Evidence From Trials

The results from the observational studies motivated the initiation of randomized, placebo-controlled intervention trials to assess the role of micronutrient supplementation in vertical HIV transmission and pregnancy outcomes. All of these trials were conducted on antiretroviral-naive pregnant women. In Malawi, 697 HIV-infected pregnant women were randomly assigned to receive daily doses of iron and folate, either alone or with vitamin A (3-mg retinol equivalent = 10,000 IU preformed vitamin A) from

Effects of Vitamins on HIV/AIDS Patients TABLE II. Vitamins and HIV Transmission

Study

Exposure

Risk of transmission and other results

Observational studies

Vertical transmission Malawi (Semba et al., 1994, 1995b)

Rwanda (Graham et al., 1993)

United States (Burns et al., 1999)

United States (Greenberg et al., 1997)

United States (Burger et al., 1997)

Horizontal transmission Rwanda (Moore et al., 1993)

India (Mehendale et al., 2001)

Kenya (MacDonald et al., 2001)

Tanzania (Villamor et al. , 2006)

Trials

Malawi (Kumwenda et al., 2002)

South Africa (Coutsoudis et al., 1999)

Tanzania (Fawzi et al., 1998, 2000b, 2002, 2004a; Villamor et al., 2002b)

Kenya (Baeten et al., 2002; McClelland et al., 2004)

Kenya (McClelland et al., 2004)

Zimbabwe (Humphrey et al., 2006)

Low maternal vitamin A

Low maternal vitamin A Low maternal vitamin A

Low maternal vitamin A

Low maternal vitamin A

Low maternal b_carotene Low maternal vitamin E

Low serum vitamin A

Low serum vitamin E Low serum carotenoids Low serum b_carotene

Low serum vitamin A

Low serum vitamin A

Vitamin A supplementation

Vitamin A plus ß-carotene supplementation

Vitamin A plus ß-carotene supplementation

Multivitamin (vitamins B, C, and E) supplementation

Vitamin A

supplementation

Multivitamin + Se supplementation

Vitamin A supplementation to either mother or infant

"; " Infant mortality

" Risk of low birth weight

$; # Risk of low birth weight and anemia in the newborn; no association with prematurity

$; No association with low birth weight, infant mortality; # risk of preterm delivery

"; No association with low birth weight, fetal mortality, severe preterm (<34 weeks), small SGA; " risk of HIV shedding through the lower genital tract

# Only among children of women who had a poorer nutritional and immunologic status at baseline; # risk of low birth weight, fetal mortality, severe preterm (<34 weeks), small SGA

$; No effect on HIV shedding in vaginal secretions

" Risk of HIV shedding in vaginal secretions

"; " Risk of infant mortality

Increased risk; decreased risk; no association; SGA, small for gestational age; Se, selenium.

18 to 28 weeks of gestation until delivery. Supplementation with vitamin A had no effect on prematurity or on HIV transmission from mother to child assessed at 6 weeks or at 24 months postpartum; however, the vitamin A group had significantly lower proportion of low birth weight infants (14% versus 21.1% in the control group; p = 0.03) and a reduced incidence of anemia in the newborn children at 6 weeks postpartum (23.4% versus 40.6%; p < 0.001) (Kumwenda et at., 2002).

In South Africa, 728 HIV-infected pregnant women were randomized to receive either 5000 IU vitamin A (1.667-mg retinol equivalent) plus 30-mg b-carotene (5-mg retinol equivalent) daily during the third trimester of pregnancy plus 200,000 IU vitamin A at delivery or placebo. No difference was found either in the risk of HIV infection or in birth weights or in the fetal/infant mortality rates in the two groups at 3 months of age. However, women in the vitamin A group were significantly less likely to have a preterm delivery (11.4% versus 17.4% in the placebo group; p = 0.03) (Coutsoudis etat, 1999).

