Systematic Review And Meta-Analysis Effect Of Vitamin D Supplementation With Anti-Viral Therapy On CD4 Levels In HIV-Infected Patients: Systematic ...
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Int J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
Systematic Review And Meta-Analysis
Effect Of Vitamin D Supplementation With Anti-Viral Therapy On CD4
Levels In HIV-Infected Patients: Systematic Review And Meta-Analysis
Fatemeh Roozbeh1, Maryam Ghajar1*
1. Mazandaran Uinversity of Medical Sciences, Sari, Iran
*correspondence: Maryam Ghajar, Mazandaran Uinversity of Medical Sciences, Sari, Iran. Email: maryam.qajar@yahoo.com
Abstract:
Introduction: Due to the effect of vitamin D on the immune response, There are controversial results
about the effect of vitamin D supplementation on the immune system of AIDS patients. This systematic
review and meta-analytical was conducted to determine the effect of vitamin D supplementation, along
with antiretroviral treatment on CD4 count of HIV-infected patients.
Methods: This systematic review and meta-analysis study was done with using specific keywords HIV
and vitamin D and CD4 and related keywords on published articles by the end of 2017 in the some
databases such as Pubmed (116 articles), Scopus (121 articles) and Web of Science (127 articles). All
articles have been export to ENDNOTE and after deleting duplicate, there was 174 articles. Review
selected articles by two individuals, first on the title and abstract. Clinical trial studies about vitamin D
supplementation on HIV-infected patients which receiving ART were selected. Quality assessment of
studies was conducted by Jadad criteria. CD4 count and viral load before and after intervention in
treatment and placebo groups, age of patients and duration of intervention were extracted.
Fiundings: Finally, 7 clinical trial studies with a sample size of 639 people were entered the meta-
analysis. The mean age of patients in the treatment group and placebo was 27.2 and 26.5 years
respectively, and mean duration of intervention was 8.3 months. The increase in CD4 after treatment was
0.73 (CI95%:-0.43 - 1.89) compared with the placebo group which was not statistically significant, but
Vitamin D use in 3 studies was near one year and this change (SMD=3.56, CI95%: 1.17-5.96) was
significantly in these studies. Egger's test results showed that there was no publication bias.
Conclusion: The results showed that at least 10 months use of vitamin D supplementation with antiviral
therapy can effectively help in increasing the CD4 level in comparison with placebo.
Keywords: Vitamin D, Antiviral treatment, CD4, AIDS, HIV
Introduction:
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In 2015, HIV/AIDS was the 12th most
highest incidence of HIV/AIDS was
common cause of death worldwide, and
reported in sub-Saharan Africa and then, in
according to estimates, 1.2 million people
Asia (2). This disease causes opportunistic
died of HIV/AIDS in this year (1).
infections and cancers in affected people by
According to the global epidemiological
weakening the immune system (3).
study of AIDS in 2014, the overall incidence
rate of this disease in people aged 15 to 49 Vitamin D is a fat-soluble vitamin that plays
years was reported to be 0.05%, and the a major role in proliferation, andInt J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
differentiation of immune cells and relationship between vitamin D levels and
regulation of immune responses (4, 5). antiretroviral drugs; vitamin D levels were
Laboratory studies indicate the crucial role measured in HIV patients before the
of this vitamin in regulating the immune beginning of antiretroviral therapy, and 6 to
system and increasing T cell count. The 12 months after that. The results indicated a
function of vitamin D as an significant reduction in vitamin D levels
immunoregulator has been suggested (6). after the use of antiretroviral drugs (12).
Vitamin D affects the immune system by
affecting endogenous antibiotics called Considering low vitamin D levels in patients
antimicrobial peptides (AMP) and through with HIV, contradictory results have been
proliferation of T cells (7). In HIV, the HIV reported in studies on the effect of vitamin D
virus leads to the destruction of T cells, and on the immune system of patients with
vitamin D increases the intrinsic immunity AIDS. Therefore, the present systematic
of the body by contributing to the production review and meta-analysis was conducted to
of immune cells and contributing to their evaluate the effect of vitamin D supplements
function (8). The causes of vitamin D and antiviral treatment on CD4 counts in
deficiency in non-infected individuals also HIV patients.
apply to HIV patients. In addition, HIV
Methods:
patients suffer from defective renal
hydroxylation, and cannot convert 25- This study is a systematic review and meta-
hydroxyvitamin D to its active form. It has analysis that was performed in clinical trial
been observed that taking antiretroviral about the effect of vitamin D copmpared
drugs increases metabolism and decreases with placebo on CD4 count of HIV-infected
vitamin D levels (9). In a cohort study by patients that was recieved antirevial therapy.
