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Journal of the International Association of Physicians in AIDS Care - Vol. 1, No. 2, April/June 2002
Neera Singhal, MBBS, MS, MHA*, and James Austin, MSc (Epi)**
*Ottawa Health Research Institute, and Canadian HIV Trials Network, Ottawa, Canada
**Community Research Initiative of Toronto, Toronto, Canada
This article reviews current literature on the role of micronutrients in human immunodeficiency virus (HIV) infection. Deficiencies of micronutrients are common in HIV-infected persons. They occur due to malabsorption, altered metabolism, gut infection, and altered gut barrier function. There is a compelling association of deficiencies of micronutrients in HIV-infection with immune deficiency, rapid disease progression, and mortality. Also, there is increased risk of vertical HIV transmission from mother to child with deficiency of vitamin A, and of neurological impairment with vitamin B12. The last five years have been exciting in micronutrient research, and there is promise that some micronutrients may be key factors in maintaining health in HIV immunodeficiency, and in reducing mortality. Selenium appears important in reducing virulence of HIV and slowing disease progression. Vitamin A supplementation in pregnant women with HIV may reduce maternal mortality and improve birth outcomes. Supplementation in children with HIV may accelerate growth. Carotenoid supplementation is being evaluated. Vitamin B12 may slow HIV immune deficiency disease progression, and reverse neurological compromise. Clinical benefit of supplementation with some micronutrients may be measurable in the presence of pre-existing deficiency. Apart from improved general nutrition, the impact of micronutrient supplements on health and their optimal use in HIV infection is controversial because there are so few controlled clinical trials. Further research is needed to elucidate the role of micronutrient deficiencies on the course of HIV infection, and the preventive and therapeutic role of supplementation in its clinical management. Nevertheless, current knowledge supports the use of routine multivitamin and trace element supplementation as adjuvant to conventional antiretroviral drug treatment as a relatively low-cost intervention.
Introduction
In recent years, the importance of nutrition in human health has received growing attention. Therapeutic and preventive supplementation with vitamins has been used successfully for a long time for many clinical conditions. This includes vitamin A for maintenance of vision, beta-carotene in erythropoietic protoporphyria, vitamin C in scurvy, niacin in pellagra, and others. In vitro and animal studies have shown immunostimulatory and anti-cancer properties of several micronutrients, leading to several large epidemiological trials of micronutrient supplementation. However, these trials did not show effect on incidence and outcomes of cancer, stroke, and heart disease.1-4 Nonetheless, a protective effect of combined supplementation with betacarotene, vitamin A, and selenium on incidence of stroke was seen in an undernourished population in China.5
Supplementation with vitamin A has reduced morbidity and mortality from childhood infectious diseases, such as measles, diarrhea, and acute respiratory infections.6-10 In trials of zinc supplementation, significant reductions were seen in severity of diarrhea, acute respiratory infections, and malaria.11 Selenium was shown to have a protective effect against certain cancers, particularly in the presence of low dietary intake.12
Assessment and correction of nutritional status in HIV infection is being recognized as an important part of comprehensive care of persons infected with HIV. This article reviews the current published literature on micronutrients in HIV infection, examines the role of supplementation with individual and combined micronutrients, and attempts to recommend direction that future research must take in order to define the place of nutrition in HIV infection.
Deficiency of micronutrients
Micronutrient deficiencies are common in HIV infection, and occur at all stages of immune deficiency, including asymptomatic infection.13-15 Serum levels of fat-soluble micronutrients and of selenium are reduced more than of others, and serum carotene levels are reduced more than any other micronutrient.16,17 Tomaka et al found no difference in prevalence of micronutrient deficiencies in patients with CD4 cells greater than 500, between 200 and 500, and fewer than 200 cells/µL.18
Helper/inducer (CD4) T-lymphocytes, disease progression, and mortality: An association was demonstrated between micronutrient deficiencies and rapid disease progression in prospective observational studies. Higher intake of micronutrients, which included riboflavin, thiamine, and niacin, was associated with higher CD4 cell counts at baseline.19-21 In a study of intravenous drug users, follow-up for 18 months showed an association between declining CD4 cell counts and development of deficient levels of vitamin A or B12. Higher CD4 cell counts were seen in those without deficient levels.22 Low serum levels of vitamin E23 and B1224 were measured in those with development of acquired immunodeficiency syndrome (AIDS). A similar association was not demonstrated for vitamin A.23
Micronutrient supplementation
Multivitamin and trace element supplementation is common in 63 percent to 73 percent of the HIV-infected population in North America. Although mutivitamin and trace element supplementation resulted in elevation of levels of micronutrients at all stages of the disease, levels in HIV-seropositive subjects were seen to be lower than in HIV-negative controls. Even with supplementation, 29 percent of HIV-infected persons had deficient levels of one or more micronutrient.25
Disease progression and mortality: Multivitamin use and intake of vitamin E, riboflavin, vitamin C, thiamine, and vitamin A were associated with slower disease progression in HIV.19 Tang et al observed slower progression of disease with moderate increase in intake of vitamins B1, B2, B6, and C, and reduced risk of mortality with all of these except vitamin C. Benefit was not significant with a great increase in intake of these micronutrients.21 These studies were observational in design, and residual confounding cannot be excluded as an explanation of results.
