Micronutrient supplementation in children and adults with HIV infection

  • Review
  • Intervention

Authors


Abstract

Background

The scale and impact of the HIV/AIDS pandemic has made the search for simple, affordable, safe, and effective public health interventions all the more urgent. Micronutrient supplements hold the promise of meeting these criteria, but their widespread use needs to be based on sound scientific evidence of effectiveness and safety.

Objectives

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

Search strategy

The Cochrane Library (CENTRAL), EMBASE, MEDLINE, AIDSearch, CINAHL, and conference proceedings were searched, and pharmaceutical manufacturers and researchers in the field were contacted to locate any ongoing or unpublished trials.

Selection criteria

Randomised controlled trials comparing the effects of micronutrient supplements (vitamins, trace elements, and combinations of these) with placebo or no treatment on mortality and morbidity in HIV-infected individuals.

Data collection and analysis

Two reviewers independently appraised trial quality and extracted data. Study authors were contacted for additional data where necessary. A meta-analysis was not deemed appropriate due to significant heterogeneity between trials.

Main results

Fifteen trials were included. Six trials comparing vitamin A/beta-carotene with placebo in adults failed to show any effects on mortality, morbidity, CD4 and CD8 counts, or on viral load. Four trials of other micronutrients in adults did not affect overall mortality, although there was a reduction in mortality in a low CD4 subgroup. In a large Tanzanian trial in pregnant and lactating women, daily multivitamin supplementation was associated with a number of benefits to both mothers and children: a reduction in maternal mortality from AIDS-related causes; a reduced risk of progression to stage four disease; fewer adverse pregnancy outcomes; less diarrhoeal morbidity; and a reduction in early-child mortality among immunologically- and nutritionally-compromised women. Vitamin A alone reduced all-cause mortality and improved growth in a small sub-group of HIV-infected children in one hospital-based trial, and reduced diarrhoea-associated morbidity in a small HIV-infected sub-group of infants in another trial.

Authors' conclusions

There is no conclusive evidence at present to show that micronutrient supplementation effectively reduces morbidity and mortality among HIV-infected adults. It is reasonable to support the current WHO recommendations to promote and support adequate dietary intake of micronutrients at RDA levels wherever possible. There is evidence of benefit of vitamin A supplementation in children. The long-term clinical benefits, adverse effects, and optimal formulation of micronutrient supplements require further investigation.

Plain language summary

There is no conclusive evidence at present that micronutrient supplementation effectively reduces or increases morbidity and mortality in HIV-infected adults. There is evidence of benefit of vitamin A supplementation in children.

Fifteen trials were included from developing and developed countries. Interventions included vitamins, trace elements, and combinations of these. Primary outcomes were morbidity and mortality. Secondary outcomes included CD4 and CD8 counts, and viral load.

Background

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

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

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

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

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

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

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

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-up1 Mean Difference (IV, Random, 95% CI)Subtotals only
2 CD8 count >= 3 months follow-up1 Mean Difference (IV, Random, 95% CI)Subtotals only
3 Viral load at < 3 months follow-up1 Mean Difference (IV, Random, 95% CI)Subtotals only
4 Mean bodyweight1 Mean Difference (IV, Random, 95% CI)Subtotals only
5 Karnofsky score1 Mean Difference (IV, Random, 95% CI)Subtotals only
Analysis 1.1.

Comparison 1 Vitamin A / beta-carotene vs placebo to adults, Outcome 1 CD4 count >=3 months follow-up.

Analysis 1.2.

Comparison 1 Vitamin A / beta-carotene vs placebo to adults, Outcome 2 CD8 count >= 3 months follow-up.

Analysis 1.3.

Comparison 1 Vitamin A / beta-carotene vs placebo to adults, Outcome 3 Viral load at < 3 months follow-up.

Analysis 1.4.

Comparison 1 Vitamin A / beta-carotene vs placebo to adults, Outcome 4 Mean bodyweight.

Analysis 1.5.

Comparison 1 Vitamin A / beta-carotene vs placebo to adults, Outcome 5 Karnofsky score.

