This document was written by Gus Cairns of Positive Nation and thus contains some United Kingdom-specific information. Please note that this document was written in 2000-2001 so some of the information needs to be updated. FIAR will be providing more information to augment this document.

Vitamins, minerals and other supplements

Taking vitamin, mineral or other supplements is probably the most popular 'complementary therapy'. The UK population currently spends over £400 million a year on vitamin and nutritional supplements - though this is dwarfed by the health-conscious Americans, who in 1999 spent $15.7 billion.

A collective term used for these compounds is 'micronutrients'. This contrasts them with the macronutrients, the proteins, carbohydrates and fats that make up the bulk of food. The term signifies that only small and in some cases minute amounts of these substances are necessary for health, though those amounts are essential.

It may also be a misleading term, however, in that it suggests that taking vitamin supplements can substitute for a good diet, or make up for a poor one. It may also reinforce the probably illusory idea that somewhere out there is a simple vitamin or herbal remedy, a few pills of which a day would do away with the need for good self-care or conventional medicine.

With certain exceptions, the best way to get vitamins and minerals is generally to eat a balanced healthy diet, rather than spending money on expensive purified chemicals. Many vitamins and minerals work best, or are only absorbed well, in combination with other substances in food.

Although the primary vitamins have been known about for nearly a century, many aspects of their functioning remain mysterious. For instance, while vitamin B2 deficiency clearly causes cracked skin and lips, the biochemistry of this effect remains unclear. There is a lot of mythology about the properties of vitamins. It is almost universally believed, for example, that vitamin C cures colds. But at least 16 double-blinded studies have found almost no benefit. A classic study by the University of Toronto ⁽²⁾ divided 3,500 people into eight groups. Six of the groups received 250, 1,000 or 2,000 mg of vitamin C daily or twice daily: the final two groups received a placebo. It was found that the vitamin C supplementation showed no ability to prevent colds, and that the most that could be said was that 250mg of vitamin C slightly decreased symptom severity for some. The higher doses produced no additional benefit.

Since the beginning of the AIDS epidemic, taking vitamins, minerals and other nutritional supplements has been one of the ways people with HIV have tried to preserve their health. In the days before antiretroviral therapy, trying different substances was an inevitable part of the search to find something that would reverse or at least slow disease progression. The following paragraph ⁽³⁾ from a 1992 article in The GHMC Newsletter of Experimental Therapies exemplifies the thinking of many people in the early 90s:

There was a hope that, in the absence of effective drugs, there had to be a cure out there somewhere in the array of 'natural' remedies, if only one could find the exact regime.

However, as the reference quoted makes clear, these experimental supplementation strategies often involved 'megadosing' - taking huge doses of vitamins, sometimes intravenously. There is little evidence that this strategy worked any better than regular supplementation, as another quote ⁽⁴⁾, from the Bulletin of Experimental Treatments for AIDS (BETA) says:

As Lark Lands says in the above quotation, however, there is an 'evidence problem' when it comes to researching the benefits of these cheap and non-patentable substances, because there is rarely the incentive for drug companies to fund large or thorough trials.

There is also a 'quality problem' in that many supplements, particularly the more expensive ones, sometimes contain little or none of the active ingredient. For instance, in a recent American survey ⁽⁵⁾, tests of supplements of the hormone DHEA found that only seven had DHEA content to within 90-110% of the label claim. In three no or virtually no DHEA was found. A similar test of ginseng products found that some contained no ginseng at all. And a test of supplements containing the supplement chondroitin sulphate, often used for arthritis and joint problems, only five of 32 products contained 90-100% of the level of active ingredient claimed, 17 containing less than half the amount on the label. On a few occasions supplements have been found to contain far more of the active ingredient than stated.

More frequently, supplements are presented in a formulation that is useless because it is not bioavailable - cannot be easily digested. One cannot, for instance, just eat chalk to get more calcium; like many minerals, it has to be in an organically-bound form.

Other supplements are antagonists. An excess of one will lead to a deficiency of the other. For instance, taking too much folic acid interferes with zinc absorption. So dosage of one substance should be carefully limited, or both substances need to be taken in a balanced formulation. Examples are vitamins B1 and B2; folic acid and B12; and calcium and magnesium.

