Subject: AIDS Treatment News #156 Date: Aug 07 1992 (661 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1992 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue # 156, August 7, 1992 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] The Conference and the Media International Conference: Major Themes International Conference: Antiretrovirals (Part I) Research Funding Disaster: House Budget Below Bush Request NIH AIDS Research: Major Report Available Neurology Funding Good News: Activists' NIH Study Pays Off Medical Marijuana: Overwhelming Support at San Francisco Hearing San Francisco: Project Inform Report on International Conference, August 26 ***** Editor's Note This issue begins our coverage of treatment information from the recent international AIDS conference in Amsterdam. We are starting with antiretroviral drugs. Many other areas also need attention, including immune-based therapies, nutrition, diagnosis and markers of disease progression, alternative treatments, treatment information specific to women, and international organizations. We will report on some of these in future issues; others might better be handled by referring to coverage elsewhere. We had hoped to cover the treatment information from the conference largely by reporting on the medical consensus that emerged. But so much information (some of it contradictory) was presented -- almost one thousand speakers in over 160 sessions, with thousands of poster presentations in addition -- that it will take some time for the medical/scientific community to digest it. A number of meetings have been organized to summarize treatment-related developments; perhaps the most useful was a one-day session in Amsterdam organized by the Chicago-based Physicians' Association for AIDS Care (PAAC), to help develop a standard of care for HIV treatment (an edited transcript, including the slides shown, will be published later this year by PAAC. We will outline some of the major themes and concepts which should be considered when treatment decisions are made. For those who want more information, our coverage will also refer to the published conference documentation, especially the audiotapes which are available for most of the oral sessions, and the three volumes of abstracts of both oral and poster presentations This issue of AIDS TREATMENT NEWS will also look at certain U. S. federal-government matters, unrelated to the Conference, which need attention. ***** The Conference and the Media The VIII International Conference on AIDS/ III STD World Congress, July 19-24 in Amsterdam, probably had more useful treatment information than any previous conference. But one would not know that from reading the news. Two media feeding frenzies occurred in Amsterdam, both focused on events far from the conference -- the publication (in Newsweek, and of separate cases in a scientific journal) of reports of persons with AIDS- like immune deficiencies who do not have HIV. While everyone agreed that this matter needs urgent followup because of the remote possibility that an undetected virus could threaten the blood supply, scientists and many reporters also agreed that these early reports had been vastly overinterpreted and overemphasized. There have always been unexplained immune deficiencies, and these cases did not suggest a new epidemic. Most had already been published in the scientific literature (one at the international conference in Florence last year); the media coverage could have happened any time for the last several months at least, and apparently occurred now only so that it could be timed to coincide with the conference. While we were disappointed at how readily an imaginary epidemic overshadowed the real one, it was not hard to see why. Many people have found ways to believe that AIDS only affects others, not them. A new virus could potentially affect anyone, and therefore even a hint of one catches the public attention. Also, hundreds of reporters were in Amsterdam for the biggest AIDS meeting of the year, and what would they do? Everyone knew that there would be no blockbuster announcements; fortunately, anything that important would not be kept quiet for the meeting. Meanwhile, the treatment news was usually unsuitable for the general press, since it was technical and consisted of many different modest advances. The major non-technical story from the conference was the sheer size of the emerging world disaster, and the absurdly inadequate response; both U. S. and international efforts, for example, are being cut back this year, while the epidemic gets increasingly out of control. Time magazine reported this story ("AIDS: Losing the Battle," August 3, 1992); other journalists may have decided that their audience had already heard too much disaster news and was not ready for more. ***** International Conference: Major Themes Here is a short list of some of the major treatment-related ideas that were prominent at the conference. These are only listed here, and will be covered in detail later. * The movement toward early treatment is continuing -- partly because