Subject: AIDS Treatment News #150 Date: May 01 1992 (819 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1992 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS #150, May 1, 1992 phone 800/TREAT-1-2, or 415/255-0588 Contents: [items are separated by "*****" for this display] ddC: AZT Combination Approval Recommended ddI: Good News, Questions Remain AZT: New Survival Data HIV/Endocrine Update ACT UP/Immigration Goes to Amsterdam: Assistance Sought ***** ddC: AZT Combination Approval Recommended by John S. James On April 21 the Antiviral Drug Products Advisory Committee of the U. S. Food and Drug Administration voted to recommend approval of anti-HIV treatment with a combination of ddC (dideoxycytidine, also called zalcitabine; brand name HIVID) and AZT for certain patients. It did not recommend approval of ddC by itself. The decision was a difficult one because of the limited information now available about this combination treatment; the split vote, eight to three, reflected this difficulty, since decisions of FDA advisory committees are generally unanimous. The FDA is not required to accept this committee's decision. But it is likely to do so and to formally approve ddC plus AZT combination treatment, after review of additional data, probably during the next few months. The Antiviral Advisory Committee is one of a number of such committees set up by the FDA but composed of outside experts (not FDA employees). Most of the work of these committees is public. Background ddC, now being developed by Hoffmann-La Roche, was one of the earliest potential anti-HIV agents tested. It is very active against the virus in the laboratory, and also has anti-HIV activity in people. But because of its toxicity -- especially peripheral neuropathy, resulting in pain or numbness in the hands or feet -- it must be used in very small doses, less than one one-hundredth the dose of AZT or of ddI (the two anti-HIV treatments now approved in the U. S.). The main question with ddC as a single-drug therapy has been whether there is a dose which can be effective without unacceptable toxicity. ddC was first tested in combination with AZT in a small study called ACTG 106, funded by the AIDS Clinical Trials Group (ACTG) of the U. S. National Institute of Allergy and Infectious Diseases. This study was designed to try various doses to make sure there was no unexpected toxicity when the drugs were used in combination. No such problem was found. But the combination treatment unexpectedly showed much greater improvement in T- helper cell counts than that seen with any known antiviral alone -- especially surprising since the volunteers in this study started with very low T-helper counts (a median of about 70). Because of the small number of patients in this study, certain problems in how the study was designed, and the fact that most researchers were not expecting any major benefit from this particular drug combination since both drugs have the same general mechanism of action, these results became a subject of controversy. Most of the debate took place behind the scenes. The study was not formally published for over a year; it finally appeared in the Annals of Internal Medicine, January 1, 1992 (it had been presented at scientific meetings during the International Conference on AIDS in Florence, Italy, during June 1991). But the results had leaked out before then, and been published by Project Inform and by AIDS TREATMENT NEWS in November, 1990. As the results became known in the medical community, several thousand people started using the combination treatment -- mostly on the recommendation of their physicians -- obtaining the ddC from buyers' clubs, since it was not approved and was not otherwise available for combination use. New Data at Committee Meeting Before the April 20-21 meeting of the Antiviral Advisory Committee, the main issue had been whether the T-helper results seen in this study (ACTG 106) were real. Few expected that the committee could recommend approval of the drug based only on that single small study. And almost no one expected ddC to be recommended for approval as a single drug, since a major study had shown that AZT alone led to a much greater reduction in AIDS deaths than ddC alone. But at the meeting new data was presented which supported the main conclusion of ACTG 106 -- that combination treatment with ddC plus AZT could produce larger and longer-lasting T- helper cell rises than treatment with AZT by itself. The most important new data was from a Burroughs-Wellcome trial which is primarily studying drug resistance. About 50 patients are receiving AZT alone, with a similar group getting AZT in combination with ddC, and a third in combination with ddI. This trial started recently; the early data now available shows a larger T-helper rise