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Vitamin D Status of HIV-Infected Women and Its Association with HIV Disease Progression, Anemia, and Mortality: "Women in the highest vitamin D quintile had a 42% lower risk of all-cause mortality, compared to the lowest quintile. Vitamin D status had a protective association with HIV disease progression, all-cause mortality"
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Saurabh Mehta1,2*, Edward Giovannucci1,2,3, Ferdinand M. Mugusi4, Donna Spiegelman1,5, Said Aboud6, Ellen Hertzmark1, Gernard I. Msamanga7, David Hunter1,2,3, Wafaie W. Fawzi1,2,8
1 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, 2 Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, United States of America, 3 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, United States of America, 4 Department of Internal Medicine, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, 5 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America, 6 Department of Microbiology and Immunology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, 7 Department of Community Health, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania, 8 Department of Global Health and Population, Harvard School of Public Health, Boston, Massachusetts, United States of America
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008770
Abstract
Background: Vitamin D has a potential role in slowing HIV disease progression and preventing mortality based on its extensive involvement in the immune system; however, this relationship has not been examined in large studies or in resource-limited settings.
Methodology/Principal Findings: Vitamin D levels were assessed in 884 HIV-infected pregnant women at enrollment in a trial of multivitamin supplementation (not including vitamin D) in Tanzania. Women were followed up for a median of 69.5 months, and information on hemoglobin levels, HIV disease progression, and mortality was recorded. Proportional hazard models and generalized estimating equations were used to assess the relationship of these outcomes with vitamin D status.
Conclusions/Significance: Low vitamin D status (serum 25-hydroxyvitamin D<32ng/mL) was significantly associated with progression to WHO HIV disease stage III or greater in multivariate models (incidence rate ratio [RR]: 1.25; 95% confidence intervals [CI]: 1.05, 1.50). No significant relationship was observed between vitamin D status and T-cell counts during follow-up. Women with low vitamin D status had 46% higher risk of developing severe anemia during follow-up, compared to women with adequate vitamin D levels (RR: 1.46; 95% CI: 1.09, 1.96). Women in the highest vitamin D quintile had a 42% lower risk of all-cause mortality, compared to the lowest quintile (RR: 0.58; 95% CI: 0.40, 0.84). Vitamin D status had a protective association with HIV disease progression, all-cause mortality, and development of anemia during follow-up in HIV-infected women. If confirmed in randomized trials, vitamin D supplementation could represent a simple and inexpensive method to prolonging the time to initiation of antiretroviral therapy in HIV-infected patients, particularly in resource-limited settings.
the relationship between continuous vitamin D levels and risk of disease progression was linear with the risk of disease progression decreasing with increasing vitamin D levels (p = 0.05; Figure 1).
the women in the highest vitamin D quintile had a 42% lower risk of all-cause mortality compared to women in the lowest quintile (Incidence Rate Ratio [RR]: 0.58; 95% CI: 0.40, 0.84; p<0.01). In analyses with continuous vitamin D levels as the exposure, a significant linear relationship was observed with all-cause mortality; the risk of all-cause mortality declined with increase in vitamin D levels (p<0.01; Figure 2).
A significant association was also observed between low vitamin D status and anemia and markers of iron deficiency (Table 4). Women with low vitamin D levels at baseline had a 46% higher risk (RR: 1.46; 95% CI: 1.09, 1.96; p = 0.01) of developing severe anemia during follow-up in multivariate models, compared to women with adequate vitamin D levels. The rate ratio for severe hypochromic microcytosis associated with low vitamin D levels at baseline was 2.56 (95% CI: 1.72, 3.79; p<0.01). No significant relationship of vitamin D status was observed with macrocytosis.
Discussion
In this study, low vitamin D levels at baseline were significantly associated with increased risk of HIV disease progression, severe anemia, and hypochromic microcytosis in HIV-infected Tanzanian women. Women in the highest quintile of vitamin D also had a significantly lower risk of all-cause mortality compared to women in the lowest quintile of vitamin D. In contrast, no significant association of vitamin D status was observed with AIDS-related mortality or T-cell counts.
There is a paucity of research on the relationship of vitamin D with HIV-related health outcomes, particularly in resource-limited settings. Most of the published studies are cross-sectional comparisons of vitamin D levels in HIV-infected patients compared to HIV-uninfected controls. For example, a small study in Switzerland found no significant difference between 25(OH)D concentrations in 6 patients with advanced AIDS, compared to 10 HIV-uninfected controls [21]. In a study from Germany, 1,25(OH)2D and 25(OH)D levels were both significantly lower among men and women with HIV-infection (asymptomatic, on ART), compared to uninfected controls [22]. In a study in Norway, mean serum 1,25(OH)2D concentrations were significantly lower in HIV-infected patients, compared to healthy, seronegative blood donors; 1,25(OH)2D levels were lowest in symptomatic patients, independent of the presence of opportunistic infections [8].
