[Disclosure: The senior authors of the NAC study reported here, Drs. LA Herzenberg, both Ph.D., of the Department of Genetics at Stanford University, are on the board of AIDS Treatment News Associates, our nonprofit arm which helps fund newsletter subscriptions for prisoners, persons with low income, and others who cannot pay for copies. The Herzenbergs have a use patent for NAC in the treatment of HIV infection, and have pledged any proceeds to further research.]
A placebo-controlled trial in over 60 HIV-positive volunteers found that NAC (N-acetylcysteine) significantly increased abnormally low blood and T-cell levels of glutathione, an important antioxidant found in every cell in the body and essential for life.(1) The report was published October 1 in the European Journal of Clinical Investigation.
Also, a follow-up two to three years after the original study found that those volunteers who had taken NAC (either by random assignment in the 8-week placebo-controlled study, or by choice in a 24-week open label period which followed, or both), had less than half the risk of death of those who had not taken NAC (this study was conducted several years ago, before protease inhibitors were available). While the survival difference was highly significant statistically (p < .0001), this study cannot prove that NAC was responsible for the difference, because it was not designed to look for survival differences, and had "a potential bias introduced by the self-selection of a proportion of placebo-arm subjects who elected for open-label NAC, and by the [inability] to obtain detailed follow-up information (drug usage, cause of death) for trial subjects once they completed the open-label trial segment."(1) NAC did not change viral load, CD4 count, CD8 count, or other currently used "surrogate markers" of HIV progression. (Low glutathione level appears to be a strong predictor of risk of death in persons with HIV(2) -- but it is not yet known if glutathione level could be a surrogate marker for drug development.)
The trial was conducted in San Francisco from 1990 to 1996, and selected HIV-positive volunteers who were in relatively good health, but were found to have a low blood level of glutathione. Its recent publication prompted an extensive literature review by the authors, who found an impressive body of recent articles on glutathione levels and health benefits of NAC treatment, not only in HIV but in many other diseases as well. (For some of the citations to articles published within the last three years, see "NAC and Glutathione: Recent Publications," in this issue.)
The authors believe that the low glutathione level which develops in many patients with HIV disease is a nutritional deficiency which can and should be corrected. "Glutathione is a central component of all cells, and glutathione deficiency is associated with poor prognosis in many, many diseases," said Leonore (Lee) Herzenberg. "The level of glutathione is tightly regulated in cells. If nature has gone to the trouble of maintaining those levels, logic says it should be restored to that level if you can. It's like a vitamin deficiency. Any vitamin deficiency would immediately be corrected, and we believe that this is equivalent to a vitamin deficiency." (Quoted from Stanford University press release, Sept. 27.)
There is reason to believe that Tat, a toxic protein produced by HIV, may strongly reduce glutathione levels, in addition to its other effects; for example, a study published this year found that mice which were genetically modified to produce HIV-1 Tat have very low glutathione levels.(3) This suggests that the low glutathione levels found in persons with HIV could be a specific effect of this virus -- not only a consequence of malnutrition or other effects of illness. And because low glutathione can cause many adverse health effects, this mechanism might be important in HIV disease progression or severity.
The authors also cite evidence suggesting that persons with HIV should avoid acetaminophen (Tylenol® and other brands), since it tends to lower glutathione levels, potentially causing problems in persons whose levels are already too low.
Since NAC is inexpensive, and safe enough to be used with minimal medical supervision, the authors note it could be made available in developing countries.
Baseline glutathione levels were significantly lower in volunteers who were taking AZT or other nucleoside analogs (the only anti-HIV drugs then available) than in those not taking these drugs. However, none of the baseline measurements in this study suggested that those who were on nucleoside analog treatment had more advanced HIV disease than those who were not -- suggesting that the nucleoside analogs in use may have been lowering glutathione levels, possibly contributing to drug toxicities which might be lessened by restoring glutathione.
The lower the glutathione level in patients, the more it was raised by NAC -- so these low levels in those taking nucleoside analogs tended to be corrected by NAC treatment. However, statistical analysis did not show any significant interaction between treatment arm (NAC or placebo) and use of nucleoside analogs. (In other words, the greater effect of NAC was explained by the lower starting level of glutathione, not by the use of antiretrovirals.)
