Summary of findings
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.
To assess whether micronutrient supplements are effective and safe in reducing mortality and morbidity in children with HIV infection.
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
The primary outcomes, as measured in the studies, were:
- HIV-related hospitalisations.
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.
One random effects meta-analysis of mortality in three vitamin A trials was performed by JI and checked by NS.
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)|
A total of eleven trials of 2412 child participants were included:
- Vitamin D (one trial; 59 participants: Arpadi 2009)
Details are reported below in the table: Characteristics of included studies
Risk of bias in included studies
|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.|
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 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).
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
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.
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) .
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) log
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.
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.
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).
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).
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).
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).
Summary of main results
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 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.
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.
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.
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).
The one trial of vitaimin D (Arpadi 2009) was assessed at low risk of bias on all criteria.
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).
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.
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.
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.
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
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. PubMed search Jan 2010 to July 2011
Appendix 2. CENTRAL search Jan 2010 to July 2011
Appendix 3. EMBASE search Jan 2010 to July 2011
Appendix 4. PubMed search June 2009 to Jan 2010
Appendix 5. CENTRAL search Jan 2009 to Jan 2010
Appendix 6. EMBASE search Jan 2009 to Jan 2010
Appendix 7. Gateway search June 2009 to Jan 2010
Last assessed as up-to-date: 27 November 2011.
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
- South African Cochrane Centre HIV/AIDS Mentoring Programme; Medical Research Council; Primary Health Care Directorate, University of Cape Town, South Africa.
- No sources of support supplied
Medical Subject Headings (MeSH)
CD4 Lymphocyte Count; Diarrhea [therapy]; HIV Infections [*complications; *mortality]; Hospitalization [statistics & numerical data]; Micronutrients [*administration & dosage; deficiency]; Randomized Controlled Trials as Topic; Vitamin A [administration & dosage]; Vitamin D [administration & dosage]; Vitamins [administration & dosage]; Zinc [administration & dosage]
MeSH check words
Adolescent; Child; Child, Preschool; Humans; Infant
* Indicates the major publication for the study