HIV. Findings raise concerns over future fracture risk in Southern Africa, where HIV clinics should consider routine bone health assessment, particularly in aging women. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

There is limited information as to whether people who experience severe acute malnutrition (SAM) as young children are at increased risk of overweight, high body fat and associated chronic diseases in later life. We followed up, when aged 7–12 years, 100 Zambian children who were hospitalised for SAM before age 2 years and eighty-five neighbourhood controls who had never experienced SAM. We conducted detailed anthropometry, body composition assessment by bioelectrical impedance and deuterium dilution (D2O) and measured blood lipids, Hb and HbA1c. Groups were compared by linear regression following multiple imputation for missing variables. Children with prior SAM were slightly smaller than controls, but differences, controlling for age, sex, socio-economic status and HIV exposure or infection, were significant only for hip circumference, suprailiac skinfold and fat-free mass index by D2O. Blood lipids and HbA1c did not differ between groups, but Hb was lower by 7·8 (95 % CI 0·8, 14·7) g/l and systolic blood pressure was 3·4 (95 % CI 0·4, 6·4) mmHg higher among the prior SAM group. Both anaemia and high HbA1c were common among both groups, indicating a population at risk for the double burden of over- and undernutrition and associated infectious and chronic diseases. The prior SAM children may have been at slightly greater risk than the controls; this was of little clinical significance at this young age, but the children should be followed when older and chronic diseases manifest.

OBJECTIVES: Children with perinatally-acquired HIV (PHIV) and taking antiretroviral therapy (ART) have a high prevalence of subclinical cardiac disease. We hypothesised that cardiac disease may be a consequence of dysregulated systemic immune activation driven by HIV infection. We examined cardiovascular and proinflammatory biomarkers and their association with echocardiographic abnormalities in children with PHIV. DESIGN: Cross-sectional analysis of soluble biomarkers from a prospective cohort of children aged 6-16 years with PHIV and age-matched HIV-uninfected comparison group. METHODS: Cryopreserved plasma samples were used to measure seven soluble biomarkers using multiplex bead assay (Luminex). Multivariable logistic regression assessed how biomarker levels related to cardiac abnormalities. RESULTS: A total of 406 children participated in this study (195 PHIV and 211 HIV-uninfected). Mean (standard deviation (SD)) ages of PHIV and HIV-uninfected participants were 10.7 (2.6) and 10.8 (2.8) years, respectively. Plasma levels of CRP, TNF-α, ST2, VCAM-1 and GDF-15 were significantly higher in the PHIV group compared to uninfected control (p

Objectives: Bone age (BA) measurement in children is used to evaluate skeletal maturity and helps in the diagnosis of growth disorders in children. The two most used methods are Greulich and Pyle (GP), and Tanner and Whitehouse 3 (TW3), both based upon assessment of a hand-wrist radiograph. To our knowledge no study has compared and validated the two methods in sub-Saharan Africa (SSA), and only a few have determined BA despite it being a region where skeletal maturity is often impaired for example by HIV and malnutrition. This study aimed to compare BA as measured by two methods (GP and TW3) against chronological age (CA) and determine which method is most applicable in peripubertal children in Zimbabwe.Methods: We conducted a cross-sectional study of boys and girls who tested negative for HIV. Children and adolescents were recruited by stratified random sampling from six schools in Harare, Zimbabwe. Non-dominant hand-wrist radiographs were taken, and BA assessed manually using both GP and TW3. Paired sample Student t-tests were used to calculate the mean differences between BA and chronological age (CA) in boys and girls. Bland-Altman plots compared CA to BA as determined by both methods, and agreement between GP and TW3 BA. All radiographs were graded by a second radiographer and 20 % of participants of each sex were randomly selected and re-graded by the first observer. Intraclass correlation coefficient assessed intra- and inter-rater reliability and coefficient of variation assessed precision.Results: We recruited 252 children (111 [44 %] girls) aged 8.0-16.5 years. The boys and girls were of similar mean ± SD CA (12.2 ± 2.4 and 11.7 ± 1.9 years) and BA whether assessed by GP (11.5 ± 2.8 and 11.5 ± 2.1 years) or TW3 (11.8 ± 2.5 and 11.8 ± 2.1 years). In boys BA was lower than CA by 0.76 years (95 % CI: -0.95, -0.57) when using GP, and by 0.43 years (95 % CI: -0.61, -0.24) when using TW3. Among the girls there was no difference between BA and CA by either GP [-0.19 years (95 % CI: -0.40, 0.03)] or TW3 [0.07 years (95 % CI: -0.16, 0.29)]. In both boys and girls, there were no systematic differences between CA and TW3 BA across age groups whereas agreement improved between CA and GP BA as children got older. Inter-operator precision was 1.5 % for TW3 and 3.7 % for GP (n = 252) and intra-operator precision was 1.5 % for TW3 and 2.4 % for GP (n = 52).Conclusion: The TW3 BA method had better precision than GP and did not systematically differ from CA, meaning that TW3 is the preferred method of assessment of skeletal maturity in Zimbabwean children and adolescents. TW3 and GP methods do not agree for estimates of BA and therefore cannot be used interchangeably. The systematic differences in GP BA assessments over age means it is not appropriate for use in all age groups or stages of maturity in this population.

