Multiple micronutrient supplementation in HIV-infected children. A randomised trial among children aged 1-5 years in Uganda
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Micronutrient deficiencies are common in children living in low-income countries, more so in malnourished and HIV-infected children. The routinely practiced interventions, such as vitamin A supplementation and other micronutrients in recommended dietary allowances (RDA), may not be sufficient to correct all the micronutrient deficiencies. Gaps still exist in determining the optimal composition, dosing and duration of supplementation. Highly active antiretroviral therapy tends to improve micronutrient status of HIV-infected persons, but most probably not back to normal concentrations, especially in areas where daily food intake is not micronutrient-rich. Aims: The study aimed at determining the effect of multiple micronutrient supplementation on mortality, growth, diarrhoea and micronutrient concentrations of Ugandan HIV-infected children aged 1-5 years at paediatric HIV clinics. Methods: Using a randomised controlled design, 847 confirmed HIV-infected children were enrolled, stratified into the highly active antiretroviral (HAART) and HAART naïve groups, and assigned to either an intervention supplement or standard of care comparative arm. The intervention consisted of 10 multivitamins and 4 minerals (vitamins A, B1, B2, Niacin, B6, B12, folate, C, D and E, plus minerals selenium, zinc, copper and Iodine) in 2 RDA doses, whereas the comparative supplement contained 6 multivitamins in 1-RDA as the ‘standard of care’ at 7 paediatric HIV clinics in Uganda. At enrolment, current and previous history of illness, anthropometric measurements and a detailed systemic examination was done. The trial supplement was administered orally, once daily for 6 months. Compliance was measured by weighing the remaining supplement at each monthly visit. The participants attended the study clinics on scheduled visits monthly for 6 months, at 9 and 12 months, and for treatment whenever the child was sick. All study clinics had in-patient facilities where very sick children could be hospitalised. Blood was drawn for a complete blood count, CD4+ cell count, C-reactive protein (CRP) and micronutrient assays, at baseline and 6 months visit. Study outcomes were measured at 12 months for mortality, 6 months for diarrhoea morbidity and the effect of supplementation on vitamin B12 and folate concentrations at 6months. Zinc status was reported as part of the baseline survey. For all the papers, data analysis was by arm and stratum. Results: Of the 847 children, 85 (10.0%) were on HAART whereas 762 (90.0%) were HAARTnaïve. Overall, 426 (50.3%) children, 43 on HAART and 383 HAART-naïve received the intervention whereas 421(49.7%), 42 on HAART and 379 HAART-naïve were treated with the comparative ‘standard of care’ supplement. The mortality rate in the participants was 6.3 % at one year of follow-up. Mortality from all causes was 25/426 (5.9%) with intervention and 28/421 (6.7%) in the comparative arm. There was no difference between arms; the risk ratio was 0.9 (95% CI; 0.5-1.5) using the Kaplan-Meier survival analysis. As expected, mortality was lower in the HAART stratum, 2/85 (2.4%). Mean survival time was similar in both groups. Generally, weight-for-height and weight-for-age improved except height-for-age z scores, and there was no difference between the 2 arms. There was no difference in the incidence and prevalence of diarrhoea in the 2 groups. The incidence of diarrhoea was 3.8 (95% CI; 3.4-4.3) in the intervention and 3.5 (95% CI; 3.1- 4.0) in the comparative arm per child-year. The rate ratio was 1.1(95%CI; 0.9-1.3). In the HAART stratum, the incidence of diarrhoea was 1.7 (95%CI; (1.0-2.7) in the intervention and 1.5 (95%CI; 0.9-2.6) in the comparative arm. Although these children had fewer episodes of diarrhoea, there was no difference between the 2 arms. The rate ratio was 1.1 (95%CI; 0.5-2.3). More than half the children had low zinc concentrations. Of the 247 children analysed for zinc status, 134 (54.3%) had zinc concentrations of < 10 mol/L; 121/203 (59.6%) in the HAART naïve, and 13/44 (29.5%) in the HAAR-treated children, Odds ratio (OR) 3.5 (95%CI; 1.7-7.1). At 6 months of supplementation, the children receiving the intervention had higher serum concentrations of vitamin B12 and folate compared to those who received the ‘standard of care’ supplement. In the intervention group, the median concentration (IQR) of vitamin B12 at 6 months was 401.5 (264.3-518.8) pmol/L compared to the baseline of 285.5 (216.5- 371.8) pmol/L, p<0.001. The median (IQR) folate concentrations also increased from 17.3 (13.5-26.6) nmol/L to 27.7 (21.1-33.4) nmol/L, p<0.001. Of the 214 children, 60 (28.0%) had low vitamin B12 (<221picomoles per litre) concentrations at baseline compared to 42/214 (19.6%) at 6 months. Sixty two children (29.0%) had low folate (<13.4 nanomoles per litre) concentrations at baseline compared to 44/214 (20.6%) at 6 months. There was minimal reduction in the prorpotion of children with low vitamin B12 and folate concentrations. There was a general increase in haemoglobin with no differences between the 2 groups, nor was there any significant change in CD4+ cell count. The supplement was well tolerated with no adverse effects. Conclusion: A supplement of 2 RDAs of 14 micronutrients given to HIV-infected children for 6 months did not reduce mortality or diarrhoea morbidity, but improved vitamin B12 and folate concentrations compared to the comparative ‘standard of care’ arm. The supplement was well tolerated with no adverse effects. More than half of the children were zinc deficient, whereas one-third was vitamin B12 or folate deficiency. Routine supplementation with 2RDAs of multiple micronutrients to HIV-infected children in Uganda is recommended to reduce the magnitude of micronutrient deficiencies. Further studies to determine the impact of prolonged supplementation, inclusion of iron (our supplement did not contain iron) and supplementation in a larger group of HAART treated children are also recommended.
Paper I: Ndeezi G, Tylleskär T, Ndugwa CM, Tumwine JK. Effect of multiple micronutrient supplementation on survival of HIV-infected children in Uganda: a randomized, controlled trial. Journal of the International AIDS Society 2010;13:18. The article is available at: http://hdl.handle.net/1956/4643Paper II: Ndeezi G, Tylleskär T, Ndugwa CM, Tumwine JK. Multiple micronutrient supplementation does not reduce diarrhoea morbidity in Ugandan HIV infected children; a randomised controlled trial. Full text not available in BORA.Paper III: Ndeezi G, Tumwine JK, Bolann BJ, Ndugwa CM, Tylleskär T. Zinc status in HIVinfected Ugandan children aged 1-5 years: a cross-sectional baseline survey. BMC Pediatrics 2010;10:68. The article is available at: http://hdl.handle.net/1956/4658Paper IV: Ndeezi G, Tumwine JK, Ndugwa CM, Bolann BJ, Tylleskär T. Multiple micronutrient supplementation improves vitamin B12 and folate concentrations of HIV-infected children in Uganda: a randomized controlled trial. Nutrition Journal 2011;10:56. The article is available at: http://hdl.handle.net/1956/5152