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Suppression of Human Immunodeficiency Virus Type 1 Viral Load With Selenium Supplementation
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A Randomized Controlled Trial
Barry E. Hurwitz, PhD; Johanna R. Klaus, PhD; Maria M. Llabre, PhD; Alex Gonzalez, BA; Peter J. Lawrence, MS; Kevin J. Maher, PhD; Jeffrey M. Greeson, PhD; Marianna K. Baum, PhD; Gail Shor-Posner, PhD; Jay S. Skyler, MD; Neil Schneiderman, PhD
Behavioral Medicine Research Center (Drs Hurwitz, Klaus, Llabre, Maher, Skyler, and Schneiderman and Messrs Gonzalez and Lawrence), Division of Endocrinology and Metabolism, Department of Medicine (Drs Hurwitz, Skyler, and Schneiderman), and Departments of Microbiology and Immunology (Dr Maher) and Psychiatry and Behavioral Sciences (Drs Shor-Posner and Schneiderman), University of Miami, and Robert Stempel School of Public Health, Florida International University (Dr Baum), Miami, Fla; and Departments of Psychology (Drs Hurwitz, Llabre, Greeson, and Schneiderman) and Biomedical Engineering (Drs Hurwitz and Schneiderman), University of Miami, Coral Gables, Fla.
Arch Intern Med. Jan 27, 2007;167:148-154.
ABSTRACT
Background Despite findings that selenium supplementation may improve immune functioning, definitive evidence of its impact on human immunodeficiency virus (HIV) disease severity is lacking.
Methods High selenium yeast supplementation (200 μg/d) was evaluated in a double-blind, randomized, placebo-controlled trial. Intention-to-treat analyses assessed the effect on HIV-1 viral load and CD4 count after 9 months of treatment. Unless otherwise indicated, values are presented as mean ± SD.
The mean pretreatment selenium level of the present cohort was 111.9 ± 12.9 μg/L (range, 78.5-158.7 μg/L), which reflects a slightly depressed value but still a nutritionally adequate level relative to healthy US residents.
Results Of the 450 HIV-1-seropositive men and women who underwent screening, 262 initiated treatment and 174 completed the 9-month follow-up assessment. Mean adherence to study treatment was good (73.0% ± 24.7%) with no related adverse events. The intention-to-treat analyses indicated that the mean change (delta) in serum selenium concentration increased significantly in the selenium-treated group and not the placebo-treated group (delta = 32.2 ± 24.5 vs 0.5 ± 8.8 μg/L; P<.001), and greater levels predicted decreased HIV-1 viral load (P<.02), which predicted increased CD4 count (P<.04). Findings remained significant after covarying age, sex, ethnicity, income, education, current and past cocaine and other drug use, HIV symptom classification, antiretroviral medication regimen and adherence, time since HIV diagnosis, and hepatitis C virus coinfection.
Follow-up analyses evaluating treatment effectiveness indicated that the nonresponding selenium-treated subjects whose serum selenium change was less than or equal to 26.1 μg/L displayed poor treatment adherence (56.8% ± 29.8%), HIV-1 viral load elevation (delta = +0.29 ± 1.1 log10 units), and decreased CD4 count (delta = -25.8 ± 147.4 cells/μL).
In contrast, selenium-treated subjects whose serum selenium increase was greater than 26.1 μg/L evidenced excellent treatment adherence (86.2% ± 13.0%), no change in HIV-1 viral load (delta = -0.04 ± 0.7 log10 units), and an increase in CD4 count (delta = +27.9 ± 150.2 cells/μL).
Conclusions Daily selenium supplementation can suppress the progression of HIV-1 viral burden and provide indirect improvement of CD4 count. The results support the use of selenium as a simple, inexpensive, and safe adjunct therapy in HIV spectrum disease.
