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Micronutrient supplementation in children and adults with HIV infection

  1. James JH Irlam1,*,
  2. Marianne ME Visser2,
  3. Nigel N Rollins3,
  4. Nandi Siegfried4

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 19 OCT 2005

Assessed as up-to-date: 1 AUG 2005

DOI: 10.1002/14651858.CD003650.pub2


How to Cite

Irlam JJH, Visser MME, Rollins NN, Siegfried N. Micronutrient supplementation in children and adults with HIV infection. Cochrane Database of Systematic Reviews 2005, Issue 4. Art. No.: CD003650. DOI: 10.1002/14651858.CD003650.pub2.

Author Information

  1. 1

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

  2. 2

    Welgemoed, Western Cape, South Africa

  3. 3

    University of Natal, Paediatrics, Durban, South Africa

  4. 4

    South African Medical Research Council, South African Cochrane Centre, Tygerberg, South Africa

*James JH Irlam, Primary Health Care Directorate, University of Cape Town, E47 Old Main Building, Groote Schuur Hospital, Observatory, Western Cape, 7925, South Africa. james.Irlam@uct.ac.za.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 19 OCT 2005

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This is not the most recent version of the article. View current version (08 DEC 2010)

 

Background

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

There is no doubt that the HIV/AIDS pandemic is one of the leading public health problems facing the world, and particularly in sub-Saharan Africa and Asia. Sub-Saharan Africa has just over 10% of the world's population, but is home to more than 60% of all people living with HIV, an estimated 25.4 million in 2004. An estimated 3.1 million people in the region became newly infected during 2004, while about 2.3 million died of AIDS (UNAIDS 2004).

HIV infection and malnutrition are inextricably interrelated in a vicious cycle of immune dysfunction, infectious disease, and malnutrition (Semba 1999). 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 micronutrient insufficiency. Like PEM, micronutrient malnutrition occurs as a result of an inadequate dietary intake, but the signs and symptoms are often lacking (Dijkhuizen 2001).

Micronutrient deficiencies are common in HIV-infected children and adults, particularly in developing communities where diets are inadequate, and they are more pronounced in individuals with advanced HIV disease (Buys 2001). Observational studies suggest that both PEM and micronutrient deficiencies may hasten 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).

Some studies (Baeten 2002b; Fawzi 1998) have shown that micronutrient supplementation can correct micronutrient deficiency states in malnourished HIV-infected individuals. It has been postulated that micronutrient supplementation can help to reduce morbidity and mortality of HIV-infected individuals (Semba 1999). This would be particularly significant for developing countries, where antiretroviral therapies are not readily available or affordable, and where nutritional deficiencies are common due to dietary insufficiencies and recurrent infections.

Many questions remain about the issues surrounding micronutrient deficiencies and supplementation. These include how to accurately assess micronutrient status in HIV-infected individuals with acute infections; how to determine biochemical cut-off points for deficiency; and how the effects of supplementation may differ between children and adults.

Most studies investigating the micronutrient status of HIV-infected populations report serum levels of micronutrients as measures of the status of many micronutrients. It is important to bear in mind, however, that serum levels have a complex relationship with dietary intake and absorption, consisting of a short-term component, reflecting recent dietary intake, and one or more long-term components, reflecting body stores, distribution and mobilisation during infections. The acute-phase response causes serum concentrations of several nutrients to decline during infections as a result of their redistribution in the body, binding to negative acute-phase proteins, or loss during the inflammatory process (Stephensen 1994). Serum levels may therefore not be the most sensitive indicator of the status of certain micronutrients (Margetts 1997), and so they must be interpreted with caution in HIV-infected individuals with acute infections (Fawzi 1998). Caution must also be exercised in using micronutrient levels at baseline to represent nutritional status prior to seroconversion, especially in pregnant women.

There is disagreement about the biochemical cut-off points that define deficiency of particular micronutrients, making direct comparisons between the micronutrient status of different study populations difficult (Semba 1999). It is also difficult to make inferences from adult populations about the effects of micronutrients in children, as these effects may be quite different for a number of reasons. Children not only have the requirements of normal growth and development, but also an immature immune system that is compromised by the early acquisition of HIV in its ability to deal with the immense burden of childhood disease.

The global scale and impact of the HIV/AIDS pandemic on health, nutrition, and overall socio-economic development has made the search for simple, affordable, safe, and effective public health interventions all the more urgent. Micronutrient supplements to improve the health status of people living with HIV and AIDS hold the promise of meeting these criteria, but their widespread use needs to be based on sound evidence of effectiveness and safety.

 

Objectives

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

The primary objective of this review is to assess whether micronutrient supplements are effective in reducing morbidity and mortality in adults and children with HIV infection.

 

Methods

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

Criteria for considering studies for this review

 

Types of studies

Only randomized controlled trials were considered for this review.

 

Types of participants

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

 

Types of interventions

Micronutrient supplements aimed at reducing the risk of mortality and morbidity in HIV-infected individuals, compared with placebo or no treatment. Micronutrients 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. Trials of vitamin A supplementation of HIV-infected pregnant women were excluded, as a Cochrane review has found no conclusive evidence that vitamin A reduces mother-to-child transmission of HIV and adverse pregnancy outcomes (Shey Wiysonge 2002).

 

Types of outcome measures

The primary outcomes considered were mortality and morbidity (HIV-associated and AIDS-defining infections, diarrhoea, lower respiratory tract infections), hospital admissions, and pregnancy outcomes. Secondary outcomes were viral load, markers of immune response (CD4, CD8 counts), serum levels of micronutrients, anthropometric measures, quality of life, and adverse effects

 

Search methods for identification of studies

The search strategy was based on that of the Cochrane HIV/AIDS Collaborative Review Group. Searches were performed of the Cochrane Library (CENTRAL), EMBASE, MEDLINE, AIDSearch, and CINAHL, using the following combination of search terms: (trace elements or vitamins or carotenoids) and (HIV-1 or HIV-2 or "HIV Infections" (MeSH) or Human Immunodeficiency Virus or Acquired Immunodeficiency Syndrome). In addition, proceedings were searched of the International Conference on HIV/AIDS in Africa (ICASA); the International Conference of Nutrition; the International Conference on Nutrition and HIV Infection; the International Conference of Dietetics; and the International Vitamin A Consultative Group. Researchers in the field and pharmaceutical companies were contacted in an effort to locate ongoing or unpublished trials.

 

Data collection and analysis

Three of the authors (JI, MV, and NR) independently reviewed abstracts of the search results to determine which should be retrieved in full text. These were then independently assessed by all three for eligibility. Two authors (JI and MV) independently appraised the eligible trials and extracted data using a standard data extraction form. The quality of each trial was appraised in terms of the method of randomisation; whether allocation was concealed; blinding; losses to follow-up; and whether the analysis was by "intention-to-treat" (ITT). The definition of an ITT that was used in this review was the requirement that participants be analyzed in the groups to which they were randomized, regardless of which intervention they actually received. The additional criterion that all participants should be included, regardless of whether their outcomes were actually collected, is contentious, and was therefore not applied in this review. Two of the authors (NS and NR) helped to resolve any queries about the methodological quality of the trials.

Data on outcomes were entered into the Review Manager (RevMan) software (version 4.2.7). Relative risks were calculated for dichotomous data and weighted mean differences for continuous data using a random effects model. . Trial authors were contacted if the outcomes data (numbers of participants with each outcome) were not presented in the published paper, and they were followed up once if no response was received at the first attempt. If no data were forthcoming, the outcome measures reported in the paper (relative risks, odds ratios, hazard ratios, or weighted mean differences) were used. Significant heterogeneity between studies precluded a meta-analysis.

