Subject: AIDS Treatment News #141 Date: Dec 23 1991 (636 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1991 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #141, December 23, 1991 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] 1992: Treatments to Watch MAC: Clofazimine Trial Finds No Benefit 1991: Ten Years of the Epidemic, Five Years for AIDS TREATMENT NEWS Announcements: California Clinical Trials Directories Published Care and Support Grants for New Organizations or New Projects Controlling Diarrhea: Sandostatin Trials Recruiting Controlling Weight Loss: Dronabinol (Marinol) Trials Recruiting Call for Information on "Alternative" Treatments ***** 1992: Treatments to Watch by John S. James Near the beginning of each year we list the treatments we are watching most closely because of their potential importance in the months ahead. This year more is happening than ever before, so readers should realize that our list is incomplete; no one can keep up with everything. These are some of the treatments to watch; but there may be others just as important. Our top-priority list of seven treatments and potential treatments appears below in order of importance (starting with the most important, the tat inhibitor). We also list two groups of treatments for AIDS-related conditions. Tat inhibitor Many leading AIDS researchers believe that blocking the "tat" gene of HIV may be the most promising approach to AIDS drug development. And new information presented at a recent conference but not yet widely known greatly strengthens the case for this kind of drug. The HIV tat gene produces a protein which greatly increases the activity of the virus; without tat, the virus becomes inactive. Because this gene has long been recognized as a potential target for an antiviral, the U. S. National Institute of Allergy and Infectious Diseases (NIAID) has provided about $700,000 a year for tat research to a consortium headed by Hoffmann-La Roche, which developed a drug code-named Ro 24-7429, which is now being tested at Johns Hopkins University. No other tat drug is now ready for human testing. Here is why this approach is important: * A major advantage of a tat inhibitor over almost all other AIDS drugs is that it would probably be effective in chronically infected as well as acutely infected cells (as Ro 24-7429 has indeed been found to be). Other antivirals, such as AZT, ddI, ddC, and the non-nucleoside RT inhibitors, at best stop HIV from reproducing; they work after the virus has infected a cell, by preventing the genetic information of the virus from being inserted into the genes of the cell. But it seems increasingly likely that much of the damage of AIDS is caused by reservoirs of the virus in chronically infected cells (including macrophages, dendritic cells in the skin, and probably other kinds of cells also). HIV does not kill these cells, but it makes them behave abnormally; they may produce toxic substances such as gp120, or inappropriate amounts of cytokines, normal chemical "messengers" between cells. This process in not affected by the drugs mentioned above (and probably not by the new class of protease inhibitors, either). An effective anti-tat drug would probably make HIV inactive in these cells, stopping the production of toxic substances -- although it would not kill the virus and, like the other drugs, would need to be taken indefinitely. * Another major advantage concerns viral resistance. Researchers have suspected that HIV might not be able to develop resistance to an anti-tat drug, because the function of tat may be critical; a mutation which could get around the drug effect would be lethal to the virus. Now there is evidence that this may indeed be the case. At the recent "New Directions in Antiviral Chemotherapy" conference in San Francisco, Douglas Richman, M. D., the leading expert on HIV resistance to antivirals, was asked about his results. In laboratory tests, he could quickly ("as early as one passage, and always within six passages") select for resistance to the non-nucleoside RT inhibitor BI-RG-587 (which, along with the Merck "L-drug", has recently shown major resistance problems in human trials). But in well over a year of tests he has not found any change in sensitivity of HIV to the tat inhibitor (Ro 5-3335, an earlier version of Ro 24-7429, which apparently was abandoned because of kidney toxicity in animal tests). In the past, one reason for skepticism about the tat inhibitor is that its chemical structure is quite similar to that of BI-RG-587. Some skeptics had thought that the Hoffmann-La Roche drug may have been mistakenly identified as a tat inhibitor, but that it really inhibited reverse transcriptase instead -- in which case it would not be special. The new resistance information (which as far as we know