Micronutrient supplementation for children with HIV infection

  • Review
  • Intervention

Authors


Abstract

Background

Micronutrient deficiencies are widespread and compound the effects of HIV disease in children, especially in poor communities. Micronutrient supplements may be effective and safe in reducing the burden of HIV disease. This review is an update of an earlier Cochrane review of micronutrient supplementation in children and adults which found that vitamin A and zinc are beneficial and safe in children exposed to HIV and living with HIV infection (Irlam 2010).

Objectives

To assess whether micronutrient supplements are effective and safe in reducing mortality and morbidity in children with HIV infection.

Search methods

The CENTRAL, EMBASE, and PubMed databases were searched for randomised controlled trials of micronutrient supplements (vitamins, trace elements, and combinations of these) using the search methods of the Cochrane HIV/AIDS Group.

Selection criteria

Randomised controlled trials were selected that compared the effects of micronutrient supplements with other supplements, or placebo or no treatment on the primary outcomes of mortality, morbidity, and HIV-related hospitalisations. Indicators of HIV disease progession, anthropometric measures, and any adverse effects of supplementation were secondary outcomes.

Data collection and analysis

Two reviewers independently screened and selected trials for inclusion, assessed the risk of bias using standardised criteria, and extracted data. Review Manager 5.1 was used to calculate the risk ratio (RR) for dichotomous data and the weighted mean difference (WMD) for continuous data, and to perform random effects meta-analysis where appropriate.

Main results

We included three new studies in addition to the eight studies in the earlier version of the review (Irlam 2010). Eleven studies with a total of 2412 participants were therefore included: five trials of vitamin A, one trial of vitamin D, two trials of zinc, and three trials of multiple micronutrient supplements. All except one trial were conducted in African children.

Vitamin A halved all-cause mortality in a meta-analysis of three trials in African children, had inconsistent impacts on diarrhoeal and respiratory morbidity, and improved short-term growth in a Tanzanian trial. No significant adverse effects were reported.

A single small trial of vitamin D in North American adolescents and children demonstrated safety but no clinical benefits. Zinc supplements reduced diarrhoeal morbidity and had no adverse effects on disease progression in one small South African trial. Another trial in South African children with and without HIV infection did not show benefit from the the prophylactic use of zinc or multiple supplements versus vitamin A in the small subgroup of children with HIV infection.

Multiple micronutrient supplements at twice the RDA did not alter mortality, growth, or CD4 counts at 12 months in Ugandan children aged one to five years. Short-term supplementation until hospital discharge significantly reduced the duration of all hospital admissions in poorly nourished South African children, and supplementation for six months after discharge improved appetite and nutritional indicators.

Authors' conclusions

Vitamin A supplementation is beneficial and safe in children with HIV infection. Zinc is safe and appears to have similar benefits on diarrhoeal morbidity in children with HIV as in children without HIV infection. Multiple micronutrient supplements have some clinical benefit in poorly nourished children with HIV infection.

Further trials of single supplements (vitamin D, zinc, and selenium) are required to build the evidence base. The long-term effects and optimal composition and dosing of multiple micronutrient supplements require further investigation in children with diverse HIV disease status.

Résumé scientifique

Supplémentation en micronutriments pour les enfants infectés par le VIH

Contexte

Les carences en micronutriments sont courantes et aggravent les effets de la maladie liée au VIH chez les enfants, en particulier dans les milieux défavorisés. Les suppléments en micronutriments pourraient être efficaces et sûrs pour réduire le poids de la maladie causée par le VIH. Cette revue est une mise à jour d’une revue Cochrane précédente sur la supplémentation en micronutriments chez les enfants et les adultes, qui avait mis en évidence que la vitamine A et le zinc étaient bénéfiques et sûrs pour les enfants exposés au VIH et infectés par celui-ci (Irlam 2010).

Objectifs

Évaluer si les suppléments en micronutriments sont efficaces et sûrs pour la réduction de la mortalité et de la morbidité chez les enfants infectés par le VIH.

Stratégie de recherche documentaire

Nous avons consulté les bases de données CENTRAL, EMBASE et PubMed afin d’identifier des essais contrôlés randomisés de supplémentations en micronutriments (vitamines, oligo-éléments et leurs combinaisons), en utilisant les méthodes de recherche du groupe Cochrane sur le VIH/SIDA.

Critères de sélection

Nous avons sélectionné les essais contrôlés randomisés qui comparaient les effets des suppléments en micronutriments à d’autres suppléments, à un placebo ou à l’absence de traitement pour les critères de jugement principaux de mortalité, morbidité et hospitalisations liées au VIH. Les indicateurs de progression de la maladie liée au VIH, les mesures anthropométriques et les éventuels effets indésirables de la supplémentation était les critères de jugement secondaires.

Recueil et analyse des données

Deux évaluateurs ont examiné et sélectionné les essais à inclure, évalué le risque de biais à l’aide de critères standardisés et extrait les données de manière indépendante. Le programme Review Manager 5.1 a été utilisé pour calculer le risque relatif (RR) pour les données dichotomiques et la différence moyenne pondérée (DMP) pour les données continues et pour réaliser une méta-analyse à effets aléatoires lorsque cela était approprié.

Résultats principaux

Nous avons inclus trois nouvelles études en plus des huit études de la version précédente de la revue(Irlam 2010). Onze études, soit un total de 2412 participants, ont ainsi été incluses : cinq essais avec la vitamine A, un essai avec la vitamine D, deux essais avec le zinc, et trois essais de supplémentation avec plusieurs micronutriments. Tous les essais, sauf un, ont été réalisés sur des enfants africains.

La vitamine A a réduit de moitié la mortalité toutes causes confondues dans une méta-analyse de trois essais menés sur des enfants africains ; elle a donné des effets inconstants sur la morbidité respiratoire et diarrhéique, et a amélioré la croissance à court terme dans un essai mené en Tanzanie. Aucun effet indésirable significatif n’a été signalé.

Un seul essai de petite taille avec la vitamine D chez des adolescents et des enfants d’Amérique du Nord a démontré l’innocuité de cette supplémentation, mais aucun bénéfice clinique. Les suppléments de zinc ont réduit la morbidité diarrhéique, sans effets indésirables sur la progression de la maladie, dans un petit essai mené en Afrique du Sud. Un autre essai réalisé sur des enfants sud-africains infectés et non infectés par le VIH n’a pas montré de bénéfice à l’utilisation prophylactique de suppléments de zinc ou de suppléments multiples par rapport à la vitamine A dans le petit sous-groupe des enfants séropositifs.

Dans une étude réalisée en Ouganda, la supplémentation avec plusieurs micronutriments à deux fois les AJR n’a pas modifié la mortalité, la croissance ou les numérations de CD4 à 12 mois d’enfants âgés de un à cinq ans. Une supplémentation de courte durée, jusqu’à la sortie de l’hôpital, a significativement réduit la durée de l’ensemble des hospitalisations d’enfants sud-africains malnutris, et une la supplémentation pendant six mois après la sortie a apporté une amélioration de leur appétit et de leurs indicateurs nutritionnels.

Conclusions des auteurs

La supplémentation en vitamine A est bénéfique et sans danger chez les enfants infectés par le VIH. Le zinc est sans danger et semble avoir des effets bénéfiques similaires sur la morbidité diarrhéique chez les enfants infectés par le VIH que chez les enfants non infectés. La supplémentations avec plusieurs micronutriments apporter quelques bénéfices cliniques dans le cas des enfants séropositifs malnutris.

D’autres essais de suppléments simples (vitamine D, zinc et sélénium) sont nécessaires pour enrichir la base des preuves. Les effets à long terme ainsi que la composition et la posologie optimales des supplémentations en micronutriments multiples nécessitent des investigations supplémentaires chez les enfants à divers stades de l’infection et de la maladie causée par le VIH.

Plain language summary

Micronutrient supplementation for children with HIV infection

This review includes 11 trials that tested the effectiveness and safety of various micronutrient supplements in children with HIV infection in a diversity of settings. All except one trial were conducted in African children. The primary outcomes were mortality, morbidity, and HIV-related hospitalisations, and secondary outcomes were HIV disease progession, measures of growth, and adverse effects of supplementation.

The review found that vitamin A supplements are beneficial and safe, and halved mortality overall in an analysis of three trials in different African countries. Zinc appeared to be safe and reduced diarhoeal morbidity in one trial. Multiple micronutrient supplements reduced the duration of hospital admissions, and improved appetite and short-term growth in poorly nourished hospitalised children.

Further research is needed on single supplements other than vitamin A, and on the long-term effects, optimal composition and dosing of multiple supplements.

Résumé simplifié

Supplémentation en micronutriments pour les enfants infectés par le VIH

TCette revue inclut 11 essais portant sur l’efficacité et l’innocuité de différents suppléments en micronutriments chez les enfants infectés par le VIH, dans des contextes très divers. Tous les essais, sauf un, ont été réalisés sur des enfants africains. Les critères de jugement principaux étaient la mortalité, la morbidité et les hospitalisations liées au VIH ; les critères de jugement secondaires étaient la progression de la maladie liée au VIH, les mesures de la croissance et les effets indésirables de la supplémentation.

La revue a découvert que la supplémentation en vitamine A est bénéfique et sans risque et qu’elle a réduit de moitié la mortalité globale dans une analyse de trois essais dans différents pays d’Afrique. Le zinc s’est avéré sans risque et a permis une réduction de la morbidité de caractère diarrhéique dans un essai. Plusieurs supplémentations en micronutriments ont réduit la durée des hospitalisation et amélioré l’appétit et la croissance à court terme des enfants hospitalisés malnutris.

D’autres recherches sont nécessaires sur des suppléments simples autres que la vitamine A, ainsi que sur les effets à long terme, la composition et la posologie optimale des supplémentations multiples.

