AIDS Treatment News
NTZ: Cryptosporidiosis New Treatmentby John S. James
A new drug which may be the best cryptosporidiosis treatment yet is now in small clinical trials. And a compassionate- access program has been announced by developer UNIMED Pharmaceuticals, Inc.
We first heard about NTZ (nitazoxanide) from a physician we know, who believes he acquired the parasite when public water supplies in the San Francisco area were heavily contaminated last winter. He received the drug by volunteering for a small trial in Mexico City. At first it did not work; he had to increase the usual starting dose (500 mg twice a day). Now the cryptosporidiosis, which had been serious enough to require TPN for several months, is largely controlled although not cured; stool tests are usually negative, but occasionally some diarrhea returns and stools become positive again. Although a course of treatment often lasts only 14 days, he has been on the drug for several months.
All 14 of the people in the Mexico City trial had their stools become negative for cryptosporidiosis. We do not know how many of them have continued with maintenance treatment.
NTZ can cause side effects of nausea and vomiting, so it is usually taken with a small amount of food. NTZ appears to be effective against many intestinal parasites; over 1,000 people have taken the drug so far, almost all outside the United States. UNIMED recently started a phase III trial for persons with AIDS in Mexico.
In the U.S., a small study is now recruiting at Cornell Medical Center in New York City, and possibly at a second site in San Francisco. Those enrolled will be randomly assigned to 14 days of treatment with 500, 1000, 1500, or 2000 mg per day, with 14 and 28 day additional courses of treatment available for those who do not have a complete response.
Also, a compassionate access program has been announced for those who cannot participate in the controlled study, due to eligibility restrictions or geography. But this program has only 30 slots, and is almost completely enrolled. It is open for persons ages 3-65, with exclusions for current infection with a number of other intestinal parasites, history of intestinal MAC or intestinal KS, concomitant use of other drugs to treat cryptosporidiosis or microsporidiosis, and some other exclusions.
We do not know of any other way to get NTZ at this time.
For more information about the trial or the compassionate access program, call Sandy Faulkner, R.N., 800/864-6330, 8-5 Central Time.
The number of slots in the expanded-access program is clearly inadequate, and certain to become an issue unless it is increased.
We have heard that the cost of producing NTZ is very low. The cost of administering a large expanded-access program could be significant. But the FDA has regulations to allow companies to charge to recover this cost. The developer could be reimbursed for any costs, and hire a contractor if necessary to administer the program.
If the program is limited because of safety concerns about a new drug, then the FDA should re-examine the risks vs. benefits. Many people die from cryptosporidiosis, and there is no approved or satisfactory treatment. The fact that all 14 participants in an early trial became negative in stool tests implies that NTZ can at least control the disease for some period of time in a great majority of cases. A thousand people have used this drug; unless there is some major safety concern we do not know about, the risks of a larger program are clearly worth taking.
Viral Load: New Confirmation by John S. James
Two clinical trials of delavirdine with a total of about 1900 patients have strongly confirmed the value of viral load (both baseline, and response to treatment) in predicting clinical outcome. Pharmacia & Upjohn first announced this result on January 17, and will summarize the data on February 1 at the Third Conference on Retroviruses and Opportunistic Infection.
Both baseline viral load, and change in viral load in response to therapy, predicted clinical outcome to a very high statistical significance, p<.0001 in each case. change response to therapy was somewhat better than baseline as a predictor if the viral load dropped or more with treatment and improvement sustained risk of clinical progression reduced effective cd4 count predicting outcome.>
The trials of delavirdine are continuing; there was only a partial unblinding for the study. Pharmacia & Upjohn will be able to apply for accelerated approval for the drug this year, based on viral load and other surrogate marker data, while the trial still continues to collect clinical-outcome information. The viral load analysis above will strengthen their application for accelerated approval, by providing additional information that viral load is a useful measurement.
Delavirdine Expanded Access, Clinical Trials: For More Information
Pharmacia & Upjohn will offer an expanded-access program for delavirdine in the U.S. and Canada, and later in Europe and Australia; they do not plan to do a lottery. The program is currently being designed; a starting date has not been announced, but it is targeted for March 1996.
