Date: Thu, 18 May 1995 17:11:56 -0700 (PDT) Reply-To: Conference "aidstreatment" From: Tadd Tobias Subject: AIDS Treatement News #223, May 19, 1995 AIDS TREATMENT NEWS Issue #223, May 19, 1995 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: New Trial Proposed for When Drugs Fail Antiviral Conference Reports Abbott: Major Protest over Lack of Access Religious Coalition Opposes Gene Patents California: New Drugs Added to AIDS Drug Assistance Program ***** New Trial Proposed for When Drugs Fail by John S. James On May 11 this writer and other community representatives met with members of the Clinical Trials subcommittee of the Inter-Company Collaboration for AIDS Drug Development (ICC). The ICC is a group of 17 major pharmaceutical companies which have agreed to share information to facilitate more rapid development of AIDS treatments, especially combination antiretrovirals. The meeting was chaired by David Barry, M.D., who is Group Director of Research and Development for Burroughs Wellcome Co., and chairman of the Clinical Trials subcommittee of the ICC. Dr. Barry said that the kind of innovative trial design which would get the most support in the ICC today would be studies of combinations of drugs (often entirely new ones) in patients who already have resistant virus. In practice, this will usually mean studies in patients who have already used AZT and/or other antiretrovirals, and for whom the drugs are no longer working well. There are different kinds of laboratory tests to tell if a patients' virus is resistant to certain drugs; patients might be selected based on those tests, or in some cases they might be selected based on clinical failure of the drugs they have been using. This emphasis on "experienced" patients -- those who have already used AZT or other drugs for some time -- is important for several reasons. First, many of the trials conducted until now have sought "naive" patients as the most desirable -- for example, the only ICC trials proposed so far insist on naive patients. This means that many people who most need a new drug are disqualified from studies (unless they lie), and also that there are large numbers of people for whom new treatments are not being developed. In addition, it is difficult to recruit naive patients for trials. This problem may seem unexpected, because there are a great many people with HIV who have never used AZT or any other treatment for their condition -- probably many more of them than of those who have received treatment. But usually these people are untreated for a reason. Many do not know they are infected. Others have chosen not to use any of the available drugs, due to concern about side effects, fear of being disqualified for clinical trials for treatment-naive patients in the future, or for other reasons. It is difficult to persuade people who have not wanted conventional treatment in the past to now be willing to enter trials of experimental drugs. By contrast, there are many who are now in the healthcare system who are willing to take drugs and know that they need new ones. There is also a scientific reason why trials with patients who already have resistant virus are important. Dr. Barry said that by studying them it may be possible to learn much that will apply to naive patients -- but much faster than by studies in the naive patients directly. This could provide what might be called a "surrogate marker" for DURATION of benefit -- a very important indication of drug usefulness which is not otherwise available. [This is possible because patients who have developed resistant virus will have developed a very large number of different "quasispecies" of HIV. If a new drug combination can suppress all of them, well enough to bring the viral load down to about 100 copies per ml or less for at least six months, then that same combination will probably suppress virus for very much longer in naive patients who have not yet build up many resistant or cross-resistant quasispecies.] Dr. Barry suggested a trial design for this purpose. First, before planning the trial in detail, it will be necessary to decide what tests to use to define who has resistant virus; today it is not certain whether "genotypic" tests (which look in the DNA of the virus for a mutation which is known to confer resistance) or "phenotypic" tests (which grow the live virus in the laboratory and see how much drug it can tolerate) would be best for this purpose. Dr. Barry left the question of definition for later. The kind of trial he proposed could use a very small number of patients (probably well under 30) with resistant virus. These patients could get one of several different drug combination regimens (ideally consisting of new drugs which the patient had never used before). The choice among the several available regimens could be made in several ways: it might depend on which particular mutation the patient had, or it might be random, or it might be the choice of the patient and treating physician, or of the experimenters. While on the new-drug regimen, both the CD4 (T-helper) count and viral load would be followed. As long as a patient does well -- as long as the viral load remains low and the CD4 count does not decline -- he or she would