In Tanzania, the Trial of Vitamins (TOV) study randomized 1078 HIV-infected pregnant women at 12-27 weeks of gestation to receive either daily vitamin A supplements [30-mg b-carotene (5-mg retinol equivalent) and 5000 IU of preformed vitamin A (1.667-mg retinol equivalent)], multivitamins (20-mg thiamine, 20-mg riboflavin, 25-mg B6, 100-mg niacin, 50-mg B12, 500-mg C, 30-mg E, and 0.8-mg folic acid), both, or neither using a 2 x 2 factorial design. At delivery, women in vitamin A groups received an additional oral dose of vitamin A (200,000 IU), whereas women in nonvitamin A groups received a placebo. In addition, all women received 120 mg of ferrous iron and 5 mg of folate tablets daily and 300 mg of Chloroquine as malaria prophylaxis weekly. Neither multivitamins [relative risk (RR) of 0.95; 95% CI: 0.73, 1.24] nor vitamin A (RR of 1.06; 95% CI: 0.81, 1.39) had an effect on the risk of HIV transmission or survival through 6 weeks postpartum. Babies born HIV-negative to the mothers supplemented with multivitamins, but not vitamin A, had higher birth weights as compared to those in the no-multivitamin arm (94 g difference in birth weights, p = 0.02) (Fawzi et at., 2000b). Moreover, the multivitamin supplements, but not vitamin A, decreased the risk of fetal death by 39% [30 fetal deaths in the multivitamin group, compared to 49 among those not on multivitamins (RR of 0.61; 95% CI: 0.39, 0.94)]. Multivitamin supplementation decreased the risk of low birth weight (<2500 g) by 44% (RR of 0.56; 95% CI: 0.38, 0.82), severe preterm birth (<34 weeks of gestation) by 39% (RR of 0.61; 95% CI: 0.38, 0.96), and small size for gestational age at birth by 43% (RR of 0.57; 95% CI: 0.39, 0.82). Vitamin A supplementation had no significant effect on these endpoints. Multivitamins, but not vitamin A, resulted in a significant increase in CD4, CD8, and CD3 counts in the women (Fawzi et at., 1998). Maternal multivitamin supplements, but not vitamin A, also led to a significant increase in the weight gain during pregnancy, along with reducing the risk of developing hypertension during pregnancy (RR of 0.62; 95% CI: 0.40, 0.94) (Merchant et al., 2005; Villamor et al., 2002b). After assessment of HIV transmission through breast-feeding, vitamin A/S-carotene resulted in a significant increase of 38% in the risk of overall vertical HIV transmission, whereas multivitamins excluding A had no effect on the risk of transmission (Fawzi et al., 2002). Children who were HIV-negative at 6 weeks of age and were born to women who were in relatively poorer nutritional or immunologic conditions at baseline and whose mothers received multivitamins experienced significant reductions in HIV transmission through breast-feeding and improvement in HIV-free survival. Vitamin A/S-carotene supplementation also led to a significant increased in shedding of the virus through the lower genital tract (Fawzi et al., 2004a). There are two important differences to note between TOV and the previously mentioned vitamin A trials—first, the supplementation of the mothers continued beyond the antenatal period, unlike the other trials; second, the effect of the supplementation regimens on the various routes of vertical transmission (intrauterine, intrapartum, and breast-feeding) could be assessed.

Another trial in Mombasa in Kenya randomized 400 HIV-infected women to receive either vitamin A (10,000 IU) supplementation daily for 6 weeks or placebo to examine difference in viral shedding in vaginal secretions between the 2 groups, if any. No such difference was seen at the end of follow-up; moreover, there was no effect observed on plasma viral load or on CD4 or CD8 counts with vitamin A supplementation in these women (Baeten et al., 2002). The same investigators then conducted a similar trial with multivitamin plus selenium supplementation versus placebo for 6 weeks to examine the same outcome. They found that micronutrient supplementation led to a 2.5 times higher risk (p = 0.001) of viral shedding and this effect was greatest among women who had normal selenium levels at baseline (McClelland et al., 2004). Moreover, this trial used a similar dose of vitamins B, C, and E as the TOV in Tanzania. These observations appear to indicate selenium as a potential risk factor for HIV transmission, an issue that needs to be examined further.

In Zimbabwe, the investigators assessed the efficacy of a single large dose of vitamin A given to women (400,000 IU) early during the postpartum period and/or to infants (50,000 IU). The authors used the data from a total of 4495 infants born to HIV-infected women and found that vitamin A supplementation to either mothers or infants resulted in an increased risk of infant HIV infection or death, although the effect of providing the supplement to both mother and infant was not different from the effect of providing a placebo (Humphrey et al., 2006).

The findings from these trials assessing the role of vitamin supplementation in the prevention of HIV transmission are summarized in Table II.

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