Advances in Infectious Diseases, 2011, 1, 20-26
doi:10.4236/aid.2011.12003 Published Online December 2011 (http://www.SciRP.org/journal/aid)
Protocol of Determining the Effect of Selenium
Supplementation on CD4 + T Lymphocyte Count
in HIV/AIDS Patients: A Randomized Double
Blind Placebo Controlled Trial
Sahar Yousefi1, Azar Hadadi2, Afshin Ostovar3, Behnaz Edalat Noor1, Mehrnaz Rasoolinejad4,
Mahboobeh Haji Abdolbaghi4, Hossien Khalili5
1Tehran University of Medical Sciences, Tehran, Iran; 2Internal Medicine Ward, Sina Hospital, Iranian Research Center for
HIV/AIDS, Tehran University of Medical Sciences, Tehran, Iran; 3School of Public Health Knowledge Utilization Research Centre,
Tehran University of Medical Sciences, Tehran, Iran; 4Department of Infectious Diseases, Imam Khomeini Hospital, Iranian Re-
search Center for HIV/AIDS, Tehran University of Medical Sciences, Tehran, Iran; 5Department of Clinical Pharmacy, School of
Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
[e-mail], [e-mail], [e-mail]
Received August 29th, 2011; revised October 10th, 2011; accepted October 26th, 2011.
ABSTRACT
Background: Acquired immune deficiency syndrome (AIDS) is believed to be both among major epidemics and a criti-
cal global health issue. The administration of antiretroviral therapy is recently proposed for all patients with CD4 + T
cell count of ≤ 350/μlit in different studies. The accessibility of combination therapy has been restricted due to high
costs of drugs, particularly in low and middle income countries. In Iran, according to WHO, drugs were distributed
among only 6% of adults and 4% - 14% of children in 2009. Moreover, new strains are created and therefore, resis-
tance to the current medication along with a considerable risk of ART-related toxic adverse effects points out the need
for more affordable, effective and safer treatments. The use of antioxidants such as Selenium (Se) has been indicated to
be beneficial in these patients. Method: In a double-blind randomized placebo control trial, 100 HIV positive,
HAART-receiving patients will be selected from more than 2000 individuals covered under IRCHA (Iranian Referral
HIV/AIDS Re- search Centre). They are then randomized to receive daily Se supplement of 200 μgr elemental Se and
placebo for 6 months. The baseline assessment of the patients who meet the inclusion and exclusion criteria includes
doing some lab tests to determine the absolute count of CD4 + T lymphocyte and the plasma levels of Se. The incidence
of opportunistic infection will be assessed during the monthly visits in the first six months of the follow-up and the one
performed at the end of the 9th month. For evaluating the trend of CD4 + T cells changes, the absolute count of CD4 +
T lymphocyte will be measured every 3 months in the 5th, 8th, and 9th visits. The plasma levels of Se will be measured in the
final follow-up session and compared with the baseline value.
Keywords: Supplementation, HIV, AIDS, Lymphocyte Count, Randomized Clinical Trial
1. Introduction
Acquired immune deficiency syndrome (AIDS) that is
currently believed to be a critical global health problem
[1]. According to WHO statistics (World Health Organi-
zation), 33.3 million (31.4 - 35.3 million) people suffered
from HIV worldwide in 2009. [2] Until 2008, the cumu-
lative number of people died of AIDS was estimated to
be more than 33 million [3]. The unpublished data in Iran
until December 2009 show that 92.7% of the total 20547
HIV-infected individuals are male. From among this
population, 2221 have been diagnosed with AIDS and
3543 died secondary to the complications. Recent studies
suggest antiretroviral therapy for patients with CD4 + T
cell count ≤ 350/μlit [4].
Despite the broader coverage of antiretroviral therapy
since 2003 [5], more than 30 million people were diag-
nosed with HIV in low and middle-income countries in
2009 [6] and from among them, only 36% with CD4 T
cell count ≤ 350 /μlit received antiretroviral therapy in

