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,2,
Departments of
* Nutrition,
Epidemiology, and
Biostatistics, Harvard School of Public Health, Boston MA;
** Department of Community Health, Muhimbili University College of Health Sciences, Dar es Salaam, Tanzania; and
University of Missouri Research Facility, Columbia, MO
2To whom correspondence should be addressed. E-mail: rkupka{at}post.harvard.edu.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • HIV/AIDS • selenium • mortality • CD4+ • Tanzania
Micronutrient deficiencies have been longstanding problems in sub-Saharan Africa with severe public health implications (1). The HIV epidemic further challenges the nutrition situation in this part of the world due to its far-reaching social and economic ramifications. Between 2.2 and 2.4 million persons succumbed to HIV disease in sub-Saharan Africa in the year 2003 alone, predominantly among the most productive age groups in society (2).
Micronutrient deficiencies and HIV disease progression are thought to interact synergistically, progressively aggravating each other (3,4). Deficiencies in antioxidants during HIV infection facilitate the development of oxidative stress and may thus contribute to immune dysregulation and HIV replication (5). The trace element selenium is a key nutrient in antioxidant defense; its deficiency, as evidenced by low plasma selenium concentrations, is common in HIV-infected populations (6–8). In industrialized countries, selenium deficiency has been associated with increased mortality among HIV-infected children (9), drug-using men and women (10), and a cohort composed of drug users and nondrug users (11).
It is difficult to extrapolate these findings to settings such as sub-Saharan Africa where access to antiretroviral therapy is limited, drug use is uncommon, but concurrent nutritional deficiencies are likely to be more pervasive. Furthermore, no studies have been conducted during pregnancy. We therefore examined the association between selenium status and HIV disease progression among HIV-infected pregnant women in Tanzania.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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At baseline, information was obtained on sociodemographic characteristics, including age, education, and income. Maternal weight, height, and mid-upper arm circumference were measured at baseline by trained staff. Disease stage at baseline was defined according to the WHO staging system for HIV disease (14). We intended to follow each woman and her child for a minimum of 18 mo after delivery; beyond that, we tracked survival of women not in active follow up by conducting regular home visits and asking neighbors, friends, and family members about the woman’s survival status if she was not found at home.
Blood samples were collected from subjects at baseline, and plasma was isolated and stored at or below –70°C. Thawed plasma samples were divided into aliquots, placed in Sarstedt tubes, refrozen, placed on dry ice, and sent to the University of Missouri Nuclear Facility, Columbia, MO. Duplicate samples were prepared for selenium and sodium and analyzed with neutron activation analysis (15). To take into account the degree of concentration or dilution of the sample, the selenium concentration was adjusted for the sodium concentration of the sample, which is tightly regulated physiologically. The adjustment was performed by regressing the selenium concentration of the sample onto the sample’s sodium concentration and obtaining the residuals from this regression. To make the residuals interpretable, the median selenium value was added back to the residuals. Even though the correlation between unadjusted and adjusted selenium concentrations was high (r = 0.89), results using unadjusted selenium concentrations were slightly attenuated, most likely due to random misclassification of selenium concentrations. We therefore present adjusted results in this paper. Plasma levels of vitamin A and E were measured at baseline using reversed-phase HPLC (16). Absolute CD4 cell counts were enumerated by using the FACScount or FACscan systems. CD4 cell counts were collected at baseline, delivery, and at 6-mo intervals thereafter.
Follow-up time for mortality analyses was calculated as time elapsed from enrollment to date of death, loss to follow up, or termination of follow up. In analyses examining the risk of progression to CD4 cell count < 200 cells/mm3, eligible women had a baseline CD4 cell count 
200 cells/mm3 and at least 1 subsequent CD4 cell count measurement. Follow-up time for this endpoint was calculated in the following manner: for nonprogressors, follow-up time was based on the average of time elapsed from baseline until the last 2 CD4 cell count measurements available. For progressors, the time periods between 1) baseline and the first test with CD4 cell count < 200 cells/mm3 and 2) baseline and the test preceding the first test with CD4 cell count < 200 cells/mm3 were initially determined; follow-up time was then calculated based on the average of 1) and 2).
The Kruskal-Wallis test (17) was used to compare means of continuous variables across quintiles of plasma selenium levels; the 
2 test (18) was constructed to compare categorical variables. Cox proportional hazards regression models were used to investigate the association between plasma selenium levels and maternal all-cause mortality and time to progression to CD4 cell count < 200 cells/mm3 (19).