You should always let your doctor know what supplements you are taking, and you should not take more than is good for you. While some supplements are not toxic, others, such as vitamins A, B6 and D, and minerals like zinc, are toxic in amounts not hugely greater than the recommended daily amount. Others like vitamin C, while not toxic as such, may cause side effects like diarrhoea or kidney stones, as well as interfering with iron absorption, as mentioned above.

Others should not be taken alone as they interfere with the absorption of other vitamins. Vitamin B1 (thiamine), for instance, if taken alone, can cause deficiency in the levels of vitamin B2 (riboflavin); too much phosphorus in the diet may interfere with calcium absorption; and long-term use of too much zinc may interfere with the body's ability to absorb copper, another important trace element. For this reason it is usually better to take a good multivitamin/mineral supplement rather than taking individual supplements, apart from those not normal found in multivitamins such as NAC and LAC.

This is often misinterpreted as a 'minimum' figure. In fact it is an average - the amount 'healthy' people, as defined by population averages, tend to take in their diet and supplements. This is why it is close to the amount taken in diets anyway. One cannot therefore tell directly from the RDA if a particular population would benefit from altering their intake of a particular vitamin - the evidence is indirect.

If the RDA is significantly larger than the 'average from diet' column in the table below, it means this particular substance may need to be taken as a supplement by the average person. US RDAs differ between men and women.

People with HIV are by definition not 'averagely healthy'. This does not mean their RDAs will be different, but it does mean that they may have additional needs that the RDAs do not meet.

The table below shows the EU and US Recommended Daily Allowance of vitamins and minerals and the recommended maximum safe doses.

Quick reference table to safe dosing of vitamins and minerals^†

This table represents a variety of different estimates from a variety of sources. Some figures are inconsistent, e.g. the 'tolerable upper intake level' (from supplements and food) estimated by one group being less than the 'upper safe limit' (from supplements alone) recommended by another. The figures also apply to the general population, not people with HIV, where the RDAs may need to be increased. These figures are best taken as a guide to staying within safe dosage limits. g = gram, mg = milligram (0.001 gram), mcg = microgram (0.001 milligram), IU = International Unit (Used for Vitamin E and sometimes for vitamins A and D)

†Sources: EU RDAs, Average from diet, upper safe limits taken from Health Supplements Information Service (http://www.hsis.org/). US RDAs and some toxicity thresholds are taken from Barrie Cassileth, The Alternative Medicine Handbook. Other information is taken from Reuters, Associated Press, and information elsewhere on Aidsmap.

*Average from diet. A European figure from the Health Supplements Information Service, based on the average European diet. This is the average for men and women: men may get up to 25% more than this form their diet, and women up to 25% less.

*Upper safe limit. A European figure from the EMEA. The upper safe level that should be taken from supplements alone assuming an average European diet is consumed.

*Tolerable upper intake level. A US figure from the Food and Drug Agency defined as "The highest total level of a nutrient consumed from both diet and supplements which is unlikely to pose adverse health effects to almost all individuals in the general population."

*Toxicity threshold. The level above which toxicities have been observed.

