The time to development of AIDS in individuals infected with HIV-1 varies considerably between individuals. The median incubation period for AIDS has been estimated at approximately 10 years . However, the range is large, with some patients progressing to AIDS within 2 years of infection whereas others may remain AIDS-free for 15 years or more [1,2]. Both viral factors and the host immune response to HIV-1 appear to be important in influencing the length of time between infection and the onset of AIDS . HIV-1 infected individuals with non-progressive disease (those who remain healthy with stable CD4+ cell counts) are thought to be infected with less virulent HIV strains or may have the ability to mount a highly effective immune response .
Nutritional status has been hypothesized to be a potential cofactor which could modify the course of HIV-1 disease progression through its effects on immune function [5,6]. Vitamins A and E are both important for optimal functioning of the immune system . Deficiencies of these vitamins have been found to impair immune responses in a variety of studies [7,8]. There is ample evidence from both human and animal studies that supplementation with vitamins A and/or E enhances immunity and resistance to various infectious diseases [7–13]. Previous studies have found significant proportions of HIV-1-seropositive individuals with low serum levels of either or both vitamins [14–18]. Low serum levels or low intakes of vitamin A in HIV-1 infection have been associated with lower CD4+ cell counts , increased maternal-fetal transmission , increased mortality from AIDS or infections , and increased risk of progression to AIDS . Low serum vitamin E levels in HIV-1-infected individuals have been correlated with a higher degree of lipid peroxidation , increased p24 antigenemia , decreased plasma levels of polyunsaturated fatty acids , and increased plasma immunoglobulin (Ig) E levels . Supplementation with vitamins A and E has been shown to improve immune parameters in several murine AIDS models [10,24–26]. There is also evidence that vitamin A supplementation in children with HIV-1 may decrease diarrhoeal symptoms .
In this study we examine the association between serum levels of vitamins A and E and subsequent disease progression in a cohort of HIV-1 infected homo-/bisexual men.
Eligible subjects were 341 men who were HIV-1 seropositive upon enrollment into the Baltimore/Washington, DC site of the Multicenter AIDS Cohort Study (MACS), a prospective study on the natural history of HIV-1 infection in homosexual and bisexual men. The objectives, design and recruitment protocol of the MACS have been described elsewhere . Of those who were eligible, 312 (91%) had serum available in the repository from their 1984 baseline study visit. The remaining HIV-1-seropositive individuals (n = 29) did not differ significantly with respect to age, race, education, cigarette smoking, CD4+ cell counts or weight (data not shown). Concentrations of vitamins A and E were estimated for 311 of the 312 subjects.
Levels were determined using high performance liquid chromatography procedures . The stability of vitamins A and E in sera stored for long periods of time has been examined in several studies and results have indicated that under optimal storage conditions, both vitamins can be quite stable for periods of several years and through several freeze-thaw cycles [30–33]. Serum albumin and C-reactive protein (CRP) levels were assessed in 308 of the subjects (by Dr Ranjit Chandra, St John's University, St John's, Newfoundland, Canada, 1993). Serum albumin concentrations were determined using a colorimetric assay, with normal range designated as 35–50 g/l. The CRP levels were determined using an enzyme-linked immunosorbent assay (ELISA). Levels below 8.0 mg/l were considered to be normal while levels ≥ 8.0 mg/l were considered to be elevated.
The majority of variables used in these analyses were based on data collected at each subject's baseline clinic visit. Usual dietary intake was assessed at baseline using a self-administered, semiquantitative food frequency questionnaire . Subjects were asked to estimate their frequency of consumption of each of the 116 food items, in terms of a typical portion size, over the previous 12 months. Nine frequency categories were available to choose from, ranging from ‘never or less than once per month’ to ‘more than six times per day’. The questionnaire also had sections for recording the brand name, frequency and amount of vitamin supplements taken, a write-in section for foods not listed, and questions on the exact brands and types of fat used for frying, cooking and baking. Completed questionnaires were reviewed and coded by a trained researcher and entered into computer data files. Estimates of food intake and total intake (food and supplements combined) of vitamins A and E were determined using the nutrient analysis program developed specifically for the questionnaire .