The "Discussion" section(1) has a number of references to studies which show glutathione deficiency in HIV disease, and link that deficiency to disease progression and decreased survival. The authors refer to recent work by Breitkreutz, Droge, and colleagues showing a massive sulfur loss in HIV infection which is not corrected by modern antiretroviral treatment(4), and showing improvement in T-cell and NK-cell function after NAC treatment, in randomized trials.(5) These trials, published earlier this year, tested NAC in HIV-positive volunteers (40 patients who were using antiretroviral treatment, and 29 who were not, in a separate study); they found "consistent improvement of several immunological functions" in both studies, which they attributed to supplementation of cysteine which had been depleted, not to general immune stimulation. Also note the Stanford team's earlier work on glutathione deficiency and impaired survival.(2)
The Stanford study used a very high dose of NAC (starting at 8000 mg per day in distributed doses, with reductions if volunteers said they could not tolerate this dose); doses were reduced to a median of 5300 mg, but the reductions were comparable in both the placebo and the NAC groups. So the adverse effects reported during the trial, mostly minor gastrointestinal complaints, may have been due to other ingredients in the NAC or placebo preparation. Much lower amounts are used in the community, usually less than 2000 mg per day divided into two or three doses It is not known if high doses would be safe for long-term use; Breitkreutz and Droge's group used large doses every other day, but decreased the dose if the plasma glutamine level became too high, to avoid any possibility of toxic ammonia accumulation.(5)
Note: Glutathione levels in whole blood or in T cells -- which in theory could be used to identify patients most in need of supplementation -- are hard to measure accurately, and these tests are unlikely to be generally available in the near future. But NAC appears nontoxic and is fairly inexpensive, so there seems to be little "down side" to using it.
Restoring Glutathione Levels
Glutathione is made up of three amino acids (glycine, cysteine, and glutamic acid). In HIV and certain other diseases there is reason to believe that cysteine is usually the limiting factor most responsible for an abnormally low glutathione level. Too low a level of glutathione is harmful in many ways (and causes death from liver damage if it becomes low enough). But cysteine cannot be taken by itself, because it is toxic if used that way.
Glutathione has been sold as a health-food supplement, but most researchers believe that it can be provided more efficiently by other substances which can safely deliver the needed cysteine. Of these, NAC is the best known and most available. Another drug, Procysteine or OTC, has been tested in clinical trials; it appears to be generally equivalent to NAC, with the main practical difference being that it is not in common use and therefore can be patented more effectively. It is not generally available today.
Oral NAC has long been used in Europe for treating bronchitis and other conditions.(6) The European preparations are packed in argon in individual doses, or provided in sealed tubes with instructions for use within a limited time after opening, or otherwise carefully protected against oxidation. In the U.S., NAC has been sold as a health-food supplement without such packaging and without necessarily the same quality control (at least one AIDS buyers club has imported a European NAC for years -- see "Availability," below). We have not heard of problems with U.S. health-food products, but the Herzenbergs are concerned about quality control, and have worked with companies to introduce a version of NAC like that used in Europe.
Historical Note on NAC and AIDS
Until recently most of the medical and research interest in NAC has been in Europe. Twelve years ago Dr. Wulf Droge in Germany wrote to colleagues around the world suggesting that NAC be researched for possible use in HIV. One of the letters came to the Herzenbergs at Stanford University, who since then have been the major champions of NAC HIV research in the U.S. But so far this treatment possibility has been largely ignored by other U.S. AIDS researchers.
Part of the reason is a report several years ago which appeared to show that NAC is not orally bioavailable. In fact, oral NAC has been tested with apparent success in a number of medical conditions -- and is even FDA-approved in the U.S. in very large doses for treatment of acetaminophen overdose poisoning. It appears that there were technical problems with the bioavailability study, as NAC quickly leaves the bloodstream since the body uses it to produce glutathione, which is difficult to measure correctly. But the impression persisted that NAC is not a serious treatment possibility. And none of the major pharmaceutical companies have tried to develop NAC as an HIV treatment, probably because it is in common use and not readily patentable (a use patent, which the Herzenbergs obtained, is the weakest kind of patent -- since it usually cannot be used against business rivals who say they are selling the product for some other purpose).
