DHEA: Mystery AIDS Treatment

DHEA, a hormone already present in the human body and related to the male hormone testosterone, has been tested secretly for several months with a few AIDS patients in Paris. Word of the study leaked out; but those who know the most are not talking, and an aura of intrigue and confusion surrounds the research. No other reporting in AIDS Treatment News has presented more ethical ambiguities and difficulties than DHEA.
On the plus side, the few persons with AIDS who have used DHEA are happy with it, and there is some scientific basis to believe the treatment might be helpful. In addition, recent epidemiological statistics showing much worse survival rates for women than men after an AIDS diagnosis--apparently because of hormonal differences between the sexes--suggests that DHEA may be a new class of treatment, working by means now unknown. If so, it could open doors to important advances in treatment development.
On the down side, only a few AIDS patients have used the drug; we have only partial, sketchy information from the Paris trial. So there is no proof that DHEA is helpful. And while experts consider the substance safe for short-term use, long- term effects are unknown, and they could possibly include increased risk of certain cancers. The treatment for AIDS requires large doses for long periods of time.
DHEA is a prescription drug in some countries, including Canada. In the U.S. it used to be sold by health-food
distributors as an aid in losing weight, but the FDA forced the vendors to remove it from the market. (In a press release
dated April 9, 1985, the agency said "FDA has few adverse reaction reports on the drug, but said the risks from long-term use are unknown".) Today DHEA is widely used in research and is available through chemical supply channels; there are also natural sources. While individuals cannot readily purchase DHEA in the U.S. at least, it is clear that the AIDS community could obtain supplies if it wants to.
For the community, the bottom line on DHEA does seem clear. It would be a mistake to ignore this treatment
possibility and just walk away. And it would also be foolish to rush into it.
For several weeks we have gathered information about DHEA. Many of our sources spoke off the record and cannot be named. This article presents what we have learned so far.

What Is DHEA?

DHEA, or dehydroepiandrosterone, is a steroid secreted by the adrenal gland and excreted in large amounts in the urine. The substance is well known to science--over four thousand published scientific or medical papers refer to it in some way- -but no one clearly understands its role in the body.
DHEA can be taken by mouth, and researchers are investigating it as a possible treatment for aplastic anemia,
diabetes, and breast cancer in women. Animal studies have found that DHEA prevents obesity in breeds which are normally fat. It also seems to extend the lifespan of animals.
Relatively few studies of human use have been published. Experts agree that DHEA seems safe for men, although women may have troublesome side effects from large doses. Results of long-term use are unknown. The drug has weak testosterone-like effects, and may have the same risks as testosterone.
DHEA seems to have gone through something of a "miracle- drug" phase several years ago (Kent, 1982); also there has been much excitement among some scientists (Kahn, 1985). Most of the published studies of human use in clinical trials came out several years ago, however, and this published record presents a confusing picture of scattered, miscellaneous attempts to treat various obscure diseases, with mixed results.
Now there has been a sudden burst of excitement about DHEA as a possible AIDS treatment, among the few persons so far who know about the small clinical trial in France. We looked behind this excitement to find solid evidence on which it is based, and we could find only a little at this time. The drug does seem to be helpful to some people. And there may be more to it than meets the eye.

The Paris Study--And Controversy

A small research project in Paris has tested DHEA for several months with at least ten subjects, including five
Americans. We have spoken with four of them, including one whom this writer knew personally before he became involved in the study. These four were able to tell us about the results with six of the people in the trial; we have heard nothing about the other four or more subjects.
Much intrigue has surrounded this research, and what you hear depends on whom you talk to. Those involved do seem to agree:
* That the two principals currently working with DHEA as a possible AIDS treatment, Irish microbiologist Patrick
Prendergast and the Irish company Elan Corp., appear to be fighting over the direction of the project.
* That Prendergast both initiated and financed the research, then went to Elan to negotiate an agreement for them
to distribute the drug.
Beyond this, viewpoints vary greatly.
At least some of subjects in the Paris trial, who talk mainly to Prendergast, believe that he wants to move quickly to
get the benefits of DHEA out to people with AIDS, whereas Elan wants to conceal the discovery until it can create a variation of the drug which is patentable and could have commercial value. (DHEA itself is already in common use and therefore largely unpatentable.) Elan has allegedly obtained a court order forbidding Prendergast from speaking with anyone about the matter--even with the subjects using the drug in Paris. Prendergast himself did not return our calls. He would have been legally forbidden to do so.
We did speak to J.G. Masterson, M.D., the President and Chief Operations Officer of Elan Corporation. He said that
Elan had licensed EL-10 (Elan's code name for the project) from Prendergast, and that the substance was in laboratory
investigation in the United States. He said no controlled clinical trials had been done to date, there was no scientific
evidence of efficacy, and that this was an extremely sensitive subject and it was premature to talk about it at all.
Dr. Masterson said that Elan's goal was to speed orderly, non-sensational, scientifically acceptable development if the product had any merit. But he was going to the Irish High Court today (January 11) and therefore it would be
inappropriate to talk to a newspaper. He said that there was no scientifically acceptable clinical evidence (of efficacy of
the drug), and that as soon as they had that, we would be the first to know.
Asked about the Paris study, Masterson suggested I talk to Prendergast; he said that Elan was not conducting any clinical trial. He asked how I knew about the matter, and especially wanted to know how I knew about the existence of a legal dispute.
We did not think to ask why Elan would license a drug without credible evidence of efficacy.
Complicating the picture is the fact that Elan's stock suffered greatly during the October crash. A public run on
this stock, of the sort which has often occurred on rumors of hot AIDS developments, could be worth tens of millions if not
hundreds of millions of dollars to the stockholders.
For additional information on the politics surrounding this trial, see Keith Griffith's article, "New Hope and New
Intrigue: Top Secret AIDS Study", published last week by AIDS Action Call (Griffith, 1988).

