Growth and health outcomes at school age in HIV-exposed, uninfected Zambian children: follow-up of two cohorts studied in infancy.

BACKGROUND: Early growth and health of HIV-exposed, uninfected (HEU) children is poorer than that of their HIV-unexposed, uninfected (HUU) counterparts but there is little information about longer term effects of early HIV exposure. We previously recruited two cohorts of HEU and HUU Zambian infants and documented the poorer infant growth and health of the HEU compared to the HUU children. We followed up HEU and HUU children from these cohorts when they were school-aged and compared their growth, health, biochemical markers of acute or chronic disease, and school grades. METHODS: We recruited 111 HEU and 279 HUU children aged 6-12 years. We measured anthropometry, determined health by questionnaire and clinical examination, viewed the child's most recent school report, and measured blood pressure, haemoglobin (Hb), HbA1c, glucose, cholesterol, and C-reactive protein (CRP). RESULTS: Anthropometric measures were lower among HEU than HUU children, significantly so for hip circumference (age- and sex-adjusted difference -1.74 cm; 95% confidence interval (CI) -3.24, -0.24; P = 0.023) and mid-upper-arm circumference (adjusted difference -0.63 cm, 95% CI -1.23, -0.04; P = 0.037) and with borderline effects for body mass index, thigh circumference and subscapular skinfolds. HEU children had significantly lower total, trunk, and limb fat percentages. All anthropometric and body composition differences became non-significant after adjustment for sociodemographic variables which differed between HEU and HUU children. More HEU than HUU children reported minor illnesses and were prescribed medication at the time of visit. There were no differences in biochemical markers between groups. HEU children had lower math grades than HUU children even after adjustment for socioeconomic variables. CONCLUSIONS: Although HEU children were smaller and had lower percent fat than HUU children, this appeared to be due mainly to their poorer socioeconomic status. Reasons for lower school grades require further research

Appetite testing in HIV-infected African adults recovering from malnutrition and given antiretroviral therapy.

OBJECTIVE: The Nutritional Support for Africans Starting Antiretroviral Therapy (NUSTART) trial was designed to determine whether nutritional support for malnourished HIV-infected adults starting antiretroviral therapy (ART) can improve early survival. Appetite is related to health outcomes in this population, but the optimal appetite metric for field use is uncertain. We evaluated two measures of appetite with the goal of improving understanding and treatment of malnutrition in HIV-infected adults. DESIGN: Longitudinal cohort study embedded in a clinical trial of vitamin and mineral-fortified, v. unfortified, lipid-based nutritional supplements. SETTING: HIV clinics in Mwanza, Tanzania and Lusaka, Zambia. SUBJECTS: Malnourished (BMI<18.5 kg/m2) HIV-infected adults starting ART. RESULTS: Appetite measurements, by short questionnaire and by weight of maize porridge consumed in a standardized test, were compared across time and correlated with changes in weight. Appetite questionnaire scores, from polychoric correlation, and porridge test results were normally distributed for Tanzanians (n 187) but clustered and unreliable for Zambians (n 297). Among Tanzanian patients, the appetite score increased rapidly from referral for ART, plateaued at the start of ART and then increased slowly during the 12-week follow-up. Change in appetite questionnaire score, but not porridge test, correlated with weight change in the corresponding two-week intervals (P=0.002) or over the whole study (P=0.05) but a point estimate of hunger did not predict weight change (P=0.4). CONCLUSIONS: In Tanzania change in appetite score correlated with weight change, but single point measurements did not. Appetite increases several weeks after the start of ART, which may be an appropriate time for nutritional interventions for malnourished HIV-infected adults

Micronutrient Adequacy and Dietary Diversity Exert Positive and Distinct Effects on Linear Growth in Urban Zambian Infants.

