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,3
,**
Departments of
* Nutrition,
Epidemiology, and
** Biostatistics, Harvard School of Public Health, Boston, MA, and
Department of Community Health, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania
3To whom correspondence should be addressed. E-mail: mina{at}hsph.harvard.edu.
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ABSTRACT |
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 TOP ABSTRACT CONCLUSIONLITERATURE CITED |
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KEY WORDS: • HIV infection • vitamins • zinc • selenium • mortality
HIV-1 infection is having a devastating impact on many developing countries. As of the end of 2003, 
38 million people were living with HIV/AIDS (1). New infections totaled 5 million in 2003, and 3 million HIV-related deaths occurred in the same year; >20 million people have died since the beginning of the epidemic in 1981. The most heavily affected geographical region is sub-Saharan Africa, which is home to about 66% (or 25 million) of the world’s total number of persons with HIV/AIDS. Over 80% of women living with HIV/AIDS worldwide reside in sub-Saharan Africa. Mother-to-child transmission of HIV-1 occurs in 30–45% of cases in the region. Further, sub-Saharan Africa accounted for 90% of the children orphaned by AIDS. The epidemic is expanding rapidly in Asia, particularly in south/southeast Asia; the region hosts about 7 million people with HIV/AIDS.
Poor nutrition and HIV disease progression are part of a vicious cycle that contributes to further deterioration of the health of patients and that ultimately leads to mortality. It is established that HIV infection can lead to undernutrition, including micronutrient deficiencies and lean body mass depletion through decreased food intake, malabsorption, and increased utilization and excretion of nutrients (2). In this paper, key evidence from epidemiologic studies that support the prospective associations between micronutrient status and immunologic and clinical outcomes will be reviewed. Comprehensive reviews on the subject were published (3,4), hence, the latest findings on the role of vitamins and minerals among HIV-infected individuals in developing countries will be provided in the context of a brief overview of the literature.
Vitamins and HIV disease progression
Lower plasma levels of vitamin A (5), vitamin E (6), and vitamin B-12 (7) were related to faster disease progression. Biochemical markers may be limited in their correlation with underlying nutritional status. Low vitamin A, for example, is associated with the acute-phase response to infection (8) and may be a marker of HIV disease stage rather than a reflection of limited liver stores of the nutrient. Reverse causality may provide another explanation for the association between low plasma concentrations and health outcomes: HIV infection could adversely affect absorption and metabolism of nutrients, leading to biochemical deficiency.
Several longitudinal observational studies have examined the associations between intakes of individual vitamins or use of multivitamin supplements and risk of HIV disease progression (Table 1). In an observational study among HIV-infected men in the United States, daily use of a multivitamin supplement was associated with a significant reduction in the risk of progression to the diagnosis of AIDS by 30% and a significantly reduced risk for low CD4+ counts (9). In another study, among HIV-infected men in the United States enrolled in the Multicenter AIDS Cohort Study, a U-shaped relation was noted between vitamin A intake (from diet and supplements) and risks of progression to AIDS and death (10,11). Levels of intake below 9000 and above 20,000 IU were associated with relatively faster disease progression, whereas individuals with intake in that range experienced lower risk. Higher intakes of niacin, vitamins B-1, B-2, B-6, and C were associated with slower progression to AIDS and with 40–60% reductions in risk of death after 8 y of follow-up (5,6). Most of the protective relations in this study were due to the intake of supplements rather than diet. To examine the relation between supplement use and survival independent of the effect of intake from food, the authors included levels of supplement intake and quartiles of food intake in the same multivariate model. Supplemental use of vitamins B-1 and B-2 at levels 5 or more times the recommended dietary allowance (RDA)4 were significantly associated with 40% reduction in mortality, compared with use at <5 times the RDA. Similarly, use of vitamin B-6 at levels 2 or more times the RDA was also associated with a significant improvement in survival, compared with intake of less than twice the RDA. It is worth noting that higher levels of intake in both U.S. studies were associated with improved health outcomes in spite of the fact that few subjects were consuming low levels, suggesting that supplementation may operate through immune enhancement, even among individuals who are not nutritionally deficient. Supplementation may also be beneficial among individuals suffering from micronutrient deficiencies. Among black South African men and women, who are more likely to suffer from poor nutrition compared with participants in the U.S. studies, daily use of B-complex vitamin supplements was associated with significantly lower risks of disease progression (12). In several of the above observational studies, the investigators adjusted for CD4+ cell count, albumin levels, and antiretroviral drug use, among other potential confounders.