INTRODUCTION
Selenium is an essential trace mineral and, when in vivo levels are deficient, syndromes involving myopathy, immune dysfunction, and cardiomyopathy occur, especially in regions with soil deficiencies, limited resources, and poverty.1-4 Selenium deficiency has been observed in human immunodeficiency virus (HIV) spectrum disease.5 Lower serum concentrations predict mortality for infected adults and children6-7 and have been linked to enhanced viral virulence, diminished natural killer cell cytotoxicity, increased mycobacterial disease risk, and progression of HIV disease.8-11 In contrast, in vitro incubation of HIV-1-infected monocytes with selenium suppresses HIV-1 replication.12 Moreover, clinical trials of selenium supplementation (200 μg/d) have resulted in lower incidence of various cancer types with no adverse effects.13
Patients with HIV now have an extended life expectancy, largely as a result of pharmaceutical advances in antiretroviral therapy (ART); nevertheless, clinicians are still faced with maintaining a delicate balance between virology and ART pharmacology in the context of patient-related factors.14-15 Strict adherence to ART is required to achieve adequate and sustained viral suppression and prevent the emergence of drug-resistant viral strains.16 Even with adequate regimen adherence, there is a significant risk of ART-induced toxic effects and metabolic dysfunction.17-18 Thus, complete control of HIV over time using ART is unlikely, and pharmacotherapeutic limitations leave a significant void in the treatment arsenal.15 Despite promising findings that selenium may improve immune functioning,19-20 definitive evidence of its impact as an adjunct treatment on the severity of HIV disease is lacking. The present study evaluated the effect of selenium supplementation on serum selenium levels and the subsequent impact on HIV-1 viral load and helper T cell (CD4) count.
PARTICIPANTS
Participants in the Miami Selenium for Heart and Immune Health Trial consisted of a convenience sample from the Miami-Dade, Broward, and Palm Beach counties of Florida. Participants were recruited from June 5, 2001, through July 14, 2005, via newspaper advertisement, flyer distribution at HIV-AIDS clinics and support groups, and physician and chain referrals. Included subjects (1) provided informed consent; (2) presented HIV-1 infection documentation; (3) were aged 18 to 55 years; (4) were not being treated pharmacologically for cardiovascular (eg, with -blockers, calcium antagonists, and angiotensin-converting enzyme inhibitors), diabetic (eg, with hypoglycemics and insulin sensitizers), psychiatric (eg, with antipsychotics and antidepressives), or endocrine (eg, with estrogen therapy) conditions; (5) had no history of diabetes or cardiovascular disorder or any other major systemic diagnosis unrelated to HIV; (6) presented no electrocardiographic evidence of myocardial infarction or atrioventricular conduction arrhythmias; (7) had no gross neurocognitive dysfunction; (8) had no surgery within 3 months of study entry; (9) were premenopausal and not pregnant and had no intent to become pregnant (for women); (10) were not in another clinical trial; and (11) discontinued use of any supplement containing more than 50 μg of selenium per pill. Participants with serum selenium levels below 75 μg/L, indicative of a biochemical deficiency, were excluded for scientific and ethical reasons. Informed consent was obtained at the initial screening and at study randomization. The trial was approved by the institutional review board of the University of Miami.
RESULTS
Of the 972 telephone-screened subjects, 450 participated in the screening assessment; of these, 310 were randomized to treatment (Figure 1). After the run-in phase, an additional 48 subjects dropped out or were excluded. Therefore, 262 subjects completed pretreatment assessment (placebo group, n = 121; selenium group, n = 141). Of these subjects, 174 completed the 9-month assessment (placebo group, n = 83; selenium group, n = 91). There were no significant differences between the treatment groups on any of the demographic or other characteristics (Table). Unless otherwise indicated, values are presented as mean ± SD.
The intervention resulted in no adverse events related to the study supplement. The 2 groups did not differ in serum selenium concentration at pretreatment (Table), but the selenium group evidenced significantly greater change in serum selenium concentration at the 9-month assessment (P<.001). The mean serum selenium change for the placebo group was 0.5 ± 8.8 μg/L and for the selenium group was 32.2 ± 24.5 μg/L. Treatment adherence did not differ between groups (eDEM, 72.9% ± 24.4% [placebo group] vs 73.1% ± 25.0% [selenium group]; pill count, 80.1% ± 20.6% [placebo group] vs 81.8% ± 20.1% [selenium group]). The eDEM adherence correlated with mean serum selenium concentration change in the selenium group (r = 0.59; P<.001), but not in the placebo group (r = -0.06).