remain on the treatment. But whoever stops doing well -- whether in six days, six weeks, or six months -- then moves to another of the available regimens. Dr. Barry believes that if the data is recorded carefully, and if the original resistance is known, then this trial could be of great benefit not only to the patients themselves, but also to others in the future, because it would tell which resistance patterns respond to which drugs. This design implies that the patients in the trial will have to be treated and followed individually. This is because every patient has a number of different quasispecies of HIV; every patient is different from every other in the collection of quasispecies they have. This means that even if two patients have the same resistance mutation (in some of their quasispecies), and are the same by all other available tests, they may still react very differently to the same drug combination. This individualizing of care makes the trial more in the patient's interest than conventional trials which use standardized treatment protocols to see which does better or worse on the average. Note also that in this proposed trial, patients and their physicians will receive their viral load, CD4, and other blood work results immediately -- not after the study is over, as in many other trials. They will need to know those results as soon as possible in order to know when it is necessary to change treatments. Other Proposals Three other proposals were also made at the meeting. (1) Small, uncontrolled trials. Bill Bahlman, of the Treatment and Data Committee of ACT UP/New York, proposed small, uncontrolled screening trials for initial tests of new combinations. (An earlier draft of this proposal was published in AIDS TREATMENT NEWS, issue #221, April 21, 1995.) Each trial will have about 30 patients, and will last about six to ten weeks, but with an additional followup phase lasting for at least a year, for those patients who choose to stay on the treatment. Bahlman would study both antiretroviral naive patients with CD4 count above 300, and antiretroviral experienced patients with CD4 under 300. A change from the earlier version of the study is that there will be no requirement that patients have a minimum viral load -- since modern tests can detect very low levels of the virus, even those who start with a low level will still be able to show if they are getting benefit from starting a new treatment regimen. This proposal is controversial because it does not randomly assign patients to two or more different treatment groups; therefore, when the results are analyzed, there will not be different groups in the same study to compare. But these are preliminary, pilot studies, to quickly screen combinations to see which are worth testing in larger, more formal trials. And these screening studies are looking for large effects, not for small differences. It should be possible to spot combinations which have outstanding short-term antiviral activity in people, by looking for large changes in viral load and CD4 count. (2) Combining different protease inhibitors. Jules Levin of the New York University Community Advisory Board brought a proposal by two NYU investigators, Roy Gulick, M.D., and Fred Valentine, M.D., to compare MK-639 (the Merck protease inhibitor) alone, vs. saquinavir (the Hoffmann-La Roche protease inhibitor) alone, vs. the two together. This would be a randomized, pilot study with about 90 patients, lasting 24 weeks, in persons with CD4 count 50 to 500 who had not previously used any protease inhibitor. It would look for safety and toxicity, changes in viral load and in CD4, and resistance patterns. The main point of this proposal was to combine two protease inhibitors; the drugs selected are those which are furthest along in clinical development. Combining protease inhibitors has been suggested, but has not yet been done in trials; the only way for a person to obtain two of the drugs would be to register for different trials under different names, and it is believed that a few people have done so. Both Merck and Roche representatives said that they have been discussing a combined protease inhibitor trial. But Roche is waiting for its new formulation, which will have about three times greater bioavailability than the current version of saquinavir. When that is available, then there will be a dose-finding study, and then a PK (pharmacokinetic) study to look for interaction between the drugs (there is concern that protease inhibitors might interact with each other in unknown ways, because most of them are metabolized by the liver). Only when these studies are done will the combined trial be run. An obvious way to speed this process would be to start now and use the existing formulation; when the new one becomes available, switch to it and adjust the dose in the ratio of the average bioavailabilities. Once it reaches the bloodstream, the new formulation is the same drug; the difference is how much of it is absorbed when taken orally. But companies are reluctant to begin a new trial with a substance they expect to abandon, and this strategy for saving time was not discussed at the meeting. (3) Computerizing medical records. Existing projects are