Subject: AIDS Treatment News #110 Date: Sep 06 1990 (952 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& copyright 1990 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #110, September 7, 1990 CONTENTS: [items are separated by "*****" for this display] Good News on ddI Toward Faster Antiviral Development: "Rapid Screening" Trials Proposed Federal Panel Seeks Drug-Approval Reforms AZT and Lymphoma Lymphoma Treatments Update Foscarnet Expanded Access Announcement ***** GOOD NEWS ON DDI A new report on the longest-running study of human use of ddI, at the U. S. National Cancer Institute, shows a very good survival rate in patients using doses of the drug which were well tolerated. A total of 58 patients were involved in the study, 22 with AIDS and 36 with related conditions; their median T- helper count when they started ddI was 47 (range 4 to 267). The survival rate after 21 months was 80 percent for patients with AIDS and 93 percent for those with symptomatic HIV infection who did not meet the definition of AIDS. (Many patients were on the study for less than 21 months, but survival to that time was estimated by the Kaplan-Meier statistical method, which is well accepted for this purpose.) The paper was published in The Lancet, September 1, 19901; additional information from interviews with scientists involved in the study appeared in The Wall Street Journal, August 31, and in other newspapers through a United Press International story. How does this survival compare with that of AZT or no treatment? The Lancet article cautions that this data may not be comparable with past experience because most patients were stable when they began the study, many received pneumocystis prophylaxis, and 10 were treated with AZT while their ddI was temporarily stopped. News stories reported that earlier studies with similar patients had found about a 50 percent survival at 21 months among those treated with AZT, and 25 percent survival with no treatment; but we do not know if those figures reflect pneumocystis prophylaxis. Other highlights of the Lancet paper: * Of the 13 patients who received long-term (median 17 months) treatment with well-tolerated doses of ddI (no more than 9.6 mg/kg per day), mean T-helper count started at 157 and increased by 50 percent (at the time of maximum increase, after nine months of treatment). T-helper cell and p24 antigen improvements continued for some patients for up to 15 months, after which there were too few patients to draw firm conclusions. * Patients with little or no prior treatment with AZT (no more than four months) showed much better T-helper improvements than those who had used AZT for much longer. But p24 antigen, a measure of viral activity, decreased substantially in both groups during ddI treatment. The article does not speculate on why the T-helper count increased less in patients who had had long-term use of AZT, but lead investigator Dr. Robert Yarchoan, interviewed in The Wall Street Journal, suggested that the reason may have been the effect of AZT on the bone marrow, which produces T-helper as well as other blood cells. (The AZT doses of these patients were not reported, but presumably they would have taken the "high" dose, 1200 mg, which was standard at that time, and which causes much more toxicity than the lower doses now in use.) * Of five patients in the study who had dementia or other cognitive dysfunction, all had improved cognitive measurements after six to 12 weeks of ddI. * Toxicities were severe at high doses of ddI, with most patients developing neuropathy, pancreatitis, or hepatitis within six months; no one died of drug effects in this study. But at doses of 3.2 to 9.6 mg/kg per day, only three of 35 patients developed any of these serious toxicities. Many patients had less severe side effects, such as insomnia, irritability, abdominal pains, and headache; we do not know what doses these patients used. To reduce pancreatitis, the most serious toxicity of ddI, the researchers now "measure serum amylase and triglyceride and temporarily stop ddI when the amylase rises to 1.5-2 times the upper limit of normal or when the triglyceride concentration rises above 7 g/l; ddI is then re-instituted when the levels approach normal." Comment This small study does not prove that ddI is better than AZT, although the good survival rate for patients with AIDS or serious symptoms, and low T-helper counts when they began the study, suggests that it might be. The important question, however, is not whether ddI is better on the average, but whether it is better for some patients. It seems clear that the answer is yes, and that the drug should be approved as a treatment option. References 1. Yarchoan R, Pluda JM, Thomas RV, and others. Long-term toxicity/activity profile of 2',3'-dideoxyinosine in AIDS or AIDS- related complex. The Lancet. September 1, 1990; volume 336, pages 526-529. ***** TOWARD FASTER ANTIVIRAL DEVELOPMENT: "RAPID SCREENING" TRIALS PROPOSED by John S. James Last year AIDS treatment activists joined with government and academic statisticians in an ongoing working group for improving the design of clinical trials. This Statistical Working Group, operating within the AIDS Clinical Trials Group of the U. S. National Institute of Allergy and Infectious Diseases, is developing a