from AZT plus ddC than from AZT alone. (The ddI combination data was not released, as it was not relevant to the committee's decision on what to recommend for ddC. Also, no data was released on the traditional "endpoints" of survival or disease progression; this trial is probably too small to show such differences, even when it has been completed.) Even with the new data confirming better T-helper count improvements with the ddC plus AZT combination than with AZT alone, the committee was left with the difficult decision of whether to recommend approval of a somewhat toxic treatment based only on laboratory-test data (T-helper counts), with no data to show whether or not there was clinical improvement in patients' survival or health. The committee was clearly willing to use T- helper counts as part of the approval decision. But it also wanted some showing of direct benefit to patients. "Accelerated Approval" Shortly before the meeting, the FDA announced a new option, called accelerated approval, "to expedite marketing approval of new drugs and biologics for patients with serious and life- threatening illnesses when a drug provides a meaningful therapeutic benefit over existing therapy." [Quotes are from an outline distributed at a meeting of the AIDS Clinical Trials Group a week before the Antiviral Advisory Committee meeting.] Accelerated approval can be used "when there is evidence of a drug or biological product's effect on a surrogate endpoint, such as a laboratory measurement or physical sign, which reasonably suggests that the drug is effective OR that the drug has an effect on a clinical endpoint other than survival or irreversible morbidity.... For drugs approved on the basis of a surrogate endpoint, the sponsor may be required to conduct any clinical studies necessary to determine the actual clinical benefit of the drug on survival, disease complications, or long-term symptoms." The drug may be withdrawn from the market if clinical benefit is not shown, if the sponsor fails to carry out the agreed studies, if the sponsor promotes the drug in a misleading way, or if other evidence shows that the drug is not safe and effective. It has been estimated that this accelerated approval system could speed the overall development of critically important drugs by one to three years. Hoffmann-La Roche asked the Antiviral Advisory Committee to consider the following language [our explanatory comments are in brackets]: "HIVID (zalcitabine) [other names for ddC] in combination with Retrovir (zidovudine, Burroughs Wellcome) [i.e., AZT] is indicated for the management of HIV-infected adult patients with AIDS or advanced HIV disease (CD4 cell count <= 300/mm3). In two independent studies (see description of studies), increases in CD4 cell counts were higher and more sustained in patients treated with the combination of HIVID and Retrovir than the clinical experience observed with Retrovir alone." The committee did not recommend any changes to this statement, not because it necessarily agreed with it, but because no data was available to support any particular change. Note, for example, that this language does not specify whether the combination should be approved only if other treatments have failed, or as a first-line treatment, or both. The dilemma here is that a new treatment is most needed when other alternatives have failed; physicians are more likely to try the better-known alternative of AZT alone as first-line treatment. Yet the available data on the combination would not support such a restriction, since it is from patients who had little or no prior experience with AZT. The Antiviral Advisory Committee supported accelerated approval of the ddC plus AZT combination with the condition that further testing be completed to prove that this treatment does have concrete value to patients. Exactly what is to be required of Hoffmann-La Roche will be determined by the FDA before approval is granted. Comment The issues raised by ddC combination treatment have been difficult for everyone involved. Scientists, physicians, and regulators were naturally reluctant to approve a drug for tens of thousands of people on the basis of one small trial (ACTG 106) which was never designed to test the drug's efficacy. But many patients and physicians, when they learned how good the results looked, were unwilling to wait for another trial to be designed, implemented, conducted, and analyzed. As a result, buyers' clubs provided ddC to thousands of people (who obtained their AZT for the combination treatment from conventional sources). This situation, of a de facto standard of care accepted by many leading AIDS physicians even though it included an unapproved drug, appears at first glance to be a problem. In fact it may have been the best possible solution to a