Birth outcomes: In a randomized, placebo-controlled trial in Tanzania, birth outcomes were studied in HIVinfected women. The women were supplemented with vitamin A and/or multivitamins (vitamins B1, B2, B6, B12, C and E, and niacin and folate, but not vitamin A) in a factorial study design. They were given routine ferrous sulphate, and folate supplements daily, and weekly prophylactic chloroquine. A statistically significant reduction of 39 percent in risk of fetal loss was observed with multivitamin supplementation, and a 40 percent reduction in low birth weight, severe pre-term birth, and small-for-dates birth. A significant improvement in CD4, CD8, and CD3 cell counts was also seen. Vitamin A supplement had a smaller treatment effect that was not statistically significant.26
Deficiency of vitamin A
Studies have shown vitamin A deficiency is common in various stages of HIV infection,13-15,22,27-31 even in 12 percent to 19 percent of asymptomatic HIV-positive persons.13,22 Levels appear to become lower as the disease progresses,22 may be more prevalent in women than in men,32 and may occur in the presence of adequate nutrition.30
Sixty-three percent of 474 HIV-positive pregnant women in Malawi had deficient levels of vitamin A, and 70 percent of their babies born with or without HIV infection had deficient levels of vitamin A, compared with age-matched maternal controls.33 Children in one study were shown to develop deficiency prior to development of AIDS.34 In general, deficiencies of fatsoluble micronutrients occur in HIV infection due to fat malabsorption, general malabsorption, diarrhea, gut infection, altered gut barrier function, and altered metabolism.35
CD4 lymphocytes, disease progression and mortality: Baum et al demonstrated an association over an 18- month period between the development of vitamin A deficiency and a significant decrease in CD4 cell count.22 Semba et al demonstrated that low vitamin A levels were an independent predictor of death from AIDS-related causes. They also showed that over a four-year period, vitamin A deficiency occurred in 20 percent of those who died from AIDS or infection, and in only 7 percent of matched HIV-positive controls who survived.31 In another study, serum retinol (vitamin A) levels were shown to be inversely associated with the risk of mortality in HIV-infected intravenous drug users.14
Vertical HIV transmission: A significant inverse relationship of prenatal vitamin A levels and viral load in breast milk of mothers with CD4 cell count below 400 cells/mm3 was demonstrated in a cross-sectional study.36 Low vitamin A levels and increased shedding of virus in vaginal secretions were demonstrated in another study.37
In an observational study of 133 HIV-infected mothers, women who were vitamin A deficient prenatally were found to be 3.69 times more likely to transmit the virus to their children. Progressively increasing rates of HIV transmission were seen with decreasing levels of vitamin A in the HIV-infected mother. Multivariate analysis showed a three- to four-fold increase in the risk of transmission. Infants of women with the lowest vitamin A levels died within one year of birth.38 Lower serum levels of vitamin A were associated with higher risk of viral transmission,39,40 and with having a dead or HIV positive baby.41 This association between low vitamin A levels and risk of vertical transmission was not seen in two observational studies with 334 and with 95 HIV-positive pregnant women.42,43
Vitamin A supplementation
Viral load: In a small placebo-controlled trial of vitamin A and beta-carotene in HIV-infected pregnant women, no effect was seen on viral load.44 Similarly, no effect was seen on viral load with vitamin A45 and betacarotene46 supplements in HIV-infected patients in two separate studies.
