Subject: AIDS Treatment News #135 Date: Sep 20 1991 (760 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 #135, September 20, 1991 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Angiogenesis Inhibitors -- New Approach to Cancer, KS Treatments AGM-1470: Interview with Donald Ingber, M. D., Ph.D. HIV and Health Workers: Union Guidelines, Physician Survey Published Announcements: 1992 AIDS Conference Moves to Amsterdam ACT UP Planning Worldwide Demonstration Targeting Daiichi on Angiogenesis Drug SP-PG HIV and Skin Disease Symposium, October 4 and 5, New York AIDS TREATMENT NEWS Begins Fax Delivery, New Benefits ***** Angiogenesis Inhibitors -- New Approach to Cancer, KS Treatments. Interview with Donald Ingber, M. D., Ph.D., Harvard Medical School by John S. James An entirely new kind of cancer treatment has been successful in animal tests and is now being prepared for human trials. This new class of drugs works by blocking angiogenesis -- the growth of blood vessels which tumors need to nourish themselves. These drugs may be useful against most if not all solid tumors, whether AIDS-related or not -- and also against Kaposi's sarcoma (KS). The two leading drugs of this class are (1) AGM-1470, being developed by Donald Ingber, M. D., Ph.D., and Judah Folkman, M. D., at Harvard Medical School, working with scientists at Takeda Chemical Industries, Ltd., in Osaka, Japan, and (2) SP-PG, developed by Daiichi Pharmaceutical Co., Ltd., in Tokyo, and tested for KS in animals by Robert Gallo, M. D., and others at the U. S. National Cancer Institute. In addition, several major U. S. pharmaceutical companies are developing other anti- angiogenesis drugs. This article will look at AGM-1470 as an example of this new class of potential cancer and KS treatments. Background -- Angiogenesis in Cancer and KS "Angiogenesis" means growth of new blood vessels. Cancers which form solid tumors must be able to turn on the body's machinery to grow new blood vessels, or else the tumor cannot nourish itself and therefore cannot grow to more than about one cubic millimeter in size -- usually too small to be harmful. Angiogenesis not only allows solid tumors to grow, it also makes them more dangerous because they are more likely to metastasize -- spread elsewhere in the body through the bloodstream. The new blood vessels in the tumor increase the chance of cancer cells getting into the blood, especially since the tumor's blood vessels are often imperfectly formed. A recent study reported that human breast cancers which became metastatic had many more blood vessels than those which did not (1). In normal adults, new blood vessel growth occurs only in wound healing and other special situations. If a drug could stop new blood vessels from forming, it could be taken for life to stop further growth of existing tumors -- with short interruptions when necessary for wound healing. What about Kaposi's sarcoma? Although this disease is often called a cancer, it is usually not a true malignancy. Instead, KS lesions are caused by abnormal growth of blood vessels (in other words, angiogenesis). So a drug which stopped this growth should be useful as a KS treatment, as well as a cancer treatment. Why do the blood vessels grow when they should not? The cause seems to be a disorder of chemicals called growth factors, chemicals which serve as messengers between cells, and can act in very small amounts to affect cell growth. In KS, certain cells seem to be transformed so that they produce abnormal growth factors, causing blood-vessel growth and producing the KS lesions. In cancer, the tumor cells produce growth factors which cause the new blood-vessel growth, which nourishes the tumor. (Not all tumors can produce the growth factors which cause blood-vessel growth, but those which cannot usually do not cause problems, and are seldom noticed.) Almost every cell in the human body contains all the body's genes -- including, for example, the genes required for the various steps of the process of growing new blood vessels. Fortunately, most of the genes are turned off most of the time. Scientists are intensely interested in understanding what regulates the genes, but so far most of the answers are not known. Today there is great interest in growth factors -- about 100 are known so far -- because they have major effects in regulating (or disregulating) cells. Blood-vessel growth is caused by activities of the endothelial cells which line the blood vessels; it is a complex process requiring a number of steps. The abnormal blood vessels seen in cancer consist of normal endothelial cells (which remain normal, although they have malfunctioned because of abnormally high levels of growth factors). AGM-1470 does not appear to affect the growth factors themselves. Nor