Protocol of Determining the Effect of Selenium Supplementation on CD4 + T Lymphocyte Count in 21
HIV/AIDS Patients: A Randomized Double Blind Placebo Controlled Trial
the same year [7].
Iranian the government offers free ART (antiretroviral
therapy) to HIV and AIDS patients; the point is that only
6% of the adults and 4 to 14% of the children managed to
receive the drugs regularly in 2009 [8]. Apart from the
toxic effects of ART, the development of new strains of
the virus and subsequently resistance to available medi-
cations, especially in areas with acceptable coverage of
the therapy, indicate that in addition to ART, other alter-
native therapies are needed in this regard [9].
Many studies have reported that in a highly oxidative
state, the progress of HIV infection can be promoted to the
host [10]. Thus, treating the patients with antioxidants
since early stages of the disease is believed to be benefi-
cial.
Selenium (Se) is a micronutrient with antioxidant and
immunoregulatory properties [10]. According to the re-
sults of several studies, lower serum Se levels correlates
with a smaller total number of CD4 + T cells, more ad-
vanced stages of infection and higher rates of mortality
caused by HIV [13-21]. Many studies have pointed out
the effect of depleted antioxidant agent-like glutathione
peroxides- resources which is a result of HIV infection in
promoting virus replication and CD4 + T cell count de-
scent [22-24]. As the infection develops, serum Se con-
centration diminishes progressively due to several causes
including malabsorption caused by chronic infection,
infectious diarrhea and HIV-related enteropathy, protein-
calorie malnutrition and the inadequate intake of Se
through diets [24,25]. Moreover, HIV contributes to the
development of an enzyme with a glutathione peroxide-
like structure—Se is a part of this enzyme structure—
which comprises Se. Hypothetically, virus replication
leads to the consumption of Se resources of infected T
cells, through the development of the abovementioned
enzyme [26]. There was a positive correlation between
serum Se level and CD4 + T cell count, CD4
CD8 ratio and a
negative correlation between this variable and indices of
HIV infection progression, i.e. activity of Thymidine ki-
nase and level of 2

microglobulin. There was also a
positive correlation between serum Se concentration and
hematocrit and serum albumin.
In a cross sectional survey conducted in the Iranian re-
search center for HIV/AIDS, Se deficiency (serum Se
level < 85 μgr/lit) was reported in 38% of the HIV positive
individuals. This is while a healthy male in the control
group had significantly lower mean serum Se concentra-
tions [19]. Not many researches have been trials with Se
in humans (Table 1). Delmas-Beavieux chose 52 HIV
positive patients randomly and supplied them with Se and
beta carotene supplements and placebo daily for 12 months.
They failed to report any improvement in CD4 + T cell
count, as for the placebo group. However, glutathione
levels—an antioxidant factor were significantly higher,
whereas malondialdehyde levels—an indicator of lipid
peroxidation were significantly lower in both treated
groups [20]. In a clinical trial, 19 HIV and AIDS patients
received 400 μgr Se supplements per day. After 70 days,
some subjective improvements in the bowel function,
appetite and severity of oral condidiasis as well as a de-
cline in the incidence rate of opportunistic infections were
achieved [21]. In another trial, taking Se supplements,
which contained lower amounts of elemental Se (80μgr
daily) for two months, significantly improved serum Se
levels in HIV and AIDS patients; it, however, had no
Table 1. Summary of clinical trials with Se.
Studies in which administration of Se supplement led to an insignificant
improvement in CD4 + T cell count.
Studies in which administration of Se supplement led to a significant
improvement in CD4 + T cell count.
1) Delmas-Beavieux supplied 52 HIV patients with 250 µgr Se or 30
mgr beta carotene for 12 months, no improvement in CD4 + T cell
count was achieved. Gl utathione levels- an antioxidant factor were
significantly higher, whereas malondialdehyde levels—an indicator of
lipid peroxidation were significantly lower in both treated groups.
2) Cirelli administered 80 µgr Se and 25 mgr vit E to 11 HIV patients
for two months. No improvement in CD4 + T cell count was achieved.
3) Look supplied 24 HIV patients with 600 mgr N-acetylcystein to-
gether with 500 µgr Se for 24 weeks, no improvement was achieved in
absolute CD4 + T cell count, but there was an increase in CD + T cell
percentage and CD4 + T/CD8 + T cell ratio.
4) Burbano investigated the effect of 200 µgr daily Se supplement on
CD4 + T cell count and hospital admissions of 186 HIV patients. No
improvement was achieved in CD4 + T cell count, but there was a
decrease in the rate of patients’ hospital admissions due to HIV com-
plications.
Hurwitz investigated the effect of 200 µgr daily Se supplement on
CD4 + T cell count of 174 HIV patients for 9 months. In the end, there
was a significant increase in CD4 + T cell count.