For more information about the expanded access program, call 800/779-0070. Physicians may want to call to be listed on a database of those interested. Patients can also call this number, but only general information is available at this time.
A major clinical trial of delavirdine by Pharmacia & Upjohn, protocol 0021, which is running at 105 sites in North America, is still recruiting persons with CD4 counts between 200 and 500, both antiretroviral experienced and naive. This is one of the trials that was partially unblinded to produce the results above. It has been modified, so that it no longer has an AZT-only arm; instead, the control arm is now AZT plus 3TC. Also, the lower doses of delavirdine have been dropped. For more information about this trial (or about other AIDS research at Pharmacia & Upjohn), patients and physicians can call 800/432-4702.
Protease Inhibitor Update: by Mark Mascolini
Representatives of the companies developing the leading protease inhibitors agreed at the January 6 protease inhibitor forum (announced in AIDS Treatment News December 22) that even the most potent of these drugs will work best in combination with the nucleoside analogs--AZT, ddI, ddC, d4T, and 3TC--and possibly with each other.
Sharon Chapman, Ph.D., said that Agouron's nelfinavir (Viracept, AG 1343) lowered viral load below the limit of detection in 5 of 5 people who took this protease inhibitor with d4T in a 4-week study. When given by itself three times a day for a total daily dose of 2250 mg, nelfinavir lowered viral load more than 1.5 log (32-fold) in 90% of people studied for 4 weeks, and to below the limit of detection in 60%. Six larger trials in people with HIV infection, which will begin in February at 40 sites across the country, will focus on nelfinavir in combination with (1) d4T, (2) AZT plus 3TC, and (3) whatever HIV drug therapy a person may be taking. Chapman said Agouron is trying to find trial sites where many women and minorities are cared for.
In a 75-person, 24-week trial of Merck's indinavir, AZT, and the two drugs combined, about 50% of those taking the combination had viral load reductions below the limit of detection, compared with 30% taking indinavir alone. Merck's Emilio Emini, Ph.D., said these proportions held true for an additional 24 weeks. In a study combining indinavir with both AZT and ddI, the proportion with undetectable circulating virus is greater than in the indinavir/AZT study, according to Emini. Results of that study will be presented at the Human Retroviruses meeting later this month. But a preliminary report last December noted that some people in this 6-month trial had a 3-log (1000-fold) drop in circulating virus. Then their viral loads began to go back up, but possibly because some stopped the indinavir/AZT/ddI treatment at that point.
Updating results from a 25-person French trial combining Abbott's ritonavir with AZT and ddC (see AIDS Treatment News #231), Abbott investigator Dave Pizzuti, M.D., said that about 40% have now attained a 3-log (1000-fold) decrease in viral load at 5 months. As this trial proceeds, the proportion of people with several-log drops in viral load continues to increase. Pizzuti also said that laboratory tests show little cross-resistance between ritonavir and saquinavir, the Roche protease inhibitor now being studied in combination with ritonavir.
The Vertex/Glaxo Wellcome protease inhibitor (VX-478 or 141W94) has not yet been studied in combination with other antiretroviral drugs. But Glaxo Wellcome's Marty St. Clair, Ph.D., reported that VX-478 does not share resistance patterns with nelfinavir, indinavir, ritonavir, or saquinavir, so it could be a good candidate for combination with any of those drugs. Another potential advantage of VX- 478 is that it appears to penetrate brain and lymph tissue better than the other protease inhibitors. But St. Clair stressed that these findings are from rat studies and must still be confirmed in humans.
Saquinavir is the only protease inhibitor already approved by the FDA; it is approved only in combination with one or more nucleoside analogs. At the New York symposium, organized by activist Jules Levin, Roche's Mickey Salgo, M.D., Ph.D., vowed that no one who wants to take saquinavir would be denied the drug because of financial need. Financial assistance specialists who can be reached at 1-800-282-7780 will help connect people with appropriate third-party payers, or, failing that, will make other arrangements for people who cannot afford the drug.
