Subject: Fluconazole; Hybridons; BETA Date: Jun 3 1988 (764 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1988 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS issue # 58, June 3, 1988 By John S. James, editor and publisher CONTENTS: [***** appears here at each new item] Fluconazole for Cryptococcal Meningitis: Another Successful Report Hybridons: Major Research Advance Rumored; Call for Information Octreotide for Cryptosporidiosis FDA Reform: Major New Position Paper BETA: New Treatment Newsletter Available; First Issue, AZT Pneumocystis Diagnosis Delays -- Nurses Statement Free Aerosolized Pentamidine Treatment in San Francisco Study Desert and Mountain States PWA Coalitions Urge Treatment Focus, Lobbying of AIDS Organizations Sunlight Harmful to Persons with HIV? Congress Looks at AIDS Research Delays, Part II Major Draft Report from Presidential Commission AIDS Treatment News Next Issue July 1 ***** Fluconazole for Cryptococcal Meningitis: Another Successful Report Last September 25 AIDS Treatment News published a full report on fluconazole, an experimental drug which seems to be a major advance in treatment of systemic fungal infections, espe- cially cryptococcal meningitis. Unlike amphotericin B, the con- ventional treatment, fluconazole is given orally, freeing the patient from long-term dependence on intravenous medication. Also it seems to have few if any side effects. The only drawback is that because of red tape, fluconazole is hard to get in the United States. Pfizer Inc., the manufac- turer, does supply it for cryptococcal meningitis and certain other conditions when all approved treatments have failed. But in practice many physicians do not know about fluconazole or how to get it, and many patients -- perhaps most -- who should get the drug, die instead. In Europe fluconazole is much more available, and thousands of people have used it, even for much less serious conditions such as skin or vaginal yeast infections. But in the U. S. there is a widespread official belief that compassionate-use drugs should not be widely available to persons with AIDS. Various excuses are used, various obstacles are allowed to block treat- ment access. Part of the problem is that little has been published on fluconazole. We only know of two case reports in the medical literature of fluconazole used for AIDS-related cryptococcal men- ingitis. One, published by physicians at the Pasteur Institute (Annals of Internal Medicine, May 1987) was cited in our earlier report (AIDS Treatment News #41). The other, the occasion for this article, appeared in the March 1988 Annals of Internal Medicine (Byrne, WR, and Wajszczuk, CP. Cryptococcal Meningitis in the Acquired Immunodeficiency Syn- drome (AIDS): Successful Treatment With Fluconazole After Failure Of Amphotericin B. Volume 108, number 3, pages 384-385.) Fluconazole was used after amphotericin B and other treatments became ineffective; the amphotericin had been used for 15 months. Two weeks after the change to fluconazole, improvement was "dramatic"; and the cerebrospinal fluid culture became negative for the first time in a year, and stayed negative. The patient has done well at home on fluconazole for a year. There have been no side effects. For medical information about fluconazole and how to obtain it, physicians only should call Pfizer Central Research, Groton, Connecticut, (203) 441-4112. Readers can help to make fluconazole and other drugs more available by lobbying AIDS organizations -- or gay, medical, or other organizations -- to educate themselves and appoint a person or committee to work to overcome the red tape, ignorance, iner- tia, mismanagement, and commercialism blocking the research which should be done and the drugs which should be accessible to physi- cians and patients. Waiting for the system to move at its own pace will result in thousands of unnecessary deaths. The major AIDS organizations, fearing controversy and loss of funding, have so thoroughly ignored this issue that even a little effort will go a long way. ***** Hybridons: Major Research Advance Rumored; Call for Information A well-informed source recently told us that researchers are excited about a designer drug being developed by major pharma- ceutical companies. We have NOT been able to confirm this report, but chose to publish what we heard, in case any of our readers have more information about this project and can help us assemble a complete picture. Apparently scientists prepared a mirror image of part of the "tat" gene of HIV -- a gene which regulates the activity of the virus. This chemical was then attached to a sulfate group to make it water soluble. In this form, according to the report, it enters every cell, and shuts down HIV, with little toxicity to the cell. The drug has not yet been tried in humans. But according to our source, the same idea was applied to a form of mouse leukemia caused by a virus, and it did work; when given to mice, the mouse version of the drug arrested the disease. A paper on this technology, called "hybridons", was pub- lished two years ago (Zamecnik and others, 1986). It has not received much attention, perhaps because the idea of a designer drug which enters cells and blocks a specific gene seems futuris- tic, not something imminent. Yet that early paper reported HIV inhibition up to 95 percent in cells in the laboratory, and sug- gested that the approach seemed