Notes de traduction

Traduit par: French Cochrane Centre 9th January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. Vitamin A for children with HIV infection
  1. 1 Number of events was low
    2 Number of participants was very low

Vitamin A for children with HIV infection
Patient or population: Children with HIV infection
Settings: South Africa, Tanzania, Uganda
Intervention: Vitamin A
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Vitamin A
All-cause mortality
Death reports
Study population RR 0.55
(0.37 to 0.82)
262
(3 studies)
⊕⊕⊕⊝
moderate 1
Coutsoudis 1995 (SA); Fawzi 1999 (Tanzania); Semba 2005 (Uganda)
381 per 1000 210 per 1000
(141 to 312)
Medium risk population
400 per 1000 220 per 1000
(148 to 328)
Child growth at 12 months - Wasting
Anthropometric measurements at monthly clinic visits
Follow-up: median 351 days
Study population RR 0.25
(0.06 to 1.05)
41
(1 study)
⊕⊕⊝⊝
low 2
Fawzi 1999 (Tanzania)
368 per 1000 92 per 1000
(22 to 386)
Medium risk population
368 per 1000 92 per 1000
(22 to 386)
Child growth at 12 months - Stunting
Anthropometric measurements at monthly clinic visits
Follow-up: median 351 days
Study population RR 0.67
(0.34 to 1.32)
29
(1 study)
⊕⊕⊝⊝
low 2
Fawzi 1999 (Tanzania)
688 per 1000 461 per 1000
(234 to 908)
Medium risk population
688 per 1000 461 per 1000
(234 to 908)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Vitamin D for children with HIV infection

Summary of findings 2. Vitamin D for children with HIV infection
  1. 1 Number of participants was very low

Vitamin D for children with HIV infection
Patient or population: Children with HIV infection
Settings: US hospital-based HIV treatment programmes
Intervention: Vitamin D
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Vitamin D
CD4 counts at 12 months
Follow-up: mean 12 months
The mean in the control group was 661 cells/mLThe mean in the intervention group was 115 higher
(74.26 lower to 304.26 higher)
 56
(1 study)
⊕⊕⊝⊝
low 1
Arpadi 2009
Viral load at 12 monthsThe mean in the control group was
2.5 RNA copies/mL
The mean in the intervention group was 0.1 lower
(0.63 lower to 0.43 higher)
 56
(1 study)
⊕⊕⊝⊝
low 1
Arpadi 2009<BR/>
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Zinc for children with HIV infection

Summary of findings 3. Zinc for children with HIV infection
  1. 1 Number of participants was low
    2 Number of events and participants was very low
    3 Number of events was low

Zinc for children with HIV infection
Patient or population: Children with HIV infection
Settings: South African hospital outpatient clinic
Intervention: Zinc
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Zinc
Viral load at 9 months
Follow-up: mean 9 months
The mean viral load at 9 months in the control groups was
5.5 RNA copies/mL

The mean Viral load at 9 months in the intervention groups was
0.1 lower

(0.4 lower to 0.2 higher)

 85
(1 study)
⊕⊕⊕⊝
moderate 1
Bobat 2005
Mortality at 9 months
Hospital records and verbal autopsies
Study population RR 0.31
(0.07 to 1.42)
96
(1 study)
⊕⊕⊝⊝
low 2
Bobat 2005
140 per 1000 43 per 1000
(10 to 199)
Medium risk population
140 per 1000 43 per 1000
(10 to 199)
CD4 % at 9 months

Follow-up: mean 9 months
The mean in the control group was 19 %

The mean in the intervention group was 1% higher

(2.87 lower to 4.87 higher)

 85
(1 study)
⊕⊕⊕⊝
moderate 1
Bobat 2005
All clinic visits - watery diarrhoea Study population RR 0.51
(0.34 to 0.76)
854
(1 study)
⊕⊕⊕⊝
moderate 3
Bobat 2005
145 per 1000 74 per 1000
(49 to 110)
Medium risk population
145 per 1000 74 per 1000
(49 to 110)
All clinic visits - URI Study population RR 0.75
(0.55 to 1.03)
854
(1 study)
⊕⊕⊕⊝
moderate 3
Bobat 2005
186 per 1000 140 per 1000
(102 to 192)
Medium risk population
186 per 1000 140 per 1000
(102 to 192)
All clinic visits - pneumonia Study population RR 0.89
(0.76 to 1.04)
854
(1 study)
⊕⊕⊕⊝
moderate 3
Bobat 2005
452 per 1000 402 per 1000
(344 to 470)
Medium risk population
452 per 1000 402 per 1000
(344 to 470)
All clinic visits - ear infection Study population RR 0.78
(0.55 to 1.11)
854
(1 study)
⊕⊕⊕⊝
moderate 3
Bobat 2005
145 per 1000 113 per 1000
(80 to 161)
Medium risk population
145 per 1000 113 per 1000
(80 to 161)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 Multiple micronutrients for children with HIV infection

Summary of findings 4. Multiple micronutrients for children with HIV infection
  1. 1 Number of events was low
    2 Number of participants was low

Multiple micronutrients for children with HIV infection
Patient or population: Children with HIV infection
Settings: Hospitals in South Africa and Uganda
Intervention: Multiple micronutrients
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Multiple micronutrients
Mortality at 12 months Study population RR 0.88
(0.52 to 1.49)
847
(1 study)
⊕⊕⊕⊝
moderate 1
Ndeezi 2010 (Uganda)
67 per 1000 59 per 1000 (35 to 100)
Medium risk population
67 per 1000 59 per 1000 (35 to 100)
CD4 countThe mean CD4 count in the control group was 1060 cells/mLThe mean CD4 count in the intervention group was 36 lower (148.53 lower to 76.53 higher) 399
(1 study)
⊕⊕⊕⊝
moderate 2
Ndeezi 2010 (Uganda); subgroup of survivors at one year
Duration of hospitalisation - All admissionsThe mean duration in the control group was 9 daysThe mean duration in the intervention group was 1.7 lower (3.39 to 0.01 lower) 106
(1 study)
⊕⊕⊕⊝
moderate 2
Mda 2010a (SA)
Change in appetite at 6 monthsThe mean change in the control group was
-1.4 g per kg bodyweight eaten
The mean change in the intervention group was 6.1 higher (0.23 to 11.97 higher) 99
(1 study)
⊕⊕⊕⊝
moderate 2
Mda 2010b (SA)
Anthropometric Z scores - WAZ at 6 monthsThe mean WAZ in the control group was 5.7The mean WAZ in the intervention group was 0.3 higher (0.04 to 0.56 higher) 99
(1 study)
⊕⊕⊕⊝
moderate 2
Mda 2010b (SA)
Anthropometric Z scores - HAZ at 6 monthsThe mean HAZ in the control group was 0.18The mean Anthropometric Z scores - HAZ at 6 months in the intervention groups was 0.04 lower (0.39 lower to 0.31 higher) 99
(1 study)
⊕⊕⊕⊝
moderate 2
Mda 2010b (SA)
Anthropometric Z scores - WHZ at 6 monthsThe mean WHZ in the control group was 0.08The mean Anthropometric Z scores - WHZ at 6 months in the intervention groups was 0.45 higher (0.02 lower to 0.92 higher) 99
(1 study)
⊕⊕⊕⊝
moderate 2
Mda 2010b (SA)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

The HIV/AIDS pandemic has severely affected sub-Saharan Africa, more than any other part of the world. With about a tenth of the world's population, the region is home to two thirds of all people living with HIV worldwide, an estimated 22.5 million in 2009 (UNAIDS 2010). About 2.3 million are children under 15 years of age, which is 92% of the global total.  An estimated 330 000 children in the region were newly infected with HIV In 2009, and approximately 230 000 died from AIDS (UNAIDS 2010). HIV-related deaths account for about 14% of all child deaths in southern Africa (Black 2010).

Malnutrition takes many forms, but in sub-Saharan Africa it most commonly refers to inadequate protein and energy intake (protein energy malnutrition or PEM), usually with associated multiple deficiencies of micronutrients, the essential vitamins and minerals required by the body in miniscule amounts (UNICEF 2009). Micronutrient malnutrition can manifest in conditions such as fatigue, anaemia (iron deficiency), reduced learning ability (mainly due to iron and iodine deficiency), goitre (iodine deficiency), reduced immunity, and night blindness (severe vitamin A deficiency) (UNICEF 2009). Micronutrient deficiencies are common in poor communities with inadequate diets and children with HIV infection in such settings are at particularly high risk as a consequence of reduced nutrient intake and excessive losses due to opportunistic and parasitic infections, diarrhoea, and malabsorption (Micronutrient Initiative 2009). Observational studies suggest that both PEM and micronutrient deficiencies hasten the progression of HIV infection, and that HIV worsens malnutrition; HIV infection and malnutrition therefore form a "vicious cycle" of immune dysfunction, infectious disease, and malnutrition (Piwoz 2000).

Micronutrient supplements are either single or multiple formulations of vitamins and trace elements that have multiple functions, including immune regulation and facilitating utilisation of macronutrients (carbohydrates, fats, and proteins) for energy and growth. Widespread supplementation may therefore lessen the effects of concurrent micronutrient deficiency and help to reduce the morbidity and mortality due to HIV, particularly in resource-poor countries (Micronutrient Initiative 2009).

Why it is important to do this review

Research into micronutrient supplementation is ongoing, and an update based on recent, quality-appraised research is therefore required to build a sound evidence base for policy and practice.

A previous Cochrane review of micronutrient supplementation in children and adults with HIV infection based on a January 2010 search of the literature (Irlam 2010) found that vitamin A and zinc are beneficial and safe in children exposed to HIV and living with HIV infection. The review included 8 trials in children out of a total of 30 studies found. The review has since been split into separate updated reviews for pregnant and lactating women, children and adolescents, and adults with HIV infection. This review should therefore be read with the other reviews for a complete picture of the evidence base for micronutrient supplementation in those with HIV infection.

Objectives

To assess whether micronutrient supplements are effective and safe in reducing mortality and morbidity in children with HIV infection.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCTs) of micronutrient supplements compared with other supplements, placebo, or no treatment.

Types of participants

Children with confirmed HIV infection (as reported in the trials) were included.

Types of interventions

Micronutrient supplements include vitamins (A, D, E, C, B1, B2, niacin, B6, B12, K, folate, beta-carotene), trace elements (zinc, selenium, magnesium, iron, iodine, copper, manganese, chromium, cobalt, molybdenum), and combinations of the above only.

Types of outcome measures

Primary outcomes

The primary outcomes, as measured in the studies, were:

  • mortality,

  • morbidity,

  • HIV-related hospitalisations.

Secondary outcomes

The secondary outcomes considered were:

  • indicators of HIV disease progression (viral load, T cell counts)

  • anthropometric measures

All adverse effects of supplementation were also considered.

Search methods for identification of studies

The CENTRAL, EMBASE, and PubMed databases were searched in July 2011 using the search methods of the Cochrane HIV/AIDS Group. The full search strategies are presented in Appendices 1 to 7.

Data collection and analysis

Selection of studies

Two authors (JI and NS) independently screened the search records, assessed them based on title or full-text, and selected the eligible studies for inclusion in the review.

Data extraction and management

Data were independently extracted from the included studies by JI and NS and entered into the Review Manager 5.1 software.

Assessment of risk of bias in included studies

The risk of bias in each included study was assessed independently by JI and NS as high, low, or unclear, as described in the Risk of Bias (ROB) tables.