Christine in the United States (2003 to Systematic search was conducted in the
2006), it was reported that vitamin D levels databases, include: Pubmed, Scopus, web of
in HIV patients were lower than healthy sciences until end of 2017. In Pubmed and
subjects and vitamin D levels in patients scopus, we used keywords in Title/Abstract
undergoing antiretroviral treatment and field. In web of sciences, we used keywords
patients who did not receive this treatment in topic field. Our query include (HIV OR
were lower than normal level. In addition, "Human Immunodeficiency Virus" OR
vitamin D levels were lower in patients who AIDS OR "Acquired Immune Deficiency
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took antiretroviral drugs compared to those Syndrome Virus") AND CD4 AND
who did not receive treatment (10). In a "Vitamin D" and keywords extracted from
study by Lattuuada et al. in Italy in 2009, the MESH. All document search was exported
result of the study demonstrated the to Endnote and then duplicate document was
ineffectiveness of antiretroviral drugs on deleted. In screenig, for study selection, two
vitamin D levels (11). Furthermore, Brown independent, blinded investigators reviewed
and McComsey (2010) conducted a study in the title and abstracts of all study,
the United States to investigate the respectively. Disagreements betweenInt J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
reviewers were resolved by discussion. vitamin D treatment compared to placebo
Study quality was assessed using Jadad was -0.17 (CI95%: -2.53 - 2.19), which
score and score 3-5 were considered good wasn't statistically significant and
quality and less than 3 as poor quality. For hetrogenity I2 index was 97.7%. Egger test
data extraction, data were extracted by two show that there wasn't publication bias for
independent and Blinded authors and viral load result in published study
recorded in checklist. Disagreements (P=0.938).
between authors were resolved by
discussion. Data extraction form contains Vitamin D use in 3 studies was near one
author, publication year, sample size in year and figure 4 show that CD4 count
intervention and placebo group, CD4 count difference (SMD=3.56, CI95%: 1.17-5.96)
befor and after treatment, viral load, patients after treatment in these studies increased
age, vitamin D dosage and route of significantly in vitamin D group compared
administration. Data were analyzed by to placebo.
STATA 11.1 and we used random effect Discussion:
method. Heterogeneity was checked by I2 This systematic review and meta-analysis
index. Publication biases was evaluated by showed that the increase in CD4 count after
Egger tests. treatment with vitamin D wasn't statistically
Findings: significant compared to placebo, but,
Vitamin D supplementation use for about
Finally, we enrolled 7 studies in this meta-
one year, have consistent benefits on either
analysis and PRISMA flowchart for
mean CD4+ cell count. Similar to our result,
inclusion of studies in the meta-analysis
Forrester et al, in a narrative review about
shown in figure 1. Characteristics of these
micronutrient intake in HIV-positive adults
studies are shown in Table 1. Generally, 639
focused primarily on the results of nine trials
patients include 355 patients in the
of multiple micronutrient supplementation;
intervention group and 304 patients in
seven trials in non-pregnant HIV-positive
placebo group were studied. The mean age
adults, and two in pregnant HIV-positive
of patients in the intervention and placebo
women. The authors reported that "five of
groups was 27.2 and 26.5 years,
the six trials that used high-dose multiple
respectively, and the mean follow up time
micronutrients showed benefits in terms of
was 8.3 months. Four of 7 studies have good
either improved CD4 cell counts or
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quality by Jadad score. As shown in Figure
survival", but also that "many of these trials
2, the increase in CD4 count after treatment
were small and of short duration, and the
with vitamin D compared to placebo was
long-term risks and benefits of high-dose
0.73 (CI95%: -0.41 - 1.89), which wasn't
multiple micronutrients are not established"
statistically significant and the hetrogenity
(20). In another narrative review by
I2 index was 97.4%. Egger test shows that
Jiménez-Sousa et al, suggests that Vitamin
there wasn't publication bias for CD4 result
D supplementation seems to reverse some
in published study (P=0.366). Figure 3
alterations of the immune system,
shows that the decrease in viral load afterInt J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
supporting the use of Vitamin D effectively help in increasing the CD4 level
supplementation as prophylaxis, especially in comparison with placebo and it is
in individuals with more severe Vitamin D recommended that a dose-response meta-
deficiency (21). However, Visser et al, in analysis study be conducted to evaluate the
one Cochrane Review show that the efficacy of different doses of vitamin D or
analyses of the available trials have not multi-center clinical trial study be designed
revealed consistent clinically important about the efficacy of high dose of vitamin D.