appears in print for the first time in this article) shows that while the two drugs are chemically similar, they are very different in their effects -- apparently because they act against different targets in the virus. It has also been found that AZT-resistant strains of HIV are equally sensitive to the tat inhibitor as non-resistant strains. * Ro 24-7429 is synergistic with AZT, meaning that the combination works better than would be expected by adding the separate effects of the two drugs. * Ro 24-7429 is a "benzodiazepine derivative" -- a member of the class of chemicals which includes the tranquilizers Valium and Librium. The extensive human experience with this kind of chemical may help in the development of the new drug. There are three main safety concerns with Ro 24-7429. In animal studies (which presumably included much higher doses than will be given to humans) it can cause kidney toxicity. And in the body, the drug is turned into a substance with a strong yellow color, which is seen in the urine; in animals, this substance could also remain in the tissues. The third concern is that many benzodiazepine derivatives can cause central nervous system toxicity; as a result, Ro 24-7429 was carefully tested for this before human trials began. The first human trial of Ro 24-7429, which administered only one dose of the drug, has now been completed. The second trial is now ongoing at Johns Hopkins University. This trial is designed only as a safety study; according to a spokesperson for Hoffmann-La Roche, no efficacy information is being collected. The three lowest doses (60, 200, and 600 mg) should be tested by early 1992; then the FDA wants to look at the data to decide whether to continue this trial with higher doses. The corporate future of the tat inhibitor has been insecure since April 1991, when developer Hoffmann-La Roche decided that for business reasons it did not want to develop this drug, and told Johns Hopkins researchers to indefinitely postpone the trial which was scheduled to start at that time. Hoffmann-La Roche is expected to announce soon that it has sold rights to the drug to another pharmaceutical company. We are concerned that the current trial of Ro 24-7429 is not collecting efficacy information, as is commonly done in other trials of AIDS treatments; we urgently need an early indication of whether or not the drug is working in people as a practical treatment for HIV. The trial has also been criticized for its exclusion criteria, especially its exclusion of women of "childbearing potential"; this trial will end with little or no safety information for women. No one yet knows if Ro 24-7429 will be successful as a drug. If it is not, then the technology which found it (screening for anti-tat activity) will be vitally important, for searching for other tat drugs. This technology was developed at least in part at public expense; it should be made available. (We have been told that the drug itself, Ro 24-7429, was an off-the-shelf chemical at Hoffmann-La Roche, discovered by luck early in the screening process. How many more tat drugs could be found if the screening were not limited to existing chemicals which a single company has the commercial rights to produce?) For more background on the history of the tat inhibitor, see "Promising AIDS Drug Looking for a Sponsor," Science, July 19, 1991, pages 262-263, and "Roche Stops Human Tests of Promising AIDS Drug," Wall Street Journal, May 30, 1991, page B4. Hypericin Hypericin, an antiviral found in small amounts in the St. John's wort plant, appears to be a broad-spectrum antiviral. It shows good anti-HIV activity in laboratory tests (including tests on "wild" virus strains in freshly-drawn blood from persons with HIV), and was found to be an effective treatment for other retroviral diseases in laboratory animals. It appears to have excellent pharmacokinetic properties: it is orally available, has a long half life, and gets into cells. It has been in human use for years (in low doses), especially in Europe, where herbal extracts have been used as an antidepressant. In animal tests, large doses can be tolerated with little toxicity. The main potential importance of hypericin is that if it works as an HIV treatment, it would provide a whole range of new treatment options, since its mechanism of action is entirely different from that of other available drugs. Also, laboratory tests have shown activity against CMV, influenza, and other viruses. Recent anecdotal reports have suggested that even the low-dose plant extracts might have a role in treating hepatitis B. Hypericin which was chemically purified from the plant extracts was ready for human trials three years ago, but it was not tested; instead, research was undertaken to improve the methods for chemically synthesizing the