Our findings show that low concentrations of retinol, β-carotene and vitamin E are very common in children living in Brazil, Argentina and Mexico exposed to HIV, regardless of HIV-infection status thus disproving our original hypothesis. The rates of low concentrations of retinol and vitamin E were very high (74% and 89%, respectively).
The lack of an effect of HIV status on rates of micronutrient low serum levels was surprising. However, this study does not provide final answers to this question and raises several additional ones. Because we did not examine a group without exposure to HIV, the rates of low serum concentrations we observed could be due to factors related to in utero
HIV exposure, including possible genetic defects in vitamin transfer proteins, fat metabolism disorders and oxidative stress which could alter vitamins requirements (28
). Cunningham-Rundles et al. (12
) reported that 70% of North American infants perinatally exposed to HIV were retinol deficient in the first months of life whereas infants with various other disorders had normal retinol levels. Another hypothesis is that in utero
or postnatal exposure to ARVs results in the low micronutrient concentrations we observed. Evidence against this though includes our finding that HIV-infected children treated with ARVs had a lower risk of retinol deficiency; this effect was not seen with β-carotene or vitamin E so may represent a chance observation. Nevertheless, a study in HIV-infected adults on highly active ARV therapy showed low rates of retinol and vitamin E deficiencies (29
A more likely explanation for the high rates of low serum levels regardless of HIV status are maternal factors such as socioeconomic and health status. Published reports and experience demonstrate that the HIV epidemic in Latin America is characterized, as in many places, by poverty and social marginalization (17
). Although we did not formally examine these factors, approximately half of the mothers of children from both groups had a limited number of years of formal education, a condition associated with poverty in these countries. In addition, a high rate of anemia was found in both groups, especially among the HIV-exposed/uninfected, which may reflect overall insufficient nutritional intake (31
For the individual micronutrients we examined, the overall rates of low serum concentrations were in the range of those previously reported in pediatric populations without HIV exposure or infection. Although definitions of retinol deficiency vary across studies, reports of retinol deficiency in pre-school children show rates up to 74.5% in Brazil (32
), 30% in Argentina (33
), and 46.3% in Mexico (34
). These studies support the idea of poor intake as the main cause for the high prevalence of retinol deficiency. Similarly, while definitions of vitamin E deficiency vary across studies, ranging from 7 to 28 μmol/l without adjustment for serum cholesterol (26
), reports of vitamin E deficiency show rates as high as 69% in apparently healthy Latino children in the United States (35
) and 70% in Mexican preschoolers (36
). In addition, vitamin E deficiency was found in 70% of HIV- infected and uninfected South African women and no significant difference by HIV status was observed (37
). The rate of β-carotene deficiency we observed was considerably lower than the rate of retinol deficiency. Although guidelines regarding the serum values for carotenoid adequacy have not been validated, definitions of β-carotene deficiency have been used, ranging from 0.35 to 4.5 μmol/l (25
). The explanation for this relative preservation of β-carotene in the face of retinol deficiency is not known. Possible explanations, none of which we were able to assess in this study, include a plant-based diet, which has been shown to have a significant impact on β-carotene serum levels but no significant effect on retinol levels (40
), the presence of another deficiency, such as zinc, that negatively affects retinol mobilization from the liver (42
) or the negative impact of the acute phase response on retinol levels as has been shown in children with malaria (43
), and in HIV-1 seropositive subjects (44
The impact of the inflammatory response related to HIV and its impact on micronutrient concentrations is unclear. Jahoor et al. have shown that AIDS elicits an acute phase response that is different from bacterial infections, as the higher concentrations and faster rates of synthesis of the positive acute phase proteins are not accompanied by lower concentrations and slower rates of synthesis of most of the negative acute phase proteins, including retinol binding protein (45
). In addition, clinically stable HIV – infected children in South Africa were evaluated for vitamin A and vitamin E and the results failed to demonstrate a correlation between these micronutrients and C-reactive protein concentrations (14
). We were unable to address the potential association between low retinol and inflammation since we did not include measurements of inflammatory markers, such as C-reactive protein. However, we did not find an association between HIV disease parameters, such as clinical status, viral load, and CD4 count, and micronutrient concentrations, suggesting that inflammation related to HIV disease itself did not play a role in our findings. However, other causes of inflammation, common to both groups, may well have played a role that we were not able to assess.
The mean age of the HIV-uninfected children corresponds to infants and younger children whose nutritional status might still be reflecting maternal nutritional status. It is known that pregnancy increases the risk of vitamin deficiency and this extends to the newborn. The prenatal dietary intake of vitamin A is frequently considered to be insufficient to meet increased requirements during pregnancy, particularly in developing countries (46
). In a Brazilian study, maternal vitamin A deficiency was strongly associated with infant vitamin A deficiency and low birth weight (47
). We did not collect maternal dietary intake or maternal plasma levels of vitamin A and vitamin E so were unable to assess their association with the plasma levels of their infants.
Other limitations of this study include the possibility of incomplete recording of nutritional supplements and no dietary intake history, which could explain, at least in part, the lack of significant associations between history of supplement intake and rates of micronutrient low serum levels. Since this study examined stored samples, processing and storage factors may have affected the results. However, retinol, β-carotene, and vitamin E appear to be stable for at least 15 years at −80°C (48
) and repeated freezing and thawing, which was not the case in our study, do not appear to affect the concentrations of these vitamins in serum (49
In summary, our findings demonstrate that low concentrations of vitamin A and vitamin E are extremely common among HIV-infected and HIV-exposed/uninfected children living in Brazil, Argentina and Mexico and similar to rates in other pediatric populations in comparable settings. Poor nutritional intake is likely the main factor contributing to the low serum values of micronutrients in these children. Factors associated with HIV disease itself did not appear to play a role, but other inflammatory processes common to both the HIV-exposed/uninfected and the HIV-infected groups were not assessed.