The association between selenium levels and mean CD4 cell counts over time was analyzed using a restricted cubic spline model that allows for arbitrary nonlinear relations (20,21). To take into account the correlated nature of repeated CD4 cell count measurements, we used a generalized estimating equations approach (PROC MIXED; SAS Institute) (22). An automatic knot selection procedure was employed using a P-value of 0.05 to determine a parsimonious model. To prevent undue influence of extreme values on the graph, observations with selenium concentrations higher than the 99th percentile were excluded from the spline-fitting procedure.
Only 21 subjects had plasma selenium levels <1.08 µmol/L (85 µg/L), a cutoff point used in previous studies on the role of selenium status in HIV disease (9,10). To indicate relative deficiency, plasma selenium concentrations were therefore modeled as quintiles. Tests for trends used median selenium concentrations of each quintile.
Based on the hypothesized synergistic interaction of selenium and vitamin E (23), we examined whether the risk of mortality and HIV disease progression was increased among those with low vitamin E levels (defined as <9.7 µmol/L, the median). We also examined whether low CD4 cell counts at baseline (<350 cells/mm3) modified the association between selenium status and risk of mortality. To determine whether effect modification was statistically significant, we created cross-product terms of selenium concentrations and the potential modifier and used the likelihood ratio test to compare nested models with and without cross product terms. All statistical analyses were performed using SAS software Version 8.2 (SAS Institute).
The study was approved by the College Research and Publications Committee of Muhimbili University College of Health Sciences, the Ethical Committee of the National AIDS Control Program of the Tanzanian Ministry of Health, and the Institutional Review Board of the Harvard School of Public Health.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The proportions of women dying in the highest to lowest quintiles were 24, 32, 36, 34, and 36%. (Table 2). In a Cox proportional hazards model that adjusted for baseline maternal age (categorized into 4 levels), plasma selenium levels were inversely related to risk of mortality (P-value, test for trend = 0.02). Adjustment for other potential confounding variables as listed in Table 2 slightly strengthened this association (P-value, test for trend = 0.01). Significant increased risks were observed in quintile 3 [rate ratio (RR) = 1.59 (95% CI = 1.08–2.35)], quintile 2 [RR = 1.51 (95% CI = 1.01–2.25)] and quintile 1 [RR = 1.60 (95% CI = 1.07–2.38)], compared with quintile 5.
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High plasma selenium levels were not protective for progression to CD4 cell count < 200 cells/mm3. Of all 700 women with data for this analysis, 314 progressed to a CD4 cell count < 200 cells/mm3 over the follow-up period (Table 3). Plasma vitamin E levels did not modify this association (P-value, test for interaction = 0.17)
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Several lines of laboratory evidence support the benefits of adequate selenium status. As a cofactor of glutathione peroxidase (GSH-Px), selenium is crucial for antioxidant defense (24,25). HIV infection induces chronic oxidative stress (26), which has been linked to apoptosis of T lymphocytes during HIV disease (27) and increased rates of HIV replication by activating the nuclear transcription factor-
B (NF-B) cell gene (28). Selenium supplementation stimulates GSH-Px activity and reduces NF-B activation in HIV-1–infected cell lines (29). HIV-1 may itself encode a truncated GSH-Px gene, which may regulate NF-B transcription factors and contribute to accelerated HIV replication when selenium levels are low (30,31).
Adequate selenium status may support humoral and cell-mediated immunity (32). Supplemental selenium increases expression of the T-cell high-affinity interleukin-2 receptor, and upregulates the activity of natural killer and cytotoxic T cells (33,34).
The association between selenium status and mortality among HIV-infected populations was examined in 3 cohorts from industrialized countries. In a French study, serum selenium levels were inversely associated with mortality risk over a 12-mo period in a cohort of 95 HIV-1–infected drug users and nonusers (11). In the United States, plasma selenium levels < 1.08 µmol/L were associated with a substantially increased risk (RR = 5.96, 95% CI = 1.32–26.81) of mortality among HIV-1–infected children over the 5-y follow-up period (9). Among 125 HIV-infected adults from the United States, plasma levels < 1.08 µmol/L were associated with a 10.8-fold increased risk of mortality (95% CI = 2.37–49.2) (10). The association observed in our cohort was more modest, possibly due to the following reasons: 1) Our study subjects had higher selenium status than the cohort of adult i.v. drug users. Even the lowest quintile in this study, defined by plasma levels <1.34 µmol/L, had fewer signs of selenium deficiency than the reference group among the i.v. drug users (defined by plasma levels < 1.08 µmol/L). Because plasma selenium levels were shown to reflect dietary selenium intake (35), higher selenium intake may be the reason for such higher selenium status. 2) Participants in the U.S. cohort were using i.v. drugs, which has been associated with oxidative stress. This may increase selenium requirements, and thus explain the higher risk estimates observed in the U.S. study (36). 3) The state of pregnancy in our population may account for the attenuated associations yet the mechanism remains unclear.
