Recent systematic reviews of randomised controlled trials published in The Cochrane Library have evaluated the evidence for the effectiveness and safety of micronutrient supplements in HIV-infected children and adults, and of vitamin A for reducing the risk of mother-to-child transmission (MTCT) of HIV. Irlam et al.37 appraised and summarised the evidence from 18 trials of single and multiple micronutrient supplements in adults, children, and pregnant or lactating women, but did not perform a meta-analysis due to substantial clinical heterogeneity across the trials. Additionally, a systematic review and meta-analysis by Shey Wiysonge et al.38 included four trials in HIV-infected pregnant women. We draw extensively on the findings of these Cochrane reviews and provide supplementary evidence from studies not included in the reviews.
Single micronutrient supplements
Five small randomised, placebo-controlled trials (sample size 21 to 120 participants) of vitamin A or beta-carotene in adults39–43 and one moderately sized trial of vitamin A (n=400 women)44 found no significant benefits or adverse effects on morbidity (HIV-associated and AIDS-defining infections), mortality, viral load, or immunological markers. A small Canadian trial of large doses of daily vitamin C (1000mg) and vitamin E (800 IU) for three months showed a non-significant reduction in mean plasma viral load (−0.45 log) versus placebo (0.5 log increase)45.
A meta-analysis of four randomised placebo-controlled trials of vitamin A supplementation in HIV-infected pregnant women in Africa found no evidence of an overall effect of vitamin A supplementation on MTCT of HIV in 3 of the trials (2022 participants; OR 1.14, 95% CI 0.93 to 1.38)38. A trial in Tanzania, however showed an increased risk of MTCT (OR 1.53, 95% CI 1.15 to 2.04 at 24 months)46. The subsequently- published results from the fourth trial, in Zimbabwe (ZVITAMBO), demonstrated no effect of either maternal or neonatal supplementation on post-natal MTCT47.
The ZVITAMBO trial used a factorial design to compare the effect of four regimens of single-large-dose supplements of postpartum maternal (400 000 IU)/ infant (50 000 IU)
vitamin A/ placebo among 14110 mother-infant pairs. There was no significant effect on overall mortality between baseline and 24 months, but there was a reduction of 28% in supplemented infants who were HIV-uninfected at baseline but HIV-infected at 6 weeks.
All three vitamin A regimens were associated with an approximate doubling of mortality in infants who were HIV-uninfected at 6 weeks (p<=0.05)47.
In two randomised trials in HIV-infected children high-dose vitamin A supplementation (200 000 IU on two successive days) compared with placebo improved immune function (a 16% increase in CD4+ counts, p=0.03)48, and reduced immune activation following influenza vaccination (viral load mean change at 14 days: vit.
A: −0.13 +/- 0.09 log copies/ml vs. placebo: +0.14 +/-0.08; p=0.02)49. Intermittent supplementation with vitamin A in a placebo-controlled trial in Durban, South Africa, halved diarrhoeal disease morbidity (OR=0.51; 95% CI: 0.27, 0.99) in a subgroup of 28 children infected with HIV50. High-dose vitamin A supplements (50 000 IU before 6 months, 100 000 IU between 6 and 11 months, and 200 000 IU every six months from age 1 to 5 years) given 6-monthly compared with placebo reduced all-cause mortality over two years in an HIV-infected subgroup (n=58) of children hospitalised with pneumonia in a Tanzanian trial (RR=0.37; 95% CI: 0.17, 0.84)51. A regimen of vitamin A (60mg retinol equivalent) every 3 months from 15 to 36 months among 181 Ugandan children halved mortality (OR=0.54; 95% CI: 0.30, 0.98) compared to placebo52.
Zinc supplementation in a trial of HIV-infected adults on ART has shown potential benefit in reducing candida and pneumocystis-related infections, increasing CD4+ counts (p<0.05), and improving or stabilising body weight (p<0.01), without any adverse effects53. This trial did not use a random method of allocation however, and was therefore excluded from the review by Irlam et al.37
Supplementation with zinc for 6 months in a randomised trial of 120 HIV-infected children in Durban, South Africa, was safe and reduced the incidence of acute diarrhoea diagnosed at clinic visits (RR = 0.51; p=0.001)54. In another trial among HIV-infected South African children in Cape Town, 3mg of zinc daily for 6 months reduced the frequency of both acute respiratory tract infections and episodes of diarrhoea. The effect of zinc on diarrhoea and acute respiratory tract infections was greater than that of a multiple micronutrient mixture, which was itself no better than placebo (unpublished data, Heloise Buys 2006). A placebo-controlled trial in 159 Peruvian adults with HIV and persistent diarrhoea found no effect of dietary zinc supplementation on the persistence and severity of diarrhoea at two weeks55.
