Micronutrients: current issues for HIV care providers

Introduction Malnutrition, often accompanied by low serum levels of micronutrients, was common in HIV-infection prior to the introduction of highly active antiretroviral therapy (HAART), and is still common in much of the world that has limited access to antiretroviral therapy (ART). Chronic diarrhea, anorexia, malabsorption, impaired nutrient storage, increased energy demands and altered metabolism were the primary contributors to these nutritional deficiencies. Today, macronutrient deficiencies are less common and less severe in HIV-infected populations living in resource-sufficient countries. However, following the introduction of HAART, new questions about the importance of micronutrients in HIV infection are emerging. One of the most vexing issues facing HIV-positive individuals in the developed world today is fat redistribution or lipodystrophy syndrome, characterized by subcutaneous fat wasting, visceral fat accumulation, lipid abnormalities, and insulin resistance or glucose intolerance. Certain aspects of this syndrome may be associated with oxidative stress, thereby increasing the body's demand for certain antioxidants and potentially the need for micronutrient supplementation. HAART medications may increase oxidative stress levels above and beyond levels caused by the virus itself. The potential for HIV infection and its treatment to be associated with an increased risk for cardiovascular disease is real and there may also be a role for antioxidants in ameliorating this risk. Other important issues that still need to be addressed are the role of micronutrients in vertical HIV transmission, disease progression, and bone health in the presence of HAART. As ART becomes more available to HIV-infected populations, these issues will recur throughout the world, particularly in populations where the ongoing potential for macronutrient and micronutrient deficiencies remains high. If a need for supplementation is found, then appropriate dosages of micronutrients need to be established. Current nutrient recommendations exist for healthy populations [1–3], however there are few guidelines for people with compromised health. With the widespread and often costly use of micronutrient supplements among HIV-positive individuals, there is a need to know whether pharmacologic dosing of micronutrients is safe, beneficial or contra-indicated. The objectives of this review are, therefore, as follows: (1) to summarize the data that has been generated on micronutrients and their impact on HIV infection in the pre-HAART era; (2) to determine the critical questions that have been answered and questions that need further research; and (3) to identify new issues dealing with the role of micronutrients in the face of a changing epidemic. This review will not focus on the proposed mechanisms of action for each particular micronutrient. Pre-HAART Prevalence of micronutrient abnormalities Micronutrients play a critical role in the proper functioning of the immune system (Table 1). Therefore, it is not surprising that at the beginning of the HIV epidemic, researchers began to notice micronutrient abnormalities in AIDS patients. Several review articles have been published examining the prevalence and consequences of micronutrient abnormalities in HIV-infection during the pre- and early HAART eras [4–9]. In brief, several studies documented lower serum levels of many specific micronutrients among HIV-infected individuals [10–13]. Blood selenium levels and glutathione peroxidase activity (a marker of selenium activity) were found to be significantly lower in individuals with HIV infection than in individuals without HIV infection [14,15] Similarly, vitamin B12[16,17] and vitamin C levels [18,19] were lower in HIV-infected individuals than in healthy controls. Low vitamin A levels were reported in various populations with HIV infection, including 2–11% of homosexual men [10,20], 15% of injection drug users [21], and 30–60% of pregnant women in developing countries [22–24]. Low plasma carotenoid levels (beta-carotene and/or total carotenoids) [12,23,25–27] as well as low zinc levels [28–30] were also found to be highly prevalent abnormalities in HIV infection.Table 1: Selected micronutrients and their functions.In laboratory, animal, and human studies, both iron deficiency and iron overload have been shown to have deleterious effects on the immune system [31–33]. In more recent studies, iron deficiency and iron deficiency anemia were found to be common in HIV-infected patients, particularly among female injection drug users [34,35]. In a cross-sectional study, the prevalence of anemia was significantly higher among HIV-infected than uninfected women (44 versus 26%; P < 0.02), with approximately 40% of both groups having low plasma ferritin levels (< 30 μg/l) [35]. Iron-deficiency anemia accounted for