Note: for more information on the use of nutrients in AIDS medical treatment,
please see our Index of AIDS Treatmentsand its file on nutrients.

Introduction

Vitamins are a diverse group of chemically unrelated compounds, present in food at minute levels, that are necessary for normal human function. By definition, the deficiency of a vitamin causes disease. Minerals are also critical to human life in minute amounts and they differ from vitamins only in that they are inorganic. (Organic in this case refers to the chemical meaning "composed of carbon," not "grown naturally" in the popular sense.) This article reviews basic background information on vitamins and minerals and examines several individual vitamins that are frequently discussed in the context of HIV.

Vitamin Requirements

An adequate diet supplies all required vitamin and minerals to a healthy individual. However, vitamins and minerals are unevenly distributed among different food sources. The 1976 Nationwide Food Consumption Survey estimated that most Americans obtain over 80 percent of their vitamin intake from 50 to 200 foods. As a result, several "core foods" have been identified that are particularly rich sources of vitamins. (See table I below.)

Vitamin and mineral requirements are established in the United States by the Recommended Daily Allowance (RDA) guidelines, a familiar item on food and dietary supplement labels. Contrary to popular belief, the RDA is not developed for prescriptive use nor do they establish target vitamin and mineral intakes for individuals. Wide individual variation exists in vitamin and mineral requirements. The RDA only provides standards for population studies of nutritional status and reference values for food labeling. The RDA is the upper limit of a range of values which has a highest probability of fulfilling the nutritional requirements of most Americans. Any one individual may have a unique requirement within the range of intakes. There is a very small probability that an individual will have a required intake above the RDA level.¹

The RDA is established in populations of healthy, normal subjects. It is unknown if vitamin and mineral requirements differ substantially in a population of people with HIV, although infection may impact vitamin requirements, according to studies of other populations.

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Biology Poorly Established

Although most vitamins were discovered over 50 years ago, still very little is known about their biological role. Vitamins are clearly essential to life, yet the full range of their biological effects and their mechanism of action is poorly established. Nutritional immunology (the study of the role of vitamins and minerals in immunity) is still in its infancy and many unanswered questions remain. For instance, Vitamin A has a well characterized role in vision, where it serves a critical function as a signal mechanism between the retina and the initiation of nerve impulses. (Vitamin A deficiency, considered one of the most serious nutritional public health problems in the world, is the leading cause of preventable blindness, primarily among children in high risk areas, such as India and east Asia.) Yet vitamin A also has a role in cell differentiation and thus is important in immunity, although it is poorly understood. Furthermore, the biological connection between specific vitamin deficiencies and their diseases is also unknown. For example, riboflavin deficiency clearly causes cracked lips and tongue, but the biological pathway that leads to these symptoms is unknown. More puzzling still, vitamin deficiency diseases seem to manifest themselves differently in different parts of the world for unknown reasons. For instance, thiamin deficiency is primarily associated with peripheral nerve disease in Asia, but central nerve disease in the Western hemisphere. Much progress is needed in understanding the biological role of vitamins.

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HIV-Related Deficiencies

Studies of nutrient levels in people with HIV find that they are either depleted, increased, or unchanged. These studies are difficult to interpret since they were not performed in a uniform manner and were often inadequately controlled. It is important to note that the literature on vitamin deficiencies does not even point in a consistent direction. Most discussion of vitamins, however, center on research that suggests nutrients are depleted, rather than unchanged or increased.

Overt signs of severe vitamin deficiency can be detected by clinical examination. However, most reported vitamin deficiencies in people with HIV are mild and subclinical, based primarily on variations from population norms in laboratory diagnosis. There are several confounding factors to consider when interpreting this level of deficiency.

Population norms of vitamin levels are sometimes based on estimated values, and thus may not be accurate. People with HIV may constitute a distinct population and may have different vitamin requirements than the normal, healthy population. Several studies indicate that metabolism may be altered in HIV disease, possibly changing nutrient requirements. However, no studies have been performed that demonstrate unique nutrient requirements in people with HIV.

Correlating mild deficiencies to clinical signs or increased risk of disease is difficult and poorly established. According to the published reports, mild laboratory-diagnosed deficiencies may indicate early signs of progressive malnutrition, a response to specific infections, nutrient-drug interactions, altered metabolism, inadequate diet, or random errors on imperfect lab tests. Although all these conditions have been documented in people with HIV, it is unknown to what degree they each contribute to specific nutrient deficiencies on an individual level.