One small longitudinal study in Norway (n = 53) assessed the association between vitamin D levels and survival among HIV-infected individuals. Patients with 1,25(OH)2D levels below 25ng/L at baseline had a shorter survival time than those with normal concentrations, after adjusting for CD4 T-cell counts. The association appeared to be stronger in individuals with CD4 counts less than 50/μL [8].
The protective association of vitamin D against HIV disease progression may be explained by its role in immune function. Vitamin D has been shown to improve phagocytic capacity of macrophages, cell-mediated immunity, and increase natural killer cell number and cytolytic activity, suggesting an important role in response to infections. Laboratory studies have identified several mechanisms by which vitamin D could slow HIV disease progression [7]. For example, 1,25(OH)2D decreases CD4 surface receptor expression in promyelocytic leukemia cell line [23] and human monocytes [24]. If confirmed, these results could constitute a mechanism to control viral entry and cytopathogenic effects. In another study, in vitro pre-treatment of human peripheral blood monocytes with 1,25(OH)2D, but not 25(OH)D, decreased HIV infection by 95% [25]. The recent elucidation of vitamin D's role in the innate immune response via toll-like receptors (TLRs) [4], suggests potential modulation of pathogen entry by vitamin D and its metabolites. This mechanism has been shown to be important in the immune system's response to tuberculosis; TLR stimulation of human macrophages up-regulates the expression of VDRs and induces the enzyme (CYP27b1) that catalyzes the conversion of 25(OH)D to 1,25(OH)2D, the biologically active metabolite of vitamin D. In presence of adequate 25(OH)D, VDR upregulation leads to cathelicidin induction, an antimicrobial peptide with direct action against intracellular pathogens including Mycobacterium tuberculosis [4], a leading cause of disease progression and mortality among HIV-infected patients [26]. Increased resistance to tuberculosis could potentially prolong survival in these patients.
Our study did not find any relationship of vitamin D with change in T-cell counts during follow-up. Though there are several laboratory studies linking vitamin D with T-cell function, no studies have found such an association in vivo in HIV-infected patients. It is possible that beneficial effects of vitamin D may be via modulation of innate immunity, rather than cell-mediated immunity.
Our finding of a relationship between vitamin D status and risk of severe anemia and iron deficiency could have several potential explanations. Iron deficiency impairs intestinal fat absorption, and may consequently decrease vitamin D absorption [27]. Conversely, vitamin D deficiency could cause anemia via increased inflammation or marrow myelofibrosis [28]. An association between low vitamin D status and lower hemoglobin levels or iron deficiency has been observed in earlier studies in individuals with renal disease in NHANES III [29] and in studies in children in minority communities in Britain. For example, in a study in 145 Asian children in Birmingham, the children with low plasma vitamin D concentrations had significantly lower hemoglobin and serum iron concentrations [30]. In Bangladeshi, Pakistani, and Indian communities in England, one-fifth of children surveyed showed signs of both deficiencies; during the winter 50% of children with low vitamin D had low hemoglobin levels (vs. 0% in children with normal vitamin D). Iron deficiency was a significant risk factor for low vitamin D levels in all three ethnic groups [31].
A limitation of the current analysis is the possibility of reverse causation; since vitamin D levels were assessed at baseline when participants were already HIV-infected, the temporal relationship between HIV and vitamin D status could not be ascertained. It is possible that advanced HIV disease may lead to lower serum 25(OH)D levels. However, most participants were stage I disease at baseline. Additionally, controlling for baseline CD4 T-cell counts and HIV disease stage strengthened the observed associations, weakening the possibility of reverse causation.
Another limitation is that the assay for vitamin D assessment does not measure vitamin D2, the form of vitamin D obtained through supplements, reliably; however supplementation was unlikely in this population. Additionally, our choice of cut-off for vitamin D is to make results clinically more relevant and comparable with other studies; however, similar effect estimates were obtained for major outcomes such as HIV disease progression and anemia by using population-based quintiles of vitamin D. Further, potential modification of vitamin D status by ART could not be examined, as study participants were not receiving ART.
Our study provides initial support for a potentially beneficial effect of adequate vitamin D status on HIV disease and related outcomes. If confirmed in randomized controlled trials, vitamin D supplementation could be a simple and low cost method to prolong the time to initiation of anti-retroviral therapy in HIV-infected patients, particularly in resource-limited settings. Evidence from larger studies and randomized trials is urgently needed to examine the effects of vitamin D in HIV-infected patients and its interaction with ART.
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