of new evidence of benefit from antiretroviral treatment at T-helper cell levels above 500, partly because better data now available is showing a clear correlation between viral load and disease severity, emphasizing that HIV disease should be treated primarily as a viral illness. * The movement toward combination therapy continues, with new data on the combination of AZT and ddI, and evidence that combination treatment can work better than alternating the same drugs. * The drug d4T, now in large trials, is generating interest because it may be more widely available soon through an expanded-access program. It may be more beneficial for some patients than AZT or ddI, but it is not yet clear what other drugs would work well in combination with d4T. * Researchers have long sought combination treatments that would attack the virus at different points in its life cycle. Now there is also interest in drug combinations that attack the same point, especially reverse transcriptase (e.g., AZT, ddI, ddC, and others). Researchers suspect that the different drugs working together might put so many constraints on the virus that mutants able to survive all the drugs may no longer be able to reproduce efficiently and cause disease. * There is also a possibility that one mutation may be making the virus worse as HIV disease progresses. The more dangerous virus is called syncytia inducing (SI), because it causes cells to merge into giant cells in test-tube studies. The SI variant may also be much less susceptible to AZT than other strains of HIV. It may be responsible for the sudden drop in T-helper count which is seen in some patients. But not everyone agrees that this virus is responsible for more serious disease. * A controversial but potentially important report added weight to the theory that acyclovir may help to improve AIDS survival, although the mechanism by which it could do so is unknown. * Much information was presented on the practical management of various opportunistic diseases, as well as on a number of experimental drugs for these infections, and for HIV. ***** International Conference: Antiretrovirals (Part I) by John S. James This article will provide an overview of the conference sessions most relevant to antiretroviral treatment. In selecting what to cover, we will be guided by the conference program, selecting those research reports which the conference organizers and advisory committees thought worthy of special attention in oral presentations. (We will not ignore the majority of submissions selected for poster- presentation only, nor those published in the conference abstract books but not given even a poster; the more innovative ideas are likely to appear here. We will cover some of these in other articles. But this conference was well organized, better than previous ones, in that the oral sessions were more consistently designed around the best research reports that came in, instead of around superstar speakers or preconceived categories. The conference organizers have seen the material longer than anyone else, and their selection is helpful for a first cut at selecting what is most important.) The conference documentation does not list degrees (M. D., Ph.D., etc.) and titles of the speakers. We have followed this convention in our conference coverage. The following sessions are most relevant to antiretroviral treatment. Usually, each session consists of several oral presentations. (The session number is for finding abstracts in the volumes published by the conference; the tape number refers to the audiotape, which has more complete and more current information for these sessions.) Overview Session: Drug Therapy and Pathogenesis (session 1, tape 4) This first technical session of the conference consisted of overview talks by Samuel Broder of the U. S. National Cancer Institute, and Luc Montagnier of Institut Pasteur. Broder gave a quick overview of some of the leading treatment research areas, mentioning many drugs and approaches, highlighting certain ones he considered particularly important. These included: * PMEA, which Broder described as a very important drug which will soon begin human trials. * A new class of protease inhibitors being developed by collaboration between researchers at the U. S. National Cancer Institute and two organizations in Japan. (AIDS TREATMENT NEWS will have more coverage of this research, which was presented at the conference in poster # PoA 2282.) * Combination antiretroviral therapy, suggesting that we don't need to wait for radical scientific advances, but meanwhile can use the knowledge we have to keep patients alive and healthy. Broder concluded by listing some unanswered research questions. Does early use of AZT or related drugs improve survival, compared to later use? Could early combination therapy improve survival? Are HIV strains which become resistant to several drugs likely to be less pathogenic? Can the immune system be brought to the point where it can control HIV without long-term antiretroviral treatment? Broder said that his own personal optimistic belief, without data, is