NAC: Is It Absorbed?

NAC (N-acetylcysteine), a variant of the amino acid cysteine
which is found in certain foods, is sold in buyers' clubs and
health-food stores and has been used as a possible treatment for
HIV infection for over two years; in San Francisco it is one of
the most popular products sold at the buyers' club. Despite
increasingly impressive laboratory science supporting the
rationale of this treatment use, and the record of safety of the
drug, NAC has followed the usual pattern in AIDS drug development
of several years wasted, for no scientific, medical, or ethical
reason, between the time a drug is known to be promising and the
time is is tested as a treatment in a scientific trial. A small
trial is now ongoing at the U. S. National Institute of Allergy
and Infectious Diseases (NIAID), near Washington, D. C. (see AIDS
TREATMENT NEWS #138, November 1, 1991), and another trial, a
collaborative effort between Stanford and Project Inform, may
soon begin.

NAC is not easily characterized as either an "antiviral" or
as an "immune-based therapy." Instead, it may intervene at
various points in the pathogenesis (development) of HIV disease,
by restoring normal levels of glutathione -- a substance
essential to life which has been found to be abnormally low in
T-helper cells and other blood cells in HIV-positive people.
Glutathione is composed of three amino acids -- glutamic acid,
cysteine, and glycine -- but the limiting factor in determining
the body's supply of glutathione is usually cysteine, which is
supplied by NAC. (Some health-food stores sell glutathione pills,
but most experts believe that taking NAC is a much better way to
raise glutathione levels than taking glutathione itself.)

NAC is used in mainstream medicine, in very large oral
doses, as an antidote for poisoning caused by an overdose of
acetaminophen (e.g. Tylenol). This poisoning causes an extremely
low level of glutathione in the liver, which can cause death; NAC
works by restoring this glutathione level.

Another drug, called procysteine, may also be effective in
raising glutathione levels; procysteine is now in clinical
trials, but is not generally available.

Glutathione is important as an antioxidant, helping to
protect cells from damage caused by oxidizing agents. Recent
laboratory studies have suggested that an antioxidant might also
have an antiviral effect. A normal signaling system inside the
cell uses low concentrations of the oxidizing agent hydrogen
peroxide -- but this same signal was also found to increase the
growth of HIV in cells infected with that virus. Abnormally low
levels of glutathione might allow the hydrogen peroxide in the
cell to increase, causing HIV to grow faster than it otherwise
would. [Note: hydrogen peroxide has sometimes been promoted as
an "alternative" AIDS treatment; the research described above
suggests that it might be harmful. AIDS TREATMENT NEWS published
a warning against using hydrogen peroxide as an AIDS treatment
(issue #132, August 9, 1991, and issue #134, September 6, 1991).]

The only way to know with confidence what role, if any, NAC
has in HIV treatment is through clinical trials. But since the
necessary trials have not been done, people need to make
decisions now on the basis of what information is available --
the laboratory science, and anecdotal reports. What we have
heard anecdotally has generally been good, but not dramatic;
clearly NAC is only part of the answer, at best, to HIV
treatment. T-helper counts seldom show large increases, although
NAC might be helping stabilize the counts. People often do
report feeling better and having more energy, an effect likely to
occur quickly, within several days after starting the treatment.
NAC may be especially useful for certain persons with AIDS-
related wasting which is not due to obvious problems such as
inadequate food intake or gastrointestinal disease.

Could NAC improve the functioning of T-helper cells,
independently of whether the counts increase? One way to explore
this possibility would be to include a delayed hypersensitivity
test, such as the Merioux "MULTITEST CMI," in a controlled study
of NAC.

One laboratory study by researchers at the Linus Pauling
Institute has suggested that combining NAC with vitamin C might
be beneficial. (Harakeh S and Jariwalla RJ. Comparative study of
the anti-HIV activities of ascorbate and thiol-containing
reducing agents in chronically HIV-infected cells. American
Journal of Clinical Nutrition. 1991; volume 54, pages 1231S-
1235S). This paper noted that a dose of about 12 grams per day
of vitamin C, given to healthy adult volunteers, had produced the
blood levels used in their laboratory tests.

