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Micronutrient supplementation for children with HIV infection

  1. James H Irlam1,*,
  2. Nandi Siegfried2,
  3. Marianne E Visser3,
  4. Nigel C Rollins4,5

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 11 OCT 2013

Assessed as up-to-date: 27 NOV 2011

DOI: 10.1002/14651858.CD010666


How to Cite

Irlam JH, Siegfried N, Visser ME, Rollins NC. Micronutrient supplementation for children with HIV infection. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD010666. DOI: 10.1002/14651858.CD010666.

Author Information

  1. 1

    University of Cape Town, Primary Health Care Directorate, Cape Town, Western Cape, South Africa

  2. 2

    University of Cape Town, Department of Psychiatry and Mental Health, Cape Town, South Africa

  3. 3

    Cape town, South Africa

  4. 4

    World Health Organization, Department of Maternal, Newborn, Child and Adolescent Health (MCA), 1211 Geneva 27, Switzerland

  5. 5

    University of Kwazulu-Natal, Department of Paediatrics and Child Health, Durban, South Africa

*James H Irlam, Primary Health Care Directorate, University of Cape Town, E47 OMB, Groote Schuur Hospital, Cape Town, Western Cape, 7925, South Africa. James.Irlam@uct.ac.za.

Publication History

  1. Publication Status: New
  2. Published Online: 11 OCT 2013

SEARCH

 

Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 
Summary of findings for the main comparison. Vitamin A for children with HIV infection

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

ControlVitamin A

All-cause mortality
Death reports
Study populationRR 0.55
(0.37 to 0.82)
262
(3 studies)
⊕⊕⊕⊝
moderate1
Coutsoudis 1995 (SA); Fawzi 1999 (Tanzania); Semba 2005 (Uganda)

381 per 1000210 per 1000
(141 to 312)

Medium risk population

400 per 1000220 per 1000
(148 to 328)

Child growth at 12 months - Wasting
Anthropometric measurements at monthly clinic visits
Follow-up: median 351 days
Study populationRR 0.25
(0.06 to 1.05)
41
(1 study)
⊕⊕⊝⊝
low2
Fawzi 1999 (Tanzania)

368 per 100092 per 1000
(22 to 386)

Medium risk population

368 per 100092 per 1000
(22 to 386)

Child growth at 12 months - Stunting
Anthropometric measurements at monthly clinic visits
Follow-up: median 351 days
Study populationRR 0.67
(0.34 to 1.32)
29
(1 study)
⊕⊕⊝⊝
low2
Fawzi 1999 (Tanzania)

688 per 1000461 per 1000
(234 to 908)

Medium risk population

688 per 1000461 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.

 1 Number of events was low
2 Number of participants was very low

 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

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

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

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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).

 FigureFigure 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.

 FigureFigure 2. Risk of bias summary: review of authors' judgements about risk of bias in each included study
 FigureFigure 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%.

 FigureFigure 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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
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 months1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Wasting
141Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.06, 1.05]

    2.2 Stunting
129Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.34, 1.32]

 
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]

 
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 visits1Risk Ratio (M-H, Random, 95% CI)Subtotals only

    4.1 Scheduled visits; watery diarrhoea
1730Risk Ratio (M-H, Random, 95% CI)0.63 [0.39, 1.03]

    4.2 Scheduled visits; pneumonia
1730Risk Ratio (M-H, Random, 95% CI)0.85 [0.57, 1.27]

    4.3 Scheduled visits; URI
1730Risk Ratio (M-H, Random, 95% CI)0.88 [0.74, 1.04]

    4.4 Scheduled visits; ear infection
1730Risk Ratio (M-H, Random, 95% CI)0.77 [0.52, 1.14]

    4.5 All visits; watery diarrhoea
1854Risk Ratio (M-H, Random, 95% CI)0.51 [0.34, 0.76]

    4.6 All visits; URI
1854Risk Ratio (M-H, Random, 95% CI)0.75 [0.55, 1.03]

    4.7 All visits; pneumonia
1854Risk Ratio (M-H, Random, 95% CI)0.89 [0.76, 1.04]

    4.8 All visits; ear infection
1854Risk Ratio (M-H, Random, 95% CI)0.78 [0.55, 1.11]

 5 Diarrhoea incidence in HIV+ children with at least one follow-up visitOther 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