Objectives Enterobacteriaceae are common pathogens causing bloodstream infection (BSI) in sub-Saharan Africa and frequently express third-generation cephalosporin (3GC) resistance; however, the impact of 3GC resistance on clinical outcomes is rarely studied. Methods We conducted a single-site prospective cohort study at Tygerberg Hospital, Cape Town, South Africa to examine the feasibility of measuring impacts of 3GC resistance in Enterobacteriaceae BSI. We included patients with 3GC-susceptible and 3GC-resistant BSIs and matched each BSI patient to two uninfected patients. We determined the concordance of initial antibiotic treatment with the corresponding isolate's susceptibility profile. We performed exploratory impact analysis using multivariable regression models. Results Between 1 June 2017 and 31 January 2018, we matched 177 Enterobacteriaceae BSI patients to 347 uninfected patients. Among these BSIs, 35% were phenotypically 3GC resistant. Parameters describing clinical comorbidity showed strong associations with mortality. We found that 18% of 3GC-R and 3% of 3GC-S BSI patient received non-concordant initial therapy. In multivariable Cox regression, we found a mortality impact over their matched patients for both 3GC-R (cause-specific hazard ratio 23.77; 95% CI 5.12–110.3) and 3GC-S (HR 7.49; 95%CI 3.08–18.19) BSI. There was a nonsignificant ratio of these ratios (HR 3.18; 95% CI 0.54–18.70), limited by the small sample size. Conclusion This form of impact estimation was feasible in one hospital in South Africa where 3GC-R status was associated with non-concordant initial antibiotic treatment. There was a possible increase in mortality among individuals with 3GC-resistant Enterobacteriaceae, but with broad confidence intervals. These analytical approaches could be applied to larger datasets to improve precision of estimates.

IntroductionExposure to maternal HIV in pregnancy may be a risk factor for impaired child neurodevelopment during the first years of life. Altered neurometabolites have been associated with HIV exposure in older children and may help explain the mechanisms underlying this risk. For the first time, we explored neurometabolic profiles of children who are HIV-exposed and uninfected (CHEU) compared to children who are HIV-unexposed (CHU) at 2-3 years of age.MethodsThe South African Drakenstein Child Health Study enrolled women during pregnancy and is following mother-child pairs through childhood. MRI scans were acquired on a sub-group of children at 2-3 years. We used single voxel magnetic resonance spectroscopy to measure brain metabolite ratios to total creatine in the parietal grey matter, and left and right parietal white matter of 83 children (36 CHEU; 47 CHU). Using factor analysis, we explored brain metabolite patterns in predefined parietal voxels in these groups using logistic regression models. Differences in relative concentrations of individual metabolites (n-acetyl-aspartate, myo-inositol, total choline, and glutamate) to total creatine between CHEU and CHU groups were also examined.ResultsFactor analysis revealed four different metabolite patterns, each one characterized by covarying ratios of a single metabolite in parietal grey and white matter. The cross-regional pattern dominated by myo-inositol, a marker for glial reactivity and inflammation, was associated with HIV exposure status (OR 1.63; 95% CI 1.11–2.50) which held after adjusting for child age, sex, and maternal alcohol use during pregnancy (OR 1.59; 95% CI 1.07 –2.47). Additionally, higher relative concentrations of myo-inositol to total creatine were found in left and right parietal white matter of CHEU compared to CHU (p=0.025 and p=0.001 respectively).DiscussionIncreased ratios of myo-inositol to total creatine in parietal brain regions at age 2-3 years in CHEU are suggestive of early and ongoing neuroinflammatory processes. Altered relative concentrations of neurometabolites were found predominantly in the white matter, which is sensitive to neuroinflammation, and may contribute to developmental risk in this population. Future work on the trajectory of myo-inositol over time in CHEU, alongside markers of neurocognitive development, and the potential for specific neurodevelopmental interventions will be useful.

This study aimed to investigate sickle cell trait (SCT) associations with physical activity, markers of insulin secretion and resistance, and glucose among people living with HIV infection (PLWH), both antiretroviral therapy (ART) naïve and experienced, and HIV-uninfected adults. This was a cross-sectional study conducted in Mwanza, north-western Tanzania. We used data of 668 participants attained from two sub-studies of CICADA study. Mean age was 40 (SD 11.5) years, 402 (61.7 %) were females and 157 (24.1 %) had SCT. PLWH were 422 (64.7 %), of these, 80 (18.9 %) were on ART. People with SCT had higher risk of having an isolated β-cell dysfunction compared to those without SCT (RRR=1.82, CI: 1.10, 3.01, P=0.02). People with SCT but without HIV infection had lower average acceleration on the trunk longitudinal axis (ACCx) and higher level of self-reported physical activity. 30 min oral glucose tolerance test among PLWH on ART was higher in those with SCT compared to those without SCT. People with SCT are at higher risk of having β-cell dysfunction and those with SCT on ART are at more risk of developing diabetes. Future studies to investigate the interaction between SCT and HIV/ART on risk of diabetes should be considered.