new kind of eight- to 15-week clinical trial to compare and prioritize new drugs which successfully complete phase I (early dosage and toxicity studies). The winners from the rapid screening process would then go immediately into larger trials designed to lead to drug approval. Dozens of potential AIDS antivirals are now coming out of laboratories, and there is no way that all could get the full- scale clinical trials required to convince the FDA that the drugs are good enough for general use. Even if more money were available, there are not enough experienced scientists, research nurses, or patients meeting entry criteria, to run so many large trials. The proposed new system could quickly screen all the promising drugs, so that the truly important ones could quickly be moved into larger, definitive trials. The importance of the Statistical Working Group is that the people needed to make the proposal work are part of the process, so most issues could be resolved immediately. At a key meeting on July 10, 1990, statistical experts from NIAID (the U. S. National Institute of Allergy and Infectious Diseases), made sure that ideas were scientifically acceptable. Sometimes they did not know what the FDA would think, but then they could ask Ellen Cooper, M. D., head of the antiviral division of the FDA, who was at the same meeting. And the AIDS activists there knew what was or was not likely to be acceptable to patients. Also at the meeting were statisticians from the U. S. National Cancer Institute, NIAID's statistical contractors from Harvard and the University of Minnesota, and at least two pharmaceutical companies involved in AIDS trials, Bristol- Myers Squibb and Hoffmann-La Roche. Pharmaceutical companies seldom run clinical trials to compare drugs, because each company only develops its own, and at any given time seldom has more than one drug at the same stage of development for the same disease. The screening trials must be sponsored by a neutral party, for example a government agency or a community-based or academic research organization. Pharmaceutical companies must be consulted early, however, because they will be involved when their drugs are tested. There is concern that some companies may be reluctant to put their drugs to an early test. The Statistical Working Group would not have succeeded without good ideas going in. The basic elements of the screening trials were already familiar to the scientific community, as a similar system has been used successfully in cancer research. How the Trials Will Work (1) Outcome Measurements For over a year, scientists have debated the use of viral or immunological "markers" to tell if a drug is working against HIV. At this time the scientific mainstream has not been willing to accept improvement in available markers, like T-cells or p24 antigen or antibody, as good enough proof of efficacy to lead to drug approval. As a result, trials take years instead of weeks, because in order to prove a treatment works, enough people must die or suffer disease progression to generate statistically significant numbers in favor of the treatment. (Note that even a perfect drug which cured instantly would also take a long time in this system, since the delay depends on what happens to the volunteers who are not treated.) Also recruitment is difficult when patients need to enter a long (e.g., two year) trial in which their treatment must be controlled by a protocol written in advance. Such trials can require long-term sacrifice of medical options which otherwise would have been chosen. However, the anti-HIV drugs which have been tested and are believed to benefit patients -- AZT, ddI, and ddC -- all cause average T-helper cells to rise within a short time, usually eight weeks of starting the treatment. There is no reason to believe that these drugs themselves raise T-cells directly; instead they appear to be inhibiting HIV, allowing the immune system to recover. Therefore other drugs which inhibit HIV at least as well would also probably cause the T-cells to rise, within the same time frame. By using T-helper count not as definitive proof of efficacy but only as a preliminary indication, the Statistical Working Group sidestepped the currently-deadlocked debate on whether such markers are good enough for final, definitive trials. (2) Placebos Brainstorming among clinical-trials experts at the July 10 meeting led to an idea for avoiding placebos in the screening trials without sacrificing their scientific power. The first suggestion was to test many drugs at the same time. Most proposed drugs will not work, so they will in effect be the placebo. As one scientist put it, if five drugs are being tested, then if there are one or two winners, these should stand out from the others (in T-helper improvement). And if by luck one of the drugs was a superwinner, that would be obvious, too. The trials would be kept short, probably two or three months, to avoid exposing participants to ineffective drugs for long. Alternatively, in some cases a placebo or no-treatment arm might be acceptable in these trials. Since many drugs would be tested, patients would have only a small chance, probably less than one in five, of receiving no treatment. And the trial would not last long. Persons who were not critically ill might be