Antioxidants May Still Have a Role in HIV Treatment
Antioxidant nutritional supplements such as vitamins A, C and E have enjoyed great popularity among people with HIV and AIDS for most of the epidemic. That popularity has endured despite continuing confusion about antioxidants' mode of action, effectiveness and safety. In the new era of highly active antiretroviral therapies, antioxidants may get a new lease on life as supportive elements of a regimen that seeks to both suppresses HIV and restore immune function as much as possible with the least toxic side effects.
Suggestive reports go back many years. In 1991, a group of researchers in Munich observed in the test tube that hydrogen peroxide, a very strong oxidant, promotes HIV replication in infected cells by causing the release of a gene-stimulating cellular protein known as nuclear factor kappa B (NF-kB). The addition of the well-known antioxidant N-acetylcysteine (NAC -- see Treatment Issues, March 1997) counteracted this effect.1 The relationship between antioxidant supplements, NF-kB and production of new HIV has since become a constant theme in the antioxidant saga.
HIV thrives in a highly oxidized environment. CD4 cells shift from their resting state into an active state of immune response via a cascade of internal oxidative reactions that ultimately elevates production of proteins and enzymes by increasing transmission of genetic instructions from the cells' genes. This activation signaling also stimulates the HIV genes to reproduce in infected cells while these cells' increased metabolism provides the cellular factors needed to build new virus particles. Activated uninfected CD4 cells are particularly susceptible to invasion and infection by HIV, again partly because of the abundance of molecules the virus needs to convert its genes from RNA to DNA and successfully integrate those genes in the cell's chromosomes.
A by-product of all this metabolic activity is electron-deficient free radicals. These highly reactive molecular entities can damage other molecules by absorbing electrons from them, a type of reaction referred to as "oxidation." Naturally occurring antioxidants -- the enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase; vitamins C and E; and various carotenoids, including vitamin A -- normally protect against this damage by donating their own electrons. But during HIV infection, it has been suggested that an abundance of free radicals are produced in an environment in which the antioxidant compounds are progressively depleted. A state of oxidative stress develops in which immune cells are kept continuously activated and various types of tissue damage occurs. In particular, the membranes on and within the immune cells contain a high percentage of polyunsaturated fatty acids (lipids) that are highly sensitive to oxidation. Free radicals can degrade these membranes and leave important cellular components (including the nucleus) unprotected and susceptible to damage. Cells' genetic material also can come under attack, resulting in mutations.
HIV stimulation aside, researchers have ascribed a very long list of tissue damage to oxidative stress: It is said to compromise immune response by altering cell functions and decreasing cellular proliferation, the movement of cells toward sites of infection (chemotaxis), and the engulfment and digestion of foreign material (phagocytosis).2 The buildup of free radicals also may heighten the inflammatory response through the production of excess tumor necrosis factor (TNF). Free radicals can also increase the incidence of CD4 cell apoptosis (a type of programmed cell death that may be caused by erroneous stimulation and is thought by some researchers to increase drastically during HIV infection). Oxidative stress has also been implicated in HIV-related muscle wasting and weight loss3 as well as dementia and neuropathy.4
In 1995, a French research team studied 95 HIV-positive volunteers for a decrease in polyunsaturated fatty acids (PUFA) and an increase in lipid peroxidation, which the authors considered a sign of oxidative stress.5 Such lipid alterations were noted in study participants with CD4 counts below 400, but no correlation was found between these markers and levels of the antioxidant nutritional components selenium, vitamins A, C and E.
There nonetheless have been a number of studies reported at various congresses and published in peer-reviewed medical journals indicating that deficiencies in antioxidant nutrients lead to more rapid HIV-associated disease progression. A retrospective Johns Hopkins University study published just a few months ago found a 34% decrease in risk of progression to AIDS for men with highest serum levels of vitamin E compared with those in the lowest quartile.6 The report noted that the men taking vitamin supplements had significantly higher levels of vitamin E than those who did not. The study found no association between vitamin A levels, disease progression or vitamin supplementation. But then, 90% of the men under study had normal to high vitamin A levels. This study covered 311 men with HIV enrolled in the Multicenter AIDS Cohort Study (MACS). Like most other studies in this field, it suffered from major limitations. In this case, nutrient intake was evaluated only at baseline -- by questionnaire, which is not a completely reliable method. Disease progression, meanwhile, was followed for the next nine years. Furthermore, in any observational study of this type, it is difficult to sort out possible confounding factors, for example overall health or economic status that might independently affect both vitamin intake and disease progression.