HIV-1 serostatus was determined by enzyme immunoassay (Genetic Systems, Seattle, Washington, USA) and a Western blot test (DuPont Co., Wilmington, Delaware, USA and Bio-Rad, Hercules, California, USA) with interpretation using standard criteria. Subjects were divided into three categories based on their CD4+ cell numbers at study entry: < 500, 500–750 and > 750 cells × 106/l. These categories were formed to give approximately equal numbers of men in each category. Those who were missing data on CD4+ counts at their baseline visit (n = 32) were assigned to one of the three categories based on data from subsequent adjacent semi-annual visits. It was possible to estimate the appropriate CD4 category for these individuals since the mean CD4+ cell decline in the cohort was 30 cells × 106/l per 6 months.
Body mass index was calculated as weight/height2. HIV-related symptoms were defined as the presence of one or more of the following most commonly reported symptoms lasting a period of 2 or more weeks: persistent/recurring fever > 37.8°C, persistent diarrhoea, oral thrush, persistent fatigue, and/or unintentional weight loss of 4.5 kg. Frequency of alcohol consumption was based on the variable ‘how often do you drink now?’ which was originally coded into eight categories ranging from ‘one to five times/year’ to ‘at least once/day’. For analyses, this variable was collapsed into two categories: less than or equal to two times per week and more than twice per week. For 23 subjects who were missing this data at their baseline visit, values from their next study visit (approximately 6 months later) were substituted. Subjects were placed into one of two categories based on their smoking status: either non-smokers or regular/occasional smokers.
Treatment variables were obtained from data collected over the follow-up period of the study. For the analyses, two binary treatment variables were created indicating ‘ever’ or ‘never’ use of antiretroviral drugs (zidovudine, didanosine, zalcitabine) and Pneumocystis carinii pneumonia (PCP) prophylaxis (aerosolized pentamidine, trimethoprim-sulfamethoxazole, dapsone) before the onset of AIDS.
The cutoff date for analysis was 31 December, 1993, slightly more than 9 years after the beginning of the Baltimore MACS. Three outcomes were examined in this study including time from baseline study visit to first AIDS diagnosis, time from baseline to death, and time from baseline to first CD4+ cell count < 200 cells × 106/l. AIDS diagnoses were based on the 1987 revision of the Centers for Disease Control surveillance case definition . Mortality data were obtained from physicians' reports, hospital records, and death certificates. CD4+ cell counts were measured at every 6-month follow-up visit.
Proportions of subjects with low serum vitamin A and vitamin E levels were determined according to cutoffs derived from the laboratory standards. All of the independent covariates were examined for their associations with serum vitamin A and E levels using Student's t tests for continuous variables and χ2 tests for categorical covariates. Univariate associations between serum micronutrient levels and each of the three outcomes were assessed using the non-parametric Kaplan-Meier product-limit method and the log-rank test. The logrank test was also used to examine associations between the covariates and disease progression.
Cox proportional hazards models were used to adjust for covariates found to be either associated with serum micronutrient levels (P < 0.15) or independent predictors of progression in the previous analyses. Variables that did not produce significant changes in the model estimates were eliminated using a step-down procedure. Serum nutrient levels were entered into the models as binary variables (low versus adequate levels) and in quartiles. All independent covariates were entered into the models as categorical variables. Separate Cox proportional hazards models were fit for each micronutrient.
Spearman rank-order correlations were used to examine the linear associations between serum nutrient levels and intake from food and vitamin supplements. The Wilcoxon rank-sum test was used to compare median serum nutrient levels between current and past/never users of multi- and single-vitamin supplements.
Table 1 shows the characteristics of the 312 eligible men in the study. The mean age of the study population at baseline was 34 years (range: 30–65). The mean CD4+ cell count was 643 ± 314 cells × 106/l with only 11 men (4%) having CD4+ cell counts below 200 cells × 106/l. Although most of the men (81%) were in the asymptomatic stage of their infection, 55% had elevated serum CRP levels (≥ 8.0 mg/l) and 71 (23%) had low serum albumin levels (< 35 g/l).
Over the 9-year follow-up period, 163 men (52%) progressed to AIDS, 162 (52%) died, and 180 (58%) reached a CD4+ cell count of lower than 200 cells × 106/l. First AIDS diagnoses were predominantly due to PCP (35%) and Kaposi's sarcoma (25%), followed by Candida albicans (8%) and Mycobacterium avium-intracellulare complex (6%). Wasting syndrome and dementia were the first AIDS diagnoses for seven (4.3%) and five (3.1%) of the subjects, respectively. Eighty-one per cent (n = 132) of the deaths were attributed to AIDS.