 
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 hospitalisation1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    3.1 All admissions
1106Mean Difference (IV, Fixed, 95% CI)-1.70 [-3.39, -0.01]

    3.2 Diarrhoea admissions
146Mean Difference (IV, Fixed, 95% CI)-1.60 [-4.35, 1.15]

    3.3 Pneumonia admissions
160Mean 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 scores1Mean Difference (IV, Fixed, 95% CI)Subtotals only

    5.1 WAZ at 6 months
199Mean Difference (IV, Fixed, 95% CI)0.30 [0.04, 0.56]

    5.2 HAZ at 6 months
199Mean Difference (IV, Fixed, 95% CI)-0.04 [-0.39, 0.31]

    5.3 WHZ at 6 months
199Mean Difference (IV, Fixed, 95% CI)0.45 [-0.02, 0.92]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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


IDSearchHits

#1MeSH descriptor HIV Infections explode all trees6278

#2MeSH descriptor HIV explode all trees2113

#3hiv 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

#4MeSH descriptor Lymphoma, AIDS-Related, this term only21

#5MeSH descriptor Sexually Transmitted Diseases, Viral, this term only19

#6(#1 OR #2 OR #3 OR #4 OR #5)10070

#7MeSH descriptor Micronutrients explode all trees13075

#8micronutrient OR micronutrients OR trace element OR trace elements OR vitamin OR vitamins10995

#9MeSH descriptor Carotenoids explode all trees2389

#10carotenoids 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.QueryResultsDate

#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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 27 November 2011.


DateEventDescription

14 October 2011AmendedRegistered as full review



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

The authors declare that they have no conflicts of interest.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