drug (without relying on plants), and this work took longer than expected. The ostensible reason for not testing the plant extract was lack of supply of the drug; but our recent discussions with an underground chemist made it clear that supply for a small trial at least would not have been a problem. Our best guess as to why a trial was not started three years ago is that there has always been general agreement that eventually this drug will be produced synthetically, if used on a large scale. And the FDA, for historical reasons, is divided between "drug" and "biologic" divisions, with different personnel and procedures. If a substance is first tested as a plant extract, and later is manufactured, it would have to start the approval process over again in the other division. The tragedy, of course, is that if the substance did work well in early tests, then resources would have been found to overcome all obstacles, no matter how the drug was manufactured. (Two years ago, the Community Research Alliance, a San Francisco organization co-founded by this writer, had completed a monitoring study of over 30 people who used the St. John's wort extracts available in buyers' clubs and health- food stores. Although T-helper counts did increase among those who started with high baseline counts, the effect was not dramatic enough to attract attention. This study was published in the Sixth International Conference on AIDS, June 1990, abstract #2063.) The first human trial with pure hypericin (as opposed to crude plant extracts, which cannot supply the doses believed likely to be effective) began a few weeks ago at New York University and two other sites. No efficacy data is yet available, but researchers are encouraged by the good pharmacology of the drug and the lack of serious toxicity. This study is not blinded, and information will be reported as it becomes available; the first two weeks of data was presented recently at a meeting of NIAID's AIDS Clinical Trials Group. One side effect has been found; a feeling of warmth in the hands and face. It has been described as the feeling of coming into a warm room after being outdoors on a cold day; one volunteer was uncomfortable enough to withdraw from the study as a result. This effect may be due to phototoxicity (abnormal sensitivity to sunlight or other strong light), a side effect expected because it occurs in animals. Volunteers have been given a sunscreen to protect the hands and face from sunlight. And a minor drawback found in this trial is that the hypericin's half-life in humans (24 to 25 hours) is less than in the two species of monkeys in which it has been measured; as a result, the drug may need to be taken three times a week instead of twice, in order to maintain antiviral levels in the blood. If hypericin does prove useful, there should be little trouble obtaining supplies, either by synthesis or by chemical extraction from plant sources. The plants grow all over the world. For more information on hypericin, including an extensive list of technical references, see AIDS TREATMENT NEWS #125, April 19, 1991; for background on the current clinical trial, see issue #138, November 1, 1991. ddC and AZT Combination This drug combination has become the de facto standard of care (for certain patients) among a number of leading AIDS physicians, even though ddC is not approved. Trial results first came out over a year ago (see AIDS TREATMENT NEWS #115, November 23, 1990); little little new information is now available. In 1992 we hope and expect to see more information for physicians about how best to use this combination; especially needed is guidance about which patients are most likely to benefit. We also hope and expect to see FDA approval of ddC. Hoffmann-La Roche has applied for approval both for single-drug use and in combination with AZT (see AIDS TREATMENT NEWS #139, November 22, 1991). Soluble Melanin We covered this potential treatment extensively last month (issue #139, November 22, 1991), and will not repeat that article here. We have received little new information since that publication; few new people have tried melanin, since it has not been available. We have talked to one person whose T-helper count went down after about a month of the treatment, and who had no symptomatic improvement. Melanin may be available soon. Here are some points to consider in deciding whether to use it: * Although researchers who have worked with melanins generally regard them as safe, this chemical has never been through the standard animal toxicity studies required before a drug can first be tested in humans. And the stories we have heard about its effectiveness, while impressive, are anecdotal; there is no proof that the drug works. Anyone considering trying melanin should realize how preliminary and nebulous