deeper structural problem, a confusion about what we as a society use FDA approval for. On one hand, FDA approval provides legal access to treatments. In theory the FDA does not regulate the practice of medicine, but rather the marketing of pharmaceuticals and other healthcare products; in practice this distinction tends to become moot, since if a drug cannot be sold or otherwise distributed, it usually cannot be obtained by patients or physicians. On the other hand, FDA marketing approval is often treated as if it established an official standard of care. Insurers often use the FDA-approved indications for a drug as an excuse to deny reimbursement for uses outside of this official labeling, even when the standard of care among leading physicians is to use a drug for an off-label purpose. And -- more to the point on the handling of ddC -- FDA approval is treated as a standard of care in that it usually results in a drug being given routinely to many thousands of people, often with little further thought or independent evaluation. The Antiviral Advisory Committee itself was confused on this matter; at one point it asked for clarification on whether its recommendation was to provide legal access to ddC for combination treatment, or to recommend the therapy itself. No one could help the Committee here, since this confusion is basic to the current regulatory system. Legal access and quasi-official medical recommendation should be separate decisions; but often they are not. We are reminded of one leading AIDS physician who was asked if he prescribed combination treatment with ddI and AZT -- both approved drugs, but not officially approved for use together. He said that he was willing to prescribe the combination for an informed patient who was participating in his or her own treatment decisions, and clearly understood that the use of both drugs together was experimental. But for those patients who preferred not to be involved and to leave medical decisions entirely to the doctor, he would not say, "Here, take this." We suspect that the ddC "underground" may have been the best solution available, because it separated access from recommendation, which the official system is not set up to do. With only one small study available, it would have been difficult to say, "Here, take this" to tens of thousands of people. Yet it would also be unacceptable to say, "You can't have this" to those who had studied the matter and made an informed choice that, in their situation, the combination treatment was their best option available. With the new data presented at the recent Antiviral Advisory Committee hearing, the case for approval became stronger -- but still not strong enough to make the committee comfortable, with one member commenting that they were moving at lightning speed (in changing how they operated), but at the same time dragging their feet. In the background during the Antiviral Advisory Committee's deliberation was ACTG 155, a major trial comparing AZT alone, ddC alone, and the combination treatment, in volunteers who have already used AZT. This well-designed and very important trial, with about 1,000 volunteers, will end later this year; it should provide definitive information about the usefulness of the ddC plus AZT combination for many patients. There was concern in the Antiviral Advisory Committee that recommending approval of the combination might damage this trial, by causing people to drop out so that they could be sure of getting the combination. If this were to happen it would cause a tragic loss of vital information, as well as making it harder to get early approval of drugs in the future. But the danger seems unlikely. ddC is still not officially approved; the actual approval will probably take weeks or months, by which time the trial will largely be over. Also, people leave trials because of their physicians' advice, and most physicians are reluctant to prescribe a treatment until it is known to improve the condition of patients, not just laboratory-test values. (A similar situation occurred in July 1991 when ddI was recommended for approval; that recommendation, and the subsequent approval of ddI in October 1991, did not damage the ongoing trial.) The FDA's new procedure of accelerated approval will help to relieve the pressure in the case of ddC, and in similar cases in the future. It will be a limited relief, because it does not address the fundamental problem of how to provide legal access for those who are informed and prepared to make their own decision, without also creating an official stamp of approval which would send an experimental treatment to many others without informed consent. Yet this problem will take a long time to solve, because of the difficult issues around standard of care in U. S. medicine -- as well as