1. Objectives

To assess the safety and efficacy of micronutrient supplementation for reducing mortality and morbidity in children with HIV infection

2. How studies were identified

The following databases were searched in July 2011:

• CENTRAL (The Cochrane Library)
• EMBASE
• PUBMED

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials

3.2 Study participants

Children with confirmed HIV infection

3.3 Interventions

Micronutrient supplements compared with other micronutrient supplements, to placebo, or to no treatment. Supplements could include the following vitamins: A, D, E, C, B1, B2, niacin, B6, B12, K, folic acid, beta-carotene; or trace elements: zinc, selenium, magnesium, iron, iodine, copper, manganese, chromium, cobalt, molybdenum; or different combinations of these micronutrients

3.4 Primary outcomes

• Mortality
• Morbidity
• HIV-related hospitalizations

Secondary outcomes were indicators of HIV disease progression (viral load, T cell counts), anthropometric measures, and adverse outcomes

4. Main results

4.1 Included studies

Eleven trials involving 2412 children were included in this review

• Vitamin A: five trials with 1120 participants
• Vitamin D: one trial with 59 participants
• Zinc: two trials with 128 participants
• Multiple micronutrient supplements: three trials with 1105 participants

4.2 Study settings

• South Africa (6 trials), the United Republic of Tanzania, Uganda (2 trials), and the United States of America (2 trials)
• Study settings included hospitals, outpatient clinics and rural primary care clinics

4.3 Study settings

How the data were analysed
Micronutrient supplements were compared to no treatment, other supplements or placebo in separate analyses for each single micronutrient with data available for analysis (vitamin A, vitamin D, zinc), and also for multiple micronutrients. Random effects meta-analysis was used to estimate pooled risk ratios (RR) for dichotomous data and mean differences (MD) for continuous data, with corresponding 95% confidence intervals (CI). Statistical heterogeneity in meta-analyses was evaluated using the I² statistic

Results
Vitamin A supplementation in HIV-infected children
Mortality
Meta-analysis of three studies in 262 HIV-infected infants and children revealed a 45% reduction in the risk of all-cause mortality with vitamin A supplementation, which included periodic boluses of 50,000 IU to 200,000 IU (RR 0.55, 95% CI [0.31 to 0.82], p=0.0031). Periodic doses (100 000 IU to 200 000 IU) of vitamin A given to 58 HIV-infected Tanzanian children admitted to hospital with pneumonia reduced AIDS-related deaths by two-thirds (RR 0.32, 95% CI [0.10 to 0.99]).

Morbidity and other outcomes
In 181 HIV-infected Ugandan children supplemented with 200,000 IU of vitamin A quarterly, the likelihood of persistent cough was more than halved (odds ratio (OR) 0.47, 95% CI [0.23 to 0.96]), and the duration of ear discharge was reduced (p=0.03) in comparison to controls. In 118 South African children born to HIV-infected mothers, periodic vitamin A supplementation (50 000 IU to 100 000 IU) reduced the likelihood of all-cause morbidity by 31% (OR 0.69, 95% CI [0.48 to 0.99]) over 18 months follow-up. Among the 28 children born HIV-positive in this trial, episodes of diarrhoea were approximately halved (OR 0.51, 95% CI [0.27 to 0.99]). In a trial of 59 HIV-infected American children receiving influenza vaccine, 200 000 IU of vitamin A for two days decreased HIV viral load at two weeks follow-up in comparison to the placebo group (p=0.02), and in an identical regimen in 75 South African children, CD4 counts were raised at four weeks (p=0.03). In the trial including 58 HIV-infected Tanzanian children admitted to hospital with pneumonia, a non-statistically significant reduction in cough and rapid respiratory rate with vitamin A supplementation was reported (RR 0.54, 95% CI [0.24 to 1.20]). However, the risk of acute diarrhoea was increased with vitamin A supplementation (non-stunted children: RR 1.37, 95% CI [1.06 to 1.79]; stunted children: RR 1.84, 95% CI [1.16 2.90]). In the same trial at four months follow-up, treatment with vitamin A had improved linear growth in comparison to placebo by 2.8 cm (95% CI [1.00 to 4.60 cm]) among children <18 months of age, but no difference in the risk of wasting or stunting was found.

