Subject: AIDS Treatment News #131 Date: Jul 27 1991 (543 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 #131, July 27, 1991 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] ddI Approval Recommendation TIBO Report: Good Pharmacokinetics, No Dramatic Benefit Marijuana: Therapeutic Access Threatened AIDS TREATMENT NEWS Confidentiality Policy -- and HIV Healthcare Hysteria Notes, Announcements: Group Helps HIV-Infected Physicians; Assistance Urgently Needed Travel/Immigration Ban: Call the White House Imuthiol Suspended San Francisco: Meet the Staff of AIDS TREATMENT NEWS AIDS Treatment Activist Conference, September 27- October 1, Washington, D. C. In Memoriam: David Stern ***** ddI Approval Recommendation by John S. James On July 19 the Antiviral Drug Products Advisory Committee, a panel of non-government experts chosen by the U. S. Food and Drug Administration (FDA), recommended that the FDA approve the AIDS antiviral dideoxyinosine (ddI, brand name VIDEX) for adults and children who cannot tolerate or are not adequately responding to AZT. The Committee's vote was 5-2. This action is only advisory; the FDA must make the final decision, and it is expected to approve ddI later this summer or fall. Approval will make ddI the second AIDS antiviral regularly available, after five years of AZT alone. The advisory committee meeting was widely reported in the press, which understood its importance in setting precedents for future evaluation of new drugs to treat life-threatening conditions. We will not repeat the news here, but look at some of these precedents and how they might affect drug approval in the future. Ideal data on the use of ddI is not available, and as a result the Committee's task differed from business as usual in two ways. First, it needed to weigh the use of "surrogate marker" data, such as T-helper counts and measures of viral load, because it did not have the efficacy data required in the past -- death or major disease progression in controlled trials. Second, it needed to decide if "phase I" data, obtained from a number of small studies which were not designed to test drug efficacy, could substitute for data from the efficacy trials. Our interpretation of the Committee's actions is that surrogate markers basically were accepted (although not unanimously) as a major contributor to drug approval, at least for nucleoside analogs -- especially since the markers are getting better. But phase-I data was basically rejected as a sole basis for drug approval. After the first day of the two-day meeting, there was much gloom among observers; many thought that the Committee would vote to reject ddI -- that although the drug did work, the evidence available did not prove it worked. On that first day, Bristol-Myers Squibb had presented the phase I data which was the basis for its new drug application (NDA); later that day, the FDA, using sophisticated statistical analysis, raised serious doubts about that evidence. Only on the second day, when preliminary data was brought in from the ongoing controlled trial ACTG 117 (comparing ddI to AZT for persons who had already received extensive treatment with AZT), and this data tended to confirm the phase I results presented the day before, was a majority of the Committee convinced that, on balance, it was better to recommend that the drug be approved than not approved. It is almost unprecedented to release data early from an ongoing trial. An important element in the Committee's decision is that there is much more safety data on ddI than on most drugs when they are approved -- due to Bristol-Myers Squibb's expanded access program, which provided ddI to about 20,000 people and collected information about side effects. Also, the fact that the drug clearly shows biologic activity (indicated by reduction in p24 antigen and other viral measures) did impress the panel. Still, the Committee was reluctant to recommend approval, for several reasons. First, the controlled-trial evidence showed only a small benefit. Average T-helper counts were only 10 to 15 higher in the group which switched to ddI as compared to those who stayed on AZT (opportunistic infection rates in the ongoing study were not released). Second, there is serious toxicity with ddI, especially neuropathy and pancreatitis. And third, there was concern that approving the drug now might end the controlled trials, if persons who think they are getting AZT in the trials drop out to purchase ddI instead. Loss of the trials would be tragic, because their data is needed not only to confirm that the decision to approve ddI was the right one, but also to give physicians guidance on the best ways to use the drug. Also, these trials will refine scientists' understanding of surrogate markers, and therefore help in the development of future drugs. Comment The likely approval of ddI, while