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Vitamins and perinatal and child outcomes
The efficacy of micronutrient supplements on the risks of adverse pregnancy outcomes, mother-to-child transmission of HIV, and early child health has been examined in 3 randomized placebo-controlled trials in Malawi, South Africa, and Tanzania. In Malawi, HIV-infected pregnant women were randomized to either 10,000 IU of vitamin A or placebo during the prenatal period. No effect was noted on transmission of the virus at 6 wk or by 12 mo or on the risk of prematurity, but an improvement in birth weight was reported (20). In South Africa, supplements of preformed vitamin A and ß-carotene during the prenatal period resulted in a reduction in prematurity but had no significant effect on birth weight or the risk of HIV infection in infants by 3 mo of age (21). Whereas both trials from Malawi and South Africa provided vitamin A or placebo regimens during the antenatal period only, pregnant women in Tanzania were randomized to daily vitamin A (preformed vitamin A and ß-carotene) and/or multivitamins (vitamins B-complex, C, and E) using a 2-by-2 factorial design, and these supplements were provided daily during the antenatal period and beyond. Multivitamin supplements (including vitamins B-complex, C, and E) but not vitamin A alone, resulted in 40% reductions in the risks of fetal loss, low birth weight and severe prematurity (22), and a significant increase in weight gain during pregnancy (23). Contrary to the original hypothesis, vitamin A resulted in a significant increase of 38% in the risk of vertical transmission of the virus (24). Vitamin A supplementation also resulted in a significant increase in lower genital viral shedding (25). Daily supplements of multivitamins provided no effect on the risk of overall vertical transmission of HIV in utero or during the intrapartum and early breast-feeding periods (up to 6 wk of age) (26). Multivitamin supplementation during breast-feeding had a modest and not statistically significant reduction in the overall risks of HIV infection through breast-feeding after 6 wk of age or mortality by 24 mo of age (24). However, children born to women on multivitamins who were in relatively poorer nutritional or immunological conditions at baseline experienced large and significant reductions in the risks of these end points. Maternal multivitamin supplementation resulted in significant benefits on child health outcomes, including lower child mortality among HIV-negative children (24), an overall significant reduction in the risk of diarrhea and a large increase in CD4+ cell counts (27), and significant improvement in attained weight by 24 mo of age (28). Although maternal vitamin A supplementation did not have an effect on child mortality or CD4+ cell counts, it is worth noting that all children were given 6-mo large doses of vitamin A starting at 6 mo of age as per standard of care in Tanzania.
Three placebo-controlled trials have examined the efficacy of direct vitamin A supplementation of children with HIV infection. In South Africa, vitamin A supplements provided to HIV-infected children born resulted in an 50% reduction in diarrheal morbidity (29). Compared with placebo, vitamin A supplements given every 4 mo to Tanzanian children resulted in significant reductions in mortality and morbidity and in improvements in growth; these effects were greater among HIV-infected children than HIV-negative ones (30–32). In another trial from South Africa among HIV-infected children, vitamin A administered before influenza vaccination was associated with a dampening in the increase in human immunodeficiency viral load associated with the vaccination (33).
Minerals
Most of the research on the roles of minerals in the context of HIV infection focused on selenium and zinc. Selenium is a critical part of the antioxidant enzyme glutathione peroxidase. In a prospective study on HIV-infected drug-using men and women in Miami, Florida, followed for 3.5 y, low plasma selenium levels were associated with a 10-fold higher risk of death compared with individuals with normal status (34). Low plasma selenium was also associated with a 3-fold increased risk for development of mycobacterial disease (35). Among HIV-infected children in Miami, low plasma selenium was associated with a statistically significant 6-fold higher risk of mortality (36). Similarly, low baseline levels of selenium were associated with an increased risk of mortality in a cohort of HIV-infected women in Tanzania (37). Observational studies that examined the relations between zinc status and HIV-related outcomes provided conflicting results. Higher levels of zinc intake were associated with significantly faster disease progression and higher mortality among men in a prospective cohort study of asymptomatic HIV-infected men in the United States (10,11). In another U.S. study of HIV-infected men, however, plasma levels of zinc were inversely associated with mortality (38). As for vitamin A, plasma zinc and selenium concentrations may be low as a result of the infection state and do not necessarily reflect poor nutritional status among individuals.
Several small intervention studies of HIV-infected individuals provide evidence suggestive of beneficial effects of selenium supplementation. For example, supplementation with 100 µg of selenium daily for 1 y resulted in higher glutathione peroxidase activity and glutathione levels among 14 HIV-infected persons (39). A small trial using a crossover design showed a significant increase in the percentage of CD4+ cells and CD4+:CD8 ratio, whereas the glutathione activity remained unchanged (40). In another randomized trial from Florida (n = 186), selenium (200 µg/d) resulted in a significant decrease in total hospital admission rates (P = 0.002) and in the percentage of hospitalizations due to infections (P = 0.01). However, fewer placebo-treated participants were using antiretroviral drugs at baseline (41). Overall, there is a body of observational evidence and several small trials that implicate selenium deficiency as an independent predictor for accelerated progression of HIV disease, but more data are needed from randomized controlled trials.