 

Results

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

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Fifteen trials involving 3643 participants met the inclusion criteria; six of these trials were of vitamin A/beta-carotene in adults, four were of other micronutrients in adults, one trial was of multivitamins in pregnant and lactating women, and four trials were of vitamin A in children. No trials in children of micronutrient supplements other than vitamin A were found. Full details of the included trials are displayed in the table Characteristics of Included Studies. Twenty-one additional trials were excluded due to inadequate randomization of participants, use of interventions that were not exclusively micronutrients, or because the outcomes were not relevant to this review.

 

Risk of bias in included studies

Vitamin A/beta-carotene in adults with HIV infection
Allocation concealment was adequate in three of the six trials supplementing adults with vitamin A or beta-carotene, and unclear in the remaining three, which did not describe the method of randomisation. Placebo was given to participants, and treatment providers and assessors were blinded to the treatment assignments in all but one trial (Constans 1996). The duration of the follow-up periods ranged from 1 to 12 months and loss to follow-up from 3% to 31%. Intention-to-treat analyses were performed in two trials (Baeten 2002a, Coodley 1996).

Baeten 2002a
There was adequate allocation concealment. Placebo was used and field researchers were blinded to treatment assignments. Forty-six of 400 (11.5%) women did not return for follow-up, and the median time to follow-up was 42 days (range 32 to 445). Participants lost to follow-up had more advanced HIV-1 disease than those who completed the study, and were more likely to be vitamin A deficient. Analyses were on an intention-to-treat basis. A multivitamin arm was added after 100 participants had been enrolled but was not included in the reported analysis.

Constans 1996
This was a brief report on a small pilot study (n=52) in a hospital clinic setting of selenium or beta-carotene or no supplements. The method of randomization was not stated, and it was not stated whether outcome assessors were blinded. It was reported that the beta-carotene recipients had more advanced disease at baseline than the other participants. Four of 52 participants (7.7%) were lost to follow-up at 12 months.

Coodley 1993
The method of allocation concealment was adequate in this crossover trial. Placebo was used and blinding of patients and assessors was performed.

Coodley 1996
The method of randomization was not stated and the adequacy of allocation concealment is therefore unclear. Placebo was used and assessors were blind to the treatment assignments. Twenty-two of 72 participants (31%) were lost to follow-up at three months. Results were analysed on an intention-to-treat basis.

Humphrey 1999
The method of randomization was not stated. Placebo was used and assessors were blind to the treatment assignments. Only one of the 40 participants was lost to follow-up at two months. An intention-to-treat analysis was not performed.

Semba 1998
Allocation concealment was adequate and placebo was used in this double-blind trial. Ten of the 120 participants (8.3%) were lost to follow-up at one month. An intention-to-treat analysis was not performed.

Other micronutrients in adults with HIV infection
The method of randomization was not described in two of the four trials of other micronutrients to adults, and the adequacy of allocation concealment was judged adequate in only one trial (Jiamton 2003). Placebo was used in all trials. The duration of the follow-up periods ranged from four weeks to 12 months and loss to follow-up from 16% to 28%. Intention-to-treat analyses were conducted in two of the trials (Allard 1998a; Jiamton 2003).

Allard 1998a
Randomization was by means of a random-number table, but the method of allocation concealment was not clear from the trial report. Placebo was used and outcome assessors were blinded. Nine of 49 participants (18.4%) had baseline and follow-up measurements (one or two months) but were unable to keep their three-month appointments. An intention-to-treat analysis was performed.

Burbano 2002
This trial was poorly reported and contained several errors. The method of randomisation was not stated, and the adequacy of allocation concealment is therefore unclear. Placebo was used and assessors were blind to the treatment assignments. Data regarding hospital admissions were not available for 73 of 259 participants (28%); excluded participants were reportedly not significantly different from the 186 included patients with respect to socio-demographic and disease status. No intention-to-treat analysis was performed.

Jiamton 2003
Randomization was computer-generated and allocation concealment was adequate. Placebo was used and study physicians were blinded to the treatment assignments. Seventy-nine (16%) of 481 trial participants were lost to follow-up at 48 weeks and 23 (5%) died. An intention-to-treat analysis was performed.

Kelly 1999
The method of randomization was not described, and the adequacy of allocation concealment is therefore unclear. Placebo capsules were not identical to the micronutrient capsules but were not identifiable by any markings. Twenty-nine of 135 participants (21%) were lost to follow-up at four weeks, and sixty (44%) at 12 weeks. No intention-to-treat analysis was performed.

Multivitamins in pregnant and lactating women with HIV infection
A trial among 1078 pregnant and lactating women in urban Tanzania (Fawzi 1998) was designed to examine the effects of daily supplements of vitamin A or multivitamins (B, C, and E) or both on disease progression and on vertical transmission of HIV. A 2x2 factorial design was used to maximize the use of limited resources. Randomization was performed in blocks of 20 participants, and concealment of allocation (pre-labelled bottles) was adequate. Placebo was used and assessors were blinded. All children received a large dose of vitamin A every six months because of evidence of its protective effect against mortality. Vitamin A was dropped from two of the regimens in September 2000 and replaced with placebo because it was found to be associated with increased vertical transmission of HIV.

There was monthly follow-up at a study clinic or at home if necessary for a minimum of 18 months. Women were questioned about signs of HIV-related complications, and weight, height, and mid-upper arm circumference were determined. The WHO stage of HIV was assessed on the basis of the history and physical examination. Verbal autopsy techniques by means of standardized interviews, review of medical records or both were used to approximate causes of death, which were then ascertained in a blinded fashion.

Analyses were on an intention-to-treat basis, but it was not clear whether this applied to all-cause mortality as well. Data were reportedly censored at the time of death when cause of death could not be ascertained or was deemed to be not AIDS-related (100 out of 343 deaths from all causes over the entire duration of the study), but the basis for allocation of 'AIDS-related deaths' was unclear. Fifty-four of 1078 participants (27 from each group) were lost to follow-up by the time of delivery and were excluded from the analysis of birth outcomes. Subsequent losses to follow-up (other than deaths) were not described.

Vitamin A in children with HIV infection
Placebo was used in all four trials of vitamin A supplements given to children, and all were reported as double-blind. The method of randomization was not stated in one of the trials, allocation concealment was adequate in one trial, and intention-to-treat analyses were conducted in two trials.

Coutsoudis 1995
The study population in this trial comprised 118 offspring, 28 of whom were HIV-infected, of HIV-infected women. A table of random numbers was used for randomization of the children, but the adequacy of allocation concealment was unclear. Placebo was used and investigators were blinded to the treatment group of the participants. One-third of the participants were lost to follow-up by 18 months. An intention-to-treat analysis was performed.

There was monthly morbidity recall; multiple episodes of the same condition in a single month were counted as one episode (per 100 months). Diarrhoea was defined as four or more loose watery stools per day; persistent diarrhoea was defined as episodes lasting >= seven days. Upper respiratory tract infection was defined as the presence of one or more of the following: rhinitis, throat, or ear infection, cough. Lower respiratory tract infection was defined as presence of cough with one or more of the following: rapid breathing, chest indrawing, crackles, or wheezing.