The ITT analyses examined whether the effect of treatment on the serum selenium concentration had an effect on HIV-1 viral load and CD4 count at the 9-month assessment, controlling for the pretreatment viral load and CD4 count (Figure 2). The model had good fit (P=.38). In this model, the path from the treatment group to the mean change in serum selenium concentration was significant (beta = 0.65). The paths from the serum selenium concentration change to the HIV-1 viral load and CD4 count at the 9-month assessment were significant (beta = -0.16 and beta= 0.10, respectively). The analysis was repeated to examine the effect on CD4 count as being partially mediated by the viral load change. This model also had good fit (P=.45). The direct path between the serum selenium concentration change and CD4 count change became nonsignificant (beta = 0.06), as indicated in Figure 2. This finding indicates that the treatment effect on the CD4 count was indirect.
Figure 3. Mean ± SE treatment effect relative to pretreatment baseline for the serum selenium level (A), and the human immunodeficiency virus type 1 (HIV-1) viral load and CD4 cell count (B) comparing placebo-treated subjects (who displayed a serum selenium change[delta]26.1 μg/L [n = 80]), selenium-treated nonresponders (who displayed a serum selenium change 26.1 μg/L [n = 40]), and selenium-treated responders (who displayed a serum selenium change >26.1 μg/L [n = 50]).
COMMENT
This study is, to our knowledge, the first double-blind, randomized, placebo-controlled trial in a community-based cohort of HIV-infected men and women to demonstrate that daily supplementation with 200 μg of selenium for 9 months elevates the serum selenium level and suppresses the progression in HIV-1 viral load. The selenium supplement resulted in no adverse events, suggesting that it may be administered safely at the dosage used\a finding consonant with that of previous oncological clinical trials.13 The treatment effects were independent of subject-related factors, including age, sex, ethnicity, income, education, and past and current drug use. In addition, the findings remained significant after correcting for the effects of disease-related factors, including ART regimen and adherence, HIV disease stage and duration, and HCV coinfection. The study showed that the induced change in serum selenium concentration significantly predicted change in the HIV-1 viral load. Moreover, there is strong evidence that the primary selenium effect was on the viral burden. In contrast, the observed benefit of treatment on the CD4 cell count was indirect via the treatment effect on the viral load. Although no previous studies have examined the relationship of serum selenium level with HIV-1 viral load, previous HIV studies have shown a relationship between a lower serum selenium level and a lower CD4 count,28-30 more opportunistic infections,31 faster disease progression, and greater HIV-related mortality.6-7 The only other randomized controlled trial of selenium supplementation (200 μg/d) in HIV-infected individuals found a significant decrease in hospital admission rates and CD4 counts declining below 50 cells/μL for those treated with selenium.32 Thus, selenium supplementation appears to have beneficial effects on HIV disease severity and progression.