Table 2 summarizes the serum and dietary intake levels of vitamins A and E for the 311 subjects. Mean and median serum levels were within the normal range for both vitamins. Thirty-one subjects (10%) had serum retinol levels below 1.40 µmol/l, and only seven (2%) had levels below 1.05 µmol/l. Twenty-nine per cent of subjects had total intakes of vitamin A (including vitamin supplements) below the recommended dietary allowance (RDA), and 27% had total vitamin E intakes below the RDA.
Subjects with low vitamin E levels (< 11.6 µmol/l) were more likely to be non-whites (χ2P-value = 0.02), not have a college degree (χ2P-value = 0.007), and not to have used antiretroviral drugs before the onset of AIDS (χ2P-value = 0.07).
No significant difference was observed in risk of AIDS progression between low versus adequate serum vitamin E levels in univariate analyses (Table 3). There was also no significant difference in risk of AIDS progression when comparing those in the lowest quartile of serum vitamin A (< 1.82 µmol/l) with those in each of the upper three quartiles. When vitamin E levels were examined by quartiles, however, a monotonic decrease in risk of progression to AIDS was observed with increasing serum vitamin E levels. The risk of progression to AIDS in the highest quartile of vitamin E level was 35% lower than the risk in the lowest quartile [(relative hazard (RH), 0.65; 95% confidence interval (CI), 0.42–1.02)]. In Kaplan-Meier analyses, median AIDS-free time for subjects in the highest quartile of serum vitamin E level was approximately 1.5 years longer than those in the lower three quartiles combined (logrank P-value = 0.07). There was also an approximate 1 year difference in median survival time between those in the highest quartile of vitamin E level compared to the lower three quartiles combined (log-rank P-value = 0.10). No differences were observed in the proportions of subjects whose CD4+ cells declined to < 200 cells × 106/l for either vitamin A or vitamin E (data not shown).
Multivariate analyses of serum nutrient levels and HIV-1 disease progression
In order to examine the independent effect of serum nutrient levels on HIV-1 disease progression, Cox proportional hazards models were used to adjust for known and putative confounders. Variables which were associated with AIDS diagnosis, mortality, CD4+ cell decline and/or serum micronutrient levels (P < 0.15) were entered as covariates into the Cox models. These included HIV-1 related symptoms, CD4+ cell count, age at baseline, serum albumin, serum CRP use of antiretroviral therapy before AIDS, and frequency of alcohol consumption. Serum albumin and CRP levels were subsequently dropped from the Cox models as they did not produce significant changes in the model estimates for any of the three outcomes.
Older age was strongly and independently associated with an increased risk of progression to AIDS, mortality and CD4+ cell decline. Higher CD4+ cell counts, more frequent alcohol consumption, and use of antiretroviral therapy before the onset of AIDS were all significantly and independently associated with a decreased risk of progression to AIDS, mortality, and CD4+ cell count decline. The presence of HIV-1-related symptoms at baseline was significantly associated with an increased risk of progression to AIDS and CD4+ cell decline, but not with mortality.
The last column of Table 3 shows the adjusted hazard ratios comparing low versus adequate serum Vitamin levels, and quartiles of serum vitamin A and E levels. For quartiles of vitamin A, there was no apparent relationship between serum levels and progression to AIDS. For vitamin E levels, however, the risk of AIDS remained lower for the highest quartile compared with the lowest quartile (RH, 0.66; 95% CI, 0.41–1.06). This effect was again statistically significant when comparing the highest quartile of serum vitamin E with the remainder of the cohort (RH, 0.67; 95% CI, 0.45–0.98). Similar trends, although not statistically significant, were observed for each vitamin when survival was used as the outcome. In these survival models, we also adjusted for use of antiretroviral therapy after the onset of AIDS, but observed no significant changes in the RH. Furthermore, no significant trends were observed when CD4+ cell decline to < 200 cells × 106/l was used as the outcome (data not shown).
Association between serum nutrient levels and self-reported nutrient intake
Data concerning food and supplemental intake of vitamins A and E were available for 271 of the 311 subjects. Those who completed and returned the self-administered food frequency questionnaire were more likely to be non-smokers (χ2P-value = 0.001), to have a college degree (χ2P-value = 0.002), and to be older (Student's t test P-value = 0.02) than those who did not return the questionnaire. There were no differences in those who did and did not return the questionnaire with respect to the other independent variables, AIDS progression, mortality or CD4+ cell decline.
Spearman's correlations were weak and non-significant between serum vitamin A levels and vitamin A intake from food alone (r = −0.02, P = 0.72) and from food and supplements combined (r = 0.02, P = 0.74). Whereas the correlation between serum vitamin E level and vitamin E intake from food alone was weak (r = −0.06, P = 0.29), the correlation between serum vitamin E level and total vitamin E intake was stronger and statistically significant (r = 0.30, P = 0.0001).