approximately half of the total anemia observed in these women. While some of these women may have been on HAART or other ARTs, no information on HIV medications was given. In the majority of studies published during this time, low serum micronutrient levels were equated with micronutrient deficiencies. However, the interpretation of serum micronutrient levels is complicated. Many trace elements and vitamins are acute phase reactants and shift between various body compartments during active infection [36–38]. For example, serum zinc and retinol levels decrease during an acute phase response, whereas serum levels of copper and ferritin increase. Since many of the participants in these earlier studies presented with opportunistic infections and AIDS, or no information about concurrent infections was given, serum levels of micronutrients may not have accurately reflected true micronutrient status. Furthermore, many of these early pre-HAART studies were cross-sectional, and thus the causes and timing of low micronutrient levels are unclear. Nevertheless the consistency of the numerous published studies at the time suggested some degree of micronutrient abnormality among HIV-infected patients who were not treated with antiretroviral drugs. Micronutrients and HIV disease progression In the mid- to late-1990s, researchers began to examine the associations between micronutrient abnormalities and HIV disease progression. Decreasing vitamin E levels over time were associated with significant declines in CD4+ cell counts and increased progression to AIDS [39]. Likewise, low vitamin B12 levels were found to be associated with more rapid disease progression as defined by time to first AIDS diagnosis or CD4+ cell decline to < 200 × 106 cells/l [40]. Low serum selenium levels increased the risk of HIV-related mortality by more than ten-fold in one study [41]. Low vitamin A levels were associated with increased risk of mortality in HIV-infected injection drug users [21,42]. Although zinc is essential for proper immune functioning and for the integrity of mucosal surfaces, increased zinc intake was shown to have potentially adverse effects on HIV progression in early observational studies [43,44]. Zinc binds to viral nucleocapsid protein Ncp7 and forms zinc fingers, which are essential in pro-viral DNA synthesis and the activity of reverse transcriptase. Thus there was some concern that zinc supplementation might promote, rather than inhibit, viral replication [45,46]. High iron status, like zinc, may also accelerate the course of HIV infection. Among HIV-positive individuals, those with a certain haptoglobin phenotype (Hp2-2) were more likely to have higher levels of serum ferritin, oxidative stress, and viral replication, and worse prognosis than those with two other haptoglobin phenotypes [47]. Infections with Candida spp., Pneumocystis carinii, and Mycobacterium spp. were significantly more common among HIV-infected patients with high bone marrow macrophage iron stores than in those with low to normal stores [48]. Furthermore, those with higher macrophage iron stores had an increased risk of death. Oxidative stress In HIV infection, reactive oxygen species may enhance viral replication by activating nuclear transcription factors, such as NF-κB, which ultimately lead to viral gene expression. In the laboratory, antioxidants have been shown to inhibit the activation of HIV transcription [49]. Further, in HIV-infected adults, zidovudine was shown to promote oxidative damage to DNA, a process that was reversible with vitamin C and vitamin E supplementation [50]. Several pre-HAART studies found that both asymptomatic HIV-infected individuals and AIDS patients had higher levels of oxidative stress, as indicated by increased plasma metabolites of lipid peroxidation and/or reduced antioxidant levels, compared with healthy controls [19,51–53]. More comprehensive reviews on this topic have been published previously [54,55]. Micronutrients and HIV transmission There has been concern of increased risk of HIV transmission to sexual partners, or from mother to child, among HIV-infected individuals with particular nutrient deficiencies. Low serum selenium levels in HIV-positive women in Kenya were associated with a three-fold increased risk of genital mucosal shedding of HIV, suggesting the possibility of increased sexual transmission in selenium-deficient women [56]. In two observational studies, low serum levels of vitamin A in HIV-infected pregnant women were significantly associated with a higher risk of vertical transmission. Among 338 HIV-infected pregnant women in Malawi, 32% of those with serum retinol < 0.70 μmol/l transmitted the virus to their offspring, compared with only 7% of women with serum retinol levels > 1.04 μmol/l (P < 0.0001) [57]. Among HIV-infected pregnant women in two US cities, those with serum retinol < 0.70 μmol/l were five times more likely