The mean pretreatment selenium level of the present cohort was 111.9 ± 12.9 μg/L (range, 78.5-158.7 μg/L), which reflects a slightly depressed value but still a nutritionally adequate level relative to healthy US residents.33 Of the cohort, about 97% had serum selenium values greater than 90 μg/L, a level considered minimally adequate for optimal selenoenzyme activity and selenoprotein synthesis.34 In the present trial, selenium-enriched yeast was selected as a vehicle because it contains high concentrations of organic, bioavailable forms of selenium.35 The selenium-treated responders had good treatment adherence (86.2%) and serum selenium concentration elevated on average 44.5% compared with pretreatment levels, whereas the serum selenium concentration of the selenium-treated nonresponders failed to substantially increase, likely a consequence of deficient treatment adherence (56.8%). However, 6 subjects (15%) in the nonresponder group had adherence to the supplement regimen of greater than 80% but showed little or no serum selenium concentration change. Supplement misadministration in these cases was ruled out by the inspection of returned capsule contents. The literature indicates that, throughout HIV disease progression, micronutrient and trace element deficiencies are prevalent and may result from malabsorption, altered metabolism, gastrointestinal tract infection, and altered gut barrier function.8 Of the 6 nonresponders who failed to display a change in serum selenium concentration, 2 had chronic diarrhea, 1 had ulcerative colitis, and 1 was diagnosed as having a benign colon tumor just before the 9-month examination. For the remaining 2 subjects, there was no clinical evidence of gastrointestinal tract complications. Recent evidence in an HIV-infected cohort has shown that malabsorption may not necessarily be associated with wasting or with current or chronic diarrhea.36 Moreover, it is possible that polymorphisms in the selenoprotein genes due to selenium deficiency or another etiology may deleteriously influence selenium intracellular trafficking and incorporation.37
The exact mechanism by which selenium exerts its effect on HIV-1 viral replication is not known, although the literature suggests several possibilities. One prominent hypothesis has been that diminished antioxidant function may be a contributing factor. The HIV virion is a powerful polyclonal activator and, in turn, stimulates high levels of proinflammatory cytokines and enhanced reactive oxygen species formation, the consequence of oxidative metabolism.38 The excessive reactive oxygen species formation, when in imbalance with antioxidant capacity, is termed oxidative stress. Excessive reactive oxygen species formation can damage cells and essential biological molecules, resulting in greater expression of proinflammatory cytokines that can further exacerbate oxidative stress.39-40 Selenium is required for the formation of glutathione peroxidase,41 which acts in the destruction of hydrogen peroxide and organic hydroperoxides, thereby reducing the further propagation of free radicals and cytotoxic agents. The HIV-1 virus may require selenium to produce its own selenoenzymes, thereby depleting selenium resources.42-43 Dietary deficiencies that are common in chronically ill, impoverished, and drug-using populations can lead to oxidative stress and alter a viral genome such that a normally benign or mildly pathogenic virus can become highly virulent.44 In particular, HIV-1 replication in vitro is facilitated by exposure to oxidative stress.45 In contrast, antioxidant multivitamin supplementation has been observed to diminish oxidative stress and HIV-1 viral burden.46 These findings support the notion that selenium may act on the HIV virus indirectly.
The cellular actions of selenium are also linked to the redox regulation of genes. Others have provided evidence that the HIV-1 virion encodes homologues of selenoproteins that influence immune-related genes that regulate cytokine production, cellular proliferation, and apoptosis.47-48 Therefore, the selenoprotein is posited to act directly on the HIV-1 virion to suppress its replication. However, supporting evidence for this hypothesis remains to be obtained. Therefore, benefits derived from selenium supplementation may be due to its indirect and direct effects, but may also be related to another, as yet unidentified, chemopreventive activity.
A major study limitation is that the analysis involved only 2 time points during 9 months of treatment, and therefore it is not known whether the effect on viral load may be sustained with continued treatment. On completion, the trial will provide an assessment after 18 months of treatment. The study cohort was heterogeneous with regard to subject variables such as race or ethnicity, HIV disease stage, ART regimen, history of drug use, and HCV coinfection, hence increasing the generalizability of the findings. Although these subject variables and others were included as covariates, they were not analyzed as specific subgroups, which might be of clinical interest. Any model derivation must balance system complexity with power constraints, and the present study model adhered to accepted statistical modeling standards. The principal study strength is that the analysis was based on participants obtained in a thorough and consistent manner, randomized to treatment and blinded to treatment group. Moreover, this study has extended previous research by evaluating the concomitant effect of selenium treatment on HIV-1 viral load and CD4 count.
The study findings indicate that 9 months of selenium supplementation appears efficacious in elevating serum selenium concentration, suppressing the progression of HIV-1 viral burden, and providing indirect improvement of CD4 count in adult HIV-infected men and women. Future research is necessary to confirm the directional relationships observed. For example, it is of interest to determine whether the indirect effect of selenium on CD4 count is restricted to the mediational role of HIV-1 viral load. An investigation of the mechanisms driving the effects of selenium on HIV-1 replication and other potential aspects of immunocellular expression and function is also indicated. Given the challenges of using conventional pharmacotherapy to achieve and maintain virologic suppression in HIV-spectrum disease, our results support the use of selenium as a simple, inexpensive, and safe adjunct therapy.
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