useful for treating patients with AIDS or ARC. What may be new, according to the report we heard, is that this approach has worked in mice, and is generating much excite- ment among the professionals who know about it. This technology could apply also to cancer, certain genetic defects, and other retroviral diseases, as well as AIDS. Apparently the drugs are fairly easy to make, with a spe- cialized machine called a DNA synthesizer. But there are bil- lions of different possible chemicals of this class, and most would be ineffective or harmful. If you have any other information about hybridons or any related project, please call or write John S. James, (415) 255- 0588, or P. O. Box 411256, San Francisco, CA 94141. References Goodchild J, Zamecnik PC, Gallo RC, and Sarin, P. Inhibition of Expression of Human T Lymphotropic Virus Type III Proteins in T Cells by Anti-Sense Oligodeoxynucleotides (Hybridons). Federa- tion Proceedings volume 45 number 6, page 1752 (abstract only), 1986. Zamecnik PC, Goodchild J, Taguchi Y, and Sarin PS. Inhibition of Replication and Expression of Human T-cell Lymphotropic Virus Type III in Cultured Cells by Exogenous Synthetic Oligonucleo- tides Complementary to Viral RNA. Proceedings of the National Academy of Sciences USA, volume 83 number 12, pages 4143-4146, June 1986. ***** Octreotide for Cryptosporidiosis Octreotide, a synthetic substitute for the naturally-occur- ring hormone somatostatin, is a new designer drug with the same general structure as peptide T. (Both are artificially created peptides with eight amino acids.) Octreotide would be expected to provide symptomatic relief for severe diarrhea, such as that caused by cryptosporidiosis, even when nothing else worked. In a case reported earlier this year, physicians found that octreotide was helpful for a patient with AIDS with severe cryp- tosporidiosis. Stool volume was reduced from five to ten liters per day to two to three, and the patient could be discharged from the hospital. The patient did well at home for five months, but then deteriorated and died from other AIDS-related causes. The octreotide (also called Sandostatin) was obtained as an experimental drug. For more information, see the report in the February 1988 Drug Intelligence and Clinical Pharmacy. (Katz MD, Erstad BL, and Rose C. Treatment of Severe Cryptosporidium-Related Diarrhea with Octreotide in a Patient with AIDS. Volume 22, pages 134- 136.) Also see the editorial and the review article in the same issue. ***** FDA Reform: Major New Position Paper A short, 12-page report published in April by a conservative think tank and now widely circulating in Washington, DC provides perhaps the best call ever written for major reform of the FDA drug-approval process. The AIDS community might consider using this proposal as a rallying point. It suggests a workable, pol- itically possible change which could solve part of the AIDS "drugjam", and remove the need to travel abroad or use under- ground sources to obtain rational, well-supported treatments. Red Tape For the Dying: The Food and Drug Administration and AIDS recommends fundamental reform, in clear language anyone can understand: "Something clearly is wrong when a regulatory program aimed at protecting the health of Americans sends thousands of its sup- posed beneficiaries into covert action to obtain potentially effective drugs. What is needed is fundamental reform of the FDA. The agency's power to block new drugs should be eliminated. While FDA should continue to certify drugs that it finds safe and effective, licensed physicians should be allowed, with the patient's informed consent, to prescribe drugs that are not so certified." The report, which applied to all serious diseases not just AIDS, is published by The Heritage Foundation, 214 Massachusetts Avenue NE, Washington, D. C. 20002, (202) 546-4400. For a copy, send $2. to this above address; be sure to ask for their "back- grounder number 644". Why It's Important * The report is accessible to anyone who can read a newspa- per; no special background is required. Yet it has enough sub- stance that we learned much from it, despite our familiarity with the subject. * The paper provides an excellent overview of what is wrong with the current FDA system, and how and why the problems developed. It summarizes previous ineffective attempts at reform, such as the "treatment IND" regulations announced last year, and explains why they failed. * It is full of authoritative references -- for example to government reports, The New York Times, The Wall Street Journal -- which individuals and organizations can use to support their case. * It arrives at a critical time when interest in drug regu- latory reform is stronger than ever. * It has its own momentum which the AIDS community can build on. For Example: Explaining Unbalanced Judgment by FDA Two kinds of error by the FDA -- wrongly approving a drug, or wrongly denying or delaying approval -- can cost lives. Yet there is so great an institutional bias toward fear of the first kind of error that the second kind is hardly considered at all. The report explained why. First it quoted a former FDA commissioner: " '...in all of FDA's history, I am unable to find a single instance where a Congressional committee investigated the failure of the FDA to approve a new drug. But, the times when hearings have been held to criticize our approval of new drugs