1. For long-term use or in pregnancy. Up to 7500mcg (25,000 IU) is safe for short-term use (a few weeks).
2. In the absence of taking a vitamin A supplement as well. 12 micrograms of β-carotene convert to approximately one microgram of vitamin A in the body.
3. Taking B1 (thiamine) or B2 (riboflavin) alone can interfere with the absorption of the other vitamin.
4. In the form of nicotinic acid. Nicotinamide seems to be safer.
5. Pantothenic acid is also provided by intestinal bacteria.
6. Taking too much pantothenic acid can interfere with absorption of vitamin B1.
7. 2.2 mg for pregnant women.
8. But interferes with absorption of vitamins B1 and B6.
9. High doses of folic acid cause problems in zinc absorption.
10. 2.2 mcg for pregnant women.
11. May be considerably lower in vegans: B12 is the only vitamin with no plant sources.
12. Folic acid and vitamin B12 potentiate each other and should preferably be taken together.
13. Experimental high-dose intravenous B12 has resulted in occasional allergic reactions.
14. Considerably more can often be tolerated if doses are built up to gradually. They should also be tapered off gradually, as the body builds up tolerance to vitamin C, and sudden reductions can cause scurvy.
15. Above this level, often causes diarrhoea, intestinal discomfort. May cause kidney stones in those susceptible.
16. The balance is usually made up by the action of sunlight on skin.
17. International Units are a measure of biological activity rather than weight. Unlike other vitamins, Vitamin E is a mixture of different compounds (alpha to delta tocopherols) with differing amounts of biological activity. So Vitamin E IUs are difficult to translate directly into milligrams as it depends on the mix of tocopherols provided.
18. Taking more than 600 IU of vitamin E a day has been observed to interfere with beta-carotene absorption and utilisation.
19. Varying amounts of vitamin K are contributed by intestinal bacteria.
20. Toxicity rare: usually restricted to people taking anti-coagulant drugs.
21. Best combined with magnesium to ensure bioavailability.
22. 1500 mg after age 65.
23. 27 mg in pregnant women - this amount is not easily available in the diet and should be supplemented. 8 mg in post-menopausal women. Men and post-menopausal women are unlikely to need iron supplementation, and it may be toxic.
24. NB: Taking more than 15mg elemental zinc a day long-term is associated with faster immune decline in PWHIVs. High doses interfere with copper absorption.

Despite the above caveats, evidence from various studies continues to accumulate that showing that carefully chosen supplementation may help. Data supporting nutritional supplementation continue to mount. But caution needs to be exercised when taking large amounts - the use of vitamins in high pharmacological doses is still poorly documented. A study from the University of Berkeley ⁽⁶⁾ in 1993, for instance, has often been cited as evidence that taking quite high doses of vitamin E slows progression to AIDS. It was flawed in that it failed to separate out patients who were already taking ordinary multivitamin supplements at the start of the study. When this was taken into account, the multivitamins were at least as important a factor as the vitamin E.

Nonetheless, we actually know more than we did in 1992 as to exactly why supplementation may improve health and survival rates in people with HIV. In the HAART era, vitamin and mineral supplementation is still useful for a variety of reasons in several key, and overlapping, areas:

Dealing with opportunistic infections

Antioxidants

The process of metabolism - of life itself - is essentially a controlled burning of carbon-based organic substances in the presence of oxygen. Oxygen, however, is also the second most reactive of the elements and can cause the devastation of a forest fire as well as the warmth of a hearth. The 'sparks' from the fire of metabolism are the so-called 'free radicals' - chemically unstable and therefore extremely reactive oxygen-containing ions (charged molecules) which cause damage to tissues by oxidising them - much as iron is oxidised to rust.

There is an arsenal of chemicals, the antioxidants, contained in food and produced in the body whose job is to mop up free radicals before they cause damage. These include the enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase; glutathione itself; vitamins C and E; various carotenoids, including vitamin A; and related plant chemicals like the bioflavonoids and polyphenols. During many diseases, especially chronic ones like HIV infection, an abundance of free radicals appear to be produced as a side-effect of immune system activation. In addition, or because of this, it appears that the body is progressively depleted of certain antioxidant compounds during HIV infection. A state of oxidative stress develops in which various types of tissue damage occurs.

Lipids (fats) are particularly vulnerable to oxidation. The membranes on and within cells, particularly immune cells, contain a high percentage of polyunsaturated fatty acids (lipids), as do arterial walls, the myelin sheath that insulates nerves, and many other vital body tissues. Free radicals can degrade these tissues, leaving important cellular components unprotected, causing hardening of the arteries and cardiovascular disease, and damage to the nervous system. Cells' genetic material also can come under attack, resulting in mutations. Supplementation with the best-known antioxidants such as Vitamins A, C and E, glutathione and alpha lipoic acid may therefore be particularly valuable for people with HIV.

Countering drug side-effects

The side effects caused by antiretroviral and other drugs may be prevented or reduced by judicious supplementation.