Fawzi 1999
The study population in this trial was 687 children aged six months to five years hospitalized for pneumonia. HIV-infected children comprised fewer than a tenth (n=58). Block randomization using pre-numbered bottles was carried out, and concealment of allocation was adequate. Placebo was used and assessors were blind to the treatment assignments.

One-quarter of participants were lost to follow-up at four months, and results were analyzed on an intention-to-treat basis. Cause of death was ascertained by means of a review of the hospital records and home verbal autopsy questionnaires. There was bi-weekly morbidity recall. Acute diarrhoea was defined as < 14 days of watery or dysenteric stools, classified as either mild or severe. No data were provided on persistent diarrhoea among HIV-infected children. Respiratory infection was defined either as cough alone, cough and fever, or cough with rapid respiratory rate (>=50 breaths per minute for infants and >40 breaths per minute for children > one year) on the day of the visit.

Hanekom 2000
Randomization was computer-generated and allocation concealment was adequate. Placebo was used and the trial was reported as double-blind. Only one of the 59 participants was lost to follow-up at one month. No intention-to-treat analysis was performed.

Hussey 1996
The method of randomization was not stated and the adequacy of allocation concealment is therefore unclear. Placebo was used and assessors were blind to the treatment assignments. One of the 75 participants was lost to follow-up at two months. Children who received vitamin A were more immuno-suppressed than those in the placebo group.

 

Effects of interventions

Vitamin A/ Beta-carotene in adults with HIV infection
There was no overall effect of either vitamin A or beta-carotene on mortality, morbidity, viral load, or on CD8 cell counts in the six trials of vitamin A or beta-carotene that were included in the review. There were significant increases in serum levels in all the beta-carotene supplemented groups.

A one-year pilot study (n=52) of three treatments (beta-carotene, selenium, and no supplements) found no improvements in mortality, morbidity (opportunistic infections), or CD4 counts for either treatment regimen (Constans 1996). Two trials of a single high dose of vitamin A, one among 40 women of reproductive age (Humphrey 1999), and the other among 120 intravenous drug users (Semba 1998), found no effects up to two months on CD4 counts or viral load. The baseline prevalence of vitamin A deficiency (< 30 microgram/dl) was under 20%, and mean serum levels remained unchanged at four weeks.

A trial of vitamin A daily for six weeks to 400 Kenyan women with a high prevalence (59%) of vitamin A deficiency at baseline reported a slight increase in CD4 counts at follow-up, but this effect was not retained in multivariate analysis. There was no effect on CD8 counts or viral load. There was a significant increase in serum levels of vitamin A at six weeks in the supplemented group (median: 29.4 versus 26.8 microgram/dl; p<0.03), but not among a severely deficient (< 20 microgram/dl) sub-group (Baeten 2002a).

In a crossover trial among 21 American outpatients (Coodley 1993), high doses of beta-carotene supplements for one month (180mg/day) increased the CD4 counts and CD4/CD8 ratios compared to placebo. A later extended evaluation by the same author, where beta-carotene and multivitamins were administered for three months, found no effect on CD4 or CD8 counts, nor on measures of body weight or quality of life (measured by Karnofsky scores) (Coodley 1996).

Minor adverse events, such as the discoloration of skin, were reported in a beta-carotene supplemented group (Coodley 1993). Humphrey et al reported adverse events (nausea, headache, vomiting, diarrhoea, and fever) in a vitamin A trial, but the incidence did not differ significantly from the placebo group (Humphrey 1999).

Other micronutrients in adults with HIV infection
Among 135 adults with persistent diarrhoea in Zambia, a daily oral supplement of multi-micronutrients (vitamins A, C, and E, selenium, zinc) for two weeks, in addition to albendazole, had no effects on mortality or on CD4 cell counts after four weeks. No differences in diarrhoeal morbidity (time with diarrhoea following completion of treatment), body mass index (BMI), Karnofsky scores or vitamin A levels were observed during a 12-week follow-up period. At baseline, 63% of participants had vitamin A concentrations compatible with vitamin A deficiency (< 20 microgram/dl), and 55% were classified vitamin E deficient (< 500 microgram/dl). Vitamin A levels did not increase significantly in supplemented patients compared with placebo (Kelly 1999).

One small (n=49) Canadian trial of large daily supplements of vitamins E and C for three months reduced measures of oxidative stress (serum lipid peroxides, serum malondialdehyde, and breath pentane) but had no significant effect on HIV viral load over three months. No significant differences in the number of new or recurrent AIDS-defining, HIV-associated or other infections (bronchitis, line sepsis, otitis media) were found during a six-month follow-up period. The vitamin E and C serum levels at three months were significantly higher in the treatment group, (mean (+/- SD) micromol/l): Vitamin E 30(21.9) versus 1.3 (5.3), p<0.005; Vitamin C 33.3 (27) versus 6 (24.5), p< 0.005), but no change was noted in the levels of vitamin A, carotenoids, zinc and selenium (Allard 1998a).

In a trial of 481 HIV-infected individuals in Thailand, daily supplementation with a comprehensive mix of vitamins and minerals at dosages up to 20 times higher than the recommended daily allowance had no effect on mortality of all enrolled participants. A trend towards a reduced death rate in those with CD4 counts <200x106/l at baseline was reported after 48 weeks of follow-up (mortality hazard ratio = 0.37; p= 0.052) and a significant effect in individuals with a CD4 count less than 100 x106/l, where mortality was reduced by 74% (HR = 0.26; 95%CI: 0.07-0.97; p=0.03). CD4 cell counts, viral load or rates of hospital admissions were not affected (Jiamton 2003).

Burbano 2002 found that daily selenium supplements for 12 months among drug users (n = 186) had no significant effect on the numbers of patients admitted for all conditions (RR = 0.89; 95% CI: 0.58-1.36). Selenium did reduce the absolute risk of admissions for opportunistic infections, HIV-related conditions and psychiatric disorders by 18.6% (RR = 0.40; 95% CI: 0.21-0.75), and the mean number of admissions per patient with these conditions (WMD = 0.24; 95% CI:-0.46, -0.02). Significantly fewer patients in the selenium group (RR = 0.53; 95% CI: 0.35-0.81) experienced a decline in CD4 counts greater than 50 cells/mm3, and fewer had lowered serum levels of selenium (< 135 microgram/L) at 12 months (RR = 0.53; 95% CI: 0.42-0.67).

Reported side effects of supplementation in the above trials included discoloration of urine, nausea, drowsiness, dizziness, headache, rash, and epigastric discomfort, but no significant differences apart from the urine discoloration were detected between treatment groups (Allard 1998a; Jiamton 2003). Kelly et al (Kelly 1999) reported no adverse events and the other trials made no mention of them.

Multivitamins in pregnant and lactating women with HIV infection
In a large Tanzanian trial in pregnant and lactating women (Fawzi 1998), multivitamins, mainly vitamins B, C and E, at doses up to 22 times recommended daily intakes, resulted in significant reductions over the entire period of follow-up (mean = 61.4 months for survival, median = 60 months for stage of disease) in the risk of progression to stage 4 disease or mortality from AIDS-related causes (Reported Hazard Ratio = 0.71; 95% CI: 0.51-0.98); in the risk of progression to stage 4 disease (Reported HR = 0.50; 95% CI: 0.28-0.90); and in the risk of progression to stage 3 disease or higher (Reported HR = 0.72; 95% CI: 0.58-0.90). Multivitamins also reduced maternal viral load and all signs of HIV-related complications, and raised maternal CD4 and CD8 counts, compared to no multivitamins (vitamin A only or placebo). The effects of vitamin A only were smaller and generally not significantly different from placebo. Adding vitamin A to the multivitamin regimen reduced the benefit with regard to all maternal outcomes. There was a modest improvement in average gestational weight gain during the third trimester in the multivitamin group (mean difference compared to no multivitamins = 304 g; 95% CI: 17- 590 between week 27 and delivery), and a reduced risk of low rate of weight gain (<= 100g per week) (RR = 0.73; 95% CI: 0.58- 0.93).