have been so frequent that we aren't able to count them. The message to FDA staff could not be clearer. Whenever a controversy over a new drug is resolved by its approval, the Agency and the individuals involved likely will be investigated. Whenever such a drug in disapproved, no inquiry will be made. The Congressional pressure for our negative action on new drug applications is, therefore, intense. And it seems to be increasing...' Then the report suggested that "in large part this is due to the fact that the victims of a mistakenly approved drug are often highly visible, while the victims of a wrongfully delayed drug rarely even realize that they have been injured." The report listed some consequences of this imbalance. U. S. drug innovation fell by 50 percent after the FDA obtained its current powers in 1962. England, for example, has four times as many new drugs which are not available in the U. S., as the U. S. has which are not available in England. In cardiovascular, respiratory, and gastrointestinal medicine, U. S. drug develop- ment has all but stopped; almost all the new drugs are available in England (and elsewhere) but not to Americans, except those who make periodic trips abroad to pick up personal supplies. And according to an article in The Washington Post, quoted in the report, unjustified FDA delays in approving the heart- attack drug TPA caused three thousand needless deaths in the United States. An Objection, and Our Reply Objection: "The proposal would allow unsafe and ineffective drugs to be marketed to desperate people, for profit." Reply: The proposal would apply only with a prescription, a prominent warning, and informed consent. It would in no way weaken the laws against false or unproven claims, or other forms of fraud. We should be very careful of the idea that seriously ill persons are "desperate" and therefore unable to decide properly for themselves. Even a decision to try a dubious therapy is often the best, most rational choice among the unattractive options available to that person. The efforts to disempower those seriously ill may stem less from efforts to protect them, than from the fact that persons facing major illness or death may free themselves from the constraints of conventional structures -- structures which have evolved to reflect the interests of the most powerful groups (here drug companies, bureaucrats, and pro- fessionals) much more than those of the patients, who in the past have not had a seat at the negotiations through which the conven- tional structures developed. In other words, persons seriously ill are deprived of the right to make their own decisions, not to protect them, but rather to control them for the benefit and protection of powerful vested interests. FDA Media Note You may have noticed the FDA much in the news recently, in its favorite role of hero and protector. The agency has an impressive ability to generate press attention when necessary to divert the thrust of widespread calls for reform. Don't be misled -- no one wants to end the legitimate and necessary consumer protection functions of the FDA. That isn't the issue. Instead, we need reforms to give patients and their physicians final say in an emergency, final say when the agency doesn't know best or has not had the time or resources to get around to making a decision, final say when commercial or bureau- cratic empire building would override the best interest of the patient. Consumer protection has nothing to do with sending thousands of people to their deaths in order to safeguard the FDA's regula- tory process, or the market shares and profits of the giant cor- porations which know best how to work the system and have the contacts and money to do so. ***** BETA: New Treatment Newsletter Available; First Issue, AZT The first issue of the Bulletin of Experimental Treatments for AIDS (BETA), published by the San Francisco AIDS Foundation, is now in press and will be available soon. Copies can be ordered now (see below). BETA "is published as an educational resource for people considering experimental treatments for AIDS, ARC and HIV infec- tion". It "reviews available scientific data on AIDS treatments as well as anecdotal information provided by physicians, researchers, people with AIDS and ARC, and individuals infected with HIV". Publication by BETA of information about a treatment does not, of course, imply endorsement of that treatment by the San Francisco AIDS Foundation. The first issue, on AZT, gives a readable, comprehensive overview on the use of the drug -- including areas of controversy where physicians disagree. About five thousands words in length, the article includes: * Dosage, toxicity, and side effects; * Combining AZT with other drugs; * AZT use by asymptomatic seropositives -- pro and con; * Experiences of people taking AZT; * Physicians' comments; * A glossary; and * A resource guide to experimental treatment information. Each issue of BETA gets a careful medical review by the Scientific Review Committee of the San Francisco AIDS Foundation. For a copy of BETA issue #1, call the San Francisco AIDS Foundation, (415) 863-AIDS; or in Northern California call toll- free (800) FOR-AIDS. It's free in San Francisco. ***** Pneumocystis Diagnosis Delays -- Nurses' Statement Delays as long as 12 days in diagnosis of pneumocystis have become a major problem. Recently the AIDS/ARC Interest Group of the Golden