Background Long-term azithromycin (AZM) treatment reduces the frequency of acute respiratory exacerbation in children and adolescents with HIV-associated chronic lung disease (HCLD). However, the impact of this treatment on the respiratory bacteriome is unknown. Method African children with HCLD (defined as forced expiratory volume in 1 second z-score (FEV1z) less than − 1.0 with no reversibility) were enrolled in a placebo-controlled trial of once-weekly AZM given for 48-weeks (BREATHE trial). Sputum samples were collected at baseline, 48 weeks (end of treatment) and 72 weeks (six months post-intervention in participants who reached this timepoint before trial conclusion). Sputum bacterial load and bacteriome profiles were determined using 16S rDNA qPCR and V4 gene amplicon sequencing, respectively. The primary outcomes were within-participant and within-arm (AZM vs placebo) changes in the sputum bacteriome measured across baseline, 48 weeks and 72 weeks. Associations between clinical or socio-demographic factors and bacteriome profiles were also assessed using linear regression. Results In total, 347 participants (median age: 15.3 years, interquartile range [12.7–17.7]) were enrolled and randomised to AZM (173) or placebo (174). After 48 weeks, participants in the AZM arm had reduced sputum bacterial load vs placebo arm (16S rDNA copies/ml in log10, mean difference and 95% confidence interval [CI] of AZM vs Placebo − 0.54 [-0.71; -0.36]). Shannon alpha diversity remained stable in the AZM arm but declined in the placebo arm between baseline and 48 weeks (3.03 vs. 2.80, p = 0.04, Wilcoxon paired test). Bacterial community structure changed in the AZM arm at 48 weeks compared with baseline (PERMANOVA test p = 0.003) but resolved at 72 weeks. The relative abundances of genera previously associated with HCLD decreased in the AZM arm at 48 weeks compared with baseline, including Haemophilus (17.9% vs. 25.8%, p Moraxella (1% vs. 1.9%, 47, p Neisseria (coefficient, [standard error]: (2.85, [0.7], q = 0.01), and Haemophilus (–6.1, [1.2], q z, respectively. An increase in the relative abundance of Streptococcus from baseline to 48 weeks was associated with improvement in FEV1z (3.2 [1.11], q = 0.01) whilst an increase in Moraxella was associated with decline in FEV1z (-2.74 [0.74], q = 0.002). Conclusions AZM treatment preserved sputum bacterial diversity and reduced the relative abundances of the HCLD-associated genera Haemophilus and Moraxella. These bacteriological effects were associated with improvement in lung function and may account for reduced respiratory exacerbations associated with AZM treatment of children with HCLD.

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD.Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI) and Moraxella catarrhalis (MC) at these timepoints. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance, respectively.Of 347 (174 AZM, 173 placebo) participants (median age 15 years (IQR 13–18), female 49%), NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18% versus 41%, pversus 16%, p=0.01) and MC (4% versus 11%, p=0.02); SP resistance to AZM (62% (18 out of 29) versus 13% (8 out of 63), pversus 21% (13 out of 63), pversus 3% (1 out of 31), pversus 13% (4 out of 31), p=0.05) and clindamycin (79% (27 out of 34) versus 3% (1 out of 31), pThe persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation.