Vertical viral transmission, maternal mortality, and birth outcomes: Randomized controlled trials of supplemental vitamin A in pregnant women at various stages of HIV infection have shown no overall effect on vertical viral transmission. In a randomized, placebocontrolled trial of prenatal supplementation with 10,000 IU of vitamin A or placebo in 700 HIV-infected pregnant women in Malawi, treatment had no effect on viral transmission at six weeks and 12 months.47 Prenatal supplementation with 5,000 IU of vitamin A and 30 mg beta-carotene or placebo in 750 women in South Africa in factorial design showed no effect of treatment on viral transmission, although a small but statistically insignificant reduction in premature births was observed. Among preterm births, women on supplements were less likely to transmit virus than women on placebo.48 In a large randomized, placebo controlled trial in Tanzania, vitamin A and multivitamins (excluding vitamin A) were administered prenatally. Follow-up showed no effect on vertical transmission compared with controls on placebo in the prenatal or intrapartum periods, or for up to six weeks of breastfeeding.49 In a placebo-controlled trial, 20,000 pregnant women in Nepal were supplemented with a weekly dose of 23,300 IU vitamin A or beta-carotene. Up to 50 percent reduction in maternal mortality was observed in both HIV-infected and uninfected women.50 In the same population, no effect of supplementation with the two micronutrients was seen on outcomes relating to birth weight, prematurity, and small-for-gestational-age births.51
Vitamin A supplementation in children: In a randomized, placebo-controlled trial in Durban, vitamin A was given in single age-adjusted doses to children of HIV-positive mothers at one and three months (50,000 IU), six and nine months (100,000 IU), and at 12 and 15 months (200,000 IU). At 16 months, the treated group showed reduction in diarrhea by 28 percent, 40 percent shorter bouts of diarrhea, and reduction in hospitalization for diarrhea by 77 percent. Treatment effect was shown by multivariate analysis to be confined to children who tested HIV-seropositive.52 In a randomized, placebocontrolled study from Tanzania, 687 children between 6 and 60 months old were admitted for pneumonia, and supplemented with 200,000 IU vitamin A (half that if under 12 months old). The dose was repeated the next day, and at four and eight months. This resulted in a significant increase in linear growth in children with HIV infection, ponderal growth in children with malaria, and reduced stunting in children with persistent diarrhea.53
Oxidative stress and antioxidants: Antioxidant imbalances in the host play a role in apoptosis that may lead to progression in HIV-infection.54-56 This apoptosis is induced by reactive oxygen species (ROS) by damage to lipid membranes, intracellular proteins, and DNA.17 ROS can activate the latent HIV state by stimulating oxygen-responsive transcription factors, especially NF-kB, which induces HIV replication in the infected Tlymphocyte. 57 Addition of antioxidant vitamins may inhibit HIV replication, and reduce ROS.
Safety of vitamin A: There is known toxicity with long-term and high-dose use of vitamin A, and there is the theoretical risk of HIV-1 expression.58 Toxicity manifests itself as hypervitaminosis A and increase in bone fractures.59 However, the risk of toxicity in the presence of HIV infection is not known.
It is believed that benefit of supplementation with vitamin A may only occur when there is pre-existing deficiency. No benefit was observed with vitamin A supplements in a largely replete population of HIV-positive American men.23 Further investigation of treatment with vitamin A is needed into the differential treatment effect of vitamin A with or without deficiency.
Carotenoids are increasingly being used in studies as a substitute for supplemental vitamin A. There are more than 600 naturally occurring carotenoid pigments, of which 50 are biologically active. Some are precursors of vitamin A, including beta-carotene that is the principal carotenoid. Many of them, including beta-carotene, are antioxidants. The provitamin carotenoids are converted to vitamin A in the jejunal mucosa and absorbed, or absorbed unchanged, while other carotenoids are absorbed unchanged. Carotenoids have been shown to be non-toxic with prolonged use,4 except for possible adverse effect of beta-carotene on cancer incidence in smokers in one trial.3 There is no recommended daily allowance (RDA) or daily limit on intake.
