DHEA and AIDS

DHEA has been available for at least seven years from some AIDS buyers' clubs, and is one of their most popular products. Also for years, there have been rumors that it might be effectively banned in the United States -- not because of any safety concern, but on the grounds that it might be misused by athletes to build muscle, like anabolic steroids (we could find no reports of such use, however). Since anabolic steroids can only be sold for approved uses in the U.S., and DHEA has no FDA-approved use, if it is defined as a steroid it could become unavailable, not only over the counter but by prescription as well.

Because of the growing fears about loss of access, AIDS TREATMENT NEWS asked freelance writer Tim Kingston to investigate this danger; due to lack of space in this issue, his report will appear later. This companion article reviews some of the published literature on DHEA and HIV disease. And for a recent clinical perspective, we interviewed Jon Kaiser, M.D., a San Francisco physician using DHEA in his HIV practice.

Background

DHEA is a hormone produced by the body. Blood levels of DHEA are low in young children, rise to a peak by age 30, and then decline, sometimes to very low levels in old age. Various diseases may be associated with low levels of DHEA, but the data are often controversial. DHEA is chemically related to testosterone and estrogen. DHEA has less masculinizing effect than testosterone, and can be used by women.

Probably the most promising clinical trial results with DHEA so far have been in the treatment of lupus, a serious immune disease which mainly affects women. A controlled phase II trial in 28 patients with mild to moderate lupus found that those who received DHEA (200 mg per day, a moderate dose) improved consistently in all measurements of disease status used in the trial, while the placebo group showed little improvement, or worsening.(1) This result was first presented in November 1993; more complete data were published in December 1995. In May 1994 Genelabs Technologies Inc. -- known in the AIDS world as the developer of Compound Q (GLQ-223) -- announced that it was starting larger lupus trials, the first one to take place at 18 U.S. medical centers. This trial will finish around the end of 1996.

Another important trial, formally published in 1994, tested low-dose DHEA for replacing blood levels lost due to aging, in otherwise healthy people.(2) Thirteen men and 17 women, ages 40-70, received DHEA or placebo in a six-month crossover study. A low dose (50 mg daily) at bedtime restored DHEA to young-adult levels within two weeks. An "improved sense of well-being" was reported by 67% of the men and 82% of the women on DHEA, compared to less than 10% on placebo; "self-reported changes include increased energy, deeper sleep, improved mood, more relaxed feeling, and better ability to handle stressful events." Five of the patients "self-reported marked improvement of preexisting joint pains and mobility" while taking DHEA. There was no increase in libido. No safety problems were found -- which was not surprising, as doses more than 30 times as high had been tested in a previous clinical trial.

We could find almost no reports of harmful effects of using DHEA in the medical literature. In the phase I/II lupus study, however, about half of the women had acne while using the drug. There have also been some reports of DHEA causing growth of facial hair in women; this seems to be uncommon, however. And there were mild adverse effects in all AIDS patients treated with a very high dose of DHEA, and no antiviral, during an early study.(3)

DHEA in AIDS

Blood levels of DHEA decline in HIV disease,(4,5,6) although one group found higher than normal levels in early HIV infection.(7) And one study found that low levels increased when AZT treatment was started, and suggested DHEA level as a tool for monitoring antiviral treatment.(8) One research team found, paradoxically, that persons with Kaposi's sarcoma (KS) had higher DHEA levels than even HIV negative controls(9) --and that high DHEA levels fell substantially after successful KS treatment with alpha interferon(10) -- leading to speculation that these high levels may contribute to the development of KS. But another group found no relationship between hormone levels, including DHEA, and KS.(11) (We have not been able to find any published case reports of this treatment worsening KS. And Jon Kaiser, M.D., interviewed below, has used DHEA in some patients with KS without problems.)

A blood test for DHEA level is available to physicians.

Early epidemiological studies reported that abnormally low levels of DHEA in the blood of persons with HIV were associated with progression to AIDS(12,13) Also, there are indications of modest antiretroviral activity of DHEA itself.(14,15,16,17,18,19)

We only know of three small clinical trials have tested DHEA as a potential HIV treatment; only two of them have been published.(20,3) Two of the three trials were run years ago, when less was known about HIV disease, and modern viral load tests were not available; no antivirals were used during those trials. The more recent trial found some indications of benefit,(20) with CD4 (T-helper) cell count increases of more than 25% in many of the volunteers; most of them were using AZT or other antivirals, with some on combination antiretroviral therapy. But a larger study produced disappointing results, with no overall improvement in CD4 counts(3); this study did not allow use of antivirals. A small semi-secret trial conducted in a Paris hotel (see AIDS TREATMENT NEWS #48, January 15, 1988), also without antiviral therapy, failed to find CD4 count increases, according to a knowledgeable source; the results of this trial were not published.