the current information is. * In all but one of the (handful of) cases reported to us, there was considerable improvement within five days -- usually within one day. This suggests that those who do decide to try the treatment might try it for only a short time, perhaps a week, and then stop unless it clearly seems to be helping. Why accept the unknown risks of long-term use unless there is a clear benefit in return? * We would very much like to hear from anyone who has first- hand information about use of melanin as an AIDS/HIV treatment, whether or not it seemed helpful. Include contact information so that we can get in touch with you; we will keep your identity confidential. Write to AIDS TREATMENT NEWS, attn: melanin, P. O. Box 411256, San Francisco, CA 94114, or call 415/255-0588. The urgent need now is to confirm or deny the suggestion (from the early anecdotal reports we published in issue #139) that this treatment may bring dramatic benefit within days for most persons with HIV-related symptoms. The research mainstream is not constituted to investigate this question properly. If the answer is No -- which historically is the case with most new drugs -- then melanin can go back to the research establishment for eventual determination of its ultimate value in AIDS/HIV treatment. NAC We are overdue for an in-depth review of NAC (N- acetylcysteine), which we covered briefly in issue #121, February 15, 1991. Laboratory work continues to look good, and the treatment, available at buyers' clubs and health-food stores, continues to be popular. There is still no efficacy data from clinical trials, which only began recently, although they should have started at least two years ago. Our impression is that the benefit of NAC appears to be limited; it may slow down the progression of HIV, especially in some patients, but it is unlikely to be a sufficient treatment by itself. This potential treatment is interesting nevertheless, because it has so little "down side"; it appears to be safe, and is inexpensive and available. Ribavirin and ddI Combination There have long been hints from laboratory studies that this combination may work well. But it is almost impossible to run trials which combine two unapproved drugs, especially drugs from different companies. Now that ddI has been approved, trials will be easier to initiate. Antisense Drugs "Antisense" technology is a means of developing drugs which bind to a specific sequence of DNA or RNA within cells. The purpose is to target and shut down specific genes. Antisense drugs may have great future impact for treating cancer, viral diseases, and other medical conditions. It is generally believed that practical antisense drugs are years away. But the technology has been advancing faster than expected. We have heard that antisense AIDS treatments might be ready for human trials as early as 1992. One immediate problem with antisense drugs is that, at present, they are very expensive to produce. ** Treatment for AIDS-Related Conditions Anti-Angiogenesis Drugs This new class of drugs, not yet tested in humans, prevents the growth of new blood vessels. In animal tests they have been effective in stopping growth of solid-tumor cancers (which must tell the body to create new blood vessels, since otherwise tumors cannot grow beyond a small size), and in KS (in which the lesions are caused by abnormal blood-vessel growth). The leading anti-angiogenesis drugs at this time are AGM- 1470 (covered in AIDS TREATMENT NEWS #135, September 20, 1991), and SP-PG (being developed by Daiichi Pharmaceutical Company of Tokyo, with the help of Robert Gallo, M. D., and his laboratory at the U. S. National Cancer Institute). The main obstacle to getting these drugs into human tests may be that both of the companies developing these drugs are Japanese, and inexperienced in working with the U. S. Food and Drug Administration. What often happens in these cases is that companies rely on consultants with long experience with the FDA -- much of it obsolete, since today the FDA should be involved much earlier than before, if companies want rapid movement on critical drugs for life-threatening conditions. (One way to overcome this bottleneck would be for the National Cancer Institute to work with the FDA on these projects, since it has much experience in working with the Agency in human tests of potential cancer treatments.) New Antibiotics Some of the important new antibiotics are clarithromycin and azithromycin (both now approved in the U. S., but for non-AIDS- related indications), and 566C80, available from Burroughs- Wellcome for pneumocystis treatment (but not prophylaxis) for patients who have failed other options. ***** MAC: Clofazimine Trial Finds No Benefit An 18-month trial by the Community Consortium, an organization of AIDS