Paris Study Results: What We Know

All four of the people we spoke to who were using DHEA in the small trial in Paris were convinced that the drug had been helpful to them and to everyone else in the study.
Of six persons in that DHEA study on whom we can find any information, at least five have AIDS. All were healthy enough before using DHEA to travel to Paris and live there in a hotel during the trial. Here is what we have learned about their response to the treatment:
* One has had T-helper cells improve from 248 to 641; his KS lesions seem to be lightening, although some new lesions have appeared.
* Another has had only slight improvement in T-helper cells, which are still under 100, but his other blood values
which had been somewhat low have all improved and moved into the normal range. All of his fungal infections have cleared up, as has his leukoplakia. Besides the DHEA, he no longer needs to take any medications whatever for these infections, nor follow dietary restrictions to avoid thrush.
* Another had T-cells go up significantly, from under 300 (with a low of 186) to 560. His fungal problems diminished.
* Another who had had pneumocystis but was overweight at the start of the study has lost the unwanted weight, and has far more energy now.
* The fifth person started doing very well, but was depressed and decided to leave the study. We don't know how he
has done since.
* The sixth had not seemed to be doing well, but then he improved dramatically after receiving a transfusion of
platelets--so dramatically that the investigators want to give platelets to another subject also, to see if there is a
synergistic effect.
Most or all of the six men were fairly healthy when they started the trial. They used large doses, always by mouth, up
to 500 mg per day (100 mg five times a day, preferably taken just before a meal). They started with smaller doses, 200 to 300 mg per day, and increased the amount gradually; at least one person increased the dose by 100 mg each week until the 500 mg maximum dose was reached.
At least one patient also tried another treatment, DNCB, which may have contributed to his improvement.
Asked how long a person should try DHEA to see if it was working for them, one of one patient suggested three months. Presumably there should be unmistakable improvement in that time if the treatment is working.
This is all we know about the results of using DHEA with AIDS, ARC, or any HIV-related condition.

An Expert Evaluation

One physician who is very experienced with AIDS spoke with us off the record. He also talked to three scientists who are expert on DHEA, and with one of the patients in Paris, to help us put this information into better perspective. Here is our summary of his report.

a. Possible Scientific Basis

DHEA has protected rats against the immune suppressing effects of severe stress (Kahn, 1985, page 258). The stressed rats without the drug showed severe immune depression, atrophy of the thymus, marked reduction in lymphocytes, and increased disease and death. DHEA protected the animals against this outcome. How it did so is not clear.
Another possible mechanism might account for benefit from the drug for persons with AIDS or ARC. DHEA stimulates the bone marrow and increases production of all bone-marrow elements, including red cells, platelets, monocytes,
macrophages, and lymphocytes. Apparently it acts on the stem cells themselves, before they are infected by HIV, and
therefore it should be safer than some of the colony- stimulating factors, which some researchers fear might stimulate growth of the virus.
Even though T-helper cells are most impaired in AIDS and ARC, other blood elements are likely to be low, too. For
example, a healthy seropositive person may be about 20 percent low on hemoglobin, platelets, and white count, and 60 to 80 percent low in T-helper cells. DHEA may help by bringing all the blood elements up toward the normal range.

b. Safety

All three experts agreed that short-term use at least was very safe for men. But women could have masculinizing side
effects comparable to those of testosterone, such as loss of menstrual period, changing of the voice, and growth of facial hair. Women who choose to use DHEA should be counseled about these possible problems.
Little is known about risks of long-term use; people have not used DHEA long enough. There is a theoretical risk that it could increase the danger of prostate cancer. Also, one breed of rats developed pituitary tumors after extended use of DHEA. (Many animals seem to have benefitted from long-term use, however, living longer and in better health than normal untreated animals.)
Another theoretical risk should be considered. DHEA is effective against obesity because it causes more of the
digested carbohydrates to be used for immediate energy, and less to be used to provide building blocks of fats and
proteins. Therefore DHEA might make it harder to gain weight, which some persons with AIDS need to do. No one had this problem in the Paris study, but as far as we know nobody was underweight to begin with.
Another physician suggested testing liver function as a precaution when using DHEA, because the drug is processed by the liver.