already computerizing medical-record information of HIV patients. But almost all of these are extracting data from existing paper records, then entering it into a database. This approach leads to transcription errors; also, much of the data is never recorded and is lost to research. Dr. Barry outlined major advantages for research if most HIV physicians would keep their primary patient records by computer, and then share data for research purposes, after names and other identifying information had been removed. For example, it would in theory be possible to find patients who had (secretly) taken more than one protease inhibitor at the same time, and check for any possible side effects which occurred; this information could make future studies safer and faster. Many other drug combinations could be checked in the same way, to look for treatment regimens which might be working unexpectedly well, or unexpectedly poorly. Confidentiality will be a major concern. It is important to bring all of a patient's records together in the research database; this could be done anonymously, by using a code number, so that the institution holding the combined data would not have the names of patients. But some problems would remain. For example, when a research team studying protease inhibitors looked for the records of all patients taking more than one, they might be able to identify one of their volunteers because some of the blood work would match their records exactly, and then they might no longer want that volunteer in their trial. Unless the system can guarantee that patients will not be harmed by participating, it will be difficult to get their cooperation. And with medical care as fragmented as it is in the U.S., it would be impossible to enforce cooperation effectively, even if this were desired. Note: Over two years ago AIDS TREATMENT NEWS reported on Medsys, an early system which computerized patients' medical records very effectively, primarily for use within the primary-care office or clinic; physicians could also share the information anonymously for research purposes, if they chose to do so. What impressed us most about this system, developed by a team led by Larry Bruni, M.D., at the National Community Research Initiative in Washington, D.C., was its ease of use; in one afternoon, medical office employees could learn how to use it effectively. But medical-record computerization has not yet caught on in AIDS practices, either public or private. For background on the NCRI system, see "New Software Available for physicians' Offices and Community-Based Research," AIDS TREATMENT NEWS #165, December 18, 1992. For current information, call Medical Management Systems, 202/546-0887. ***** Antiviral Conference Reports by John S. James The Eighth International Conference on Antiviral Research took place April 23-28, 1995, in Santa Fe, New Mexico. In our last issue, AIDS TREATMENT NEWS reported results on d4T, and on the Agouron protease inhibitor, which were presented at this meeting. But over two hundred other research reports were also given. Two hundred and fifty six abstracts of conference presentations were published in the March 1995 issue of ANTIVIRAL RESEARCH, a journal published by the International Society of Antiviral Research, which sponsored the Santa Fe conference. This article summarizes some of those published abstracts. Note that they were submitted to the journal months before the conference, so they represent the state of the research at that time. NIM 811 NIM 811 is a derivative of cyclosporin (an immune suppressive drug used in organ-transplant patients; cyclosporin has anti- HIV activity and has been proposed for treatment use, but could be dangerous because of its immune effects). NIM 811 has no immune suppressive activity, but still is active against HIV. This research team at Sandoz, the Austrian pharmaceutical company which sells cyclosporin, reported that the mechanism of action of NIM 811 is different than that of all other known anti-HIV agents; it binds with cyclophilin A, and inhibits HIV at two different stages in its life cycle. B. Rosenwirth and others, Mode of Action of SDZ NIM 811, a Non-Immunosuppressive Cyclosporin A Analog with Activity against Human Immunodeficiency Virus Type 1 (HIV-1). Abstract #4. Ingenol Derivatives, in Kansui Plant In laboratory tests, a compound derived from dried roots of Euphorbia Kansui Liou, inhibited HIV in extremely low concentrations, 0.1 nanomolar, which is thousands of times lower than the amount of AZT required. The concentration toxic to cells was 100,000 times the antiviral concentration. This series of compounds was also effective against virus resistant to AZT, virus resistant to non-nucleoside reverse transcriptase inhibitors, and HIV-2. It is believed that these compounds work by preventing the entry of viruses into cells. This work was done by researchers at a number of Japanese universities and companies. M. Fugiwara and others, Ingenol Derivatives, Ingredients of Kansui, are Highly Potent Inhibitor of HIV. Abstract #6. Burroughs-Wellcome's 1592U89 1592U89 is a potential HIV treatment now in early clinical trials. It is chemically related to carbovir, an antiviral proposed as an HIV treatment for many years; but 1592U89 is more active against HIV, more bioavailable, and has better penetration into the brain in animal tests. It is about as active against HIV as AZT, but seems to be synergistic with AZT; several mutations are required to give low-level resistance to 1529U89, and some of those mutations restore some susceptibility to AZT. In monkeys, very high doses were necessary to cause side effects in 90-day tests. S.M. Daluge and others. 