Table 4 shows the median serum micronutrient levels according to use or non-use of single and/or multi vitamin supplements. Subjects who reported current use of multivitamin or single vitamin A supplements (n = 167) had only a slightly higher median serum vitamin A level than the 104 past/never users. However, current users of multivitamin or single vitamin E supplements (n = 170) had a significantly higher median serum vitamin E level than past/never users (n = 101).
We examined the associations of serum levels of vitamins A and E with three key outcomes in the course of HIV-1 disease progression: development of first AIDS diagnosis, CD4+ cell decline to < 200 cells × 106/l, and mortality. The results of this study showed that subjects in the highest quartile of serum vitamin E levels (≥ 23.5 µmol/l) had a 35% decrease in risk of progression to AIDS compared with those in the lowest quartile, after adjusting for several covariates. A dose-response relationship was evident in univariate analyses. Similar trends were observed for both vitamins when mortality was used as the outcome, but serum levels of neither vitamin were associated with CD4+ cell decline to < 200 cells × 106/l.
Previous studies have measured serum levels of vitamin E in HIV-1-infected patients, but ours is the first study to demonstrate a link between increased serum tocopherol levels and decreased risk of progression to AIDS. The prevalence of overtly or marginally low serum vitamin E levels has been documented to range between 8% and 20% in studies of HIV-1-positive individuals [14–16,36–38]. None of these studies have examined the consequences of low serum vitamin E levels on HIV-1 disease progression nor have the mechanisms leading to vitamin E depletion during HIV-1 infection been clearly elucidated. In this study we found that 22% of our population had low concentrations of serum vitamin E (< 11.6 µmol/l), but we found no apparent relationship between low vitamin E levels and risk of progression to AIDS. Instead, we found that subjects in the highest quartile of serum tocopherol levels (≥ 23.5 µmol/l) demonstrated a significant decrease in risk of progression to AIDS compared with those in the lower three quartiles combined.
The effects of various states of vitamin E nutrition on immune function and the potential benefits of vitamin E therapy in HIV-infected patients have been reviewed in several published articles [12,13,39]. The majority of evidence put forth by these reviews suggests that vitamin E is not only necessary for proper functioning of the immune system, but also has important immunostimulatory properties. Studies in both humans and animal models have shown that vitamin E supplementation, in approximately two- to 10-fold excess of the recommendations, significantly increases humoral and cell-mediated immune responses to antigens and enhances phagocytic functions . More specifically, high doses of vitamin E along with a nutritionally adequate diet has been repeatedly shown to enhance in vitro and in vivo antibody production, phagocytosis, lymphoproliferative responses, and resistance to viral and infectious diseases . Studies in the elderly have examined the effects of vitamin E supplementation on immune dysfunctions associated with the ageing process [9,40]. Daily supplementation of healthy elderly individuals with 800 mg dl-α-tocopheryl acetate for 1 month significantly improved delayed-type hypersensitivity reactions and enhanced in vitro response to the mitogen, concanavalin A . Other epidemiological studies in the elderly have found lower incidences of cancer and infectious diseases in those who maintain high plasma vitamin E levels [40,41].
In a recent study , the effects of dietary vitamin E supplementation on immune dysfunctions were examined in mice with murine AIDS, a retrovirus-induced infection similar to human AIDS. In this study, infected mice treated with vitamin E showed an increase in secretion of interleukin (IL)-2 and interferon (IFN)-γ, and an improvement in mitogenesis of splenocytes and natural killer cell activity compared with retrovirus-infected, but non-treated mice. At the same time, vitamin E supplementation was associated with a reduction in levels of IL-4, IL-5, IL-6, and tumour necrosis factor (TNF)-α, cytokines which were elevated in non-treated mice which had murine AIDS. This suggests that vitamin E supplementation may serve to normalize the immune abnormalities observed in murine retrovirus infection. Whether or not these results can be extrapolated to human HIV-1 infection, however, remains unclear.