To describe the features of HIV-associated chronic lung disease (CLD) in older children and adolescents living with HIV and to examine the clinical factors associated with CLD. This is a post hoc analysis of baseline data from the BREATHE clinical trial (ClinicalTrials.gov, NCT02426112).Children and adolescents aged 6-19 years were screened for CLD (defined as a FEV1 z-score-1 with no reversibility post-bronchodilation with salbutamol) at two HIV clinics in Harare, Zimbabwe, and Blantyre, Malawi. Eligible participants with CLD (cases) were enrolled, together with a control group without CLD [frequency-matched by age group and duration on antiretroviral therapy (ART)] in a 4:1 allocation ratio. A clinical history and examination were undertaken. The association between CLD and a priori-defined demographic and clinical covariates was investigated using multivariable logistic regression.Of the 1585 participants screened, 419 (32%) had a FEV1 z-score-1, of whom 347 were enrolled as cases [median age 15.3 years (IQR 12.7-17.7); 48.9% female] and 74 with FEV1 z-score0 as controls [median age 15.6 years (IQR 12.1-18.2); 62.2% female]. Among cases, current respiratory symptoms including cough and shortness of breath were reported infrequently (9.3% and 1.8%, respectively). However, 152 (43.8%) of cases had a respiratory rate above the 90th centile for their age. Wasting and taking second-line ART were independently associated with CLD.The presence of CLD indicates the need to address additional treatment support for youth living with HIV, alongside ART provision, to ensure a healthier adulthood.Décrire les caractéristiques de la maladie pulmonaire chronique (MPC) associée au VIH chez les enfants plus âgés et les adolescents vivant avec le VIH et examiner les facteurs cliniques associés à la MPC. Il s'agit d'une analyse post-hoc des données de référence de l'essai clinique BREATHE (ClinicalTrials.gov, NCT02426112 ). MÉTHODES: Les enfants et adolescents âgés de 6 à 19 ans ont été dépistés pour la MPC (défini comme un score z FEV1-1 sans réversibilité post-bronchodilatation avec du salbutamol) dans deux cliniques VIH à Harare, au Zimbabwe et à Blantyre, au Malawi. Les participants éligibles atteints de MPC (cas) ont été inscrits, ainsi qu'un groupe témoin sans MPC (fréquence appariée par groupe d'âge et durée sous ART) dans un rapport d'allocation de 4:1. Une histoire clinique et un examen ont été entrepris. L'association entre la MPC et les covariables démographiques et cliniques définies a priori a été étudiée en utilisant une régression logistique multivariable. RÉSULTATS: Sur les 1.585 participants dépistés, 419 (32%) avaient un score z FEV 1-1, dont 347 étaient inscrits comme cas (âge médian 15,3 ans [IQR 12,7 -17,7]; 48,9% de sexe féminin), et 74 avec un score z FEV10 comme témoins (âge médian 15,6 ans [IQR 12,1 -18,2]; 62,2% de sexe féminin). Parmi les cas, les symptômes respiratoires en cours, y compris la toux et l'essoufflement, n’ont pas été rapportés fréquemment (9,3% et 1,8%, respectivement). Cependant, 152 (43,8%) des cas avaient une fréquence respiratoire supérieure au 90La présence de MPC indique la nécessité d’un soutien thérapeutique supplémentaire aux jeunes vivant avec le VIH, à côté de à la fourniture de l’ART, pour assurer un âge adulte en meilleure santé.

This study aimed to assess the association between suicidal ideation among mothers living with HIV in Zimbabwe and the cognitive development of their children. Participants were mother–child dyads recruited from two rural districts in Zimbabwe. Data were collected at baseline and 12 months follow-up. Suicidal ideation was assessed using item-10 from the Edinburgh postnatal depression scale. Mixed-effects linear regression was used to assess the association of child cognitive outcomes at follow-up (using the Mullen scales of early learning) with maternal suicidal ideation. Mothers with suicidal ideation at baseline (n = 171) tended to be younger, unmarried, experienced moderate to severe hunger, had elevated parental stress and depression symptoms compared with non-suicidal mothers (n = 391). At follow-up, emerging maternal suicidal ideation was associated with poorer child cognitive outcomes (adjusted mean difference − 6.1; 95% CI − 10.3 to − 1.8; p = 0.03). Suicidal ideation affects child cognitive development and should be addressed, particularly in HIV positive mothers.

BackgroundWe investigated risk factors for sustained virological non-suppression (viral load ≥ 1000 copies/ml on two tests 48 weeks apart) among children and adolescents accessing HIV care in public sector clinics in Harare, Zimbabwe and Blantyre, Malawi.MethodsParticipants were enrolled between 2016 and 2019, were aged 6–19 years, living with HIV, had chronic lung disease (FEV z-score ResultsAt enrolment 258 participants (64.6%) were on first-line ART and 152/347 (43.8%) had virological non-suppression. After 48 weeks 114/313 (36.4%) were non-suppressed. Participants non-suppressed at baseline had almost ten times higher odds of non-suppression at follow-up (OR = 9.9, 95%CI 5.3–18.4,p p = 0.014) and with older age. Twelve participants switched regimen in Zimbabwe and none in Malawi.ConclusionsViral non-suppression was high among this group and many with high viral load were not switched to a new regimen, resulting in continued non-suppression after 48 weeks. Further research could determine whether improved adherence counselling and training clinicians on regimen switches can improve viral suppression rates in this population.Trial registrationSecondary cohort analysis of data from BREATHE trial (Clinicaltrials.govNCT02426112).

Introduction There is a growing population of children who are HIV‐exposed and uninfected (HEU) with the successful expansion of antiretroviral therapy (ART) use in pregnancy. Children who are HEU are at risk of delayed neurodevelopment; however, there is limited research on early brain growth and maturation. We aimed to investigate the effects of in utero exposure to HIV/ART on brain structure of infants who are HEU compared to HIV‐unexposed (HU). Methods Magnetic resonance imaging using a T2‐weighted sequence was undertaken in a subgroup of infants aged 2–6 weeks enrolled in the Drakenstein Child Health Study birth cohort, South Africa, between 2012 and 2015. Mother–child pairs received antenatal and postnatal HIV testing and ART per local guidelines. We compared subcortical and total grey matter volumes between HEU and HU groups using multivariable linear regression adjusting for infant age, sex, intracranial volume and socio‐economic variables. We further assessed associations between brain volumes with maternal CD4 cell count and ART exposure. Results One hundred forty‐six infants (40 HEU; 106 HU) with high‐resolution images were included in this analysis (mean age 3 weeks; 50.7% male). All infants who were HEU were exposed to ART (88% maternal triple ART). Infants who were HEU had smaller caudate volumes bilaterally (5.4% reduction, p < 0.05) compared to HU infants. There were no group differences in other subcortical volumes (all p > 0.2). Total grey matter volume was also reduced in infants who were HEU (2.1% reduction, p < 0.05). Exploratory analyses showed that low maternal CD4 cell count (