physicians in San Francisco, was stopped early by the Consortium's Data Safety and Monitoring Board (DSMB) after seven of 56 volunteers on clofazimine developed evidence of disseminated MAC (based on blood cultures), compared to six of 54 untreated patients. A report in the October 1991 Synopsis, which is published by the Community Consortium, pointed out that this result does not prove conclusively that clofazimine does not work. But there were too few volunteers remaining in the study to prove statistically that it did work -- even if everyone given no treatment developed MAC, and no one else who was taking clofazimine did. The DSMB stopped the study because, after the results seen so far, a positive outcome would have been impossible. This trial strongly suggest that clofazimine does not work for MAC prophylaxis. For more information, contact the Community Consortium, 3180 18th Street, Suite 201, San Francisco, CA 94110, 415/476-9554 ***** 1991: Ten Years of the Epidemic, Five Years for AIDS TREATMENT NEWS by Denny Smith 1991 marks the tenth year of the global catastrophe of AIDS, a decade in which half a million lives were damaged or lost forever. Under this staggering cost, we cannot speak of silver linings; but we can honor those who are gone by naming some victories their lives made possible. * The search for treatments for AIDS has significantly advanced medical research in general, and in particular it has exposed many of the counterproductive ways in which such research is designed and conducted, and by which corporate profits can be placed ahead of human life. * A generation of people has been emboldened to question the neglectful, bureaucratic failures of the U. S. health system, and to teach themselves how to advocate for their own interests and those of their communities. * In a culture where democracy is often confused with military intervention, the most lasting legacy of AIDS could be to democratize access to medical care. For the staff of AIDS TREATMENT NEWS, this year represents another, more heartening, anniversary: our fifth year of reporting on treatment developments. Thanks largely to the support of our readers, we have survived a number of difficult times. We are determined to provide this service for as long as necessary. ***** Announcements ** California Clinical Trials Directories Published Two updated HIV clinical trials directories have just been published, covering Southern California and the San Francisco Bay Area. They contain useful information for anyone interested in participating in a clinical trial, and include community-based trials and observational databases as well as government and pharmaceutical company research. Directory of HIV Clinical Trials in the Bay Area, Winter 1991 is published by the San Francisco Community Consortium. It lists 79 open trials in the Bay Area, arranged by disease or symptom treated. It includes a glossary, lists of community resources and trial sites, how to enroll in a trial, and information for women and injection drug users. Call 415/476- 9554 or write to: Community Consortium, 3180 - 18th Street, Suite 201, San Francisco, CA 94110 for a free copy. Southern California HIV Treatment Directory, Vol. 1, No. 3 lists 64 trials in the Los Angeles area, including those conducted outside major medical centers or without Investigational Review Board (IRB) approval. It is also organized by symptom or disease treated and includes a glossary. People with HIV can get a free copy of the directory, and a $10.00 donation is requested of others. It is also possible to pay $40.00 for a year's subscription of four volumes. Call 213/469-5888 or write to: Southern California HIV Treatment Directory, 1800 N. Highland Ave., #610, Hollywood, CA 90028. ** Care and Support Grants for New Organizations or New Projects People Taking Action Against AIDS (PTAAA), an all-volunteer fundraising organization, is seeking applications for grants to newly-formed groups or new projects to offer care or support to people with AIDS. Underfunded groups outside of major urban areas will be given priority, as will 501(C)3 organizations. To apply, request a grant application form no later than January 24, 1992, from: PTAAA, 31 West 26th St., Second Floor, New York, NY 10010, or by fax to 212/481-1373. For more information, call Don Hall at 212/481-1374. Note: PTAAA has raised funds for AIDS research and care organizations since 1987, mainly through an annual event on Long Island. In 1990, it gave 12 grants of $2,000 to $5,000 each, and also several larger grants totaling $187,000. Projects funded included hot meals, hospital equipment not covered by Federal grants, malpractice insurance for rural volunteer nurses, an AIDS support center in rural Georgia, and Bailey House and AIDS Treatment Registry, agencies well known