benefits with routine multiple micronutrient
supplementation in people living with HIV. Acknowledgments:The authors would
Larger trials might reveal small but like to thank of Reza Alizadeh-Navaei for
important effects. These findings should not statistical analysis
be interpreted as a reason to deny References:
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Figure 1: PRISMA flowchart for inclusion of studies in the meta-analysis
Identification
Records identified through database searching
(Pubmed=116, Scopus=121, web of science=127 )
Records after duplicates removed
(n = 174 )
Screening
Records screened Records excluded
(n = 174 ) (n = 163 )
Full-text articles assessed Full-text articles excluded, with
Eligibility
for eligibility reasons (n = 4 )
(n =11 )
Without placebo group=3
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there wasn't insifficient data=1
Studies included in
qualitative synthesis
(n =7 )
Included
Studies included in quantitative
synthesis (meta-analysis)
(n = 7 )Int J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
Table 1: Characteristics of inclusion of studies in the meta-analysis
CD4 Viral load
Mean (SD) Mean (SD) Mean age
Interventio
Follow up time
N Intervention Placebo n Placebo
Intervention
Intervention
Jadad score
Intervent
Placebo
Placebo
Before
Before
Before
Before
After
After
After
After
Year
ion
Study
2
Steen 0 1.7 1.55 1.46 1.57 4000-
hoff 1 758 693 820 765 (0.6 (0.5 (0.2 (0.6 19. 7000
(13) 5 30 30 (540) (451) (421) (334) 2) 4) ) 2) 19.5 5 3 daily 5
2
Stalli 0 3.29 3.12 3.06 3.78
ngs 1 616 646 784 612 (0.9 (0.8 (1.0 (1.0 1 7000
(14) 5 28 27 (190) (222) (288) (20) 2) 1) 2) 6) 21.3 20 2 daily 2
2
Overt 0 346 551 337 526 4.5 4.5
on 1 (42.8 (53.1 (33.6 (53.6 (0.1 (0.1 1 4000
(15) 5 79 86 ) ) ) ) 6) 8) 36 31 2 daily 3
595.
9 626 300000
(283. (303. 45. 1 mothly
67 3) 2) - - - - 45.2 7 0 oral 2
2 585. 586. 541. 581.
Falas 0 4 8 5 5 25000
ca 1 (271. (231. (298. (312. 45. 1 mothly
(16) 4 47 39 5) 6) -6) 3) - - - 44.2 7 0 IM 2
1.22 1.8 1.63 1.68
799 774 (0.2 (0.2 (0.2 (0.2 10. 800
2 18 (411) (413) 7) 5) 9) 6) 10.6 7 6 daily 2
Kakal 0 0.8 0.8 1.63 1.68
ia 1 1115 945 862 882 (0.2 (1.5 (0.2 (0.2 10. 1600
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(17) 1 18 17 (545) (351) (392) (503) 7) 5) 9) 6) 10.3 7 6 daily 2
2
0 511
Bang 1 507 (538. 463 483
(18) 2 19 22 (268) 1) (197) (213) - - - - 48 45 4 100000 4
2
Arpa 0 2.8 2.4 2.5 100000
di 0 771 776 719 661 (0.9 (0.9 2.9 (1.1 10. 1 biomon
(19) 9 29 (328) (359) (382) (363) ) ) (1) ) 10.2 6 2 thly 3Int J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
Figure 2: Forest plot for CD4 count difference after treatment with vitamin D compared to placebo
[ Downloaded from intjmi.com on 2023-10-11 ]Int J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
Figure 3: Forest plot for viral load difference after treatment with vitamin D compared to placebo
[ Downloaded from intjmi.com on 2023-10-11 ]Int J Med Invest 2018; vol 7; num 3; 1-10 http://www.intjmi.com
Figure 4: Forest plot for CD4 count difference after treatment with vitamin D compared to placebo by
duration of vitamin D use
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