Gate Nurses Association (Region 12 of the California Nurses Association) published a statement on the problem. Their statement may help AIDS service organizations elsewhere obtain more effective (and incidentally less costly) medical services in their localities. To obtain the statement, or for more information, call Jo Anne Powell, Executive Coordinator, Golden Gate Nurses' Associa- tion, (415) 821-7400. ***** Free Aerosolized Pentamidine Treatment in San Francisco Study Persons who have had pneumocystis in the last six months may be able to receive aerosol pentamidine without charge, in a study by the Institute for HIV Research and Treatment at the Davies Medical Center in San Francisco. Patients may continue using AZT or other antivirals during this study. No placebo will be used. Instead there will be two doses, 30 mg and 150 mg, every two weeks. There has been some controversy over whether 30 mg is enough; also, no one knows for sure how large a dose will prove safe for long-term use. We are hearing that when pneumocystis does occur in persons using aerosol pentamidine, it tends to be mild; there have been very few deaths from pneumocystis in such studies, even at the low 30 mg dose. In any case, and indepen- dent company will audit the charts of patients in this study, so that the trial can be stopped if the low dose turns out to be too small. Other Options Persons at risk for pneumocystis should know that there are other options -- such as dapsone, or Septra -- if they cannot obtain aerosol pentamidine. These are more likely to cause side effects, but seem to work well if patients can tolerate them. They are much less expensive. What is most important is that those at risk for pneumocystis should use some form of prophy- laxis. AIDS Treatment News has published several warnings about fansidar, another drug sometimes used for pneumocystis prophy- laxis; it can cause serious or fatal reactions, and patients using it must get appropriate warnings from their physicians so that they will stop the drug and get medical help immediately if symptoms develop. Recently we have heard that fansidar is much more likely to cause problems if used by patients who are also taking AZT. ***** Desert and Mountain States PWA Coalitions Urge Treatment Focus, Lobbying of AIDS Organizations At a meeting on May 14 and 15, People With AIDS Coalitions in six states issued a call for AIDS organizations to work toward a unified approach with more attention to treatment access issues. The Desert and Mountain States Regional Conferences of Peo- ple With AIDS Coalitions, representing PWA coalitions in Albu- querque, Denver, Phoenix, Salt Lake City, and Tucson, urged the National Association of People With AIDS (NAPWA), NAPWA board members, and the AIDS community, to: * Focus and direct political action by AIDS organizations. "We feel that the time has come for a single focus, rather than a thousand voices crying in the wind." * Work for the release and availability of lifesaving treat- ments. * Lobby all AIDS organizations to involve themselves in mak- ing treatments more available. * Urge persons with AIDS and their friends to pressure the FDA and other agencies or organizations to speed the study and release of treatments. * Ask all PWA groups and leaders to work toward finding appropriate treatments and making them available. The group will meet again in Boston in July, 1988. For a copy of the statement, or for more information, call Chuck Mayer, PWA Coalition of Tucson, (602) 792-3775, or call Earl Thomas, PWA Coalition of Colorado, (303) 837-8214. ***** Sunlight Harmful to Persons with HIV? The "guerilla clinic" movement, best known for its interest in DNCB as a possible AIDS treatment, has collected and distri- buted evidence that sunlight or other ultraviolet light might stimulate the growth of HIV and be harmful to persons with HIV infection. Now a new laboratory study, published May 5, 1988 in Nature, greatly increased the concern. * It has long been known that ultraviolet light can damage or suppress the Langerhans cells of the skin. These cells are an important part of the immune system, and have recently become a focus for intensive research on AIDS. * Researchers at the Centers for Disease Control have found the onset of AIDS, as well as almost all opportunistic infec- tions, peak in the summer, when ultraviolet exposure from sun- light is highest. * The recent article in Nature reported that ultraviolet light increased the activity of HIV genes as much as 150 times in laboratory tests. (An unrelated virus, tested as a control, showed little or no such effect.) Exposure to half an hour of direct sunlight increased the HIV activity 12 times. HIV is known to infect Langerhans cells in the skin, which are exposed to ultraviolet light from the sun or other sources. We asked two AIDS-knowledgeable physicians what they knew about the dangers of sunlight to persons with AIDS, ARC, or asymptomatic HIV infection. Neither had seen the Nature article; both urged normal caution. One warned especially that a number of drugs used by persons with AIDS make the skin much more sensi- tive to the sun than usual. For more information, see "A Warning About Sun Exposure From the Guerilla Clinics". This short article has 20 technical references. For a free copy send a self-addressed stamped envelope to: Jim Henry, 700 Taylor St. Apt. 201, San Francisco, CA 94108. ***** Congress