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

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Arpadi 2009 {published data only}
  • Arpadi SM, McMahon D, Abrams EJ, Bamji M, Purswani M, Engelson ESetal. Effect of bimonthly supplementation with oral cholecalciferol on serum 25-hydroxyvitamin D concentrations in HIV-infected children and adolescents. Pediatrics 2009;123(1):e121-6.
Bobat 2005 {published data only}
  • Bobat, R, Coovadia, H, Stephen, C, et al. Safety and efficacy of zinc supplementation for children with HIV-1 infection in South Africa: A randomised double-blind placebo-controlled trial. Lancet 2005;366(9500):1862-7.
Coutsoudis 1995 {published data only}
  • Coutsoudis A, Bobat RA, Coovadia HM, Kuhn L, Tsai WY, Stein ZA. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. American Journal of Public Health 1995;85(8):1076-81.
Fawzi 1999 {published data only}
  • Fawzi WW, Mbise R, Hertzmark E, Fataki MR, Herrera MG, Ndossi G, et al. A randomized trial of vitamin A supplements in relation to mortality among human immunodeficiency virus-infected and uninfected children in Tanzania. The Pediatric Infectious Disease Journal 1999;18(2):127-33.
  • Fawzi WW, Mbise R, Spiegelman D, Fataki M, Hertzmark E, Ndossi G. Vitamin A supplements and diarrheal and respiratory tract infections among children in Dar es Salaam, Tanzania. The Journal of Pediatrics 2000;137(5):660-7.
  • Villamor E, Mbise R, Spiegelman D, Hertzmark E, Fataki M, Peterson KE, et al. Vitamin A supplements ameliorate the adverse effect of HIV-1, malaria, and diarrheal infections on child growth. Pediatrics 2002;109(1 (E6)):1-10.
Hanekom 2000 {published data only}
  • Hanekom WA, Yogev R, Heald LM, Edwards KM, Hussey GD, Chadwick EG. Effect of vitamin A therapy on serologic responses and viral load changes after influenza vaccination in children infected with the human immunodeficiency virus. The Journal of Pediatrics 2000;36(4):550-2.
Hussey 1996 {published data only}
  • Hussey G, Hughes J, Potgieter S, Kessow G, Burgess J, Beatty Detal. Vitamin A status and supplementation and its effect on immunity in children with AIDS. XVII International Vitamin A Consultative Group (IVACG) Meeting, Guatemala City. 1996:81.
Luabeya 2007 {published data only}
  • Chhagan MK, Van den Broeck J, Luabeya KK, Mpontshane N, Tomkins A, Bennish ML. Effect on longitudinal growth and anemia of zinc or multiple micronutrients added to vitamin A: a randomized controlled trial in children aged 6-24 months. BMC public health 2010;10:145. [PUBMED: 20298571]
  • Chhagan MK, Van den Broeck J, Lubaeya KK, Mpontshane N, Tucker KL, Bennish ML. Effect of micronutrient supplementation on diarrhoeal disease among stunted children in rural South Africa. European journal of clinical nutrition 2009;63(7):850-7.
  • Luabeya, K. K, Mpontshane, N, Mackay, M, et al. Zinc or multiple micronutrient supplementation to reduce diarrhea and respiratory disease in South African children: A randomized controlled trial. PLoS ONE 2007;2(6):e541.
Mda 2010a {published data only}
  • Mda S, van Raaij JM, de Villiers FP, MacIntyre UE, Kok FJ. Short-term micronutrient supplementation reduces the duration of pneumonia and diarrheal episodes in HIV-infected children. The Journal of nutrition 2010;140(5):969-74. [PUBMED: 20335632]
Mda 2010b {published data only}
  • Mda S, van Raaij JM, Macintyre UE, de Villiers FP, Kok FJ. Improved appetite after multi-micronutrient supplementation for six months in HIV-infected South African children. Appetite 2010;54(1):150-5. [PUBMED: 19815042]
Ndeezi 2010 {published data only}
  • Ndeezi G, Tylleskar T, Ndugwa CM, Tumwine JK. Effect of multiple micronutrient supplementation on survival of HIV-infected children in Uganda: a randomized, controlled trial. Journal of the International AIDS Society 2010;13:18. [PUBMED: 20525230]
Semba 2005 {published data only}
  • Semba RD, Ndugwa C, Perry RT, Clark TD, Jackson JB, Melikian Getal. Effect of periodic vitamin A supplementation on mortality and morbidity of human immunodeficiency virus-infected children in Uganda: A controlled clinical trial. Nutrition 2005;21(1):25-31.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Chatterjee 2010 {published data only}
  • Chatterjee A, Bosch RJ, Hunter DJ, Manji K, Msamanga GI, Fawzi WW. Vitamin A and vitamin B-12 concentrations in relation to mortality and morbidity among children born to HIV-infected women. Journal of tropical pediatrics 2010;56(1):27-35. [PUBMED: 19502599]
CIGNIS 2010 {published data only}
  • Chilenje Infant Growth, Nutrition and Infection (CIGNIS) Study Team. Micronutrient fortification to improve growth and health of maternally HIV-unexposed and exposed Zambian infants: a randomised controlled trial. PloS one 2010;5(6):e11165. [PUBMED: 20567511]
  • Filteau S, Baisley K, Chisenga M, Kasonka L, Gibson RS. Provision of micronutrient-fortified food from 6 months of age does not permit HIV-exposed uninfected Zambian children to catch up in growth to HIV-unexposed children: a randomized controlled trial. Journal of acquired immune deficiency syndromes (1999) 2011;56(2):166-75. [PUBMED: 21119523]

