Micronutrient supplementation in children and adults with HIV infection

  • Protocol
  • Intervention


  • JH Irlam,

    Chief Scientific Officer, Corresponding author
    1. University of Cape Town, Paediatrics and Child Health - Child Health Unit, Cape Town, SOUTH AFRICA
    • JH Irlam, Chief Scientific Officer, Paediatrics and Child Health - Child Health Unit, University of Cape Town, 46 Sawkins Rd, Rondebosch, Cape Town, 7700, SOUTH AFRICA. jirlam@cormack.uct.ac.za.

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  • ME Visser,

  • N Rollins,

  • N Siegfried


This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess whether micronutrient interventions are effective in reducing morbidity and mortality among HIV-infected children and adults.


HIV infection is a major public health problem worldwide, but particularly in sub-Saharan Africa and Asia. In sub-Saharan Africa it is estimated that one in ten people is infected with HIV (Piwoz 2000).

HIV infection and malnutrition are inextricably interrelated in a "vicious cycle" of immune dysfunction, infectious disease, and malnutrition. Malnutrition takes many forms and includes protein-energy malnutrition (PEM) and micronutrient malnutrition. PEM occurs as a result of a deficiency in energy and protein and is usually measured in terms of body size. Common PEM indicators in children include low height-for-age (stunting), low weight-for-age (underweight), and low weight-for-height (wasting). Low body mass index (BMI) is the best indicator of PEM in adults (Piwoz 2000).

"Micronutrients" is the collective term used to describe vitamins and trace elements, which are required in only small amounts in the body. Like PEM, micronutrient malnutrition occurs as a result of an inadequate dietary intake, but the signs and symptoms of micronutrient malnutrition are often lacking (Dijkhuizen 2001). Research indicates that both PEM and micronutrient deficiencies increase the progression of HIV infection, and that HIV worsens malnutrition by means of its impairment of the immune system and its impact on nutrient intake, absorption, metabolism and storage (Piwoz 2000; Semba 1999). Current knowledge suggests that micronutrient deficiencies are common in HIV-infected children and adults, particularly those in developing communities where diets are inadequate, and that these deficiencies are more pronounced in individuals with advanced HIV disease (Buys 2001).

Although there are few well-conducted randomised clinical trials evaluating the efficacy of micronutrient interventions in HIV-infected populations, some published studies have shown that micronutrient supplementation can correct micronutrient deficiency states in some cases, even in malnourished individuals, and can thus help to reduce morbidity and mortality of HIV-infected individuals (Buys 2001). This is particularly important in places where anti-retroviral therapies are not readily available or affordable and where nutritional deficiencies are common because of dietary insufficiencies and recurrent infections. This is the case in many developing countries, where micronutrient supplements may be the only intervention available.

Many questions remain however regarding the changes in micronutrient metabolism and the consequent assessment of micronutrient status in HIV disease; the biochemical definitions of deficiency; the associations between deficiencies and clinical outcomes; the appropriate doses for supplementation; and how the effects of micronutrient supplements differ between children and adults.

Most studies investigating the micronutrient status of HIV-infected populations have employed serum or plasma levels of micronutrients, a widely used method for assessing the status of many micronutrients. It is important to bear in mind that serum or plasma levels have a complex relationship with dietary intake, comprising of both a short-term component reflecting recent dietary intake and one or more long-term components, reflecting body stores. Thus, for certain micronutrients, serum or plasma levels may not be the most sensitive indicator of micronutrient status (Margetts 1997). Serum concentrations of several nutrients decline during the acute phase response, either because they are re-distributed in the body or because they are bound to negative acute phase proteins (Fleck 1989) or because they are lost during the inflammatory process e.g. vitamin A in urine (Stephenson 1994). The serum micronutrient status of HIV-infected individuals with acute infections should therefore be interpreted with caution due to potential misclassification (Fawzi 1998). There is also disagreement as to which biochemical cut-off point defines "deficiency" of a particular micronutrient, making direct comparisons between the micronutrient status of different study populations difficult (Semba 1997; Semba 1999).