The side effects where there is evidence of vitamins and supplements having a helpful role include various ones associated with the nucleoside drugs. These include hyperlactatemia, an excess of lactic acid, a waste product of metabolism, in the blood, which occasionally progresses to the life-threatening complication lactic acidosis. This can also manifest as myopathy or damage to the muscles, including damage to the heart muscle. Similar toxicities can cause nerve damage, which may manifest as peripheral neuropathy; and an accumulation of fat in the liver, known as hepatic steatosis. Whether these have a common underlying cause is yet to be proved, but they may all be connected to damage to the mitochondria, the energy-producing components of cells.

The B vitamins, in particular vitamins B1, B2 and niacin, have been used as 'emergency therapy' in cases of lactic acidosis, and may protect against such damage occurring in the first place. The vitamin-like compound carnitine, which transports substances across the membranes of the mitochondria, is also part of this rescue therapy. It has also been shown to repair damaged nerves in cases of peripheral neuropathy, and has also been used to protect the kidneys from damage by drugs like adefovir. Some doctors are willing to prescribe this supplement. The compound coenzyme Q-10 or ubiquinone performs a similar energy-transporting function in muscles, particularly in heart muscle, and may protect against myopathy. And the anti-oxidants help to protect liver cells against damage.

Protease inhibitor therapy may increase the risk of cardiovascular disease: taking vitamin C may protect against this, as may folic acid, which acts as an antagonist to a substance called homocysteine which is associated with a greater tendency to heart disease in certain individuals. Vitamin E may also protect against heart disease.

A group of side effects that have more recently come to light are bone problems such as osteoporosis and osteonecrosis. While the cause of these remains unclear, balanced supplementation with calcium, magnesium and vitamin D may help to preserve bone strength.

Both protease inhibitors and HIV infection can cause diarrhoea: supplements that many people find help relieve this again include calcium, the amino acid l-glutamine, and probiotic supplements of intestinal bacteria (Lactobacillus, etc), while potassium supplementation may be necessary in chronic cases.

The anti-PCP drug Septrin (co-trimoxazole, Bactrim) works by interfering with micro-organisms' ability to use folic acid: although folate supplementation has not been shown to reduce Septrin allergy, the drug may interfere with the body's ability to use folate in a longer-term way. Vitamin B12 and folic acid work in conjunction with each other and should be taken together.

Vitamins and minerals in HIV

[More information on certain vitamins and other micronutrients, and more details of key research, will be found under individual entries in the NAM Treatments Directory and in the 'micronutrients' section of the Treatments part of Aidsmap]

Vitamin research in HIV suffers from the same limitations as research into other complementary therapies. There is little funding available for research into inexpensive and unpatentable treatments, and even this has tended to dry up in the HAART era. Compared with drug trials recruiting hundreds of volunteers, many of the studies quoted below included handfuls of people, with all the problems this brings with it regarding statistical significance and adequate controls. I have tried to exclude animal studies except where these suggest further avenues of research.

A lot of the general, as opposed to specific, evidence of the benefit of vitamin supplementation in people with HIV comes from two early studies; one by Abrams in San Francisco, reported in August 1993⁽⁶⁾, and one by Tang of the Johns Hopkins University in Baltimore, reported in December 1993⁽⁸⁾.

The Tang study took 280 patients out of the Multicentre Aids Cohort Study (MACS) and analysed their micronutrient intake both from diet and supplements. Certain micronutrients were found to have considerable influence on both progression to AIDS and death. High intakes of vitamins B1, niacin and C were associated with slower progression to Aids. The 25 per cent of the patients with the highest intake of vitamin C, for instance (they averaged 715mg/day) had 55 per cent of the average chance of progressing to Aids over the course of the study.

Only two micronutrients broke the pattern. The lowest risk of progression or death was associated with the patients taking moderately increased, as opposed to high, doses of beta-carotene; and any zinc intake more than 5mg over the RDA of 15mg was associated with greater risk of Aids or death.

In terms of the risk of death, as well as vitamins B1, niacin and C, vitamins B2 and B6 considerably reduced the risk. Patients taking about twice the RDA of vitamin B6, for instance, had less than half the risk of dying.

The Tang study could not prove that it was the micronutrients that were slowing progression to AIDS and death, or if so, how. The diet questionnaires they gave people at the start of the study were not repeated, so the study could not factor in changes in diet (for example if people ate less well as they became more ill). Nor could it control for those who ate better and took supplements also looking after themselves better in other ways. And this pre-HAART era study cannot factor in the additional influence on morbidity and mortality of using vitamins to combat the side effects of anti-HIV drugs.