Background: Right heart abnormalities and pulmonary hypertension (PH) may be secondary to chronic lung disease. Chronic lung disease is common in children with HIV. In the BREATHE trial (Trial registration: NCT02426112), azithromycin (AZM) reduced the risk of acute respiratory exacerbations in children aged 6–19 years with HIV-associated chronic lung disease (HCLD) taking antiretroviral therapy. We assessed the possible effect of AZM on right heart dysfunction and/or PH in the trial. Methods: A standardised transthoracic echocardiogram using M-mode, two-dimensional and Doppler was performed, at baseline and at completion of weight-based AZM given weekly for 48 weeks. Linear regression was used to compare trial arms. Results: A total of 169 participants (82 AZM arm; 87 placebo arm) were included. Participants in the placebo arm were older, median age 16.2 (13.0–18.2) vs 15.3 (12.9–17.4) years, p = 0.184 in the AZM arm. At baseline, right heart abnormalities (right ventricular systolic dysfunction (RVSD), dilatation, or PH) were observed in 7(4%). Following treatment, there was no difference in prevalence of RVSD between arms (p = 0.761). There was one incident case of suspected PH, and overall, no difference in pulmonary pressures. Conclusion: In children with HCLD, there was evidence of secondary cardiac effects, but AZM had no effect on right heart function. Long-term follow-up in children with HIV should be part of future research to understand the clinical implications of right heart abnormalities.

ImportanceAnemia affects millions of pregnant women and their children worldwide, particularly in low- and middle-income countries. Although anemia in pregnancy is a well-described risk factor for cognitive development, the association with child brain structure is poorly understood.ObjectiveTo explore the association of anemia during pregnancy and postnatal child anemia with brain structure in early life.Design, Setting, and ParticipantsThis neuroimaging nested cohort study was embedded within the Drakenstein Child Health Study (DCHS), a population-based birth cohort in South Africa. Pregnant individuals were enrolled into the DCHS between 2012 and 2015 from 2 clinics in a periurban setting. Mother-child pairs were assessed prospectively; follow-up is ongoing. A subgroup of children had brain magnetic resonance imaging (MRI) at age 2 to 3 years from 2015 to 2018. This study focused on the 147 pairs with structural neuroimaging and available hemoglobin data. Data analyses were conducted in 2021 and 2022.ExposuresMothers had hemoglobin measurements during pregnancy, and a subgroup of children had hemoglobin measurements during early life. Anemia was classified as hemoglobin levels less than 11 g/dL based on World Health Organization guidelines; children younger than 6 months were classified using local guidelines.Main Outcomes and MeasuresChild brain volumes of global, subcortical, and corpus callosum structures were quantified using T1-weighted MRI. Linear regression models were used to analyze the associations between maternal and child anemia with child brain volumes, accounting for potential confounders.ResultsOf 147 children (mean [SD] age at MRI, 34 [2] months; 83 [56.5%] male) with high-resolution MRI scans, prevalence of maternal anemia in pregnancy was 31.3% (46 of 147; median [IQR] gestation of measurement: 13 [9-20] weeks). Maternal anemia during pregnancy was significantly associated with smaller volumes of the child caudate bilaterally (adjusted percentage difference, −5.30% [95% CI, −7.01 to −3.59]), putamen (left hemisphere: −4.33% [95% CI, −5.74 to −2.92]), and corpus callosum (−7.75% [95% CI, −11.24 to −4.26]). Furthermore, antenatal maternal hemoglobin levels were also associated with brain volumes in the caudate (left hemisphere: standardized β = 0.15 [95% CI, 0.02 to 0.28]; right hemisphere: β = 0.15 [95% CI, 0.02 to 0.27]), putamen left hemisphere (β = 0.21 [95% CI, 0.07 to 0.35]), and corpus callosum (β = 0.24 [95% CI, 0.09 to 0.39]). Prevalence of child anemia was 52.5% (42 of 80; median [IQR] age of measurement: 8.0 [2.7 to 14.8] months). Child anemia was not associated with brain volumes, nor did it mediate the association of maternal anemia during pregnancy with brain volumes.Conclusions and RelevanceIn this cohort study, anemia in pregnancy was associated with altered child brain structural development. Given the high prevalence of antenatal maternal anemia worldwide, these findings suggest that optimizing interventions during pregnancy may improve child brain outcomes.

