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Meta-Analysis
. 2017 May 18;5(5):CD003650.
doi: 10.1002/14651858.CD003650.pub4.

Micronutrient supplementation in adults with HIV infection

Marianne E Visser  1 , Solange Durao  2 , David Sinclair  3 , James H Irlam  4 , Nandi Siegfried  1
Affiliations
Meta-Analysis

Micronutrient supplementation in adults with HIV infection

Marianne E Visser et al. Cochrane Database Syst Rev. .

Abstract

Background: Micronutrient deficiencies are common among adults living with HIV disease, particularly in low-income settings where the diet may be low in essential vitamins and minerals. Some micronutrients play critical roles in maintenance of the immune system, and routine supplementation could therefore be beneficial. This is an update of a Cochrane Review previously published in 2010.

Objectives: To assess whether micronutrient supplements are effective and safe in reducing mortality and HIV-related morbidity of HIV-positive adults (excluding pregnant women).

Search methods: We performed literature searches from January 2010 to 18 November 2016 for new randomized controlled trials (RCTs) of micronutrient supplements since the previous review included all trials identified from searches prior to 2010. We searched the CENTRAL (the Cochrane Library), Embase, and PubMed databases. Also we checked the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and the ClinicalTrials.gov trials registers. We also checked the reference lists of all new included trials.

Selection criteria: We included RCTs that compared supplements that contained either single, dual, or multiple micronutrients with placebo, no treatment, or other supplements. We excluded studies that were primarily designed to investigate the role of micronutrients for the treatment of HIV-positive participants with metabolic morbidity related to highly active antiretroviral therapy (HAART). Primary outcomes included all-cause mortality, morbidity, and disease progression.

Data collection and analysis: Two review authors independently selected trials for inclusion, and appraised trial quality for risk of bias. Where possible, we presented results as risk ratios (RR) for dichotomous variables, as hazard ratios (HRs) for time-to-event data, and as mean differences (MD) for continuous variables, each with 95% confidence intervals (CIs). Since we were often unable to pool the outcome data, we tabulated it for each comparison. We assessed the certainty of the evidence using the GRADE approach.

Main results: We included 33 trials with 10,325 participants, of which 17 trials were new trials. Ten trials compared a daily multiple micronutrient supplement to placebo in doses up to 20 times the dietary reference intake, and one trial compared a daily standard dose with a high daily dose of multivitamins. Nineteen trials compared supplementation with single or dual micronutrients (such as vitamins A and D, zinc, and selenium) to placebo, and three trials compared different dosages or combinations of micronutrients. Multiple micronutrientsWe conducted analyses across antiretroviral therapy (ART)-naive adults (3 trials, 1448 participants), adults on antiretroviral therapy (ART) (1 trial, 400 participants), and ART-naive adults with concurrent active tuberculosis (3 trials, 1429 participants). Routine multiple micronutrient supplementation may have little or no effect on mortality in adults living with HIV (RR 0.91, 95% CI 0.72 to 1.15; 7 trials, 2897 participants, low certainty evidence).Routine supplementation for up to two years may have little or no effect on the average of mean CD4+ cell count (MD 26.40 cells/mm³, 95% CI -22.91 to 75.70; 6 trials, 1581 participants, low certainty evidence), or the average of mean viral load (MD -0.1 log10viral copies, 95% CI -0.26 to 0.06; 4 trials, 840 participants, moderate certainty evidence). One additional trial in ART-naïve adults did report an increase in the time to reach a CD4+ cell count < 250 cells/mm³ after two years of high dose supplementation in Botswana (HR 0.48, 95% CI 0.26 to 0.88; 1 trial, 439 participants). However, the trial authors reported this effect only in the trial arm that received multiple micronutrients plus selenium (not either supplementation alone), which is inconsistent with the findings of other trials that used similar combinations of micronutrients and selenium.In one additional trial that compared high-dose multiple micronutrient supplementation with standard doses in people on ART, peripheral neuropathy was lower with high dose supplements compared to standard dose (incidence rate ratio (IRR) 0.81, 95% CI 0.7 to 0.94; 1 trial, 3418 participants), but the trial was stopped early due to increased adverse events (elevated alanine transaminase (ALT) levels) in the high dose group. Single or dual micronutrientsNone of the trials of single or dual micronutrient supplements were adequately powered to assess for effects on mortality or morbidity outcomes. No clinically significant changes in CD4 cell count (data not pooled, 14 trials, 2370 participants, very low or low certainty evidence) or viral load (data not pooled, seven studies, 1334 participants, very low or low certainty evidence), were reported. Supplementation probably does increase blood concentrations of vitamin D and zinc (data not pooled, vitamin D: 4 trials, 299 participants, zinc: 4 trials, 484 participants, moderate certainty evidence) and may also increase blood concentrations of vitamin A (data not pooled, 3 trials, 495 participants, low certainty evidence), especially in those who are deficient.

Authors' conclusions: The analyses of the available trials have not revealed consistent clinically important benefits with routine multiple micronutrient supplementation in people living with HIV. Larger trials might reveal small but important effects.These findings should not be interpreted as a reason to deny micronutrient supplements for people living with HIV where specific deficiencies are found or where the person's diet is insufficient to meet the recommended daily allowance of vitamins and minerals.

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Conflict of interest statement

Marianne Visser (MV) has no known conflicts of interest. Solange Durao (SD) has no known conflicts of interest. David Sinclair (DS) has no known conflicts of interest. James Irlam (JI) has no known conflicts of interest. Nandi Siegfried (NS) has provided consultancies to several World Health Organization (WHO) guidelines processes within the HIV department including nutritional interventions.