the philosophical issues about what freedom means when growing complexity blurs the lines between informed choice and manipulation. The Antiviral Advisory Committee recommendation and expected FDA approval of ddC/AZT combination treatment will put old issues behind us, clearing the way for focusing on what is important now. Approval will help to defuse potential conflict over buyers' club access to ddC (as happened with other important AIDS-related treatments which were subsequently approved, especially clarithromycin and fluconazole, which were made available by buyers' clubs before approval, but not afterwards). It will let Hoffmann-La Roche focus its people and resources on the important tat and protease drugs, instead of spending more efforts on getting ddC approved. It will show the pharmaceutical industry that there are advantages, not only drawbacks, to developing urgently-needed drugs. And it will further the development of new combination regimens, applying to AIDS the multi-drug approaches which have proven successful against cancer and other difficult diseases. ***** ddI: Good News, Questions Remain by John S. James New data released April 13 at a meeting of the AIDS Clinical Trials Group suggested that patients who had been using AZT and then switched to low-dose ddI did better than those who continued with AZT. But several major questions remain, and important new information is expected over the next several months. We will be watching to see how the consensus of leading AIDS physicians develops -- especially after the International Conference on AIDS in July, where important additional data is expected. The new information concerns patients who had been on AZT more than 16 weeks before being randomized either to continue AZT or to switch to one of two doses of ddI. To qualify for the study, they either had to have a T-helper count of 300 or less and have AIDS or ARC, or have a count of 200 or less, in which case they could be asymptomatic. Over 900 volunteers participated in this study, with only five percent lost to followup. The volunteers were randomly assigned to three groups: continue AZT (600 mg per day), switch to 500 mg ddI (low dose), or switch to 750 mg ddI (high dose). [Note on doses: The newer tablet form of ddI is better absorbed than the powdered form used in the study. A 400 mg dose of the tablets is equivalent to a 500 mg dose of the powder.] The basic results were: * Patients assigned to the low-dose ddI did best. Those who had ARC or were asymptomatic had significantly fewer new AIDS- defining events than those assigned to continue AZT; the high- dose ddI group was intermediate. However, this difference was not seen in patients with AIDS. * Those assigned to either ddI group had higher T-helper counts over time than those in the AZT group. * However, there was no difference in survival between any of the groups. * Also, it did not matter how long the study volunteers had been taking AZT before switching to ddI; the benefit was the same in any case. * The AZT group had more side effects than the ddI groups, as measured by the average time until the first dose modification (if any) was required. But the high-dose ddI group had the most serious side effects, with 31 cases of pancreatitis, including two deaths. Major questions remain: * Why was there no survival benefit if there was a benefit (of low-dose ddI compared to continued AZT) in reducing serious opportunistic infections? It is possible that this surprising result occurred because of the way the study was conducted. For ethical reasons, patients' treatments were changed if they were not doing well on the treatment to which they were randomly assigned; 80 percent of the deaths occurred 30 days or more after the assigned treatment had been discontinued. At this time no one knows if there really was no survival benefit, or if this study did not show it because those who died had gone off the assigned treatment long before. * Why was benefit seen only for those less seriously ill, but not for those with AIDS? No one knows the answer at this time. [We hope that in addressing this question researchers will consider some of the less orthodox theories, including the possibility that some of the benefit of AZT may be due to immune suppression -- of autoimmune or otherwise inappropriate immune responses caused by the disease.] * A major mystery to researchers is why the length of prior AZT use (before the study) had no effect on the benefit of switching to ddI. The expectation had been that those who had taken AZT longer might have viral strains which had developed more resistance to AZT, and therefore they would benefit most from ddI. This did not happen. There was a great range of length of prior AZT use. All volunteers had to have tolerated AZT for at least 