Correlating antioxidant levels with disease progression is not the same as determining that taking extra vitamins will slow that progression by retarding HIV replication in any specific way. Unfortunately, data on the safety and efficacy of antioxidant therapy are usually even more sketchy than those of the Johns Hopkins study, and the medical establishment is reluctant to fund definitive research. For example, the NIH's Community Programs for Clinical Research on AIDS (CPCRA) recently canceled oft-delayed plans to conduct a sorely needed major trial looking at vitamin C supplements. (Beta-carotene was also supposed to be part of the trial at one point, but that aspect of the study was eliminated early in the planning.) The lack of concerted research is a major difficulty since simple errors, such as the wrong dose (too much or too little), insufficient follow-up time or too few trial participants can obscure the benefits to be gleaned from a given agent. Still, as we report below , a significant amount of data has been reported over the last few years regarding the potential benefits of antioxidant supplementation.
Vitamin E may be the most promising of the antioxidants at this point. Interest in vitamin E was greatly increased first by the MACS article cited above and then a month later by an article in the Journal of the American Medical Association that reported on vitamin E supplementation in 88 persons over 65 years old.7 The JAMA authors concluded that vitamin E "enhances certain clinically relevant in vivo indexes of T-cell-mediated function in healthy elderly persons." The trial participants attaining the highest serum vitamin E levels experienced the most improvement.
Vitamin E is a fat-soluble vitamin composed of several tocopherols and tocotrienols; the most biologically active being alpha-tocopherol. The main sources of vitamin E are vegetable and seed oils, including soybean, safflower and corn. Other sources include nuts, sunflower seeds, and wheat germ.8 In cells, a large proportion of vitamin E is found in the membranes and can attach to free radicals to protect the membrane from oxidation. The resulting tocopheroxy radical can then be recycled by vitamin C to be used again.9
Some studies indicate that vitamin E levels are deficient in persons with HIV: University of Miami investigators detected low plasma levels of vitamin E in 18 of 100 HIV-positive volunteers, while all HIV-negative homosexual men were found to have adequate plasma vitamin E levels.10 The researchers measured higher levels of immunoglobulin E (IgE) levels in the men considered vitamin E deficient. They noted that elevation of IgE has been associated with T-cell dysregulation, opportunistic infections andincreases in allergic manifestation in patients with AIDS. Other researchers have correlated a deficiency of vitamin E with a decline in the immune response, supposedly as a result of heightened levels of both the highly reactive oxidant hydrogen peroxide and prostaglandin E2.11 In a study of mice with a murine version of AIDS, vitamin E supplementation seemed to improve the balance of immune cytokines such as IL-2, interferon gamma (both increased) and tumor necrosis factor (reduce d) while increasing immune cell activity.12
Finally, Barbara Abrams and her colleagues at UC Berkeley found intake of vitamin E from supplements was significantly associated with a reduced risk of progression to AIDS among 296 HIV-positive men in the San Francisco Men's Health Study. Those whose vitamin E consumption was in the highest third at the study's time zero were about half as likely to develop AIDS as those with lower intake during the following six years.13 But this study was of similar design to the MACS retrospective study on vitamins A and E and had the same weaknesses.
Beta-Carotene and Vitamin A
Megadosing with beta-carotene was highly popular at one time, but interest in this supplement has recently faded. A member of the carotenoid family, beta-carotene is a pigment molecule found in plants and microorganisms. It has antioxidant activity in its own right, and in the human body, it is converted to vitamin A, whose primary function is to aid in the formation of visual pigment, bone and teeth growth. The role of vitamin A as an antioxidant is not entirely understood, but vitamin A deficiency has been linked to oxidative stress in HIV-positive patients.14 A deficiency of beta-carotene/vitamin A may cause atrophy of the thymus gland and other lymphoid tissue, a decrease in white blood cells and lowered antibody response.15
In a 1993 report of injection drug users with HIV, Richard Semba and colleagues reported that vitamin A deficiency was associated with decreased circulating CD4 cells and increased mortality in people with HIV/AIDS.16 A deficiency of vitamin A has also been correlated with increased vertical transmission from mother to fetus, and increased illness in HIV-infected pediatric patients born to women with HIV who are deficient in vitamin A.17
A positive association between plasma vitamin A levels and dietary intake has been suggested, although adequate intake -- attaining the United States Recommended Daily Allowance (RDA) -- frequently still results in below-normal serum levels, given that malabsorption and increased vitamin metabolism are common among people with HIV.18 When taken in high doses over a long period of time, vitamin A can cause serious liver and skin toxicities. It also has a tendency to cause birth defects. Because of this, beta-carotene is often preferred over vitamin A in clinical studies, given its close relationship to vitamin A and its rather benign toxicity profile (primarily reversible yellowing of the skin).