willing to risk entering a no-treatment arm for two or three months. (3) Blinding An administrative problem with a trial comparing many drugs is the difficulty of making all the pills look the same, to maintain "blinding" -- not let patients, physicians, or staff know who is getting what drug. But recent thinking among clinical- trials experts is de-emphasizing the importance of blinding for studies with objective outcome measures like T- helper counts. What is important is randomization -- assigning patients randomly among different arms in the trial. If volunteers choose which drug they will get instead of being randomly assigned, it would be impossible to be sure there were no hidden biases caused by certain groups of patients, with better or worse prognosis, choosing certain drugs. Without randomization it would be impossible to fully trust the result. If trial designers can avoid blinding the rapid-screening trials -- no decision has yet been made -- it would greatly simplify trial administration, especially since these trials will be testing many drugs. (4) How Many Patients? Statisticians are still working out the details, but preliminary discussions suggested that trial size might be about 30 to 50 patients for each drug being tested. (5) Efficiency: Rapid Screening Trial and Master Protocol This system would not need to be limited to comparing any particular group of drugs. New drugs could be added at any time, provided there were enough volunteers. Drugs would be finishing at different times, as their respective study arms were filled and the volunteers completed the two- or three-month test. Administration could be greatly streamlined by use of a master protocol -- a concept which has been used in cancer research. The protocol for the trial is developed in advance, even before all the drugs to be tested are known. With each new study arm, only the drug and method of administration must change. Everything else -- entry criteria, blood work, data collection forms, data analysis, etc. -- stays the same. Of course each new drug would have to be approved by the FDA, and by all IRBs (institutional review boards) involved. But it's much easier and faster to approve just one drug, under the master protocol, than an entire study design. Another advantage of using a master protocol is that all the different drugs can be compared, because entry criteria, measurements made, etc. are the same. Because the epidemic changes over time, exact comparisons can only be made between two or more treatments when patients have been randomized among them at the same time. But even when some drugs become available later and are tested months or even a year or more after others, comparisons between them will be much better than comparisons between drugs tested in different, unrelated studies. To a large extent, each new drug tested could be compared with all previous ones in the same master protocol. Overall Picture This drug-screening system would be testing several different drugs at any one time. Any volunteer who met the entry criteria would be randomized to one of the currently available drugs, and take it for a short time, probably about 12 weeks. About 30 to 50 patients would be given each drug. Improved T-helper count would be the primary measure of efficacy, although other data would of course be collected and analyzed. The drugs would be compared to pick those few which stood out from the others. These would quickly go into larger, more conventional trials designed for fast-track drug approval. They might also be made available for early access, through a system like parallel track. Interviews with the Developers We attended the July 10 meeting, but this article is based mainly on phone interviews with some of the people who have developed the screening-trial concept. There are different versions of the idea, however, and to simplify this presentation we combined them into the unified picture above. So far only one article has been published on this rapid- trial idea -- "New Screening Proposal Could Speed AIDS Drug Trials," by Sari Staver, American Medical News (published by the American Medical Association), August 10, 1990. Ms. Staver interviewed Daniel Hoth, M. D., director of the AIDS program at the National Institute of Allergy and Infectious Diseases, and Ellen Cooper, M. D., from the FDA, who was at the meeting. Both endorsed the idea. Dr. Hoth said it might be implemented in 12 to 18 months. We spoke with Susan Ellenberg, Ph.D., Chief of the Biostatistics Research Branch of the Division of AIDS at NIAID. She is one of the organizers of the Statistical Working Group, and clarified several points about the rapid screening trial idea: * It is still in the discussion phase, primarily among statisticians. Physicians and pharmaceutical companies still need to be convinced of its value. * Testing four or five drugs at at time, in a short trial looking at virological or immunological markers for a preliminary screen, seems "a very sensible idea; clearly many people were interested." While some concerns were raised at the meeting, the general consensus was positive; no one said the idea could not work. * The main concern is that some drugs may be valuable but not show benefits early. Pharmaceutical companies may be afraid that their products