The effects of zinc supplementation on pregnancy outcomes and hematologic and T-cell counts were examined among HIV-infected pregnant women in Tanzania (42). Women were randomized to receive a daily dose of 25 mg of zinc or placebo from enrollment until the end of the study at 6 wk postpartum. All women received ferrous sulfate and folate daily, as well as multivitamin supplements, including B complex, C, and E. Zinc supplements had no effect on adverse pregnancy outcomes, including low birth weight, prematurity <37 wk, small-for-gestational age, or fetal loss. While both zinc and placebo groups experienced an increase in hemoglobin levels between baseline and 6 wk postpartum, the rise in hemoglobin was significantly lower in the zinc group compared with the placebo group. The effect on hematologic status may have been due to an adverse effect of zinc on iron absorption, as previously observed in other studies (43). Zinc supplements had no effect on CD4+ cell counts.
Current WHO recommendations include daily iron-folate supplements (400 µg of folate and 60 mg of iron) during 6 mo of pregnancy to prevent anemia, and twice daily supplements to treat severe anemia. Although there are concerns about potential adverse effects of iron supplementation in the context of HIV infection (44), more data are needed before this recommendation is changed.
Comment
Other than for vitamin A, no randomized trials have examined the efficacy of direct micronutrient supplementation of children born to HIV-infected mothers. Intervention trials with high-dose vitamin A supplementation among children at or above 6 mo of age showed significant reductions in child mortality among children who were presumably uninfected with HIV (45). Vitamin A supplements also resulted in improvements in health outcomes among children hospitalized with measles and other common infections in childhood. Periodic vitamin A supplementation every 4–6 mo should be promoted among children who are 6–59 mo old, as recommended by the WHO.
Among adults, the adverse effects of vitamin A noted in observational and randomized trials are a reason for concern. The mechanism by which vitamin A may result in increased infection is not understood. It has been hypothesized that by increasing the multiplication and differentiation of lymphoid and myeloid cells, preformed vitamin A leads to increased density of CCR5, a chemokine receptor, receptors that are expressed on these cells and are necessary for attachment and subsequent replication of the virus (46). It is also possible that the adverse effect noted in the Tanzania study is due to the ß-carotene component of the vitamin A intervention. Although high doses of ß-carotene provided for short periods of time to HIV-infected individuals were apparently safe (13–15), there is no study of the safety of prolonged supplementation. Further research on the safety and the efficacy of vitamin A supplementation in the context of HIV infection is needed. Whereas there is no strong evidence in support of providing vitamin A supplements to HIV-infected adults, vitamin A is an essential nutrient, and HIV-infected individuals should ensure dietary intake at the RDA (47).
Multivitamin supplements (including vitamins B-complex, C, and E) were efficacious in reducing adverse pregnancy outcomes, including fetal loss, low birth weight, and prematurity, and in improving weight gain during pregnancy. Provision of these supplements during lactation also reduced child mortality and morbidity, and enhanced child CD4+ cell counts. Provision of multivitamins to HIV-infected pregnant and lactating women has been adopted in various settings. In light of the lack of beneficial effects of zinc on adverse pregnancy outcomes in the Tanzania trial (42) and in several other trials in Asia and Latin America (48), there is no compelling evidence to add zinc to prenatal supplements provided to HIV-infected women.
The latest findings on the efficacy of multivitamins on clinical progression in the Tanzania trial (19) confirm findings from other studies among HIV-infected men and women in the controlled trials from Canada (17) and Thailand (18), and several large, well-designed, and analyzed observational studies (reviewed above). These findings are probably generalizable to HIV-infected women in early stages of disease in developing countries, including those who are not pregnant or breast-feeding. Although women in the Tanzania trial were pregnant at enrollment, only a small proportion of follow-up time (6%) was during pregnancy. In a study from Kenya, it was hypothesized that breast-feeding may result in higher mortality among women (49), possibly through depletion of maternal nutrition status. These findings were not observed in a smaller study from South Africa (50). In the same cohort of Tanzanian women who enrolled in the trial above, no relations were noted between duration of breast-feeding and mortality, decline in CD4+ cell counts, or risks of weight loss and anemia (51). Finally, men and women in many developing countries experience similar environmental, dietary, and infectious disease conditions. It would be problematic to withhold the supplements from HIV-infected men who are early in their disease and who are not yet eligible for antiretroviral therapy (ART). The protective effects of multivitamins on pregnancy and child outcomes among HIV-infected women may not be generalizable to HIV-negative women, and research among the HIV-negative pregnant and lactating women is needed.
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CONCLUSION |
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TOPABSTRACTCONCLUSIONLITERATURE CITED |
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FOOTNOTES |
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2 This work is supported in part by the National Institute of Child Health and Human Development (R01 HD32257), the National Institute of Allergy and Infectious Diseases (U01 AI45441) and the Fogarty International Center (D43 TW00004).
4 Abbreviations used: ART, antiretroviral therapy; RDA, recommended dietary allowance; RR, relative risk.
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LITERATURE CITED |
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TOPABSTRACTCONCLUSIONLITERATURE CITED |
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