Vitamin D supplementation in HIV-infected children
Fifty-nine HIV-infected children and adolescents were administered 100,000 IU of vitamin D plus calcium or placebo bimonthly in an American trial, in which significant increases in serum 25-hydroxyvitamin D (p<0.0001) were observed in the supplemented group. No differences in HIV disease progression, as measured by CD4 counts (p=0.18) and viral load (p=0.66), were found between treatment groups.

Zinc supplementation in HIV-infected children
Daily zinc (10 mg) given to 96 HIV-infected South African children for six months had no significant effect on mortality (RR 0.31, 95% CI [0.07 to 1.42]), viral load (MD -0.10 log₁₀ HIV-1, 95% CI [-0.40 to 0.20]), or mean percentage of CD4 (MD 1.00%, 95% CI [-2.87 to 4.87]), but significantly reduced diarrhoeal morbidity (RR 0.51, 95% CI [0.34 to 0.76]; p=0.001). In another study including HIV-infected children (n=32) in rural South Africa, zinc supplementation with or without vitamin A and other micronutrients was related to a higher incidence of persistent and severe diarrhoea compared with vitamin A supplementation alone.

Multiple micronutrient supplementation in HIV-infected children
In a study of 847 children aged one to five years attending HIV clinics in Uganda, a supplement containing twice the recommended dietary allowance (RDA) of 14 micronutrients was compared with a standard-of-care supplement. No treatment effect was found on mortality (RR 0.88, 95% CI [0.52 to 1.49]), CD4 count (MD -36.00, 95% CI [-148.53 to 76.53]), or anthropometric outcomes. In a study of 106 four to 24 month-old HIV-infected South African children admitted to hospital for diarrhoea or pneumonia, multiple micronutrient supplementation at an RDA for a one-year old resulted in a reduced duration of hospital stay compared with placebo (MD -1.7 days, 95% CI [-3.39 to -0.01]). In a further study by the same group, six months of multiple micronutrient supplementation in 99 HIV-infected children previously admitted with pneumonia or diarrhoea improved appetite (MD 6.10 g food consumed per kg bodyweight per day, 95% CI [0.23 to 11.97]), and weight-for-age Z-score (WAZ) (MD 0.30 WAZ, 95% CI [0.04 to 0.56]), but had no effect on height-for-age or weight-for-height Z-scores.

5. Additional author observations*

While random sequence generation was judged to be at low risk of bias in most included trials, six of the 11 trials were judged to be at unclear risk of allocation concealment bias. Using GRADE criteria, evidence for the primary outcome mortality was rated as moderate quality for vitamin A trials, low quality for zinc, and moderate quality for multiple micronutrients. For the outcome morbidity, evidence from one zinc trial was rated as moderate, and for the outcome hospitalization, evidence from one multiple micronutrient trial was judged to be moderate quality. Evidence for viral load and CD4 count outcomes was rated as low for vitamin D, moderate for zinc, and high for multiple micronutrients. Evidence for anthropometric outcomes was judged to be low quality for vitamin A and high quality for multiple micronutrients.

While evidence of the benefit of micronutrient supplements in children with HIV is limited, the findings of this review support periodic vitamin A supplementation of HIV-infected children over six months of age in resource-limited settings, which is consistent with findings in HIV-uninfected children. Zinc supplements reduced diarrhoeal morbidity and had no adverse effects on disease progression among South African HIV-infected children, and thus children with HIV should receive the same treatment with zinc supplements for diarrhoea and severe acute malnutrition as HIV-uninfected children.

Further research into the effects of selenium, vitamin D and zinc on health outcomes in children with HIV infection is warranted. Future trials should include participants diverse with respect to stage of disease, use of antiretroviral therapy (ART), immune status, and nutritional status. However, it must be recognized that ART consistently reduces morbidity and mortality and improves the nutritional status of children infected with HIV/AIDS, and thus future research should not be to the detriment of this crucial intervention.