Nonetheless, the considerable differences in morbidity and life expectancy associated with some vitamins are very suggestive. There is probably no point in waiting for better evidence: detailed cohort studies of how individual micronutrients influence the course of HIV infection will probably never be done.

But the cheapness and availability of most micronutrients mean that PWHIVs can, and maybe should, be encouraged to 'self-medicate', as long as doses are kept within the limits on the table above. (NB a multivitamin supplement should be one, ideally, with higher levels of B vitamins and lower levels of vitamin A and zinc. Men and post-menopausal women should avoid multivitamins containing iron).

It is important to emphasise that the Johns Hopkins study quoted above ⁽⁸⁾ found a 'U-shaped' dose-response in terms of progression to AIDS with beta carotene - in other words both those who took a lot and those who took very little progressed more quickly than those who took moderate amounts. Vitamin A itself was not associated with any benefit.

The study divided the group into 'quartiles' - the 25 per cent of patients who took high, high middle, low middle and low doses of beta-carotene. The patients who either took more than an average of 20,268 IUs a day (c.6.1mg) or less than 9,062 IUs (c.2.7 mg) did 55 per cent as well as the patients who took amounts in between these figures. This one study, therefore, comes out with an 'ideal dose' in both food and supplements of around 4mg/day. Considering that the amount obtained from the average European diet is 3.2mg/day, this would seem to indicate that more than very modest beta-carotene supplementation might not benefit health.

One non-HIV related study that also suggests this was a large study of smokers in Finland which found that far from protecting them against lung cancer, subjects that took 20mg of beta-carotene a day actually had an 18 per cent higher risk of developing it.

NB: In individuals with liver dysfunction, diabetes or hypothyroidism - all of them side effects of antiretroviral drugs - it is not possible for the liver to convert beta-carotene into vitamin A. In these individuals, who may have problems absorbing fat, it is possible to take vitamin A in a water soluble form. Heavy use of alcohol and other drugs may interfere with vitamin A absorption. Furthermore, taking vitamin A supplement in the presence of alcohol and smoking increases a person's chances of liver damage, liver cancer and pulmonary cancer ⁽⁹⁾.

What does it do?

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. A fashion for taking megadoses of beta-carotene as an antioxidant in the early 1990s has somewhat declined, as other antioxidants gain a higher profile.

In 1995, a French research team ⁽¹⁹⁾ studied 95 HIV-positive volunteers for a decrease in polyunsaturated fatty acids and an increase in lipid peroxidation, which the authors considered a sign of oxidative stress. 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.

The Tang study quoted above ⁽⁸⁾ found no association between vitamin A levels, disease progression or vitamin supplementation. But then, 90 per cent of the men under study had normal to high vitamin A levels. 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, but supernormal levels are not achievable, not to mention tolerable, in the body.

Although the B vitamins all have different biochemical functions, the jobs they do in the body overlap, and deficiency of one or more B vitamins, or the presence of conditions they normally prevent, present similar symptoms. For this reason it makes sense to deal with them all together. In addition, taking one B vitamin as a supplement in isolation tends to lower levels of the others in the body.

These vitamins are involved in the release of energy from food, in the synthesis of red blood cells, in the health of nerve cells, and in the synthesis of steroid hormones such as adrenalin.

Vitamin B deficiency presents a common picture of fatigue, weakness, nausea, digestive problems, aching muscles, damage to the liver and pancreas cells, and sometimes confusion or dementia.

Until recently the B vitamins were not as popular or fashionable as supplements among people with HIV as other supplements such as beta carotene or n-acetyl cysteine (NAC). The one exception was vitamin B12, seen by some nutritionists as chronically deficient in people with HIV and a possible cause of dementia. This has all changed with the toxicities seen in the longer-term use of antiretroviral drugs, and particularly the nucleosides.

