In this randomized, double-blind, placebo-controlled trial, nutritional levels of zinc supplementation given to HIV-infected adults resulted in a four-fold decrease of the likelihood of immunological failure defined as a drop of CD4+ cell count <200 cells/mm3, after 18 months of use, as compared to placebo. Viral load indicated poor control with ART but was not affected by zinc supplementation. Zinc supplementation also significantly reduced diarrhea compared to placebo. Respiratory diseases or HIV mortality were not affected by supplementation. There were no adverse effects associated with the dose of zinc supplementation used.
In this trial, we defined immunological failure as a drop of CD4+ count <200 cells/mm3
with or without ART, since this definition is predictive of HIV-related morbidity and mortality as well as non-AIDS-related morbidity.20,29,30
Moreover, patients with CD4+ counts <200 cells/mm3
remain susceptible to opportunistic infections despite ART and have an increased risk of mortality.19-30
Although this cohort was at risk for several factors associated with defective immune reconstitution,31
including poor access to therapy, previous therapeutic failure, intermittent duration, and low adherence to ART, a nutritional dose of zinc over 18 months prevented immunological failure as compared to placebo. In addition, zinc supplementation provided immunological and clinical benefits despite persisting detectable HIV-viral load in the majority of the participants. Similar findings were reported by Grabar et al.32
who found that improvement in immunological response is associated with favorable clinical outcomes regardless of virologic response. The adherence to our study regimen was higher than to ART, most likely due to a low pill burden, lack of adverse effects, and active case management with the study supplement.28
We used similar active case management strategies to refer participants to treatment and increase their adherence and compliance with ART.28
Because zinc is also obtained from the diet, zinc therapy might not require as strict adherence as that needed to maintain the benefits of antiretrovirals.
Due to early reports that intakes of zinc above nutritional levels were associated with disease progression,16
this study included only participants whose baseline plasma zinc levels were under 0.75 mg/L, which has been recognized in the literature as low levels of zinc with clinical implications.8,33
The use of plasma zinc levels to detect true zinc deficiency has been controversial, as zinc is an acute-phase reactant.34
To distinguish between true zinc deficiency and acute-phase reaction due to inflammation, hsCRP was used to control for acute-phase reaction.35
The cautious approach to zinc supplementation, by using nutritional levels of zinc to supplement HIV-seropositive individuals with low plasma zinc levels, might have producedthe a delayed (18-month) effect on preventing immunological failure and morbidity observed in this study.
Zinc supplementation may prevent immunological failure through its action on thymic function, expression of interleukin-2, T-cell proliferation, and potential reduction of mitochondrial toxicity and oxidative stress.36
Thymulin, a thymic peptide important for the maturation and differentiation of immature thymocytes,37
is active only when bound to zinc, and its activity is reduced in immune-suppressed and zinc-deficient conditions.38
Improved ability to reconstitute CD4+ cells, as shown in this clinical trial, may be related to the effects of supplementation on increasing the levels of the active zinc-bound thymulin, offering an additional mechanism for slowing HIV disease progression.
Zinc supplementation also affected morbidity in this population. Long-term zinc supplementation significantly decreased the rate and prevented new episodes of diarrhea over time, as compared to placebo. Findings in the literature have been contradictory, mostly due to the use of variable doses of zinc and variable duration of therapy, and whether zinc supplementation was used for prevention or as a treatment of diarrhea. High doses of zinc for short periods of time and during episodes of diarrhea have shown adverse outcomes or no effect,39,40
while preventive zinc supplementation in low doses over long periods had successful results.15
mechanism that supports these conclusions demonstrates that Tat (viral peptide essential for HIV replication) stimulates active fluid secretion from the serosal to the luminal side of enterocytes. Addition of zinc prevents the Tat-induced fluid secretion,41
which may explain the clinical benefits of zinc supplementation in preventing HIV-related diarrhea.
We did not observe significant differences in upper or lower respiratory infections, or in mortality between the zinc-supplemented and the placebo groups, although other studies have reported a reduction in rates of tuberculosis, pneumonia and mortality with zinc supplementation in HIV+ populations in developing countries.42,43
Our results may be limited by the small number of cases of pneumonia (N=4) and tuberculosis (N=1), and although we confirmed 19 HIV-related deaths, the lack of significant difference by study group might be due to the equal use of ART in both arms of the study.
The study had a strong design, adequate power and modest drop-out rates. Our findings may be extended to other HIV-infected cohorts with high prevalence of zinc deficiency such as men-who-have-sex-with-men (MSM), children, and those in developing countries.5,8,15,43
However, because of the high prevalence of substance abuse and poor viral control with ART, these findings might not be generalizable to populations on ART with adequate viral control. Subset analyses of participants on stable ART with controlled viral load (N=40), however, indicate that those receiving zinc supplementation had no immunological failure compared to 4 events in the placebo group. While this subset analysis had a small sample size, it appears that it may broaden our findings to cohorts with adequate viral control. Further studies with adequate sample size and power are needed to confirm our findings in populations on stable ART with adequate viral control.
Nutritional levels of zinc supplementation given to HIV-infected adults resulted in a four-fold decrease of the likelihood of immunological failure defined as a drop of CD4+ count <200 cells/mm3
in this randomized, double-blind, placebo-controlled trial after 18 months of use, with no effect on viral load. Zinc supplementation also significantly reduced the morbidity associated with HIV-related diarrhea compared to placebo. Respiratory diseases or mortality were not affected by zinc supplementation. Viral load indicated poor control with ART but was not affected by zinc supplementation. The results of this study can be generalized primarily to HIV-infected populations with prevalent zinc deficiency such as drug users, children, MSM, and populations in developing countries.5,8,15,43
as well as those with poor viral control on ART. This evidence supports the recommendation of zinc therapy as a safe, simple and cost-effective tool to improve the immune response and reduce morbidity and should be considered as an adjunct therapy in HIV infection.