At present, it is not known whether low serum or plasma levels of these micronutrients merely reflect disease progression in the way that an acute phase protein responds to an inflammatory process, or whether they indicate true deficiencies and independently contribute to HIV/AIDS disease progression. This distinction is important in order to determine whether it is worth intervening to correct poor micronutrient status and whether correction of blood micronutrient parameters can slow or alter the course of disease. (Piwoz 2000). In addition, it is not clear how well baseline micronutrient levels in study populations of HIV+ individuals represent nutritional status prior to seroconversion.

Finally, the effect of micronutrients given as daily supplements or as a treatment intervention for a limited period of time may be quite different between children and adults. Children have the additional requirements of normal growth and development, as well as an immature immune system that, while responding to the immense burden of disease of childhood, is compromised by the early acquisition of HIV.

In addition to these clinical questions, is the question of whether micronutrient interventions meet the public health criteria of necessity, safety, feasibility, affordability and applicability (Bijlsma 2000).

In conclusion, there is a need to systematically review the available evidence on the effectiveness of micronutrient supplementation in HIV-infected children and adults in order that clear recommendations can be made for clinical and public health practice and for further research.


To assess whether micronutrient interventions are effective in reducing morbidity and mortality among HIV-infected children and adults.

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) of any micronutrient intervention aimed at decreasing the risk of any infections and of mortality due to HIV infection compared with placebo or no treatment.
RCTs comparing any two or more micronutrient interventions aimed at decreasing the risk of any infections and mortality due to HIV infection.
Quasi-randomised trials will be excluded.

Types of participants

Children and adults with HIV1 or HIV2 infection in a hospital, outpatient clinic, or home care setting.

Types of intervention

  • 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)

  • Combinations of the above only

Types of outcome measures

  • Primary outcomes:

Mortality (HIV-related; all-cause);
Morbidity (frequency, type and duration of episodes of opportunistic infections; incidence of AIDS (as defined by each study); hospital admissions; and other illness types as measured in the studies)

  • Secondary outcomes:

-biochemical markers of micronutrient status;
-energy and micronutrient intakes;
-anthropometry and measures of body composition;
-indices of viral load;
-markers of immune response (absolute CD4+ counts; CD4+ percent of total lymphocytes);
-cognitive function;
-developmental indices;
-quality of life;

Outcome measures will be standardised where possible.
Any adverse events associated with supplementation will be described.

Search strategy for identification of studies

See: Unavailable search strategy

The search strategy will be based on that of the HIV Collaborative Review Group. This includes searches of the CENTRAL/CCTR databases in the Cochrane Library, MEDLINE, AIDSLINE, EMBASE, CINAHL, and Dissertation Abstracts International (DAI).
Hand searching will also be performed where necessary of journals, reference lists of articles, and conference proceedings (International AIDS conference; International Conference on HIV/AIDS in Africa (ICASA) ; International Conference of Nutrition; International Conference on Nutrition and HIV Infection; International Conference of Dietetics; International Vitamin A Consultative Group meetings; International Association of Physicians in AIDS Care (IAPAC); International Conference on Retroviruses and Opportunistic Infections; Global Strategies Conference For The Prevention Of Mother-To-Child-Transmission.
The search strategy will be iterative, in that references of included studies will be searched for additional references. All languages will be included.

Methods of the review

JI, MV and NR will review abstracts (or title and keywords if no abstract is available from the electronic search) independently to determine whether to retrieve the entire paper. Full text will not be examined in instances where all three reviewers agree that the study was not a randomised controlled trial.
All studies that appear to fit the criteria for inclusion will be selected independently for review by the three reviewers (JI, MV and NR).
A fourth reviewer (NS) will review the application of the inclusion criteria in the event of any disagreement.

Potential conflict of interest

None known.

Sources of support

External sources of support

  • No sources of support supplied

Internal sources of support

  • UCT Child Health Unit SOUTH AFRICA

  • South African Cochrane Centre SOUTH AFRICA

  • Medical Research Council SOUTH AFRICA