does it attack all growing cells, as cancer chemotherapy does. Instead, AGM-1470 acts on normal endothelial cells to prevent new blood vessels from starting to grow, and on growing vessels to inhibit their further expansion. Angiogenesis and AGM-1470 Angiogenesis was first proposed as a target for cancer drugs in the early 1970s by Judah Folkman, M. D., of Harvard Medical School. The idea first met with disbelief and skepticism, probably because it is so different from other approaches for treating cancer. And in the beginning, there was no way to develop anti-angiogenesis drugs, because no one knew how to test potential drugs for their effect on blood-vessel growth. Dr. Folkman first had to learn how to culture blood vessels, and then needed to develop practical assays (tests) for the activity of candidate drugs. The discovery of AGM-1470 started with a laboratory accident. Dr. Ingber (see interview below) was culturing capillary endothelial cells when one dish became contaminated with a fungus. Dr. Ingber noticed that the fungus produced a substance which induced cell rounding, which his previous work showed was associated with inhibition of capillary growth. Further research showed that this substance was fumagillin, a drug developed in the 1950s for treating amebas and other intestinal parasites, but largely abandoned today. (It is not used in the United States, but may still be used as a medicine in a few countries.) Use of Dr. Folkman's assays confirmed that fumagillin could inhibit angiogenesis. However, animal tests showed that this drug was not promising as a cancer treatment, because the doses required were toxic; animals lost weight and the drug had to be discontinued. Drs. Ingber and Folkman then began working with Takeda Chemical Industries, which had the facilities to synthesize hundreds of chemical variants of fumagillin for further testing. The best fumagillin analog to emerge from this process was AGM-1470. AGM-1470 has been found effective against a number of solid mouse tumors, including breast cancer, colon cancer, and melanoma; against tumors in three different animal species -- mice, rats, and rabbits; and also against human tumors implanted into immune-deficient mice. It has worked against every solid tumor tested so far. The cancers do not disappear, but they stop growing, and metastasis is greatly suppressed. Studies are now underway to determine if AGM-1470 could be combined with conventional cancer treatments; the latter would shrink the tumors, while AGM-1470 would prevent further growth. In the animal tests so far, little or no toxicity has been seen. In contrast to fumagillin, AGM-1470 allows animals to gain weight, even while the tumors are shrinking. One advantage of AGM-1470 and other anti-angiogenesis drugs is that there is no problem with the blood-brain barrier, with tissue absorption, or with any other barrier to getting the drug to the site of action. Since these drugs act at the endothelial cells which line the blood vessels, they only need get into the bloodstream (e.g. by injection) to be delivered directly to their site of action everywhere in the body. Also, for reasons explained in the interview below, drug resistance would not be expected to be a serious problem with this class of drugs, as it is with cancer chemotherapy. No drug resistance to AGM-1470 has yet been found; more exacting tests are now ongoing to see if any may exist. A technical article by Dr. Ingber, Dr. Folkman, and others was published last December (2), and an article by Takeda scientists was published in February 1991 (3). The U. S. press has largely missed this story of angiogenesis inhibitors as cancer treatments. AIDS TREATMENT NEWS mentioned Dr. Ingber's work briefly, in a section on anti-angiogenesis research in Michelle Roland's special issue on KS (issue #122, March 1, 1991). We hope that this article, and the interview below, will help alert the press and the public to a major emerging development in the treatment of both KS and cancer. References 1. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis -- correlation in invasive breast carcinoma. New England Journal of Medicine. January 3,1991; volume 324, number 1, pages 1-8. 2. Ingber D, Fujita T, Kishimoto S, and others. Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature. December 6, 1990; volume 348, pages 555- 557. 