Figures

1
1
Study flow diagram
2
2
'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
1.1
1.1. Analysis
Comparison 1 Multiple micronutrients versus placebo, Outcome 1 Mortality.
1.2
1.2. Analysis
Comparison 1 Multiple micronutrients versus placebo, Outcome 2 Hospital admissions.
1.3
1.3. Analysis
Comparison 1 Multiple micronutrients versus placebo, Outcome 3 Clinical disease progression.
1.4
1.4. Analysis
Comparison 1 Multiple micronutrients versus placebo, Outcome 4 CD4+ cell count.
1.5
1.5. Analysis
Comparison 1 Multiple micronutrients versus placebo, Outcome 5 CD4+ cell count at longest follow‐up; subgrouped by participant characteristics.
1.6
1.6. Analysis
Comparison 1 Multiple micronutrients versus placebo, Outcome 6 Viral load.
1.7
1.7. Analysis
Comparison 1 Multiple micronutrients versus placebo, Outcome 7 Viral load at longest follow‐up; sub‐grouped by participant characteristics.
2.1
2.1. Analysis
Comparison 2 High dose multivitamins versus standard dose, Outcome 1 Mortality.
2.2
2.2. Analysis
Comparison 2 High dose multivitamins versus standard dose, Outcome 2 CD4+ cell count.
2.3
2.3. Analysis
Comparison 2 High dose multivitamins versus standard dose, Outcome 3 Viral load.
3.1
3.1. Analysis
Comparison 3 Vitamin D versus placebo, Outcome 1 Mortality.
4.1
4.1. Analysis
Comparison 4 Zinc versus placebo, Outcome 1 Mortality.
4.2
4.2. Analysis
Comparison 4 Zinc versus placebo, Outcome 2 Persistence of diarrhoea.
4.3
4.3. Analysis
Comparison 4 Zinc versus placebo, Outcome 3 Rate of diarrhoea.
5.1
5.1. Analysis
Comparison 5 Selenium versus placebo, Outcome 1 Hospital admissions.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

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Baum 2013 BWA {published data only}
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Guwatudde 2015 UG {published data only}
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Hurwitz 2007 USA {published data only}
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Isanaka 2012 TZA {published data only}
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Jiamton 2003 THA {published data only}
    1. Jiamton S, Pepin J, Suttent R, Filteau S, Mahakkanukrauh B, Hanshaoworakul W, et al. A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV‐infected individuals living in Bangkok. AIDS 2003;17(17):2461‐9. - PubMed
Kamwesiga 2015 RWA {published data only}
    1. Kamwesiga J, Mutabazi V, Kayumba J, Tayari JK, Smyth R, Fay H, et al. Effect of selenium supplementation on CD4 T‐cell count recovery, viral suppression, morbidity and quality of life of HIV‐infected patients in Rwanda: study protocol for randomized controlled trial. Trials 2011;12:192. - PMC - PubMed
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Kelly 1999 ZMB {published data only}
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Kelly 2008 ZMB {published data only}
    1. Kelly P, Katubulushi M, Todd J, Banda R, Yambayamba V, Fwoloshi M, et al. Micronutrient supplementation has limited effects on intestinal infectious disease and mortality in a Zambian population of mixed HIV status: a cluster randomized trial. American Journal of Clinical Nutrition 2008;88(4):1010‐7. - PMC - PubMed
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Lawson 2010 NIG {published data only}
    1. Lawson L, Thacher TD, Yassin MA, Onuoha NA, Usman A, Emenyonu NE, et al. Randomized controlled trial of zinc and vitamin A as co‐adjuvants for the treatment of pulmonary tuberculosis. Tropical Medicine & International Health 2010;15(12):1481‐90. - PubMed
McClelland 2004 KEN {published data only}
    1. McClelland RS, Baeten JM, Overbaugh J, Richardson BA, Mandaliya K, Emery S, et al. Micronutrient supplementation increases genital tract shedding of HIV‐1 in women: results of a randomized trial. Journal of Acquired Immune Deficiency Syndromes 2004;37(5):1657‐63. - PubMed
Overton 2015 USA {published data only}
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Range 2006 TZA {published data only}
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Semba 1998 USA {published data only}
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Semba 2007 MWI {published data only}
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Semba 2007 USA {published data only}
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Stallings 2014 USA {published data only}
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Villamor 2008 TZA {published data only}
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Wejse 2009 GNB {published data only}
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Zhao 2010 CHN {published data only}
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References to studies excluded from this review

Aghdassi 2010 {published data only}
    1. Aghdassi E, Arendt BM, Salit IE, Mohammed SS, Jalali P, Bondar H, et al. In patients with HIV‐infection, chromium supplementation improves insulin resistance and other metabolic abnormalities: a randomized, double‐blind, placebo controlled trial. Current HIV Research 2010;8(2):113‐20. - PubMed
AIDS Policy Law 2012 {published data only}
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Arpadi 2012 {published data only}
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Austin 2006 {published data only}
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Balasubramanyam 2011 {published data only}
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Brown 2015 {published data only}
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Coelho 2015 {published data only}
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Currier 2010 {published data only}
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Daneshpajouhnejad 2011 {published data only}
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Etminani‐Esfahani 2012 {published data only}
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Gharakhanian 2011 {published data only}
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Havens 2012a {published data only}
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Havens 2012b {published data only}
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Havens 2012c {published data only}
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Havens 2012d {published data only}
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Hemsworth 2012 {published data only}
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Hummelen 2011 {published data only}
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Kaiser 2006 {published data only}
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Kakalia 2011a {published data only}
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Kakalia 2011b {published data only}
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Lachmann 2014 {published data only}
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Ladep 2010 {published data only}
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Lange 2009 {published data only}
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Lange 2011 {published data only}
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Lescoat 2012 {published data only}
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Lin 2013 {published data only}
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References to studies awaiting assessment

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References to ongoing studies

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References to other published versions of this review

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