Measures of treatment effect

We used Review Manager 5.1 to calculate the risk ratio (RR) for dichotomous data, and the weighted mean difference (WMD) for continuous data, with 95% confidence intervals and we report these results below. Where this was not possible due to missing primary data, we report only the results as presented in the published studies. We used GradePro software (GradePro 2008) to produce Summary of Findings tables.

Dealing with missing data

Where data was missing or unclear, authors were contacted where possible. Back calculations were performed of percentages without denominators.

Assessment of heterogeneity

Studies were assessed for clinical heterogeneity by examining variability in the participants, interventions and outcomes. Statistical heterogeneity was assessed visually and by means of the chi-squared test for heterogeneity. Inconsistency across the studies in the meta-analysis was quantified by means of the I-squared statistic.

Data synthesis

One random effects meta-analysis of mortality in three vitamin A trials was performed by JI and checked by NS.

Results

Description of studies

Results of the search

The PRISMA flow diagram (Figure 1) summarises the results of the search for 2011. We identified three new studies (Mda 2010a; Mda 2010b; Ndeezi 2010) and two new papers analysing the outcomes from a study (Luabeya 2007) included in the previous version of the review (Irlam 2010). Eleven trials were therefore included in this review; three new studies in addition to the eight trials reviewed previously (Irlam 2010).

Figure 1.

Results of search of PubMed, EMBASE, and CENTRAL from Jan. 2010 to July 2011 (RCTs in child populations only)

Included studies

A total of eleven trials of 2412 child participants were included:

Details are reported below in the table: Characteristics of included studies

Excluded studies

Three papers from two potentially eligible studies (Chatterjee 2010; CIGNIS 2010) were excluded for the reasons given in the table: Characteristics of excluded studies.

Risk of bias in included studies

The Risk of Bias (ROB) tables motivate the authors' assessments on the risk of bias in each study (high, low, or unclear). Figure 2 and Figure 3 present a summary of the ROB assessments.

Figure 2.

Risk of bias summary: review of authors' judgements about risk of bias in each included study

Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

All trials except one (Hussey 1996) adequately described methods of randomisation. Six trials reported adequate concealment of allocation; the risk of selection bias was unclear in the other five trials due to inadequate description of allocation concealment.

Blinding

Blinding of participants, treatment providers and outcome assessors was judged adequate in all studies and therefore the risk of performance and detection bias is low.

Incomplete outcome data

Six trials were assessed to have a low risk of attrition bias. Attrition bias was judged high in one vitamin A trial due to significant losses to follow up that were insufficiently explained (Coutsoudis 1995). Two multiple micronutrient trials were assessed to have a high risk of attrition bias; Ugandan children lost to follow up (14.6% of the total) were more likely to be ill (underweight and CRP-positive) than those who remained in the trial (Ndeezi 2010), and there was a high drop out (29%) in the South African trial examining appetite (Mda 2010b). Insufficient information on losses to follow up in two trials motivated ratings of unclear risk of attrition bias (Fawzi 1999; Hussey 1996).

Selective reporting

The study protocol is available for three studies and all pre-specified outcomes of interest are reported on (Arpadi 2009; Luabeya 2007; Ndeezi 2010). Insufficient information was provided to permit judgment of bias due to selective reporting of outcomes in the other studies.

Other potential sources of bias

Six trials were judged to be free of other potential sources of bias. The risk of bias was assessed unclear for the remainder, as four studies did not declare on potential conflicts of interest (Coutsoudis 1995; Fawzi 1999; Hanekom 2000; Hussey 1996) and one (Luabeya 2007) experienced a delay in shipment which prevented 243 children from receiving their supplements for eleven weeks.

Effects of interventions

See: Summary of findings for the main comparison Vitamin A for children with HIV infection; Summary of findings 2 Vitamin D for children with HIV infection; Summary of findings 3 Zinc for children with HIV infection; Summary of findings 4 Multiple micronutrients for children with HIV infection

Vitamin A

In Ugandan children (n=181), quarterly vitamin A supplementation (60mg RE or 200 000 IU) from 15 to 36 months reduced all-cause mortality by 46% (RR = 0.54; 95% CI: 0.30-0.98 after adjusting for baseline weight-for-height Z score in Cox proportional hazards analysis) after follow-up for a median of 17.8 months, a shorter period than planned due to early stopping of the trial (Semba 2005). We calculated a Mantel-Haenszel RR of 0.63 [0.38, 1.04] using the random effects analysis model in Review Manager in the absence of primary data for the adjusted effect (Analysis 1.1). A number of morbidity effects were reported in the paper without primary data for our own calculations. These included a halving of persistent cough (OR = 0.47; 95% CI: 0.23-0.96) and chronic diarrhea (OR = 0.48; 95% CI: 0.19-1.18), and reduced duration of ear discharge (p=0.03).There was no significant effect on modified point prevalences of fever, ear discharge, bloody stools, or hospitalizations per child-month of follow-up.

In a study of Tanzanian children (n=687) admitted with pneumonia, the authors reported that periodic doses (100 000 IU to infants; 200 000 IU to 1-5 year olds) for 24 months halved all-cause mortality (RR = 0.51; 95% CI: 0.29-0.90) and significantly reduced the risk of severe watery diarrhoea (adjusted OR = 0.56; 95% CI: 0.32-0.99) (Fawzi 1999). In a subgroup of 58 children with HIV infection, it was reported that all-cause mortality was reduced by 63% (RR = 0.38; 95% CI: 0.17-0.84) and AIDS-related deaths by two-thirds (RR = 0.32; 95% CI: 0.1-0.99). We included the study data for all-cause mortality in our Review Manager analysis (Analysis 1.1).

Periodic vitamin A supplementation (50 000 IU at 1 and 3 months; 100 000 IU quarterly thereafter) of all children born to 118 South African women with HIV infection reportedly reduced all-cause morbidity by a third (OR = 0.69; 95% CI: 0.48-0.99) during 18 months of follow-up (Coutsoudis 1995). The supplements were well tolerated. In a subgroup of 28 children with HIV infection at birth, no effect on mortality was reported although episodes of diarrhoea were halved (OR= 0.51; 95% CI: 0.27-0.99). We calculated in Review Manager a RR of 0.58 [0.18, 1.86].

A meta-analysis of the effect of vitamin A on mortality in 267 HIV+ children, based on the three trials above, showed an overall approximate halving of mortality overall (RR = 0.55 [0.37, 0.82]) (Analysis 1.1). Statistical heterogeneity across the studies was very low as evidenced by inspection of the forest plot (Figure 4) and an I-squared statistic of 0%.

Figure 4.

Meta-analysis of mortality in Vitamin A trials

In the Tanzanian study subgroup of HIV-infected children, the authors reported a non-significant reduction in cough and rapid respiratory rate (RR = 0.54; 95% CI: 0.24-1.20) and a small risk of acute diarrhoea in normally nourished (RR = 1.37; 95% CI: 1.06-1.79) and in growth-stunted children hospitalised with pneumonia (RR = 1.84; 95% CI: 1.16-2.90) (Fawzi 1999). A mean increase in height of 2.8 cm (95% CI: 1.0-4.6) four months after the first two doses were given was also reported in HIV-infected children under 18 months of age. We calculated a non-significant reduction in the risk of wasting and stunting of child growth at 12 months (Analysis 1.2).

A small trial (n=59) of 200 000 IU of vitamin A for two days in North American children receiving influenza vaccine reportedly decreased HIV viral load at 14 days from the time of vaccination, compared to an increase in the placebo group (p = 0.02) (Hanekom 2000). An identical regimen was reported to raise CD4 counts at four weeks in 75 South African children (p = 0.03) (Hussey 1996).

No or minor adverse effects of vitamin A were reported in the above studies.

Vitamin D

A small trial (n=59) of vitamin D (100 000 IU cholecalciferol bimonthly) and calcium versus double placebo to evaluate the effect on monthly serum vitamin D concentrations over 12 months in North American children and adolescents with HIV infection, reported significant increases in vitamin D levels (p< 0.0001) in the supplemented group, and no adverse effects on HIV disease progression, as measured by CD4 counts (p=0.18) and viral load (p=0.66) (Arpadi 2009). We calculated the mean differences in CD4 counts (Analysis 2.1) and viral load with Review Manager (Analysis 2.2) .

Zinc

A placebo-controlled equivalence trial to determine the safety of zinc supplementation in HIV- infected children was conducted in 96 South African children aged 6 to 60 months (Bobat 2005).  A daily dose of 10mg zinc sulphate for up to 6 months did not increase the primary outcome of viral load at any timepoint; the reported mean difference at 9 months was 0.05 (-0.24 to 0.35) log10 HIV-1 viral load in unadjusted analysis and no significant difference was reported in the adjusted analysis either. Our analysis found a mean difference of 0.10 [-0.40, 0.20]) (Analysis 3.1). We calculated no difference in mortality between the zinc and placebo groups (Analysis 3.2), nor in the mean percentage of CD4 (Analysis 3.3). There was a significant reduction in diarrhoeal morbidity, as measured by the proportion of all clinic visits (scheduled and illness) where a diagnosis of watery diarrhoea was made (RR = 0.51 [0.34, 0.76]) (Analysis 3.4).

Diarrhoeal and respiratory morbidity in 341 HIV-uninfected and 32 rural South African children with HIV infection, aged 4 to 6 months, was measured by maternal report during home visits (pneumonia also confirmed by measurement of rapid respiratory rate) in a trial that compared supplementation for prophylaxis for a median of 14.9 months with 10 mg zinc plus vitamin A, or with zinc plus vitamin A and multiple supplements, to vitamin A alone (Luabeya 2007). There were no differences reported between the treatment arms in prevalent days or incidence density of diarrhoea among the children with or without HIV infection. Diarrhoeal morbidity (episodes per year) in all stunted children was reportedly reduced with zinc suppplements, and with zinc and multiple micronutrients (p=0.024). Children with HIV had a higher incidence of diarrhoea than uninfected children, and among the 28 HIV-infected children included in the analysis, those receiving zinc (n=9) or multiple supplements (n=11) were reported to have a higher incidence of persistent and severe diarrhoea than those supplemented with vitamin A alone (Analysis 3.5). A second paper on this study published in 2010 reported on the effect of supplementation on growth (longitudinal length-for-age Z-scores) and exploratory analyses of the effect on anemia. The authors reported that multiple micronutrients that included vitamin A and zinc were beneficial in improving growth among all children with stunting. The small number of HIV-infected children (n=32), and the substantial effect of missing data in this sub-group, precluded them from making any inferences for HIV-infected children.