16 weeks to qualify, but many had taken that drug for over 48 weeks. The reason is that this study (which is named ACTG 116-B/117) had originally begun as two separate studies; part of ACTG 116 (those patients who had taken AZT for more than 16 weeks) was combined with ACTG 117 (for patients who had taken AZT for over 48 weeks); those recruited later in the combined study had to have taken AZT for over four months. Could ddI be the better drug for some patients even for first-line therapy (for those who had no prior use of AZT)? This study cannot answer that question. Researchers are waiting for the results of ACTG 116A, comparing AZT and ddI in patients who had taken AZT for less than 16 weeks. That study is not finished yet. (ACTG 116-B/117 was stopped early, because it had already shown that one treatment was working better than another.) Comment All that is known today from ACTG 116-B/117 is based on a rapid, very early analysis of the data. More will be learned as analysis proceeds, and as other trials finish. A number of people are guessing -- based partly on rumors from ongoing European studies -- that ddI may prove to be a better drug in general than AZT. It is also possible that the best dose of ddI will be even less than the "low" dose used in ACTG 116-B/117. But at this time, much of the information we would want is not available. We do expect that the information already released will influence medical practice. An April 13 backgrounder, "ACTG 116-B/117: Questions and Answers," released by the U. S. National Institute of Allergy and Infectious Diseases, concludes: "Further analysis of this study will need to be completed before any final recommendations can be made. Completion of other, on-going comparative studies of ddI (ACTG 116-A and ACTG 118) will help in determining the full impact of these results on patient management. While it is not possible at this time to make recommendations for all HIV-infected patients, patients should discuss this information with their primary care providers in order to devise treatment strategies to meet individual needs." ***** AZT: New Survival Data by John S. James A statistical study of over 2,500 HIV-positive men, published April 16 in the NEW ENGLAND JOURNAL OF MEDICINE, found that early AZT use and early pneumocystis prophylaxis each independently increased the chance of survival. ("Early" treatment in this study was defined as treatment beginning before the first AIDS-defining event.) According to an April 15 press release from the U. S. National Institute of Allergy and Infectious Diseases, "Early treatment with AZT reduced the risk of death at six months by 57 percent, whether or not it was combined with a drug that prevented Pneumocystis carinii pneumonia (PCP). Moreover, investigators found that, after two years, early treatment reduced the risk of death by 33 percent, when compared to those who did not take AZT before a diagnosis of AIDS." The benefits were seen especially in men who started AZT with T-helper counts between 200 and 350. In those with T-helper counts above 350 there were not enough deaths in this study to collect reliable survival data. The MACS Study This survival analysis was done with data from the Multicenter AIDS Cohort Study (MACS). The MACS cohort consists of over 5,000 gay and bisexual men in four metropolitan areas: Chicago, Pittsburgh, Los Angeles, and Baltimore/Washington; most of them were enrolled in the study between April 1984 and March 1985, and followed since at twice-yearly visits. About half of the volunteers in the MACS study are HIV-negative; only those who are HIV-positive were included in the survival analysis. Deaths and AIDS diagnoses through April 1, 1991, were included. This study is not a randomized clinical trial, as the treatments used were chosen by the patients and their physicians, not assigned at random. Therefore there could be self-selection bias, and precautions were taken in the analysis to minimize it. The study is a prospective one, however, meaning that the volunteers were selected first and followed forward in time, whatever outcome occurred. This kind of study, which the MACS cohort makes possible, is more reliable than a retrospective study of medical records. Discussion The recent paper discusses earlier studies of survival with and without AZT treatment. One observational study in Maryland, published in 1991, found a median survival of 690 days for AZT users, compared with 280 days for those who never used AZT. An Australian study showed an even larger difference. But these studies were in patients with AIDS; they did not compare the effect of AZT as early treatment. The paper also discusses the controversial Veterans Affairs Cooperative Zidovudine Study, published February 13, 1991 in the NEW ENGLAND JOURNAL OF