Several selenium trials were conducted among HIV-infected populations; however, the small sample size of these studies limits their statistical power and may not have adequately resolved differences in confounding factors between treatment and placebo groups. Selenium supplements (200 µg/d) were significantly associated with a lower risk of hospitalization in a trial among 186 HIV-positive individuals from the United States (37). Among 14 HIV-1–infected persons with low starting levels of plasma selenium (median 0.71 µmol/L), 100 µg selenium/d for 1 y increased GSH-Px activity during parts of the follow-up period (38). In a small trial with a partial crossover design, a daily antioxidant combination of 1800 mg N-acetylcysteine and 500 µg sodium selenite increased the percentage of CD4 cells and the CD4:CD8 ratio; GSH-Px activity, on the other hand, remained unchanged (39). Two antioxidant regimens including (but not limited to) 100 and 200 µg selenium increased plasma selenium levels, enhanced GSH-Px activity, and decreased lipid peroxide levels among 48 HIV-positive individuals from Australia (40). These results were obtained even though the study population had high baseline plasma selenium levels (mean = 2.24 µmol/L). Hence, the limited evidence available from trials is consistent with our findings describing benefits of selenium levels > 1.08 µmol/L. Results from a case-control study among HIV-1–infected drug users, in which selenium levels < 1.71 µmol/L were associated with a 3-fold increased risk of developing mycobacterial disease, further support our findings (41).
Plasma selenium levels were not associated with time to progression to CD4 cell count < 200 cells/mm3. When CD4 counts were modeled as repeated measurements, high selenium levels appeared to have a benefit in the first years of follow up, but the benefit disappeared in later years of follow up. This difference may be real or it may be due to measurement error because baseline selenium levels may become increasingly unrepresentative of recent selenium level as time proceeds. Because the association between selenium levels and CD4 counts was less apparent than for mortality, selenium status may lead to clinical improvements not mediated by CD4 cells. Findings from a micronutrient trial among Thai HIV-infected men and women support this hypothesis (42). In that trial, the multimicronutrient supplement reduced the risk of mortality without affecting surrogate immunological endpoints such as CD4 cell counts. In 1 cross-sectional study, selenium levels were correlated with CD4 cell count (11), but the authors are not aware of other studies that investigated the relation between selenium levels and longitudinal CD4 counts.
A limitation of this observational study is that plasma selenium levels may be depressed in the presence of acute disease and inflammation despite adequate tissue levels (43–45). In that case, plasma levels may have only limited ability to represent the body’s selenium status. Even though we excluded subjects with clinical AIDS and adjusted for proxy indicators of immunological status, it is difficult to rule out the acute-phase response to infection as an alternative explanation of our findings. In addition, some experimental evidence cautions against augmenting selenium levels, and thus GSH-Px activity, during HIV disease. In the early phase of the viral replication cycle, high expression of GSH-Px may stimulate HIV replication, possibly by inhibiting host cells to undergo apoptosis (46). Later in the viral life cycle, however, high antioxidant status may benefit the host by reducing oxidative stress, which may subsequently lower HIV replication rates (28,46).
In summary, our findings suggest that plasma selenium levels above commonly used cutoff levels may be of benefit for survival and possibly CD4 counts among HIV-1–infected pregnant women in Tanzania. However, selenium supplementation programs for HIV-infected populations are not yet warranted due to the limitations of the existing body of evidence. Randomized, controlled trials of sufficient sample size are required to resolve existing uncertainties. If proven effective, selenium supplements may be of public health benefit among HIV-infected populations as a stand-alone therapeutic approach and potentially as an adjuvant to antiretroviral therapy.
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FOOTNOTES |
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Manuscript received 26 April 2004. Initial review completed 26 May 2004. Revision accepted 11 July 2004.
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LITERATURE CITED |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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