Multiple supplements

A supplement containing twice the RDA of 14 micronutrients was compared to a "standard-of-care" supplement in 847 children aged one to five years attending HIV clinics in Uganda (Ndeezi 2010). It was well tolerated, but did not significantly alter mortality (RR = 0.88 [0.52, 1.49] (Analysis 4.1) or CD4 counts at 12 months (Analysis 4.2). The authors reported no effect on anthropometry, which we were not able to calculate ourselves due to missing denominator data for these outcomes.

Two trials by the same study group in related populations of South African children examined the effect of a similar composition of multiple micronutrient supplements with RDAs recommended for one-year old children compared to placebo. The one trial recruited children aged 4 to 24 months with HIV infection who had been admitted with diarrhoea or pneumonia to an academic hospital (Mda 2010a). Short-term supplementation until hospital discharge significantly reduced the duration of all hospital admissions by 1.7 days [-3.39, -0.01], from 9 days (SD=4.9) to 7.3 (SD=3.9) days, but there was no effect on specific admissions for diarrhoea or pneumonia (Analysis 4.3).

The second trial examined the effect of 6 months of supplementation on the appetite of 140 poorly nourished children previously admitted with diarrhoea or pneumonia to the paediatric wards and followed up at the paediatric OPD (Mda 2010b). We assumed appetite as the primary outcome, although it was not specifically stated in the published study, and we were unable to obtain the study protocol from the authors. Appetite improved in the supplemented group, as measured by a greater change in the amount eaten (4.7 +/- 14.7 g/ kg bodyweight vs. 1.4 +/- 15.1 g/kg in the placebo group) (Analysis 4.4). The weight-for-age Z scores (WAZ) and weight-for-height Z scores (WHZ)), which are considered to be standard nutritional indicators of underweight and wasting, were reported to have improved significantly from enrolment until 6 months, compared to the placebo group (p<0.05). We calculated the mean differences for each of the indicators and found significant differences for WAZ and near significant differences for WHZ (Analysis 4.5).The authors reported that serum concentrations of zinc and ferritin improved significantly within the supplement group from enrolment to six months, and in the case of ferritin, the change was significantly greater than in the supplement group (p<0.05). They reported no significant changes in the appetite hormone levels, either within or between groups.

GRADE assessments

Vitamin A

The level of evidence was rated as moderate for the critical outcome of all-cause mortality, reported by three small African trials. The quality of the evidence was downgraded for imprecision of results as the overall number of events was low (27 in the vitamin A vs. 51 in the control groups). The important anthropometric outcomes (wasting and stunting at 12 months) were reported in only one small study and the evidence was therefore downgraded to low quality due to high imprecision (Summary of findings for the main comparison).

Vitamin D 

Both outcomes of CD4 counts and viral load at 12 months were reported in only one small trial on 56 participants and the quality of evidence was therefore rated low due to very serious imprecision of the results (Summary of findings 2).

Zinc

The quality of evidence was rated as low for the critical outcome of mortality reported by one trial, as the number of deaths (n=9) and participants was very low and imprecision was consequently high. The important morbidity outcomes (scheduled and illness visits, all-cause and cause-specific) were rated as moderate quality as the number of events was higher but still based on only one trial. The evidence for the viral load and CD4% at 9 months were from the same trial and were also rated of moderate quality (Summary of findings 3).

Multiple micronutrients

The evidence for multiple micronutrients was derived from three trials, one large Ugandan trial (Ndeezi 2010; n=847) and two small (n<150) South Afircan trials (Mda 2010a; Mda 2010b). The critical outcome of mortality from the Ugandan trial was downgraded to moderate quality due to the small number of deaths (n=53 in both groups). The important anthropometric outcomes in the same trial (Z scores at 12 months) and CD4 counts, were rated high quality. The important outcomes of hospitalisation and change in appetite in the South African trials were rated of moderate quality due to the lower number of participants in each (Summary of findings 4).

Discussion

Summary of main results

Vitamin A

Vitamin A is standard care in children without HIV infection who present with persistent diarrhoea and severe acute malnutrition (UNICEF 2009; UNICEF 2007; WHO/UNICEF 2004). Six monthly regular supplements of vitamin A are also recommended for all children between 6 months and five years to support growth and development and to reduce all-cause mortality, irrespective of HIV status (WHO 2009).

There is high quality evidence from a few African trials of clinical benefits of vitamin A on mortality in children with HIV infection, and moderate evidence for morbidity and growth benefits (Fawzi 1999; Coutsoudis 1995; Semba 2005). A meta-analysis of these three trials (Figure 4) shows that vitamin A halved all-cause mortality, although the children with HIV infection were small subgroups in two of the trials. There is inconsistent evidence on the effects of vitamin A on morbidity, with some benefits and adverse effects on diarrhoeal and respiratory morbidity being reported, which may be due to the small sample sizes. The clinical benefits may be consequent to an improvement in immune function and to the rehabilitation of mucosal integrity (Filteau 2001), leading to a reduction in the severity and incidence of diarrhoeal infection, and an improvement in short-term growth.

Vitamin D

Vitamin D supplementation in individuals with HIV infection has not been substantially studied, but evidence from the study reviewed here indicates that it does not have an adverse effect on HIV disease progression (Arpadi 2009). Further research is recommended to determine what level of supplementation with vitamin D, together with daily calcium supplementation, will lead to clinically significant gains in bone mass accrual in children and adolescents with HIV, as well as other potential benefits.

Zinc

In children without HIV infection, zinc supplementation has been shown to reduce the risk and severity of diarrhoea and pneumonia in several studies (Aggarwal 2007; Baqui 2002; Bhandari 2002; Bhutta 1999; Bhutta 2000; Strand 2002; Zinc Investigators Collaborative Group 2000). The reported benefits on diarrhoeal morbidity in South African children with HIV infection (Bobat 2005) are consistent with the evidence from these earlier studies. The primary finding in the South African trial that HIV-1 viral load was not raised, suggests that zinc supplementation may be considered safe as a specific therapy in children with HIV infection who present with diarrhoea. A subsequent study in rural South African children, including 32 with HIV infection (Luabeya 2007), did not provide support for the prophylactic use of zinc or multiple supplements to reduce diarrhoeal or respiratory morbidity, although it did show benefit in stunted children. Further research is therefore needed in larger and diverse populations of children with HIV infection that represent the range of disease severity and ages.

Multiple supplements

Short-term multi-micronutrient supplementation with RDAs recommended for a one-year old child significantly reduced the duration of pneumonia or diarrhoea in infants and children with HIV infection who were not yet receiving antiretroviral therapy and who remained alive during hospitalization with diarrhoea or pneumonia (Mda 2010a). Supplementation for six months after discharge improved the appetite of the previously hospitalised children (Mda 2010b). Twice the RDAs of a similar supplement in Ugandan children with HIV infection did not significantly alter mortality, growth, or CD4 counts at 12 months (Ndeezi 2010).

Quality of the evidence

The quality of the evidence reviewed to date has some important limitations (Figure 3). Methods of random sequence generation and blinding were judged to be at low risk of bias in the majority of studies, but insufficient information about allocation concealment in six of the studies mean that the risk of bias is unclear. Six of the eleven studies were judged to be of low risk of bias with respect to attrition (incomplete outcome data) or other bias. The majority of studies provided insufficient information to assess the risk of bias due to selective outcome reporting. The quality of evidence with respect to each of the interventions is presented below and summarised by study in Figure 2.

Vitamin A
Five placebo-controlled trials were included (Coutsoudis 1995; Fawzi 1999; Hanekom 2000; Hussey 1996; Semba 2005), four with adequately described methods of randomisation and two with allocation concealment clearly described. All were adequately blinded studies to minimise performance and detection bias. Two trials were assessed to have a low risk of attrition bias (Hanekom 2000; Semba 2005), and one a high risk (Coutsoudis 1995). The risk of reporting bias due to selective outcome reporting was unclear in all trials. One trial was assessed to have a high risk of other bias due to early termination (Semba 2005).

Vitamin D

The one trial of vitaimin D (Arpadi 2009) was assessed at low risk of bias on all criteria.

Zinc

The two trials of zinc were judged to be at low risk of bias on all criteria with the exception of selective reporting (unclear) in the Bobat trial (Bobat 2005) and an unclear risk of bias due to an interruption in the supply of supplements in the other trial (Luabeya 2007).

Multiple supplements

The risk of bias in two South African trials (Mda 2010a, Mda 2010b) was judged unclear for allocation concealment and selective reporting. There was a high risk of attrition bias in the trial examining the effect on the appetite of children (Mda 2010b) consequent to a high overall dropout (29%) due to death, taking ARVs, relocation, or other reasons. Differences in deaths and relocations were higher in the supplemented group, but did not reach statistical significance. The risk of attrition bias was judged high in the Ugandan trial of mortality by 12 months (Ndeezi 2010), as those lost to follow up were more likely to be ill (underweight and CRP-positive) than those who completed the study.

Potential biases in the review process

Biases in the review process were minimised by performing a comprehensive and systematic search of the literature, and by two authors independently selecting the studies, extracting the data, and assessing the risk of bias in all studies using the standard RoB tool.

For the purpose of the review, the HIV status of children determined by each study was accepted as sufficient. Laboratory methods have improved in in recent years and become more sensitive and specific, thereby reducing the likelihood of false positive or false negative attribution of HIV status. However, further analysis or validation of children's status was beyond the scope of this review. 

The effect of micronutrient supplements on HIV exposed but not infected infants and children was outside the scope of this review and was not formally evaluated. The few studies that did include these children in their reports (Luabeya 2007) did not suggest a differential response to micronutrient interventions of HIV exposed but uninfected children compared with children born to HIV-uninfected mothers.

Agreements and disagreements with other studies or reviews

In July 2007 the Academy of Science of South Africa (ASSAf) published HIV/AIDS, TB and Nutrition, a scientific inquiry into the nutritional influences on human immunity with special reference to HIV infection and active TB in South Africa (ASSaf 2007). The inquiry found a dearth of reliable and informative studies, and recommended improved nutritional policy and practice informed by high-quality research. It was recognised that nutritional interventions should be part of a comprehensive, integrated approach to HIV and TB, but are no substitute for anti-retroviral drugs in preventing transmission; that nutritional care should focus on diversified diets of available, affordable and culturally acceptable foods, as well as safe levels of macro- and micronutrients; and that priority should be accorded to pregnant and lactating women with HIV infection and their babies.