Another mechanism by which vitamin E enhances immune functions is through its antioxidant properties. Rapidly proliferating cells of the immune system are highly susceptible to peroxidative damage by free radicals, peroxides and superoxides . Vitamin E acts as a free radical scavenger and prevents the lipid peroxidation of cell membranes. Vitamin E also modulates the production of prostaglandin E2 (PGE2) in the body. Elevated levels of PGE2 decrease the production of IL-2, a cytokine critical for the growth and differentiation of T and B lymphocytes, and increases the differentiation of PGE2-receptor-bearing T-cells into T-suppressor cells. PGE2 also inhibits activation of natural killer cells, which are a major source of IFN-γ, another important cytokine in the host defence system. It is believed that downregulation of PGE2 by vitamin E serves to increase the production of IL-2 and IFN-γ, thereby stimulating the immune system. Other proposed actions of vitamin E on the immune system are through its direct interaction with macrophages, causing upregulation of IL-1 and IL-2. Vitamin E is also believed to decrease levels of TNF-α through its antioxidant properties. Thus, in addition to its role as a free-radical scavenger, the impact of vitamin E on the regulation of various cytokines in the immune process is believed to play a major role in inhibiting HIV-1 replication.
The results of our study support the hypothesis that these immune-enhancing effects of vitamin E may delay the onset of AIDS in HIV-1-infected individuals. The strong correlation between vitamin E supplementation and increased serum vitamin E levels in our subjects suggests that oral vitamin E therapy may be beneficial in slowing progression to AIDS, even in nutritionally-replete populations.
Vitamin A is essential for many aspects of immune function, including both B- and T-cell growth and function. In animal models, vitamin A deficiency has been associated with diminished resistance to infections , reduced antibody responses to diphtheria and tetanus toxoids , and decreased lymphocyte responses to mitogens [7,43]. In humans, the morbidity and mortality of many infectious diseases (e.g. measles, pneumonia and diarrhoea) have been associated with low vitamin A status [8,44–46]. Studies of serum vitamin A levels in HIV-1-infected populations have found that levels below 1.05 µmol/l are commonly observed, with prevalence generally ranging from 10–20%. Semba et al.  showed that low serum vitamin A levels in HIV-1-infected mothers were significantly associated with a three- to fourfold increase in rates of transmission of HIV-1 to their infants and that HIV-1-infected mothers whose infants died before reaching 1 year of age had the lowest serum vitamin A levels. In another study by Semba et al. , low serum vitamin A levels (< 1.05 µmol/l) were significantly associated with a four- to fivefold increase in risk of mortality from AIDS and infections in a population of adult injection drug users. Since biological function is thought to be compromised when serum retinol levels fall below 1.05 µmol/l , we did not have large enough numbers to examine associations with HIV-1 disease progression in this lower range. The vast majority of our subjects had retinol levels in the high-normal range (median = 2.44 µmol/l) so it is not surprising that we found no relationship with disease progression. These data, taken with other studies of retinol status in HIV-1 and other infectious diseases suggest that the risk only significantly increases in those with frank or marginal deficiency [17–19]. Furthermore, given individuals with increased serum CRP levels, we still had a vitamin A-replete population, which shows that better vitamin A nutriture can protect against drops in serum retinol into the deficient ranges seen in the acute phase response.
As might be expected since plasma vitamin A levels are homeostatically controlled and do not tend to fluctuate with dietary intake, we found little association between serum vitamin A levels and vitamin A intake from food and/or supplements in our subjects. In a previous study of dietary intake in this population , we found that high vitamin A intakes were not associated with a decreased risk of progression to AIDS, wheras moderate intakes were associated with an approximate 40% decrease in risk of AIDS progression.
We compared serum nutrient levels from our population with those from studies of other HIV-1-infected populations in order to determine if concentrations fell within the range of those measured from fresh sera of comparable populations. The mean vitamin A level in our study population (2.62 ± 1.08 µmol/l) was, in fact, higher than the mean vitamin A levels found in most other published studies of HIV-1-seropositive populations [14–18,22,38,47,48]. The mean vitamin A levels in these studies ranged from 0.91 µmol/l to 4.54 µmol/l, with only one study  reporting vitamin A levels above the mean level found in our subjects. The mean vitamin E level in our study population was 19.4 µmol/l, which is in the range reported by most studies [14–16,21–23,38,49].
In conclusion, the results of this study suggest that elevated serum levels of vitamin E were associated with a subsequent decrease in risk of progression to AIDS and mortality. High serum vitamin E levels were strongly associated with current use of multi- or single-vitamin E supplements, indicating that vitamin E supplementation may be beneficial in slowing the risk of progression to AIDS. Higher serum vitamin A levels were not associated with intake of vitamin A supplements in this study, however. These data suggest that vitamin E supplementation trials should be considered in HIV-1 infected individuals given the non-toxic nature of the vitamin, its potential therapeutic effects, and the relative sensitivity of serum levels to supplementation.
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