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.