important for providing a second treatment option, should be kept in perspective. ddI could have been tested and approved several years ago, at about the same time as AZT. It has taken years for government and academia to realize that the chances of developing drugs rapidly enough to meet the needs of the epidemic are near zero so long as statistical differences in death or major disease progression are required for drug approval. AZT was approved by a fluke, probably depending in large part on luck and/or experimental error. In any case, only one drug can go through that door, as new agents cannot ethically be compared to placebos in similar trials, but must be compared with AZT, requiring trials which are large, expensive, slow, and hard to interpret. It is better to accept the risk that a drug will be approved in error, based on blood tests and other rapidly-measurable indicators of improvement, than to face the near certainty of years of delay during an epidemic. The drug-approval evolution now seen with ddI is very important and welcome, but it applies only to the last and most public stage of development, when a drug ready for use is awaiting final FDA action. Early problems -- such as patent delays, excessive and unworkable animal-test requirements, and poorly designed phase I trials, have as much impact on the ultimate date of new-drug availability. But these problems are much less visible, and therefore harder to influence through public opinion. The drug-development system is like an iceberg, in that only a fraction is easily visible; only that tip is now being reformed. Should Activists Reconsider Placebo Trials? The most important single implication for the future to come from the Committee's meeting on ddI is that, in certain cases, improvements in laboratory test results (such as T-helper counts) can have a major role in drug approval -- but they must be obtained in well-conducted, controlled trials, and there must be some supporting evidence of clinical improvement (such as weight gain). For many new drugs, this means that the fastest way to get them approved will be short (perhaps three months) relatively small trials comparing the new drug to no treatment, using immunological or virological "surrogate markers" as major endpoints of the trial (instead of waiting for death or disease progression, as in earlier trials). Volunteers entering these studies can be relatively healthy (with T-helper counts around 300, for example), so that a few weeks of no treatment would be unlikely to do serious harm. Also, these trials can be designed so that anyone found to be doing badly can quickly be taken out of the trial and given appropriate treatment, or switched to the active drug if they had been receiving the placebo. During the first day of the Committee's consideration of ddI, when it looked like the vote would be to reject the drug, such a study would have made all the difference in building a consensus for approval. Fortunately, the AIDS community was rescued this time by the data from ACTG 117 which was brought in on the second day. But ACTG 117 is slow, cumbersome, and expensive -- because it was designed to look primarily for death or disease progression, not for surrogate markers -- and in most future cases of needed drugs, no such study will be available. The reason AIDS activists have strongly opposed placebos in the past is that trials were designed to look for death or major opportunistic infections; many people had to die on the placebos, or suffer major health problems, in order to prove the drug. It is widely believed that important treatment or prophylaxis had sometimes been forbidden to study participants so that people would get sick faster, making it easier to get statistical proof that the drug worked. But surrogate-marker trials do not need to count people getting sick in order to prove a drug is effective. Therefore they can be ethical in their treatment of volunteers, and at the same time greatly accelerate the availability of proven new treatments for everyone. The conventional wisdom among many scientists and government or drug-company officials is that AIDS activists will not tolerate trials in which some volunteers receive only a placebo. But in our discussions with activists we have found widespread agreement, or at least openness to the possibility, that there can be situations where properly-designed placebo trials are appropriate. We urge further discussion and consideration of this issue. ***** TIBO Report: Good Pharmacokinetics, No Dramatic Benefit by John S. James TIBO derivatives are a class of very selective inhibitors of HIV; because of their selectivity, they are expected to have low toxicity as drugs. TIBO derivatives are reverse- transcriptase inhibitors, but (unlike AZT, ddI, and ddC) not nucleoside analogs. Low-profile human studies of