The clinical picture presented by B deficiency looks very similar to the symptoms of mitochondrial toxicity, and to its often fatal complication, lactic acidosis. Although the exact clinical picture has yet to be understood, it is known that the nucleoside drugs, to a greater or lesser degree, damage the genetic material of the mitochondria, the 'powerhouses' in the cells that turn food into energy. Specific nucleosides are associated with specific kinds of damage to other cells, too: AZT to red blood and muscle cells, d4T and ddC to nerve cells, ddI to the pancreas, and so on.

It was a reasonable hypothesis, then, that supplementing with B vitamins might help the remaining mitochondria work more efficiently and preserve other types of cell from damage.

In emergency cases this supposition has been quite dramatically confirmed.

A team of Dutch doctors ⁽²⁰⁾ treated patients with lactic acidosis (defined as a serum lactate level of over 5 mmol/L and a bicarbonate level of under 20 mmol/L) with the following twice-daily intravenous 'rescue regimen':

• vitamin B1 - 100 mg
• vitamin B2 - 20 mg
• Niacin (as nicotinamide) - 200 mg
• pantothenic acid - 20 mg
• L-carnitine - 1,000 mg

Vitamin B1/Thiamine

Niacin/Vitamin B3

Vitamin B6/pyridoxine

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. Vitamin B-6 deficiency can also lead to impaired antibody production and fewer antibody-producing cells in animals, according to various studies.

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 production or leave it unchanged.

A study amongst HIV-positive gay men ⁽²⁹⁾ suggested that those deficient in vitamin B6 were more likely to be depressed and anxious and that when this deficiency was corrected, there was a significant decrease in depression.

Anecdotally, B-6 has been used successfully in controlling peripheral neuropathy, the side effect of certain nucleoside analogues like d4T, ddC and ddI. A report in Aids Treatment News ⁽³⁰⁾ says that a simple regimen of calcium, magnesium and vitamin B6 has been used to protect the nerves or treat peripheral neuropathy.

Dr Jon Kaiser, author of Healing HIV, recommends taking calcium 500mg, magnesium 250mg and vitamin B6 100mg twice a day, particularly for people taking d4T. If neuropathy is present, he recommends doubling the dose of B6. Another San Francisco doctor, Virginia Cafaro, recommends 1000mg calcium and 500mg magnesium twice a day, but only 100mg of B6 once a day, combined with acupuncture.

Cafaro's caution may be founded in the fact that high doses of B6 (above 1,000 and certainly above 2,000mg a day) actually cause nerve damage and peripheral neuropathy. Some high-dose B vitamin supplements can contain amounts approaching this level. The neurologist Oliver Sacks, in his famous book The Man who Mistook his Wife for a Hat, witnessed an 'epidemic' of sensory neuropathy in the 1970s among people who saw B6 as a panacea for depression.

Vitamin B12 (cyanocobalamin) and folic acid (folate)

Vitamin B-12 and folate are separate vitamins, but have similar biological roles and work together in vivo. Folate is critical to the synthesis of the genetic materials RNA and DNA. Folate deficiency can also cause neural tube defects (a birth defect in children born to mothers who consume inadequate amounts of the nutrient), and is now recommended as a supplement for pregnant women for this reason.

The main biological effect of Vitamin B-12 is probably on folate metabolism. Folate is found in most foods, although its 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 that live in the human gut, although it is also found in meat. Vitamin B-12 deficiency used to be considered rare, except in some strict vegetarians who nonetheless manage to endure 20 to 30 years of inadequate intake, suggesting there are considerable body stores of the vitamin. Folate and Vitamin B-12 deficiency result in clinically similar syndromes, producing anaemia and neurologic symptoms.

Most Vitamin B-12 deficiency is thought to result from altered intestinal flora (perhaps due to antibiotic use) and malabsorption. Certain nutritionists have long thought that some people with HIV are chronically B12-deficient because of this.

Recent evidence supports the theory that B-12 deficiency is more common than was thought, and not just in people with HIV. According to a report in a recent issue of The American Journal of Clinical Nutrition ⁽³¹⁾, investigators found that 39 per cent of all individuals had low-to-normal levels of the vitamin in their blood and 17 per cent had levels low enough to cause symptoms of deficiency.

Age did not seem to matter, as those aged 26 to 49 years had the same vitamin B-12 status as those aged 65 to 83 years.