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

ObjectiveHIV-associated chronic lung disease (HCLD) is a common comorbidity in children and adolescents in sub-Saharan Africa (SSA). The pathogenesis of HCLD is unclear and may be driven by underlying dysregulated systemic immune activation and inflammation. We investigated the association between 26 plasma soluble biomarkers and HCLD.DesignCase--control analysis of baseline biomarker data from 336 children and adolescents (6-19 years old) with perinatal HIV infection (PHIV) and HCLD (cases) and 74 age-matched and sex-matched controls with PHIV but no CLD. HCLD was defined as having a forced expiratory volume in one second (FEV1) z score less than -1 with no reversibility.MethodsCryopreserved plasma collected at recruitment was used in a multiplex bead assay (Luminex) to measure baseline levels of soluble biomarkers. Logistic regression alongside data-reduction and techniques quantifying the interconnectedness of biomarkers were used to identify biomarkers associated with odds of HCLD.ResultsBiomarkers of general immune activation and inflammation (β2M, CRP, sCCL5, GCSF, IFN-γ, IP-10), T-cell activation (sCD25, sCD27), platelet activation (sCD40-L), monocyte activation (sCD14), coagulation (D-Dimer), cellular adhesion (E-selectin), and extracellular matrix degradation (MMP-1, MMP-7, MMP-10) were associated with increased odds of HCLD. Exploratory PCA and assessment of biomarker interconnectedness identified T-cell and platelet activation as centrally important to this association.ConclusionHCLD was associated with a large number of soluble biomarkers representing a range of different pathways. Our findings suggest a prominent role for T-cell and platelet activation in HCLD.

Background Consumption of unhealthy snack foods and beverages (USFBs) in low- and middle-income countries (LMICs) is rising, with global awareness increasing about risks of overnutrition. However, little is known about the relation between USFB consumption and young children's diet/nutritional outcomes in contexts where nutrient density of complementary foods is often low. Objectives This study assessed the association of high USFB consumption, compared with low consumption, with nutrient intakes, dietary adequacy, iron status, and growth in young children in Kathmandu Valley, Nepal. Methods A cross-sectional survey was conducted in a representative sample of 745 primary caregivers of children aged 12–23 mo. Food consumption was measured through quantitative 24-h recalls, and child anthropometric measurements and capillary blood samples were collected. Using adjusted linear/logistic regression models, nutrient intakes, dietary adequacy, length-for-age and weight-for-length z-scores (LAZ and WLZ, respectively), and iron status were compared between lowest and highest tertiles of consumption based on the contribution of USFBs to total energy intakes (TEIs). Mediation of the relation between USFB consumption and LAZ via lowered dietary adequacy was explored using structural equations modeling. Results On average, USFBs contributed 46.9% of TEI among the highest tertile of consumers, compared with 5.2% of TEI among the lowest. Compared with low-USFB consumers, high-USFB consumers had lower nutrient intakes and a greater proportion were at risk of inadequate intakes for 8 nutrients. Mean LAZ was nearly 0.3 SD lower among high-USFB consumers than low consumers (P = 0.003), with this relationship partially mediated through dietary adequacy. No associations were found with stunting prevalence or iron status. Prevalence of overweight/obesity was low. Conclusions In this LMIC context, high USFB consumption among young children was associated with inadequate micronutrient intakes, which can contribute to poor growth outcomes. Addressing increased availability of USFBs in LMIC food systems should be a priority for policies and programs aiming to safeguard child nutrition.

Background A high prevalence of cardiac abnormalities has been reported in children with human immunodeficiency virus (HIV) taking antiretroviral therapy (ART) in sub-Saharan Africa. We investigated the incidence and progression of cardiac abnormalities among children taking ART in Zimbabwe. Methods A prospective cohort study was conducted at a pediatric HIV clinic from 2014 to 2017. Children with HIV aged between 6 and 16 years and taking ART ≥6 months were enrolled. Transthoracic echocardiography was performed at baseline and after 18 months. Results Of 197 participants recruited at baseline, 175 (89%; 48% female; median age 12 years, interquartile range 10–14 years) were followed up. The incidences of left and right heart abnormalities were 3.52 and 5.64 per 100 person-years, respectively. Stunting was associated with the development of any cardiac abnormality (adjusted odds ratio 2.59, 95% confidence interval 1.03–6.49; P = .043). Right ventricular (RV) dilatation persisted at follow-up in 92% of participants and left ventricular (LV) diastolic dysfunction in 88%. Cardiac abnormalities present at baseline reverted to normal over the follow-up period in 11 (6%). There was an overall increase in mean z scores for LV, left atrium (LA), RV, interventricular septum, and LV posterior wall diameters at 18 months (P < .001). Conclusions Despite ART, children with HIV have a high incidence of cardiac abnormalities, with only a minority being transient. Mean z scores for LV, LA, RV, interventricular septum, and LV posterior wall diameters increased over a relatively short follow-up period, suggesting the potential for progression of cardiac abnormalities. Longer follow-up is required to understand the clinical implications of these abnormalities., Older children and adolescents with human immunodeficiency virus (HIV) who are receiving antiretroviral therapy in sub-Saharan Africa have a high incidence of echocardiographic abnormalities, which are likely primary HIV-related heart muscle disease and have the potential for progression over time.

