Selenium -Suppression of Human Immunodeficiency Virus Type 1 Viral Load With Se

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Though this is well known already, I wanted to share this -

http://www.natap.org/2007/HIV/012507_01.htm

Suppression of Human Immunodeficiency Virus Type 1 Viral Load With Selenium

Supplementation

A Randomized Controlled Trial

Barry E. Hurwitz, PhD; Johanna R. Klaus, PhD; M. Llabre, PhD;

, BA; J. Lawrence, MS; J. Maher, PhD; M. Greeson,

PhD; nna 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 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 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 & #956;g/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

& #956;g/L (range, 78.5-158.7 & #956;g/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

& #956;g/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 & #956;g/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/ & #956;L).

In contrast, selenium-treated subjects whose serum selenium increase was

greater than 26.1 & #956;g/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/ & #956;L).

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 & #956;g/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 & #956;g of selenium per pill. Participants

with serum selenium levels below 75 & #956;g/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 & #956;g/L and for the

selenium group was 32.2 ± 24.5 & #956;g/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 ( comparing placebo-treated subjects (who

displayed a serum selenium change[delta]26.1 & #956;g/L [n = 80]),

selenium-treated nonresponders (who displayed a serum selenium change 26.1

& #956;g/L [n = 40]), and selenium-treated responders (who displayed a serum

selenium change >26.1 & #956;g/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 & #956;g 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 & #65533;\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

& #956;g/d) in HIV-infected individuals found a significant decrease in hospital

admission rates and CD4 counts declining below 50 cells/ & #956;L 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

& #956;g/L (range, 78.5-158.7 & #956;g/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

& #956;g/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.