Micronutrient Supplementation as Adjunct Treatment for HIV‐Infected Patients

There has been considerable interest in the potential role of micronutrients in the prevention and management of infectious diseases among adults and children [1, 2]. The case of vitamin A in the reduction of mortality associated with measles is well established [3], and supplementation with vitamin A is an integral part of the management of measles in developed and resource- limited settings [4]. In the case of human immunodeficiency virus (HIV) infection, several randomized trials and well-conducted and analyzed observational studies have demonstrated the benefits of micronutrient supplementation, including a reduction in the risk of HIV disease progression, particularly among individuals in the early stages of disease [5–8]. Micronutrient supplementation has also been shown to decrease the risk of adverse pregnancy outcomes among HIVinfected women [9]. Although highly active antiretroviral therapy (HAART) results in significant improvement in health outcomes, the risks of opportunistic infections and mortality are still high [10], and immune reconstitution is often incomplete [11, 12]. The question of whether micronutrient supplements have a role in treatment of individuals who are already receiving HAART is an area of active investigation. In this issue of Clinical Infectious Diseases, Baum et al [13] report findings of a randomized, controlled trial of zinc supplementation among HIV-infected adults in the United States. They examined the efficacy of daily supplementation with nutritional doses of zinc (12 mg of elemental zinc for women and 15 mg of elemental zinc for men) for 18 months among 231 HIV-infected patients, who had plasma zinc levels <0.75 µg/mL, in delaying HIV disease progression and in preventing associated morbidity and mortality. The authors found that 18 months of zinc supplementation reduced 4-fold the risk of immunological failure, defined as CD4 T cell counts of <200 cells/mm3; however, there was no effect on viral load or mortality. Zinc supplementation also decreased the rate of diarrhea by more than half, compared with placebo. There are several biologically plausible mechanisms that can explain these findings. Zinc deficiency is associated with suppression of cell-mediated immunity, which may explain the protective effect on immunological failure. For example, zinc deficiency has been shown to lead to decreased levels of serum thymulin, a zincdependent thymic hormone known to induce T cell differentiation [14]. Zinc deficiency was also associated with decreased T4/T8 ratio, interleukin 2 levels, and natural killer cell lytic activity in the same study [14]. Zinc is also required for the regeneration of new CD4 T cells and for maintenance of T cytolytic cells [15]. The importance of zinc supplementation for treatment of diarrhea, particularly among children, is relatively well established [16, 17]. The enteropathy associated with HIV infection involves increased gastrointestinal inflammation and decreased levels of mucosal repair [18, 19]. The benefits of zinc in such a situation may be mediated by stimulating absorption of water and electrolytes such as sodium, faster regeneration of gut epithelium, improvement in the immune status, and increase in the concentrations of enterocyte brush-border enzymes [20]. Zinc also inhibits cyclic adenosine monophosphate-induced chloride secretion, the driving force behind fluid secretion, by inhibiting basolateral potassium channels in in vitro studies of rat ileum [21]. Additionally, zinc may also help to reduce inflammation by inhibiting nuclear factor kB activation and consequently decreasing the generation of inflammatory cytokines [22]. Zinc also directly prevents fluid secretion induced by Tat (transactivating peptide produced by HIV-1) in vitro [23]. Findings from prior studies of zinc supplementation trials involving HIV-infected individuals that examined HIV disease progression or immunological outcomes have been equivocal. An early study of zinc supplementation for 15 days found evidence of lymphocytic stimulation and increased phagocytosis by polymorphonuclear neutrophils [24]. Zinc supplementation led to an increase in CD4 T cells and a decrease in the frequency of opportunistic infections due to Pneumocystis jiroveci and Candida species in another trial involving HIV-infected patients receiving zidovudine [25]. In a trial in South Africa, HIV-infected children were randomized to receive either oral zinc supplementation or placebo daily for 6 months. There were no differences in viral load, CD4 T cell counts, and hemoglobin concentrations between the 2 groups; however, zinc supplementation reduced the incidence of watery diarrhea [26]. On the other hand, zinc supplementation did not demonstrate an effect on either duration (persistence of diarrhea at day 14) or remission (time to cessation) of diarrhea among 159 HIV-infected adults with at least 7 days of diarrhea in Peru [27]. In a randomized trial in Tanzania, zinc supplementation had no effect on CD4/8 and CD3 T cell counts in HIVinfected women during follow-up or on the risk of low birth weight, vertical HIV transmission, preterm delivery, fetal death, or neonatal mortality among the infants born to them [28, 29]. There are several strengths of the trial conducted by Baum et al [13]. Targeting of zinc supplementation to only those patients who had zinc levels <0.75 µg/mL and the use of nutritional doses of zinc reduce potential zinc toxicity and the possibility of increased HIV disease progression with higher intakes of zinc [30]. The duration of the trial was reasonably long (18 months) to observe a clinical effect. Furthermore, the study participants also demonstrated high levels of adherence to the study regimen, because of a combination of active case management, lack of adverse effects, and low pill burden. These findings strengthen the evidence in favor of using zinc supplementation as an adjunct to antiretroviral treatment for HIVinfected individuals—specifically, targeted supplementation for individuals with poor zinc status, who are likely to benefit the most from this intervention. Resources to enable such targeting, such as tests for plasma zinc and C-reactive protein levels (to rule out low plasma zinc levels due to the acute phase response) in the case of zinc supplementation, should be invested in, because the cost savings associatedwith improving the quality of life and outcomes for patients receiving antiretroviral treatment may be tremendous. Zinc deficiency is known to affect approximately a third of the world's population [31] and is also widespread among HIV-infected individuals [32]. Although the role of zinc in preventing morbidity and mortality associated with diarrhea and pneumonia, particularly among children in developing parts of the world, is well recognized [17, 33], further research is needed to fully understand its role in HIV/AIDS management. Future studies need to examine whether the benefits noted among injection drug users with advanced HIV disease are generalizable to other parts of the world, particularly resource-limited settings where coinfections and multiple nutritional deficiencies coexist with HIV infection. Further research is also needed to determine whether these benefits are observed in patients with well-controlled HIV disease, as defined by undetectable viral load. By enhancing immune function, micronutrient supplements provided to individuals in the early stages of HIV disease slow the disease progression and could prolong the time before HAART is indicated. As we move toward an era of more widespread use of HAART, particularly in developing countries, micronutrient supplements also hold promise as low-cost adjunct treatments to decrease morbidity associated with both disease and treatment and to improve the quality of life of people infected with HIV. Potential conflicts of interest. S.M. and W.W.F.: no conflicts.