that the answer to all these questions will be yes. Montagnier's more technical talk reviewed some of the theories of pathogenesis and AIDS, especially the role of cofactors -- other infections which might greatly accelerate the development of AIDS, or may even be necessary, along with HIV, for AIDS to develop. [His theory that mycoplasma infection may be a cofactor has met considerable skepticism, in the U. S. at least. Most researchers accept the idea that there may be cofactors, but there are many different guesses as to what they might be.] One theory Montagnier discussed which is generating much interest lately is that many T-helper and also CD8 cells are killed by a process called apoptosis, or programmed cell death. Since Montagnier did not explain apoptosis in this talk, non- scientist members of the audience had trouble following it. The necessary background is that this kind of programmed cell death occurs normally before birth, and is part of the way the immune system learns to tell self from non-self. When the immune system is developing, different cells are created, by random chance, to recognize millions of different shapes of proteins. Some of these cells would recognize the body's own proteins, which would cause autoimmune disease. But at a certain point in development, a self-destruct mechanism is turned on, and then any immune- system cells which are activated (because they have recognized a protein) are killed. The only cells left, therefore, are those which do not recognize the body's proteins, although they will recognize others, such as from invading bacteria. Naturally this self-destruct mechanism must later be turned off, or the immune system could not function. Some researchers believe that somehow this mechanism is turned on again in HIV disease, and then those immune cells which recognize foreign substances are killed, leading to the loss of many more cells than are directly infected with HIV. (Two articles on apoptosis, one relating directly to HIV, appeared recently in Science, July 10, 1992). ** New Antiretrovirals: Non Reverse Transcriptase Inhibitors (session 11 tape 14) 1. Pentoxifylline An important talk in this session by Bruce Dezube of Beth Israel Hospital, Dana-Farber Cancer Institute, in Boston, concerned pentoxifylline (brand-name Trental, a prescription drug which has been used worldwide for over a decade), which is being tested in a trial by the AIDS Clinical Trials Group (ACTG) because it might be able to reduce excessive levels of tumor necrosis factor (TNF). TNF can increase the replication of HIV, cause wasting syndrome, and, in laboratory studies, almost completely reverse the antiretroviral effect of AZT or ddC (ddI was not tested in that study). Several years ago it was learned that concentrations of pentoxifylline which could be achieved in patients could reduce TNF levels in cells in laboratory tests. Pentoxifylline was also shown to decrease HIV activity in laboratory cells, apparently by lowering TNF. A separate poster at the international conference indicated that pentoxifylline enhanced the activity of ddI in a laboratory test (poster # PoA 2326). The report at the Amsterdam conference presented a preliminary analysis on 17 patients who had completed eight to 16 weeks of a phase I trial. This trial was a non- randomized, open-label test with a dose of 400 mg three times a day -- a dose approved by the FDA for treating vascular disease. All patients had T-helper counts less than 300 -- but 15 of the 17 had counts of about 100 or less. All patients were on AZT, ddI, ddC, or a combination of these drugs. TNF levels fell in 11 of the 13 patients analyzed so far, but it never fell below normal levels (this is important because low levels of TNF may have a beneficial effect). Also, fasting triglycerides were measured, because high triglyceride levels, which have been found in up to a third of AIDS patients, can indicate excessive activity of TNF, interferon, and other cytokines. (Triglycerides are much easier to measure than TNF.) There was a "dramatic" decrease of excessive triglyceride levels. Quantitative HIV titers also fell. In the six patients with the highest HIV titers, the levels fell in all six -- in five of the six, to less than a tenth of the pretreatment value. The average decrease in all patients was 33 fold -- a 97 percent decrease. Weight loss slowed down during treatment, but this effect was not statistically significant in this data. Only one adverse effect -- recurrent fevers on the drug, in one patient -- was found. Dezube called for a larger controlled study to confirm these preliminary results. Meanwhile, the researchers are trying twice the dose to see if even better effects are found. (The higher dose level trial is being conducted at the AIDS Clinical Trial Units at Beth Israel Hospital, Boston, and at Case Western Reserve University, in Cleveland. For more information, call 800/TRIALS-A.) One unidentified questioner reported his negative experience in treating 17 patients with pentoxifylline; only two had T- helper count improvements. Dr. Dezube