this class of drugs have been occurring in Europe for over a year. AIDS TREATMENT NEWS covered TIBO derivatives in issue #97 (February 16, 1990), but we did not include them in our survey of new-generation antivirals (issue #129, April 12, 1991) because little information was available, and the reports we did hear about human testing were mostly unfavorable. On July 20 The Lancet published a report of a 50-week, 22- patient study in England of R 82913, one of the drugs in this class1; this study was also described at the recent International Conference on AIDS in Florence2. The drug was well tolerated and showed good pharmacokinetics, with stable blood values when given intravenously, but evidence for efficacy was small. (The recent publication was widely reported in the press, but sometimes mistakenly attributed to the wrong journal, Nature instead of The Lancet.) The study reported was not primarily designed to look for efficacy. Instead, for each volunteer daily doses were escalated from 10 to 300 mg; the latter gave trough levels (the lowest blood concentrations during the day) which were enough to inhibit HIV in laboratory tests. All 22 volunteers had advanced HIV infection; all T-helper counts were below 300, all had opportunistic infections before the study began, and all but one were p24 antigen positive. Average T-helper counts rose slightly when the maximum drug level was attained. Also, p24 antigen fell 41 percent during the first month of treatment; before treatment, it had been rising. None of the volunteers showed great clinical improvement, however, and most continued to lose weight. Seven patients died during the study: two of them had KS, four began the trial with T- cell counts below 20, and the other died of PML (progressive multifocal leukoencephalopathy). Nine others who left the trial are still alive; the other six were still receiving treatment in January 1991. The data suggested that larger doses of R 82913 may be needed; it is often difficult to predict required levels of antivirals based on laboratory tests. However, the drug is difficult to make, and there was little available when this trial was run -- perhaps not enough to test higher doses. A graph published with the paper showed that there was about a 10-fold difference between peak and trough blood concentrations of the drug -- despite daily dosing and an elimination half-life of three days. It is possible that more frequent dosing would help. The lack of toxicity of R 82913 suggests that this drug might prove useful when enough of it becomes available to test higher doses. References Pialoux G, Youle M, Dupont B and others. Pharmacokinetics of R 82913 in patients with AIDS or AIDS-related complex. The Lancet. July 20,1991; volume 338, pages 140-143. Pialoux G, Youle M, Dupont B, Gazzard B, Cauwenbergh G, and Janssen PAJ. Early clinical evaluation of R 82913 TIBO compound in patients with severe HIV infection. Abstract #Th.B. 86, Seventh International Conference on AIDS, Florence, June 16-21, 1991. ***** Marijuana: Therapeutic Access Threatened by Denny Smith In 1978 the Food and Drug Administration (FDA) approved a compassionate use program to make marijuana (Cannabis sativa) available to people diagnosed with glaucoma, multiple sclerosis or cancer. Outside of this access, of course, the government has made possession of marijuana a crime and a target of its war on drugs. A few years ago the FDA was pressured, over the objections of the Drug Enforcement Administration, into expanding marijuana access to people with HIV. But over the past several weeks, the news media have carried reports of the FDA's intentions to reverse this access. Among those actively involved in this saga is the Marijuana AIDS Research Service (MARS), a project of the Alliance for Cannabis Therapeutics (ACT). MARS has helped many people with AIDS and their physicians obtain and complete the labyrinthine forms required by the FDA for compassionate release of marijuana. We spoke to Robert Randall, the president of ACT and the first person to obtain marijuana for treating glaucoma. Robert told us that the FDA received more requests for marijuana in the first six months of 1991 than in the entire previous 13 years of the program's existence. Dronabinol is a pharmaceutical version of marijuana's active agent THC, and is available by prescription under the trade name Marinol. Robert has been told by many people that dronabinol is not as effective for them as marijuana, for several reasons. For one, smoking marijuana can bring relief from nausea or poor appetite almost immediately, while dronabinol is an oral medication which may not take effect for over an hour. For another, marijuana consumption is easy to control, since it is smoked, while dronabinol is only available in specifically-dosed capsules. The Nursing 91 Drug Handbook cautions