Role of Micronutrients in HIV-Infected Intravenous Drug Users

Nutritional deficiencies are widespread among HIV-1-seropositive male and female drug abusers (injecting drug users, or IDUs), among men who have sex with men (MSM), and among children, although the prevalence of nutritional alterations varies among the groups. Low levels of vitamin A, vitamin B₁₂, zinc, and selenium are common and have been demonstrated to be associated with disease progression and HIV-1 related mortality, independent of CD4 count <200 cells/mm³ at baseline and CD4 count over time. When all nutrient factors that are associated with survival are considered together, only selenium deficiency is a significant predictor of mortality. The profound effect of selenium on disease progression may reflect selenium's action in antioxidant defense systems, as well as gene regulation.

NUTRITIONAL ABNORMALITIES IN HIV-1 INFECTED COHORTS

A major focus of our research investigations over the past decade has been to evaluate the role of nutritional status as a cofactor in HIV-related disease progression and survival. Three distinct HIV-seropositive populations have been observed during longitudinal follow-up including 122 male and female injecting drug users (IDUs), 130 asymptomatic men who have sex with men (MSM), and 24 children. Multiple micronutrient deficiencies, known to influence immune function, have been observed in all HIV-1-infected cohorts, although the prevalence of nutritional alterations varies among the groups. Each of these populations has characteristic socioeconomic, psychological, and physiologic factors that modulate and influence nutritional status, which, in turn, has the potential for influencing the rate of HIV-1 transmission, disease progression, and mortality, in ways that are closely related to the specific nutrition-related risk factors of each population. By following large populations of HIV-1-infected individuals over time, our studies have evaluated the influence of specific nutrient deficiencies on immune function, disease progression, and mortality. The proportion of nutrient deficiency among participants in the three HIV-seropositive cohorts is shown in Table 1.

Table 1

HIV-1-Seropositive Male and Female Drug Users

The nutritional profile of the Miami cohort of HIV-1-seropositive IDUs, who were recruited from a street-drug-using population, is characterized by widespread nutritional abnormalities ^(1,2). Clinical assessments of this cohort were performed every 6 months over 3.5 years and included determination of immune function, dietary intake, nutritional status, plasma levels of proteins, vitamins and trace elements, and anthropometric measurements. Inadequate nutritional status with respect to at least one nutrient was evident in most (89%) of the IDUs. Multiple abnormalities were noted in 41% of the group, with low plasma levels of antioxidants (vitamins A, E, C, and zinc), most predominant. Although immune parameters were similar in the HIV-1-infected men and women, women had significantly poorer overall nutritional status, as measured by plasma proteins, which are considered to be sensitive markers of malnutrition ⁽¹⁾.

HIV-1-infected IDUs may be particularly vulnerable to nutrient deficiencies due to drug-nutrient interactions as well as relatively poor dietary intake. Addictive drugs of abuse have been shown to produce significant nutritional alterations ^(3,4), which can contribute to the immunodeficiency observed in HIV-1 disease.

HIV-1-Seropositive Men Who Have Sex With Men

The presence of nutrient alterations has been well established in HIV-1-infected MSM, even during the early stages of disease ^(5,6). Although MSM have better dietary intakes, compared with IDUs, multiple nutritional alterations have also been noted in this group. Examination of plasma levels of vitamins and trace elements revealed that up to 67% of the seropositive men had inadequate nutritional status with respect to at least one nutrient and 36% of the population exhibited multiple biochemical abnormalities. Nutritional alterations were apparent, despite dietary intakes that met or even exceeded recommended dietary allowances ⁽⁷⁾, suggesting that intake of nutrients at levels recommended for the general population may not be adequate in HIV-1 disease. Specific micronutrient deficiencies, including zinc and vitamins B_2, B₆, B₁₂, A, and E, were evident in these relatively asymptomatic HIV-1-infected patients ⁽⁵⁾. Low levels of micronutrients have also been reported in a small proportion of HIV-1-seropositive men and women participating in a study of heterosexual HIV-1 transmission ⁽⁸⁾.

Although nutritional deficiencies are common in both HIV-seropositive IDUs and MSM, the prevalence of nutritional alterations differs between the groups. Decreased plasma levels of antioxidants, vitamins A and E, which were observed in between 40% and 50% of the HIV-infected male and female IDUs, were not as apparent in HIV-infected MSM who exhibited only a 10% to 15% deficiency of these nutrients ^(2,5). Inadequate zinc levels, evident in both MSM and IDUs, support this nutrient's role as a sensitive marker of disease progression ⁽⁹⁾.

HIV-1-Infected Children

There has been limited research on the role of micronutrients in pediatric HIV infection. Nutrient abnormalities known to be associated with the immune system have been observed in one report ⁽¹⁰⁾, which is consistent with our findings indicating a significant association between nutritional status and immune dysfunction in HIV-1-infected children ⁽¹¹⁾. Miami pediatric patients aged 15 to 108 months (n = 24), have been observed since 1990. All these children were perinatally exposed to the virus and had symptomatic disease at the time nutritional status was determined. Most (83%) were receiving antiretroviral treatment (zidovudine). Assessments of blood samples, which were limited, identified low levels of zinc among 71% and deficient levels of selenium among 33% of the children, respectively.