The report's authors say that early symptoms of deficiency include reduced sensation in the limbs, and memory and balance disturbances. Ultimately, B-12 deficiency can cause irreversible nerve damage. But since many of these symptoms are general, they are often not attributed to a vitamin B-12 deficiency, they report.

For most people, taking a regular multivitamin or eating breakfast cereal fortified with vitamin B-12 can easily prevent deficiency. Although the vitamin is found naturally in meat, it does not appear to be as well absorbed, the study reveals. Vitamin B-12 is tightly bound to protein in meat and requires sufficient stomach acidity to break it apart before it can be absorbed. In some people, particularly the elderly, insufficient levels of stomach acid mean that the vitamin is not taken up in sufficient quantities.

B12, folate and immunity

Although these two vitamins are not considered to play a key role in immunity, they have received considerable attention in HIV disease because of vitamin B-12's potential role in neurologic disease. Several studies have shown low levels of vitamin B12 in HIV-positive people ^(32,33). It is unclear whether low vitamin B12 levels influence HIV disease progression, or whether they are merely a consequence of disease progression. An eighteen month study ⁽³⁴⁾ of HIV-positive people found that the onset of low serum vitamin B12 levels was associated with CD4 cell count decline, and that normalisation of vitamin B12 levels was associated with an improvement in CD4 count. Another study ⁽³⁵⁾, which followed 310 men for 9 years, found that low serum vitamin B12 levels at entry to the study were associated with an 89 per cent increased risk of progression for AIDS after controlling for disease stage, antiretroviral therapy, alcohol intake and age. Depletion in body tissues may begin to occur at least a year before blood levels become abnormally low.

For the above reasons, B12 was a popular supplement particularly in pre-HAART days. Nutritionists such as Lark Lands have long theorised that chronically low levels of B12 are a causative factor in HIV-related dementia. Numerous studies detected low serum levels of the nutrient in this population. The mechanism of these deficiencies is not known, although gastrin was elevated in one study population - a sign of defective B-12 absorption.

The theory that vitamin B-12 deficiency may be an important cause of neuropathy, dementia and anaemia in people with HIV led some physicians to offer periodic B-12 injections to their patients. According to Dr Richard Beach ⁽³⁶⁾ injected B-12 supplements appear to improve mental functioning. Another study ⁽³⁷⁾ also showed that vitamin B12 supplementation for at least six months improved mental functioning in HIV-positive people who had been deficient; an untreated control group did not show improvement.

The clinical efficacy of this intervention remains largely unproven, however.

Since peripheral neuropathy can be caused by vitamin B12 deficiency as well as nucleoside drugs or HIV itself, this should always be ruled out before assuming that the neuropathy is HIV or drug-related. As yet there is no evidence that prophylactic treatment with vitamin B12 will reduce the likelihood that neuropathy will develop in those receiving d4T, ddI or ddC.

Absorption of vitamin B12 in HIV-positive people with gastro-intestinal problems is poor unless the vitamin is injected or taken in a form that will dissolve in the mouth and be absorbed across the mucous membranes, according to some nutritionists. This vitamin treatment is available on NHS prescription for dietary deficiency. It needs to be taken in conjunction with folate and a general B-vitamin supplement.

Vitamin B12 and AZT anaemia

Folate levels, on the other hand, may be increased in HIV infection, according to several studies. One study suggested that intravenous drug users might 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.

Folate utilisation can be impaired (producing a functional deficiency despite adequate intake) if B-12, methionine (an amino acid) or zinc are deficient. Some drug therapy such as the anti-PCP drugs Dapsone and Septrin (co-trimoxazole) can also cause functional folate deficiency.

Leucovorin, the active form of folate, is used medically as an antidote to drugs that decrease levels of folic acid. Leucovorin is used to reduce anaemia in people taking Dapsone. Leucovorin is also taken to decrease the bone marrow toxicity of sulfa drugs such as Septrin (co-trimoxazole) and in combination with pyrimethamine to decrease the toxicity of toxoplasmosis treatment. Leucovorin is used in combination with the anti-cancer drugs trimetrexate and methotrexate. Folate supplement is not that effective with Septrin because it is the ability of the body to use folate that Septrin affects rather than folate levels.