Key recommendations of the ASSAf Scientific Panel with respect to micronutrient supplementation included:

  • promoting adequate dietary intake of micronutrients at recommended Individual Nutrient Intake levels at 2 standard deviations above mean population intake (INL98)

  • providing elevated levels of micronutrients (at least 1-2 INL98s) through food fortification or supplements in settings where micronutrient deficiencies are endemic,

  • offering multivitamin supplementation at INL98 levels to women with HIV infection

  • better definition of the indicators of vitamin and mineral micronutrient levels in individuals and populations

A 2009 review (Investing in the Future: A United Call to Action on Vitamin and Mineral Deficiencies) prepared by the Micronutrient Initiative (an international not-for-profit organization) in partnership with UNICEF, the World Health Organisation (WHO) and others (Micronutrient Initiative 2009), reported that the 2008 Copenhagen Consensus, a group of world-renowned economists, ranked micronutrient supplements (high-dose vitamin A, and zinc supplements for children with diarrhoea) as the top development priority out of more than 40 interventions considered (Horton 2008). The benefit to cost ratio, as well as the feasibility and sustainability of the interventions, were considered. Vitamin A supplementation every 4 to 6 months for children from age 6 months to 5 years has been shown to reduce all-cause mortality by 23% (Baeten 1993), and 10 to14 days of therapeutic zinc supplementation for diarrhoea up to the age of 5 can halve diarrhoeal mortality (Baqui 2002).

Large scale vitamin A supplementation began in the late 1990’s with mass polio immunization campaigns following WHO recommendations, and coverage has been adopted as an indicator of progress toward the Millennium Development Goal (MDG) of reducing child mortality by 2015 (Wagstaff 2004). There has been less progress in achieving universal post-partum vitamin A supplementation for breastfeeding mothers, which is recommended to boost the immune system of infants in the first months of life (UNICEF 2007). A review of recent research has suggested that neonatal mortality can be reduced by supplementing newborns within the first few days of life (Haider 2008), but there is as yet no international WHO recommendation on this. Low-dose supplementation of pregnant women with xerophthalmia, which may be due to systemic vitamin A deficiency, has also been recommended but not widely adopted (Horton 2008).

HIgh quality evidence about the benefits of therapeutic zinc together with low osmolarity oral rehydration salts for reducing childhood diarrhoea (Baqui 2002; Bhutta 2000; Robberstad 2004; Zinc Investigators Collaborative Group 2000) resulted in a joint WHO/ UNICEF recommendation in 2004 of 10 to 14 days of therapeutic zinc for children under 5 years of age with diarrhoea (WHO/UNICEF 2004).

The WHO/UNICEF report concludes with a number of priority interventions by national governments, industry and international organizations for achieving the MDG on child mortality by 2015. These interventions include:

  • six monthly vitamin A supplementation for children aged between 6 months and five years, to achieve at least 80% coverage on a recurrent basis

  • zinc supplementation as part of national diarrhoea management policy

  • multiple micronutrient supplements for children in non-malaria endemic regions

  • improved iron intake by young children in malarial areas

  • iron and folic acid supplementation for all women of childbearing age, with special focus on pregnant women

  • testing the feasibility of providing women with multiple vitamin and mineral supplements

Although the international reviews above primarily refer to HIV-uninfected populations, their recommendations also apply to populations with HIV infection unless there is evidence of adverse effects.

Authors' conclusions

Implications for practice

The evidence base for the specific effect of micronutrient supplements in children with HIV is limited, but is sufficient to make some recommendations for practice. 

  • Periodic vitamin A supplementation of children with HIV infection over six months of age in resource-limited settings is supported by three African trials in this review, which is consistent with evidence of benefit that supports supplementation of HIV-uninfected children.

  • Zinc supplements reduced diarrhoeal morbidity and had no adverse effects on disease progression in a single safety trial in South African children. Children with HIV should receive zinc supplements in the management of diarrhoea and severe acute malnutrition in the same way as HIV-uninfected children with the same conditions.

In keeping with WHO recommendations (WHO 2003), everything possible should be done to promote and support adequate dietary intake of micronutrients at INL98 levels, while recognising that this may not be sufficient to correct specific micronutrient deficiencies in all individuals with HIV infection.

In situations where micronutrient deficiencies are endemic, these nutrients should be provided through food fortification or micronutrient supplements where available that contain at least one to two INL98s. Importantly however, micronutrient deficiencies and immune dysfunction in children with HIV infection may only be restored when there is effective suppression of viral replication of HIV.

Implications for research

In view of the potential significance of preliminary results in populations with HIV infection or the proven benefits in populations without HIV, some specific micronutrients warrant particular investigation, namely selenium, vitamin D and zinc. The optimal composition and dosage of multiple supplements requires investigation, as these can vary considerably among commercial supplements and therefore may not have equivalent effects. Research participants should be diverse with respect to stage of disease, use of antiretroviral therapy (ART), immune status, and nutritional status.

Future research should also determine the effect of lifelong ART on micronutrient concentrations, independent of inflammatory markers, and whether micronutrient supplements affect HIV-related outcomes in children receiving ART.

Research into identifying optimal, cost-effective nutritional interventions and operational strategies is required, without detracting from the use of ART, which has consistently been shown to reduce morbidity and mortality and to improve the nutritional status of children with HIV.

Acknowledgements

We are grateful to the South African Cochrane Centre, the editorial base of the HIV/AIDS Cochrane Review Group and the Cochrane HIV/AIDS Review Mentoring Programme for assistance and support in preparing this review.

Ms Claudia Naidu (CN), a research assistant to Mr Irlam, was supported by funding from the SA Cochrane Centre for preparing this update.

Data and analyses

Download statistical data

Comparison 1. Vitamin A
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All-cause mortality3262Risk Ratio (M-H, Random, 95% CI)0.55 [0.37, 0.82]
2 Child growth at 12 months1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Wasting141Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.06, 1.05]
2.2 Stunting129Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.34, 1.32]
Analysis 1.1.

Comparison 1 Vitamin A, Outcome 1 All-cause mortality.

Analysis 1.2.

Comparison 1 Vitamin A, Outcome 2 Child growth at 12 months.

Comparison 2. Vitamin D
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 CD4 counts at 12 months156Mean Difference (IV, Random, 95% CI)115.0 [-74.26, 304.26]
2 Viral load at 12 months156Mean Difference (IV, Random, 95% CI)-0.10 [-0.63, 0.43]
Analysis 2.1.

Comparison 2 Vitamin D, Outcome 1 CD4 counts at 12 months.

Analysis 2.2.

Comparison 2 Vitamin D, Outcome 2 Viral load at 12 months.

Comparison 3. Zinc
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Viral load at 9 months185Mean Difference (IV, Random, 95% CI)-0.10 [-0.40, 0.20]
2 Mortality at 9 months196Risk Ratio (M-H, Random, 95% CI)0.31 [0.07, 1.42]
3 CD4 % at 9 months185Mean Difference (IV, Random, 95% CI)1.0 [-2.87, 4.87]
4 Clinic visits1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4.1 Scheduled visits; watery diarrhoea1730Risk Ratio (M-H, Random, 95% CI)0.63 [0.39, 1.03]
4.2 Scheduled visits; pneumonia1730Risk Ratio (M-H, Random, 95% CI)0.85 [0.57, 1.27]
4.3 Scheduled visits; URI1730Risk Ratio (M-H, Random, 95% CI)0.88 [0.74, 1.04]
4.4 Scheduled visits; ear infection1730Risk Ratio (M-H, Random, 95% CI)0.77 [0.52, 1.14]
4.5 All visits; watery diarrhoea1854Risk Ratio (M-H, Random, 95% CI)0.51 [0.34, 0.76]
4.6 All visits; URI1854Risk Ratio (M-H, Random, 95% CI)0.75 [0.55, 1.03]
4.7 All visits; pneumonia1854Risk Ratio (M-H, Random, 95% CI)0.89 [0.76, 1.04]
4.8 All visits; ear infection1854Risk Ratio (M-H, Random, 95% CI)0.78 [0.55, 1.11]
5 Diarrhoea incidence in HIV+ children with at least one follow-up visit  Other dataNo numeric data
5.1 Any diarrhoea  Other dataNo numeric data
5.2 Persistent diarrhoea  Other dataNo numeric data
5.3 Severe diarrhoea  Other dataNo numeric data
Analysis 3.1.

Comparison 3 Zinc, Outcome 1 Viral load at 9 months.

Analysis 3.2.

Comparison 3 Zinc, Outcome 2 Mortality at 9 months.

Analysis 3.3.

Comparison 3 Zinc, Outcome 3 CD4 % at 9 months.

Analysis 3.4.

Comparison 3 Zinc, Outcome 4 Clinic visits.

Analysis 3.5.

Comparison 3 Zinc, Outcome 5 Diarrhoea incidence in HIV+ children with at least one follow-up visit.

Diarrhoea incidence in HIV+ children with at least one follow-up visit
StudyVitamin A (n=8)Vitamin A + Zinc (n=9)Vitamin A + Zinc + multiple supplements (n=11)
Any diarrhoea
Luabeya 20074.16 [2.40; 7.25]5.15 [3.05, 8.71]3.93 [2.36, 6.56]
Persistent diarrhoea
Luabeya 20070.050.27 (0.10, 0.71)0.39 (0.19, 0.78)
Severe diarrhoea
Luabeya 20070.050.27 (0.11, 0.66)0.39 (0.21, 0.74)
Comparison 4. Multiple micronutrients
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality at 12 months1847Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.52, 1.49]
2 CD4 count1399Mean Difference (IV, Fixed, 95% CI)-36.0 [-148.53, 76.53]
3 Duration of hospitalisation1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
3.1 All admissions1106Mean Difference (IV, Fixed, 95% CI)-1.70 [-3.39, -0.01]
3.2 Diarrhoea admissions146Mean Difference (IV, Fixed, 95% CI)-1.60 [-4.35, 1.15]
3.3 Pneumonia admissions160Mean Difference (IV, Fixed, 95% CI)-1.90 [-4.08, 0.28]
4 Change in appetite at 6 months199Mean Difference (IV, Fixed, 95% CI)6.1 [0.23, 11.97]
5 Anthropometric Z scores1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
5.1 WAZ at 6 months199Mean Difference (IV, Fixed, 95% CI)0.30 [0.04, 0.56]
5.2 HAZ at 6 months199Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.39, 0.31]
5.3 WHZ at 6 months199Mean Difference (IV, Fixed, 95% CI)0.45 [-0.02, 0.92]
Analysis 4.1.

Comparison 4 Multiple micronutrients, Outcome 1 Mortality at 12 months.

Analysis 4.2.

Comparison 4 Multiple micronutrients, Outcome 2 CD4 count.

Analysis 4.3.

Comparison 4 Multiple micronutrients, Outcome 3 Duration of hospitalisation.

Analysis 4.4.

Comparison 4 Multiple micronutrients, Outcome 4 Change in appetite at 6 months.

Analysis 4.5.

Comparison 4 Multiple micronutrients, Outcome 5 Anthropometric Z scores.