Is NAC Absorbed?

An early report from the ongoing NIAID trial of NAC has
raised doubts as to whether NAC is absorbed well enough when
taken orally to be useful as a treatment. This writer was
present when the data was presented at a meeting of the AIDS
Clinical Trials Group in April. We believe that most physicians
present left that room thinking that orally administered NAC was
dead as a potential AIDS/HIV treatment. We, too, would have
thought so, if we had not been following this treatment closely.
But the report was preliminary; the NIAID research team had been
asked to provide the interim results from its work in progress.
The researchers conducting the trial do not believe that the drug
has been ruled out; they are continuing the study.

The data first addressed the question of whether NAC was
absorbed when taken orally, by comparing blood levels after oral
doses of the drug vs. blood levels after intravenous doses. This
is an obvious test to run, and one that the FDA usually requires
for a drug intended for oral use. The result was that the
intravenous administration led to high concentrations of NAC in
the blood, while the oral administration led to almost none.

That result would seem fairly conclusive, but NAC experts we
talked to explained that there is more to the story. First, that
test was not new; NAC has long been used orally in Europe (for
treating bronchitis), and similar tests of oral absorption had
been done before. And they had found similar results; as with
many drugs, only a small part of the NAC taken orally is found in
blood tests for NAC.

But the tests are limited, because NAC is quickly changed
into other compounds by the time it reaches the bloodstream.
Testing only for NAC will miss these other chemicals, which still
may help to increase the glutathione level in cells; apparently
it has not been feasible to test for everything which NAC might
become.

But in that case, why would much higher levels of NAC be
found in the blood when the drug was given by injection? One
likely possibility is that intravenous administration could
supply NAC faster than the body could transform it (to substances
which would not show up on the tests being used).

Another reason for being skeptical of the idea that NAC
could not work as an oral drug is that it does work as an
antidote for acetaminophen overdose -- meaning that it must be
absorbed when taken orally, in a form that can raise the
glutathione level within liver cells, which NAC must do to treat
acetaminophen poisoning, and which is also the effect being
sought when NAC is used in HIV treatment. (On the other hand,
the case could be made that the liver is unique, because it gets
the "first pass" blood circulation from the stomach, and is often
exposed to higher levels of oral drugs than is the rest of the
body. Yet this may not be relevant in the case of NAC, since the
liver in involved with its normal metabolism and supply to other
tissues.)

Some investigators believe that a better test of NAC is
whether it raises the level of glutathione, within T-helper and
other white blood cells. This measurement is somewhat difficult,
as it requires special equipment and skill. Preliminary results
were given at the same meeting which presented the absorption
data; in these tests, the laboratory workers who analyzed the
data were blinded as to which samples were from persons receiving
NAC, and which were from an untreated HIV-negative control. All
the samples tested (from volunteers in the small NIAID study
mentioned above) showed normal glutathione levels both before
treatment with NAC, and after it.

This result has been questioned since several published
studies have shown that HIV-positive persons have lower than
normal levels of glutathione; here, everyone in the trial was
HIV-positive, but nobody's glutathione level was low. If it was
simply a case of the NAC not working, one would have expected the
glutathione levels to be low both before and after treatment.
(And if the levels were normal to begin with, NAC would not have
been expected to raise them; glutathione levels are regulated by
the body, so NAC probably could not increase the amount of
glutathione if it already was normal.)

These measurements of intracellular glutathione levels are
fairly difficult; in the NIAID trial, the fresh blood samples had
to be shipped 2,500 miles to a laboratory which had the necessary
equipment. Confirmatory tests, including some at a different
laboratory, are now in progress.

Early results of the NIAID trial had previously been
examined at an invitation-only meeting of NAC and glutathione
experts in February 1992. We were not at that meeting, but have
heard that these issues were raised. In the ACTG meeting in
April, however, there was little time on the agenda for NAC, only
a few minutes -- just enough to present the data itself, but not
enough to consider different interpretations, or address the
questions which had been raised.