Multivitamins reduced adverse pregnancy outcomes, including foetal deaths by 39% (RR = 0.61; 95% CI: 0.39-0.94), low birth weights (LBWs) by 45% (RR = 0.55; 95% CI: 0.38-0.81), severe preterm births (<34 weeks) by 39% (RR = 0.61; 95% CI: 0.38-0.95), and those who were small for gestational age (SGA) at birth by 43% (RR = 0.57; 95% CI: 0.40-0.83). Mean birthweight was significantly higher in infants born HIV-negative to mothers in the supplemented group (mean difference = 94 g, p = 0.02 in multivariate analysis).

In women with low immunological or nutritional status, significant reductions were reported in child mortality by 24 months: 70% (RR = 0.30; 95% CI: 0.1-0.92) in women in the lowest quartile of lymphocyte counts (<1340/ mm3); 60% (RR = 0.40; 95% CI: 0.17-0.98) in women with low baseline vitamin A (<20 microgram/dl); and 69% (RR = 0.31; 95% CI: 0.13-0.73) in women with low baseline vitamin E (<9.7 micromol/l). No effects were seen when these outcomes were analysed according to CD4 and CD8 counts.

Maternal supplementation during breastfeeding reduced the risk of diarrhoea up to 24 months in all children by 17% (RR = 0.83; 95% CI: 0.71-0.98), and it raised their CD4 counts (WMD = 153.00 cells/microl; 95% CI: 67.6- 238.4) by six months of age.

Vitamin A in children with HIV infection
Large doses of vitamin A given intermittently to children aged 6-59 months admitted with pneumonia to a Tanzanian hospital (n = 687) reduced all-cause mortality by 49% (RR = 0.51 ; 95% CI: 0.29-0.90) and deaths from diarrhoea by 93% (RR = 0.07 ; 95% CI: 0.00-0.49) during a two-year follow-up period. In 58 HIV-infected children (9% of the total), all-cause mortality was reduced by 63% (RR = 0.37; 95% CI: 0.17-0.84) and the AIDS-related deaths by 68% (RR = 0.32; 95% CI: 0.1-0.99 compared to placebo. A marginal reduction in cough and rapid respiratory rate was reported (RR = 0.54; 95% CI: 0.24-1.20), but there was no effect on the risk of acute diarrhoea. After four months of supplementation, the mean difference in attained height between HIV-infected children under 18 months of age and controls was 2.8 cm (95% CI: 1.0-4.6) (Fawzi 1999).

Supplementation at 3-month intervals of all children born to a population of 118 HIV-infected women in South Africa, reduced all-cause morbidity by a third (OR = 0.69; 95% CI: 0.48-0.99) during 18 months of follow-up post-partum. In 28 children who were known to be HIV-infected at birth, diarrhoea-associated morbidity was reduced by 38% (RR = 0.62; 95% CI: 0.39-0.98) (Coutsoudis 1995).

Vitamin A given to 59 HIV-infected American children before influenza vaccination did not enhance serologic responses, but did dampen the increase in the HIV viral load 14 days after immunisation (p = 0.02) (Hanekom 2000). In 75 children with AIDS attending a South African children's hospital, vitamin A supplementation was associated with increased CD4 counts at four weeks (p = 0.03) (Hussey 1996).

Adverse effects of vitamin A in children included vomiting and bulging fontanelle (Coutsoudis 1995); an increased risk of cough and rapid respiratory rate, and an increased risk of diarrhoea in normally nourished (RR = 1.3 ; 95% CI: 1.06-1.79) and growth-stunted children (RR = 1.84 ; 95% CI: 1.16-2.90) (Fawzi 1999).

Other micronutrients in children with HIV infection
There have been no studies published to date of the effect of supplements such as zinc, given alone, or in combination with vitamin A or other micronutrients, in HIV-infected children with acute or persistent diarrhoea.

 

Discussion

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

Vitamin A/beta-carotene in adults with HIV infection
Despite the evidence from a number of longitudinal studies (Semba 1993; Semba 1995; Tang 1993) of the relationship between low serum levels of vitamin A and HIV disease progression and mortality in adults, six vitamin A trials reviewed failed to show any short-term benefits of vitamin A or beta-carotene supplements on mortality, morbidity, CD4 and CD8 counts, or viral load in adults. None of the trials, with the exception of one small pilot study (Constans 1996), followed up participants for longer than three months and were therefore unable to evaluate long-term effects.

The study populations in two of the trials (Humphrey 1999; Semba 1998) were not generally vitamin A deficient, which may account for the absence of effect of supplementation on mean serum levels. But in a trial among Kenyan women with a high prevalence of deficiency (Baeten 2002a), supplementation did not raise vitamin A levels among severely deficient women. A possible explanation for this is that low vitamin A levels reflected more active HIV infection rather than true deficiency.

High doses of beta-carotene had no effect in American outpatients, although the authors suggest that the multivitamin supplement used in both study groups may have masked any real differences (Coodley 1996).

Other micronutrients in adults with HIV infection
A Zambian trial of daily oral supplements for two weeks of multi-micronutrients (vitamins A, C, and E, selenium, zinc) (Kelly 1999) was primarily designed to test whether micronutrient supplementation improves the clinical response to albendazole in the treatment of persistent diarrhoea in adults with HIV-wasting, rather than the direct efficacy of the micronutrients. This fact may account for the absence of effect on morbidity and mortality. The lack of effect on serum vitamin A levels and all clinical outcomes may be a real finding or may be due to impaired absorption or mobilisation of retinol stores, inadequate duration of supplementation, or the acute phase response. Although supplements of vitamin A with zinc are routinely used for treating persistent diarrhoea in HIV-uninfected children, they may not be effective in HIV-infected adults due to significant differences in the causes of diarrhoea.

Increased oxidative stress, which is postulated to enhance replication of HIV, has been measured in HIV-infected populations (Allard 1998b; Walmsley 1997). Although a small Canadian trial of vitamin C and E reported a significant reduction in measures of oxidative stress, it failed to demonstrate a significant reduction in viral load or morbidity (Allard 1998a). Nevertheless, the trend towards reduction in viral load may be worthy of investigation in larger clinical trials with morbidity as a primary outcome.

Although a large trial in Thailand of multiple high dose micronutrients in HIV-infected adults reported no effect on CD4 count, viral load or overall mortality, it did show a significant reduction in the death rate in the most immuno-compromised sub-group (CD4<100x106/l at baseline) and a trend in those less compromised (Jiamton 2003). This was the first trial of multiple micronutrients to demonstrate a clinical benefit, one that appeared to be independent of viral load and CD4 count. The authors suggest that several micronutrients, such as selenium, zinc, and vitamin A, enhance T-lymphocyte function or improve one or more components of the innate immune response, whereas antioxidants limit tissue damage resulting from inflammatory responses. The lower-than-expected death rate reduced the power of the trial however, and was ascribed to factors such as a selection bias favouring healthier participants, loss to follow-up of sicker participants, access to antiretroviral drugs, and improved counselling and care of participants.