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Diagnosis

Diagnosis for most mild vitamin and mineral deficiencies is technically complex and may be open to considerable variation among laboratories. There are two distinct methods of biochemical diagnosis of vitamin deficiencies. One method involve examining vitamins (or their metabolites) in blood, urine, or tissue samples. These levels are compared with a population reference range for the nutrient, which, as described earlier, may or may not reflect the nutrient needs of HIV-infected people.

The other method of diagnosis involves loading tests of vitamins and tests of enzymatic function. While these tests do not need population reference ranges, and are considered more reliable by some, they are routinely available. The acute phase response (APR) may also affect observed vitamin levels. The APR is a set of metabolic changes, induced by cytokines (immune chemicals) such as Interleukin-6 (IL-6) and Tumor Necrosis Factor (TNF), which naturally occur in response to infection, cancer, or inflammation. Observed nutrient may be considerably altered during the APR because they are sequestered in intracellular compartments. Whether deficiencies observed during the APR are functional or just signs of altered vitamin metabolism and circulation is unknown.

Hair analysis is a method of diagnosis used by some physicians and alternative health practitioners. However, hair analysis is not an established, validated method for clinical practice. It is primarily a research tool and may have some use detecting heavy metal poisoning in populations. Hair analysis is not reliable for individual nutrient analysis for several reasons. Vitamin and mineral levels in hair have not been correlated to the clinical or biochemical condition in the body. Hair care products and other environmental factors may also impact vitamin and mineral levels in hair. Furthermore, some reports suggest that hair analysis laboratories are not standardized, with wide variation among them. At its worst, some authors suggest that hair analysis is more a marketing tool than a method of diagnosis. In some cases, even healthy people are told to purchase many types of vitamin supplements based on hair analysis diagnosis of "deficiency."

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Vitamin Supplementation

At present, there is no convincing evidence that vitamin and mineral supplements positively impact on progression of disease or death in people with HIV. No well-controlled studies have examined the relationship between supplements and disease in people with HIV. Universal recommendations for specific supplementation regimens in people with HIV are, therefore, based on speculation and uncontrolled anecdotes.

The presence of a vitamin or mineral deficiency does not imply that supplementation will correct it. Deficiencies may be caused by many factors, including some which may not respond to supplementation. HIV-induced metabolic changes or malabsorption can result in vitamin deficiency, although they will not respond to supplementation. Importantly, several studies demonstrated vitamin and mineral deficiencies in people with HIV although the subjects ate properly and, in some cases, even took supplements. Furthermore, correct vitamin and mineral doses are not been established to correct specific levels of deficiency.

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Mega-Dosing

Beneficial claims are frequently for very large doses of vitamins ("mega-dosing"), often hundreds or thousand times higher than nutritionally required levels. Using vitamins in this manner is more similar to drug therapy than nutrition, and should be considered in pharmacological terms. Some "mega-doses" of vitamins may have legitimate pharmacologic uses, although none have been demonstrated for HIV disease. Certain vitamins, like Vitamin A and Vitamin D, produce very serious toxicities not far above their nutritionally required levels. Other vitamins, like Vitamin E, appear to have no upper limits for safe consumption. (See table II below.)

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Vitamin A and beta-Carotene

Vitamin A (and beta-Carotene - a pro-vitamin that is converted into vitamin A by the body), first discovered in 1915, is found in both animal and plant products. Vitamin A has a role in many physiological functions, including reproduction, skin, vision, the immune system, and bone. Vitamin A deficiency can cause numerous non-specific signs, although nyctalopia and xerophthalmia (two diseases of the eye) are the best described syndromes. Vitamin A deficiency is considered extremely rare in the developed world because many common foods, including margarine, are fortified with the vitamin, and because the body can store Vitamin A successfully in the liver and intestine for long periods of time, compensating for periodic deficiencies. Diseases associated with vitamin A deficiency occur only after prolonged periods of deprivation.

