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Supplemental review
   Last updated: 27.10.04
Which vitamins, minerals and antioxidants are worth taking, by Gus Cairns
Besides HAART and my other HIV-related medications, I take another 19 pills a day. This is a cocktail of vitamins, minerals and other compounds collectively termed micronutrients – in order to distinguish them from macronutrients; the fats, carbohydrates and proteins that make up the bulk of our diet.
I take them because research I’ve done around the edges of HIV science – in the grey area between conventional and complementary medicine – strongly suggests that they may help my body to combat the residual damage done by HIV and, perhaps more importantly, drug toxicities.
A lot of physicians would say that all I am doing is creating very expensive urine. An adequate western diet, they say, should contain all the micronutrients I need. And yet, for what it’s worth, my doctor tells me I’m one of the few patients he knows who has been on AZT, ddI, d4T and ddC and shows no sign of facial wasting or other fat redistribution and has only ever had very mild neuropathy. Though I acknowledge that I could just have good genes, I believe my daily supplements also help.


The rationale behind supplementation
These days, reputable proponents of supplementation would not make extravagant claims about curing AIDS. But they would say that certain problems may be helped with the right mix of micronutrients.
HIV medications, as well as HIV itself, place unusual stresses on the system. These include:
  • oxidative damage done to cells – a documented phenomenon which causes, among other things, HIV-related dementia

  • mitochondrial toxicity and high lactate levels – responsible for muscle-wasting and neuropathy

  • alterations in lipid metabolism, resulting in fat redistribution

  • malabsorption of nutrients due to diarrhoea and gut inflammation

Numerous studies over the past three decades have shown that people with HIV have deficiencies in various micronutrients – or in the body chemicals that these help to build – and many of these studies associate these deficiencies with increased mortality or faster disease progression.


Glutathione/NAC
One of most intensively researched micronutrients has been the naturally occurring substance glutathione. This is the most abundant antioxidant in the body. Antioxidants are substances designed to mop up and neutralise the reactive oxygen ions that are created as by-products of metabolism and which would otherwise damage cells and tissues. An impressive number of studies have shown that people with HIV are deficient in glutathione and that deficiency is very strongly associated with higher mortality. In one pre-HAART study1 90% of a group of HIV-positive individuals with near-normal glutathione levels survived for three years, whereas only 30% with glutathione levels less than 75% of normal survived the same period.
The problem with glutathione deficiency is to know whether it predicts illness or is simply a marker for it. However, a smaller number of studies have shown survival and CD4 improvements in people given n-acetyl cysteine (NAC), a precursor of glutathione, since glutathione itself is not well absorbed orally.
Another study2 compared 19 HIV-positive volunteers with 21 HIV-negative ones. The HIV-negative people lost three grams or so of the sulphur-contaning amino acid cysteine, – which forms part of glutathione – in their urine every day, which is the approximate amount eaten in a healthy diet. However, the HIV-positive volunteers appeared to be excreting 10 grams a day. NAC supplementation restored the cysteine and glutathione levels, but although it improved the activity of natural killer cells, it did not boost CD4 cell counts.


Alpha lipoic acid
Another antioxidant studied in people with HIV is alpha lipoic acid (ALA) – a water- and fat-soluble vitamin-like substance that can cross most cell membranes. It is the most powerful antagonist known of a human cellular protein called nuclear factor kappa B, which has to be activated in order for HIV to transcribe its genes3. Some pre-HAART studies4 have shown a direct inhibition of HIV replication in patients given ALA.


Carnitine
The amino acid l-carnitine (LC) is not an antioxidant, but acts as a transporter of cellular fuel into the mitochondria, the cellular sub-organs that are the body’s powerhouses. It is generally prescribed in the more biologically active form of l-acetyl carnitine (LAC). Supplementation with LAC has been shown to regenerate peripheral nerves5 and LC may reduce cholesterol and triglyceride levels (see below).


Glutamine
Another amino acid, l-glutamine, is known to help protect and repair the gut wall and to improve absorption. A recent Brazilian study6 found that supplements containing l-glutamine or alanyl-glutamine can improve the diarrhoea and reduced absorption of antiretroviral drugs seen in people with advanced HIV disease. While glutamine is poorly soluble and unstable in solution, this study demonstrated that its more stable derivative alanyl-glutamine, when given in a high dose, is as effective as glutamine in alleviating chronic diarrhoea and wasting. This, in turn, increases the absorption of antiretroviral drugs in the gut, reducing the likelihood of the development of resistance and further disease progression.


Vitamin B12
Another substance that has attracted attention is vitamin B12. Research from the pre-HAART era consistently showed low serum levels of this vitamin, which is crucial in maintaining the health of the nervous system and red blood cells. Deficiencies of it are implicated in anaemia and dementia. Vitamin B12 is also relatively poorly absorbed by the gut, and malabsorption may be a particular problem for people with diarrhoea.
For these reasons, lack of B12 was seen as a prime candidate for all kinds of maladies, including anaemia and dementia, in the era of AZT monotherapy. One study7 found an average of four years’ increase in AIDS-free time for the period from 1984 to 1996 in those who had adequate levels of B12 compared to those with low levels.