in New York City. A unique kind of project -- not sponsored by any organization except PTRAA -- is a Dallas-wide scholarship essay competition for high school seniors "designed to stimulate discussion in the high school classroom on issues of AIDS these young people are facing today." The larger grants were to the Children's AIDS Foundation, Friends of Clinical Care Center, the Pediatric AIDS Foundation, the Long Island Association for AIDS Care, and to New York's Community Research Initiative for specific research projects. ** Controlling Diarrhea: Octreotide (Sandostatin) Studies Recruiting Dangerous weight loss (cachexia) in people with AIDS can result from malabsorption and chronic diarrhea as well as loss of appetite (anorexia). Some of the choices for countering diarrhea include diphenoxylate (Lomotil), loperamide (Imodium), cholestyramine (Qestran), and tincture of opium (Paregoric). A newer, somewhat experimental option is somatostatin, a naturally-occurring peptide-inhibitor associated with the regulatory activities of the digestive system. Somatostatin can be given intravenously to treat the processes that contribute to diarrhea, but unfortunately the half life of this substance is impractically short. Octreotide is a synthetic agent given sub-cutaneously that approximates somatostatin's activity, only with a much extended half life. Octreotide is now approved for certain non-AIDS- specific indications, and is marketed by Sandoz under the label Sandostatin. Sandoz has designed a protocol to study Sandostatin in people with HIV-related diarrhea which has not responded to other treatments. There are 19 local sites for this study; their locations and the details of exclusion and inclusion criteria can be obtained by calling 800/TRIALS-A. ** Controlling Weight Loss: Dronabinol (Marinol) Trials Recruiting Dronabinol is a manufactured version of THC, the principal active agent in marijuana. Dronabinol and marijuana have both been reported to control nausea and stimulate appetite in people with AIDS or cancer. For background information see issues #131 and #139 of AIDS TREATMENT NEWS . Developed jointly by UNIMED and Roxane Laboratories under the trade name Marinol, dronabinol is approved by the FDA to treat nausea. The makers would like the labeling expanded to include treatment for loss of appetite, which is a serious problem for many people fighting cancer or opportunistic infections. Robert Gorter, M. D., an Assistant Professor of Medicine at the University of California San Francisco who has studied dronabinol in patients with HIV infection, discusses it in "Management of Anorexia-Cachexia Associated With Cancer and HIV Infection," published in the September 1991 supplement of the journal Oncology. There are 25 sites recruiting for the current Marinol protocol that is hoped to demonstrate appetite improvement. To locate the closest local study, interested persons may call 800/TRIALS-A. ** Call For Information on "Alternative" Treatments A number of alternative or complementary treatment approaches have enjoyed several years of support in the HIV/AIDS- affected communities. But for the most part, when these approaches involve unrefined or imported substances, they have been casually dismissed by mainstream research, and therefore lack the rigorous clinical data necessary to assess their therapeutic value. AIDS TREATMENT NEWS has tried to call attention to some of these potential treatments in the past, but often we cannot pursue each of them adequately or comprehensively. Following is a list of some we have covered and some we have not. We would like to hear from readers who have had recent substantial experience, negative or positive, with any of these. We understand that such information must be considered anecdotal, and so can only lead to suggestions and not conclusions. If the response to this call is significant, we will report the results -- anonymously, of course. We have not included NAC or hypericin in this list, since these are now in clinical trials. * silymarin (milk thistle extract) * aspirin * glycyrrhizin * co-enzyme Q-10 * Artemesia annua * Iscador (Viscum album or mistletoe extract) * vitamin C or other vitamins * DHEA * acupuncture * Chinese (or other) herbal treatments This list is only suggestive. If you have strong feeling for or against other treatments due to your experience or first- hand observation, please let us know. Reports of experiences can be mailed to: Denny Smith, AIDS TREATMENT NEWS, P. O. Box 411256, San Francisco, CA 94110, or call Denny at 415/255-0836. Please include the dosage and duration of each treatment, as well as other drugs or therapies used concurrently. It would help if you tell us how we could contact you for more information. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display