to transmit HIV to their infants than those with adequate retinol levels, after controlling for percentage CD4+ cells, gestational age, duration of membrane rupture, and mode of delivery [58]. While data from these early observational studies suggested strong associations between inadequate micronutrient levels and disease progression or vertical transmission, clinical trials examining this issue have revealed somewhat mixed The following the of clinical trials of various micronutrient supplements that have been to trials of micronutrients and HIV of micronutrient supplementation among populations of early trials in the and ongoing trials in and other countries that have or no access to antiretroviral of earlier trials among HIV-infected and have been the several clinical trials of micronutrient supplementation have been in the US with less than The of these trials have been previously trials in HIV-positive patients on zidovudine therapy no beneficial of B12 on early clinical of supplementation for immune an published revealed no significant in cells, or body between the and groups Similarly, a vitamin A had no on HIV viral or CD4+ cell counts in a among injection drug users in However, were published from a of vitamin C and vitamin E supplementation The reported significantly reduced levels of several of oxidative stress and a a in HIV viral after only Several clinical trials of micronutrient supplementation have been among HIV-infected populations in with or no access to antiretroviral medications (Table A of trials in the effects of vitamin A supplementation on transmission and the and mortality of HIV-infected and their In infants of HIV-infected women were to vitamin A or to of HIV of the infants was at of Among the had a lower lower and than the (P < Among the with HIV infection, those with vitamin A had a significant in not compared to the There was no of supplementation among to be uninfected with In a clinical the more than HIV-infected pregnant women to a or of and 30 of during and 200 of at The found no in by of between the vitamin A and groups versus In there were no in of or mortality between the two However, women in the vitamin A were significantly less likely to have a delivery than women in the versus P Among a of women from this clinical there was no of vitamin A supplementation on or during the pre- or or on among these women However, there was a of vitamin A supplementation on of particularly among women with low serum retinol levels or with CD4+ cell counts < 200 × 106 cells/l at from clinical trials of micronutrient supplementation in and over HIV-infected pregnant women in were a micronutrient supplementation that women were one of study vitamin without vitamin with vitamin or women in the vitamin A groups an of vitamin whereas women in the and only groups a of age, infants to the in the of vitamin and were that not vitamin was significantly associated with and in and cell counts among these women supplements were also found to during the of In and were published on the effects of supplementation on vertical transmission and early mortality There to be no of vitamin A or supplementation on mortality or risk of vertical transmission to of age, supplementation reduced the risk of mortality among who were HIV at and reduced the risk of vertical transmission among to who were and compromised A supplementation had no on was associated with a significant increase in risk of vertical transmission supplementation of to to their their first of of women in the significantly less and had higher CD4+ cell counts than of women who not While intake of vitamin A had no on the or CD4+ cell it the risk for a of with a rapid of have been published on the effects of vitamin supplementation on HIV disease progression and mortality in these women supplements were found to the risk of progression to disease and by approximately compared to A to have no such A in the effects of micronutrient supplementation as an to therapy among HIV-infected patients with were to or a vitamin vitamin and Although low serum levels of vitamins A and E at were associated with a higher supplementation not increase serum levels, CD4+ cell time with diarrhea, or mortality during the first following a clinical in the of a on and disease progression among HIV-positive patients were to a or a The found that the significantly reduced after only among the of participants with CD4+ cell counts < × 106 cells/l There was also some of micronutrient supplementation on among those with CD4+ cell counts < 200 × 106 this was only supplements had no on CD4+ cell counts or viral of pre-HAART studies As with other issues of importance in HIV studies were the first to in the serum micronutrient levels were and levels of vitamins and and zinc were often found to be Many early studies associated these low micronutrient levels with adverse clinical including progression to