Selenium and zinc supplementation in HIV-infected patients
An umbrella systematic review
Abstract
Abstract:Background: The Human Immunodeficiency Virus (HIV) epidemic is still a public health concern. Micronutrient deficiencies can fasten the progression of this syndrome. Selenium and zinc are essential trace elements, which exert antioxidant and anti-inflammatory activities in HIV infection. The present overview aimed to evaluate the current knowledge from systematic reviews (SRs) of the effects of selenium and zinc supplementation in HIV patients to show the most updated and comprehensive summary of previous SRs. Methods: The current study was performed according to the guidelines of the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) statements. To assess the quality of articles we used the Measurement Tool to Checklist Assess Systematic Reviews (AMSTAR). PubMed/Medline, Web of Science, Scopus, and EMBASE databases and Google Scholar web search engine were searched up until March 2022, using relevant keywords. Results: Among 3731 articles assessed, five and four studies met the inclusion criteria for selenium and zinc supplementation, respectively. Four studies found that selenium supplementation can be effective in delaying CD4 decline in HIV-infected patients. In four SRs, the dosage of selenium supplementation was 200 μg/day. Three studies, however, reported no significant effect of zinc supplementation on CD4 cell counts, and HIV viral load. The dosage of zinc supplementation ranged from 12 to 100 mg/day. The intervention duration ranged from 2 weeks to 18 months. Conclusion: In the present study, we identified some clinical evidence of a potential beneficial effect of selenium supplementation in HIV-infected patients.
Introduction
The Human Immunodeficiency Virus (HIV) epidemic is still a public health concern with no definitive cure [1, 2]. Acquired immunodeficiency syndrome (AIDS) causes several complications, including elevated resting metabolic rate, gastrointestinal problems, increased oxidative stress, and impaired immune system, which in turn result in increased CD4+ T lymphocytes counts [3]. In 2020, 37.7 million people throughout the world were living with HIV, and 1.5 million people became newly infected with the virus [4]. As possible interventions to postpone HIV development, micronutrients have received widespread and recent attention [3]. However, the risk of micronutrient deficiencies has been shown to be contributed to morbidity and mortality in HIV+/AIDS patients [5].
Some micronutrients, including zinc and selenium, have impacts on the immune system and antioxidant defense in AIDS [6, 7]. Thus, micronutrient deficiencies can fasten the progression of the syndrome. HIV infection, in turn, exacerbates micronutrient deficiencies and leads to a vicious cycle [8]. Selenium and zinc are essential trace elements, which exert antioxidant and anti-inflammatory activities in HIV infection [3, 9]. In addition, several laboratory markers, including CD4 cell count and viral load count, have been used in monitoring HIV progression and/or treatment outcomes [10]. There is evidence that zinc and selenium deficiency is prevalent in people living with HIV, which may have a role in inappropriate maturation of CD4 count cells. This may weaken the immune response and lead to a higher viral load [3].
As routine treatments in HIV, antiretroviral therapies (ART) should be initiated among all adults with HIV, regardless of World Health Organization (WHO) clinical stage and the level of CD4 cell count. However, due to adverse effects and metabolic dysfunction of ART, having a balanced and adequate diet is crucial in the infected people under therapy [11].
Although micronutrient interventions for people living with HIV have been systematically reviewed, as far as we know there is no scoping review article. Accordingly, the present overview aims to evaluate the current knowledge from systematic reviews (SRs) of the effects of selenium and zinc supplementation in HIV patients to show the most updated and comprehensive summary of previous SRs.
Method and materials
Search strategy
We followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) extension for scoping reviews, and used the Measurement Tool to Checklist Assess Systematic Reviews (AMSTAR) to assess the quality of articles. Two reviewers (LR, SP), in duplicate, searched PubMed/Medline, Web of Science, Scopus, and EMBASE databases, and Google Scholar web search engine from inception to March 2022 (last update). The search was done using the following search terms:
Selenium
(((“selenium”[MeSH Terms] OR “selenomethionine”[MeSH Terms] AND “HIV”[Title/Abstract]) OR “human immunodeficiency virus*”[Title/Abstract] OR “AIDS”[Title/Abstract] OR “Acquired Immunodeficiency Syndrome”[Title/Abstract] OR “HIV&AIDS”[Title/Abstract] OR “People Living with HIV”[Title/Abstract] OR “PLWHIV”[Title/Abstract] OR “PLHIV”[Title/Abstract] OR “hiv positive”[Title/Abstract] OR “hiv positive”[Title/Abstract] OR “HIV”[MeSH Terms] OR “Acquired Immunodeficiency Syndrome”[MeSH Terms]) AND (meta-analysis[Filter] OR systematicreview[Filter]).