could be rejected too early. But any drug showing potential would be followed up; the screening trials are to help set priorities, not to kill drugs which have other evidence in their favor. Another key person in the development of this rapid screening proposal is David Schoenfeld, Ph.D., a statistician at Harvard Medical School and Harvard School of Public Health, who has worked with a similar system in cancer research for several years. The cancer trials tested many drugs for melanoma, brain tumors, and other cancers. They used tumor size as the outcome measure, but Dr. Schoenfeld thinks that the T-helper count may be a more useful measure, potentially making the rapid screening trials even more successful in AIDS than they have been in cancer. We asked Dr. Schoenfeld about the contributions of AIDS activists in the development of the screening-trials concept. He said that the activists had been "very important and helpful in the AIDS Clinical Trials Group. They have been in a sense the initiative" for ideas like the screening trials. And they bring to the statisticians knowledge of what patients are thinking, what their concerns are. Usually the statisticians who design trials do not have contact with patients; and yet if trials are not acceptable to potential volunteers, they will not be able to recruit, and cannot be run. The activists "keep things moving in the ACTG, reminding us this is a crisis. They are very knowledgeable about clinical trials, and have good ideas." Dr. Schoenfeld explained that a key advantage of the rapid screening trials is to speed the development of really new therapies -- that now there is no good vehicle for quickly testing them. Another member of the Statistical Working Group saw in the rapid screening trials a rapprochement between the short-term needs of patients and the long-term needs of research. "They are short enough to ask questions without putting people in a bad situation. For example, in a 12-week trial patients could risk a sub-active dose. Trials using means such as response- surface methodology could show optimum doses for combination therapies." She noted that the United States is not doing well at this time in trial design, and that the "pre-trial trial" of the screening system will help us minimize the consequences. (Note: response-surface methodology, a technique developed in chemical engineering, is a way of designing studies to find the best doses of two drugs used in combination.) Memos written by Bob Huff of the Treatment and Data Committee of ACT UP/New York, and other activists in the Statistical Working Group list some advantages and problems of the concept. "A screening trial could identify early activity in a high-quality study before phase II trials begin." It would "provide information to support prioritization decisions for phase II trials," "give the earlier definition of a drug's efficacy profile," and "provide much useful information to phase II trial designers." The system would also allow combination therapies to be tested as easily as single drugs. The single study would cost less than multiple small trials. The trials could easily find volunteers, both because of the short time commitment required, and because it would be easier to publicize one trial than many separate ones. Limitations and problems include lack of long-term data, the possibility that entry and safety criteria unique to one drug might have to be applied to others to allow randomization, and the fact that "the trial only identifies 'winners' according to the criteria of the 'AZT model,' i.e., early T-cell count increases," meaning that a better drug that takes longer to be effective might be missed. There is also the question of whether drug companies will be willing "to go head to head with competitive drugs" and support the program. Another issue (not mentioned in the above document) is whether there are enough promising new drugs that a screening system is even needed. Today some researchers are even saying that they do not know what drugs to test. There are many scientifically promising compounds; the problem is the great bottleneck in getting them through (or even into) the pre- clinical development required for the all-important IND (Investigational New Drug approval, the FDA's permission to test the drug in humans) and then through the early phase I human test. The new proposal for screening trials will not solve this problem, which must be handled separately (for example, by improving incentives for pharmaceutical companies by facilitating earlier marketing approval for critically important drugs). Screening trials cannot overcome all the bottlenecks in medical research, but they do address one of the major points of delay. What Happens Next? Dr. Schoenfeld is now developing technical details of the proposal, and is preparing a paper for presentation to the next ACTG meeting in November. Notes from the July 10 meeting will also be available. Activists are circulating concept sheets among members of the Statistical Working Group for their comments. Community-based research organizations and others should work with the rapid screening trial proposal; with more support, it may not take the predicted year or two to implement. Also, research groups which are too small to run the full system and