A randomised trial of zinc supplementation compared with placebo given to Tanzanian women daily from 12 to 27 weeks of gestation until 6 weeks after delivery demonstrated no effect on pregnancy outcomes or immunological indicators56. In this study there was a rise from baseline to 6 weeks postpartum in haemoglobin, red blood
cellcount and packed cell volume in women in both groups, but these increases were all significantlylower in the group receiving zinc group than in those on placebo.
In a further placebo-controlled trial, daily selenium supplements of 200 μg for 12 months among 186 drug users decreased the risk of CD4+ counts declining below 50 cells/μl (p=0.01), and reduced the hospitalisation rate for opportunistic infections, HIV-related conditions and psychiatric disorders combined (overall RR=0.40; 95% CI:
0.21−0.75)57. Hurwitz et al. evaluated a similar regimen for 9 months in a placebo- controlled trial of 262 HIV-infected adults, and found that greater serum levels predicted decreased type 1 viral load ( p<0.02), which predicted increased CD4+ count (p<0.04)58. Multiple micronutrient supplements
A randomised placebo-controlled trial of high doses of vitamins A, C and E, zinc, and selenium daily for 2 weeks in Zambian adults showed no effect on the response to albendazole of persistent diarrhoea59. The patients had advanced HIV disease with diarrhoea-wasting syndrome, however, and absorption of the micronutrients may therefore have been inadequate.
In Thailand a randomised trial in 481 HIV-infected outpatients of a commercial supplement containing 18 micronutrients and taken twice daily for 48 weeks was associated with a non-significant reduction in mortality compared with placebo, which was most pronounced in the subgroup of 96 participants with a low CD4+ count (<200 cells/mm3) (HR=0.37; 95% CI: 0.13, 1.06)60. There were no effects on CD4+ count or viral load, however, suggesting that the reductions in mortality could be due to reductions in the risks of other infections or the maintenance of lean body mass36.
A large randomised factorial-design trial among 1078 pregnant and lactating Tanzanian women found that high-dose multivitamins (mainly vitamins B, C and E and excluding vitamin A) reduced the risk of progression to stage 4 disease or AIDS-related mortality by 29% over the entire 4−8 year supplementation and follow-up period (RR = 0.71; 95% CI: 0.51 to 0.98) compared with no multivitamins (vitamin A only or placebo).
Mean CD4+ counts were significantly higher by 48 cells/mm3 (95% CI: 10 to 85) in the multivitamin-supplemented versus placebo group, and viral load significantly lower (−0.18 log; 95%CI: −0.32 to −0.03)61, which probably also accounted for the reductions in episodes of HIV-related morbidity. Vitamin A alone had no effect on the above outcomes.
Multivitamins improved weight gain during pregnancy (mean difference during the third trimester = 304 g; 95% CI: 17 to 590)62, and reduced the risk of adverse pregnancy outcomes, including foetal loss (RR=0.61; 95% CI: 0.39 to 0.94), prematurity (RR=0.61;
95% CI: 0.38 to 0.95 for severe preterm births), and low birth weight (RR=0.55; 95%
CI: 0.38 to 0.81)63. Children born to mothers receiving multivitamin supplementation during pregnancy had higher CD4 counts (mean difference = 153 cells/µl; 95% CI: 67.6
to 238.4) and less diarrhoea (RR=0.83; 95% CI: 0.71 to 0.98 at 24 months)64, as well as improved growth during the first two years of life (weight-for-age: mean difference = 0.42; 95% CI 0.07 to 0.77)65 compared with placebo. Mortality was reduced among the children of supplemented women with low lymphocyte counts (<1340/ mm3) (RR=0.30;
95% CI: 0.1 to 0.92 at 24 months)46.
A randomised, placebo-controlled trial among Zimbabwean women found that multimicronutrient supplementation was associated with higher birth weight overall (49 g; 95% CI: −6 to 104). The effect was greater for the third of the population that was HIV-infected than among the HIV-negative women, although the interaction was not significant66.