MICRONUTRIENTS, HIV-1 DISEASE PROGRESSION, AND MORTALITY

The potential consequences of nutritional alterations in HIV-1 disease are manifold. There is substantial evidence to indicate that specific nutritional deficiencies may accelerate disease progression and increase the risk for HIV-1-related mortality. Most deficiencies that are highly prevalent in the HIV-1-seropositive cohorts have been well documented to impair immunologic function ⁽¹²⁾. Interactions between immune function and specific nutrient deficiencies in HIV-1 disease have been reported in relationship to lipid status ^(13,14), trace elements (selenium and zinc), and vitamins A, B₆, and B₁₂^(6,15-17).

Micronutrients and HIV-1 Disease Progression in Injecting Drug Users

We have evaluated the effects of immune parameters and nutrients known to affect immune function (vitamins A, B₆, B₁₂, E, zinc, and selenium) on survival in HIV-1-seropositive male (n = 82) and female (n = 43) IDUs ⁽¹⁷⁾. Most study participants were black (88%), with a smaller proportion of Hispanics (8%) and whites (4%). The mean CD4 count at baseline was 428 + 322 cells/mm³; 27% of the participants had CD4 counts <200 cells/mm³.

Over the course of a 3.5-year follow-up, 21 participants died of HIV-related causes. Impaired nutritional status (overly low levels of prealbumin), and deficiencies of vitamin A, vitamin B₁₂, zinc and selenium over time were significantly associated with mortality. Neither vitamin B₆ nor vitamin E deficiency was associated with mortality, nor was use of zidovudine and other antiviral regimens, most likely due to a very low frequency of use over the course of the study. Table 2 shows the multivariate analysis for nutrient status and survival in this cohort. An almost threefold increased relative risk for HIV-1-related mortality was demonstrated with low plasma zinc levels. Consistent with Semba's study of drug users in Baltimore ⁽¹⁶⁾, vitamin A deficiency was associated with a threefold increase in relative risk of mortality. Low plasma vitamin B₁₂ levels were also associated with accelerated disease progression and an increased relative risk of mortality, affirmed by Tang's study ⁽¹⁵⁾.

Table 2

Selenium Deficiency and Mortality in HIV-1-Seropositive Cohorts

The micronutrient deficiency associated with the highest risk for mortality was selenium. Selenium deficiency developed in only 7% of the IDUs, but was correlated with almost a 20-fold increase in relative risk of mortality ⁽¹⁷⁾. When the joint effect of deficiencies that had singly predicted mortality was evaluated, only selenium deficiency was an independent predictor of survival (relative risk 10.8;p < .002). A significant effect for selenium was shown even when controlling for CD4 count <200 cells/mm³ at baseline, and CD4 count over time.

In other high-risk cohorts, selenium status has been demonstrated to be predictive of HIV-related prognosis and survival ^(18,19). In our group of MSM, selenium deficiency was associated with a decreased length of survival of 31.4 months, compared with 57.4 months for those with normal plasma selenium levels. Selenium deficiency in the HIV-infected pediatric patients was associated with immune dysfunction ⁽¹¹⁾ and decreased survival ⁽¹⁹⁾. The dramatic impact of selenium on HIV-1-related mortality in these cohorts may reflect its role in antioxidant defense and possible modulation of viral expression ^(20-23).

Selenium, an essential trace element, is required for activity of glutathione peroxidase, a major protective enzyme against oxidative stress, which increases in HIV-1 disease ⁽²⁴⁾. At the genetic level, selenium appears to exert its effects by means of selenoproteins, affecting termination of protein synthesis. Several genomic features required for the expression of potential selenoprotein genes in HIV have been experimentally confirmed ^(25,26), and several selenium compounds have been shown to specifically inhibit HIV cytopathic effects ⁽²¹⁾. Thus, the potential ability of selenium to increase the enzymatic defense systems ⁽²⁰⁾ and inhibit HIV-1 replication ^(25-27) could be particularly significant in slowing disease progression and increasing survival, particularly in groups for whom protease treatments are generally not readily available.

CONCLUSIONS

Multiple and widespread nutritional alterations are evident in HIV-1-infected cohorts and may dramatically affect disease progression and survival. The micronutrient deficiency associated with the highest risk for mortality is selenium, which may reflect its role in antioxidant defense systems and action in gene regulation. These compelling findings have provided the basis for our current investigations to determine possible mechanisms and evaluate the effect of selenium supplementation on HIV disease progression and survival.

Acknowledgments:

This work was financially supported by U.S. National Institute of Mental Health (NIMH) grant #1RO1MH50239, U.S. National Institutes of Health and Fogarty International Center grant #2D43TW00017, and NIMH grant P50MH42455. The technical assistance of N. Rodriguez is greatly appreciated.