Appendices

Appendix 1. PubMed search Jan 2010 to July 2011

SearchMost Recent QueriesTimeResult
#21Search #15 AND #16 AND #19 Limits: Publication Date from 2010/01/01 to 2011/07/1908:08:45141
#20Search #15 AND #16 AND #1908:01:461578
#19Search #17 OR #1808:01:231039559
#18Search “24,25-dihydroxyvitamin D 3” OR “25-hydroxyvitamin D 2” OR “4-aminobenzoic acid” OR acetylcarnitine OR alpha-tocopherol OR aminobenzoic acids OR ascorbic acid OR beta carotene OR beta-tocopherol OR biotin OR boron OR cadmium OR calcifediol OR calcitriol OR carnitine OR cholecalciferol OR chromium OR cobalt OR cobamides OR cod liver oil OR copper OR dehydroascorbic acid OR dihydrotachysterol OR dihydroxycholecalciferols OR ergocalciferols OR flavin mononucleotide OR folic acid OR formyltetrahydrofolates OR fursultiamin OR gamma-tocopherol OR hydroxocobalamin OR hydroxycholecalciferols OR inositol OR iodine OR iron OR leucovorin OR manganese OR magnesium OR molybdenum OR niacin OR niacinamide OR nickel OR nicorandil OR nicotinic acids OR palmitoylcarnitine OR pantothenic acid OR pteroylpolyglutamic acids OR pyridoxal OR pyridoxal phosphate OR pyridoxamine OR pyridoxine OR riboflavin OR selenium OR silicon OR tetrahydrofolates OR thiamine OR thiamine monophosphate OR thiamine pyrophosphate OR thiamine triphosphate OR thioctic acid OR tin OR tocopherols OR tocotrienols OR ubiquinone OR vanadium OR zinc08:01:02895117
#17Search micronutrients OR micronutrient OR trace element OR trace elements OR vitamins OR vitamin OR carotenoids OR carotenoid OR carotenes OR carotene08:00:45555041
#16Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])08:00:322417318
#15Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MESH:NoExp]08:00:21274955

Appendix 2. CENTRAL search Jan 2010 to July 2011

ID Search Hits
#1 MeSH descriptor HIV Infections explode all trees6278
#2 MeSH descriptor HIV explode all trees2113
#3 hiv OR hiv-1* OR hiv-2* OR hiv1 OR hiv2 OR HIV INFECT* OR HUMAN IMMUNODEFICIENCY VIRUS OR HUMAN IMMUNEDEFICIENCY VIRUS OR HUMAN IMMUNE-DEFICIENCY VIRUS OR HUMAN IMMUNO-DEFICIENCY VIRUS OR HUMAN IMMUN* DEFICIENCY VIRUS OR ACQUIRED IMMUNODEFICIENCY SYNDROME OR ACQUIRED IMMUNEDEFICIENCY SYNDROME OR ACQUIRED IMMUNO-DEFICIENCY SYNDROME OR ACQUIRED IMMUNE-DEFICIENCY SYNDROME OR ACQUIRED IMMUN* DEFICIENCY SYNDROME9996
#4 MeSH descriptor Lymphoma, AIDS-Related, this term only21
#5 MeSH descriptor Sexually Transmitted Diseases, Viral, this term only19
#6 (#1 OR #2 OR #3 OR #4 OR #5)10070
#7 MeSH descriptor Micronutrients explode all trees13075
#8 micronutrient OR micronutrients OR trace element OR trace elements OR vitamin OR vitamins10995
#9 MeSH descriptor Carotenoids explode all trees2389
#10 carotenoids OR carotenoid OR carotene OR carotenes1523
#11 "24,25-dihydroxyvitamin D 3" OR "25-hydroxyvitamin D 2" OR "4-aminobenzoic acid" OR acetylcarnitine OR alpha-tocopherol OR aminobenzoic acids OR ascorbic acid OR beta carotene OR beta-tocopherol OR biotin OR boron OR cadmium OR calcifediol OR calcitriol OR carnitine OR cholecalciferol OR chromium OR cobalt OR cobamides OR cod liver oil OR copper OR dehydroascorbic acid OR dihydrotachysterol OR dihydroxycholecalciferols OR ergocalciferols OR flavin mononucleotide OR folic acid OR formyltetrahydrofolates OR fursultiamin OR gamma-tocopherol OR hydroxocobalamin OR hydroxycholecalciferols OR inositol OR iodine OR iron OR leucovorin OR manganese OR magnesium OR molybdenum OR niacin OR niacinamide OR nickel OR nicorandil OR nicotinic acids OR palmitoylcarnitine OR pantothenic acid OR pteroylpolyglutamic acids OR pyridoxal OR pyridoxal phosphate OR pyridoxamine OR pyridoxine OR riboflavin OR selenium OR silicon OR tetrahydrofolates OR thiamine OR thiamine monophosphate OR thiamine pyrophosphate OR thiamine triphosphate OR thioctic acid OR tin OR tocopherols OR tocotrienols OR ubiquinone OR vanadium OR zinc27133
#12 (#7 OR #8 OR #9 OR #10 OR #11)33228
#13 (#6 AND #12)484
#14 (#6 AND #12), from 2010 to 2011130
#15 (#6 AND #12), from 2010 to 201129

Appendix 3. EMBASE search Jan 2010 to July 2011

No.QueryResultsDate
#7 #1 AND #2 AND #5 AND [humans]/lim AND [embase]/lim AND [1-1-2010]/sd NOT [19-7-2011]/sd12719 Jul 2011
#6 #1 AND #2 AND #585919 Jul 2011
#5 #3 OR #4145428619 Jul 2011
#4 '24,25-dihydroxyvitamin d 3'/de OR '24,25-dihydroxyvitamin d 3' OR '25-hydroxyvitamin d 2'/de OR '25-hydroxyvitamin d 2' OR '4-aminobenzoic acid'/de OR '4-aminobenzoic acid' OR 'acetylcarnitine'/de OR acetylcarnitine OR 'alpha-tocopherol'/de OR 'alpha-tocopherol' OR 'aminobenzoic acids'/de OR 'aminobenzoic acids' OR 'ascorbic acid'/de OR 'ascorbic acid' OR 'beta carotene'/de OR 'beta carotene' OR 'beta-tocopherol'/de OR 'beta-tocopherol' OR 'biotin'/de OR biotin OR 'boron'/de OR boron OR 'cadmium'/de OR cadmium OR 'calcifediol'/de OR calcifediol OR 'calcitriol'/de OR calcitriol OR 'carnitine'/de OR carnitine OR 'cholecalciferol'/de OR cholecalciferol OR 'chromium'/de OR chromium OR 'cobalt'/de OR cobalt OR 'cobamides'/de OR cobamides OR 'cod liver oil'/de OR 'cod liver oil' OR 'copper'/de OR copper OR 'dehydroascorbic acid'/de OR 'dehydroascorbic acid' OR 'dihydrotachysterol'/de OR dihydrotachysterol OR 'dihydroxycholecalciferols'/de OR dihydroxycholecalciferols OR 'ergocalciferols'/de OR ergocalciferols OR 'flavin mononucleotide'/de OR 'flavin mononucleotide' OR 'folic acid'/de OR 'folic acid' OR 'formyltetrahydrofolates'/de OR 'formyltetrahydrofolates' OR 'fursultiamin'/de OR fursultiamin OR 'gamma-tocopherol'/de OR 'gamma-tocopherol' OR 'hydroxocobalamin'/de OR hydroxocobalamin OR 'hydroxycholecalciferols'/de OR hydroxycholecalciferols OR 'inositol'/de OR inositol OR 'iodine'/de OR iodine OR 'iron'/de OR iron OR 'leucovorin'/de OR leucovorin OR 'manganese'/de OR manganese OR 'magnesium'/de OR magnesium OR 'molybdenum'/de OR molybdenum OR 'niacin'/de OR niacin OR 'niacinamide'/de OR niacinamide OR 'nickel'/de OR nickel OR 'nicorandil'/de OR nicorandil OR 'nicotinic acids'/de OR 'nicotinic acids' OR 'palmitoylcarnitine'/de OR palmitoylcarnitine OR 'pantothenic acid'/de OR 'pantothenic acid' OR 'pteroylpolyglutamic acids'/de OR 'pteroylpolyglutamic acids' OR 'pyridoxal'/de OR pyridoxal OR 'pyridoxal phosphate'/de OR 'pyridoxal phosphate' OR 'pyridoxamine'/de OR pyridoxamine OR 'pyridoxine'/de OR pyridoxine OR 'riboflavin'/de OR riboflavin OR 'selenium'/de OR selenium OR 'silicon'/de OR silicon OR 'tetrahydrofolates'/de OR tetrahydrofolates OR 'thiamine'/de OR thiamine OR 'thiamine monophosphate'/de OR 'thiamine monophosphate' OR 'thiamine pyrophosphate'/de OR 'thiamine pyrophosphate' OR 'thiamine triphosphate'/de OR 'thiamine triphosphate' OR 'thioctic acid'/de OR 'thioctic acid' OR 'tin'/de OR tin OR 'tocopherols'/de OR tocopherols OR 'tocotrienols'/de OR tocotrienols OR 'ubiquinone'/de OR ubiquinone OR 'vanadium'/de OR vanadium OR 'zinc'/de OR zinc127475919 Jul 2011
#3 'micronutrient'/syn OR 'micronutrients'/syn OR 'trace element'/syn OR 'trace elements'/syn OR 'trace mineral'/syn OR 'vitamin'/syn OR 'vitamins'/syn OR 'carotenoid'/syn OR 'carotenoids'/syn OR 'carotene'/syn OR carotenes49528319 Jul 2011
#2 random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/de OR 'crossover procedure' OR 'double-blind procedure'/de OR 'double-blind procedure' OR 'single-blind procedure'/de OR 'single-blind procedure' OR 'randomized controlled trial'/de OR 'randomized controlled trial' OR allocat*:ti OR allocat*:ab110831519 Jul 2011
#1 'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus'/exp OR hiv:ti OR hiv:ab OR 'hiv-1':ti OR 'hiv-1':ab OR 'hiv-2':ti OR 'hiv-2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab OR 'acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab33297819 Jul 2011

Appendix 4. PubMed search June 2009 to Jan 2010

SearchMost Recent QueriesTimeResult
#5Search ("2009/06/01"[Publication Date] : "2010/01/29"[Publication Date]) AND (#1 AND #2 AND #3)04:12:5115
#4Search #1 AND #2 AND #304:10:19802
#3Search trace elements OR carotenoids OR vitamins04:09:59469770
#2Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])04:09:222198940
#1Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MESH:NoExp]04:09:00253650