test many drugs at once might still be able to borrow parts of it -- for example, by testing one particularly important treatment against a no-treatment arm, using the same study design which the full screening proposal will use. Few people have known about the concept until now; we hope this article helps get the word out. To contact the Statistical Working Group, which is developing the proposal, call Bob Huff, ACT UP/New York, 212/674-8381. ***** FEDERAL PANEL SEEKS DRUG-APPROVAL REFORMS by John S. James Two years ago, then Vice-President George Bush asked the President's Cancer Panel to study the Federal role in new-drug development and approval of treatments for cancer and AIDS, and to suggest changes to speed research, improve patient access to new therapies, and facilitate their transfer to standard medical practice. The President's Cancer Panel appointed the National Committee to Review Current Procedures for Approval of Drugs for Cancer and AIDS -- usually called the Lasagna Committee, after its chair, Louis Lasagna, M. D. The Lasagna Committee held ten hearings between January 1989 and April 1990; on August 15 it issued its final report, a 25-page document with 20 recommendations for improving the drug- approval process. Recommendations include: * Adopting "a national policy...to foster the development of new drugs for AIDS and cancer." A permanent oversight committee, appointed by and reporting to the Secretary of Health and Human Services, would monitor the needs and performance of the FDA in drug regulation. (Note: the importance of this recommendation is that today there is no such national policy, and no one responsible when the system as a whole is not working. Each office just does its own job, even when it is clear that disaster will result.) * Severe staff and equipment shortage at the FDA can be addressed not only by providing more resources, but also by allowing institutional review boards, and outside contractors approved by the FDA, to do some of the reviews now done by staff. The Committee recommended that phase I trials could optionally be approved by a qualified institutional review board (IRB) instead of by the FDA. Also, pharmaceutical companies could optionally pay the FDA to rapidly review an NDA (marketing) application by contracting the work to outside experts. These changes are necessary because "Congress has placed many new responsibilities on the FDA in the last decade, while the number of employees in the agency has decreased... In the short term no quick solution is apparent to these inadequate resources." * FDA advisory committees should have a much larger role, with their own staffs, and responsibility for their own agendas. * Medicare, Medicaid, and private insurance should pay for experimental drugs and unlabeled uses of approved drugs, and all associated medical care, "if the use has been approved by expert government agencies, in authoritative medical compendia, or by a committee established by the Secretary of Health and Human Services." Coverage should be the same under Medicare, Medicaid, and all private insurance, and should not vary between geographic areas. Individual insurance companies "should have no discretion with respect to such matters." * Earlier marketing approval for AIDS and cancer drugs should occur as soon as there is credible evidence of efficacy, with other research being completed after approval. The Committee noted that the large phase III trials, which commonly take years, have little practical impact on approval, since 90 percent of drugs which pass phase II also pass phase III. In addition, "It is only after initial NDA approval of the drug as a single entity that its full potential is realized, because physicians are then free to use it in combination with other drugs in accordance with their best clinical judgment. While still under investigation, such combination uses occur only infrequently and with little opportunity for full clinical exploration. For all of these reasons, large phase III studies have been, and should continue to be, conducted in the post- approval setting." * Other recommendations include support for community-based trials, for parallel track if it does not delay trials, and for the FDA's responsiveness to patient advocacy groups. It urged improved relationships between FDA and pharmaceutical- company personnel, with more open communication. To obtain a copy of the report, contact the Committee's executive secretary: Dr. Elliott H. Stonehill, National Cancer Institute, Bethesda, MD 20892, 301/496-1148. ***** AZT AND LYMPHOMA by John S. James Non-Hodgkin's lymphoma, a cancer of certain blood cells, has been associated with AIDS since early in the epidemic; published reports go back to 1982, and one article reported 90 cases, in 19841. More recently physicians have seen a major increase in the number of patients with AIDS and lymphoma (which has also increased in the general population, for unknown reasons). There is concern that as treatment for pneumocystis and other opportunistic infections improves, non- Hodgkin's lymphoma could become one of the major opportunistic diseases. Most physicians suspect that the main cause of the increase in AIDS-related lymphoma is that patients are living longer today, and therefore there is more time for the