BACKGROUND: In the monitoring of infant and young child feeding, dietary diversity is used as an indicator of micronutrient adequacy; however, their relation may have weakened with the increasing use of fortified complementary foods. OBJECTIVE: The objectives were to assess the relation between dietary diversity and micronutrient adequacy in an urban infant population with a high consumption of fortified foods and to investigate whether dietary diversity and micronutrient adequacy were independently associated with subsequent growth. METHODS: We used longitudinal data on 811 infants in the Chilenje Infant Growth, Nutrition, and Infection Study conducted in Lusaka, Zambia. The relation between mean micronutrient adequacies and dietary diversity scores derived from 24-h diet recalls at 6 mo of age was investigated with the use of Spearman rank correlation. Multiple linear regression was used to assess the association between micronutrient adequacy, dietary diversity, and subsequent growth to 18 mo of age. RESULTS: Overall mean micronutrient density adequacy (MMDA) and MMDA of "problem micronutrients," defined as those micronutrients (calcium, iron, zinc) with mean density adequacies less than half of estimated needs, were correlated with dietary diversity scores (ρ = 0.36 and 0.30, respectively, both P < 0.0001). Consumption of "sentinel foods" (iron rich, fortified, animal source, dairy) showed better correlation with MMDA than with dietary diversity (ρ = 0.58-0.69, all P < 0.0001). In fully adjusted analyses, MMDA calcium, iron, zinc, and dietary diversity, but not overall MMDA, were associated with linear growth to 18 mo (both P ≤ 0.028). CONCLUSIONS: Micronutrient adequacy in infants consuming fortified foods may be more accurately assessed using locally specific sentinel food indicators rather than dietary diversity scores. Nonetheless, dietary diversity has a positive effect on subsequent linear growth apart from that of micronutrient adequacy, warranting its continued monitoring and further investigation into the mechanisms underlying this finding. This trial was registered at www.controlled-trials.com as ISRCTN37460449

Anthropometry, body composition, early growth, and chronic disease risk factors among Zambian adolescents exposed or not to perinatal maternal HIV.

Early life exposures and growth patterns may affect long-term risk of chronic non-communicable diseases (NCDs). We followed up in adolescence two Zambian cohorts (N=322) recruited in infancy to investigate how two early exposures - maternal HIV exposure without HIV infection (HEU), and early growth profile - were associated with later anthropometry, body composition, blood lipids, haemoglobin (Hb) and HbA1c, blood pressure and grip strength. Although in analyses controlled for age and sex, HEU children were thinner, but not shorter, than HIV-unexposed, uninfected (HUU) children, with further control for sociodemographic factors, these differences were not significant. HEU children had higher HDL cholesterol than HUU children and marginally lower HbA1c but no other biochemical or clinical differences. We identified three early growth profiles - adequate growth, declining and malnourished - which tracked into adolescence when differences in anthropometry and body fat were still seen. In adolescence, the early malnourished group, compared with the adequate group, had lower blood triglycerides and higher HDL, lower grip strength (difference: -1.87 kg, 95% CI: -3.47, -0.27; P=0.02) and higher HbA1c (difference: 0.5%, 95% CI 0.2, 0.9, P=0.005). Lower grip strength and higher HbA1c suggest the early malnourished children could be at increased risk of NCDs in later life. Including early growth profile in analyses of HIV exposure reduced the associations between HIV and outcomes. The results suggest that perinatal HIV exposure may have no long-term effects unless accompanied by poor early growth. Reducing the risk of young child malnutrition may lessen children's risk of later NCDs

Effects on anthropometry and appetite of vitamins and minerals given in lipid nutritional supplements for malnourished HIV-infected adults referred for antiretroviral therapy: results from the NUSTART randomized controlled trial.

BACKGROUND: The evidence base for effects of nutritional interventions for malnourished HIV-infected patients starting antiretroviral therapy (ART) is limited and inconclusive. OBJECTIVE: We hypothesized that both vitamin and mineral deficiencies and poor appetite limit weight gain in malnourished patients starting ART and that vitamin and mineral supplementation would improve appetite and permit nutritional recovery. DESIGN: The randomized controlled Nutritional Support for Africans Starting Antiretroviral Therapy trial was conducted in Mwanza, Tanzania, and Lusaka, Zambia. ART-naive adults referred for ART and with body mass index <18.5 kg/m received lipid-based nutritional supplements either without (LNS) or with added vitamins and minerals (LNS-VM), beginning before ART initiation. Participants were given 30 g/d LNS from recruitment until 2 weeks after starting ART and 250 g/d from weeks 2 to 6 of ART. RESULTS: Of 1815 patients recruited, 365 (20%) died during the study and 813 (45%) provided data at 12 weeks. Controlling for baseline values, anthropometric measures were consistently higher at 12-week ART in the LNS-VM than in the LNS group but statistically significant only for calf and mid-upper arm circumferences and triceps skinfold. Appetite did not differ between groups. Using piecewise mixed-effects quadratic models including all patients and time points, the main effects of LNS-VM were seen after starting ART and were significant for weight, body mass index, and mid-upper arm circumference. CONCLUSIONS: Provision of high levels of vitamins and minerals to patients referred for ART, delivered with substantial macronutrients, increased nutritional recovery but did not seem to act through treatment group differences in appetite

Anthropometry, body composition and chronic disease risk factors among Zambian school-aged children who experienced severe malnutrition in early childhood.