Zinc
(((“Zinc”[MeSH Terms] OR “Zinc Compounds”[MeSH Terms] OR “Zinc”[All Fields]) AND (“HIV”[Title/Abstract] OR “human immunodeficiency virus*”[Title/Abstract] OR “AIDS”[Title/Abstract] OR “Acquired Immunodeficiency Syndrome”[Title/Abstract] OR “HIV&AIDS”[Title/Abstract] OR “People Living with HIV”[Title/Abstract] OR “PLWHIV”[Title/Abstract] OR “PLHIV”[Title/Abstract] OR “hiv positive”[Title/Abstract] OR “hiv positive”[Title/Abstract])) OR (“HIV”[MeSH Terms] OR “Acquired Immunodeficiency Syndrome”[MeSH Terms])) AND (meta-analysis[Filter] OR systematicreview[Filter]).
Furthermore, the reference lists of the included studies and related reviews were searched for any eligible study.
Inclusion and exclusion criteria
All SRs had to meet the following criteria: i) to be published as a systematic review of randomized controlled trials, comparing selenium and zinc supplementation to a placebo; ii) to be performed on adults with a confirmed diagnosis of HIV, and iii) to be limited to adults and published in English language. The primary outcomes were delay in CD4 decline and suppression of HIV viral load.
Data extraction
The search results obtained from the library databases were imported into Endnote reference manager program. Removing the duplicate articles, two reviewers (HT and LR) independently perused the titles and abstracts of all remaining articles to omit irrelevant articles. Any disagreement was resolved after a discussion with team supervisor (ARO). The full text of all retrieved eligible articles was evaluated for final decision. Final included studies were extracted in pre-conceived data extraction sheets and individuated duplicates. The flowchart of excluded and included studies is presented in Figures 1 and 2. Extracted information included first author name, publication year, the databases searched, number of included articles in each SR, sample size, dose of supplement, intervention duration, endpoint, final result and conclusion.
Quality assessment of included reviews
Two authors assessed the quality of included SRs using A Measurement Tool to Checklist Assess Systematic Reviews (AMSTAR) [12]. AMSTAR is a practical appraisal tool for SRs performed on randomized and/or nonrandomized studies of healthcare interventions. It contains 11 domains. The AMSTAR guided us in classifying and reporting the quality of SRs in three categories; “high” (8–11 points out of 11), “moderate” (4–7 points) and “low” (3 or fewer scores categories).
Results
Study selection
After electronic and manual search, a total of 519 and 3212 potentially eligible articles were identified for zinc and selenium, respectively. Removing duplicates, we included 365 and 1872 articles by screening of the titles and abstracts for zinc and selenium, respectively.
Regarding selenium, the full text of 86 articles was evaluated carefully. At the end, five SRs evaluating the effect of selenium supplementation in adults with HIV were included in the current study (Figure 1). For zinc, the full text of 61 articles was carefully assessed, within which 4 studies met the inclusion criteria (Figure 2). The reasons for exclusion were differences in target population, primary outcomes, as well as studies that evaluated other immune deficiency diseases.
Characteristics of included studies
Selenium
Table 1 shows the characteristics of the five included SRs of the effects of selenium supplementation in HIV positive adults. Three of the five included SRs were Cochrane Systematic Reviews [13, 14, 15]. Most of included studies in the SRs were searched at least in two databases, including EMBASE and PubMed/Medline. The dosage of selenium supplementation in four SRs was 200 μg/day [1, 13, 14, 15], and in one SR was 100–200 μg/day [16]. The intervention duration ranged from 9 to 24 months in 3 SRs [1, 15, 16]. In the remaining two SRs, the duration ranged from 9 to 12 months for one study [13], and 6 months for the other one [14].
The primary outcomes of all included studies were CD4 cell counts and viral load. The serum selenium level and GPX were only reported in the study performed by Kayode et al. [16]. In this study, at the end of a 12-month period, a significant increase was observed in plasma selenium level (p < 0.02) and GPX activity (p < 0.04) of the selenium group, compared to baseline [16].
As shown in Table 1, four studies reported that selenium supplementation can be effective in delaying CD4 decline, among HIV-infected patients [1, 13, 15, 16]. Moreover, in three studies, supplementation of selenium either suppressed or reduced HIV viral load, significantly [13, 15, 16]. Furthermore, the study conducted by Muzembo et al. [1] reported that a high selenium status can predict decreased HIV viral load in HIV-infected adults. However, they did not report any quantifiable evidence that selenium supplementation could either suppress or decrease HIV viral load.
Zinc
The general characteristics of the four included SRs which assessed the effects of zinc supplementation in HIV positive adults are presented in Table 2.
Three SRs were Cochrane Systematic Reviews [13, 14, 15]. Most of included studies were searched in at least three databases, including EMBASE, PubMed/Medline, and CENTRAL. The dosage of zinc supplementation ranged from 12 to 100 mg/day. The intervention duration ranged from 2 weeks to 18 months.
The CD4 cell counts and viral load were assessed in most of the included studies. Zinc supplementation did not have any significant effect on CD4 cell counts, in all three SRs [13, 14, 16]. In addition, zinc supplementation did not change HIV viral load, in all of the reviewed studies [13, 14, 15, 16]. However, in the study conducted by Visser et al. [15], zinc supplementation increased the median level of CD4+ in patients with zinc deficiency at baseline (P=0.042), but not in those with normal zinc level.