Comparison 2. Other micronutrients vs placebo to adults
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality (all cause) by 48 weeks1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2 Mortality by 48 weeks (baseline CD4 < 200)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3 Mortality by 48 weeks (baseline CD4 >= 200)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4 Mortality by 48 weeks (baseline CD4 < 100)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5 Mortality by 48 weeks (baseline CD4 >=100)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6 New AIDS -defining infections1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
7 New HIV-associated infections1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
8 New other infections1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
9 Recurrent HIV-associated infections1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
10 Recurrent other infections1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11 Hospital admissions for all conditions1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
12 Mean number of hospitalisations (OIs, HIV-related, psychiatric) per patient1 Mean Difference (IV, Random, 95% CI)Subtotals only
13 Number of patients hospitalised for all conditions1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
14 Patients hospitalised for OIs, HIV-related conditions and psychiatric disorders1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
15 Decline in CD4 counts > 50 cells per cubic mm after 12 months1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
16 Lowered plasma selenium levels (< 135 microg/L) after 12 months1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
17 Change in HIV viral load over 3 months1 Mean Difference (IV, Random, 95% CI)Subtotals only
18 Mortality (all cause) by 48 weeks1 Hazard ratio (Random, 95% CI)Subtotals only
19 Mortality by 48 weeks (baseline CD4 < 200)1 Hazard ratio (Random, 95% CI)Subtotals only
20 Mortality by 48 weeks (baseline CD4 >= 200)1 Hazard ratio (Random, 95% CI)Subtotals only
21 Mortality by 48 weeks (baseline CD4 < 100)1 Hazard ratio (Random, 95% CI)Subtotals only
22 Mortality by 48 weeks (baseline CD4 >=100)1 Hazard ratio (Random, 95% CI)Subtotals only
Analysis 2.1.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 1 Mortality (all cause) by 48 weeks.

Analysis 2.2.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 2 Mortality by 48 weeks (baseline CD4 < 200).

Analysis 2.3.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 3 Mortality by 48 weeks (baseline CD4 >= 200).

Analysis 2.4.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 4 Mortality by 48 weeks (baseline CD4 < 100).

Analysis 2.5.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 5 Mortality by 48 weeks (baseline CD4 >=100).

Analysis 2.6.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 6 New AIDS -defining infections.

Analysis 2.7.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 7 New HIV-associated infections.

Analysis 2.8.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 8 New other infections.

Analysis 2.9.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 9 Recurrent HIV-associated infections.

Analysis 2.10.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 10 Recurrent other infections.

Analysis 2.11.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 11 Hospital admissions for all conditions.

Analysis 2.12.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 12 Mean number of hospitalisations (OIs, HIV-related, psychiatric) per patient.

Analysis 2.13.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 13 Number of patients hospitalised for all conditions.

Analysis 2.14.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 14 Patients hospitalised for OIs, HIV-related conditions and psychiatric disorders.

Analysis 2.15.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 15 Decline in CD4 counts > 50 cells per cubic mm after 12 months.

Analysis 2.16.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 16 Lowered plasma selenium levels (< 135 microg/L) after 12 months.

Analysis 2.17.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 17 Change in HIV viral load over 3 months.

Analysis 2.18.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 18 Mortality (all cause) by 48 weeks.

Analysis 2.19.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 19 Mortality by 48 weeks (baseline CD4 < 200).

Analysis 2.20.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 20 Mortality by 48 weeks (baseline CD4 >= 200).

Analysis 2.21.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 21 Mortality by 48 weeks (baseline CD4 < 100).

Analysis 2.22.

Comparison 2 Other micronutrients vs placebo to adults, Outcome 22 Mortality by 48 weeks (baseline CD4 >=100).

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 months1 Mean Difference (IV, Random, 95% CI)Subtotals only
2 CD4 >= 3 months1 Mean Difference (IV, Random, 95% CI)Subtotals only
3 CD4 difference (< 3 months)1 Mean Difference (IV, Random, 95% CI)Subtotals only
4 CD4 difference (>= 3 months)1 Mean Difference (IV, Random, 95% CI)Subtotals only
5 CD8 < 3 months1 Mean Difference (IV, Random, 95% CI)Subtotals only
6 CD8 >= 3 months1 Mean Difference (IV, Random, 95% CI)Subtotals only
7 CD8 difference (< 3 months)1 Mean Difference (IV, Random, 95% CI)Subtotals only
8 CD8 difference (>= 3 months)1 Mean Difference (IV, Random, 95% CI)Subtotals only
9 Total maternal weight gain1 Mean Difference (IV, Random, 95% CI)Subtotals only
10 Maternal weight gain in third trimester1 Mean Difference (IV, Random, 95% CI)Subtotals only
11 Progression to stage 4 or death from AIDS-related causes1 Hazard ratio (Random, 95% CI)Subtotals only
12 Death from AIDS-related causes1 Hazard ratio (Random, 95% CI)Subtotals only
13 Progression to stage 4 disease1 Hazard ratio (Random, 95% CI)Subtotals only
14 Progression to stage 3 disease or higher1 Hazard ratio (Random, 95% CI)Subtotals only
15 HIV-related complications: thrush1 Hazard ratio (Random, 95% CI)Subtotals only
16 HIV-related complications: gingival erythema1 Hazard ratio (Random, 95% CI)Subtotals only
17 HIV-related complications: angular cheilitis1 Hazard ratio (Random, 95% CI)Subtotals only
18 HIV-related complications: oral ulcer1 Hazard ratio (Random, 95% CI)Subtotals only
19 HIV-related complications: reported mouth and throat ulcers1 Hazard ratio (Random, 95% CI)Subtotals only
20 HIV-related complications: painful tongue or mouth1 Hazard ratio (Random, 95% CI)Subtotals only
21 HIV-related complications: difficult or painful swallowing1 Hazard ratio (Random, 95% CI)Subtotals only
22 HIV-related complications: nausea and vomiting1 Hazard ratio (Random, 95% CI)Subtotals only
23 HIV-related complications: diarrhoea1 Hazard ratio (Random, 95% CI)Subtotals only
24 HIV-related complications: dysentery1 Hazard ratio (Random, 95% CI)Subtotals only
25 HIV-related complications: fatigue1 Hazard ratio (Random, 95% CI)Subtotals only
26 HIV-related complications: rash1 Hazard ratio (Random, 95% CI)Subtotals only
27 HIV-related complications: acute upper respiratory tract infection1 Hazard ratio (Random, 95% CI)Subtotals only
Analysis 3.1.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 1 CD4 < 3 months.