Some early studies of beta-carotene supplementation in people with HIV/AIDS reported significant increases in immune function. In one case, Oregon Health Science University investigators reported that their placebo-controlled study of beta-carotene supplementation in 21 volunteers with HIV found a statistically significant increase in total white blood cell count, CD4 count and CD4/CD8 ratio due to the vitamin A.19 A second, larger study in 1996 by the same research team failed to duplicate the original findings, but this 50-person, three-month study was not really placebo-controlled. It compared outcomes in those receiving beta-carotene (180 mg/day) plus multivitamins to the results experienced by those receiving only multivitamin supplements.20 The multivitamins themselves contained a substantial amount of Vitamin A (5,000 IU). Although beta-carotene levels in the first group were ten times levels in the other group, vitamin A levels in both groups were the same. This study indicated only that high, pharmacological doses of beta-carotene are no better than more modest doses of vitamin A in terms of blood counts of CD4 and other white blood cells. A 30-person, eight week study presented last winter and a recently presented 14-person, six-week study also detected no viral load or other benefit from six weeks of beta-carotene.21 All but one of the participants in these two studies started with vitamin A levels that were normal or above normal.
These findings contrast with an earlier study by the Johns Hopkins group,22 which observed, among other things, that moderate intakes of beta-carotene and vitamin A, as self-reported by a 281-man MACS subcohort in 1984, were associated with lower disease progression over the next eight years. Men with the highest intake seemed to receive no benefit in terms of disease progression. The group noted that the body tightly controls vitamin A levels, and it is very hard to increase them beyond a certain point. In people who have reached this maximal level, massively consuming beta-carotene does not seem to effect any further suppression of HIV or increase in CD4 count. So high concentrations of vitamin A might inhibit HIV in lab experiments,23 but supernormal levels are not achievable, not to mention tolerable, in the body.
Earlier this year, doctors from the Toronto Hospital in Canada summarized results from a placebo-controlled study24 combining comparatively high dose supplements of vitamin E (800 IU/day) with relatively moderate amounts of vitamin C (1,000 mg/day). After observing 40 volunteers for three months, the investigators observed that the group receiving the supplements had significantly reduced oxidative stress (as measured by such markers as lipid peroxides) compared to those on placebo. The group receiving the vitamins also had an average threefold drop in viral load while those in the placebo group went up threefold, but this trend was not quite strong enough to be statistically significant.
Vitamin E is a well-established antioxidant at this point, but the role of vitamin C (ascorbate, ascorbic acid) still is unclear. One hypothesis is that vitamin C not only helps to neutralize free radicals but also aids in replenishing other antioxidants with electrons, especially vitamin E and glutathione.25
The antioxidant effects of ascorbate have been reported to play a significant role in reducing HIV replication, too. Steve Harakeh and colleagues found that in the test tube, ascorbate lowers HIV reverse transcriptase (RT) activity by more than 99% and p24 antigen levels by 90%.26 The anti-HIV activity was the result of curtailed viral protein production in infected cells and reduced stability of the HIV reverse transcriptase enzyme in extracellular virions. This group, from the Linus Pauling Institute, has consistently argued that vitamin C does not inhibit the activation of HIV genes by NF-kB or similar mechanism, but instead blocks some specific enzyme that HIV requires to complete its lifecycle.27 The Pauling Institute researchers and others have further reported recently on the effect of very high concentrations (up to 500 micrograms/ml) of vitamin C. These researchers claim that the higher concentrations are better in the test tube at inactivating HIV28 or killing infected cells,29 but research on humans with HIV continues to be scarce. One report on various treatments for people with motor disability (paraparesis) associated with infection by HTLV-1 (a virus that is somewhat related to HIV) noted that high dose vitamin C was of only limited effectiveness:30 Only four of 20 patients taking high-dose vitamin C improved compared to 91 of 131 patients receiving the anti-inflammatory steroid prednisolone.