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Vitamin A and the Immune System

Numerous studies have documented that Vitamin A has a critical role in the function and differentiation of many cell types, including immune cells, although its mechanism of action is undefined. Animal studies indicate that vitamin A deficiency causes immune system dysfunction and pathology. Chickens that are experimentally infected with Newcastle disease virus (a serious respiratory and nervous disease in fowl that can cause transient conjunctivitis in humans), when fed a diet deficient in Vitamin A, show increased pathology and an altered disease pathogenesis.²

Another study of chicks infected with Newcastle disease virus demonstrated that immunoglobulin levels were decreased during vitamin a deficiency.³ Rats infected with Angiostrongylus cantonesis (a parasite transmitted by shellfish, that causes a lung infection in rodents and may infect humans) show increased susceptibility and more disease when deprived of Vitamin A.⁴

Chicks infected with Escherichia coli (an intestinal protozoan parasite) have decreased resistance to infection and an altered immune response when fed diets either high or low in Vitamin A.⁵ Vitamin A-deficient rats have impaired phagocyte activity during bacterial infection.⁶ Antibody synthesis and T cell proliferation are increased in chickens supplemented with Vitamin A.⁷ Finally, lymphoid organs appear atrophied and underdeveloped in Vitamin A-deficient rats.⁸

Several clinical studies of Vitamin A deficiency and supplementation confirm that also has a role in human immune function. The most convincing study of the benefits of Vitamin A supplementation on reduced infections and mortality was conducted in India, where deficiencies of the vitamin are common.⁹ The well-designed, blinded study enrolled 15,419 preschool children in an area of Southern India where Vitamin A deficiency is common. They were randomized to receive weekly Vitamin A supplements (8333 IU) or Vitamin E (20 mg) for over one year. The study reports a startling 54 percent reduction in childhood mortality, primarily through reductions in diarrhea and infections. An editorial in The New England Journal of Medicine that accompanied the article said that "the available evidence now supports the immediate implementation of Vitamin A programs in specific cases - wherever there is evidence that a population has a vitamin a deficiency, wherever protein-energy malnutrition is common, and wherever there is an excess of measles deaths."¹⁰

Other clinical trials have pointed to the same conclusions about Vitamin A supplementation in high-risk populations, although they were not as large nor as well-designed as the Indian study. An Australian study of 147 young children found that daily vitamin A supplements reduced the incidence of respiratory infection compared with placebo.¹¹ A randomized study of 450 villages in Sumatra (an Indonesian Island) found that children in villages randomized to receive one or two vitamin a supplements (200,000 IU) over several months had a 50 percent reduction in mortality compared with children in villages which received placebo.¹² A South African study of 189 young children hospitalized with measles found that vitamin a given in a total dose 400,000 IU reduced the length of recovery from pneumonia and diarrhea, shortened hospitalization, and improved survival compared with placebo.¹³

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Vitamin A and AIDS

Vitamin A deficiency may occur in people with HIV through an unknown mechanism, according to several preliminary reports. Vitamin A deficiency may be secondary to an overall state of protein-energy malnutrition in people with HIV or could be related to the host response to infection. Infection and fever increase the metabolism of Vitamin A, increase its urinary excretion, impair its intestinal absorption, and can diminish hepatic stores of the vitamin, all leading to systemic deficiency.¹⁴ Vitamin A deficiency may lead to increased risk of infection and further vitamin deficiency, leading several investigators to describe this relationship as a "vicious cycle."^{15, 16, 17, 18}

However, serum vitamin A levels may be affected by the APR, so serum diagnosis is difficult and can not be considered definitive. A study from Baltimore examined serum Vitamin A levels in 179 intravenous drug users (126 HIV-infected, 59 uninfected).¹⁹ Fifteen percent of the HIV-infected people had serum levels consistent with Vitamin A deficiency. Overall, the infected group had lower mean plasma levels of the vitamin compared with the uninfected controls. Vitamin A deficiency was associated with lower CD4 counts and an increased risk of mortality. An abstract presented at the 1992 International AIDS Conference found that people with HIV were more likely than historical, uninfected controls to have lower serum vitamin A levels and deficiencies.²⁰ Vitamin A levels were only partially associated with decreased dietary intake in this study. Serum vitamin A levels were also reduced in 18 percent of asymptomatic HIV-infected people, according to a 100-person study from the University of Miami.²¹

Despite growing evidence that vitamin A deficiency can occur in some people with HIV, the mechanism(s) of the deficiency and the clinical significance of this finding are unknown. Furthermore, it remains unclear if vitamin A supplementation can reverse the deficiency and, more importantly, improve the clinical outcome of patients. This uncertainty is increased by evidence that Vitamin A can both increase and decrease HIV replication, depending on cell type, in vitro (in the test tube).^{22, 23}

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Vitamin B-6 (pyridoxine)

Vitamin B-6 (discovered in 1934) is crucial to many biological processes, including, most importantly, amino acid metabolism and biosynthesis. Vitamin B-6 is found in most foods, but meat provides the most usable form of the substance. White bread, and other grains, are often fortified with the vitamin. Vitamin B-6 deficiency is considered rare in human populations, although marginal deficiency may occur more frequently. Deficiency of vitamin B-6 produces profound skin and neurological changes, such as peripheral neuropathy. Vitamin B-6 is often co-administered with isoniazid (a tuberculosis treatment) to reduce drug-related toxicities. Other uses of Vitamin B-6 (some of which are controversial) include: as a stimulant of hematopoiesis (formation of blood cells) in patients with certain kinds of anemia, as a treatment for iron-storage disease, as a treatment for schizophrenia, and as a treatment to reduce the incidence of seizures in alcoholics.