Analysis 3.2.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 2 CD4 >= 3 months.

Analysis 3.3.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 3 CD4 difference (< 3 months).

Analysis 3.4.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 4 CD4 difference (>= 3 months).

Analysis 3.5.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 5 CD8 < 3 months.

Analysis 3.6.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 6 CD8 >= 3 months.

Analysis 3.7.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 7 CD8 difference (< 3 months).

Analysis 3.8.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 8 CD8 difference (>= 3 months).

Analysis 3.9.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 9 Total maternal weight gain.

Analysis 3.10.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 10 Maternal weight gain in third trimester.

Analysis 3.11.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 11 Progression to stage 4 or death from AIDS-related causes.

Analysis 3.12.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 12 Death from AIDS-related causes.

Analysis 3.13.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 13 Progression to stage 4 disease.

Analysis 3.14.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 14 Progression to stage 3 disease or higher.

Analysis 3.15.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 15 HIV-related complications: thrush.

Analysis 3.16.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 16 HIV-related complications: gingival erythema.

Analysis 3.17.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 17 HIV-related complications: angular cheilitis.

Analysis 3.18.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 18 HIV-related complications: oral ulcer.

Analysis 3.19.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 19 HIV-related complications: reported mouth and throat ulcers.

Analysis 3.20.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 20 HIV-related complications: painful tongue or mouth.

Analysis 3.21.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 21 HIV-related complications: difficult or painful swallowing.

Analysis 3.22.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 22 HIV-related complications: nausea and vomiting.

Analysis 3.23.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 23 HIV-related complications: diarrhoea.

Analysis 3.24.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 24 HIV-related complications: dysentery.

Analysis 3.25.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 25 HIV-related complications: fatigue.

Analysis 3.26.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 26 HIV-related complications: rash.

Analysis 3.27.

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 27 HIV-related complications: acute upper respiratory tract infection.

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)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2 Total mortality by 24 months including foetal deaths1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3 Mortality by 24 months among all live births1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4 Mortality by 24 months among HIV-infected live births1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5 Mortality by 24 months among HIV-infected infants at 6 weeks of age1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6 Mean birthweight1 Mean Difference (IV, Random, 95% CI)Subtotals only
7 Birthweight < 2000 g1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
8 Birthweight < 2500 g1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
9 Preterm birth (<37 weeks)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
10 Severe preterm birth (<34 weeks)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
11 Small for gestational age1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
12 CD4 count >= 3 months1 Mean Difference (IV, Random, 95% CI)Subtotals only
Analysis 4.1.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 1 Foetal death (miscarriage+stillbirth).

Analysis 4.2.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 2 Total mortality by 24 months including foetal deaths.

Analysis 4.3.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 3 Mortality by 24 months among all live births.

Analysis 4.4.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 4 Mortality by 24 months among HIV-infected live births.

Analysis 4.5.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 5 Mortality by 24 months among HIV-infected infants at 6 weeks of age.

Analysis 4.6.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 6 Mean birthweight.

Analysis 4.7.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 7 Birthweight < 2000 g.

Analysis 4.8.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 8 Birthweight < 2500 g.

Analysis 4.9.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 9 Preterm birth (<37 weeks).

Analysis 4.10.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 10 Severe preterm birth (<34 weeks).

Analysis 4.11.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 11 Small for gestational age.

Analysis 4.12.

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 12 CD4 count >= 3 months.