Carotene deficiency
Deficiencies of carotene and other carotenoids are common in HIV infection,17,18,60 are more marked than of other micronutrients,17 and occur even in the absence of symptoms or diarrhea.60 Long-standing fat malabsorption occurs even in early HIV disease due to villous atrophy and impaired enterocyte function in the absence of gut infection.61 Scavenging of singlet oxygen by carotene leads to depletion of carotene.62 The prevalence of low serum carotene levels is between 30 percent and 77 percent of adult patients with HIV disease.15,60,63 A correlation was demonstrated between serum carotene levels and CD4 cell counts, and serum carotene and CD4/CD8 ratio, in 116 HIV-infected individuals in various stages of HIV disease.60
Twenty-five HIV-infected patients in early-stage, and 18 patients in late-stage HIV immune disease, were followed for six months. Low serum carotene levels and plasma carotenoids were observed in all patients. Paradoxically, persons in US Centers for Disease Control and Prevention (CDC) stage II had a more rapid fall in serum carotene levels than persons in CDC stage IV.64 The authors hypothesized that this paradox may be due to higher anti-oxidant activity at the early stage, and increased consumption of carotene by oxygen free radicals. Lacey et al demonstrated low levels of several carotenoids in 35 HIV-positive individuals. While correlation of some carotenoids with CD4 cell counts was demonstrated, similar correlation with CD4 cells was not demonstrated with beta-carotene, and vitamins A, C, and E.17
In one study, low serum vitamin A levels were observed in 37 percent of HIV-positive women in the third trimester of pregnancy. Serum carotene and vitamin A concentrations correlated significantly with percentage of CD4 lymphocytes, absolute CD4 cell counts, and CD4/CD8 ratios.65
Carotene deficiency in children: In a study of 15 African- American and Hispanic HIV-infected children, a correlation was observed between severity of disease and serum carotene levels. Those with HIV infection had a 6.5-fold decrease from baseline in serum carotene levels, compared with age-matched controls, whereas children with AIDS had a 13-fold decrease. However, vitamin A and E levels did not vary with severity of disease.66 Periquet et al described low levels of lycopene (a carotenoid) and retinol (vitamin A) in ten children with AIDS, but no deficiency of carotene.34
Carotenoids supplementation
CD4 lymphocytes: Supplementation in 17 healthy HIVnegative volunteers with 180 mg (30,000 IU) betacarotene daily for 14 days showed a 30 percent elevation of CD4 cells.67 In another study, seven AIDS patients showed a transient lymphocyte count increase of 66 percent when they were treated with 60 mg beta-carotene twice daily for four weeks, and followed for another six weeks.68
Garewal et al observed significant increases in Leu 11 (a marker for natural killer cells) with beta-carotene supplementation, and elevations in Ia antigen transferrin receptor and measurements of lymphocyte activation. Sixty mg beta-carotene was administered daily for four months to HIV-positive veterans. No changes were observed in lymphocyte percentages of CD4, CD8, or CD11.69 Eleven HIV-seropositive subjects with oral candidiasis were treated with 60-120 mg beta-carotene daily for three to seven months. Treatment showed no improvement in the infection or in lymphocyte counts or percentages.70
A 60-mg dose of beta-carotene or placebo was administered randomly daily for four weeks to HIV-positive patients in a crossover trial. In both cases, the treatment group showed significant increases in leucocyte counts and CD4/CD8 ratio.71 A prospective, placebo controlled, randomized study compared beta-carotene plus multivitamins and trace elements, to multivitamins and trace elements for three months,72 in which Coodley et al were not able to replicate the results of their earlier study.71 The authors hypothesized that vitamin A in the multivitamins given to both groups in the second study may have resulted in reduction of the apparent treatment effect of beta-carotene.
These studies of beta-carotene supplementation are small and findings range from no effect to varying and transient increase in immune cells. No definite conclusions can be drawn from them of the effect of beta-carotene supplementation on immune cells.
Disease progression and mortality: In a study of 11 patients with AIDS-related complex symptoms, treatment with 60 mg beta-carotene daily for 20 days per month resulted in alleviation of symptoms in all the patients over a period of 24 to 36 months. Two patients progressed to AIDS, while the others showed an increase in CD4 cell count.73
A randomized, placebo-controlled, double-blind, clinical trial of natural mixed carotenoids was conducted in patients with advanced AIDS on antiretroviral therapy. They were all given a specially designed multivitamin and trace element preparation, including vitamin A (see Table 1). Further study is required to corroborate and investigate findings that suggested an effect of carotenoids on survival.74
Oxidative stress: Delmas-Beauvieux et al randomized 52 HIV-seropositive persons into three groups to receive 250 µg/L selenomethionine daily, or 30 mg beta-carotene twice daily, or placebo. At 12 months, neither treatment group showed improvement in CD4 cell counts, compared to controls. However, glutathione levels were significantly higher, and malondialdehyde levels were significantly lower in both treatment groups. Glutathione indicates increased anti-oxidant activity, and malondialdehyde is an indicator of lipid peroxidation. The authors reported that median serum carotene levels increased from 3 µg/L to a surprising 305 µg/L with 30 mg beta-carotene administered twice daily.75
In another study, 36 HIV-positive subjects were divided into three groups. Each group received 250 µg of selomethionine daily, or 30 mg beta-carotene twice daily, or placebo, for 12 months. Other indicators of endothelial damage remained unchanged in all groups, but stable levels of thrombomodulin and von Willebrand factor (markers of endothelial damage) were reported in both treatment groups. These were elevated in controls, and believed by the authors to be evidence of possibly antioxidant-mediated prevention of endothelial damage.76
Further studies are needed to evaluate carotenoids as vitamin A precursors, and to evaluate treatment effects in relation to deficiencies, and in relation to antiretroviral therapy.