Note concerning limit of detection of viral load, referred to above: Agouron used a research bDNA assay with a 100-copy cutoff; Merck used the Roche PCR assay with a 200-copy cutoff.
Ritonavir: Expanded Access Begins, by John S. James
The new protease inhibitor ritonavir is now becoming available through an expanded access program from Abbott Laboratories. This drug must be used very carefully, because it has strong interactions with many other drugs. The main problem is that ritonavir blocks a liver enzyme which normally destroys certain drugs, causing normal doses of the other drug to accumulate to toxic levels. Doses of the other drug may need to be greatly reduced -- and in many cases they should not be used together with ritonavir at all.
This same kind of effect is caused by some other drugs, such as ketoconazole. But the effect is much stronger with ritonavir than with any other drug physicians have experience with. This is a critical time in the development of ritonavir, as the drug has previously been used only in tightly controlled clinical trials, and is now moving into the less controlled expanded access program.
The concern was increased by the unexpected death of Philadelphia treatment activist Jonathan Lax on January 11, a day and a half after he switched to taking open-label ritonavir, after participating in a placebo-controlled trial during which he was convinced he was receiving the placebo. He was reportedly taking many other medications, although we do not know which ones. We do not know whether ritonavir had anything to do with his death; about 1500 people have taken ritonavir so far, and no similar case has ever been reported. Still, this incident emphasizes the need for caution. Abbott is working closely with the medical examiner's office in Philadelphia to determine the cause of death.
A partial list of over 20 drugs which should not be taken together with ritonavir is available from Project Inform. For a current copy of the list, contact the Project Inform hotline at 800/822-7422, or 415/558-9051, 10 a.m. to 4 p.m. Pacific time, Monday through Saturday. Persons using ritonavir need to talk with their physicians, who should have the latest information from Abbott concerning dose adjustments, or drugs which must be avoided entirely.
Stanford NAC Study, San Francisco,
Anyone who was screened for the Stanford NAC study and gave blood to be tested -- regardless of whether they were accepted or rejected for the trial -- should contact the researchers if you have not already been in touch with them recently. The researchers are examining the relationship between blood glutathione levels and survival, and they want to contact as many screened participants as possible to get the most reliable results. The office visits and blood draws for this study were both in San Francisco.
If you were screened for this study and have not been contacted since October 1995, please call Greg Dubs, Ph.D., or Sharon O'Leary, R.N., 415/863-8090.
Needle Exchange: by John S. James
On January 17, 32 leading experts on needle exchange released a strongly worded letter to Health and Human Services (HHS) Secretary Donna Shalala, concerning her statements to THE NEW YORK TIMES that there is "controversy over research," and to CNN that "different experts disagree" on needle exchange. The experts said her statements "grossly mischaracterize the enormous body of research on needle exchange programs," and cited the "astonishing unanimity among researchers who have looked at this issue in detail."
The letter cited six Federally-funded reviews of needle exchange. All found that these programs reduce HIV transmission, and do not increase drug use. Four recommended ending the Federal ban on funding needle exchange, and also recommended that states consider changing laws that limit access to clean syringes. (The other two did not have a mandate to make any policy recommendations, but their data supported the same conclusions.)
For more information, contact Peter Lurie, M.D., M.P.H., at the Center for AIDS Prevention Studies, University of California, San Francisco.
Retroviruses Conference Notes
DHEA and AIDSby John S. James
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.
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.
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.
DHEA Clinical Experience: by John S. James
Jon Kaiser, M.D., has been treating HIV in San Francisco since 1987. He has been known for combining complementary and mainstream treatment approaches, and is the author of IMMUNE POWER: A COMPREHENSIVE TREATMENT PROGRAM FOR HIV (1993, St. Martin's Press). In 1995 he joined the Conant Medical Group in San Francisco.
Dr. Kaiser has been using DHEA in HIV treatment since late 1994, and now has about 200 HIV patients using it.
ATN: Who seems to benefit most from DHEA?