that dronabinol's effects may persist for days after the drug is taken. In addition to relief from nausea attributed to both dronabinol and marijuana, some people have also reported to MARS increased emotional well-being and relief from neuropathy with marijuana use. Theoretically, access for HIV use is still in place, but only for people already accepted into the program. Robert has heard various reasons for this move, mostly involving disputes within the government about the politics of admitting that marijuana has important medical value. The DEA in particular has long argued that marijuana holds no therapeutic benefits. But last year, the U. S. Court of Appeals ordered the DEA to reconsider its position. MARS continues to assist physicians with completing the compassionate-use forms. Only physicians can apply to the FDA, and only for patients who present with nausea, vomiting or rapid weight loss. A donation of $15 is appreciated but not required for help from MARS. Interested persons can call 202/328-6391, or write to MARS, P. O. Box 21210, Kalorama Station, Washington, D. C., 20009. ***** AIDS TREATMENT NEWS Confidentiality Policy -- and HIV Healthcare Hysteria by John S. James AIDS TREATMENT NEWS never has and never will sell or share its subscriber list with any other organization. We restate this policy for two reasons: * In our last issue, when we added the masthead on page 2, we inadvertently left out the confidentiality statement. The original text is back in this issue, and of course there never was a policy change. * The growing hysteria over HIV-infected healthcare workers is increasingly threatening medical practice. Persons with AIDS are wondering who will treat them, if HIV-positive physicians are driven out of medicine, and others become more reluctant to treat AIDS. At a recent medical conference, some physicians noticeably avoided the AIDS TREATMENT NEWS table -- something we had not seen before. Most or all of them were undoubtedly HIV-negative, with no reason to fear having their HIV status exposed, but in the present climate of fear, they did not want to be seen as associated with AIDS. This situation has arisen because of the understandable fear patients may have in any major medical situation -- in a hospital or doctor's office surrounded by unfamiliar technology, and often facing unknown or serious illness. This normal fear and vulnerability is being exploited by right-wing politicians in pursuit of their own advancement, to the detriment of the entire medical system, not only in regard to AIDS. For example, a new bill to impose 10-year prison sentences on doctors who know they are HIV-positive and do not tell their patients -- introduced by Jesse Helms (Republican, North Carolina) and passed by the Senate -- would also set a precedent for direct Federal regulation of physicians' practices. According to a report in The New York Times, (July 19, page 1) the bill would create a new category of U. S. criminal law. Undue focus on the negligible risk of HIV infection from a surgeon -- estimated to be comparable to the risk of death by traffic accident during the trip to the hospital, less than the risk of death by lightning, and 500 times less than the risk of death from anesthesia -- distracts attention from the far greater danger of patient-to- patient disease transmission if proper infection-control procedures are not followed. Perhaps the most serious effect of policies such as the Helms bill, or the U. S. travel ban on foreign visitors and immigrants, is that they give everyone in the world an incentive not to know their HIV status, not to be tested, not to interact with the medical system. Most persons with HIV do not know that they are infected, and therefore do not take precautions to avoid transmission; as a result, they are more likely to spread the virus than those who do know their status. The crucial trust upon which cooperation depends must not be destroyed by self- serving politicians. A way must be found to reassure the public about the safety of medical care, without spending tens of millions of dollars on unnecessary testing, driving thousands of health-care workers out of medicine, making HIV care harder to obtain, and threatening all the public-health efforts which employ voluntary cooperation in AIDS prevention. ***** Announcements ** Group Helps HIV-Infected Physicians; Assistance Urgently Needed The Medical Expertise Retention Program (see AIDS TREATMENT NEWS #125, April 19, 1991), a project of the American Association of Physicians for Human Rights, assists HIV-infected physicians and also speaks publicly for rational policies on healthcare workers with HIV. Due to the recent national interest in this issue, MERP is being flooded with information requests from the media, as well as calls for help from individual physicians. This program, started