Deficiency of B-complex vitamins
Deficient serum levels of vitamins of the B-complex occur in HIV disease, even in early disease and in the absence of symptoms.22 Beach et al assessed micronutrient concentrations in HIV, and found low riboflavin levels in 26 percent, low B6 levels in 53 percent, and low B12 levels in 23 percent men belonging to CDC stage III.13 Low choline levels,25 and low vitamin B12 and B6 levels77 were shown in HIV-infected men and women. Low erythrocyte and serum folate levels were seen in 64 percent of 74 HIV-infected persons at all stages of the infection.78
Supplementation with B-complex vitamins
In a study of micronutrient supplementation, Abrams et al showed an inverse relationship between increased intake of thiamine and niacin and progression to AIDS.19 Significantly slower disease progression to AIDS was also observed with increased intake of B-complex vitamins in other studies.20,79
Deficiency of vitamin B6
Vitamin B6 deficiency was shown to be common in CDC stage III HIV-infected persons with adequate nutrition. Thirty-four percent of 44 persons were deficient in vitamin B6, and another 30 percent had marginally deficient levels. Patients who were deficient showed decreased lymphocyte mitogen responsiveness and reduced natural killer cell cytotoxicty, compared with HIV-positive persons who were not deficient.80
Deficiency of vitamin B12
Deficiency of vitamin B12 is common in HIV infection, and its prevalence varies between 10 percent and 35 percent, depending on the stage of the disease.78,81-85 Deficiency was more common in HIV-infected individuals than in those not infected,13,77,86-88 even in early and asymptomatic disease.13,24,27,82,83,90,91 Deficiency is attributed to malabsorption due to gastric and parietal cell antibodies, duodenal and colonic inflammation,92 and gastric cell acid hyposecretion.93 It is possible that increased lymphocyte turnover in HIV infection might deplete vitamin B12, just as fetal growth can deplete vitamins B12 and folate to produce the megaloblastic anemia of pregnancy.
Disease progression and mortality: Follow-up for two years showed that HIV-seropositive persons with deficiency of vitamin B12 had 50 percent mortality, compared with 22 percent among persons without deficiency. However, the latter group had more AIDS patients, and the groups may not be comparable. A significant association was demonstrated between low serum B12 levels and lower hemoglobin, leucocytes, CD4 cell counts, and CD4/CC8 cell ratios, compared with normal B12 levels.94
Baum et al, in a follow-up of 108 HIV-positive men, showed a significant association between the development of B12 deficiency and declining CD4 cell count. There was a significant increase in CD4 cell counts in those who had normalization of serum vitamin B12. Low baseline serum B12 levels were shown to be significant predictors of AIDS.22 In an observational study of 310 homosexual men, after adjusting for confounders, lower levels of serum vitamin B12 significantly increased the risk of progression to AIDS by 89 percent, compared with normal levels of B12.24
Although the studies that link B12 deficiency with HIV disease progression are observational by design, and confounding of associated factors may explain results, the association is strong. Randomized, controlled clinical trials must elucidate if low B12 levels are just a marker of advanced disease, or actually cause disease progression, and confirm if supplementation can slow disease progression.