MEDICINE, which found that early AZT use greatly reduced the progression to AIDS, but did not find any survival difference: "In the Veterans Affairs trial, 338 patients with CD4+ lymphocyte [T-helper cell] counts of 0.2 to 0.5 cells x 10(9) per liter (200 to 500 per cubic millimeter) were randomly assigned to early zidovudine therapy (at the beginning of the study) or later treatment (when the CD4+ lymphocyte count fell below 0.2 cells x 10(9) per liter). After two years of followup, the early- treatment group had significantly fewer AIDS-defining events than the late-treatment group (25 vs. 44, p = 0.02) but no significant differences in numbers of deaths (23 vs. 19). The small numbers of outcomes [deaths], the use of high-dose treatment regimens (1500 mg per day), and alterations to the protocol during the study suggest that these mortality data may not reflect the true treatment effect in persons taking zidovudine at currently recommended doses (500 mg per day)." [Brackets indicate explanatory notes added by AIDS TREATMENT NEWS.] The paper concludes "both antiviral [treatment] and anti-PCP prophylaxis are necessary to maximize the survival benefit." For more information, see "The Effects on Survival of Early Treatment of Human Immunodeficiency Virus Infection," by NM Graham, SL Zeger, LP Park, and others, The NEW ENGLAND JOURNAL OF MEDICINE, April 16, 1992, pages 1037-1042. ***** HIV/Endocrine Update by Denny Smith HIV infection apparently fosters problems of the endocrine system that may be both common and commonly overlooked. At least some of these are treatable in symptomatic people, and so lately have been attracting attention. The endocrine system comprises a network of glands that secrete hormones -- complex messengers which evolved to instruct the body on an enormous number of activities, including daily metabolism, sexuality and reproduction, and responses to stress. Because HIV disease can dampen an effective endocrine response to illness, hormones may fill a therapeutic role to facilitate recovery or stop a progressive debilitation. Last December, an article in AIDS TREATMENT NEWS #140 discussed the association between HIV progression and deficiencies of the hormones dehydroepiandrosterone (DHEA) and hydrocortisone (cortisol). In the meantime, several people have shared with us information or experience that helps expand that discussion. In our first report, we said that physicians generally do not advocate hormone treatments except as replacement therapy when a particular gland is diseased, such as in CMV infection of the thyroid. However, that assertion paints an incomplete picture, for a couple of reasons. For one, hormones administered as drugs are not uncommon treatments for a variety of disease effects which are not related per se to endocrine problems. For example, dexamethasone (Decadron) is one part of a frequently used cancer chemotherapy combination; megestrol acetate (Megace) is a synthetic compound related to progesterone and is sometimes used to assist weight gain in people with cancer or AIDS; erythropoietin (EPO) is used to treat anemia; tamoxifen may be valuable for preventing breast cancer, osteoporosis and heart disease. All of these are derivatives of endogenous (naturally occurring) hormones. The scope of their abilities shows that hormones perform an extensive array of natural functions, and that they may become a constituent of medical therapies even in the absence of clear endocrine dysfunction. Secondly, and more to the point, HIV clinicians are now treating some patients with certain hormones to directly compensate for chronic endocrine insufficiencies which are associated with HIV infection but do not result necessarily or exclusively from acute opportunistic infections. Corticosteroids For example, doctors at Mt. Sinai Medical Center in New York have treated HIV-associated myopathy successfully with prednisone (Simpson DM and others, 1991). Myopathy is an inflammatory degeneration of muscle fibers which can cause pain or tiredness and which can resemble wasting syndrome. Unfortunately, prednisone's capacity for quieting the inflammation also means that it can suppress the immune system generally, or cause hyperglycemia in some people. But Mt. Sinai clinicians did not find this to be the case at the doses used -- beginning with 60 mg given daily, then every other day, tapering further as the patients' myopathy was controlled. In addition, prednisone is sometimes given orally to control mouth sores which are related to HIV infection but not caused by herpes, or to ease the disabling pain of HIV-associated arthritis. But prednisone is a powerful hormone, and the short-term benefits should be balanced against long-term concerns. (It is an analog of cortisone, which is produced by the adrenal cortex.) The