told us that for each such negative anecdotal report they have heard, they get many positive ones. These differences underscore the need for additional studies to learn more about the drug, to make sure it can be useful and learn how and when to use it. Two Other Pentoxifylline Trials Recruiting in New York and Boston; Wichita Soon? The Community Research Initiative on AIDS (CRIA) is now running a controlled trial of pentoxifylline in New York City. This 16-week trial has about ten more openings; about thirty volunteers are already on the study. Volunteers are randomly assigned to pentoxifylline (the same dose as reported above) or a placebo; TNF, weight, and viral culture will be measured. This trial also is for persons with T- helper counts of 300 or less. For more information, call Bette Smith, CRIA, 212/889-1958. Also, the Community Research Initiative of New England (CRI/NE) is actively recruiting for their controlled trial of pentoxifylline. Their study design is unique, as participants receive the drug during four out of five months; during the other month, selected at random, they receive a placebo. A total of 60 volunteers are needed; only five of them are on the trial already. This is the only study that is measuring indicators of quality of life, in addition to laboratory markers such as fasting triglycerides. For more information, contact Jeanne Day at CRI/NE, 617/424-1524. This study may also open an arm in Wichita, Kansas. ** Comment Pentoxifylline could be important because it is generally safe, readily available by prescription, and inexpensive (U. S. price, $300 to $350 per year). A number of physicians are using it already, especially in Eastern U. S. ; it has been slower to come to public attention in California. Trials are needed to learn more about this treatment. We hope that people will be willing to volunteer, at the risk of a short time on a placebo for pentoxifylline (they will still be on their other treatments, such as AZT or ddI), even though they could get pentoxifylline without joining a study. (to be continued) ***** Research Funding Disaster: House Budget Below Bush Request by John S. James The U. S. House of Representatives has appropriated $165 million dollars less for medical research (for all diseases) than requested by President Bush. There is widespread fear that lifesaving projects in many fields could be delayed, if not cancelled entirely. A lobbying effort by scientists and others who can travel to Washington is being organized for September, in the hope that some of the damage can be undone in the Senate. Those who cannot go to Washington can help through home visits and letters. Why did this occur? Organizers have been told "a million different excuses." The most credible theory we have heard is that it does not reflect a lack of commitment to AIDS by Congress. Instead, the problem seems to have resulted from two causes. First, the creation of this budget was greatly constrained by overall funding decisions that had been made earlier, both by the White House and by Congress. And second, in so far as research is concerned, Congress is unhappy that it has poured billions of dollars into the U. S. National Institutes of Health for years, for many diseases, with disappointing practical results -- a problem many believe stems from the management and bureaucracy of the U. S. National Institutes of Health, rather than the research itself. Instead of walking away from diseases like AIDS and cancer, we need higher funding priorities from Congress, along with the political and administrative leadership lacking in recent administrations, that will give medical researchers the support they need to do their jobs. Advocates of AIDS research, prevention, and care are working together on a three-track lobbying effort, with home-state visits to senators in August, and the Washington trip in September, probably on the 14th and 15th. The research part of this effort is being coordinated by Project Inform. It is especially important for scientists to explain to Congress what they want to do, and what will be lost due to inadequate funding. (Project Inform has arranged for a $238 round-trip fare to Washington from major cities.) To find out more about this effort and how you can help, contact Anne Donnelly or John Bouffard at Project Inform, 415/558-8669. Or call the Sheridan Group, 202/462-7288, which is coordinating the part of the effort which focuses on funding for AIDS care. [Note: Since this issue went to press, the dates of the lobbying visits have been changed from Sep. 14-15 to Sep. 8-9, 1992.] ***** NIH AIDS Research: Major Report Available A detailed report on AIDS research in each of the institutes of the National Institutes of Health, prepared by the Treatment Action Group, a treatment activist organization in New York, was released July 21 at the international AIDS conference in Amsterdam. This two-volume report, of almost 200 pages, will be a source document for anyone who wants to investigate Federal AIDS research, making it possible for journalists and policy experts to approach this