A recent laboratory study in lupus might help shed light on AIDS trial results. In lupus, the blood cells which normally produce IL-2 have been found to produce greatly reduced amounts of it. DHEA levels are also very low in lupus; and when cells from persons with lupus were treated with DHEA in laboratory tests, IL-2 production became normal.(21)

Could low DHEA levels in AIDS be contributing to CD4 cell loss by reducing the body's normal production of IL-2, which stimulates the growth of CD4 cells? In trials of IL-2 therapy, some patients have had great increases of CD4 counts. But IL-2 also increases the growth of HIV, as well as the growth of CD4 cells. It must be used together with antivirals to prevent this HIV increase. Also, IL-2 treatment has usually not been successful in persons with advanced HIV disease (CD4 count under 200); this might be because the antivirals available have not been effective enough to control the stimulation of HIV by IL-2 at that stage of disease. Since DHEA levels are lowest in advanced AIDS, it is possible that those patients who most need DHEA to restore normal levels would also need very good antiviral coverage for the resulting IL-2 production to be beneficial -- possibly explaining why DHEA has usually shown little CD4 benefit. This is suggested by the three existing clinical trial
results; the one trial in which
most of the volunteers were on antiviral therapy reported modest CD4 improvements, but the early trials without antiviral therapy reported none.

Could replacing abnormally low levels of DHEA restore the body's own production of IL-2 in HIV disease, as it may do in lupus -- possibly providing the potential benefits of IL-2 treatment, without the side effects and enormous financial cost? This should be tested by treating patients who have abnormally low baseline DHEA levels, while they are on a very effective antiviral therapy, such as antiviral combinations including a protease inhibitor, to see if DHEA causes a CD4 increase under those conditions. Changes in viral load, and in blood levels of IL-2, should also be measured.

Much is still unknown about DHEA. At this time there is little evidence of specific benefit in HIV disease, since this treatment resulted in no CD4 improvement in two of the three clinical trials which administered DHEA to people, and only modest improvement in the third. All of these trials were far too small to detect any changes in clinical progression. While there are suggestions that DHEA might have HIV-specific benefit, there has been no research to tell one way or the other.

But we have heard repeatedly that DHEA helps many persons with HIV feel better. This is consistent with the research which has shown, in a placebo-controlled trial, that most older people felt better when their levels of DHEA were supplemented -- and other research which has shown that HIV infection, like aging, causes abnormally low blood levels of DHEA. We believe that DHEA deserves consideration as a treatment which may improve quality of life. Until more is known, however, viral load tests might be advisable to make sure that it does not increase HIV growth -- since theory suggests that it might, and there has been no trial which measured viral load when DHEA was used.

Technical Notes, and Comments

A related form of DHEA is DHEA sulfate, often called DHEA-S. The body can convert DHEA into DHEA-S and vice versa. Most of the DHEA in the body is in the form of DHEA-S; blood levels of it can be hundreds of times higher than those of DHEA itself.

The chemical name of DHEA is dehydroepiandrosterone. It is also called prasterone.

A search of the AIDSLINE database found 42 published articles or conference presentations on DHEA. MEDLINE, which covers the entire medical field, has 1133 DHEA references to published articles since 1966.

Concerning the legal status of DHEA, one lawyer told us that it is a cholesterol derivative, and therefore defined by current Federal law as a food supplement, unless it is promoted with medical claims. He also explained that court decisions have clearly held that the regulation of medical practice is a state power, under the Tenth Amendment to the U.S. Constitution. He said he checked two months ago and found no rule-making activity regarding DHEA, either at the FDA or the DEA. And on January 17, we did a FEDERAL REGISTER computer search since 1988, and found no reference to DHEA.

Also, one researcher now studying DHEA said that reclassification as schedule III is unlikely, because the DEA has only used schedule III to regulate the prescribing of approved or approvable drugs, and DHEA is not recognized as such at this time. And an FDA official we spoke with also thought that a schedule III ban was unlikely unless significant dangers were found. He pointed to the case of GHB, which is sometimes used as a party drug; it does have known dangers, and at least one person has been jailed for selling it, but still it has not been classified as a controlled substance.

Despite these encouraging indications, Tim Kingston's investigative report, to appear later in AIDS TREATMENT NEWS, shows that there is a possibility that DHEA might be banned, either in the entire U.S. or in certain states, despite the lack of any indication of serious side effects or of abuse. Authorities may be motivated to prevent a repeat of melatonin -- a drug with many unknowns which became very popular before it could be controlled. We believe this would be a mistake, since for the elderly, DHEA appears to be less dangerous and more likely to be beneficial than melatonin -- and the research needed to know for sure is unlikely to be done any time soon.

The most compelling argument against widespread DHEA use by the elderly -- that we do not know *why* their DHEA levels have dropped -- may not survive a close look. Throughout almost all of human evolution, few people even lived to be over 50, let alone lived to reproduce at a late age. As a result, there was no evolutionary pressure one way or the other on DHEA levels in the elderly, and therefore there is no reason to suspect that the low level serves any purpose. But bureaucrats may not think this way; they are more concerned about not losing control. Without continued public vigilance, persons with HIV may lose treatment options as a result.