Comparison 5. Vitamin A vs placebo to children
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All-cause mortality1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2 All-cause morbidity1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3 Diarrhoeal morbidity1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
4 Persistent diarrhoea (>= 7 days)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
5 Lower respiratory tract infections (LRTI)1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
6 Hospitalised for diarrhoea1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
7 Hospitalised for LRTI1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
8 Mean change in viral load after influenza vaccination1 Mean Difference (IV, Random, 95% CI)Subtotals only
Analysis 5.1.

Comparison 5 Vitamin A vs placebo to children, Outcome 1 All-cause mortality.

Analysis 5.2.

Comparison 5 Vitamin A vs placebo to children, Outcome 2 All-cause morbidity.

Analysis 5.3.

Comparison 5 Vitamin A vs placebo to children, Outcome 3 Diarrhoeal morbidity.

Analysis 5.4.

Comparison 5 Vitamin A vs placebo to children, Outcome 4 Persistent diarrhoea (>= 7 days).

Analysis 5.5.

Comparison 5 Vitamin A vs placebo to children, Outcome 5 Lower respiratory tract infections (LRTI).

Analysis 5.6.

Comparison 5 Vitamin A vs placebo to children, Outcome 6 Hospitalised for diarrhoea.

Analysis 5.7.

Comparison 5 Vitamin A vs placebo to children, Outcome 7 Hospitalised for LRTI.

Analysis 5.8.

Comparison 5 Vitamin A vs placebo to children, Outcome 8 Mean change in viral load after influenza vaccination.

What's new

DateEventDescription
29 October 2008AmendedConverted to new review format.

History

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

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

None.

Sources of support

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.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Allard 1998a

Methods

Duration of enrolment: Apr 1995 - Aug 1996

Method of randomisation:
random number table

Blinding:
Patient: yes
Provider:yes
Assessor:yes

Lost to follow-up at 3 months:
Treatment group: 3 (12%)
Control group: 6 (26%)

Intention-to-treat: carried out

Participants

47 men and 2 women with stable HIV-infection.

Exclusion criteria:
Active opportunistic infection, smoking, prior antioxidant therapy, hyperlipidaemia, kidney/liver dysfunction, intractable diarrhea ( >= 6 liquid stools/d), vomiting, GI bleeding

Setting: not stated

Interventions800 IU Vitamin E, and 1000 mg Vitamin C or placebo daily for 3 months.
Outcomes

Main outcomes:
*Viral load
*Plasma lipid peroxides, Plasma malondialdehyde
*Breath pentane
*Plasma vitamin E, C, A carotenoids, zinc, selenium

Additional outcomes:
*Total number of new and recurrent AIDS-defining, HIV-associated and other infections

Notes

Number of patients on anti-retroviral therapy:
Treatment group: 22/ 23 (85%)
Control group: 18/ 26(78%)
Controlled diet 2 weeks prior to randomization and throughout study period, and dietary counseling.

Adverse events: Epigastric discomfort (2 vs. 0)

Financial support: research grant
Conflicts of interest: not stated
Justification: yes
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Baeten 2002a

Methods

Duration of enrolment: Sep 1998 - Jun 2000.

Method of randomisation:
Computer-generated block randomisation

Blinding:
Patient: yes
Provider:yes
Assessor:yes

Lost to follow-up after 445 days:
Treatment group: 24 (12%)
Control group: 22 (11%)

Intention-to-treat: carried out

Participants

400 women enrolled.
Confirmed HIV-1 infection.

Exclusion criteria:
< 18 or > 45 years, pregnancy, use of oral contraceptive pill or vitamin supplements

Setting: hospital outpatient clinic, Mombasa, Kenya.

InterventionsVitamin A (10 000 IU retinyl palmitate) or placebo daily for 6 weeks.
OutcomesMain outcomes:
Vaginal HIV-1 DNA and RNA
*Viral load
*CD4 count -absolute
*CD8 count -absolute
Notes

Multivitamin arm (20mg vit B1, 20 mg vit B2, 25 mg vit B6, 100mg niacin, 50 microg vit B12, 500 mg vit C, 30 mg vit E and 0.8 mg folic acid + 200 microg selenium) added after 100 participants were enrolled, but not included in this analysis.

59% of study subjects had plasma vit A <=30microg./dl

Adverse events: None reported

Financial support: research grant and commercial (reagents)
Conflicts of interest: not stated
Justification: yes
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Burbano 2002

Methods

Duration of enrolment: 1998 - 2000.

Method of randomisation:
Unclear.

Blinding:
Patient: yes
Provider:yes
Assessor:yes

Lost to follow-up at 12 months:
Total sample:73 (28%)

Intention-to-treat: not performed

Participants

259 HIV-infected Drug Users (147 men and 112 women) enrolled.

Exclusion criteria: < 18 years, plasma selenium < 85 microg/l.