Selenium
The trace element selenium combines with glutathione to make the antioxidant enzyme glutathione peroxidase. In another pre-HAART study8, individuals deficient in selenium were nearly 20 times more likely to die from HIV-related causes than those with adequate selenium levels. Extraordinarily, low plasma selenium was a significantly greater risk factor for mortality than low CD4 count, by a factor of 16, and conferred a more significant risk than deficiency of any other micronutrient. Again, however, the question must be: is low selenium a cause or a consequence of illness?


The Kaiser study
Although many studies show deficiencies of various micronutrients among people with HIV, fewer show any clinical benefit from supplementation. Funding and recruitment are both problems, as few drug companies would sponsor such studies and manufacturers of supplements probably have a vested interest in not testing their products. Even fewer studies are placebo-controlled.
An exception was the recent 12-week study by Dr Jon Kaiser9, which randomised 40 people with neuropathy, and who were taking either d4T or ddI, to either a high-dose vitamin, mineral and antioxidant formula or to placebo. The two groups were essentially similar, except that the placebo group had a shorter duration of neuropathy symptoms (12.2 versus 21.4 months) and a higher CD4 count (467 vs 356 cells/mm3) than the micronutrient group.
The major components of the formula were micronutrients known for their antioxidant effects, including ALA, NAC, l-acetyl carnitine, vitamins C and E, and selenium. Even though the purpose of the study was to see if the supplements could improve symptoms of neuropathy, no significant improvement was seen. Surprisingly, however, the mean absolute CD4 cell count improved significantly in those on micronutrients compared with placebo (+65 vs. -6 cells/mm3; p <0.03). This represents a 26% increase in CD4 cells over 12 weeks.
Although this is the first double-blind, placebo-controlled study to show that vitamins, minerals and amino acids do appear to make a difference in CD4 counts, it must be noted that the study sample was small, and the micronutrient formula used in the study was especially manufactured without the fillers, binders or lubricants found in commercially-available supplements.
Additionally, with baseline levels of around 350 cells/mm3 in those on the supplement, an extra 65 CD4 cells is unlikely to have had a substantial clinical impact. There was also no information regarding the diets or nutritional status of those in the study, or details of their HAART regimens. There is, therefore, only an association with increased CD4 cell counts in the 18 people given this expensive micronutrient formula.


The Thai study
Last year a Thai10 study showed for the first time that a much cheaper multivitamin/mineral tablet – which costs around 60p a month – increased survival in those with CD4 counts below 200 not on antiretrovirals. The Kaiser formula, on the other hand, costs US$142.95 (£76) a month. This was the first ever double-blind, placebo-controlled, randomised trial to assess the clinical significance of vitamins and minerals in people with HIV, and offers some small comfort to those people living in countries where access to HAART is limited or non-existent.
Just under 500 people with CD4 counts between 50 and 550 cells/mm3 were enrolled in the trial and 242 were randomly assigned to take supplements and 239 to take a placebo. At the end of 48 weeks, 23 (5%) had died and 379 (79%) were known to have survived. The rest were lost to follow-up. Eight deaths occurred in the supplement arm, 15 in the placebo arm. The mortality rate was significantly lower in the supplement arm in those who began the study with CD4 counts below 200 cells/mm3. Those with CD4 counts between 101-200 cells/mm3 were three times more likely to survive, and those with CD4 counts below 100 cells/mm3 were four times more likely to survive than the people with similar CD4 counts not taking the supplements.


Some other studies
Numerous small studies among people with HIV occurred in the early years of AIDS and continue at a lower rate. They use different single substances or different mixtures, are trialled on very different populations and are designed to treat different conditions. Here are just a few, chosen purely to illustrate the variety of approaches. It is important to remember, however, that there are probably just as many, if not more, studies to show that supplements make no difference:
  • A study11 combining vitamin E supplementation with exercise found that while aerobic exercise was associated with the best improvements in blood triglyceride levels, vitamin E intake was associated with a reduction in insulin resistance and a significant reduction in high blood pressure.

  • In a study of pregnant women in Nepal12, both HIV-positive and -negative, supplementation with 23,300 IUs of vitamin A or beta carotene a week reduced maternal mortality by as much as 50%. In a South African study13, three high doses of vitamin A given at the ages of three, six and nine months to HIV-positive babies reduced hospitalisation for diarrhoea by 77%.

  • A randomised 12-week open-label study14 gave 35 men with diarrhoea, who were taking nelfinavir or Kaletra, probiotic supplements of ‘friendly’ bacteria (Lactobacillus acidophilus and Bifidobacterium) combined with soluble fibre. If there was no improvement after four weeks, the amino acid l-glutamine, or ‘standard of care’ remedies such as loperamide were added. Diarrhoea resolved completely in nine of 16 on the supplements but did not change significantly in people taking loperamide alone.