References

1. Van Vollenhoven, RF, Engleman EG, and McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus. ARTHRITIS AND RHEUMATISM December 1995; volume 38, number 12, pages 1826-1831.

2. Morales AJ, Nolan JJ, Nelson JC, and Yen SSC. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM 1994; volume 78, number 6, pages 1360-1367.

3. Dyner TS, Lang W, Geaga J, and others. An open-label dose-escalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease. JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES May 1933; volume 6, number 5, pages 459-465.

4. Wisniewski TL, Hilton CW, Morse EV, Svec F. The relationship of serum DHEA-S and cortisol levels to measures of immune function in human immunodeficiency virus-related illness. AM J MED SCI February 1993; volume 305, number 2, pages 79-83.

5. Socolov IA, Pokrovsky VV, Emelianov BA, Semenov VA, Yurin OG, and Gruzdev BM. Great disturbances of steroids excretion of AIDS patients. International Conference on AIDS, Yokohama, August 7-12, 1994 [abstract PB0020].

6. Sonnabend J, Fleischer T, and Seaman JD. DHEA and DHEA-S in AIDS. International Conference on AIDS, Montreal, June 4-9, 1989 [abstract C602].

7. Christeff N, Gharakhanian S, Thobie N, Rozenbaum W, and Nunez EA. Evidence for changes in adrenal and testicular steroids during HIV infection. JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES. 1992; volume 5, number 8, pages 841-846.

8. Mulder JW, Krijnen P., Coutinho RA, Endert E, Goudsmit J, and Lange JM. Dehydroepiandrosterone (DHEA) as surrogate marker for monitoring zidovudine treatment. International Conference on AIDS, Amsterdam, July 19-24, 1992 [abstract PoB 3495].

9. Christeff N, Winter C, Gharakhanian S, and others. Difference of androgens of HIV positive patients with and without Kaposi's sarcoma. JOURNAL OF CLINICAL PATHOLOGY June 1995; volume 48, number 6, pages 513-518.

10. Christeff N, Gharakhanian S, Thobie N, Wirbel E, Rozenbaum W, and Nunez EA. Effects of interferon alpha 2A on serum androgen in HIV+ men with Kaposi's sarcoma. International Conference on AIDS, Yokohama, August 7-12, 1994 [abstract PB0120].

11. Rosenthal E, Formanto JL, Giudicelli J, and others. Estrogen, progesterone, and androgen and their receptors in epidemic Kaposi's sarcoma. International Conference on AIDS, Berlin, June 6-11, 1993 [abstract PO-B12-1605].

12. Jacobson MA, Fusaro RE, Galmarini M, and Lang W. Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200-499. JOURNAL OF INFECTIOUS DISEASES November 1991; volume 164, number 5, pages 864-868.

13. Mulder JW, Frissen PH, Krijnen P, and others. Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men. JOURNAL OF INFECTIOUS DISEASES March 1992, volume 165, number 3, pages 413-418.

14. Bradley WG, Kraus LA, Good RA, and Day NK. Dehydroepiandrosterone inhibits replication of feline immunodeficiency virus in chronically infected cats. VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY May 1995; volume 46, number 1-2, pages 159-168.

15. Yang JY, Schwartz A, and Henderson EE. Inhibition of 3'azido-3'deoxythymidine-resistant HIV-1 infection by dehydroepiandrosterone in vitro. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. June 30, 1994; volume 201, number 3, pages 1424-1432.

16. Yang JY, Schwartz A, and Henderson EE. Inhibition of HIV-1 latency reactivation by dehydroepiandrosterone (DHEA) and an analog of DHEA. AIDS RESEARCH AND HUMAN RETROVIRUSES August 1993; volume 9, number 8, pages 747-754.

17. Henderson E, Yang JY, and Schwartz A. Dehydroepiandrosterone (DHEA) and synthetic DHEA analogs are modest inhibitors of HIV-1 IIIB replication. AIDS RESEARCH AND HUMAN RETROVIRUSES May 1992; volume 8, number 5, pages 625-631.

18. Schinazi RF, Eriksson BF, Arnold B, Lekas P, and McGrath MS. Effect of dehydroepiandrosterone (DHEA) in lymphocytes and macrophages infected with HIV-1. International Conference on AIDS, Montreal, June 4-9, 1989 [abstract M.C.P.55].

19. Jacobson MA, Lekas P, and McGrath MS. Possible protective effect of dehydroepiandrosterone (DHEA) and/or DHEA-sulfate (DHEA-S) in HIV infection. International Conference on AIDS, Montreal, June 4-9, 1989 [abstract M.C.P.111].

20. Hasheeve D, Salvato P, and Thompson C. DHEA: A potential treatment for HIV disease. International Conference on AIDS, Yokohama, August 7-12, 1994 [abstract PB0322].

21. Suzuki T, Suzuki N, Engleman EG, Mizushima Y, and Sakane T. Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus (SLE). CLINICAL AND EXPERIMENTAL IMMUNOLOGY February 1995; volume 99, number 2, pages 251-255.