AIDS and death. is that of micronutrient are often In the presence of acute and infection, nutrient metabolism is altered and a redistribution of certain the interpretation of low serum micronutrient the of clinical trials of micronutrient supplements have been somewhat supplementation trials in the US found or no of or vitamin A supplements on immune or viral among HIV-infected in found a of vitamin A supplementation in among their who were also with However, studies from found of vitamin A on of among HIV-infected groups and found of vitamin A or supplementation on vertical transmission. in found a significant increase in risk of HIV transmission among vitamin The for this increase in risk remains unclear. A supplementation may enhance the of and cells, which have been associated with an increased of to an increase in to HIV infection. the increased risk of transmission may be the of of thus to HIV-infected for The of this be particularly in countries with ongoing vitamin A supplementation for not vitamin to some on HIV-infected women and their supplementation was associated with increased CD4+ cell more during the of and higher and lower In supplements reduced mortality among HIV-positive with more in supplements had no on CD4+ cell time with diarrhea, or it that a of vitamins may some to HIV-infected populations, particularly those with more However, the role of A and in is less HAART Since HAART has the of in the treatment of HIV infection in the resource-sufficient world, the of opportunistic infections and has significantly in these A few recent have the effects of HAART on micronutrient to determine the clinical of HAART have to in micronutrient levels studies of micronutrient in the highly active antiretroviral therapy one study, the micronutrient of patients, drug was over a and after the of HAART In HAART was had low plasma selenium levels (< had low plasma zinc levels (< and had low iron levels (< Low selenium levels were significantly more prevalent among patients with CD4+ cell counts < than > × 106 In data were on 30 of the patients, of had HAART. that time, had low selenium levels, had low zinc levels, had low iron levels, had low vitamin A levels (< and had low vitamin E levels (< A and E were not in Among patients who were on HAART in there were no significant in levels of of the micronutrients compared to in micronutrient levels over the of were not in this A few studies have the of HAART use on vitamin B12 and In a cross-sectional study, the prevalence of low vitamin B12 levels was significantly lower in patients HAART than in controls who were not treated with HAART versus However, the not for other that may have between the two time that have the In a study examining B12 and levels and after of there was a significant increase in not levels after of ART HIV was associated with increased levels of B12 (P after for use and other potential effects of zidovudine or were found in this In a study, serum B12 levels in a of HIV-positive individuals were significantly higher during in which use was reported However, the prevalence of low B12 levels (< was between of use and users were significantly less likely to increase their serum B12 levels intake compared to suggesting of B12 to cross-sectional studies reported that plasma zinc and retinol levels were lower in HIV-positive patients on HAART than among patients these studies not in serum micronutrient levels after HAART However, the majority of these studies have been cross-sectional with of the studies compared levels among a of or pre-HAART users with levels among HAART without at be that the nutritional of patients with HAART use the of clinical likely in lower prevalence of severe and diarrhea, and However, the for this is still studies of vitamin B12 need to be to determine may of B12 intake as suggested previously One of the studies that few HIV-infected patients with low serum B12 levels were B12 as by levels which increase in true B12 and deficiencies abnormalities in B12 increased oxidative stress levels, and/or increased of immune system activation are to be the of low serum B12 mechanisms be less to B12 supplementation or B12 More studies are to determine the clinical of increased serum micronutrient levels after HAART, found to be the This is important from the and that many HIV-infected patients are still vitamin some at high in with HAART If low serum levels are not a marker of deficiencies then the of high levels of supplementation Oxidative stress in the HAART In populations of HIV-infected patients treated with HAART, the role of oxidative stress in disease progression has more complicated. HIV oxidative stress levels replication, of the virus with antiretroviral therapy may as one might oxidative stress levels, as the medications may increase oxidative In one study, serum levels of vitamin and were significantly higher among HIV-positive on HAART than