Setting: Community-based clinic, Miami, USA.

Interventions200 microg selenium or placebo daily for 12 months.
Outcomes

Main outcomes:

CD4 (absolute count)
*Number of hospital admissions
*Type of hospital admissions (opportunistic infection, other HIV-related conditions, psychiatric diagnoses, drug-abuse-related and other conditions)
*Risk of hospitalisation
Hospitalisation cost
Plasma selenium

Notes

Number of patients on anti-retroviral therapy:
Selenium group: 64 (76%)
Control group: 60 (53%)

Number, type and duration of hospital admissions recorded 2 years prior and during study period. Medical records reviewed by team of physicians.

Adverse effects: None reported.

Financial support: research grant and commercial (materials)
Conflicts of interest: not stated
Justification: not stated
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Constans 1996

Methods

Duration of enrolment: not stated

Method of randomisation:
unclear

Blinding:
Patient: no
Provider:no
Assessor: not stated

Lost to follow-up at 1 year:
Beta-carotene group: 2 (13%)
Selenium group: none
Control group: 2 (9%)

Intention-to-treat: not performed

Participants52 HIV-positive adults with CD4 counts < 400/mm3
Interventions100 microgram selenium (L-seleno-methionine) daily or 30 mg Beta-carotene twice daily or none for 1 year
Outcomes

Main outcomes:

*Mortality
*CD4 count at 3 and 12 months
Beta-2-microglobulin
Plasma malondialdehyde
Plasma beta-carotene, selenium
RBC superoxide dismutase, glutathione peroxidase, catalase

NotesThis was a brief report on a pilot study.
Beta-carotene recipients had more advanced disease at baseline than other subjects. Adverse events: none reported
Financial support: research grant and commercial funding
Conflicts of interest: not stated
Justification: not stated
Informed consent: yes
Confidentiality: not stated
Research Ethics Committee approval: yes
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Coodley 1993

Methods

Randomised cross-over trial

Duration of enrolment: not stated

Method of randomisation:
Central randomisation.

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up at 4 weeks:
Treatment arm: 5 (24%)
Control arm: 7 (33%)

Intention-to-treat: not performed

Participants

21 HIV-positive adults (20 men, 1 woman)

Exclusion criteria:
Hepatic or renal dysfunction, active opportunistic infection, fever

Setting: hospital outpatient clinics, Oregon, USA

Interventions60mg Beta-carotene three times daily for 4 weeks, followed by placebo for 4 weeks or vice versa .
Outcomes

Main outcomes:

White blood cell count
Lymphocyte count
B-lymphocytes
*CD4 count at 4 weeks
*CD4 mean change after weeks
*CD4:CD8 at 4 weeks
* CD4:CD8 mean change after 4 weeks
Additional outcome:
*Serum beta-carotene

Notes

16 patients received anti-retroviral therapy.

Adverse events: Skin discoloration in treatment group

Financial support: Commercial funding
Conflicts of interest: not stated
Justification: not stated
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Coodley 1996

Methods

Duration of enrolment: not stated

Method of randomisation:
unclear

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up at 3 months:
Total sample: 22 (31%)

Intention-to-treat: carried out

Participants

72 HIV-positive adults (69 men and 9 women)

Exclusion criteria:
CD4 counts < 50 or > 600 /mm3, commencement of anti-retroviral therapy within 60 days prior to study entry, hepatic or renal dysfunction, vitamin A or beta-carotene supplementation within 30days prior to study entry.

Setting: hospital outpatient clinics and private practice, Oregon, USA

Interventions60mg Beta-carotene three times daily plus multivitamins or placebo plus multivitamins for 3 months.
Outcomes

Main outcomes:

White blood cell count Lymphocytes
Neutrophils
*CD4 count -absolute
*CD8 count -absolute
*CD4:CD8 ratio
CD3 count
CD19 count
Natural killer cells
HIV p24 antigen levels

Additional outcomes:

*Karnofsky score
*Weight
*Serum beta-carotene
*Serum vitamin A

Notes

Number of patients on anti-retroviral therapy:
Treatment group: 10 (28%)
Control group: 17 (47%)

Adverse events: none reported

Financial support: research grant and commercial (materials)
Conflicts of interest: not stated
Justification: yes
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Coutsoudis 1995

Methods

Duration of enrolment: Apr 1991-Nov. 1993

Method of randomisation:
Random number table

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up:
Vitamin A group: 17%(6mo); 36%(12 mo); 58%(18mo)
Placebo-group: 25% (6 mo); 33% (12 mo); 63% (18 mo)

Intention-to-treat: carried out

Participants

118 pregnant women enrolled. Confirmed HIV-1 infection.