disease to develop. But there are also suspicions that AZT might be contributing to the increase. In the August 15 issue of the Annals of Internal Medicine, researchers from the U. S. National Cancer Institute, and other branches of the National Institutes of Health, published a report on AZT therapy and incidence of non-Hodgkin's lymphoma2. While the figures on lymphoma are indeed alarming, we believe that a close look at the paper shows less reason to worry about AZT than first impressions might suggest. Results To obtain long-term data on AZT, the researchers analyzed all patient records from three early trials of the drug at the National Cancer Institute; the patients are among the first to use AZT. A total of 55 patients were included. Eight of them (14.5 percent) had developed a high-grade non-Hodgkin's B-cell (or in one case, null-cell) lymphoma, after a median of two years of AZT treatment. However, statistical projections were that 28.6 percent (of patients equally ill to begin with) would develop lymphoma by 30 months of AZT treatment, and 46.4 percent by three years. These figures do not apply to people who start AZT earlier, and at lower doses, today. Clearly these results imply that lymphoma will become an increasingly serious problem. But in evaluating the risk of lymphoma, and especially the question of whether AZT has any role in causing it, other facts also presented in the paper must be considered: * These eight patients had advanced illness before they began treatment with AZT. All had AIDS or symptomatic HIV infection, and their median T-helper count when they started treatment was 26 (range 8-135). Their median T-helper count when they developed lymphoma was six. All eight had less than 50 T- helper cells for at least five months (median time 15.3 months with a count under 50) before they developed lymphoma. The median T-helper count for all 55 patients when they started treatment was 74 (range 0-973), compared to the median of 26 for the eight who developed lymphoma -- suggesting that those with higher T-helper counts did not develop lymphoma, although they also were taking AZT. * These results must be considered in view of the fact that even before AIDS, and certainly before the use of AZT, it was well known that immune suppression due to other causes increased the risk of lymphoma. As of 1987, over 200 cases of non- Hodgkin's lymphoma were known among persons with hereditary immune deficiencies. In addition, patients using immune suppressing drugs to control rejection after organ transplants have a high incidence of cancers, and 36 percent of those cancers were found to be non-Hodgkin's lymphomas. Immune suppression is known to cause lymphomas, without AIDS or AZT being involved. * The lymphomas found in this study were the same kind as those generally found in AIDS, whether or not patients are taking AZT. This suggests that immune deficiency, not AZT, is more likely the cause of the lymphoma. * If AZT did contribute to causing lymphoma, large doses would probably be more dangerous than smaller ones. All the patients in this study started AZT early, when the recommended dose was 1200 mg per day. Today most patients are using half that much or less. At this time there seems to be a consensus among most physicians and scientists that while AZT cannot be ruled out as a cause of lymphoma, it is much more likely that the increase in this cancer is because patients with serious immune deficiency are living longer. The possibility that AZT could help cause the disease must be investigated. But meanwhile, experts are not recommending changes in treatment as a result of this study, and we have not heard of any physicians changing their practices because of it. Note: for an overview of treatments for lymphoma, see "Lymphoma Treatments Update," below. References 1. Ziegler JL, Beckstead JA, Volberding PA, and others. Non- Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome. New England Journal of Medicine. 1984; volume 311, pages 567-570. 2. Pluda JM, Yarchoan R, Jaffe ES, and others. Development of non-Hodgkin's lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Annals of Internal Medicine. August 15, 1990; volume 113, number 4, pages 276-282. ***** LYMPHOMA TREATMENTS UPDATE by Denny Smith Options for treating lymphoma have not increased much in number but have, like other AIDS-related therapies, grown in refinement. For background information on lymphoma, see AIDS TREATMENT NEWS #93, December 15, 1989. Radiation and Chemotherapy Radiation was one standard approach to lymphoma discussed at the Sixth International Conference on AIDS in June. A three- year chart review of 25 cases of non-Hodgkin's lymphoma of the central nervous system was described by researchers from New York's Montefiore Medical Center/Albert Einstein College of Medicine1. All patients received total cranial irradiation; few side effects were noted and twelve patients showed symptom improvement. Subsequently, opportunistic infections claimed more lives than the lymphomas. Clinicians at the same institutions presented another chart review of 20 patients discussing various aspects of chemotherapy for lymphoma2. Although radiation or chemotherapy are often the most appropriate treatment choice and can achieve a complete tumor response in many people, they