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

Vitamin D 3 and calcium carbonate supplementation for adolescents with HIV to reduce musculoskeletal morbidity and immunopathology (VITALITY trial): study protocol for a randomised placebo-controlled trial

Background: Of the 2 million children living with HIV globally, 90% live in sub-Saharan Africa. Despite antiretroviral therapy, longstanding HIV infection is associated with several chronic complications in children including growth failure, particularly stunting and delayed puberty. Vitamin D deficiency, which is highly prevalent among children living with HIV in sub-Saharan Africa, has a further adverse impact on bone health. This trial aims to establish whether supplementation with vitamin D3 and calcium carbonate improves musculoskeletal health among peripubertal children living with HIV. Methods/design: We will conduct an individually randomised, double-blinded, placebo-controlled trial of weekly high-dose vitamin D3 (20,000 IU) plus daily calcium carbonate (500mg) supplementation for 48 weeks. Eight hundred and forty children living with HIV aged 11–19 years taking ART for ≥6 months will be enrolled and followed up for 96 weeks. The primary outcome is total body less-head bone mineral content for lean mass adjusted for height (TBLH-BMCLBM) Z-score at 48 weeks, measured by dual-energy X-ray absorptiometry (DEXA). Secondary outcomes are DEXA-measured lumbar spine bone mineral apparent density Z-score, number of respiratory infections, lean muscle mass and grip strength at 48 and 96 weeks and TBLH-BMCLBMZ-scores at 96 weeks. Sub-studies will investigate the effect of the intervention on vitamin D3 pathway metabolites and markers of bone turnover, intestinal microbiota, and innate and acquired immune function. Discussion: This is the largest trial to date of vitamin D supplementation in children living with HIV. Intervening to address deficits in bone accrual in childhood is critical for optimising adolescent and early adult bone health and prevention of later adult osteoporotic fractures. Trial results will draw attention to the need to screen for and treat long-term comorbidities in children living with HIV in resource-limited settings. Trial registration: Pan African Clinical Trials Registry PACTR20200989766029. Registered on 3 September 202

Association Between Vitamin D Insufficiency and Impaired Bone Density Among Adolescents With Perinatally Acquired HIV Infection

Background: Stunting and pubertal delay are common among children growing up with human immunodeficiency virus (HIV) and are associated with bone and muscle impairments. We investigated factors associated with bone density and muscle function in adolescents living with HIV (ALWH). Methods: The VITALITY trial (PACTR202009897660297) investigated whether vitamin D and calcium supplementation improves musculoskeletal health among ALWH. A total of 842 ALWH aged 11–19 years, established on antiretroviral therapy (ART) for ≥6 months, were enrolled from HIV clinics in Zambia and Zimbabwe. Clinical history and examination were undertaken, and serum 25-hydroxyvitamin D3 (25[OH]D3) was measured. Dual-energy X-ray absorptiometry measured total-body-less-head bone mineral density adjusted for height (TBLH-BMDHT), and lumbar spine bone mineral apparent density (LS-BMAD) z scores. The association between a priori–defined covariates and musculoskeletal outcomes were investigated using baseline enrollment data and multivariable logistic regression. Results: TBLH-BMDHT z scores were impaired (mean, −1.42 for male and −0.63 female participants), as were LS-BMAD z scores (mean −1.15 for male and −0.47 for female participants). In bivariate analysis, early pubertal stage, less physical activity, and older age at ART initiation were associated with lower TBLH-BMDHT z scores. Younger age, early pubertal stage, and low socioeconomic status were associated with lower LS-BMAD z scores. Grip-strength-for-height and jump-power-for-height z scores were associated with lower TBLH-BMDHT and LS-BMAD z scores. Low dietary vitamin D and calcium were associated with lower adjusted TBLH-BMDHT z scores. Lower 25(OH)D3 was associated with lower adjusted TBLH-BMDHT and LS-BMAD z scores. Conclusions: Deficits in bone density are common in ALWH. Vitamin D and calcium supplementation and promotion of exercise may improve musculoskeletal health among perinatally infected ALWH