1592U89 Succinate -- A Potent, Selective Anti-HIV Carbocyclic Nucleoside. Abstract #7. And S.S. Good and others, 1592U89 Succinate -- Preclinical Toxicological and Disposition Studies and Preliminary Clinical Pharmacokinetics. Abstract #8. PMEA PMEA is chemically related to the anti-CMV drug cidofovir (HPMPC); but unlike HPMPC, PMEA is active against HIV, as well as against CMV and other herpes viruses. This abstract describes a placebo-controlled study in which escalating doses of a prodrug of PMEA (a drug which is changed to PMEA inside the body, since PMEA itself has poor oral bioavailability) are given to successive groups of volunteers; 24 patients have received the drug so far. Comment: PMEA is also being developed in Holland. Some of the researchers there believe that it would be better to give PMEA by injection once per week, than to use the oral prodrug. In the U.S., there has long been an assumption that an HIV treatment which must be injected indefinitely would not be acceptable to the marketplace; therefore much delay occurs due to oral bioavailability problems. This assumption should be re-examined, especially for drugs which would only need to be injected infrequently. P.A. Barditch-Crovo and others, A Randomized, Double-Blind, Placebo-Controlled Phase I/II Evaluation of 9-[-2- (Bispivaloyloxy-Methyl) phosphonyl-Methoxy]Adenine (bis-POM PMEA), an Orally Bioavailable Prodrug of the Anti-HIV Nucleotide, PMEA. Abstract #9. The researchers are from Johns Hopkins University, and Gilead Sciences. Antabuse Antabuse is a prescription drug used for treating alcoholism; it makes people very sick if they drink alcohol. This abstract notes that Antabuse, as well as a number of new proprietary compounds, may have anti-HIV action through a mechanism of action which is different from other drugs -- targeting the "zinc fingers" in HIV proteins. In laboratory tests, these compounds are synergistic with approved HIV treatments. Antabuse and the other chemicals are now being tested for antiviral activity in both rodents and primates. Comment: A few patients tried Antabuse as an AIDS treatment many years ago; it was used as a substitute for the French drug Imuthiol, which was later abandoned when a long-term trial found that those assigned to the drug did worse than those assigned to the placebo. Despite this unpromising history, Antabuse should be tested again, using viral load tests; it may have some potential benefit which was missed in the early experience. Since Antabuse is an approved, available drug, and antiviral effects (if any) can be seen quickly, within days or weeks, in humans, it is unfortunate that time should be spent on monkey trials when a small human trial would be faster and more definitive. W.G. Rice and others. New Classes of Reagents That Attack Conserved and Chemically Reactive Zinc Fingers in Retroviral Nucleocapsid Proteins: A Strategy for Rational Drug Design. Abstract #18. The researchers are from PRI/DynCorp and the U.S. National Cancer Institute. PETT Compounds In laboratory tests, some substances in this series of non- nucleoside RT inhibitors cause HIV resistance to develop ten times slower than other non-nucleoside compounds such as TIBO derivatives or nevirapine. And one advantage of this approach is that there are many PETT compounds to choose from. B. Oberg and others. Anti-HIV Activities of New PETT Compounds in Cell Cultures. Abstract #19. The researchers are from Medivir AB in Sweden, the Karolinska Institute in Sweden, and Eli Lilly and Company in Indianapolis. Foscarnet Resistance and AZT Foscarnet is an approved drug usually used for treating CMV, but it also has anti-HIV activity. This study of foscarnet resistance found that HIV which had become resistant to foscarnet was hypersusceptible to AZT and to non-nucleoside RT inhibitors, suggesting that combination therapy might be useful. J. Mellors and others. Novel Mutations in the Reverse Transcriptase of HIV-1 Reduce Susceptibility to Phosphonoformate in Laboratory and Clinical Isolates. Abstract #20. The researchers are from several U.S. universities, and from the Military Medicine Consortium for Applied Retroviral Research. New Combinations Vs. Drug Resistance A new series of non-nucleoside RT inhibitors (NNRTs) was found to cause different mutations than the NNRTs now known. Certain combinations of two drugs could greatly delay the development of resistant HIV. Some combinations of three NNRT drugs did even better. Comment: About two years ago NNRT drugs were largely abandoned, although they are very effective at first, because HIV rapidly developed resistance to them. At that time it was widely believed that when HIV became resistant to one of these drugs, it would also be resistant to the others. But since then it has been