Zinc Supplementation, Inflammation, and Gut Integrity Markers in HIV Infection: A Randomized Placebo-Controlled Trial

<b>Background:</b> Low levels of zinc are prevalent in patients living with HIV and are associated with higher morbidity. Zinc has major immunomodulatory effects. This study aimed to assess the effect of zinc supplementation on inflammatory and gut integrity markers and on zinc levels among HIV patients with zinc deficiency. <b>Methods:</b> This was a double-blind randomized placebo-controlled trial assessing the efficacy and safety of zinc supplementation on inflammation and gut markers in people with HIV (PWH) ≥ 18 years old, on stable antiretroviral therapy (ART) with undetectable HIV-1 viral load, and with zinc levels of ≤0.75 mg/L. Participants were randomized 2:1 to zinc gluconate tablets at a dose of 90 mg of elemental zinc or a matching placebo daily for 24 weeks. At baseline and at week 24, we measured plasma levels of zinc and markers of inflammation and gut barrier integrity. <b>Results:</b> Among the 95 participants enrolled in this study, 74% were male, and 65% were non-white, with a median CD4 count of 722 cells/μL. The primary analysis showed an increase in zinc levels in the active group. A decrease in the monocyte activation marker soluble CD14 was observed in the treatment group at -56.31 ng/mL (-263.24; 134.19), compared to an increase in the placebo group of 101.71 ng/mL (-90.50; 243.20); <i>p</i> = 0.021. The stratified analysis showed that the group with the lowest zinc levels at baseline had the greatest improvements in soluble CD14 levels during zinc supplementation. No changes were seen in other inflammation markers or gut integrity markers. <b>Conclusions:</b> This is the most comprehensive study on the effect of zinc supplementation in PWH on inflammatory and gut integrity markers. Decreases were seen in the monocyte activation marker sCD14. In the contemporary HIV era with potent effective therapies, suppressed viremia, and high CD4 cells, zinc supplementation does not offer consistent benefits on inflammation.