Methodological quality of the included reviews
The methodological quality of the included SR articles is depicted in Table 3. According to AMSTAR quality assessment tool, three included SRs which evaluated the effects of selenium supplementation in HIV positive adults had low quality, and two studies possessed high quality (Table 3). Moreover, half of the included SRs for zinc supplementation had high quality and the remaining had low quality.
Discussion
Despite the increase in the number of studies that systemically reviewed the effects of zinc and selenium supplementation on health outcomes in people with HIV, there is controversy over the relationships between selenium and zinc supplementation and HIV disease. Selenium and zinc deficiency is thought to be associated with a high risk of mortality in HIV-infected patients. The effects of zinc and selenium on HIV have been discussed in current literature [8, 13, 15, 17]. These two essential trace elements have beneficial effects, such as improving of the immune system, confronting with viral infections and diseases, and having antioxidant and anti-inflammatory properties [18].
In the present study, we reviewed five SRs of the effects of selenium supplementation in HIV positive adults. Four out of five studies showed that selenium supplementation can be effective in delaying CD4 decline, and three studies concluded that it can significantly reduce HIV viral load [1, 11, 13, 14].
In the previous SRs, the heterogeneity of included trials did not allow authors to conduct a meta-analysis. This heterogeneity had numerous reasons, including differences in clinical stage of HIV infection, ART status (receiving or not receiving ART), selenium co-supplementation with other micronutrients and vitamins, differences in primary outcomes, and the length of interventions [1]. Moreover, recent evidence have confirmed that there is a U-shaped relationship between selenium intake and health [8]. Therefore, it is recommended to evaluate the selenium status before supplementation, which seems to have been neglected in the most of previous SRs.
Geographical difference may be another important factor that should be considered while generalization of the results of a study to other populations [19].
The underlying mechanisms of selenium on HIV progression may be the improvement of immunity and antioxidant defense system, such as glutathione peroxidase (GSH-Px) enzyme system [3, 20]. Selenium deficiency is associated with decreased GSH-Px activity, which may result in oxidative stress, and thus induced apoptosis of T lymphocytes, increased HIV viral load, and an indirect CD4 cell counts decline [20]. Therefore, it can be assumed that the effects of selenium in HIV-infected patients may be directly through the activation of antioxidant defense system, which indirectly strengthens the immune system, and thereby reduces the progression of the disease.
We also reviewed four SRs of the effects of zinc supplementation in HIV positive adults, within which three SRs were Cochrane Systematic Reviews [11, 12, 13]. In only one SR, Zinc supplementation was found to be with significant effect on CD4 cell counts [15]. In all five studies, Zinc supplementation was reported to be with no effect on HIV viral load [11, 12, 13, 14]. Kayode et al. stated that the positive effects of zinc supplementation on CD4 cell count and viral load of the patients may have been masked, due to the small sample size and short duration of the included studies, and also the possibility of multiple nutrient deficiencies among the included patients [16]. In addition, Irlam et al. concluded that short duration and high attrition rates in the included studies might be the main factors attributed to the lack of significant effect of zinc supplementation in a majority of their included trials [13].
There is evidence that in healthy adults, zinc supplementation can decrease oxidative-stress and inflammation by reducing the production of malondialdehyde, 4-hydroxyalkenals, 8-hydroxydeoxyguanine, and serum tumor necrosis factor (TNF) alpha, and IL-1β levels [21]. Zinc deficiency can cause a variety of adverse effects, including weak immunity system, impaired oxidant-antioxidant system, diarrhea, and alopecia. Moreover, low zinc status was associated with increased HIV mortality [22, 23]. Poudel et al. [24] found that high serum zinc level could decrease inflammation, but their results were not statistically significant. In addition, a recent Cochrane systematic review reported no beneficial effects of zinc supplementation on CD4+ cell count and viral load, but it could increase serum zinc levels particularly in patients who had zinc deficiency at baseline [15]. The effect of zinc supplementation on HIV patients remains to be contradictory, and the authors identified no significant change in CD4%, viral load and/or survival rate [13, 14, 16, 23].
Strengths and limitations
As a strength, this present review was the first systematic review of SRs of randomized controlled trials in this field. Furthermore, a majority of the included studies were Cochrane studies, which summarized reliable evidence with strong methodological approach. However, a limitation of the included studies was the variations identified in gender, ethnicity, socio-demographic status, and age of study populations. Additionally, the number of published studies on zinc and selenium supplementation in HIV positive patients which has the eligibility to be included in this review was insufficient, and thus impede us to conduct Meta-analysis.
Conclusion
In the present study, we identified some clinical evidence of a potential beneficial effect of selenium supplementation in HIV-infected patients. However, we did not identify any favorable outcome of zinc supplementation in these patients.
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