And NAC is a different kind of HIV treatment than the others. It is not an antiretroviral in patients. Also, it is not primarily an immune-based treatment (although there might be some immune benefit -- the data are not yet clear). Rather, NAC is a treatment to correct one specific consequence of HIV infection -- the low glutathione levels in many patients, which could cause many health problems. Since NAC does not reduce viral load, conventional treatments will also be needed. But many people with HIV either do not need antiretrovirals (if they are long-term non-progressors), or do not need them yet, choose not to use them, or cannot obtain them -- and in such cases NAC might be used alone.
The Stanford study was supported largely by grants from the U.S. National Cancer Institute, with additional assistance from the University of California University-wide AIDS Research Program, the Unicorn Foundation (Chicago), and Project Inform (San Francisco). The Elan Pharmaceutical Corporation provided the NAC and placebo.
The Herzenbergs have worked with a Canadian company, BioAdvantex Pharma Inc., which plans to introduce a NAC supplement similar to the European products (except that it is formulated to not contain lactose, for persons who are lactose intolerant); it should be available under the brand name PharmaNAC (or Thiolex) later this month. When it becomes available it can be ordered at 1-888-550-5350.
Also, at least one HIV buyers' club, the PWA Health Group in New York, has imported a European NAC product for years. Recently the PWA Health Group merged with DAAIR (Direct Access Alternative Information Resources), http://www.daair.org, which currently offers a number of NAC products, including at least one European formulation.
We have no independent information on the quality of these or other NAC products.
Unfortunately, the U.S. has done much worse than Europe in regulating the quality control of nutritional supplements, herbal products, or other health products that people use, but which are not fully recognized by the medical-industrial complex. Much of the reason for this failure may be the lack of a middle ground between the extremes of little regulation, vs. banning many of the products entirely. At least one private company, Consumer Labs, is trying to fill part of this gap with a rating service; it tests supplements, at the request of the manufacturer or otherwise, lists the products that pass on its Web site (http://www.consumerlabs.com), and offers to license its seal of approval to these manufacturers. (A recent testing of SAMe formulations -- a somewhat expensive supplement which might be useful to some persons with HIV or AIDS, but has not yet come to the attention of the AIDS community -- found that half of the products examined did not pass quality control tests.) Consumer Labs may test NAC in the future.
De Rosa SC, Zaretsky MD, Dubs JG, Roederer M, Anderson M, Green A, Mitra D, Watanabe N, Nakamura H, Tjioe I, Deresinski SC, Moore WA, Ela SW, Parks D, Herzenberg LA, and Herzenberg LA. N-acetylcysteine replenishes glutathione in HIV infection. European Journal of Clinical Investigation 2000; volume 30, pages 841-856.
Herzenberg LA, De Rosa SC, Dubs JG, and others. Glutathione deficiency is associated with impaired survival in HIV disease. Proceedings of the National Academy of Sciences, USA. 1997; volume 94, number 5, pages 1967-1972.
Choi J, Leu RM, Kunda RK, and others. Molecular mechanism of decreased glutathione content in human immunodeficiency virus type 1 Tat-transgenic mice. Journal of Biological Chemistry. 2000; volume 275, number 5, pages 3693-3698.
Breitkreutz R, Holm S, Pittack N, and others. Massive loss of sulfur in HIV infection. AIDS Research and Human Retroviruses. 2000; volume 16, number 3, pages 203-209.
Breitkreutz R, Pittack N, Nebe CT, and others. Improvement of immune functions in HIV infection by sulfur supplementation: Two randomized trials. Journal of Molecular Medicine. 2000; volume 78, number 1, pages 55-62.
De Flora S, Grassi C, and Carati L. Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. European Respiratory Journal. 1997; volume 10, number 7, pages 1535-1541.
ISSN # 1052-4207
Copyright 2000 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.
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