part time last November, must expand immediately to meet today's needs. You can help by contributing to AAPHR-MERP, 2940 16th Street #105, San Francisco, CA 94103. For more information, call Ben Schatz or Naphtali Offen at 415/864-0408. ** Travel/Immigration Ban: Call the White House ACT UP and other groups are asking people to call the White House switchboard at 202/456-1414 to tell them the following: "I do not condone discrimination in any form, therefore I support the removal of all immigration and travel restrictions based on a person's HIV status." They are asking people to call on August 1 or 2, the last days for official public comment; but it DOES count if you call after those dates. (The August 2 deadline is for written comments received at the U. S. Centers for Disease Control in Atlanta.) ** Imuthiol Suspended On July 24 Reuters reported that Imuthiol (also called DTC) is being withdrawn at least temporarily by the French company, Institut Merieux, when new results from a large clinical trial failed to show any benefit. Only sketchy information is available at this time, but according to a reliable report we have heard, there was more progression to AIDS in the treatment group than in the placebo group. Previous studies of Imuthiol have found benefit, although the interpretation of these studies has been controversial. The reason for the contradictory results is unclear. ** San Francisco: Meet the Staff of AIDS TREATMENT NEWS The owners of Dottie's True Blue Cafe invite Bay Area readers to meet the staff of AIDS TREATMENT NEWS for dinner on Wednesday, August 21. The restaurant, whose food was rated "excellent" in the November 11, 1990, San Francisco Chronicle, is located at 522 Jones (between Geary and O'Farrell) in San Francisco. This special evening will feature a three-course vegetarian pasta dinner, including choice of dessert and coffee; other beverages and gratuities are extra. There will be just 35 places for each of two seatings, 6:00 and 7:30 p.m. Dinner tickets will be $12 in advance ($15 at the door, if available), and may be purchased directly from any staff member of AIDS TREATMENT NEWS, by calling 415/255-0588 for Visa or MasterCard reservations, or by sending a check or money order to ATN Publications, P. O. Box 411256, San Francisco, CA 94141. ** AIDS Treatment Activist Conference, Sept. 27- October 1, Washington, DC ATAC2 (the second AIDS treatment activist conference) and subsequent demonstrations for national leadership in the AIDS crisis and for national healthcare are scheduled for Washington, D. C., in about two months. Organizers are from ACT UP/DC, ACT UP/New York, and other groups. ATAC2 will meet from Friday evening, September 27, through Sunday, September 29. The agenda is not yet final; if you have suggestions, call the numbers below immediately. The first ATAC, held in November 1990, drew 350 treatment activists. A White House demonstration on Monday, September 30, will protest the lack of leadership by President Bush, and specifically demand "that the President appoint a national AIDS czar. The proposed cabinet-level officer would be given broad authority to lend direction to the government's AIDS policies and programs; to weed out duplicative and wasteful research projects; to broaden the definition of AIDS; and to make AIDS education, care, and research a national priority." Demonstrators plan to deliver to the White House 130,000 obituaries of persons whose deaths are AIDS related. A march on Congress for national health, organized by ACT UP Network, is planned for Tuesday, October 1; it may include a funeral procession to call attention to deaths caused by lack of universal healthcare. For more information, call Robert Warnock, ACT UP/DC Media Coordinator, 202/328-8253, or Treatment and Data Committee, ACT Up/New York, 212/564-AIDS. ***** In Memoriam: David Stern San Francisco activist David Stern died on June 27, four years after he was given nine months to live. During that time, David worked ceaselessly to improve HIV treatment research and treatment access, and to expose the U. S. government's criminal neglect of the epidemic. David was familiar with the importance of political activism long before his diagnosis. Since the early 1970s he had worked for the rights of California farmworkers to unionize through the United Farm Workers, for the independence of Puerto Rico through Prairie Fire Organizing Committee, and for the freedom of lesbians and gay men through Bay Area Gay Liberation. Those experiences made him an articulate and respected member of ACT UP/San Francisco, in which he helped to organize the People With Immune System Disorders (PISD) Caucus and the Treatment Issues Committee. David's death is a serious loss of leadership and expertise for the AIDS community. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display