Setting: attendance at antenatal clinic and delivered in hospital, Durban, South Africa

Exclusion criteria:
Living further than 10 miles from hospital; had not attended antenatal clinic

InterventionsRepeat doses of 50 000 IU retinyl palmitate to infants at 1 and ,3 months and 100 000 IU at 6,9,12 and 15 months or placebo.
Outcomes

Main outcomes:

*All morbidity
*Acute diarrhoea
*Persistent diarrhoea
*Hospitalised for diarrhoea
Thrush
Upper respiratory tract infection
*Lower respiratory tract infection (LRTI)
*Hospitalised for LRTI
Isolated fever
Rash

Notes

Monthly morbidity recall.

Multiple episodes of same condition in a single month counted as one episode (per 100 months).

Adverse events: Vomiting and bulging fontanelle monitored by history and, when possible, by clinical exam.

Financial support: research grant and commercial (materials)
Conflicts of interest: not stated
Justification: yes
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Fawzi 1998

Methods

Trial with two-by-two factorial design.

Duration of enrolment: Apr 1995 - Jul 1997.

Duration of follow-up: from enrollment until end of study (Aug. 2003). Median=71 mo. (IQR: 46 to 80) wrt survival

Method of randomisation:
Block randomisation.
Pre-numbered bottles, administered serially

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up at delivery:
54 mother-infant pairs (5.9%)

Intention-to-treat: carried out

Participants

1078 pregnant women (12-27 wks. gestation) enrolled. Confirmed HIV-1 infection.

Setting: Dar es salaam, Tanzania.

Exclusion criteria:
non-resident in Dar es Salaam from baseline until 1-year post-delivery

InterventionsDaily oral dose throughout study of one of four regimens: Vitamin A alone (30 mg beta-carotene plus 5000 IU preformed vitamin A) or vitamin A plus multivitamins 20mg vit B1, 20 mg vit B2, 25 mg vit B6, 100mg niacin, 50 microg vit B12, 500 mg vit C, 30 mg vit E and 0.8 mg folic acid) or multivitamins without vitamin A or placebo. At delivery, women receiving any vitamin A were given an additional 200 000 IU vitamin A, while the other women received placebo.
Outcomes

Maternal outcomes:

*Mortality from AIDS-related causes
*HIV-related complications
* Progression to stage 4 disease
* Progression to stage 3 disease or higher
*Viral load
*Total maternal weight gain during pregnancy
*Trimester-specific weight gain
*Postpartum CD4 (absolute count, %)
*Postpartum CD8 (absolute count, %)
Postpartum CD3 (absolute count,%)

Infant outcomes:

HIV infection in infant
*Fetal death (miscarriage or stillbirth)
*Birthweight
*Low birth weight (< 2500g ; < 2000g)
*Preterm birth (< 37, < 34 weeks)
* Mortality by 24 months among live births
*Mortality (6 wks-24 mo.) among HIV-infected infants at 6 weeks of age
*Diarrhoea (all, acute, watery, dysenteric)
* Respiratory tract infection (cough, cough and fever, cough and rapid respiratory rate)
*CD4 (absolute count)
Psychomotor development index
Mental development index

Notes

All women received 400mg ferrous sulphate and 5 mg folate daily, plus weekly doses of chloroquine antenatally

All infants received 100000 IU vitamin A at 6 months and 200000 IU every 6 months thereafter.

Vitamin A dropped from two of the regimens in Sept. 2000 and replaced with placebo due to safety concerns.

No adverse effects of multivitamin supplementation reported

Financial support: research grant and commercial (materials)
Conflicts of interest: not stated
Justification: yes
Informed consent: yes (verbal)
Confidentiality: yes
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Fawzi 1999

Methods

Duration of enrolment: Apr 1993 - Jul 1997.

Method of randomisation:
Block randomisation.
Pre-numbered bottles, administered serially.

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up::
Total sample 25% (4 months)
Total sample 26% (8 months)

Intention-to-treat: carried out.

Participants

687 children aged 6 - 60 mo. enrolled on hospital admission for pneumonia. 58 of 648 (9%) children were HIV-infected.

Exclusion criteria: treatment with vit A for 4 mo prior to study entry, severe malnutrition, measles, pulmonary tuberculosis, diphteria, whooping cough, xerophthalmia.

Setting: Dar es Salaam, Tanzania.

InterventionsSingle doses of vitamin A or placebo on hospital admission, on the day thereafter and at 4,8 months after discharge. 200,000 IU per dose to 1-5 yrs; 100,000 IU per dose to infant.
Outcomes

Main outcomes:

*All-cause mortality *Cause-specific mortality - AIDS, diarrhoea, pneumonia, malaria, anaemia and other infections (measles, meningitis, dysentery, fever of unknown origin, malnutrition)

*Acute diarrhoea
*Respiratory tract infection

*Height
*Weight
Risk of stunting
Risk of wasting

Notes

Variable follow-up periods.