Protocol of Determining the Effect of Selenium Supplementation on CD4 + T Lymphocyte Count in
22
HIV/AIDS Patients: A Randomized Double Blind Placebo Controlled Trial
effect on CD4 + T cell count, CD4 T
CD8T

 ratio, serum al-
bumin, hemoglobin or ESR (Erythrocyte sedimentation
rate). Lower amounts of Se, compared to other similar
trials, may have contributed to the finding [27]. Similarly,
taking 200 μgr daily Se supplements for 2 years consid-
erably improved Se levels but had no effect on CD4+T
cell count. The number of patients with a decline in CD4
+ T cell count of ≤50/μlit, however, was significantly
greater in the placebo treated group (46% in contrast with
24% in Se treated group). Hospital admissions due to
opportunistic infections were significantly more common
in the placebo group (94% in contrast to 42% in the Se
group) [28]. A recent trial, stressed that individuals who
experienced an increase of at least 26μgr/lit in serum Se
levels following the administration of 200μgr daily Se
supplements for 9 months (Se responders) were more
likely to have a higher CD4 + T count, but a lower viral
load. Despite the fact that the effect of Se supplement on
CD4 + T cell count was secondary to and a consequence
of its impact on viral loud, there was no significant
change in CD4 + T count in Se nonresponders and the
placebo group [29]. In another trial, 24 asymptomatic
HIV patients were supplied with 1800 mgr N-acetyl cys-
tein along with 500 μgr Sodium Selenite daily. In the end,
total CD8 + T cell count and its proportion decreased and
the proportion of CD4 + T cell and CD4T cell count
CD8T cell count


ratio increased significantly. No improvement was achie-
ved in CD4 + T cell absolute count. In 9 accidentally cho-
sen patients, the number of HIV RNA copies/μlit did not
differ; in 44% of them, however, this value was steady
(no increase) after this time [30]. Considering the results
of these studies, more documents regarding the beneficial
effects of Se supplementation in HIV + /AIDS patients
are needed.
2. Aim
Determining the effect of Se supplementation on CD4 +
T lymphocyte count in HIV patients
3. Objectives
Determining the effects of Se supplementation on
 CD4 + T lymphocyte count in HIV patients;
 Body mass index (BMI) values of HIV patients;
 Hb levels of HIV patients;
 The rate of developing opportunistic infections in
HIV patients.
4. Study Population
From among 2000 HIV + /AIDS patients covered under
the Iranian Research Center for HIV/AIDS (IRCHA), one
hundred HIV seropositive HAART-receiving individuals
will be selected. IRCHA, located in Imam Khomeini
hospital in Tehran is working under the supervision of
Tehran University of Medical Sciences. It offers free
services such as para-clinical and clinical treatment and
consultation to about 2000 HIV positive individuals as
well as others at risk of developing HIV or any other
sexually transmitted disease.
5. Recruitment
Subjects of the study consist of individuals diagnosed
with HIV through Western blotting test. Eligible patients
meeting the inclusion criteria will be recruited and the
others will be excluded (see Table 2). We will recruit 100
HIV infected patients with either sufficient or inadequate
serum levels of Se (the deficiency criterion is having
serum Selenium levels of 85 µg/dl or lower). A detailed
written explanation of the study process, names of indi-
viduals and institutions in charge, possible benefits and
probable adverse effects of the interventions is given to
the participants and additional information would be pro-
vided upon request. Informed participants will be asked
to sign a written informed consent. After baseline as-
sessment completion and signing the informed consent,
all patients will be randomized based on age, sex, HIV
infection and AIDS by permuted block randomization
with 4 numbers block into two groups, each consisting of
50 HIV positive patients. One group will receive placebo,
whereas the other will receive Se supplements. The patients
and the researchers are both blinded (see Figure 1).
6. Baseline Assessments
In their first visit all participants are required to complete
a questionnaire on their demographic information, route
Table 2. Inclusion and exclusion criteria.
Inclusion Criteria
 Age 18 to 60 years
 Confirmed HIV-1 infection with western blotting test
 Signing an informed written consent
 Receiving HAART treatment
Exclusion criteria
 Pregnancy
 Consumption of any other supplements except for those under
 investigation in the present study
 History of Hypersensitivity reaction to Se supplement
 History of chronic kidney disease or cirrhosis
 Active HBV infection with liver enzyme > 100 unit/µlit of
 serum
 Acute or chronic diarrhea or any acute illness with anorexia