have a tendency to further impair the immune system by damaging the bone marrow's capacity to generate new blood cells. The authors of this abstract elaborated on the danger, suggesting that bone marrow toxicity from more than two cycles of chemotherapy may increase the chance of developing an opportunistic infection. The authors also note that the risk for lymphomas appearing in the central nervous system, which is largely impervious to intravenous chemotherapy, warrants a chemotherapy prophylaxis, which is administered intrathecally (injected into the cerebrospinal fluid), to people under treatment for AIDS- related lymphoma. We spoke to Lawrence Kaplan, M. D., and James Kahn, M. D., who supervise the lymphoma protocols at San Francisco General Hospital, and who discussed with us the current results from several lymphoma studies there. Dr. Kahn described good responses from a chemotherapy regimen treating Hodgkin's disease: tumor regression, and little toxicity, was obtained from a combination of four chemotherapeutic agents -- bleomycin, vincristine, streptozocin, and etoposide. Hodgkin's disease is much less common among AIDS-related cancers, however, than non-Hodgkin's lymphoma. Another study at San Francisco General involved a new drug called chlorodeoxyadenosine (CDA), which was given to nine people who had failed standard chemotherapy for non- Hodgkin's lymphoma. Two partial responses were obtained from this agent; Dr. Kaplan surmised that CDA could be more useful in combination with other drugs. Controlling Toxicity: GM-CSF Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) is perhaps the best-known of many human growth factors now under investigation. GM-CSF is already widely considered to be useful for controlling the bone-marrow toxicity of such treatments as AZT, ganciclovir, and interferon. A trial at San Francisco General comparing lymphoma chemotherapy regimens with and without GM-CSF found that neutropenia, a common side-effect of chemotherapy, was reduced for those participants receiving GM- CSF3. This abstract reported an initial drop in p24 antigen levels for both groups in the study, probably because of cell killing by the chemotherapy drugs. We interviewed Dr. Kaplan, who gave us later information not included in the abstract. The group receiving GM-CSF required fewer hospitalizations, due to the reduction in neutropenia. However, after falling in both groups, the p24 level later rose above baseline in the group receiving GM-CSF with chemotherapy, but not in the group treated with chemotherapy alone. Neither group was receiving AZT or other anti-HIV drugs. Dr. Kaplan cautioned that this is a laboratory observation, not a finding in a clinical care setting. Other Approaches San Francisco General was also the site of a trial examining anti- idiotype antibody therapy, a relatively new technique to enhance a natural anti-tumor mechanism of the immune system. Dr. Kaplan said that because of the difficulty identifying tumors with shared idiotypes, this approach was largely unsuccessful. Other "immune-based" therapies are likely to be developed in the future for treating lymphoma. But for now, the practical question is whether chemotherapy is more effective and less toxic when given in low doses, or in large doses with GM-CSF used to control side-effects. An important consideration during treatment for lymphoma, as with treatment for opportunistic infections, is the continuation of some anti-HIV therapy. But the combined toxicities of chemotherapeutic drugs and AZT or ddI can make this goal difficult to maintain. Dr. Kaplan suggests designing a treatment combination which avoids parallel toxicities, such as from vincristine and ddI. References 1. Goldstein J, Dickson D, Valentine E, Davis L. Radiation therapy of the central nervous system in AIDS related non- Hodgkin's Lymphoma. Sixth International Conference on AIDS, June 1990, abstract #2102. 2. Sparano J, Goldstein J, Gucalp R, Davis L, Wiernik P. Patterns of failure and toxicity of chemotherapy in AIDS related non- Hodgkin's Lymphoma. Sixth International Conference on AIDS, June 1990, abstract #2092. 3. Kaplan L, Kahn J, Crowe S, Volberding P, Grossberg H, McManus N, Mills J. A randomized trials of chemotherapy with or without recombinant granulocyte monocyte colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. Sixth International Conference on AIDS, June 1990, abstract #S. B. 510. ***** FOSCARNET EXPANDED ACCESS ANNOUNCEMENT by Michelle Roland Astra Pharmaceuticals, the manufacturers of the anti-viral drug foscarnet (Foscavir), has instituted an "expanded access" program for specified patients with acyclovir resistant herpes and CMV infections including retinitis, colitis, hepatitis, encephalitis, and pneumonia. Physicians of patients who meet the criteria described in this announcement should call 1-800- 388- 4148 to discuss enrolling individual patients in this program. Astra requests that physicians have the patient's chart with them when they make the call. Astra's expanded access program is basically an individual compassionate use protocol which requires that each patient's request for the drug be approved by both Astra and the FDA. According to Astra spokesperson Pat Williams, the application process should take one to three days to complete, at