Update: Vitamin D 3 and calcium carbonate supplementation for adolescents with HIV to reduce musculoskeletal morbidity and immunopathology (VITALITY trial): study protocol for a randomised placebo-controlled trial

Background: Of the 2 million children living with HIV globally, 90% live in sub-Saharan Africa. Despite antiretroviral therapy, longstanding HIV infection is associated with several chronic complications in children including growth failure, particularly stunting and delayed puberty. Vitamin D deficiency, which is highly prevalent among children living with HIV in sub-Saharan Africa, has further adverse impact on bone health. This trial aims to establish whether supplementation with vitamin D3 and calcium carbonate improves musculoskeletal health among peripubertal children living with HIV. This paper is an update to an already existing protocol that was previously published in Trials in 2022 and details changes in the trial outcomes. Methods/design: We will conduct an individually randomised, double-blinded, placebo-controlled trial of weekly high-dose vitamin D3 (20,000 IU) plus daily calcium carbonate (500 mg) supplementation for 48 weeks. Eight hundred and forty children living with HIV aged 11–19 years taking ART for ≥ 6 months will be enrolled and followed up for 96 weeks. The primary outcome is DXA-measured total body less-head bone mineral density Z-score (TBLH-BMD) at 48 weeks and is an update to the previous primary outcome total body less-head bone mineral content adjusted for lean mass (TBLH-BMCLBM) Z-score. The primary outcome was updated to address the substantial differences in distributions of TBLH-BMCLBM Z-score between the two sites as a result of software differences of the DXA machines. Secondary outcomes are DXA-measured TBLH-BMD Z-score adjusted for height at 48 weeks a new secondary outcome, lumbar spine bone mineral apparent density Z-score, number of respiratory infections, lean muscle mass and grip-strength at 48 and 96 weeks, and TBLH-BMD Z-score at 96 weeks. Sub-studies will investigate the effect of the intervention on vitamin D3 pathway metabolites and markers of bone turnover, intestinal microbiota, and innate and acquired immune function. Discussion: This is the largest trial to date of vitamin D supplementation in children living with HIV. Intervening to address deficits in bone accrual through childhood is critical for optimising adolescent and early adult bone health, and prevention of later adult osteoporotic fractures. Trial results will draw attention to the need to screen for and treat long-term comorbidities in children living with HIV in resource-limited settings. Trial registration: Pan African Clinical Trials Registry PACTR20200989766029. Registered on September 3, 2020. URL of trial registry record: https://pactr.samrc.ac.za Trial status: Participant follow-up completed; data analysis ongoing

Effects on body composition and handgrip strength of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.

Lipid-based nutrient supplements (LNS) may be beneficial for malnourished HIV-infected patients starting antiretroviral therapy (ART). We assessed the effect of adding vitamins and minerals to LNS on body composition and handgrip strength during ART initiation. ART-eligible HIV-infected patients with BMI <18·5 kg/m2 were randomised to LNS or LNS with added high-dose vitamins and minerals (LNS-VM) from referral for ART to 6 weeks post-ART and followed up until 12 weeks. Body composition by bioelectrical impedance analysis (BIA), deuterium (2H) diluted water (D2O) and air displacement plethysmography (ADP), and handgrip strength were determined at baseline and at 6 and 12 weeks post-ART, and effects of LNS-VM v. LNS at 6 and 12 weeks investigated. BIA data were available for 1461, D2O data for 479, ADP data for 498 and handgrip strength data for 1752 patients. Fat mass tended to be lower, and fat-free mass correspondingly higher, by BIA than by ADP or D2O. At 6 weeks post-ART, LNS-VM led to a higher regain of BIA-assessed fat mass (0·4 (95 % CI 0·05, 0·8) kg), but not fat-free mass, and a borderline significant increase in handgrip strength (0·72 (95 % CI -0·03, 1·5) kg). These effects were not sustained at 12 weeks. Similar effects as for BIA were seen using ADP or D2O but no differences reached statistical significance. In conclusion, LNS-VM led to a higher regain of fat mass at 6 weeks and to a borderline significant beneficial effect on handgrip strength. Further research is needed to determine appropriate timing and supplement composition to optimise nutritional interventions in malnourished HIV patients