Protocol of Determining the Effect of Selenium Supplementation on CD4 + T Lymphocyte Count in 23
HIV/AIDS Patients: A Randomized Double Blind Placebo Controlled Trial
Figure 1. Study flowchart: recruitment & randomization
process of treatment and treatment provision.
of HIV transmission and the number of opportunistic
infections during one year prior to the study. A compre-
hensive physical exam will be performed, a complete me-
dical history will be taken and essential primary lab tests
will be performed by the trial clinician in charge (see
Table 3).
7. Intervention
This double-blind randomized placebo control trial has 2
arms including the supplement and placebo groups. There
will be a treatment course for 6 months and supplement
capsules which contain 200 µgr elemental Se or placebo
capsules with an inert material will be given to patients
for daily administration. Active supplement and placebo
capsules will be indistinguishable in colour and taste.
Pharmacology faculty laboratory will produce the placebo
and supplement capsules. The patients should take one
capsule a day and will be recommended to take capsules
with a glass of water one hour before lunch. In order to
prevent Se toxicity, they will be recommended to take
only one capsule per day and not to take two or several
capsules together in case they forget to use daily capsules.
They will also be asked to bring back the package in the
next visit. There will be a 3-month follow up period and
a follow up visit in the end.
8. Follow-Up Assessments
Altogether, we will perform 9 visits (see Table 4), the
first one is the enrolment session in which patients that
meet the inclusion and exclusion criteria will be identi-
fied and informed. In the second visit, baseline assess-
ment will be performed and the participants will sign the
informed consent. 100 patients will be randomized to
receive either supplement or placebo. Finally, the patients
Table 3. Baseline parameters.
Baseline parameters
 General and life style
 Age
 Sex
 Gravity (if female)
 Infection duration
 History of Smoking, alcohol consumption and other kinds of
addiction (oral, inhalation)
 Rout of infection transmission (History of unsafe sex, using
illegal intravenous drugs (IVDU), consumption of blood products,
mother to child transmission)
 Comprehensive physical examination, medical and drug history
 Lab tests
 complete blood count-differentiation (CBC-diff)
 Kidney function test (BUN/Cr)
 Liver function test (LFT: SGOT, SGPT, ALP)
 HBS Ag
 Anti HBs Ab
 Anti HCV Ab
 Absolute CD4 + T lymphocyte count
 Plasma level of Selenium (Se)
 Erythrocyte sedimentation rate (ESR)