Neurological impairment: In 64 asymptomatic HIV seropositive subjects, a significant association was found between low levels of vitamin B12 and cognitive impairment, such as deficits in information-processing time and visual-spatial problem-solving skills.87 In another study of 64 HIV-positive persons, peripheral neuropathy and myelopathy were associated with low serum B12 levels. A positive Schilling test or a low serum B12 level was reported in 20 percent of patients.85
No association between neurological abnormalities and B12 deficiency was demonstrated in some studies. Keating et al found no association between serum vitamin B12 levels and low cerebrospinal fluid methylation ratios in HIV positive patients, indicating that myelopathy was probably due to a mechanism other than vitamin B12 deficiency.95 In another study of 153 HIV-seropositive subjects, no association was found between low serum vitamin B12 levels or impairment of B12 metabolism, and neuropsychiatric disturbances such as peripheral neuropathy, mood disturbances, and dementia in subjects.96
In a longitudinal observational study of 84 HIV-infected homosexual men, the association between cognitive function and low levels of serum vitamin B12 was examined in four groups of subjects, based on vitamin B12 levels, at six monthly intervals over a period of 18 months. Normalization of serum B12 levels resulted in improved speed of retrieving over-learned information from long-term memory, although the clinical significance of this finding has not been explained.97 All the studies of association between vitamin B12 levels and neurological impairment are observational in design, and all except one are cross-sectional, implying the presence of confounding influences.
Vitamin B12 treatment
In separate case reports of vitamin B12 injection treatment, one patient with AIDS-related dementia showed improvement in dementia over a two-month period,97 five of eight patients showed improvement of neuropathic symptoms,85 and CSF methylation ratios normalized in patients with B12 deficiency.95 The evidence for reversal of neurological deficit with B12 treatment is based largely on case reports. Randomized, controlled trials are needed to confirm this effect. Controversy surrounds oral versus parenteral use of vitamin B12. However, parenteral administration is recommended in conditions that need specific vitamin B12 therapy.98
Interaction of vitamin B12 and zidovudine therapy: There may be increased toxicity of zidovudine (AZT) therapy in the presence of vitamin B12 deficiency, as each is associated with bone marrow depression manifested as anemia and neutropenia. In a placebocontrolled trial of AZT therapy, AIDS patients with lower baseline levels of B12 had increased incidence of hematological side effects of AZT therapy, such as anemia, leukopenia, and neutropenia. No benefit of vitamin B12 injection in reducing hematological toxicity of AZT therapy was seen in other small studies.99-101
Deficiency of vitamin E
Low serum concentration of vitamin E was seen in observational studies. In a study of 100 asymptomatic HIV-seropositive men, 26 percent had intake of vitamin E that was 50 percent less than RDA, and 27 percent had overt or marginal deficient levels.13 In another study, 50 percent of 18 AIDS patients, 58 percent of 12 ARC patients, and 38 percent of 13 HIV-positive persons had intake of vitamin E less than 50 percent of RDA.102
Oxidative stress: Oxidative stress in HIV infection and opportunistic infections results in high level of free radicals and depletion of vitamin E. Resulting deficiency of vitamin E may then increase susceptibility to further infection.103
Vitamin E supplementation
Viral load and oxidative stress: In a randomized, placebo controlled clinical trial, supplementation of 40 HIVseropositive persons with 800 IU vitamin E and 1000 mg vitamin C, resulted in a significant reduction in oxidative stress and viral load, compared with the placebo group.104 In another study, significant reduction in viral load was seen with large doses of vitamin E and C.105
Disease progression and mortality: Among 296 HIV seropositive men followed for six years, doubled intake of vitamin E showed a decreased risk of progression to AIDS.19 Among 310 HIV-seropositive homosexual men studied over nine years, subjects in the highest quartile of serum vitamin E had a significantly decreased risk of progression to AIDS, compared to subjects in all other quartiles combined after adjusting for several confounders. An increase in serum levels of vitamin E was also seen with vitamin E or multivitamin supplements.23
Few controlled clinical trials have been done with vitamin E, but they support the immunostimulatory and antioxidant effects demonstrated in animal studies. Further research is needed to establish the role of vitamin E deficiency in disease progression, and the therapeutic effect of restoring normal levels with vitamin E supplements.