3. Kusaka M, Sudo K, Fujita T, and others. Potent anti- angiogenetic action of AGM-1470: Comparison to the fumagillin parent. Biochemical and Biophysical Research Communications. February 14, 1991; volume 174, number 3, pages 1070-1076. ***** AGM-1470:Interview with Dr. Ingber Donald Ingber, M. D., Ph.D., is assistant professor of pathology at Harvard Medical School, and also on the faculty at Children's Hospital and at Brigham and Women's Hospital, Boston. We interviewed him by phone on September 11. JJ: What is happening now with cancer results in animals? What is new since the Nature paper which you, Dr. Folkman, and others published last December? DI: In the Nature article, we showed that a variety of different mouse tumors responded to a synthetic analog of fumagillin. We called this class of fumagillin-related compounds "angioinhibins." We now have found that the results we reported are not limited to mouse tumors; we have found similar effectiveness in inhibiting the growth of solid tumors in rats and rabbits. And we tested some human tumors in nude mice -- human cells growing in immunocompromised mice. In all these systems, we continue to find that a variety of different tumors, and now tumors in different species, are sensitive to the drug. JJ: Have there been any failures, any solid tumors that this drug did not work on? DI: Not to my knowledge. We haven't found any. JJ: What about side effects? Has AGM-1470 been tested in larger doses than necessary to inhibit tumor growth? DI: That is currently under way. We are doing the tests needed to bring the drug to phase I trials. I have not heard specific results yet; that work is being carried out in Japan. In our studies, when we did dose ranging in the past and went to very high doses, we did see some weight loss; but that's far above the dose that we used normally. At the dosage at which the drug is very effective in inhibiting tumor growth, we still see weight gain. When there is significant toxicity, the animals usually lose weight -- and then it can be hard to tell if the tumors are shrinking due to a specific anti-cancer effect of the drug, or because of generalized toxicity. For this reason, we believe it is very significant that the animals continue to gain weight while the tumors remain small. JJ: Do tumors shrink much, or just not continue to grow? DI: The drug primarily inhibits further growth and expansion. Tumors stay small, or slightly decrease in size. In humans, one approach might be surgery to remove a tumor, then put the patient on an anti-angiogenesis drug for life. For example, in breast cancer, physicians have tools to see it when it is small. They can remove it surgically, and patients do fairly well. But many of the women come back with metastases a few years later. This is something that might be prevented with this drug. Another example is colon cancer. Fifty percent of certain classes of colon cancer will come back with metastases after surgical removal; you don't know which patients will develop metastases, and there is no way to inhibit them. In theory, if AGM-1470 works in humans the way it works in animals, even if there are small nodules of tumor cells already implanted, which is what people think goes on with metastases, they will not grow at distant sites. "Micrometastases" survive off diffusion of oxygen and nutrients. They can grow to approximately a cubic millimeter in size. In autopsies of people with cancer you find many of these small nodules. But they will not kill patients as long as they do not start growing. Once they start growing, often many begin to grow simultaneously, and then it's rampant. JJ: What do you see as most important at this time? DI: My own view is that if this agent does not work, there will be another one like it in the future. AGM-1470 is the first progenitor of a new class of anti-cancer drugs with a totally different mechanism than conventional chemotherapy, which means they may have to be used in a totally different way. It will be confusing not only for patients to think about, but also for doctors. Patients think chemotherapy means toxic effects: you lose your hair, you vomit, and you lose your immune response and get infections. All three of those side effects of chemotherapy are due to drugs which inhibit the growth of every kind of rapidly proliferating cell. The most rapidly proliferating cells are your hair follicles, your intestines, and your immune cells, which is why you get those three side effects from chemotherapy. Angiogenesis inhibitors do not work that way, so they should not have those types of side effects. They offer a new type of therapy that has to be viewed in a different way. Doctors now think you have to kill the tumor cells. Angiogenesis inhibitors often have no effect on tumor cells at all; tumor cells in culture can grow as well in the presence of AGM-1470 as if the drug were not there. You're inhibiting the tumor cells indirectly by inhibiting the blood vessels; the lack of oxygen and nutrients inhibits tumor cell growth. So you might not use this treatment the same way as a cancer drug where you're trying to get tumor kill. In classic cancer drugs, you have concerns