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. Additional references
  21. References to other published versions of this review
Aggarwal 2007
  • Aggarwal R, Sentz J, Miller MA. Role of zinc administration in prevention of childhood diarrhea and respiratory illnesses: a meta-analysis. Pediatrics 2007;119(6):1120-30. [PUBMED: 17545379]
ASSaf 2007
  • Irlam J, Hussey G, Dhansay M. The effects of nutritional interventions in HIV/AIDS: Micronutrients. In: Assaf Study Panel, editor(s). HIV/AIDS, TB and Nutrition: Scientific inquiry into the nutritional influences on human immunity with special reference to HIV infection and active TB in South Africa. Pretoria: Academy of Science of South Africa, 2007:143-51.
Baeten 1993
  • Beaton G, Martorell R, Aronson KJ, Edmonston B, McCabe G, Ross AC, Harvey B. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN State of the Art Series, Nutrition Policy Paper No 13 1993.
Baqui 2002
  • Baqui AH, Black RE, El Arifeen S, Yunus M, Chakraborty J, Ahmed S, et al. Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial. British Medical Journal 2002;325(7372):1059.
Bhandari 2002
  • Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, et al. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics June 2002;109(6):e86.
Bhutta 1999
  • Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, Hidayat A, et al. Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Zinc Investigators' Collaborative Group. The Journal of pediatrics 1999;135(6):689-97. [PUBMED: 10586170]
Bhutta 2000
  • Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A, et al. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. The American journal of clinical nutrition 2000;72(6):1516-22. [PUBMED: 11101480]
Black 2010
  • Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I,   Bassani DG, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 2010;375(9730):1969-87. [PUBMED: 20466419]
Filteau 2001
  • Filteau SM, Rollins NC, Coutsoudis A, Sullivan KR, Willumsen JF, Tomkins AM. The effect of antenatal vitamin A and beta-carotene supplementation on gut integrity of infants of HIV-infected South African women. Journal of pediatric gastroenterology and nutrition 2001;32(4):464-70. [PUBMED: 11396815]
GradePro 2008
  • Jan Bozek, Andrew Oxman, Olger Schunemann. Gradepro. 3.2.2 for Windows. GRADE Working Group, 2008.
Haider 2008
  • Haider B, Bhutta Z. Review of vitamin A supplementation in the neonatal period. Web appendix to Bhutta et al, 2008. Available at: http://www.globalnutritionseries.org/web_appendices (accessed on 24.09.2008) 2008.
Horton 2008
  • Horton S, Begin  F, Greig  A, Lakshman A. Copenhagen Consensus best practices paper on Micronutrient supplements for child survival (Vitamin A and Zinc). Copenhagen Consensus Center Working Paper 2008.
Micronutrient Initiative 2009
  • The Micronutrient Initiative. Investing in the Future: A United Call to Action on Vitamin and Mineral Deficiencies. http://www.unitedcalltoaction.org/flashreport.asp (accesssed 8 June 2010) 2009.
Piwoz 2000
  • Piwoz EG, Preble EA. HIV/AIDS and Nutrition: A Review of the Literature and recommendations for Nutritional Care and Support in sub-Saharan Africa. Refugee Studies Centre. Washington: Support for Analysis and Research in Africa (SARA) Project, Academy for Educational Development, 2000.
Robberstad 2004
  • Robberstad B, Strand T, Black RE, Sommerfelt H. Cost-effectiveness of zinc as adjunct therapy foracute childhood diarrhea in developing countries. WHO Bulletin 2004;82(7):523-31.
Strand 2002
  • Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N, et al. Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young children. Pediatrics 2002;109(5):898-903.
UNAIDS 2010
  • UNAIDS. UNAIDS Report on the Global AIDS Epidemic 2010. http://www.unaids.org/globalreport/ Accessed 14 Novemeber 2011.
UNICEF 2007
  • UNICEF. Vitamin A Supplementation - A decade of progress. UNICEF report 2007.
UNICEF 2009
  • UNICEF. Tracking Progress on Child and Maternal Nutrition: A survival and development priority. New York: UNICEF Division of Communication, November 2009. [: ISBN 978-92-806-4482-1]
Wagstaff 2004
  • Wagstaff A, Cleason M. The Millennium Development Goals for health: rising to the challenges. Washington DC: World Bank 2004.
WHO 2003
  • World Health Organisation. WHO Technical Consultation on Nutrient Requirements for People Living with HIV/AIDS. Nutrient Requirements for People Living with HIV/AIDS. Geneva: World Health Organisation, 2003.
WHO 2009
  • World Health Organization. Handbook IMCI Integrated Management of Childhood Illness for High HIV Settings. Geneva: World Health Organization, 2009.
WHO/UNICEF 2004
  • WHO/UNICEF. Clinical Management of Acute Diarrhea. WHO/UNICEF Joint Statement 2004.
Zinc Investigators Collaborative Group 2000
  • Zinc Investigators Collaborative Group. Therapeutic effects of oral zinc in acute and persistent diarrhoea in children in developing countries: Pooled analysis of randomized controlled trials. Am J Clin Nutr 2000;72:1516-22.