Supplements of folate are also prescribed to many symptomatic HIV-positive people due to deficiencies caused by malabsorption in the intestine. Folate deficiency is also common in smokers. Serious deficiency can lead to platelet disorders, a decrease in white blood cells and neuropathy.

Folic acid may defend against certain types of cancer to which people with HIV are particularly vulnerable. Both women and gay men infected with high-risk forms of the human papilloma virus (HPV) are some 35-70 times more likely to develop anal or cervical cancer than the general population. In one Polish study ⁽⁴⁰⁾, HIV negative women who did develop cervical cancer were 7.5 times more likely to have low blood levels of folic acid, an effect exacerbated if they also had low levels of vitamins A, C and E.

Folic acid, homocysteine and cardiovascular disease

Vitamin C/Ascorbic Acid/Ascorbate

Vitamin C is a micronutrient that is present in some food and is necessary for normal human function. Unlike virtually every other animal and plant species, humans cannot manufacture sufficient quantities of vitamin C for themselves. Instead, it has to be obtained from food. Vitamin C is found naturally in tomatoes, potatoes, many fruits and green vegetables, liver and kidney.

Vitamin C is critical to electron transport, collagen synthesis, and various metabolic processes. Its most important role is synthesising collagen, the building block of new tissue. When we get a wound, we need vitamin C to heal. It assists in the absorption of the mineral iron, the activation of the vitamin folic acid, the conversion of the amino acid tryptophan to the neurotransmitter serotonin, and the synthesis of the amino acid carnitine from dietary amino acids. A diet deficient in Vitamin C produces scurvy, the bane of sailors for hundreds of years. This is characterised by connective tissue disorders, impaired wound healing, bleeding gums, and other serious symptoms. Unlike other vitamins, marginal Vitamin C deficiency is somewhat better characterised. It may produce fatigue, muscle weakness, and impaired wound healing.

There are probably more 'myths' about the health properties of vitamin C than any other vitamin. For instance, it is an almost universal belief that it can 'cure colds'. Yet at least 16 double blinded studies have found no benefit ⁽²⁾.

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. Vitamin C was also able to inactivate other viruses in vitro, including herpes simplex, rabies, and tobacco mosaic virus. Massive doses of Vitamin C were used as a polio treatment, although they were ineffective.

There is contradictory statistical evidence about the ability of vitamin C to protect against cancer.

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, though not to a statistically significant level.

However, a study in the American Journal of Clinical Nutrition ⁽⁴³⁾ found that the 25 per cent of adults in the general population with the lowest blood levels of vitamin C had a 57 per cent higher mortality rate from all causes. The researchers did not find this was associated with a greater risk of cardiovascular disease, and suggested it was caused by a greater susceptibility to cancer. (Later studies found that vitamin C did protect against heart disease - see below.)

A study by the US National Cancer Institute in April 2001⁽¹⁷⁹⁾ of 600 people who were at risk of developing stomach cancer due to active infection by the bacterium Helicobacter pylori found that 1000mg of vitamin C twice a day, 30mg of beta-carotene, an antibiotic against H. pylori, or any combination of these three treatments, were four times as likely to experience shrinkage of precancerous abnormalities in the stomach lining than patients given a placebo.

Because of its association with the reduction on cancer and heart disease, the EU RDA of vitamin C was recently doubled from 60mg/day (a scurvy-preventing amount) to 120mg/day.

Different forms of vitamin C are available. Ascorbic acid is a highly acidic powder, which can cause stomach pain and discomfort when taken in large doses. Calcium ascorbate is a less acidic form of vitamin C buffered with calcium which tastes so unpleasant it makes some people sick. It can be dissolved in fruit juice or any liquid to mask the taste. Tablets are a much more expensive way of taking the vitamin in large quantities, but some manufacturers claim that one form of tableted ascorbate, ester-C, yields three times as much vitamin C in the body i.e. a 1 g tablet yields 3 g when metabolised.

If stopping vitamin C, the dose use should be reduced gradually, because the body develops tolerance, and sudden cessation may result in `rebound scurvy'.

Vitamin C and immunity

Current use in HIV