with tumor cell resistance; that should not be as big a problem with anti-angiogenesis drugs. Doctors will have to try this drug recognizing that it may require a different type of administration or regimen than used before. For example, AGM-1470 might be useful as an adjunct. You might shrink the tumor using existing drugs, while preventing its regrowth using anti-angiogenic drugs. These ideas will need to be brought out again and again over the next few years. JJ: Do tumors develop resistance to AGM-1470? DI: We haven't seen any resistance yet. Dr. Folkman's lab is currently exploring whether resistance can develop, to see if this is a major advantage of the drug. So far it seems to be a major advantage. If you stop the drug in a treated animal, the tumor starts growing, and if you restart the drug, the tumor stops growing again. Most conventional cancer drugs can shrink a tumor, but if you stop treatment the tumor comes back, and if you give the drug again there is often no effect. The reason we do not expect resistance with anti- angiogenesis drugs, or would expect much less, is that the target cell is a normal endothelial cell, and there is much greater fidelity in its repair and replication processes. Tumor cells are much more inaccurate than normal cells; they have a higher rate of mutation, as each time they divide there are errors being made. That increases the chance that drug-resistant variations will develop. So we would expect to see much less resistance develop in animals that are treated with anti-angiogenesis drugs, than we see with conventional cancer chemotherapy. That's what we have seen in the animals, but again we don't know what will happen in humans. The major advantage of this drug, and the reason we have seen low toxicity, I believe, is that AGM-1470 does not kill the endothelial cells (or any other cells). It stops growing endothelial cells from proliferating further, and stops non- growing endothelial cells from beginning to grow. For example, some of the cells in your intestine are growing all the time, with a replacement time of about three days. That's why if a cancer drug kills growing cells, you have problems with your digestive tract, such as nausea and vomiting. Endothelial cells that line your blood vessels have turnover times of the order of once every thousand or ten thousand days. They normally don't grow, except when you have a wound, or in other special cases. So if you use a drug that only inhibits growing endothelial cells, it will not affect normal vessels. But if a capillary cell begins to grow because of a tumor, the drug will inhibit it. That's why we think we are getting specificity and low toxicity. In animals, at sites other than where the tumor is, the cells do not appear to be affected by this drug. JJ: Has AGM-1470 been tested against KS in animals? DI: This drug is going into phase I clinical trials, and to expedite the process we decided to do it through the National Cancer Institute, in cooperation with the National Institute of Allergy and Infectious Diseases. Patients with Kaposi's sarcoma would be among the first to receive the drug -- along with those with cancers, although it is not yet clear which types of tumors will be targeted first. Breast and colon cancers would be excellent candidates, for the reasons I described above. Now we are doing the toxicology and other tests for pre- clinical development -- giving high doses and looking for side effects, studying pharmacokinetics, choosing the formulation, deciding how it will be administered and stored, making sure the drug is pure, etc. This is going quite well right now. We are ready to try AGM-1470 with patients once it has gone through those protocols. This work will be done in the same way and at the same speed whether or not we test the drug against KS in animals. Recently we have had a limited drug supply for such animal tests, because we are using large amounts of it in the studies mentioned earlier. JJ: In other words, the same steps have to be followed whether or not you run KS tests in animals? DI: Yes. And the data is so good with other tumors, the FDA and NCI and NIAID all feel this drug could go into humans as soon as it meets the criteria for phase I. My own view is that whether it worked or did not work for KS in animals, we would probably try it for KS in humans anyway. I've given two talks to AIDS meetings and both times people have asked why it is taking so long. It's not taking long at all. We went to the government people only at the end of last year. We need to get these final studies done; basically we have the OK to move to phase I when we do all the standard studies that are required for phase I. It's been very quick from the government end. JJ: What support would make it possible