Protocol of Determining the Effect of Selenium Supplementation on CD4 + T Lymphocyte Count in
HIV/AIDS Patients: A Randomized Double Blind Placebo Controlled Trial
24
Table 4. Visits schedule.
Visits 1st Visit 2nd Visit3rd Visit4th Visit5th Visit 6th Visit 7th Visit 8th Visit 9th Visit
Period Case finding BaselineEnd of 1th
month
End of 2nd
month
End of 3rd
month
End of 4th
month
End of
5th month
End of 6th
month End of 9th month
Inclusion & Exclusion criteria  
Education         
Inform consent 
Medical history        
Physical exam        
Questionnaire 
Lab tests  
CD4 + T cell count    
Serum Se level  
Adverse effects       
Opportunistic infection        
will receive the package including 30 Se or placebo cap-
sules with the trial clinician explanation of using the cap-
sules 1 hour before lunch. Then, there will be 5 monthly
visits at the end of 1st, 2nd, 3rd, 4th, 5th and 6th months. All
patients will be visited at the end of the 3rd month after
intervention termination which will be the 9th visit. Dur-
ing every monthly and follow up visit, the physician in
charge will take a brief history of the last month, focus-
ing on the incidence of opportunistic infection and mani-
festations of supplement toxicity. A goal directed physic-
cal examination based on the taken history will be perfor-
med to evaluate the two subjects mentioned above. Phy-
sical examination will also include weight, height and blood
pressure measurement. Measuring the absolute count of
CD4 + T lymphocyte will be repeated every 3 months at
5th, 8th and 9th visits in order to evaluate the trend of CD4
+ T cells changes. In the 2nd and 6th visits, we will meas-
ure the plasma level of Se and compare it with the initi-
ating value to determine whether there has been any sig-
nificant changes. Values of hemoglobin and hematocrite
will also be measured in the visit.
9. Measures of Compliance
The patients will be asked to bring the unused capsules
back in the next monthly visit to determine their compli-
ance with taking the drug. The proportion of unused cap-
sules to the total number of the capsules
(unused capsuls number
total number of capsules) will be used as an indicator
of the participants’ compliance.
10. Concealment
This study will be double blinded, implying that both
participants and the conductors of the trial (individuals
providing the patients with their drugs, those performing
physical examinations and taking histories in addition to
those in charge of performing lab tests) will be unaware
whether each patient is receiving supplements or placebo.
In this regard, the placebo that contains inactive material
will be indistinguishable from supplements based on their
color and taste. Additionally, all drug packages will be
randomly coded and the statistical analyzer will be the
only informed person.
11. Conclusions
The authors hope that this study helps clarifying the ef-
fectiveness of Selenium on increasing CD4 + T lympho-
cyte level in HIV + /AIDS Patients.
12. Competing Interests
The authors declare that they have no competing interests.
13. Ethical Approval
The trial is approved by the ethics committees of the Te-
hran University Medical Sciences.
14. Acknowledgements
This study is supported by grant of Tehran University of
Medical Sciences. The authors would like to thank IRCH
Research center and Mrs. Sorati for their help in conduct-
ing this study as well as Sina Research Development
Center, Mrs Pourmand, Dr. Patrishia Khashayar and Dr.
Mehdi Aloosh for editing the manuscript.
15. Efficacy Assessment
CD4 + T lymphocytes count: The absolute count of pe-

Protocol of Determining the Effect of Selenium Supplementation on CD4 + T Lymphocyte Count in 25
HIV/AIDS Patients: A Randomized Double Blind Placebo Controlled Trial
ripheral blood CD4 + T lymphocytes is measured by
flowcytometric method
Opportunistic infections: all infectious diseases and
malignancies detected in immune compromised individu-
als like HIV infected individuals and is rare with normal
immune system function and is clinically or par clinically
diagnosed. In our study, these would be HSV infection,
mycobacterial infections, Hairy leukoplakia, oral can-
didiasis, recurrent bacterial pneumonia, Kaposi’s sar-
coma and cervical cancer.
BMI: An index which is explained in


2
weight kg
height(m) ,
the measuring accuracy would be 0.01.
Hemoglobin: Blood tetrapyrrolic protein which car-
ries O2 and is measured in gr/dl.
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