Background The prevalence, pathology, and existence of malnutrition-associated diabetes remain uncertain, especially with respect to adult-acquired undernutrition. Objective The aim was to investigate the association of prior undernutrition (low BMI, in kg/m2), acquired in adulthood and insulin during an oral glucose tolerance test (OGTT). Methods We followed up 630 adults recruited 7–14 y previously for other studies. Plasma insulin was measured fasting and at 30 and 120 min during an OGTT. The main exposure was BMI measured 7–14 y prior. The main outcome of interest was plasma insulin, controlling for time during the OGTT using generalized estimating equations, and exploratory outcomes were early insulin response (relative change in insulin and glucose from 0–30 min) and relative insulin and glucose AUCs from 0 to 120 min. Current confounding factors were age, sex, BMI, HIV, socioeconomic status, and physical activity. Results In unadjusted analyses, increasing severity of prior malnutrition was associated with lower insulin concentration. In multivariate adjusted analyses, only current BMI was a strong predictor of overall insulin concentration. Associations with prior BMI of insulin responses accounting for glucose were also seen in unadjusted but not adjusted analyses. For insulin concentration but not the outcomes accounting for glucose, there was a sex interaction with prior BMI such that only men had lower insulin if previously malnourished: insulin (pmol/L) at 120 min was 311 (95% CI: 272, 351) for prior BMI ≥18.5, 271 (95% CI: 221, 321) for prior BMI 17.0–18.5, and 237 (95% CI: 194, 297) for prior BMI

Background HIV-associated chronic lung disease (CLD) is common among children living with HIV (CLWH) in sub-Saharan Africa, including those on antiretroviral therapy (ART). However, the pathogenesis of CLD and its possible association with microbial determinants remain poorly understood. We investigated the prevalence, and antibiotic susceptibility of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) among CLWH (established on ART) who had CLD (CLD+), or not (CLD-) in Zimbabwe and Malawi. Methods Nasopharyngeal swabs (NP) and sputa were collected from CLD+ CLWH (defined as forced-expiratory volume per second z-score NCT02426112), and from age- and sex-matched CLD- CLWH. Samples were cultured, and antibiotic susceptibility testing was conducted using disk diffusion. Risk factors for bacterial carriage were identified using questionnaires and analysed using multivariate logistic regression. Results A total of 410 participants (336 CLD+, 74 CLD-) were enrolled (median age, 15 years [IQR = 13–18]). SP and MC carriage in NP were higher in CLD+ than in CLD- children: 46% (154/336) vs. 26% (19/74), p = 0.008; and 14% (49/336) vs. 3% (2/74), p = 0.012, respectively. SP isolates from the NP of CLD+ children were more likely to be non-susceptible to penicillin than those from CLD- children (36% [53/144] vs 11% [2/18], p = 0.036). Methicillin-resistant SA was uncommon [4% (7/195)]. In multivariate analysis, key factors associated with NP bacterial carriage included having CLD (SP: adjusted odds ratio (aOR) 2 [95% CI 1.1–3.9]), younger age (SP: aOR 3.2 [1.8–5.8]), viral load suppression (SP: aOR 0.6 [0.4–1.0], SA: 0.5 [0.3–0.9]), stunting (SP: aOR 1.6 [1.1–2.6]) and male sex (SA: aOR 1.7 [1.0–2.9]). Sputum bacterial carriage was similar in both groups (50%) and was associated with Zimbabwean site (SP: aOR 3.1 [1.4–7.3], SA: 2.1 [1.1–4.2]), being on ART for a longer period (SP: aOR 0.3 [0.1–0.8]), and hot compared to rainy season (SP: aOR 2.3 [1.2–4.4]). Conclusions CLD+ CLWH were more likely to be colonised by MC and SP, including penicillin-non-susceptible SP strains, than CLD- CLWH. The role of these bacteria in CLD pathogenesis, including the risk of acute exacerbations, should be further studied.

Introduction Maternal and newborn infections are important causes of mortality but morbidity data from low- and middle-income countries is limited. We used telephone surveillance to estimate infection incidence and risk factors in women and newborns following hospital childbirth in Dar es Salaam. Methods We recruited postnatal women from two tertiary hospitals and conducted telephone interviews 7 and 28 days after delivery. Maternal infection (endometritis, caesarean or perineal wound, or urinary tract infection) and newborn infection (umbilical cord or possible severe bacterial infection) were identified using hospital case-notes at the time of birth and self-reported symptoms. Adjusted Cox regression models were used to assess the association between potential risk-factors and infection. Results We recruited 879 women and interviewed 791 (90%). From day 0–7, 6.7% (49/791) women and 6.2% (51/762) newborns developed infection. Using full follow-up data, the infection rate was higher in women with caesarean childbirth versus women with a vaginal delivery (aHR 1.93, 95%CI 1.11–3.36). Only 24% of women received pre-operative antibiotic prophylaxis before caesarean section. Infection was higher in newborns resuscitated at birth versus newborns who were not resuscitated (aHR 4.45, 95%CI 2.10–9.44). At interview, 66% (37/56) of women and 88% (72/82) of newborns with possible infection had sought health-facility care. Conclusions Telephone surveillance identified a substantial risk of postnatal infection, including cases likely to have been missed by hospital-based data-collection alone. Risk of maternal endometritis and newborn possible severe bacterial infection were consistent with other studies. Caesarean section was the most important risk-factor for maternal infection. Improved implementation of pre-operative antibiotic prophylaxis is urgently required to mitigate this risk.