Cause of death ascertained by review of hospital records and home verbal autopsy questionnaire by two physicians. Discrepancies resolved by third physician.

Bi-weekly morbidity recall.
No data provided on episodes of persistent diarrhoea or hospitalisation of HIV-infected children.

Adverse events: increased risk of respiratory tract infections in HIV-negative children, and of diarrhoea among normally nourished or growth-stunted children.

Financial support: research grant and commercial (materials)
Conflicts of interest: not stated
Informed consent: yes (verbal) by primary caretaker
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Hanekom 2000

Methods

Duration of enrolment: not stated.

Method of randomisation:
Computer-generated by pharmacy.

Blinding:
Patient: yes
Provider: yes
Assessor: yes

Lost to follow-up at 1month::
Vit A group: 1 (3%)
Placebo group: none

Intention-to-treat: not performed.

Participants

59 HIV-infected children aged 25 - 209 mo.

Exclusion criteria: hypersensitivity to eggs, acute febrile illness, receipt of intravenous gammaglobulin or vaccination within 14 and 28 days of study entry, respectively.

Setting: HIV clinic at a children's hospital, Chicago, USA

Interventions200 000 IU retinyl palmitate or placebo for two days
Outcomes

Main outcomes:

*Viral load
Antibody levels (H1N1, H3N2)

Notes

All children received inactivated influenza vaccine on study day 14.
All were receiving anti-retroviral therapy
Patients who had antiretroviral drug changes excluded from viral load analysis (number not shown)

No adverse events reported

Financial support: not stated
Conflicts of interest: not stated
Justification: not stated
Informed consent: not stated
Confidentiality: not stated
Research Ethics Committee approval: not stated

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Humphrey 1999

Methods

Duration of enrolment: Jan - July 1996.

Method of randomisation:
Unclear.

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up at 2 months::
Total sample: 1 (3%)

Intention-to-treat: not performed.

Participants

40 HIV-infected women of reproductive age

Exclusion criteria: < 18 and > 45 years, pregnancy, lactation, CD4 count < 200 cells/mm3.

Setting: HIV Clinic, Baltimore, USA.

InterventionsSingle dose of 300 000 IU Vitamin A or placebo
Outcomes

Main outcomes:

*Viral load
*CD4%
CD8CD38 %
In vitro responsiveness to mitogens

Additional outcomes:
*Serum retinol concentrations

Notes

Number of patients on anti-retroviral therapy:
Vit A group: 12 (60%)
Control group: 7 (35%)

10% of women had plasma vit A levels < 1.05 micromol/l (< 30 microgram/dl).

Adverse events: none

Financial support: research grant and commercial (materials)
Conflicts of interest: not stated
Justification: not stated
Informed consent : yes
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Hussey 1996

Methods

Duration of study: 1994-1995.

Method of randomisation:
Unclear.

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up at 2 months:
Total sample: 1 (3%)

Intention-to-treat: not performed.

Participants

75 children with AIDS (median age was 17 mo)

Exclusion criteria: acute infections, fever

Setting: HIV clinic at a children's hospital, South Africa.

Interventions200 000 IU vitamin A or placebo for two successive days.
Outcomes

Main outcomes:

lymphocyte count
*CD4(absolute count)
CD56 (absolute count)
CD29 (absolute count)

Additional outcomes:

vitamin A levels

Notes

Children who received vitamin A were more immunosuppressed

50% of children had vitamin A < 20 microg/dl.

No adverse events reported
Financial support: not stated
Conflicts of interest: not stated
Justification: not stated
Informed consent: unclear
Confidentiality: not stated
Research Ethics Committee approval : not stated

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Jiamton 2003

Methods

Duration of enrolment: Mar 2000- Jan 2001.

Method of randomisation:
Centralised block randomisation.

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up at 48 weeks:
Intervention group: 41 (17%)
Control group: 38 (16%)

Intention-to-treat: carried out.

Participants

481 HIV-infected adults (189 men and 292 women)
with CD4 count between 50 and 550
Exclusion criteria:
<18 years, not taking ARV or micronutrients for at least a month prior to enrollment

Setting: hospital outpatient clinic in Bangkok, Thailand

InterventionsVitamin A (3000 micrograms), 6mg beta-carotene, 20 micrograms vitamin D, 80 mg vit E , 180 micrograms vitamin K, 400 mg vitamin C, 24mg vit B1, 15 mg vit B2, 40 mg vit B6, 30 microg vit B12, 0.1 mg folic acid, 40 mg pantothenic acid , 10 mg iron, 200 mg magnesium, 8 mg manganese, 30 mg zinc, 300 micrograms iodine, 3 mg copper, 400 micrograms selenium, 150 micrograms chromium, 60 mg cysteine versus placebo, twice daily for 48 weeks.
Outcomes