The maximal dose of vitamin C absorbed by the human body is unknown, but it is believed that megadosing of vitamin C can result in kidney stones due to excess acidity. For individuals planning on taking more than 12 grams of vitamin C a day, urine should be regularly monitored for oxalic acid excretion. If oxalic acid levels increase significantly, 50 to 100 mg of vitamin B6 and a magnesium supplement should be given in conjunction with vitamin C to prevent formation of kidney stones. Vitamin C also can cause diarrhea, nausea and cramps. In addition, ultrahigh doses of Vitamin C may upset the acid/base balance in the body, promote the destruction of B12 and interfere with the action of vitamin E.31
Selenium, part of the enzyme glutathione peroxidase, is an essential trace element with antioxidant properties. Selenium may also work synergistically with vitamin E in blocking the rate of lipid peroxidation.32 Foods containing selenium include animal (seafood, meat) and plant sources (grains, seeds); the latter's concentration in food is dependent on the mineral content of soil, which varies geographically. L-selenomethionine is absorbed more efficiently than inorganic selenium and is a less toxic form of the mineral.33 Selenium taken in excess may be immunosuppressive and result in toxicity, with symptoms including loss of hair and nails, skin lesions, nervous system disorders, vomiting and diarrhea.34 Dosages should not exceed 1 mg/day,35 although some nutritionists have cautioned against exceeding a quarter of this amount, 250 mg (microgram)/day.36
In 1996, results from an open-label, non-randomized study of selenium and beta-carotene were published by a group of investigators in Bordeaux, France.37 Forty-five HIV-positive volunteers were enrolled. Over a 12-month period, 18 received placebo, 14 received selenium (100 mg L-selenomethionine every day), and 13 received beta-carotene (60 mg/day). The volunteers were checked every three months for changes in antioxidant enzyme concentrations (superoxide dismutase, glutathione peroxidase, and catalase) and plasma levels of selenium. Significant increases in glutathione peroxidase were associated with selenium supplementation but not with beta-carotene supplementation. In contrast, both selenium and beta-carotene were associated with significant increases in overall glutathione status after 12 months of therapy.
This spring German investigators reported on a small study that measured changes in actual immune parameters as well as antioxidant enzyme levels.38 Twenty-four volunteers received N-acetylcysteine (600 mg thrice daily) and sodium selenite (500 mg/day) for either 12 or 24 weeks. The results were equivocal with no definite pattern emerging.
Clinical and immunological efficacy studies of selenium are limited, at best. Back in 1989, one small, uncontrolled study provided open-label selenium supplementation of 400 mg to HIV-positive patients in the form of selenium yeast.39 Of 19 patients studied, 14 reported subjective improvements in clinical symptoms, including decreased cramping, improved appetite and improved neurologic and psychological changes. One patient reported deteriorated health, and three had a decrease in appetite.
Zinc is a mineral that is necessary for protein and energy metabolism, as well as DNA and RNA synthesis. Zinc appears to be essential for T-cell differentiation and maturation as well as lymphocyte activation.40 A few studies have reported lower levels of zinc in individuals with HIV or AIDS. The University of Miami group found a higher percentage of HIV-positive homosexual men to have low plasma zinc levels in contrast to HIV-negative homosexual men.41 The investigators also observed that normalization of plasma zinc levels was linked to slower disease progression in both AZT-treated and untreated individuals.
A number of studies using small patient populations have demonstrated modest improvements in lymphocyte counts, CD4/CD8 ratios, body weight and quality of life.42 But the only data from a large pool of study subjects, reported on 281 men from the MACS cohort,43 suggest that high zinc actually speeds up disease progression. Higher consumption of zinc from food and supplements was associated with poorer survival, despite the fact that approximately 50% of the subjects had zinc intake levels significantly less than the RDA. Study participants who were taking zinc supplements at baseline had a 50% greater chance of dying during the eight-year observation period.
If this observation is accurate, the reason may lie in the essential functions zinc performs in HIV's lifecycle (involving the packaging of genetic material in new virions and, later on, the integration of HIV genes into those of uninfected cells.) Further research is needed to establish the optimum levels of zinc in individuals infected by the virus.
Thioctic acid, also known as alpha-lipoic acid, is a natural, thiol (sulfur-containing) antioxidant that has a potent neutralizing effect on many free radicals. The compound is used extensively in Europe as a treatment for such toxic effects as mushroom poisoning, radiation sickness, alcoholic hepatitis and diabetic neuropathy.