to move faster? DI: I think it's moving as fast as it can right now. We have had complete support from both the NCI and NIAID. Even representatives of the FDA came to some of the meetings, so everyone is talking on the same terms. Also, manufacturing enough of the drug does not seem to be a problem. There were various problems that had to be worked through, like choosing how to stabilize and package the compound. These are classic pharmaceutical-company concerns. However, the Japanese company is working double time doing very impressive work; every time they hit a stumbling block they come up with a creative answer. These studies take a certain amount of time -- sometimes weeks to months to test certain doses and regimens. You have to wait for this time to elapse. You do the next study based on that result. I think it is going very well. JJ: Why was there so much scientific skepticism in the past? DI: The concept of angiogenesis as a target for anti- cancer drugs was pioneered by Dr. Judah Folkman. When he first presented it in the early 1970s, because it was different, many people resisted the idea. When I read the AIDS media today, I feel that you are well informed about science and give a good critique, asking why people keep doing the same things. There are always people trying to do new things, but their voices are not always heard. We published studies of many angiogenesis inhibitors in the past; this is the first one that we have felt comfortable going all the way with. Some groups might take the first drug that has any activity in an animal and try to quickly move it into the clinic. We did not want one to turn out to be just moderately effective, or questionable. That may be why AGM-1470 has not been in the media that much. If anything we have tried to minimize the media. However, I think it is important to get accurate information out. We want patients to understand the opportunity, and doctors to understand that there's something different out there. Note: Trials are not recruiting at this time. The first human study is unlikely to begin before winter, and it could be later than that, depending on results of further toxicity tests. The earliest human trials will probably be conducted at the U. S. National Cancer Institute. AGM-1470 will be called TNP-470 when it enters clinical trials. ***** HIV and Health Workers: Union Guidelines,Physician Survey Published by Denny Smith ** The HIV Book: Information for Workers The HIV Book: Information for Workers, a new edition of a handbook by the Service Employees International Union (SEIU), describes the proper precautions for healthcare workers in medical or dental settings where HIV may be present. This booklet is based on the generally accepted "universal precautions" for protecting both healthcare workers and patients from HIV and all other blood-borne infections. Universal precautions require the consistent use of sterile techniques and garments, whenever and wherever blood or body fluids may be present. Besides providing practical precautions and addressing the concerns of healthcare workers and patients, the booklet also lists public and private health benefits available to persons with HIV, and discusses studies on the use of AZT following an accidental exposure. To obtain copies of the handbook ($3 each for non-SEIU members) write to SEIU Health and Safety Department, 1313 L Street, N. W., Washington, D. C. 20005, or call 202/898-3443. ** New Survey of Healthcare Workers with HIV On September 10, the Medical Expertise Retention Program (MERP) of the American Association of Physicians for Human Rights released its recent survey of HIV-positive and "high risk" untested healthcare workers. 196 physicians, nurses and dentists responded to MERP's survey, two thirds of whom have tested positive for HIV. Among the results were: * 73% of those health workers who have HIV are afraid of losing their jobs; * 67% have avoided seeking treatment or submitting HIV- related insurance claims; * 65% are in their twenties or thirties, having completed their professional training only recently and acquiring large debts in the process; * 50% believe that most of their patients would change doctors if they were told that their current provider had HIV; * 30% provide care primarily to patients who have no private insurance. The Director of MERP, Benjamin Schatz, notes in the report: "The loss of tens of thousands of HIV-positive health professionals would exacerbate the existing national shortage of health care workers, potentially harming all patients ...the wide-scale and seemingly punitive removal of HIV-positive health professionals would be likely to discourage people from entering the health care field. It will also diminish the overall quality of health care by