NAC: First Controlled Trial, Positive Results

NAC (N-acetylcysteine), a low-cost potential treatment approved for certain non-HIV medical uses, has for years been one of the most popular "alternative" treatments sold by the AIDS buyers' clubs in the U.S. For many years researchers have had well-designed research protocols ready to go to scientifically test whether NAC can be helpful in HIV infection, but finding the funds for this work has been extraordinarily difficult. The first controlled trial started in late 1993 at Stanford University; now its results have been publicly reported at the May 21-24, 1996 meeting OXIDATIVE STRESS AND REDOX REGULATION: CELLULAR SIGNALING, AIDS, CANCER, AND OTHER DISEASES, at the Institut Pasteur in Paris.(1)

Although the design of this study was too limited to tell definitively if NAC improves patient survival, it did show that the condition NAC is intended to correct (low glutathione levels in blood cells) strongly predicts poor survival. NAC was found to increase glutathione levels, and possibly to improve survival. (Glutathione is an antioxidant found in all cells, and is the primary intracellular defense against oxidative stress. It is critical for energy metabolism, cell division, and other functions, and is essential for the life of the cell. Glutathione is a small peptide, consisting of three amino acids; NAC supplies cysteine, which is the limiting amino acid for the production of glutathione. In addition to the need to maintain glutathione levels to prevent oxidative damage, it is possible that low glutathione levels may accelerate HIV replication.)

History

NAC has been controversial in the U.S. medical community, because several years ago a small study conducted at the U.S. National Institutes of Health reported that NAC was not found in the blood when taken orally. Other scientists replied that the NAC was well known to be absorbed but was quickly changed by the liver into other chemicals which did not show up in the tests which were used in that study. But the case against NAC being absorbed in useful amounts is the only one that got widespread attention.

(Several years ago, this writer asked the lead researcher on the NIH NAC study how he would answer the argument that the test he used could not usefully determine bioavailability, as the NAC would be changed into related chemicals which that test would not measure. He told us that his trial was the kind required by the FDA for a pharmacokinetic study -- and that in addition his results were consistent with other reports in the literature. We did not think that this defense addressed the issue. At about that time, we were in a room with hundreds of AIDS physicians and research assistants where the NIH trial results were presented. Those doctors walked out of that room convinced that NAC was not absorbed and therefore useless. We would have thought the same thing too, if we had not talked to the parties involved. This is why most of the U.S. AIDS medical community today is convinced that NAC is not absorbed and therefore ineffective.)

The Stanford Trial

Now there is new data. The recent NAC trial was done at Stanford's Herzenberg Laboratory, one of the world's leading research groups on flow cytometry, the technology which is widely used to measure CD4 and CD8 counts, and which can also count many other kinds of cells. Flow cytometry works by treating cells so that different kinds will glow differently when exposed to a particular wavelength of light (which is usually provided by a laser). The cells move individually past the laser beam, and the fluorescence (glowing) of each is measured by a sensor and counted by computer. This technology allows cells to be divided into different populations based on many different characteristics. And by chemically reacting glutathione so that it will fluoresce, this method is also able to measure the glutathione level within each cell while simultaneously detecting if it is a CD4 cell, a CD8 cell, or some other cell type. As explained above, glutathione is a vital antioxidant in the cell -- and low intracellular glutathione is the condition which NAC is proposed to correct.

The Stanford study collected baseline data on over 200 HIV-positive volunteers; 83 of them were enrolled in a double-blind placebo-controlled trial designed primarily to test whether HIV-infected people can absorb NAC (since the earlier NIH study had raised doubts). Since all but two deaths occurred in those who entered the study with a CD4 count under 200, further survival analysis was limited to this group. Two to three years later (depending on how soon people enrolled in the trial), the researchers surveyed all subjects who contributed baseline data, to see who had survived. Some of the details of the study are complex, but basically the findings were:

(1) Low glutathione levels in CD4 T-cells mean increased risk of death. This analysis was done in those volunteers who for any reason did NOT take NAC in the study (so the researchers could see the natural-history association of mortality with glutathione levels, in the absence of treatment to restore those levels). Statistical analysis showed that those with glutathione levels equal to the group mean (0.98) had a two- to three-year survival rate of 65%. But of those with glutathione levels of 0.6, only 25% survived. The group mean itself was below normal, as glutathione levels are lower than normal in people with AIDS, as with many other serious illnesses.

(2) Oral use of NAC increases glutathione levels in blood cells. A comparison of the 27 subjects who received NAC and for whom data was available, vs. the 26 who received placebo for the 8 weeks of the formal trial, showed that those on placebo had essentially no change; but in those who took NAC, glutathione levels went up about two thirds of the way to normal. (While the amount of change was only 10-12%, it could be meaningful since glutathione levels are fairly tightly regulated by the body, and normally cannot change very much.)

(3) This study found that NAC was safe; there were no adverse effects attributed to the drug. (There have been other reports of gastrointestinal distress at high doses.)

(4) Taking NAC was associated with increased survival -- although causality could not be proved by this study. In this trial, a direct survival comparison between those assigned to take NAC vs. those assigned to placebo was not meaningful, for two reasons. First, volunteers in both groups were offered open-label NAC for six months after the 8-week formal study was completed -- and most accepted the offer. This means that most of those assigned to "placebo" really took almost as much NAC as those assigned to the NAC group. Since this trial was not designed to test survival, there was no one who received placebo for the whole time.

So the researchers looked at other comparisons -- which made the interpretation of the data more difficult and more uncertain. They found that on the average, the group that took NAC (for six to eight months) survived about six to eight months longer than the group that didn't take NAC.

However, this was not a comparison between randomized groups, because this trial was not designed to allow such a comparison; those who took NAC were self-selected, and it is possible that these patients were healthier, or took better care of themselves in other ways, or had a better prognosis for some other unknown reason. This means that from this trial there is no way to be sure that using NAC contributed to survival.

Therefore the investigators could only state that they see the results as consistent with the idea that NAC may improve survival. They hope to find funding as soon as possible for a proper prospective clinical trial to test this possibility.


[Note on acetaminophen (Tylenol, etc.): NAC in very large doses has long been approved by the FDA for treating poisoning caused by acetaminophen overdose. NAC is an antidote because overdoses of acetaminophen drastically deplete the glutathione in the liver, resulting in severe liver damage, and NAC provides the cysteine necessary to replenish the glutathione.

The FDA has warned heavy drinkers that alcohol use can reduce levels of glutathione, and acetaminophen can depress these levels further, causing risk of liver toxicity. Since HIV infection also causes reduced glutathione levels, Leonard Herzenberg, Ph.D., and Lenore Herzenberg, Ph.D., both of Stanford University Genetics Department and principle investigators in the NAC study described above, have long been concerned that acetaminophen or other medications which reduce glutathione levels might be harmful for persons with AIDS or HIV, and that patients and physicians could be cautious about using these drugs.

References

1. Herzenberg LA, De Rosa S, and Herzenberg LA. Low glutathione (GSH) Levels in CD4 T Cells Predict Poor Survival in AIDS; N-Acetylcysteine (NAC) May Improve Survival. OXIDATIVE STRESS AND REDOX REGULATION: CELLULAR SIGNALING, AIDS, CANCER, AND OTHER DISEASES, Institut Pasteur, Paris, May 21-24, 1996.