Appendix 5. CENTRAL search Jan 2009 to Jan 2010

Appendix 6. EMBASE search Jan 2009 to Jan 2010

No. Query Results Date
#5 #1 AND #2 AND #3 AND [humans]/lim AND [embase]/lim AND [2009-2010]/py229 Jan 2010
#4 #1 AND #2 AND #36829 Jan 2010
#3 trace AND ('elements'/de OR 'elements') OR 'carotenoids'/de OR 'carotenoids' OR 'vitamins'/de OR 'vitamins'6526329 Jan 2010
#2 random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/de OR 'crossover procedure' OR 'double-blind procedure'/de OR 'double-blind procedure' OR 'single-blind procedure'/de OR 'single-blind procedure' OR 'randomized controlled trial'/de OR 'randomized controlled trial' OR allocat*:ti OR allocat*:ab95489229 Jan 2010
#1 'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus'/exp OR hiv:ti OR hiv:ab OR 'hiv-1':ti OR 'hiv-1':ab OR 'hiv-2':ti OR 'hiv-2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab OR 'acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab30031929 Jan 2010

Appendix 7. Gateway search June 2009 to Jan 2010

Search
Number
SearchItems
Found
#4 Search: (("HIV Infections"[MeSH] OR "HIV"[MeSH] OR hiv [tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw]) OR (((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "Sexually Transmitted Diseases, Viral"[MeSH:NoExp])) AND ((randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR drug therapy OR randomly OR trial OR groups) NOT (animals [mh] NOT humans [mh])) AND (trace elements OR carotenoids OR vitamins) Limit: 2009/06/01:2010/01/29250 
#3 Search: trace elements OR carotenoids OR vitamins505930 
#2 Search: (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR drug therapy OR randomly OR trial OR groups) NOT (animals [mh] NOT humans [mh])3008540 
#1 Search: ("HIV Infections"[MeSH] OR "HIV"[MeSH] OR hiv [tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw]) OR (((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "Sexually Transmitted Diseases, Viral"[MeSH:NoExp])367979 

What's new

DateEventDescription
14 October 2011AmendedRegistered as full review

Contributions of authors

J. Irlam (JI) initiated the 2010 review (Irlam 2010) and contributed to all stages of this updated subgroup review.
M. Visser (MV) assisted with all stages of the 2010 review.
N. Siegfried (NS) assisted with all stages of the 2010 review.

N. Rollins (NR) assisted with study selection for the 2010 review and commented on the report.

Declarations of interest

The authors declare that they have no conflicts of interest.

Sources of support

Internal sources

  • South African Cochrane Centre HIV/AIDS Mentoring Programme; Medical Research Council; Primary Health Care Directorate, University of Cape Town, South Africa.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arpadi 2009

Methods

Country: US

Setting: 4 hospital-based HIV treatment programmes

Duration of recruitment: 2004-2005

Design: Placebo-controlled, parallel group

Participants

INCLUSION CRITERIA:

Perinatally-infected children and adolescents, aged 6-16 years.

EXCLUSION CRITERIA:
severe vitamin D deficiency

Participants randomised: 59

- 26 M and 33 F

- mean age = 10.4 yrs

Participants analysed: 56

Loss to follow-up/ withdrawal: 6

Exclusions post-randomisation: 0

Interventions

Vitamin D 100 000 IU bimonthly, and 1000 mg calcium (2 chews) per day for 12 months

CONTROL: double placebo

Outcomes

PRIMARY OUTCOMES:

Total Body Bone Mineral Content (listed in registered protocol)

SECONDARY OUTCOMES:

Serum 25 hydroxyvitamin D (25-OHD) concentrations

Serum and urine calcium

HIV disease progression (CD4 count, viral load, ARV failure)

NotesNo adverse events reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised randomisation
Allocation concealment (selection bias)Low riskCentral allocation by study statistician
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow attrition (3 of 59 failed to complete the study)
Selective reporting (reporting bias)Low riskStudy protocol is available and all pre-specified outcomes of interest are reported on
Other biasLow riskDeclared no conflict of interest

Bobat 2005

Methods

Country: South Africa

Setting: hospital outpatient clinic

Duration of recruitment: Mar - Dec 2003

Design: Placebo-controlled, parallel group

Participants

INCLUSION CRITERIA:

Children aged 6-60 months with HIV-1 infection attending hospital clinic in Pietermaritzburg, South Africa

EXCLUSION CRITERIA: Children receiving ARVs

Participants randomised: 96

- 49 F and 46 M

- median age (zinc group): 40.1 months (27.4 to 48.4)

- median age (placebo group): 36.6 months (25 to 49.4)

Participants analysed: 85

Losses to follow-up/ withdrawal: 11

Exclusions post-randomisation: 0

Interventions

Zinc sulphate 10 mg daily for 6 months

CONTROL: placebo

Outcomes

PRIMARY OUTCOME:
Viral load

SECONDARY OUTCOMES:

% CD4 cells

Haemoglobin concentrations

Mortality

Morbidity (Watery diarrhoea; Pneumonia; URTI; Ear infection)

NotesNo adverse events reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised randomisation in blocks of size 8
Allocation concealment (selection bias)Low riskAllocation by investigator at hospital who were unaware of the allocation until follow up was completed
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskSmall loss to follow up and reasons were given
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol not available
Other biasLow riskDeclared no conflict of interest

Coutsoudis 1995

Methods

Country: South Africa

Setting: Tertiary hospital study clinic

Duration of recruitment: April 1991-November 1993

Design: Placebo-controlled, parallel group

Participants

INCLUSION CRITERIA:

Infants of women with HIV infection who had attended the antenatal clinic, delivered in hospital, and who lived within 10 miles of the hospital.

EXCLUSION CRITERIA:

Preterm infants

Participants randomised: 118

- 28 with HIV infection (13 in vitamin A group)

- 66 M and 52 F

- mean maternal age = 25 yrs (vitamin A) vs. 24.8 yrs (placebo)

Loss to follow-up:

17% (vitamin A) vs. 25% (placebo) at 6 months

36% (vitamin A) vs. 33% (placebo) at 12 months

58% (vitamin A) vs. 63% (placebo) at 18 months

Exclusions post-randomisation: 0

Interventions

Vitamin A 50 000 IU retinyl palmitate at 1 and 3 months and 100 000 IU at 6, 9,12 and 15 months

CONTROL: placebo

Outcomes

PRIMARY OUTCOMES:

Overall morbidity

SECONDARY OUTCOMES:

Acute diarrhoea
Persistent diarrhoea (> or = 7 days)
Hospitalised for diarrhoea
Thrush
Upper respiratory tract infection
Lower respiratory tract infection (LRTI)
Hospitalised for LRTI
Rash

NotesSide effects (vomiting and bulging fontanelle) were monitored by history and, when possible, by clinical examination.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Unclear riskThe capsules looked identical and were placed in number-coded envelopes from which they were removed when appropriate.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
High riskConsiderable losses to follow up were insufficiently explained
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol not available
Other biasUnclear riskDid not declare on conflict of interest

Fawzi 1999

Methods

Country: Tanzania

Setting: Hospital inpatient and outpatient follow-up

Duration of recruitment: April 1993 - March 1997.

Design: Placebo-controlled, parallel group

Participants

INCLUSION CRITERIA:

Admitted to hospital for pneumonia; aged 6 - 60 months; no eye signs or symptoms of vitamin A deficiency

EXCLUSION CRITERIA:

treatment with vitamin A for 4 months prior to study entry; severe malnutrition; measles; pulmonary tuberculosis; diphtheria; whooping cough; xerophthalmia

Participants randomised:687

- 58 with HIV infection of 648 with known status (9%)

- 353 M and 295 F

- mean maternal age = 25.6 yrs (vitamin A group) vs. 26.2 (placebo)

Participants analysed: 648

Loss to follow-up/ withdrawal:76

Exclusions post-randomisation: 0

Interventions

Vitamin A single dose on hospital admission, on day 2 and at 4, and at 8 months after discharge (100,000 IU dose for infants; 200,000 IU for children)

CONTROL: placebo

Outcomes

PRIMARY OUTCOMES:

All-cause mortality

Cause-specific mortality (AIDS, diarrhoea, pneumonia, malaria, anaemia and other infections (measles, meningitis, dysentery, fever of unknown origin, malnutrition))

Diarrhoea
Acute respiratory infection

SECONDARY OUTCOMES:

Hospitalisation

Visits to health center

Notes

Sera from children were tested for HIV antibodies by enzyme- linked immunosorbent assay and Western blot tests. For positive children <15 months of age, HIV infection was confirmed by amplified heat-denatured HIV-p24 antigen assays with confirmatory neutralization assays.

Cause of death ascertained by review of hospital records and home verbal autopsy questionnaire by two physicians. Discrepancies resolved by third physician.

Bi-weekly morbidity recall. No data provided on episodes of persistent diarrhoea or hospitalisation of children with HIV infection.

Source of funding: Thrasher Research Fund; International Development Research Center

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation in blocks of 20
Allocation concealment (selection bias)Low riskVitamin A and placebo were dispensed out of a dropper from identical 25-ml opaque bottles that were labelled with one of four batch numbers. The batch number code was retained by the manufacturer until the end of the study
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo reasons for losses to follow up were given
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol not available
Other biasUnclear riskDid not declare on conflict of interest

Hanekom 2000

Methods

Country: USA

Setting: Hospital HIV clinic

Duration of recruitment: Not stated

Design: Randomised placebo-controlled trial

Participants

INCLUSION CRITERIA:

Clinic patients who were eligible for non-primary annual influenza vaccination

EXCLUSION CRITERIA:

Hypersensitivity to eggs, acute febrile illness, recent receipt of intravenous gammaglobulin or vaccination.

Participants randomised: 59 children

- M : F ratio = 0.6 (vitamin A) and 1.3 (placebo)

- median (range) age = 84 (31-209) months in vitamin A group; 77 months (25-142) in placebo group

Participants analysed: 59

Loss to follow-up/ withdrawal: 1

Exclusions post-randomisation: 0

Interventions

Vitamin A 200 000 IU retinyl palmitate daily for 2 days

CONTROL: placebo

Outcomes

PRIMARY OUTCOMES:

Viral load changes after vaccination

Antibody levels (H1N1, H3N2) after vaccination

SECONDARY OUTCOMES:

T-cell counts

Vitamin A levels

NotesNo adverse events reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated by pharmacy
Allocation concealment (selection bias)Unclear riskNo method of concealment was described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskOne exclusion due to incomplete follow up
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol not available
Other biasUnclear riskDid not declare on funding sources or conflicts of interest

Hussey 1996

Methods

Country: South Africa

Setting: HIV clinic at a children's hospital

Duration of recruitment:1994-1995.