  • In a small study15 involving 24 individuals, calcium supplements reduced nelfinavir-induced diarrhoea in as little as 48 hours. Before supplementation, half reported moderate or severe diarrhea and half, mild diarrhoea. After supplementation with 500mg of calcium twice a day all 24 reported improvement, with 67% reporting normal stools and the rest, mild diarrhoea.

  • Muller16 gave high doses of NAC and vitamin C to eight patients with HIV not on HAART. In the five patients with CD4 counts under 200, there was a significant rise in CD4 counts and a 0.8 log drop in plasma viral load.

  • A team of Dutch doctors17 treated patients with NRTI-related lactic acidosis with a twice-daily intravenous “rescue regimen” consisting of doses similar to the Kaiser study of the B vitamins thiamine(B1), riboflavin (B2), niacin, pantothenic acid plus LAC. All of the six patients recovered between four days to three weeks later.

  • In a German study18, 1000 mg of L-carnitine (LC – not the same as LAC) was given twice daily to 12 men who had experienced lipodystrophy. After twelve weeks of treatment, no improvements in body shape changes were reported, but there was a drop in both total cholesterol and LDL (so-called ‘bad’ cholesterol).



Choose wisely
Not all micronutrients are benign and interactions with HIV drugs have been very poorly researched. However, a recent study19 found that high-dose vitamin C (1000mg/day) reduced plasma indinavir levels by 26% – although these were in HIV-negative people given unboosted indinavir.
Some vitamins and minerals are toxic if taken at high doses.
  • Vitamin A is toxic above 20,000 international units (IUs) or 3mg. Beta-carotene is a safer alternative.

  • Vitamin B6, often given to reduce neuropathy symptoms, can cause neuropathy in doses of more than 200mg a day.

  • Vitamin C is very acidic and doses above 1,000mg can cause severe diarrhoea and stomach cramps. The body develops tolerance for high doses and sudden withdrawal can cause scurvy. High doses can also cause kidney stones.

  • Vitamin D is toxic above 10,000 IUs (250mcg).

  • Vitamin E is not exactly toxic but high doses can thin the blood in the same way as drugs such as aspirin and warfarin.

  • Zinc may be problematic, since HIV uses zinc as a component of its nucleocapsid protein. One study found doses well above 11.6 mg a day were associated with higher mortality in HIV-positive individuals20. Another study found zinc supplementation boosts lymphocyte counts . A sensible limit is 15mg a day.



Recommendations
“I’d never recommend any particular supplement or regimen of supplements,” says Sean Hosein of the Canadian Aids Treatment Information Exchange. “Instead, I’d suggest people talk to open-minded doctors and to pharmacists.”
Health food shops are probably not the best source of advice for HIV-positive people. Beware also that substances marketed as food supplements do not have to undergo the same rigorous testing as prescribed or over-the-counter drugs, and there are widely differing standards of manufacture and quality. “One size does not fit all,” adds Hosein, “and there is no magic substance.”
Professor Edzard Ernst of Exeter University, the only professor of complementary therapy in the UK, echoes Hosein’s caution.
“An ‘alternative’ cure for HIV is a contradiction in terms. If an ‘alternative’ therapy was shown to be as powerful as antiretrovirals, it would become the standard of care, and the pharmaceuticals would be patenting the active ingredients.
“A rule of thumb is that if a substance’s properties sound too good to be true, they probably are,” concludes Professor Ernst. “Raising hope is a very good thing in medicine, but raising false hopes is not.”


References
1.Herzenberg LA et al. Proceedings of the National Academy of Sciences 94:1967-1972, 1997.
2.Breitkreutz R et al. AIDS Res Hum Retroviruses 16(3):203-9, 2000.
3.Suzuki YJ et al. Biochem Mol Biol Int. 36(2):241-6, 1995
4.Baur A et al. Klin Wochenschr. 2: 69(15):722-4, 1991.
5.See ‘Enduring Pain’, ATU 137, 2-5, 2004.
6.Bushen O Y et al. Clin Infect Dis 38: 1764-1770, 2004.
7.Tang et al. International AIDS Conference, Vancouver, abstract Mo.C.320, 1996.
8.Baum MK et al. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 15(5):370-374, 1997.
9.Kaiser J et al. 11th CROI, San Francisco, abstract 494, 2004.
10.Jiamton et al. AIDS 17:2461-2469, 2003.
11.Gavrila A et al. Clinical Infectious Diseases 36:1593-1601, 2003.
12.West KP et al. BMJ 318:570-575, 1999.
13.Coutsoudis A et al. Am J Public Health 85:1076-1081, 1995.
14.Heiser CR et al. Antiviral Therapy 8:L71, 2003.
15.Perez-Rodriguez E et al. 39th ICAAC, San Francisco, abstract 1308, 1999.
16.Muller F et al. European Journal of Clinical Investigation 30(10):905-14, 2000.
17.Brinkman K et al. AIDS 14(17):2801-2803, 2000.
18.Slain D et al. 43rd ICAAC, Chicago, abstract A-1610, 2003.
19.Tang AM et al. American Journal of Epidemiology 138 (11):937-951, 1993.
20.Isa L et al. Int J Clin Lab Res 22:45-47, 1992.