adrenal cortex also produces cortisol (hydrocortisone), although insufficiently in some people with AIDS. People with adrenal insufficiency may present with low sodium and high potassium levels, and fatigue and weight loss that cannot be attributed to other causes. Some experienced HIV physicians now give cortisol to treat adrenal insufficiency in some patients. Many patients' symptoms have improved with such treatment. (Cortisone and cortisol are often called corticosteroids.) Paradoxically, some Miami researchers have observed evidence of elevated cortisol levels in the development of AIDS. Their findings will be presented in depth at the VIII International Conference on AIDS in July. (This may or may not be connected to the fact that emotional depression is associated with elevated cortisol in some people.) Androgenic anabolic steroids Stewart E. Springstead, M. D., contacted us after our first report to share some of his patients' experiences with hormones known as androgenic (male) anabolic (tissue mass- increasing) steroids. Dr. Springstead's specialty is psychopharmacology, but he has substantial clinical experience in his New York practice treating some of the constitutional symptoms presented by his patients with AIDS. In the process, he discovered that many of his patients had testosterone levels low enough to warrant replacement therapy, and that most were experiencing progressive loss of body mass. Consequently, he has offered those patients a trial of the androgenic anabolic steroid nandrolone. According to Dr. Springstead, the benefits of nandrolone are both physiological and psychological. Physically, there have been general increases in muscle mass, strength, body weight and hemoglobin. The psychological benefits include an increase in appetite and subsequent improved nutrition, and increases in energy, libido and feeling of well being. Androgenic anabolics have a variable absorption rate in the gastrointestinal tract, and they can cause minor, if reversible, liver dysfunction when given orally. To avoid these problems, Dr. Springstead administers the injectable nandrolone. He believes there is no clinical evidence that androgenic anabolic steroids, as opposed to the corticosteroids, are immunosuppressive. In fact, he suspects, as others do, that they may have a protective effect on the immunologic and hematopoietic systems. After three months on androgenic anabolic therapy, one of his patients experienced an increase in p24 antibodies, and a reversal of p24 antigen from positive to negative. DHEA is also an androgen, though a mild one, and contributes to the production of testosterone. In the medical literature DHEA has been associated with a decreased risk of heart disease and certain cancers, a modest inhibition of the HIV and Epstein- Barr viruses, and enhanced interleukin-2 synthesis by activated T cells. Because its normal levels were found to drop before progression to AIDS, DHEA was reported by researchers in San Francisco last year to be a potential marker, if not a treatment itself, for HIV progression. A more recent report from Amsterdam this year suggested the same thing (Mulder JW and others, 1992). Whether replacing DHEA could have a therapeutic effect on HIV progression remains a good question, even after it had been available through community HIV buyers' clubs for several years. Dr. Springstead feels that DHEA offers minimal anabolic activity when compared to nandrolone. We inquired about the masculinizing effects of androgenic steroids on women. Dr. Springstead feels that such effects develop slowly and are easily monitored, and that women with HIV, unless they are pregnant, can effectively use nandrolone if they are adequately informed about the potential side effects. Dr. Springstead pointedly addressed the controversy surrounding the misuse of androgenic anabolics by athletes. He noted that these substances were widely used in the 1940s, 50s and 60s to treat a variety of chronic infections, anemic conditions, muscle wasting diseases, and protein deficiencies, and to protect hematopoiesis (the formation of new blood cells) after irradiation and chemotherapy. But then the medical application of, and research into, anabolic steroids virtually ceased following the 1970s notoriety arising from the inappropriate use of steroids by athletes. Consequently, a lot of valuable clinical data has been ignored -- data that Dr. Springstead feels could be of use now in the treatment of HIV disease. Finally, Dr. Springstead recommends three background texts: Anabolic Steroids, by H. L. Krskemper, Basic and Clinical Endocrinology, edited by F. S. Greenspan, and Depressive Disorders and Immunity, edited by A. H. Miller. He describes the latter as a major step toward an understanding of the complex relationship between the