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Vitamin B-6 and Immunity

Little is known about this vitamin's role in immunity or its mechanism of action, although it appears to play a significant role. Animal studies suggest that B-6 deficiency has a range of effects on cell mediated immunity. Delayed-type hypersensitivity reactions to tuberculin antigen are decreased in guinea pigs fed a B-6 deficient diet.²⁴ Lymphocyte proliferation and cytotoxicity are reduced in mice after five weeks on a B-6 deficient diet.^{25, 26} Vitamin B-6 deficiency in animals may also lead to lymphoid organ atrophy and impaired thymic function²⁷, reduced T lymphocytes numbers and function²⁸, and defective lymphocyte maturation.²⁹ Vitamin B-6 deficiency can also lead to impaired antibody production and fewer antibody-producing cells in animals, according to various studies.^{30, 31, 32}

Few human studies address the issue of vitamin B-6 and immunity, and those that have examined the question demonstrate no consistent direction of effect. Two studies of vitamin B6 deficiency in humans show that it may slightly impair antibody production³³ or leave it unchanged.³⁴

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Vitamin B-6 and AIDS

There has been little research directed at Vitamin B-6 and AIDS. No study has shown that Vitamin B-6 supplements delay disease progression or improve survival. One study examined Vitamin B-6 levels in a group of HIV-infected people and that 35 percent of subjects had overt deficiency and an additional 18 percent had marginal deficiency. The authors suggest that CD4 cell counts were lower in patients with reduced vitamin B-6. The authors also suggest that vitamin B-6 intake was inadequate in these subjects, based on food intake surveys. However, the diagnosis of vitamin B-6 serum levels is difficult and may be affected by the APR. Food intake surveys are also not considered a reliable method for diagnosing vitamin deficiency.

Vitamin B-6 may be reduced when tumor necrosis factor (an inflammatory cytokine) is increased, according to a study of rheumatoid arthritis patients.^{35, 36} Furthermore, Vitamin B-6 is stored in muscle and deficiency may be related to decreased lean body weight.

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Vitamin B-12 and Folate

Vitamin B-12 and folate are separate vitamins, although they have similar biological roles and work together in vivo (in the body). Folate is critical to the synthesis of RNA and DNA. The main biological effect of Vitamin B-12 is probably on folate metabolism. Folate is found in most foods, although folate deficiency is common in the developed world, affecting an estimated 8 to 10 percent of the population. Vitamin B-12 is produced mainly by bacteria which live in the human gut, although it is also found in meat. Vitamin B-12 deficiency is considered rare, except in some strict vegetarians who endure 20 to 30 years of inadequate intake, suggesting there are considerable body stores of the vitamin. Most Vitamin B-12 deficiency is thought to result from altered intestinal flora (the 'good' bacteria that helps you digest your food) and malabsorption (poor nutrient absorption through the intestines). Folate and Vitamin B-12 deficiency result in clinically similar syndromes, producing anemia (low red blood cells, iron) and neurologic symptoms (confusion, nerve problems).

The efficient use of folate by the body can be impaired (thus producing a functional deficiency despite adequate intake) in the context of Vitamin B-12, methionine (an important amino acid) or zinc deficiencies. Some drug therapy can also cause functional folate deficiency. Folate deficiency can also cause certain kinds of birth defects in mothers who consume inadequate amounts of the nutrient.