Some observational studies suggest that a low serum selenium status is predictive of disease progression and mortality in HIV-infected adults and children (Baum 1997, Campa 1999). An American clinic-based trial of daily selenium supplements for 12 months in drug users found that they reduced admissions for opportunistic infections, HIV-related conditions and psychiatric disorders of patients who were not selenium-deficient at baseline, but the numbers were small and the trial was poorly reported (Burbano 2002). This finding requires confirmation in trials of other HIV-infected populations. .

Multivitamins in pregnant and lactating women with HIV infection
Multivitamin supplements (MVS) to pregnant and lactating women in a large Tanzanian trial appeared to slow HIV-disease progression and reduce AIDS-related mortality (Fawzi 1998). There are, however, several issues to be considered before generalising these results to other HIV-infected populations.

As with the Thai study discussed above (Jiamton 2003), the doses of some of the vitamins provided were significantly in excess of normal requirements, ranging from twice to 22 times the RDA. The formulation was not based on preliminary pharmacokinetic studies, but on the prevalence of deficiencies according to self-reported intakes of HIV-infected homosexual men in Miami USA (Baum 1994). It is not possible to determine from the data currently available whether a markedly lower dosage micronutrient regimen would have been equally effective. The addition of 'Vitamin A' (both preformed retinol and a high dose of beta-carotene (30mg)) apparently reduced the benefits of the multiple micronutrient supplement. When preformed retinol only was given to HIV-infected pregnant women in other African studies (Friis 2004, Kumwenda 2002, Semba 2001, Humphrey 1999), it resulted in beneficial outcomes or had no effect at all. Beta-carotene has been found to have adverse outcomes in cancer studies (ATBC 1994, ATBC 1996, Omenn 1996) however, possibly because it became a pro-oxidant rather than behaving as expected as an antioxidant. This change in the function of beta-carotene might be due to its use in combination with multivitamins or high dose iron, rather than as a single supplement. In addition, the reduced morbidity that was reported may not strictly be an HIV-specific effect, as HIV-free women in a nutritionally depleted population might also benefit from similar supplementation; an uninfected study group would therefore be required to determine this with certainty.

Multivitamin supplements also appeared to benefit the children of supplemented women, improving the mean birthweight of those born HIV-negative and reducing the risks of adverse pregnancy outcomes. There was also a reduction in early mortality (0-24 months) of children born to immunologically and nutritionally compromised infected women. These benefits may have been due to an improvement in the micronutrient and immunological quality of the mothers' breastmilk, which consequently improved the micronutrient intake and thus enhanced the immune systems of their children. It is also possible that an improvement in mothers' health status enabled them to provide better care for their children.

Further investigation is required to determine whether these benefits are reproduced in other settings. If so, this would have important implications for the developing world especially, where many people with advanced disease have no access to anti-retroviral treatment.

Vitamin A in children with HIV infection
The beneficial effects of vitamin A supplementation on child mortality, morbidity, and growth reported from Tanzania (Fawzi 1999) may be due to an improvement in cellular and humoral immunity, and the rehabilitation of mucosal integrity. This may in turn lead to a reduction in the severity and incidence of diarrhoeal infection, which would improve short-term growth.

Intermittent supplementation reduced all-cause morbidity in children of HIV-infected women and diarrhoeal morbidity among the subgroup of HIV-infected children in a South African trial (Coutsoudis 1995). This effect may be explained by vitamin A limiting oxidative damage, and thus enabling an effective immune response and promoting epithelial repair in the gut. The reduction in morbidity was stronger with increasing severity of diarrhoea, suggesting that the benefits were due to a reduction in the severity, rather than in the frequency, of diarrhoeal episodes.

Other micronutrients in children with HIV infection
Vitamin A and zinc supplements are considered standard care in children without HIV infection presenting with persistent diarrhoea. Vitamin A is given as a prophylactic measure to reduce the likelihood of recurrence of severe diarrhoea, and does not appear to influence the early phase of recovery. Zinc improves recovery of gut mucosa (Alam 1994; Roy 1992) and reduces the duration of diarrhoea and the likelihood of recurrence of persistent diarrhoea in children without HIV infection (Baqui 2002; Bhandari 2002; Strand 2002). No published studies of the effects of zinc in HIV-infected children with acute or persistent diarrhoea were found however.

 

Authors' conclusions

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

 

Implications for practice

There is no conclusive evidence at present that micronutrient supplementation effectively reduces or increases morbidity and mortality in HIV-infected adults, including pregnant and lactating women.

In the absence of this evidence, it is reasonable to support the WHO recommendations that everything possible should be done to promote and support adequate dietary intake of micronutrients at RDA levels, while recognising that this may not be sufficient to correct nutritional deficiencies in HIV-infected individuals (WHO 2003).

There is evidence of clinical benefit from two trials in children that supports the current WHO recommendation of periodic (every 4-6 months) vitamin A supplementation in children, including those infected with HIV, living in resource-limited settings (100 000 IU for infants 6 to 12 months, and 200 000 IU for children older than 12 months). Although the HIV-infected subgroups in each trial were small, the evidence indicates that the benefit that they derived from supplementation is the same as for children without HIV

 
Implications for research

Large trials with sufficient duration of follow-up are required to answer many remaining clinically important questions. These questions include a description of the clinical benefits and adverse effects of micronutrient supplements in the long term, especially in individuals who are HIV-infected and not yet symptomatic, and in those not fulfilling the requirements for anti-retroviral treatment (ARV).

Further valid research questions include the interactions between micronutrients and ARVs; the optimal dosage and composition of supplements; the question of whether immuno-compromised individuals benefit more from multiple micronutrient supplements than those with normal immune function; and the effects of supplementation other than vitamin A in children.

 

Acknowledgements

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

We are grateful to the South African Cochrane Centre and the editorial base of the HIV/AIDS Cochrane Review Group for their assistance in preparing this review, to Dr Lize van der Merwe of the Medical Research Council for her assistance with interpretation and presentation of the statistics, and to Dr Charles Shey Wiysonge for his comments on the draft. A bursary award from the Cochrane Child Health Field is also gratefully acknowledged.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Vitamin A / beta-carotene vs placebo to adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CD4 count >=3 months follow-up1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 CD8 count >= 3 months follow-up1Mean Difference (IV, Random, 95% CI)Subtotals only

 3 Viral load at < 3 months follow-up1Mean Difference (IV, Random, 95% CI)Subtotals only

 4 Mean bodyweight1Mean Difference (IV, Random, 95% CI)Subtotals only

 5 Karnofsky score1Mean Difference (IV, Random, 95% CI)Subtotals only

 
Comparison 2. Other micronutrients vs placebo to adults

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality (all cause) by 48 weeks1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 2 Mortality by 48 weeks (baseline CD4 < 200)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 3 Mortality by 48 weeks (baseline CD4 >= 200)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 4 Mortality by 48 weeks (baseline CD4 < 100)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 5 Mortality by 48 weeks (baseline CD4 >=100)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 6 New AIDS -defining infections1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 7 New HIV-associated infections1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 8 New other infections1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 9 Recurrent HIV-associated infections1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 10 Recurrent other infections1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 11 Hospital admissions for all conditions1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 12 Mean number of hospitalisations (OIs, HIV-related, psychiatric) per patient1Mean Difference (IV, Random, 95% CI)Subtotals only