fostering a climate of suspicion and fear detrimental to the health care setting ...A recent San Francisco General Hospital estimate described as 'conservative' indicates that an HIV testing and restriction program that identifies only one HIV-positive surgeon annually could cost $860,000 -- double the hospital's entire budget for infection control! And a study by the Pennsylvania Department of Health estimates that a periodic testing program for the state's health care workers would cost $54 million annually, more than twice the amount Pennsylvania spends annually on AIDS prevention." Naphtali Offen, also of MERP, noted that "The danger of contracting HIV from your doctor is far lower than the risk of dying from other hospital-acquired infections, from pregnancy complications, or from reactions to anesthesia. Why is a risk which approaches zero being singled out for extraordinary measures? " Complete copies of the survey results can be obtained by sending a request with $7 to MERP, 273 Church St., San Francisco, CA, 94114, or by calling 415/864-0408. Larger donations to MERP are also needed and welcomed. Comment Combining phrases like "knowledge of HIV status" with "criminal offense if ever there was one," Senator Jesse Helms has herded his colleagues into voting for a decade of prison and $10,000 fine for healthcare providers who know they have HIV and fail to notify their patients. His ammunition was provided by reports that a Florida dentist with HIV, Dr. David Acer, had infected five of his patients, probably through failure to observe infection control guidelines known as "universal precautions". One dentist's disregard for universal precautions (the case of David Acer) has been transformed into a congressional disregard for civil rights (the case of Jesse Helms). Trampled in the process was the fact that public health policies can and must employ universal precautions to create a safe medical-care setting for patients as well as providers, without irrational legal requirements which divert resources and attention from responsible medical risk reduction. ***** Announcements ** 1992 AIDS Conference Moves to Amsterdam On September 11, the Harvard AIDS Institute announced that the Eighth International Conference on AIDS, the major AIDS meeting of the year, will take place in Amsterdam in July 1992. It had been planned for Boston; Harvard moved it because "given the continued uncertainty about United States policy restricting entry of HIV-infected people, it was no longer possible to continue planning for the Conference to be held in Boston. Harvard decided to seek a new location for the Conference in order to allow the meeting to proceed." The International AIDS Society and the World Health Organization, principle co-sponsors of the conference, supported the decision to move. Note It is our understanding that organizers will aim for a more international focus at this conference than at previous ones. Due to the travel restrictions, U. S. political issues dominated the last two annual conferences (San Francisco in 1990, and Florence in 1991), distracting attention from critical needs in the Third World and elsewhere. ** ACT UP Planning Worldwide Demonstration Targeting Daiichi on Angiogenesis Drug SP-PG ACT UP/Golden Gate is asking other organizations to join in a worldwide demonstration targeting Daiichi Pharmaceutical Co., Ltd., which is headquartered in Tokyo and has subsidiaries in Fort Lee (New Jersey), Taipei, Bangkok, Dusseldorf, and Hong Kong. The purpose is to call attention to the slow development of the anti-angiogenesis drug SP-PG, which showed very good results against Kaposi's sarcoma in animals over a year and a half ago. It is also being developed as a treatment for cancer, especially breast cancer. SP-PG, formerly known as "the secret Gallo KS drug" until Robert Gallo, M. D., identified it at the June 1991 International Conference on AIDS in Florence, may be similar in effect to AGM- 1470 (see article and interview elsewhere in this issue), although the mechanism of action of the two drugs is probably different. The frustratingly slow development of of SP-PG was outlined in an article by Martin Delaney of Project Inform in The Advocate, June 2, 1991 (headlined "Is There a Ready Cure for Kaposi's Sarcoma? : Bungling and Bureaucracy from Tokyo to Washington Prevent Production and Distribution of New AIDS Drug," pages 66-68). Delaney, who has worked behind the scenes for a year and a half to speed development of SP-PG and has visited Daiichi in Japan, recently told AIDS TREATMENT NEWS that the issue in Daiichi has been "willingness to commit resources to the development of this product for KS. This has been a long-running debate within the company." Daiichi, according to Diamond's Japan Business