Looks at AIDS Treatment Delays -- Part II Issue #57 of AIDS Treatment News published part I of our interview with Dr. Steve Morin, legislative assistant to Congresswoman Nancy Pelosi. Part II continues here. (We commented to Dr. Morin that the staffing problem could also explain the inability to investigate the suspicion that the AL 721 now being used in NIH (NIAID) trials may be seriously deficient and perhaps ineffective. After hearing the reports, NIH planned to conduct its own quality control through a govern- ment or commercial laboratory; we have heard ambiguous reports about whether it did so. And one well-informed source told us that NIH refused to allow physicians running the trials to pro- vide samples of the material to the buyers clubs, which routinely test AL 721 substitutes and wanted to the same tests on this AL 721 at their own expense.) "We heard one after another after another of that kind of story (at the hearings). It spoke eloquently of the lack of coordination, the lack of staff to actually monitor the implemen- tation of the studies that the scientific advisory groups were giving high priority. Fauci admitted as much in the Friday hear- ings. "The next witness was Jeffrey Beal, a physician from Tulsa, Oklahoma. He's one of the primary caregivers in Tulsa, he has 80 patients who are HIV positive. He told us that the average time from diagnosis to death in Tulsa was five months -- compared to about 14 months median in San Francisco. "Apparently many people (in Tulsa) delay seeking treatment for fear of discrimination. People arrive very sick, they're fearful of losing jobs and insurance, as well as being ostracized by the community. "There seem to be real problems in Tulsa. The nearest of the original 19 AIDS Treatment Evaluation Units is 500 miles away. They don't have the kind of information that's available on the coasts. A lot of people come home to die there, they have a lot of people who do not seek active treatment, coming from somewhere else. "The Thursday afternoon panel was mostly activist groups from New York and San Francisco: ACT UP, Community Research Ini- tiative, Project Inform. They told how the Community Research Initiative model had developed. People had been frustrated with FDA and NIAID. They wanted to be involved in the whole process. "Martin Delaney (co-founder of Project Inform in San Fran- cisco) focused on problems with the treatment INDs, how that was really more of a public-relations effort than an actual option. (The "treatment IND", a plan purportedly to speed access to drugs to persons with serious or life-threatening diseases, was imple- mented on paper last May, but has almost no practical effect since then.) "Day 2 of the hearings opened with Admiral Watkins, who presented in essence the recommendations of the Presidential Com- mission on the HIV Epidemic. He was wonderful, the recommenda- tions were wonderful, very critical of the FDA and NIH. Then Fauci and others (from NIAID) were questioned for about three hours. As reported in The New York Times (cited above), Fauci requested 127 new positions and got only 11 from the Reagan Administration. "Fauci sounded completely frustrated in being able to get anything done, in a way he hasn't sounded before in interviews. "Probably the most heat came out of the discussion of aero- sol pentamidine, and their 13-month delay on that. Fauci said one of the major reasons was that they didn't have a single staff person they could assign to be on top of it. It became abun- dantly clear, whatever the cost of that one staff person, if you calculate the cost of Medicaid of all the hospitalizations, even aside from human suffering, how much it was costing the govern- ment not to have a person escort that drug and speed it up, it's just ridiculous. "We also heard from LyphoMed, Inc., the manufacturer of aerosol pentamidine, on the pricing issue. I thought the LyphoMed people had a good explanation for the pricing. They showed the cost of the research that would lead to the eventual licensing of the drug for that use. They paid the cost of sup- plying the drug through the Community Research Initiative (which is doing a study supported by LyphoMed). Also they have people in the field, staff which drives up prices. It has to do with the hoops they have to jump through for the FDA. LyphoMed didn't have to do any of that (earlier) when pentamidine was only an orphan drug; they weren't trying to license it then. "LyphoMed outlined exactly what they had to do, and how much it cost, and it all computed. It was a reasonable explanation. "The corporate drama around aerosol pentamidine is a good sign, because it indicates people really believe it is going to be effective, a long-term hopeful approach. "Frank Young (the Commissioner of the FDA) was on the entire afternoon, along with Ellen Cooper and some of the others there. That was quite a lengthy question session. A lot focused on the treatment IND issue. They basically maintained that none of the drugs they knew of were good enough to qualify." (We asked how a lay person could challenge such an argument. The FDA has secret information on the drugs. Do they simply have to say that none of the drugs is good enough to release? Must the rest of the world simply accept such statements with no cri- ticism, no checks and balances, as an ultimate truth from on high?) "Commissioner Young had just had an