 13 Number of patients hospitalised for all conditions1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 14 Patients hospitalised for OIs, HIV-related conditions and psychiatric disorders1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 15 Decline in CD4 counts > 50 cells per cubic mm after 12 months1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 16 Lowered plasma selenium levels (< 135 microg/L) after 12 months1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 17 Change in HIV viral load over 3 months1Mean Difference (IV, Random, 95% CI)Subtotals only

 18 Mortality (all cause) by 48 weeks1Hazard ratio (Random, 95% CI)Subtotals only

 19 Mortality by 48 weeks (baseline CD4 < 200)1Hazard ratio (Random, 95% CI)Subtotals only

 20 Mortality by 48 weeks (baseline CD4 >= 200)1Hazard ratio (Random, 95% CI)Subtotals only

 21 Mortality by 48 weeks (baseline CD4 < 100)1Hazard ratio (Random, 95% CI)Subtotals only

 22 Mortality by 48 weeks (baseline CD4 >=100)1Hazard ratio (Random, 95% CI)Subtotals only

 
Comparison 3. Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes]

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 CD4 < 3 months1Mean Difference (IV, Random, 95% CI)Subtotals only

 2 CD4 >= 3 months1Mean Difference (IV, Random, 95% CI)Subtotals only

 3 CD4 difference (< 3 months)1Mean Difference (IV, Random, 95% CI)Subtotals only

 4 CD4 difference (>= 3 months)1Mean Difference (IV, Random, 95% CI)Subtotals only

 5 CD8 < 3 months1Mean Difference (IV, Random, 95% CI)Subtotals only

 6 CD8 >= 3 months1Mean Difference (IV, Random, 95% CI)Subtotals only

 7 CD8 difference (< 3 months)1Mean Difference (IV, Random, 95% CI)Subtotals only

 8 CD8 difference (>= 3 months)1Mean Difference (IV, Random, 95% CI)Subtotals only

 9 Total maternal weight gain1Mean Difference (IV, Random, 95% CI)Subtotals only

 10 Maternal weight gain in third trimester1Mean Difference (IV, Random, 95% CI)Subtotals only

 11 Progression to stage 4 or death from AIDS-related causes1Hazard ratio (Random, 95% CI)Subtotals only

 12 Death from AIDS-related causes1Hazard ratio (Random, 95% CI)Subtotals only

 13 Progression to stage 4 disease1Hazard ratio (Random, 95% CI)Subtotals only

 14 Progression to stage 3 disease or higher1Hazard ratio (Random, 95% CI)Subtotals only

 15 HIV-related complications: thrush1Hazard ratio (Random, 95% CI)Subtotals only

 16 HIV-related complications: gingival erythema1Hazard ratio (Random, 95% CI)Subtotals only

 17 HIV-related complications: angular cheilitis1Hazard ratio (Random, 95% CI)Subtotals only

 18 HIV-related complications: oral ulcer1Hazard ratio (Random, 95% CI)Subtotals only

 19 HIV-related complications: reported mouth and throat ulcers1Hazard ratio (Random, 95% CI)Subtotals only

 20 HIV-related complications: painful tongue or mouth1Hazard ratio (Random, 95% CI)Subtotals only

 21 HIV-related complications: difficult or painful swallowing1Hazard ratio (Random, 95% CI)Subtotals only

 22 HIV-related complications: nausea and vomiting1Hazard ratio (Random, 95% CI)Subtotals only

 23 HIV-related complications: diarrhoea1Hazard ratio (Random, 95% CI)Subtotals only

 24 HIV-related complications: dysentery1Hazard ratio (Random, 95% CI)Subtotals only

 25 HIV-related complications: fatigue1Hazard ratio (Random, 95% CI)Subtotals only

 26 HIV-related complications: rash1Hazard ratio (Random, 95% CI)Subtotals only

 27 HIV-related complications: acute upper respiratory tract infection1Hazard ratio (Random, 95% CI)Subtotals only

 
Comparison 4. Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes]

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Foetal death (miscarriage+stillbirth)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 2 Total mortality by 24 months including foetal deaths1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 3 Mortality by 24 months among all live births1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 4 Mortality by 24 months among HIV-infected live births1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 5 Mortality by 24 months among HIV-infected infants at 6 weeks of age1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 6 Mean birthweight1Mean Difference (IV, Random, 95% CI)Subtotals only

 7 Birthweight < 2000 g1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 8 Birthweight < 2500 g1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 9 Preterm birth (<37 weeks)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 10 Severe preterm birth (<34 weeks)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 11 Small for gestational age1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 12 CD4 count >= 3 months1Mean Difference (IV, Random, 95% CI)Subtotals only

 
Comparison 5. Vitamin A vs placebo to children

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All-cause mortality1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 2 All-cause morbidity1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 3 Diarrhoeal morbidity1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 4 Persistent diarrhoea (>= 7 days)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 5 Lower respiratory tract infections (LRTI)1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 6 Hospitalised for diarrhoea1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 7 Hospitalised for LRTI1Risk Ratio (M-H, Random, 95% CI)Subtotals only

 8 Mean change in viral load after influenza vaccination1Mean Difference (IV, Random, 95% CI)Subtotals only

 

What's new

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

Last assessed as up-to-date: 1 August 2005.


DateEventDescription

29 October 2008AmendedConverted to new review format.



 

History

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

Protocol first published: Issue 4, 2003
Review first published: Issue 4, 2005


DateEventDescription

2 August 2005New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

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

J. Irlam (JI) initiated the review and contributed to all stages.
M. Visser (MV) assisted with all stages of the review.
N. Rollins (NR) assisted with study selection and review of the report.
N. Siegfried (NS) mentored JI and MV and assisted with study selection and review of the report.

 

Declarations of interest

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

None.

 

Sources of support

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

Internal sources

  • SACC HIV/AIDS Mentoring Programme, South Africa.
  • South African Cochrane Centre, South Africa.
  • Medical Research Council, South Africa.
  • UCT Primary Health Care Directorate, South Africa.
  • UCT Child Health Unit, South Africa.

 