Design: Randomised placebo-controlled trial.

Lost to follow-up at 2 months:
Total sample: 1 (3%)

Intention-to-treat: not performed.

Participants

INCLUSION CRITERIA:

Child attendees at HIV clinic

EXCLUSION CRITERIA:

Acute infections, fever

Participants randomised: 75

- mean age = 17 mo.

Participants analysed: 75

Loss to follow-up/ withdrawal: 0

Exclusions post-randomisation: 0.

Interventions

Vitamin A 200 000 IU daily for 2 days

CONTROL: placebo

Outcomes

PRIMARY OUTCOMES:

T-Cell counts (absolute; CD4; CD56; CD29)

SECONDARY OUTCOMES:

Vitamin A levels

NotesConference abstract only
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskSequence generation method not described
Allocation concealment (selection bias)Unclear riskNo method of concealment was described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInsufficient information on losses to follow up
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol and full report not available
Other biasUnclear riskDid not declare on funding sources or conflicts of interest

Luabeya 2007

Methods

Country: South Africa

Setting: Five rural primary care clinics

Duration of recruitment: June 2003 - Oct 2004

Design: Randomised controlled trial

Participants

INCLUSION CRITERIA:

children 4-6 months old

EXCLUSION CRITERIA:

underweight for age; nutritional oedema; persistent diarrhoea; taking vitamin or micronutrient supplements in past month

Participants randomised: 373

- 32 with HIV infection; 154 born to mothers with HIV infection; 187 born to mothers without HIV

- 173 M and 162 F

- mean age = 5.5 months

Participants analysed: 335

Loss to follow-up/ withdrawal: 88

Exclusions post-randomisation: 0

Interventions

Zinc (10mg), vitamin A (1250 IU) and multiple micronutrients (B vitamins; vitamins C, D, E, K; copper, iron, iodine) vs. zinc and vitamin A; daily for median duration of 14.9 months

CONTROL: Vitamin A

Outcomes

PRIMARY OUTCOMES:

Incidence of diarrhoea per child (% of days)

SECONDARY OUTCOMES:

Distribution of diarrhoeal morbidity

Severity of diarrhoea

Prevalence (% of weeks) of upper respiratory symptoms

Percentage of children who ever had pneumonia (maternal and field worker reports)

Longitudinal growth (length-for-age Z-scores or LAZ)

Anaemia

NotesVomiting reported post-supplementation in 9 children by fieldworkers
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised randomisation in blocks of 6
Allocation concealment (selection bias)Low riskPre-packed sequentially numbered study supplements
Blinding of participants and personnel (performance bias)
All outcomes
Low riskInvestigators, study staff and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing data addressed used appropriate statistical methods
Selective reporting (reporting bias)Low riskStudy protocol is available and all pre-specified outcomes of interest are reported on
Other biasUnclear riskDelay in shipment of supplements prevented 243 children from receiving supplements for 11 weeks

Mda 2010a

Methods

Country: South Africa

Setting: academic hospital

Duration of recruitment: November 2005 and May 2007

Design: Placebo-controlled trial: individual randomised stratified by diarhoea or pneumonia

Participants

INCLUSION CRITERIA: children with HIV infection aged between 4 mo and 2 y; admitted with diarrhoea or pneumonia to the paediatric wards of an academic hospital

EXCLUSION CRITERIA: diarrheal episode longer than 72 h on admission; pneumonia complicated by respiratory failure; children on ART or those who had received vitamin or micronutrient supplementation; children with chronic illness unrelated to HIV

Participants randomised:118

Exclusions post-randomisation: 0

Deaths: 12

Participants analysed:106

Interventions

Multi-micronutrient supplement until hospital discharge with RDAs for one-year old: vitamin A 300 mcg, vitamin B1 0.6 mg, vitamin B2 0.6 mg, vitamin B3 8 mg, vitamin B6 0.6 mg, vitamin B12 1 mcg, folic acid 70 mcg, vitamin C 25 mg, vitamin D 5 mcg, vitamin E 7 mg, copper 700 mcg, iron 8 mg, selenium 30 mcg and zinc 8 mg.

CONTROL: Placebo

Outcomes

PRIMARY OUTCOMES:

Duration of hospitalization in children with HIV infection admitted with acute diarrhea and pneumonia who are not yet receiving ART

SECONDARY OUTCOMES:

Appetite and levels of appetite regulating hormones

NotesNo adverse events reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomization by independent person
Allocation concealment (selection bias)Unclear riskConcealment of allocation insufficiently described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll survivors were included in the analysis
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol not available
Other biasLow riskAll the authors declare that they have no conflict of interests.

Mda 2010b

Methods

Country: South Africa

Setting: paediatric outpatient department of academic hospital

Duration of recruitment: November 2005 until November 2006

Design: Placebo-controlled trial

Participants

INCLUSION CRITERIA: children with HIV infection aged between 6 and 24 months; previously admitted with diarrhoea or pneumonia to the paediatric wards of an academic hospital

EXCLUSION CRITERIA: Children on ARV or who had received micronutrient supplementation in the previous two months; children diagnosed with a chronic illness unrelated to HIV infection.

Participants randomised:140

Exclusions post-randomisation: 0

Deaths: 22

Participants analysed: 99

Interventions

Multi-micronutrient supplement for 6 months with RDAs for one-year old: vitamin A 300 mcg, vitamin B1 0.6 mg, vitamin B2 0.6 mg, vitamin B3 8 mg, vitamin B6 0.6 mg, vitamin B12 1 mcg, folic acid 70 mcg, vitamin C 25 mg, vitamin D 5 mcg, vitamin E 7 mg, copper 700 mcg, iron 8 mg, selenium 30 mcg and zinc 8 mg.

CONTROL: Placebo

Outcomes

PRIMARY OUTCOMES:

Appetite of children

SECONDARY OUTCOMES:

Anthropometric measures (WAZ, HAZ, WHZ) at enrolment, 3 and 6 months

Micronutrient status (Zinc, iron, ferritiin) at enrolment, 3 and 6 months

Levels of appetite-regulating hormones (insulin, leptin) at enrolment, 3 and 6 months

NotesNo adverse events reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomization by independent person
Allocation concealment (selection bias)Unclear riskConcealment of allocation insufficiently described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStudy personnel and participants were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded for the outcome of appetite testing
Incomplete outcome data (attrition bias)
All outcomes
High risk29% dropout overall, due to death, taking ARVs, relocation, or other reasons. Differences in deaths and relocations were higher in the supplemented group, but did not reach statistical significance.
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol not available
Other biasLow riskThe authors declare that they have no conflict of interests.

Ndeezi 2010

Methods

Country: Uganda

Setting:Paediatric HIV clinics of the national referral hospital

Duration of trial:June 2005-June 2008

Design: Placebo-controlled trial

Participants

INCLUSION CRITERIA: children aged 1 - 5 years whose mothers had attended the clinic at least once, and who adhered to a regular study follow-up schedule for one year.

EXCLUSION CRITERIA: Children enrolled in other studies, those residing more than 15 kilometres from the clinic and those whose parents or caretakers were anticipating moving from the study area

Participants randomised:847

- 56% were less than 36 months

Participants analysed:695

Loss to follow-up/ withdrawal:152

Exclusions post-randomisation: 0

Interventions

Multiple micronutrient supplements (2 x RDA) for 6 months: vitamin A 800 mcg, vitamin B1 1.2 mg, vitamin B2 1.2 mg, vitamin B3 1.6 mg, vitamin B6 1.2 mg, vitamin B12 2.4 mcg, folic acid 400 mcg, vitamin C 50 mg, vitamin D 400 IU, vitamin E 14 mg, copper 800 mcg, selenium 60 mcg, zinc 10 mg, iodine 180 mcg.

CONTROL: RDA of six multivitamins: vitamin A 400 mcg, vitamin B1 0.6 mg, vitamin B2 0.6 mg, vitamin B3 0.8 mg, vitamin C 25 mg, vitamin D 200 IU

Outcomes

PRIMARY OUTCOMES:Mortality at 12 months

SECONDARY OUTCOMES:Growth (weight-for-height at 12 months); CD4 counts

NotesMinor adverse effects were reported in 16 children (1.9%) and these included vomiting in 12 children and diarrhoea in four children; there was no difference between study arms.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe eligible participants were block randomized to either the intervention or "standard-of-care" in two strata (ART; non-ART) using a computer-generated code
Allocation concealment (selection bias)Low riskThe randomization code was not generated by a study team member and was made available to the investigators only upon completion of data collection
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll investigators, staff and parents or caretakers were blinded to treatment assignment
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded to treatment assignment
Incomplete outcome data (attrition bias)
All outcomes
High riskBy 12 months, 124 (14.6%) children were lost to follow up: 15.7% in the intervention arm and 13.5% in the comparative arm. Those lost to follow up were more likely to be ill (underweight and CRP-positive) than those who remained.
Selective reporting (reporting bias)Low riskStudy protocol is available and all pre-specified outcomes of interest are reported on
Other biasLow riskThe authors declare that they have no competing interests.

Semba 2005

Methods

Country: Uganda

Setting:Hospital clinic

Duration of recruitment:Jan. 1995 - June 1998

Design: Placebo-controlled trial

Participants

INCLUSION CRITERIA:

Children aged 6 months; resident near hospital for duration of trial

EXCLUSION CRITERIA:

Evidence of vitamin A deficiency

Participants randomised: 181 at age 15 months

- 90 M and 91 F

- mean age = 15 months

Participants analysed: 168

Loss to follow-up/ withdrawal: 0

Exclusions post-randomisation: 0

Interventions

Vitamin A 200 000 IU every 3 months from 15 to 36 months

CONTROL: placebo

Outcomes

PRIMARY OUTCOMES:

Mortality

SECONDARY OUTCOMES:
Morbidity (diarrhoea, cough, fever, ear discharge, hospitalisation)

NotesNo adverse events reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated, random codes
Allocation concealment (selection bias)Low riskSequentially numbered pill cards were used
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants, paediatrician and clinic staff were blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStudy personnel were blinded to treatment assignment
Incomplete outcome data (attrition bias)
All outcomes
Low riskSurvival analysis used to account for differences in duration of follow up due to early termination of the trial
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement; study protocol not available
Other biasHigh riskTrial stopped early due to change in national guideline on vitamin A supplementation

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Chatterjee 2010Prospective study of children born to Tanzanian women with HIV infection within a RCT setting (Fawzi et al 1998)
CIGNIS 2010Outcomes analysed by maternal HIV status, not child HIV status

Ancillary