task without a major research investment just to get oriented. From the one-page abstract: "Our goal was to obtain a comprehensive picture of the AIDS programs administered by the U. S. National Institutes of Health (NIH) in order to recommend changes to expedite a cure. We reviewed the $800,000,000 NIH AIDS program from fiscal year (FY) 1991, including 2,625 extramural grants and contracts and hundreds of intramural projects. We read abstracts of these projects generated by the NIH Office of AIDS Research (OAR) AIDS Research Information System (ARIS) database. We reviewed the NIH Annual Report to Congress on AIDS achievements for FY 1991, the quarterly Institute AIDS Science Reports, and the list of new programs requested by NIH for AIDS in FY 1993, which cannot be funded due to President Bush's budget cuts. Finally, we compared a draft of "The NIH Strategic Plan for HIV-Related Research," the Institute of Medicine's 1991 report on the AIDS program, and the recommendations of the National Commission on AIDS to the government. From the Foreword, by Larry Kramer: "Never before has there been such a look at all the AIDS programs at all the institutes that comprise the National Institutes of Health. Even the report issued by the Institute of Medicine only dealt with broad structural issues, deferring the idea of looking at the programs themselves in detail to some future unspecified moment in far-off time. "Why is this report so important for you to read? "Because, for the first time, eighteen institutes, each with its own programs, each with its own goals, each with many strengths and many weaknesses, each completely unable to criticize itself, comes under a long-needed scrutiny. "What does this report conclude? "The AIDS plague is utterly and completely devoid of leadership. At the NIH, no one is at the center, nothing is coordinated, no one is asking the life-saving (and money-saving) questions: what is missing from our efforts, what is being duplicated, why are we being forced into competition with our own fellow institutes, right here on our own campus, when budgets are shrinking and shrinking?... "May bureaucrats learn from this report and gain courage to speak out at last. May activists learn from this report and renew their commitment, now so understandably wounded from discouragement. With this information, may we all enter a new stage of holding our system -- now so dreadfully and woefully off-course -- accountable." For a copy of the report, send $10 to: TAG, 147 2nd Avenue, Suite 601, New York, NY 10003. ***** Neurology Funding Good News: Activists' NIH Study Pays Off Intense behind the scenes negotiations between AIDS activists in New York and San Francisco and the National Institute of Neurological Disorders and Stroke (NINDS) over the past year have paid off with a grant budget between one million and three million dollars larger than last year's NINDS research budget devoted to studying the neurological impact of AIDS. While the amount may not seem like much in comparison with overall Federal research spending, in the field of neurology it is a desperately needed infusion of cash. The new funds will go to research in the seriously underfunded area of AIDS complications in the central nervous system such as AIDS dementia, peripheral neuropathy, and PML -- progressive multifocal leukoencephalopathy, an opportunistic infection of the brain that may affect as many as five percent of people with AIDS. "It is fabulous," said Derek Link of the New York based Treatment Action Group (TAG), one of the activists who were instrumental in helping to develop the new program. "It is more money for AIDS research. It is money for a neglected area of AIDS research and it will increase the efficiency of research." [Derek Link is one of the authors of the in-depth report on NIH, reviewed in the article above.] One example of the benefits of the additional funding is that more sophisticated studies can be undertaken. To study peripheral neuropathy it is essential to have both a neurologist and complex and expensive nerve conduction data and analyses to get objective results on the efficacy and toxicity of drugs. And PML studies are likely to need protocols that use potentially highly toxic drugs in an inpatient setting with not only a neurologist but study nurses as well. In both cases, such studies have usually been impossible within the ACTG neurological sites. Neurology has been called the "ugly duckling" of HIV research -- underfunded, and with few neurologists available, because ACTG principal investigators have considered neurology as a peripheral issue, and few have applied for funding or designed protocols that specifically address neurological implications of HIV and opportunistic infections. Studies that have been done have often been unsophisticated due to lack of resources to pay for the advanced testing and technology required, or because neurologists were not involved in the early stages of drafting the protocol. Matt Chappell, of ACT UP Golden Gate, said that of the nine ACTG sites funded in April for neurology, only