External sources

  • Cochrane Child Health Field, Canada.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Allard 1998a {published data only}
  • Allard JP, Aghdassi E, Chau J, Tam C, Kovacs CM, Salit IE, et al. Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects. AIDS 1998;12(13):1653-9.
Baeten 2002a {published data only}
  • Baeten JM, McClelland RS, Overbaugh J, Richardson BA, Emery S, Lavreys L, et al. Vitamin A supplementation and human immunodeficiency virus type 1 shedding in women: results of a randomized clinical trial. The Journal of Infectious Diseases 2002;185(8):1187-91.
Burbano 2002 {published data only}
  • Burbano X, Miguez-Burbano MJ, McCollister K, Zhang G, Rodriguez A, Ruiz P, et al. Impact of a selenium chemoprevention clinical trial on hospital admissions of HIV-infected participants. HIV Clinical Trials 2002;3(6):483-91.
Constans 1996 {published data only}
  • Constans J, Delmas-Beauvieux MC, Sergeant C, Peuchant E, Pellegrin JL, Pellegrin I, et al. One-year antioxidant supplementation with beta-carotene or selenium for patients infected with human immunodeficiency virus: a pilot study. Clinical Infectious Diseases 1996; Vol. 23, issue 3:654-6.
Coodley 1993 {published data only}
Coodley 1996 {published data only}
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 1998 {published data only}
  • Fawzi WW, Msamanga GI, Hunter D, Renjifo B, Antelman G, Bang H, et al. Randomized trial of vitamin supplements in relation to transmission of HIV-1 through breastfeeding and early child mortality. AIDS 2002;16(14):1935-42.
  • Fawzi WW, Msamanga GI, Hunter D, Urassa E, Renjifo B, Mwakagile D, et al. Randomized trial of vitamin supplements in relation to vertical transmission of HIV-1 in Tanzania. Journal of Acquired Immune Deficiency Syndromes 2000;23:246-54.
  • Fawzi WW, Msamanga GI, Spiegelman D, Urassa E, McGrath N, Mwakagile D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. The Lancet 1998;351:1477-82.
  • Fawzi WW, Msamanga GI, Spiegelman D, Wei R, Kapiga S, Villamor E, et al. A randomized trial of multivitamin supplements and HIV disease progression and mortality. The New England Journal of Medicine 2004;351(1):23-32.
  • Fawzi WW, Msamanga GI, Wei R, Spiegelman D, Antelman G, Villamor E, et al. Effect of providing vitamin supplements to HIV-infected lactating mothers on the child's morbidity and CD4+ cell counts. Clinical Infectious Diseases 2003;36:1053-62.
  • Villamor E, Msamanga GI, Spiegelman D, Antelman G, Peterson KE, Hunter DJ, et al. Effect of multivitamin and vitamin A supplements on weight gain during pregnancy among HIV-1-infected women. The American Journal of Clinical Nutrition 2002;76(5):1082-90.
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.
Humphrey 1999 {published data only}
  • Humphrey JH, Quinn T, Fine D, Lederman H, Yamini-Roodsari S, Wu LS, et al. Short-term effects of large-dose vitamin A supplementation on viral load and immune response in HIV-infected women. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1999;20(1):44-51.
Hussey 1996 {published data only}
  • Hussey G, Hughes J, Potgieter S, Kessow G, Burgess J, Beatty D, et al. 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.
Jiamton 2003 {published data only}
  • Jiamton S, Pepin J, Suttent R, Filteau S, Mahakkanukrauh B, Hanshaoworakul W, et al. A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok. AIDS 2003;17:2461-9.
Kelly 1999 {published data only}
  • Kelly P, Musonda R, Kafwembe E, Kaetano L, Keane E, Farthing M. Micronutrient supplementation in the AIDS diarrhoea-wasting syndrome in Zambia: a randomized controlled trial. AIDS 1999;13(4):495-500.
Semba 1998 {published data only}
  • Semba RD, Lyles CM, Margolick JB, Caiaffa WT, Farzadegan H, Cohn S, et al. Vitamin A supplementation and human immunodeficiency virus load in injection drug users. The Journal of Infectious Diseases 1998;177(3):611-6.

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Austin 2003 {published data only}
  • Austin J, Voigt R, Smaill F, Gill J, Walmsley S, Gilmour J, et al. A randomised controlled trial of daily multivitamin with or without mixed carotenoid supplementtation in advanced HIV disease. International Conference on AIDS. 2000.
Baeten 2002b {published data only}
  • Baeten JM, McClelland RS, Richardson BA, Bankson DD, Lavreys L, Wener MH, et al. Vitamin A deficiency and the acute phase response among HIV-1-infected and -uninfected women in Kenya. Journal of Acquired Immune Deficiency Syndromes 2002;31(2):243-9.
Batterham 2001 {published data only}
  • Batterham M, Gold J, Naidoo D, et al. A preliminary open label dose comparison using an antioxidant regimen to determine the effect of viral load and oxidative stress in men with HIV/AIDS. European Journal of Clinical Nutrition 2001;55(2):107-114.
Coutsoudis 1997 {published data only}
  • Coutsoudis A, Moodley D, Pillay K, Harrigan R, Stone C, Moodley J, et al. Effects of vitamin A supplementation on viral load in HIV1-infected pregnant women. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1997;15(1):86-87.
Coutsoudis 1999 {published data only}
  • Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban, South Africa. South African Vitamin A Study Group. AIDS 1999;13(12):1517-24.
Delmas-Beauvieu 1996 {published data only}
  • Delmas-Beauvieux MC, Peuchant E, Couchouron A, Constans J, Sergeant C, Simonoff M, et al. The enzymatic antioxidant system in blood and glutathione status in human immunodeficiency virus (HIV)-infected patients: effects of supplementation with selenium or beta-carotene. The American Journal of Clinical Nutrition 1996;64(1):101-7.
Fawzi 2000 {published data only}
  • Fawzi WW, Msamanga G, Hunter D, et al. Randomized trial of vitamin supplements in relation to vertical transmission of HIV-1 in Tanzania. Journal of Acquired Immune Deficiency Syndromes 2000;23(3):246-54.
Filteau 2001 {published data only}
  • 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.
Gomo 2003 {published data only}
  • Gomo E, Filteau SM, Tomkons AM, Ndhlovu P, Fleischer Michaelsen K, Friis H. Subclinical mastitis among HIV-infected and uninfected Zimbabwean women participating in multimicronutrient supplementation trial. Transactions of the Royal Society of Tropical Medicine and Hygiene 2003;97:212-6.
Jaruga 2002 {published data only}
  • Jaruga P, Jaruga B, Gackowski D, Olczak A, Halota W, Pawlowska M, et al. Supplementation with anti-oxidant vitamins prevents oxidative modification of DNA in lymphocytes of HIV-infected patients. Free Radical Biology & Medicine 2002;32(5):414-420.
Kennedy 2000 {published data only}
  • Kennedy CM, Coutsoudis A, Kuhn L, PIllay K, Mburu A, Stein Z, et al. Randomized controlled trial assessing the effect of vitamin A supplementation on maternal morbidity during pregnancy and postpartum among HIV-infected women. Journal of Acquired Immune Deficiency Syndromes 2000;24(1):37-44.
Kennedy-Oji 2001 {published data only}
  • Kennedy-Oji, Coutsoudis A, Kuhn L, Pillay K, Mburu A, Stein Z, et al. Effects of vitamin A supplementation during pregnancy and early lactation on bodyweight of South African HIV-infected women. Journal of Health, Population, and Nutrition 2001;19(3):167-76.
Kumwenda 2002 {published data only}
  • Kumwenda N, Miotti PG, Taha TE, Broadhead R, Biggar RJ, Jackson JB, et al. Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi. Clinical Infectious Diseases 2002;35(5):618-24.
Li-Weber 2002 {published data only}
  • Li-Weber M, Weigand MA, Giaisi M, Suss D, Treiber MK, Baumann S, et al. Vitamin E inhibits CD95 ligand expression and protects T cells from activation-induced cell death. The Journal of Clinical Investigation 2002;110(5):681-90.
Look 1998 {published data only}
  • Look MP, Rockstroh JK, Rao GS, Barton S, Lemoch H, Kaiser R, et al. Sodium selenite and N-acetylcysteine in antiretroviral-naive HIV-1-infected patients: a randomised, controlled pilot study. European Journal of Clinical Investigation 1998;28(5):389-97.
Mocchegiani 1995 {published data only}
  • Mocchegiani E, Veccia S, Ancarani F, Scalise G, Fabris N. Benefit of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS. International Journal of Immunopharmacology 1995;17(9):719-27.
Nimmagadda 1998 {published data only}
  • Nimmagadda AP, Burri BJ, Neidlinger T, O'Brien WA, Goetz MB. Effect of oral beta-carotene supplementation on plasma human immunodeficiency virus (HIV) RNA levels and CD4+ cell counts in HIV-infected patients. Clinical Infectious Diseases 1998;27(5):1311-3.
Salmon-Ceron 1995 {published data only}
  • Salmon-Ceron D, Fontbonne A, Saba J, May T, Raffi F, Chidiac C, et al. Lower survival in AIDS patients receiving dapsone compared with aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia. Study Group. The Journal of Infectious Diseases 1995;172(3):656-64.
Shor-Posner 2003 {published data only}
  • Shor-Posner G, Lecusay R, Miguez MJ, Moreno-Black G, Zhang G, Rodriguez N, et al. Psychological burden in the era of HAART: impact of selenium therapy. International Journal of Psychiatry in Medicine 2003;33(1):55-69.
Spada 2002 {published data only}
  • Spada C, Treitinger A, Reis M, Masokawa IY, Verdi JC, Luiz MC, et al. An evaluation of antiretroviral therapy associated with alpha-tocopherol supplementation in HIV-infected patients. Clinical Chemistry and Laboratory Medicine 2002;40(5):456-59.
Stanczuk 2002 {published data only}
  • Stanczuk GA, Thomsen M, Soerensen AM, Sibanda EN. Acetyl salicic acid (aspirin), micronutrients and chloroquine in the management of acquired immunodeficiency syndrome (AIDS). Central African Journal of Medicine 2002;48(3-4):42-9.