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Folate/B-12 and Immunity

Very little published information addresses the role of folate and Vitamin B-12 in immunity. Folate deficiency causes anergy to DNCB in pregnant women and impaired lymphocyte proliferation.³⁷ Folate deficiency causes lymphoid organ atrophy, reduced T-cell numbers, and lymphocyte proliferation in laboratory animals.³⁸ Vitamin B-12 deficiency, but not folate, reduces phagocytosis and bacterial killing by neutrophils in humans.³⁹

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Folate and Vitamin B-12 in AIDS

Although these two vitamins are not considered to play a key role in immunity, have received considerable attention in HIV disease because of vitamin B-12's potential role in neurologic disease. Numerous studies detected low serum levels of the nutrient in this population.^{40, 41, 42} The mechanism of these deficiencies is not known, although gastrin (a hormone that aids digestion) was elevated in one study population - a sign of defective B-12 absorption. Vitamin B-12 deficiency may be an important cause of neurological disorders and anemia in people with HIV, leading some physicians to offer periodic B-12 injections to their patients. The clinical efficacy of this intervention remains unproved, however. Folate levels may be increased in HIV-infection, according to several studies. One study suggested that IV-drug users may have reduced folate levels because of poor access to fresh fruits and vegetables - key sources of folate. Gay men, the authors speculate, probably do not have reduced folate because of better access to fresh foods, although they present no evidence to support this hypothesis.^{43, 44, 45}

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Vitamin C

Vitamin C (ascorbic acid) is found in many foods, including citrus fruits, green vegetables, berries, and organ meats. Most animal and plant species do not need to consume Vitamin C in their diet as they are able to produce sufficient quantities naturally. Humans and guinea pigs are the only animals that can not produce Vitamin C naturally and thus must consume it. Vitamin C is critical to electron transport, collagen synthesis, and various metabolic processes. The deficiency of Vitamin C produces connective tissue disorders, impaired wound healing, bleeding gums, and other serious symptoms. The deficiency of Vitamin C is called scurvy, the bane of sailors for hundreds of years. Unlike other vitamins, marginal Vitamin C deficiency is somewhat better characterized. It may produce fatigue, muscle weakness, and impaired wound healing.

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Vitamin C and Immunity

Vitamin C supplementation has not been shown to delay progression or improve survival in people with HIV. Vitamin C deficiency does not impair lymphocyte proliferation or CD4 and CD8 levels in humans.⁴⁶ In guinea pigs, Vitamin C deficiency impairs tuberculin skin reactions, cell-mediated cytotoxicity, and decreases the bactericidal capacity of neutrophils.^{47, 48} Vitamin C can induce interferon (immune cell chemicals) production in vitro.⁴⁹ Animal and human studies demonstrate conflicting results on Vitamin C's impact on antibody (immune proteins) formation.^{50, 51, 52, 53, 54} Several in vitro and animal studies indicate, however, that Vitamin C may play a more significant role in cellular immunity.^{55, 56}

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Vitamin C and Viral Diseases

Vitamin C has been proposed an antiviral agent for several diseases, beginning with a report from 1935 on the nutrient's ability to inactivate polio virus in vitro.⁵⁷ Vitamin C was also able to inactivate other viruses in vitro, including herpes simplex, rabies, and tobacco mosaic virus. Not surprisingly, massive doses of Vitamin C were used as a polio treatment, although they were ineffective.

Vitamin C has also been proposed as a treatment for the common cold. One investigator claimed that regular doses of Vitamin C would reduce the incidence of the common cold.⁵⁸ This claim was later disproved.^{59, 60, 61} Vitamin C was also proposed as a cancer treatment, by the same investigator who suggested it could prevent colds. These results remain controversial, although studies which claim a beneficial effect suffer from serious methodological flaws. A study conducted by the Mayo Clinic found that Vitamin C was not beneficial as a cancer treatment. In fact, those who received Vitamin C had shorter survival, but not to a statistically significant degree.⁶²

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Vitamin C and AIDS

It should come as no surprise, perhaps, that massive doses of Vitamin C are now proposed as an AIDS treatment. There have been no clinical studies designed to address this question. Claims for the efficacy of Vitamin C in AIDS are based entirely on reports of the nutrient's ability to inactivate HIV in vitro.

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Vitamin Discovery

Christian Eijkman, a Dutch physician, was the first to isolate a vitamin, although initially he did not understand his discovery. An advocate of the recently proposed germ theory of disease and a student of Robert Koch, the great German bacteriologist, Eijkman first believed that he had found an "antidote" to the "microbe" that causes beri-beri disease. Eijkman later realized that he had, in fact, discovered what would be known as thiamin (Vitamin B-1), the deficiency of which causes beri-beri. In 1929 Eijkman received the Nobel Prize for his discovery.

The discovery of thiamin sparked a world-wide effort that lead to further discovery of other vitamins. Casimir Funk, a Polish biochemist, is credited as the first to coin the term vitamin after he discovered that thiamin's chemical structure contains an ammonia molecule. He merged two words - "vital" and "amine" (the chemical suffix for ammonia) - to create the term vitamin. By 1948, all thirteen presently-recognized vitamins had been discovered.