Deficiency of selenium
In different studies in HIV, both plasma and red blood cells were found to be deficient in selenium. This was reported in both HIV-positive and AIDS patients,106-108 and occurred even in early disease when malabsorption and malnutrition were unlikely contributors.109 In another study, deficient levels were found in 15 percent, and marginally low levels in 57 percent of 54 asymptomatic HIV-infected males.110 In a study of 23 HIV-infected children, 61 percent had low selenium levels which correlated with weight, serum albumin, and CD4 cell counts.111
Disease progression and mortality: Association of lower selenium levels with progression of disease was found in several studies. It was independent of malabsorption and correlated with CD4 cell counts.107,108,112 Constans et al also demonstrated correlation between both CD4 cells and serum selenium with mortality and opportunistic infections in 95 HIV-positive individuals.113
Baum et al showed that HIV-positive patients with low levels had a significant 20-fold risk of death from HIV related causes than those with adequate serum levels. The risk was 16 times greater than of low CD4 cell count, and greater than with any other micronutrient.114 In a study of 24 HIV-infected children, investigators showed that low plasma selenium concentration and CD4 cell count below 200/µl were independent predictors of mortality and faster disease progression.115
Selenium supplementation
CD4 cells and clinical improvement: Administration of 80 µg selenium and 25 mg vitamin E to eight patients with advanced AIDS and three patients with symptomatic HIV infection, resulted in a doubling of serum selenium levels, but no improvement in CD4 cells.108 Supplementation with 400 µg of yeast-based selenium for 70 days in 19 symptomatic HIV and AIDS patients resulted in elevation of serum selenium levels, while there was no difference in the control group.
Fourteen of the subjects reported improvement of symptoms.116 In another study, ten patients with cardiomyopathy, eight of them selenium-deficient, were supplemented with 360 µg selenium for 15 days, followed by 180 µg for eight days. This resulted in normalizing of left-ventricle shortening in six patients, while one patient died.117
Anti-oxidant activity: In a study of supplementation of 14 HIV-positive persons with 100 µg selenium, results were compared with 18 HIV-positive persons on placebo, and with 26 HIV-negative healthy persons on no supplementation. Significantly lower baseline glutathione levels were observed in both the HIV-infected groups. On follow-up for one year, the treated group showed significantly higher glutathione peroxidase and reduced glutathione levels than each of the other groups.75
All the studies of selenium in HIV-infection are small and observational in design, making confounding a possible explanation of findings. Randomized controlled trials are needed to investigate the association of deficiency with poor outcome, and possible therapeutic effect of supplementation.
Zinc deficiency
Zinc deficiency is common in the HIV-infected population. 118 Zinc levels are known to be depressed during acute phase reaction to infections, reflecting increased uptake by the liver,119 In a cross-sectional study of 228 hospitalized AIDS patients, 29 percent had low zinc levels and another 21 percent had levels characterized as marginal. A higher incidence of bacterial infections was reported in persons with low zinc levels.120
Malabsorption, altered metabolism, anorexia, and diarrhea may produce low levels of micronutrients and trace elements.121 Low zinc levels were also seen in early disease, and in the absence of symptoms.13,64,122 Some studies reported no effect on serum zinc levels in HIV infection,123-125 and others reported lower levels with more advanced stages of the disease.122,126
Disease progression and mortality: In a large study, a positive association was seen between dietary intake of zinc and CD4 cell counts, but no association was demonstrated with progression to AIDS.19 Progression to AIDS was associated with lower baseline serum zinc levels, as compared both to those who did not develop AIDS and to those who were HIV-negative.122 In another study, an association was demonstrated between low baseline zinc levels and AIDS mortality among men in Miami. When adjusted for baseline CD4 cell counts and serum concentrations of other nutrients, this association lost statistical significance.114
Since zinc deficiency and zinc-dependent immunity are responsive to acute and subsequent chronic phase reaction,127 levels of thymulin (a thymic hormone activated only by binding with zinc ions) may be a more sensitive marker of deficiency than serum zinc levels.128 Thymulin levels have been shown to be low even in the presence of normal serum zinc levels.127
Zinc supplementation
CD4 cells: Eleven men with AIDS, whose baseline zinc levels did not differ from controls, were treated for ten months with 0.4 mg/kg/day. This was shown to result in significant increase in CD4 cell counts, a significant increase in CD3 cells, and a mean increase in weight of seven pounds that could not be explained by caloric intake alone.129
CD4 cells in children: Oral zinc supplements of 1.8-2.2 mg/kg/day were given for three to four weeks to 13 stable HIV-infected children with a mean age of six years. The number of children with normal levels of zinc increased from six at baseline to nine, two children showed significant increases in CD4 counts, and four showed improved clinical scores.130 In another small trial, supplementation of HIV-seropositive children with 2 mg zinc per day for three weeks showed significant increases in total lymphocyte count, and a doubling of CD4/CD8 ratio.131
Zinc safety: There is some concern surrounding supplementation with zinc. Intake of zinc beyond 11.6 mg/day in 281 HIV-1 seropositive men was associated with increased relative risk for disease progression after controlling for confounders.20 The findings of this study were controversial and uncorroborated, and in other studies, zinc supplementation did not show increased disease progression with high doses.19,122
Interaction between antiretroviral therapy and zinc: There is a suggested relationship between AZT treatment and zinc deficiency. In one study, 64 percent of those who were treated with AZT had a deficiency of zinc, compared with 24 percent of those who were not treated with AZT.90 Treated patients not deficient in zinc had significant mitogen response while treated patients who were zinc deficient did not. Mocchegiani et al followed HIV patients on 12 mg elemental zinc supplements daily for 30 days. Eighteen patients were on AZT monotherapy, and 28 were on two nucleoside analogue drugs and one protease inhibitor. Of the 18 patients on AZT, there was a lower risk of opportunistic infections with supplement than without. In patients on three-drug HIV treatment, there was no increased risk of opportunistic infection in those unsupplemented with zinc. These patients also had improved zinc absorption, and higher serum zinc levels that might be attributed to improved intestinal mucosal absorptive function.132
Observational studies show that zinc deficiency is common in HIV infection. It is associated with opportunistic infections, and also with lower CD4 cell counts. The role that correction of deficiency may have in prevention or amelioration of HIV immune deficiency needs investigation in randomized, controlled trials.