Although the NIAID trial was not designed to test the
efficacy of NAC, it did measure T-helper counts, and indicators
of viral burden (both acid-dissociated p24, and plasma viremia).
None of the study volunteers showed improvement in any of these
measures.

Because of the possible importance of NAC and of the
approach to therapy which it represents -- because of the great
need for safe and affordable treatments, and for treatments which
may reduce HIV activity in chronically infected cells, which AZT,
ddI, and ddC do not do -- we believe that it would be a mistake
to abandon oral NAC based on doubts raised by the early data from
an unfinished study. The critical question remains the same as
it has been for the last several years: Can NAC help in the
treatment of AIDS or HIV? The answer remains unknown.

Project Inform Will Assist New Study

The NIAID trial mentioned above was designed primarily to
test safety and absorption of different doses of NAC. Another
study, cosponsored by Project Inform, has been developed to
examine earlier reports that NAC can raise glutathione levels in
T-helper cells and other white blood cells. This study was
designed in a team effort including: Stanley Derezinski, M. D.,
of the AIDS Community Research Program in Redwood City,
California; Leonard Herzenberg and Leonore Herzenberg, both Ph.D.
and both members of the genetics department at Stanford
University, and their associates; and staff of Project Inform.
The Herzenbergs have been the driving force in bringing this
potential treatment to the attention of the U. S. scientific and
medical community.

This study, now seeking the required approvals, will monitor
glutathione levels while patients use 600 mg twice per day of a
NAC formulation which is widely used in Europe. There will be 30
subjects in this trial, ten in each of three groups. One group
will be persons with T-helper counts over 200, and a second will
be those with under 200; both of these groups will start using
NAC immediately. The third group will have five persons with T-
helper counts over 200 and the other five with under 200; it will
delay starting NAC for seven weeks, to serve as a control group
during this time. Volunteers will be assigned at random to the
immediate or delayed treatment groups. Glutathione levels in
blood cells will be measured twice before treatment begins, and
four times afterwards. Also, if funding permits, viral load
measures, including acid-soluble p24 and DNA/RNA PCR, will be
done before treatment, and on days 14 and 42 after treatment
begins.

No placebo will be used, but the researchers will be blinded
when they measure the blood samples -- they will not know which
are from persons taking NAC and which are not.

This trial has not started yet. When approvals are
received, Project Inform will handle all of the recruiting.

For More Information

* AIDS TREATMENT NEWS has published background articles on NAC.
The major ones are in issues #88 (October 6, 1989), #92 (December
1, 1989), and #121 (February 15, 1991).

* A two-page fact sheet on NAC is available from the PWA Health
Group, the buyers' club in New York, 212/255-0520. It examines
the difference between brands, possible problems if NAC is mixed
with certain antibiotics, and the preliminary results of the
NIAID study described above.

* Dozens of technical articles have been published. A handful of
the most important recent ones are listed below. They include
bibliographies of other articles, for those who want to study
this subject in more depth.

Selected Bibliography

Staal FJT, Ela SW, Roederer M, Anderson MT, Herzenberg LA, and
Herzenberg LA. Glutathione deficiency and human immunodeficiency
virus infection. THE LANCET. April 11, 1992; volume 339, pages
909-912.

Roederer M, Ela SW, Staal FJT, Herzenberg LA, and Herzenberg LA.
N-Acetylcysteine: A New Approach to Anti-HIV Therapy. AIDS
RESEARCH AND HUMAN RETROVIRUSES. 1992; volume 8, number 2, pages
209-217.

Staal FJT, Roederer M, Israelski DM, and others. Intracellular
glutathione levels in T-cell subsets decrease in HIV-infected
individuals. AIDS RESEARCH AND HUMAN RETROVIRUSES. 1992; volume
8, number 2, pages 305-311.

Kalebic T, Kinter A, Poli G, Anderson ME, Meister A, and Fauci
AS. Suppression of human immunodeficiency virus expression in
chronically infected monocytic cells by glutathione, glutathione
ester, and N-acetylcysteine. PROCEEDINGS OF THE NATIONAL ACADEMY
OF SCIENCES, USA. February 1991; volume 88, pages 986-990.