Directory 1990, "is one of the larger pharmaceutical companies and noted for its high technological level, high earning power, and excellent financial standing." For more information about proposed demonstrations, call Linda Dolan, KS Working Group of ACT UP/Golden Gate, 415/861- 2066. Or contact ACT UP/Golden Gate, 415/252-9274, or 415/252- 9277 (fax). ** HIV and Skin Disease Symposium October 4 and 5, New York On October 4 and 5, the Center for Continuing Education of the College of Physicians & Surgeons of Columbia University will sponsor a symposium "HIV & Skin Disease: Issues in Diagnosis & Management," at the Waldorf-Astoria Hotel in New York City. Intended for physicians and other health professionals, the meeting will cover a variety of skin ailments including bacterial infections, syphilis, fungal infections, nail diseases, viral infections, parasitic diseases, drug sensitivity, KS, and cancers, plus a number of special topics. Over 25 physicians and other health professionals will teach. The cost is $395 (physicians) or $195 (other health professionals or non-medical attenders). For more information, call the Center for Continuing Education, 212/305-3682. ***** AIDS TREATMENT NEWS Begins Fax Delivery, New Benefits (1) Fax Delivery Worldwide Starting with our next issue, #136, AIDS TREATMENT NEWS will be available by fax, anywhere in the world. Fax copies avoid all printing and mailing delays and will usually arrive at least 48 hours before any printed copies are received. In many countries, the difference between fax and mail delivery times will be much greater. The single worldwide price for AIDS TREATMENT NEWS by fax delivery is $495 per year (24 issues). To begin your fax subscription, send payment and telephone number of fax machine to: AIDS TREATMENT NEWS, P. O. Box 411256, San Francisco, CA 94141, or call us at 800/TREAT-1-2, or at 415/255-0588. Credit- card and purchase-order subscriptions can be faxed to us at 415/255-4659. (2) Subscription Price Changes A new price structure, reflecting a small average increase, begins with this issue. The $100 yearly individual rate will stay the same. But we will offer a $5 discount for prompt renewal, within three weeks of the first bill. Therefore, current subscribers who renew early will see a price decrease to $95. The subsidized rate of $40 will increase to $45. But with the $5 prompt-payment discount, the cost for renewing the one- year subscription will stay at $40. In the past, this low (subsidized) rate was for persons with AIDS or HIV who had financial difficulties. Now it will be for anyone with financial hardship, so that we are not asking for health information. For persons with financial difficulties we offer a sliding scale from $45 to $100 (or less than $45 is that is what one can afford). It is critical that subscribers pay the regular rates if they can afford to, as we could not maintain the newsletter at subsidized rates. Half-year subscription prices will increase, because of the expense of sending the additional bills. The nonprofit rate will increase from $100 to $115, and the business/government/professional-office rate from $200 to $230. The $5 prompt-payment discount applies here as elsewhere for early renewals. The new rates will be effective immediately, with a grace period until October 1. After the grace period, payments received at the old rate will be prorated; for example, a nonprofit paying $100 instead of $115 would be entered for 21 issues (ten and a half months) instead of 24 issues (one year). The new prices reflect our efforts to keep cost down and yet provide the resources we need to operate. These prices are below average for AIDS newsletters, or for newsletters generally, although our research and service costs are high, and we have no outside subsidies. (3) New Benefits for Subscribers Starting immediately, subscribers who begin or renew at the regular rates ($95 per year or more) will receive additional benefits. These include a free yearly index to AIDS TREATMENT NEWS (scheduled for publication early next year), and a free coupon book offering savings on selected AIDS books and other items of potential interest to our readers. $115 subscribers will also receive The HIV/AIDS Book: Information for Workers (see brief review in this issue), and free replacement for lost or missing issues of your subscription to AIDS TREATMENT NEWS. $230 subscribers will receive all the benefits listed above, plus a complimentary copy of AIDS TREATMENT NEWS: Book One (which reprints our first 75 issues). They will also receive a 20 percent discount on a fax subscription to AIDS TREATMENT NEWS. Other benefits are being developed. A complete list will be mailed with renewal notices. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display