References to studies awaiting assessment

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Bobat 2004 {unpublished data only}
  • Bobat R. Moving Zinc into the Micronutrient Program Agenda. International Zinc Nutrition Consultative Group Symposium (Symposium 1. Advances in Zinc and Human Function), Lima, Peru. 2004.
Fawzi 2005 {published data only}
  • Fawzi WW, Villamor E, Msamanga GI, Antelman G, Aboud S, Urassa W, et al. Trial of zinc supplements in relation to pregnancy outcomes, hematologic indicators, and T cell counts among HIV-1-infected women in Tanzania. The American Journal of Clinical Nutrition 2005;81(1):161-7.
Semba 2005 {published data only}
  • Semba RD, Ndugwa C, Perry RT, Clark TD, Jackson JB, Melikian G, et al. 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.

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Alam 1994
  • Alam AN, Sarker SA, Wahed MA, Khatun M, Rahaman MM. Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation. Gut 1994;35(12):1707-11.
Allard 1998b
  • Allard JP, Aghdassi E, Chau J, Salit I, Walmsley S. Oxidative stress and plasma antioxidant micronutrients in humans with HIV infection. American Journal of Clinical Nutrition 1998;67(1):143-7.
ATBC 1994
  • The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The New England Journal of Medicine 1994;330(15):1029-35.
ATBC 1996
  • Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, et al. Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. Journal of the National Cancer Institute 1996;88(21):1560-70.
Baeten 2002b
  • Baeten JM, McClelland RS, Richardson BA, Bankson DD, Lavreys L, Wener MH, et al. Vitamin A deficiency and the acute phase response among HIV-1-infected and -uninfected women in Kenya. Journal of Acquired Immune Deficiency Syndromes 2002;31(2):243-9.
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.
Baum 1994
  • Baum M, Cassetti L, Bonvehi P, Shor-Posner G, Lu Y, Sauberlich H. Inadequate dietary intake and altered nutrition status in early HIV-1 infection. Nutrition 1994;10(1):16-20.
Baum 1997
  • Baum MK, Shor-Posner G, Lai S, Zhang G, Lai H, Fletcher MA, et al. High risk of HIV-related mortality is associated with selenium deficiency. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1997;15(5):370-4.
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 109;6(e86).
Buys 2001
  • Buys H, Hussey G. Micronutrients in the case management of HIV /AIDS. In: H Friis editor(s). Micronutrients and HIV. London: CRC Press, 2001:201-218.
Campa 1999
  • Campa A, Shor-Posner G, Indacochea F, Zhang G, Lai H, Asthana D. Mortality risk in selenium-deficient HIV-positive children. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1999;20(5):508-13.
Dijkhuizen 2001
  • Dijkhuizen MA. Vitamin A, Iron, and Zinc deficiency in Indonesia: Micronutrient Interactions and Effects of Supplementation.. Ph.D. thesis. Wageningen University, The Netherlands. June 2001.
Friis 2004
  • Friis H, Gomo E, Nyazema N, Ndhlovu P, Krarup H, Kaestel P, et al. Effect of multimicronutrient supplementation on gestational length and birth size: a randomized, placebo-controlled, double-blind effectiveness trial in Zimbabwe. The American Journal of Clinical Nutrition 2004;80(1):178-84.
Kumwenda 2002
  • Kumwenda N, Miotti PG, Taha TE, Broadhead R, Biggar RJ, Jackson JB, et al. Antenatal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi. Clinical Infectious Diseases 2002;35(5):618-24.
Margetts 1997
  • Margetts B, Nelson M. Design Concepts in Nutritional Epidemiology. Second Edition. Oxford: Oxford University Press, 1997.
Omenn 1996
  • Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. Journal of the National Cancer Institute 1996;88(21):1550-9.
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. Washington: Support for Analysis and Research in Africa (SARA) Project, Academy for Educational Development, 2000.
Roy 1992
  • Roy SK, Behrens RH, Haider R, Akramuzzaman SM, Mahalanabis D, Wahed MA, et al. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome. Journal of Pediatric Gastroenterology and Nutrition 1992;15(3):289-96.
Semba 1993
  • Semba RD, Graham NM, Caiaffa WT, Margolick JB, Clement L, Vlahov D. Increased mortality associated with vitamin A deficiency during human immunodeficiency virus type 1 infection. Archives of Internal Medicine 1993;153(18):2149-54.
Semba 1995
  • Semba RD, Miotti PG, Chiphangwi JD, Liomba G, Yang LP, Saah AJ, Dallabetta GA, Hoover DR. Infant mortality and maternal vitamin A deficiency during human immunodeficiency virus infection. Clinical Infectious Diseases 1995;21(4):966-72.
Semba 1999
  • Semba R, Tang A. Micronutrients and the pathogenesis of human immunodeficiency virus infection. British Journal of Nutrition. 1999; Vol. 81:181-9.
Semba 2001
Shey Wiysonge 2002
  • Shey Wiysonge CU, Brocklehurst P, Sterne JAC. Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection. The Cochrane Library 2003, Issue 2. [Art. No.: CD003648. DOI: 10.1002/14651858.CD003648.pub2]
Stephensen 1994
  • Stephensen CB, Alvarez JO, Kohatsu J, Hardmeier R, Kennedy JI Jr, Gammon RB Jr. Vitamin A is excreted in the urine during acute infection. American Journal of Clinical Nutrition 1994, (60):388-92.
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.
Tang 1993
  • Tang AM, Graham NM, Kirby AJ, McCall LD, Willett WC, Saah AJ. Dietary micronutrient intake and risk of progression to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus type 1 (HIV-1)-infected homosexual men. The American Journal of Epidemiology 1993;138(11):937-51.
UNAIDS 2004
  • UNAIDS. Factsheet on sub-Saharan Africa. www.unaids.org/wad2004/EPI_1204_pdf_en/Chapter3_subsaharan_africa_en.pdf Accessed 18 April 2004.
Walmsley 1997
  • Walmsley SL, Winn LM, Harrison ML, Uetrecht JP, Wells PG. Oxidative stress and thiol depletion in plasma and peripheral lymphocytes from HIV-infected patients: toxicological and pathological implications. AIDS 1997;11:1689-97.
WHO 2003
  • World Health Organisation. WHO Technical Consultation on Nutrient Requirements for People Living with HIV/AIDS. Geneva: World Health Organisation, 2003.