*Mortality
*Hospital admissions
*CD4 counts
* Viral load,

Addtional outcomes: Plasma vitamin E and selenium

Notes

Monthly morbidity recall
Telephonic follow-up every 4 weeks.
Cause of death determined from hospital records or death certificate

Adverse events: Discoloration of urine

Financial support: commercial funding
Conflicts of interest: none declared
Justification: yes
Informed consent: not stated
Confidentiality: not stated
Research Ethics Committee approval : yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Kelly 1999

Methods

Duration of enrolment: Not stated.

Method of randomisation:
Unclear.

Blinding:
Patient: yes
Provider: not stated
Assessor: not stated

Lost to follow-up:Total sample: 29 (21%) at 4 weeks, 60 (44%) at 12 weeks

Intention-to-treat: not performed

Participants

135 HIV-infected adults (79 men and 56 women) with persistent diarrhea for more than 1month, enrolled.

Exclusion criteria: < 18 years, pregnancy, administration of antibiotics in the week prior to recruitment, Karnofsky scores > 80 or <50.

Setting:Home care service of Ndola Central Hospital, Zambia

Interventions10 500 IUVit A, 300mg Vit C, 300mg Vit E, 150 microg Se and 200mg Zinc sulphate or placebo for 2 weeks.
Both treatment groups received 5mg folic acid and 800mg albendazole twice daily.
Outcomes

Main outcomes:

*Mortality
*Diarrhoeal morbidity :

Additional outcomes:
*Body Mass Index
*CD4 (absolute count)
*CD8 (absolute count)
Serum vitamin A,E

Notes

Diarrhoeal morbidity not presented as episodes, but as weeks during which diarrhoea occurred on any day of that week.

Adverse events: none recorded.

Financial support: Commercial funding
Conflicts of interest: not stated
Justification: yes
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?UnclearB - Unclear

Semba 1998

Methods

Duration of enrolment: Not stated.

Method of randomisation:
Sequentially numbered envelopes containing capsule.

Blinding:
Patient: yes
Provider:yes
Assessor: yes

Lost to follow-up at 1 month::
Total sample: 10 (8.3%)

Intention-to-treat: not performed

Participants

120 HIV-infected Intravenous Drug Users (89 men and 31 women) participating in ALIVE (AIDS Linked to Intravenous Experiences) Cohort (n=630).

Exclusion criteria: , 18 years, CD4 > 500 cells/mm3, intake of > 10000IU vit A daily, pregnancy.

Setting: Community-based clinic, Baltimore, USA.

InterventionsSingle dose of 200 000 IU Vitamin A or placebo.
Outcomes

Main outcomes:

*viral load
*CD4 (absolute count)

Additional outcomes:
*plasma vitamin A

Notes

Number of patients on anti-retroviral therapy:
Treatment group: 30 (50%)
Control group: 25 (43%)

18% of patients had plasma vit A levels < 1.05 micromol/l (< 30 microgram/dl).

Adverse events: None reported.

Financial support: research grant
Conflicts of interest: not stated
Justification: yes
Informed consent: yes (written)
Confidentiality: not stated
Research Ethics Committee approval: yes

Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesA - Adequate

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Austin 2003Trial terminated prematurely due to unstable intervention.
Baeten 2002bNo outcomes of relevance to this review
Primary outcomes reported in Baeten 2002a
Batterham 2001Two treatment groups, but no placebo group.
Coutsoudis 1997Included in Shey Wiysonge 2002 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection.
Coutsoudis 1999Included in Shey Wiysonge 2002 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection.
Delmas-Beauvieu 1996No outcomes of relevance to this review
Fawzi 2000Included in Shey Wiysonge 2002 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection
Filteau 2001Included in Shey Wiysonge 2002 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection
Gomo 2003No outcomes of relevance to this review
Jaruga 2002No outcomes of relevance to this review
Kennedy 2000Included in Shey Wiysonge 2002 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection
Kennedy-Oji 2001Does not meet inclusion criteria for participants
Kumwenda 2002Included in Shey Wiysonge 2002 review:
Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection
Li-Weber 2002No outcomes of relevance to this review
Look 1998Not an exclusive micronutrient intervention
Mocchegiani 1995Method of allocation (alternation) not random.
Nimmagadda 1998Method of allocation (alternation) not random
Salmon-Ceron 1995Not an exclusive micronutrient intervention
Shor-Posner 2003No outcomes of relevance to this review
Spada 2002Method of allocation not stated
Stanczuk 2002Not an exclusive micronutrient intervention

Ancillary