Objective: Studies on phenotypes of diabetes in Africa are inconsistent. We assessed the role of β-cell dysfunction and insulin resistance on pre-diabetes and diabetes.Methods: We included 1890 participants with mean age of 40.6 (SD11.9) years in a cross-sectional study among male and female adults in Tanzania during 2016 to 2017. Data on C-reactive protein (CRP), alpha-acid glycoprotein (AGP), HIV, oral glucose tolerance test (OGTT), body composition, and insulin were collected. Insulinogenic index and HOMA-IR were used to derive an overall marker of β-cell dysfunction and insulin resistance and categorized as: normal β-cell function and insulin sensitivity, isolated β-cell dysfunction, isolated insulin resistance, and combined β-cell dysfunction and insulin resistance. Pre-diabetes and diabetes were defined as 2-hour OGTT glucose between 7.8-11.1 and ≥11.1 mmol/L, respectively. Multinomial regression assessed the association of β-cell dysfunction and insulin resistance with outcome measures.Results: β-cell dysfunction, insulin resistance, and combined β-cell dysfunction and insulin resistance were associated with higher pre-diabetes risk. Similarly, isolated β-cell dysfunction (adjusted Relative Risk Ratio (aRRR) 4.8 (95% confidence interval (CI) 2.5, 9.0), isolated insulin resistance (aRRR 3.2 (95% CI 1.5, 6.9), and combined β-cell dysfunction and insulin resistance (aRRR 35.9 (95% CI 17.2, 75.2) were associated with higher diabetes risk. CRP, AGP and HIV were associated with higher diabetes risk, but fat mass was not. 31%, 10% and 33% of diabetes cases were attributed to β-cell dysfunction, insulin resistance and combined β-cell dysfunction and insulin resistance, respectively.Conclusions: β-cell dysfunction seemed to explain most of diabetes cases compared to insulin resistance in this population. Cohort studies on evolution of diabetes in Africa are needed to confirm these results.

Background: Anaemia affects millions of women and children worldwide, particularly in low- and middle-income countries. Although anaemia in pregnancy is a well-described risk factor for poor child neurodevelopmental outcomes, little is known about the impact on the structural development of the human brain. We explored the relationship between maternal anaemia, child anaemia, and brain structure at 2-3 years of age. Methods: Pregnant women were enrolled into the Drakenstein Child Health Study, a South African population-based birth cohort. Mother-child pairs were followed prospectively and a subgroup of children had magnetic resonance imaging at 2-3 years of age. Mothers had haemoglobin measurements during pregnancy, and a group of children during early life. Linear regression models were used to analyse the effects of maternal and child anaemia on child brain volumes. Findings: Prevalence of maternal anaemia in pregnancy (haemoglobin 0.05). Associations between antenatal anaemia with child putamen and corpus callosum volumes increased in magnitude when adjusting for child anaemia. Interpretation: Maternal anaemia may influence brain development during a critical window with persistent impact. Funding: Gates Foundation, SAMRC, NIH, Wellcome Trust Declaration of Interests: No conflicts of interest. Ethics Approval Statement: The DCHS was approved by the Faculty of Health Sciences, Human Research Ethics Committee (HREC), UCT (401/2009), Stellenbosch University (N12/02/0002), and the Western Cape Provincial Health Research Committee (2011RP45). The neuroimaging sub-study was further approved by the UCT HREC (525/2012).

Background: Long-term azithromycin (AZM) therapy is increasingly used to prevent acute exacerbations of chronic lung diseases (CLD). However, selection for resistance to macrolides and other antibiotics remains a concern. We investigated the impact of 48 weeks of AZM therapy on the carriage and antibiotic resistance of common respiratory bacteria in children and adolescents with HIV-associated CLD. Methods: Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from children and adolescents with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention up to 72 weeks. The primary outcomes were the prevalence of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) and their antibiotic resistance between the trial arms at 48 and 72 weeks. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance, respectively. Findings: Between June 2016, and September 2018, 347 participants (174 AZM, 173 placebo arm) were enrolled (median age, 15 years [IQR = 13–18], females, 49%). NP carriage was significantly lower in the AZM compared to placebo arm at 48 weeks for SP (18% [29/159] vs 41% [64/153], adjusted odds ratio (aOR) 0·2 [95% CI 0·1–0·4]), HI (7% [11/159] vs 16% [24/153], aOR 0·3 [0·1–0·8]), or MC (4% [7/159] vs 11% [17/153], aOR 0·3 [0·1–0·8]). SP resistance to AZM (62% [18/29] vs 13% [8/63], p