Studies have variously reported no deficiency,124 low serum levels in 30 percent to 65 percent of subjects,133,134 and low levels correlated with CD4 cell counts.133 In one study, 59 percent of 64 HIV positive persons in all stages of infection showed deficiency of magnesium unrelated to stage of the disease, compared with 9 percent in HIV-negative controls.25
The results of micronutrient treatment studies are difficult to interpret due to various study designs, doses, lengths of follow-up time, and study outcomes. Serum micronutrient levels are used to characterize micronutrient deficiencies, but they may not be a true reflection of nutritional status. Micronutrient levels are influenced by factors such as gender, time of day of measurement, acute infection, liver disease, technical parameters, and recent intake. There may be interaction between micronutrients,135 and between micronutrients and concomitant antiretroviral drug treatment therapy, making generalization of findings to diverse populations difficult.
It remains unclear if supplementation with micronutrients has any measurable impact on the clinical course of HIV disease. Further research is needed to elucidate clinical benefit of supplementation in different clinical settings, and with different micronutrients. Still, there is considerable collective evidence that nutritional compromise adversely affects the course of HIV disease. It has also been shown that micronutrient supplements may alleviate symptoms, delay progress to AIDS, reduce mortality, accelerate growth in children, improve birth outcomes, and reduce maternal mortality.
Ideally, every individual diagnosed with HIV infection should be screened for micronutrient deficiencies, and a nutritionist consulted, especially in later stages of disease. However, this is not always feasible. Multivitamin and trace element supplements should be considered for all persons with HIV infection. Priestley et al reported that multivitamin supplementation of HIVinfected patients resulted in stabilization of CD4 cell counts and improved survival, compared to survival of patients with similar counts in other studies.136 Rigorous evaluation is still needed with controlled clinical trials.
The routine use of multivitamin supplementation in the general population is considered more beneficial than harmful.137 Thirty percent of the population of the United States takes multivitamin supplements.138 Multivitamin use is also common in the HIV-infected population in North America, and between 63 percent and 73 percent take such supplements.25,139,140 The guidelines of the Institute of Medicine list RDAs and upper limits of micronutrients for different life stages.141 The RDAs of micronutrients are used in the currently available multivitamin preparations. However, RDAs refer to requirements for healthy individuals, and may not constitute appropriate supplementation in HIV infection.
Baum et al showed that even with the consumption of vitamins at or above RDA, deficiencies of vitamins B12, B12, B2, A, C and E may occur in those with HIV infection. They recommended that HIV-infected patients take doses higher than RDA, especially of these vitamins.142 Risk of toxicity of nutrients in HIV infection is not known, and could well be lower than in those not infected. Table 1 shows the specially designed multivitamin and trace element supplement, given with additional natural mixed carotenoids, which is being evaluated in patients with advanced AIDS.74 There is a need to formulate a micronutrient plus trace element supplement for use in HIV infection, with caution against potential toxicities of excessive vitamin A, selenium, and zinc.
There is the possibility of inadequate utilization of the micronutrients in a supplement due to malabsorption. Still, routine use of one of the currently available multivitamins and trace element preparations is advisable for HIV-positive patients until a specific coformulation is developed. This should be considered as adjuvant to conventional antiretroviral therapy, and may prove to be a relatively low-cost intervention.
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