Suzuki and Packer treated an HIV-infected human T-cell line with thioctic acid. Complete inhibition of NF-kB activation was reported using approximately two-thirds of the dose used in clinical practice, and a quarter of that needed to produce the same effect with N-acetylcysteine.44 These investigators concluded by anticipating that "antioxidants which eliminate [oxidizing free radicals] should block the activation of NF-kB and subsequently HIV transcription, and thus antioxidants can be used as therapeutic agents for AIDS." And, in fact, thioctic acid has also been found to inhibit HIV infectivity and replication in laboratory cell lines.45
In an open and unblinded pilot study of thioctic acid's effects on humans, the short-term effect of thioctic acid (600 mg/day) was investigated in ten HIV-positive volunteers.46 Compared to baseline values, thioctic acid significantly increased plasma ascorbate in nine of ten study participants, total glutathione levels in seven of ten, and total plasma thiol (a class of organosulfur compounds that includes glutathione and thioctic acid) in nine of ten. A trend toward increased CD4 lymphocyte counts and decreased lipid peroxidation occurred, but was not deemed statistically significant. The same group of investigators is now conducting a blinded, controlled study of thioctic acid in HIV-infected subjects in Germany.
Thioctic acid is sometimes available in the United States as an over-the-counter supplement of uncertain quality. The German pharmaceutical-grade product can be ordered through the PWA Health Group, a buyer's club in New York (telephone: 212/255-0520). The cost is $75 for a 60-day supply. Most demand for the product apparently comes from people interested in protecting themselves against drug-induced liver toxicities rather than further suppressing HIV.
Lecithinized Superoxide Dismutase
Superoxide dismutase (SOD), one of the more potent antioxidants produced by the body, is slowly but surely making itself known as a dietary supplement. Lecithinized superoxide dismutase, commonly referred to as PC-SOD in scientific literature, is a synthetic version of the natural compound. Japanese scientists have carried out a number of laboratory studies of PC-SOD. They describe PC-SOD as basically a SOD "prodrug." According to two studies conducted by Rie Igarashi and colleagues at Kagoshima and St. Marianna Universities in Japan, PC-SOD enhances SOD's antioxidant activity, both by elevating levels of SOD and increasing SOD's activity.47 The same Japanese group reported further this spring that PC-SOD was found to pack a powerful punch against HIV replication in vitro.48 When PC-SOD was added to test tubes containing HIV-infected cells, replication of HIV was halted. The reason for this effect is not yet understood as virus-cell binding, DNA and RNA synthesis, and reverse transcriptase and protease enzyme activity could still be seen. This study also demonstrated PC-SOD to be synergistic, albeit under laboratory conditions, with AZT, ddI, ddC, Kyoto Pharmaceutical's protease inhibitor KNI-272 and dextran sulfate. The authors of the study advocated proceeding with human trials.
Without a doubt, vitamins and minerals offering antioxidant support to HIV-infected immune systems still remain, for the most part, controversial. Research data are conflicting and most studies completed and now underway suffer from a lack of rigor. Nonetheless, data supporting nutritional supplementation continue to mount. No one vitamin is probably any good on its own, but each probably complements the others. It is still not known how to effectively administer single vitamins as medicine, and caution needs to be exercised when taking large amounts -- the use of vitamins in high pharmacological doses is still poorly documented. It is worth recalling that participants in the UC Berkeley study cited above, who at baseline were taking just daily multivitamins also had a reduced risk of AIDS and low CD4 count when the study commenced.49 There is an important distinction between the pharmacologic use of high dose antioxidants as antiviral medicine and the lower dose administration of nutritional support of the immune response to HIV. The latter seems logical and is supported by observational studies, but the utility of nutritional supplements in directly suppressing HIV remains controversial.
Before investing a large amount of money in many different products, it may be wise to consult with a nutritionist regarding your own blood work. Of course a healthy diet is the best way to insure proper nutrient intake, since it contains many nutrients not available in pills. But people with HIV frequently have depleted levels of many important vitamins and antioxidants, and such individuals may well require additional supplementation. Especially in the age of protease inhibitors, when megadoses of vitamins need not be used as desperate measures, taking a multivitamin to supplement an effective antiviral combination may be healthful and beneficial.
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This article was provided by Gay Men's Health Crisis. It is a part of the publication GMHC Treatment Issues. Visit GMHC's website to find out more about their activities, publications and services.