among HIV-positive or no antiretroviral suggesting that oxidative stress levels might be lower among individuals HAART This after for drug use of vitamin and More a cross-sectional study levels as a marker of oxidative stress in HIV-infected individuals, of were antiretroviral medications levels were significantly associated with lower HIV viral and use of the stress levels were not increased in with viral that the of viral replication on oxidative stress is by the of the on oxidative In a cross-sectional study, no in plasma or cell glutathione levels were found between HIV-positive patients and not HAART In of the from these cross-sectional studies, studies on the role of antiretroviral on oxidative stress need to be Thus two clinical trials have been published examining the effects of antioxidant supplementation on oxidative stress in the of HAART. In an earlier the effects of supplementation with vitamins E and C on oxidative stress levels by plasma lipid and were in HIV-infected patients, of approximately were on a antiretroviral therapy the had lower oxidative stress levels, by than the were In a study, 30 HIV-infected patients on to a or a vitamin vitamin and vitamin for The significant declines in levels of DNA and reactive as well as an in the activity of antioxidant The HIV-infected as a had lower antioxidant activity and higher of DNA and levels than a of higher levels of oxidative Although these two clinical trials were not to determine the effects of HAART use on oxidative stress, that antioxidant supplementation oxidative stress levels of the However, the clinical of this still need to be The effects of selenium supplementation on clinical cell decline and were in a clinical among HIV-infected drug users in 200 HIV-infected of had selenium levels < μg/l) were to selenium supplementation or for half the participants reported HAART supplementation was shown to the risk of of antiretroviral age, CD4+ cell and viral at were to opportunistic infections other HIV-related and and drug The also had a higher of individuals with a decline in CD4+ than × 106 cells/l compared with the versus P Micronutrients and other of HIV and its therapy One of the most vexing that has in the HAART is the of the lipodystrophy syndrome, the of which are body and abnormalities that are likely to be in The body abnormalities subcutaneous fat and visceral or fat The abnormalities in serum and total of serum levels, and in There are also of asymptomatic in serum associated with the use of and in bone on the role that micronutrient deficiencies may play in the of these abnormalities thus been metabolism and plasma The use of reverse has been associated with fat A of antioxidant supplementation was among HIV-infected patients who were treated with had as a decrease in fat in at two of the following or by and by the and an or for prior to study were a vitamin vitamin E vitamin C and a of there were no in fat glucose and of insulin resistance significantly increased over the course of the to the and of a it is whether these were to the progression of or to the antioxidant supplementation. by may lead to the of asymptomatic in In a study two groups of HIV-infected patients on therapy were compared One was various antioxidant and the other was groups were for fat accumulation, of oxidative stress, plasma micronutrients and plasma The had significantly lower levels compared to the versus However, may have been a in this study as supplements were from a that nutritional supplementation as of its treatment In the supplements were not to clinical and plasma stress There is that bone metabolism in HIV infection is studies suggested that HIV infection might be in bone However, the is less from recent studies as to whether HIV or antiretroviral therapy is for bone In one study, of HIV-infected individuals were treated with a HAART In study, a high prevalence of reduced bone was found among HIV-infected individuals, with further reduced among those on HAART duration of HAART use was associated with a of bone among HIV-positive men Similarly, duration of therapy was associated with low In in one cross-sectional study, was significantly lower in HIV-positive than in no in was found between HIV-positive on various of antiretroviral that bone was more likely to HIV study reported of the bone as by serum of bone and bone during of antiretroviral therapy of the active of vitamin were found to be among HIV-infected had serum levels the normal and had with the levels found among those with the most HIV disease Micronutrients play a critical role in the of immune mucosal and With the of HIV infection and and the of clinical it is not surprising that studies of the role of micronutrients in HIV have somewhat other of is to researchers who have been and to questions about micronutrient and the progression of HIV infection. 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