operation. Ms. Pelosi asked what he would do if it turned out that he were given con- taminated blood and had an HIV infection, would he take any of these alternative treatments that showed theoretical potential but had not been proven effective? He admitted yes he would take them, because they would be the only option he had. "They tell you one thing in the official capacity, and then they tell you that they would go ahead and take the drugs (if it were for themselves personally). What kind of message is that? It's a message that the bureaucratic stuff is just that. (We told Morin that we saw the FDA's standard dog-and- pony-show at the Presidential Commission, which did not question the FDA witnesses in any serious way, just patted them on the back. The witness sitting next to me said he had seen the same presentation time and time again, that the FDA's top officials are in the business of making a living giving this show to high- level officials. The slick, well-designed presentation simpli- fies the whole confusing situation on AIDS drugs -- provides clean, strong, simple concepts like phase I, phase II, phase III -- it wraps up everything in a nice package for officials. The FDA becomes the focus point, the nerve center, the central gate- way of the whole drug development process, so all the complexity now fits into place. The officials -- confused, uniformed, at sea in all the complexity -- love it.) "They had all of that, the (same) graphs. It was well pack- aged. Linguistically it sounded very compassionate." (We com- mented that linguistically it also sounded very rational, to appeal also to those who think that way.) "But they (FDA) do have expedited review, they do have a lot of things that NIAID does not have, that speed things along. But they have so many hoops to go through." (They'll speed up the paperwork, yes.) "But the things they say in the paperwork that people have to go through to get to the next step are very time consuming." "To sum things up, there is a human element to this. Alter- native treatments that are safe and have theoretical potential to be effective but haven't been proved effective, do give people hope. And giving people hope is very important in an epidemic like this, where there isn't that much hope in the media. The media doesn't talk much about the people who are long term sur- vivors. "What could be done to give people hope, was the focus. The FDA was not being a helpful participant in thinking of it that way." Morin commended Chairman Weiss for his continuing leadership on AIDS issues. "The hearings gave me new hope." ***** Major Draft Report from Presidential Commission Just before going to press we received the recommendations of Retired Admiral James D. Watkins, Chairman of the Presidential Commission on the HIV Epidemic, to be considered by the full Com- mission before it issues its final report. This important docu- ment includes hundreds of specific recommendations for better management of the AIDS epidemic. We cannot review it now; for more information see the story in The New York Times, Friday June 3, page one. ***** AIDS Treatment News Next Issue July 1; Other Announcements Due to our trip to Stockholm for the June 12-16 AIDS confer- ence, AIDS Treatment News will not publish a June 17 issue. Instead, issue #59 will be published on July 1. All subscrip- tions will be extended so everyone will receive the expected number of issues. The Stockholm conference is the most important one of the year. For daily coverage, check major newspapers such as The New York Times, wire service reports in other newspapers, and the TV news. We cannot compete with these media for daily coverage; instead AIDS Treatment News will report in depth during the next several weeks on important Conference news relevant to treat- ments. Back issues available. The long-awaited back issues one through 50, reprinted with an extensive index, have now been mailed to most of the subscribers and others who ordered them. If you ordered back issues before May and have not received them yet, call Denny Smith at AIDS Treatment News, (415) 255-0588. Price, subscription changes July 1. On July 1 we will slightly lower subscription prices for persons with AIDS or ARC, while raising the regular rate for back issues. We will also discontinue the three-month subscription, replacing it with a six-month minimum in order to reduce our billing costs. (We will still send out a free sample issue on request; and each new sub- scriber will get five free back issues, as now.) After July 1, the new rates will be: * Regular rate, $100 per year (same as now), $55.00 per half year, $50.00 for back issues. * Reduced rate for persons with AIDS or ARC, $30.00 per year (down from $32.00), $16.00 per half year, back issues $12.00. (unchanged). We are losing money on the back issues at the reduced rate. Later this year we will probably prepare a volume of highlights of back issues, removing the material of only historical interest, to reduce printing and mailing costs and keep the price low. Then we will continue to provide the complete set to libraries, professionals, collectors, etc., but at the regular rate. We will maintain the reduced rate until the highlights volume is available. Anyone subscribing before July 1 can use the old rates (below). ***** [Obsolete subscription information has been removed. 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