learned that these drugs can have very different resistance patterns, and that by combining different drugs, resistance could be greatly delayed. The best three-drug combinations reported in this abstract, however, used drugs which are not available; as far as we know, two of the three have never been tested in people. J. Balzarini and others. Thiocarboxanilide Derivatives Synergistically Suppress the Breakthrough of Human Immunodeficiency Virus Type 1 (HIV-1) in CEM Cell Cultures When Used in Combination with TSAO Derivatives. Abstract #21. The authors are from research institutions in Belgium, Spain, and Sweden. DuPont Merck Protease Inhibitor This abstract reports laboratory work with the DuPont Merck protease inhibitor DMP450. D.L. Winslow and others. DMP450, A New Cyclic Urea Inhibitor of HIV Protease with Potent IN VITRO Antiviral Activity. Abstract #22. New Kind of NNRT This abstract reports results with a new series of non- nucleoside RT inhibitors. The best one was active in quite small concentrations (4 to 13 nanomolar) in laboratory tests; it took about 10,000 times that concentration to be toxic to cells. M. Fujiwara and others. Thiadiazole Derivatives as Highly Potent Inhibitor of Human Immunodeficiency Virus Type 1 (HIV- 1). Abstract #51. The authors are researchers at universities and companies in Japan. AZT Plus ddI Combination: Better Ratio Possible? This study tested different ratios of AZT and ddI in laboratory tests. It did not look at antiviral activity, however, because it did not use live HIV; instead, it measured the biochemical activation of the drugs within cells. Comment: This study suggests further research to see if it is possible to lower the dose of one or the other of the drugs in this combination (or in other widely used combinations) while maintaining efficacy. A simple laboratory test of different combinations against HIV could guide clinical trials, which could use viral load measurements to quickly see if it is possible to reduce the dose of one drug. The laboratory work would not cost much, and the clinical trial could be done in a community-based research setting -- at least to check for initial antiviral activity -- without the need for industry support. The dose of one or the other drug would be lowered, in several steps, to see when the antiviral activity of the combination was affected. S. Palmer and S. Cox. Intracellular Activation and Cytotoxicity of Combinations of 3'-Azido-3'-Deoxythymidine and 2',3'-Dideoxyinosine. Abstract #53. The research was done at the Karolinska Institute in Sweden. [This review of the International Conference on Antiviral Research will be continued in future issues.] ***** Abbott: Major Protest over Lack of Access Hundreds of people across the U.S. are calling and faxing the executives and directors of Abbott Laboratories, of Abbott Park, Illinois, over the company's refusal to provide any compassionate access to ABT-538, Abbott's experimental protease inhibitor. The first phase of the protest was scheduled from May 16 through May 22. Representatives of some of the largest U.S. AIDS organizations have called for this protest. They want Abbott to set up a program by this summer so that persons with CD4 (T-helper) count under 50, who have failed approved treatments and have no other options, can receive ABT-538. (Those with CD4 under 50 are excluded from most clinical trials.) Calls and faxes are going to 20 of Abbott's top executives (the chairman, president, several vice presidents, and presidents of subsidiaries), officials in the protease program, and members of the board of directors who are in educational or medical fields. You can obtain a four-page packet with background information, a sample letter to fax Abbott, and the phone and fax numbers of the Abbott officials, by leaving a message with your fax number or address on the voicemail of ACT UP/Golden Gate, 415/252-9200. Background ABT-538, now in clinical trials, is one of the three protease inhibitors furthest advanced in human testing. The makers of the other two, Hoffmann-La Roche, and Merck & Co., were reluctant to provide any form of expanded access to their drugs, but both agreed to limited programs after public pressure. The protest was called by the Protease Working Group, which consists of a representative from twelve major AIDS organizations, including Gay Men's Health Crisis, San Francisco AIDS Foundation, ACT UP/New York Treatment and Data Committee, and ACT UP/Golden Gate. Comment This protest is powerful because it informs the whole chain of command, from the officials directly concerned all the way up to the top of the company. Many of the phone and fax numbers are unpublished, making the communications difficult to ignore, and assuring that top officials will become aware of the issue. This matters because -- to a much greater extent than generally realized -- bureaucrats at every level of an organization work hard to keep certain information away from those above them, to contain problems at their level so that higher-ups do not get involved. But in this case, Abbott's top management not only will hear about the problem but also will have reason to pay attention, to avoid possible embarrassment in front of their