psychological state of the individual and the immune system, and how antidepressive therapy and the anabolic steroids could have a positive impact on the course of HIV disease. Growth Hormone -- Study Recruiting One of the most innovative developments in the endocrine arena of HIV treatment concerns the use of growth factors to counter AIDS-associated wasting syndrome. Endogenous growth hormone is produced by the pituitary gland, and is important for the making of new protein. For that to happen, however, growth hormone is "mediated" by another hormone called insulin-like growth factor-I (IGF-I). IGF-I is manufactured by the liver and other tissues, and is a protein itself. Stanford University and the Palo Alto Veterans' Affairs Hospital are now conducting a study of IGF-I to test its capacity to reverse the muscle/weight loss and weakness which contribute to wasting syndrome. We spoke to an investigator of the study, endocrinologist Steven Lieberman, M. D., about the rationale of IGF-I in the treatment of AIDS. Dr. Lieberman explained that the goal of using such a hormone is similar to the use of androgenic anabolics, but avoids their side effects. In addition to reversing protein loss, IGF-I might improve immune function. He said that so far, the participants have tolerated the protocol well. The study is still open for recruitment. Interested persons should call 415/493-5000, extension 4148. It should be noted that part of the study involves staying at the study unit for fourteen days, and that upon completion participants will receive $500. Comment We very much appreciate the clinical expertise and technical advice that Drs. Lieberman and Springstead offered to this update. We understand that many physicians have misgivings about the use of steroids, but perhaps this is an appropriate time to reassess their value in situations where other options have been exhausted. Steroids are obviously not appropriate for asymptomatic HIV infection, or an alternative to accurate diagnosis and treatment for AIDS-related infections. Also, men and women have different hormonal systems, and may respond differently to treatments; clearly more research is needed on the impact of HIV on women, particularly on the endocrine system. But it seems that the endocrine response to AIDS is frequently wanting, and that it might be finessed to make a critical difference for many people who every day face a lessening of their physical and emotional being. References Following are some references to published endocrine/HIV reports. For a more extensive list, see AIDS TREATMENT NEWS #140, mentioned above. Mulder JW, Jos Frissen, Krihnen P and others. Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men. The Journal of Infectious Diseases, number 168, pages 413-418, 1992. Cieslak TJ, Ascher DP, Zimmerman PA and others. Adrenal insufficiency presenting as HIV wasting syndrome in a child: initial successful response to megestrol. Pediat. AIDS HIV Infect. Fetus Adoles., volume 2, number 5, pages 279-283, October, 1991. Lepage P, Van de Perre P, Van Vliet G, Nsengumuremyi F and others. Clinical and endocrinologic manifestations in perinatally human immunodeficiency virus type 1-infected children aged 5 years or older. American Journal Dis. Child., volume 145, number 11, pages 1248-1250, November, 1991. Simpson DM and Wolfe DE. Neuromuscular complications of HIV infection and its treatment. AIDS, number 5, volume 8, pages 917-926, 1991. Turner R. Deca-Durabolin and cytotoxic drugs. Acta Endocrinologica 1985, Supplementum 271, pages 70-79. Kopeva H. The history of anabolic steroids and a review of clinical experience with anabolic steroids. Acta Endocrinologica 1985, Supplementum 271, pages 11-18. Griffen HR and others. Mode of action and use of anabolic steroids. The British Journal of Clinical Practice, volume 30, number 1, pages 3-9, January 1976. ***** ACT UP/Immigration Goes to Amsterdam: Assistance Sought The Immigration Working Group of ACT UP/San Francisco and ACT UP/Golden Gate "is going to Amsterdam for the Eighth International Conference on AIDS to call attention to the restrictive immigration and travel policies of the United States. The international conference is the crucial time and place to call attention to the public health consequences of the U. S. policies. During the conference, the committee is planning several high-visibility presentations and hopes to mobilize global support for the removal of all HIV-based immigration restrictions." The committee is seeking cash donations, portable computer and fax equipment, frequent flyer miles, and lodging/office space near the conference center. For more information, call or fax Tomas Fabregas, 510-451-9354, between 10 a.m. and 8 p.m. Pacific Time only. 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