four had levels of support that were even nearly adequate. (The new money will provide up to a million dollars of funding independent of the ACTG to four ACTG sites.) It was those problems that drew Link, Chappell, and others into trying to figure out how neurologists working with HIV disease could find more research dollars. Derek Link began perusing the budgets of various federal agencies in an effort to discover any other groups that are doing neurological research, in the hope that they could be persuaded to direct some of their funds to HIV studies. Chappell says they discovered that NINDS had a budget of $16 million for neurological studies and that the National Institute of Mental Health had $80 million to do HIV studies. After contacting both agencies they learned that NINDS was not funded for outreach and coordination with other NIH agencies. The activists helped facilitate communication between the NINDS and the neurological committee of the ACTG. Researchers have credited ACT UP for its role in making the new funding possible. According to Joseph Berger, M. D., professor of neurology at the University of Miami, "There is a move afoot that in no small measure has been stimulated by ACT UP to make neurological issues a more important issue." Another leading HIV neurologist noted, "The involvement of ACT UP and other interest groups has [had] a very positive influence on many aspects of the established researchers as they try to put together a response. ... This is another example of some bright people who have worked hard and given us an opportunity that is important." ** Medical Marijuana: Overwhelming Support at San Francisco Hearing by John S. James In November 1991, almost 80 percent of San Francisco voters supported a ballot proposition to make marijuana legally available when medically necessary for patients with cancer, AIDS, glaucoma, and other serious diseases. But San Francisco cannot overrule state and federal laws, and recently new restrictions by the Bush administration prevented legal use of marijuana by all except 12 patients in the United States (one of them a person with AIDS); for the first time ever, an FDA compassionate-access program was stopped by higher officials for political reasons. (See "Anti-Drug Politics Impede Medical Use of Marijuana, AIDS TREATMENT NEWS #148, April 3, 1992.) Recently the San Francisco Board of Supervisors held hearings on a proposal to implement the ballot proposition by asking the Police Commission and the district attorney not to arrest or prosecute persons using marijuana for medical purposes. Of the 26 speakers who addressed the August 4 hearing, all supported the proposal. Speakers included a former San Francisco Police Commissioner, who had survived colon cancer and said that without marijuana, she would not be alive today. A member of the Board of Supervisors said that her husband had been allowed to use marijuana when he was dying of cancer, but "Then they took it away, and that is reprehensible." For more information about medical use of marijuana, contact the Alliance for Cannabis Therapeutics, P. O. Box 21210, Kalorama Station, Washington, DC 20009, 202/483-8595. Comment The trip to Amsterdam for the international conference illustrated a striking contrast in government attitudes. Not only is medical access to marijuana not a problem, even recreational use, while technically illegal, is tolerated in coffeeshops. [Caution: Marijuana should be sterilized before use by persons with immune deficiencies, to avoid risk of aspergillus infection.] Yet there is no underclass in Amsterdam, and much less violence than in U. S. cities. One American who was taking care of a person with AIDS at the conference asked a Dutch physician how to dispose of needles used for infusion equipment, so that the Americans would not risk arrest. The answer was that there was no law against possessing the needles, so there was no need to conceal them. In another instance, this writer was initially reluctant to talk to a Dutch journalist about leading-edge "underground" treatment work in Amsterdam, since in the U. S. such publicity would generate pressures to shut the work down -- a serious matter which inhibits discussion of important AIDS treatment developments here. In Amsterdam that was not a problem. What we glimpsed on this trip was the price that is paid when government makes war on its citizens over how they live their lives. Lightening up is not only an issue of respect and consideration for individuals; it would also improve the quality and effectiveness of public life in many other ways. ***** San Francisco: Project Inform Report on International Conference, August 26 On Wednesday, August 26, Project Inform will report on the VIII International Conference on AIDS in Amsterdam. The meeting, free and open to all, will be at 7:30 p. m. at the Everett Middle School Auditorium, 450 Church Street (between 16th and 17th). For more information call Project Inform, 415/558-9051, 10 a.m. to 4 p. m. Monday through Saturday. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display