colleagues and the public. ***** Religious Coalition Opposes Gene Patents by John S. James On May 18, a coalition of mainstream religious leaders, working with Jeremy Rifkin of the Foundation for Economic Trends, who has long opposed many uses of biotechnology, will hold a press conference opposing the patenting of human and animal life forms, body parts, and genes. The biotechnology industry has been surprised by this movement and very concerned, because it sees such patents as essential for companies to raise the investment money to develop new products, including treatments for diseases. According to the Biotechnology Industry Organization, "Virtually all of the 29 biotech drugs that are on the market have been developed as a result of patents on genes... Patents are particularly important because they indicate that a company's research tool has significant value, and they encourage venture capitalists to invest their dollars into that specific company." Major articles about this controversy have appeared in THE NEW YORK TIMES, May 13, THE WASHINGTON POST, May 13, THE WALL STREET JOURNAL, May 15, and also in the May 15 BIOCENTURY, a weekly faxed newsletter published by BioCentury Publications Inc. in San Carlos, California. According to THE NEW YORK TIMES, "Leaders from virtually every major religion in the Unites States plan to issue a joint statement next week asking the Government to prohibit the current patenting practices for genetic engineering." While business appears to be united in opposing restrictions on the patenting of human or animal genes, not all scientists agree. Some are troubled for both religious and scientific reasons by certain practices, especially patents on human genes or body parts such as stem cells. One told us of a number of dysfunctions of the current system of proprietary ownership of biological products. [For example, a number of scientists believe that the cholesterol-lowering drug lovastatin may be useful in the treatment or prevention of pancreatic, breast, and other cancers, but cancer research could hurt the drug's commercial value; publicity about the research would cause some patients to fear that their physicians were really treating them for cancer but not telling them, making physicians reluctant to prescribe the drug. Merck & Co., which owns lovastatin, says that "Merck is not developing lovastatin as a cancer treatment, because our review of the reports on the use of lovastatin is that its effectiveness as a cancer treatment is minimal. However, this same review has spawned one of the largest research programs at Merck in what we hope will be the fruitful area of cancer research."] (The religious coalition opposed to gene patents is not targeting pharmaceutical patents. Also it is not targeting plant patents, perhaps to avoid arousing the agricultural industry.) Comment This issue will not go away; both sides are powerful and deeply concerned, and we believe that many small compromises and procedural changes will occur over the years. What is important is that the interests of persons with serious illness -- and persons who may have serious illness in the future, which means everyone -- be well represented in any negotiations and changes which occur. It is not enough to "just say no" to gene patents and let people die. But unless workable alternatives are developed before current procedures are blocked, that is what will happen. ***** California: New Drugs Added to AIDS Drug Assistance Program In March 1995, 18 new drugs were added to the California AIDS Drug Assistance Program; these are in addition to the 25 drugs already there. These drugs can be fully or partially reimbursed for persons with HIV with moderate incomes. Funding is from the Federal Ryan White Title II program. The following drugs are now in the program (the asterisk indicates the new additions): acyclovir, alpha interferon*, amphotericin B, atovaquone, azithromycin, bleomycin sulfate*, clarithromycin, clindamycin, clofazimine, clotrimazole, cyclophosphamide*, dapsone, ddC, ddI, dexamethasone*, doxorubicin*, dronabinol*, epoetin alfa*, ethambutol, filgrastim*, fluconazole, flucytosine, foscarnet, ganciclovir, itraconazole*, ketoconazole, leucovorin calcium*, megestrol acetate*, methotrexate*, nystatin, paromomycin, pentamidine, prednisone*, pyrimethamine, rifabutin, stavudine*, sulfadiazine, trimethoprim*, trimethoprim-sulfamethoxazole, trimetrexate glucuronate*, vinblastine sulfate*, vincristine sulfate*, zidovudine (AZT). Note: The new oral ganciclovir has also been added to the formulary. Comment New drugs could be added at this time because of reduced expenditures for AZT, often due to the widespread discouragement about treatment caused by misinterpretation of the European Concorde study, which was published in April 1993. That study legitimately raised doubt about certain early uses of AZT, but was widely misunderstood as meaning that HIV treatment did not work. ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews@igc.apc.org Editor and Publisher: John S. James Reader Services and Business: Richard Copeland Thom Fontaine Tadd Tobias Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1995 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.