Dr. Kaiser: There are two groups. Some patients are asymptomatic, but blood tests show a lower than optimal level of DHEA. Others with low blood levels have symptoms which optimal levels of DHEA can treat: fatigue, depression, weight loss, and chronically not feeling well. DHEA seems to protect the body against effects of stress.
DHEA declines as AIDS patients get sicker. I believe that everyone with HIV should have a test for DHEA level.
ATN: What are optimal levels of DHEA?
Dr. Kaiser: The standard test gives a range of 180 to 1200 (nanograms/dl) as "normal" -- this just means the range which is prevalent in the population, not the best value. I try to maintain a range of 300-600 for men, and 200-500 for women, which is typical for a young adult.
There is also a test for DHEA sulfate (DHEA-S). The blood levels for DHEA-S are much higher than those for DHEA, but the units of the test are different, so the numbers come back about the same. The lab I use, Immunodiagnostic Laboratories Inc., in San Leandro, has developed an in-house test for DHEA-S which costs about $100, compared to about $200 for the standard test for DHEA.
ATN: How accurate are these tests?
Dr. Kaiser: I have sent identical blood samples for each test, and the results come back fairly close. The tests do seem to be consistent.
ATN: What doses do you recommend?
Dr. Kaiser: If the goal is to maintain a level of 300-600, and patients come in between 100 and 300, I recommend 200 mg once per day, in the morning with food. This gets about 90 percent of the patients into the optimal range.
If they come in with under 100 -- and quite a few patients with HIV do -- I recommend 200 mg twice a day.
After at least four weeks, it's good to get a second blood test, so that the dose can be adjusted if necessary.
ATN: What side effects have you seen?
Dr. Kaiser: There are almost never reports of side effects with DHEA. Occasionally a patient will have an unpleasant or uncomfortable reaction to it -- maybe one person in 100.
ATN: What is the cost, say of the lower dose, 200 mg once per day?
Dr. Kaiser: Through the pharmacy I suggest, it comes to about $1.50 per day.
DHEA is not a standard drug at this time. Few pharmacies carry it; you have to get it through a compounding pharmacy. I use Medical Center Pharmacy, in Virginia (800/723-7455); they seem to have good quality assurance, as we consistently see blood levels rise. They require a doctor's prescription. DHEA is also available from some of the buyers' clubs.
ATN: Do you see rises in CD4 counts?
Dr. Kaiser: I do not usually see short-term effects on viral load or CD4 counts.
In order to get definitive results about DHEA, I would propose a large simple trial, with some patients randomly assigned to optimize their DHEA level as I described, and others not put on DHEA. Do a two or three year study on symptoms, incidence of infections, and mortality. These differences will probably only show up in a long-term study. You might get a faster result by using quality of life measures.
But DHEA is inexpensive and largely unpatentable. So it is an uphill battle to get any clinical trials done. [No trials are listed by the AIDS Clinical Trials Information Service, 800/TRIALS-A, at this time.]
ATN: When people do seem to benefit, how long does it takes for them to notice feeling better?
Dr. Kaiser: About two to four weeks. That's how long it take for them to obtain a steady-state level of the hormone. If there is just a small change, say from 200 to 300, they may not notice any difference; it may take a larger change, such as 200 to 500 to feel the difference.
ATN: What experience do you have in treating women?
Dr. Kaiser: I have put a number of women on DHEA. You aim for a lower optimum range, and are a bit gentler with the dosage. I have not had any women have androgenic (masculinizing) side effects; most are doing quite well with the treatment. The optimal range for women is 200-500.
ATN: How does DHEA fit into overall HIV treatment?
Dr. Kaiser: My philosophy of HIV treatment includes normalizing almost any hormone that falls below normal or to low normal levels -- whether it is testosterone, or estrogen, or DHEA. I think that optimizing those levels to what a normal, healthy young adult had, makes patients the strongest and healthiest.
I have also treated HIV-negative men in their 50s or 60s for other conditions; some of them have very low DHEA levels, and we use DHEA as part of an overall treatment program.
ATN: If DHEA becomes classified as a Schedule III controlled substance, could you still prescribe it?
Dr. Kaiser: Hopefully I could continue to use it as I do today.