c. Form and Method of Intake

The experts said plain DHEA would be absorbed better by the body than DHEA sulfate or other variants of the chemical. (Incidentally, we do know that the Paris study used DHEA itself, not the sulfate form or any other variant.)
Two of the three experts suggested taking DHEA rectally. They felt that taking it by mouth would be unreliable, since
the circulating blood goes directly from the stomach to the liver, which destroys most of the drug.
Another physician feared that rectal use might be dangerous, however, since it bypasses many of the body's
defenses, and there seems to be no human experience using DHEA this way. This physician, who has used DHEA in smaller amounts for other conditions, suggested staying with the oral administration which was tested in Paris, even though it is not an efficient way to administer the drug.

d. Physician's Overall Evaluation

The physician we interviewed sees DHEA as having relatively little toxicity. But he also notes that we have
little hard evidence for its effectiveness for AIDS or ARC at this time. We only have anecdotal stories of a handful of
patients who improved. He believes that DHEA might have value, but does not want hundreds of people to start using it on the basis of the little evidence we have now.

Miscellaneous

(1) A recent study found that AIDS seems to be worse in women than in men; women in several cities had a much shorter survival time after diagnosis, for reasons that do not seem explainable by differences in quality of care. Biochemical differences between the sexes seem to be responsible. (For more information see New York Times, October 18, 1987.) DHEA is related to the male hormone testosterone. A common mechanism may explain its action and also the different survival times for men and women. If so, DHEA may open the door to a whole new approach to the treatment of AIDS and related conditions.
(2) There are reasons to suspect that the DHEA normally present in the body may be abnormally low in persons with AIDS. If so, use of DHEA may help by replacing the levels which should be there. It is easy to measure DHEA concentrations; apparently no one has done so in persons with AIDS or ARC because scientists did not suspect that DHEA had any relationship to this disease until now.
(3) DHEA may have a direct antiviral effect. In the Paris study, researchers expected that there would be an initial drop in T-helper cells as the DHEA caused the killing of infected cells. They did find a large drop immediately in most of the patients--although not in one person who started with a very low T-helper count.
The researchers also hope that DHEA can attack HIV infection in the macrophages, an important reservoir of HIV
infection in the body. At this time we have no evidence to either support or contradict this theory.
At least two leading U.S. research centers are doing laboratory tests in conjunction with the Paris DHEA study.
Apparently the researchers cannot talk, but we have learned that one found some antiviral effect but nothing spectacular in laboratory tests.
(4) In the Paris study, improvement was often gradual. For example, the person who went from a low of 186 to over 500 T-helper cells had been taking DHEA for five months, and described his improvement as very slow. T-helper cell counts kept fluctuating, but both the low and the high values kept improving.
(5) The people in the Paris study were fairly healthy to start with, even though almost all of them had AIDS.
Apparently no one has yet tried DHEA when they were acutely ill.
(6) DHEA has two different names in common use: "dehydroepiandrosterone" and "dehydroisoandrosterone". These are two different names for the same chemical. The latter name is used more often in Europe.

Availability

DHEA cannot be sold as a drug in the United States. Chemical supply houses do carry it, but they are unlikely to
sell to individuals without the credentials to convince them that the material will be used only for research and not for
human use.
The wholesale chemical cost for the largest dose (500 mg per day) can be as low as 50 cents a day. Retail prices may be much higher.
DHEA is available by prescription in Canada, and it is also used as a drug in Italy. It is used all over the world
and presumably is readily available in many countries, sold either as a drug and/or in quantity as a chemical. But we do
not know which countries at this time.
Alan S. Levin, M.D., a San Francisco immunologist who has previously prescribed DHEA for other purposes, is considering setting up a small study of its use with AIDS and ARC. (See our article about Dr. Levin in AIDS Treatment News, January 1, 1988.)
Clearly the AIDS/ARC community will be able to obtain DHEA if it wants to; some are already taking steps to do so. But since this drug may not be harmless, and hard evidence of effectiveness is thin at this time, it may be best to wait and see what the pioneers report, rather than rushing too quickly into widespread use.

References

Griffith, Keith. New hope and new intrigue: Top secret AIDS Study. AIDS Action Call January 1988. (AIDS Action Call
is the newsletter of AIDS Action Pledge. For a copy, call them at (415) 821-9087, or send a self-addressed stamped envelope to: AAP, Box 146693, San Francisco, CA 94114.) Kahn, Carol. Beyond the helix: DNA and the quest for
longevity. Times Books, 1985. Kent, Saul. DHEA: "Miracle" drug? Geriatrics volume 37 number 9 page 157, September 1982.

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