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.
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.
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.
Description of 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).
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.
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.
The method of allocation concealment was adequate in this crossover trial. Placebo was used and blinding of patients and assessors was performed.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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 <200x10
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/ mm
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.
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.
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.
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
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Last assessed as up-to-date: 1 August 2005.
Protocol first published: Issue 4, 2003
Review first published: Issue 4, 2005
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
Sources of support
- 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.
- Cochrane Child Health Field, Canada.
Medical Subject Headings (MeSH)
*Dietary Supplements; *HIV Infections [complications; mortality]; beta Carotene [*administration & dosage]; HIV-1; HIV-2; Micronutrients [*administration & dosage; deficiency]; Pregnancy Complications, Infectious [mortality]; Randomized Controlled Trials as Topic
MeSH check words
Adult; Child; Female; Humans; Pregnancy
* Indicates the major publication for the study