which time the drug will be Federal Expressed to the physician. It does require the physician's willingness to order lab tests, monitor the patient clinically, and complete necessary initial and on- going paperwork. It also requires three days of hospitalization to monitor allergic or other adverse reactions. Like Bristol-Meyers' ddI expanded access program, Astra's program requires that patients requesting foscarnet not be eligible for any clinical trial with the drug, whether that trial is sponsored by Astra, the government ACTG (AIDS Clinical Trial Group) program, or any other sponsor. Patients and physicians should call 1-800-TRIALSA to determine if there are clinical trials for which the patient would be eligible within a reasonable geographical area. Eligibility Criteria for People with CMV Three categories of patients with CMV retinitis may qualify for foscarnet through expanded access: 1) Patients who have been diagnosed with CMV retinitis who are ineligible for ganciclovir (also known as DHPG) therapy because of current and on-going myelosuppression (neutrophil count <500 cells/ml or platelet count <50,000/ml) or hypersensitivity to ganciclovir. Note that Ms. Williams indicated that there would be some flexibility in the required neutrophil count if the physician felt that failure could be documented with more than 500 cells/ml (up to 750 cells/ml) and that continued treatment with ganciclovir would be dangerous to the patient. 2) Patients on ganciclovir who are experiencing ganciclovir toxicity (neutrophil count <500 cells/ml or platelet count <50,000/ml or other dose limiting toxicities considered on an individual basis) during either the induction or maintenance phase of treatment. Again, there will be some flexibility with the neutrophil count as described above. 3) Patients on ganciclovir therapy who are experiencing progression of their retinitis during induction or the first two weeks of maintenance therapy. Astra will require re-induction with ganciclovir in patients who are failing maintenance more than two weeks after their last induction phase. Ms. Williams stated that they want to ensure that ganciclovir failure has occurred before providing foscarnet to this group of patients. Studies for which patients with CMV retinitis may be eligible include an Astra sponsored study in Houston for ganciclovir failure. All other studies with foscarnet at this time are comparative studies using ganciclovir in some patients and so should not interfere with eligibility for expanded access. (For more information call 1-800-TRIALSA about ACTG 129, and about a Phase I study at the National Eye Institute using laser therapy and ddI with foscarnet or ganciclovir.) Patients with other manifestations of CMV infection, including colitis, pneumonia, hepatitis and encephalitis, who are not responding to or cannot tolerate ganciclovir may also qualify for this program. Ms. Williams encouraged the doctors of such patients to call Astra. Eligibility Criteria for Acyclovir Resistant Herpes Patients must have experienced no improvement in their herpes lesions after at least ten days of intravenous acyclovir therapy at a dose of 10 mg/kg every eight hours. Alternatively, acyclovir resistance can be demonstrated by an in vitro resistance test. Patients must not be eligible for (or able to get to) Astra's studies in Los Angeles or Houston on acyclovir resistant herpes. Additional Requirements for Women All women must have a negative pregnancy test and agree to use contraception during treatment and for three months following treatment. The supply of foscarnet will be stopped if a female patient becomes pregnant. When asked about evidence of teratogenicity (harm to the fetus) with foscarnet, Ms. Williams stated that there is no evidence of danger in animal studies but that no human data exist about effects on the fetus. Note that this is the usual process in the U. S. with respect to testing drugs in women; i.e., the drug gets approved with either very little or no experience in women and the specific effects on women and fetuses are discovered in post marketing studies or during clinical experience. Physician Responsibility The physician must be willing to complete a case report form and regulatory paperwork. Ms. Williams estimated that the total time required for paperwork would be about 1 hour in the first week and 20 minutes weekly for the duration of the treatment. The physician must have hospital privileges; hospital review board approval is also required. The people at Astra are concerned about physicians lying about kidney problems in their patients in order to get them foscarnet since foscarnet's major side effect is on renal function. Ms. Williams suggested that if a physician is found to be lying about significant clinical or lab history, future applications by that physician may be denied. Costs The drug is supplied at no cost and any "special studies" required by Astra will be paid for by them. However, the first three days of treatment must be administered in the hospital in order to monitor acute toxic or allergic reactions. All hospital associated costs must be paid for by insurance or the patient. In addition, routine lab work, also required by Astra, must be paid for by the insurance company or the patient. During the induction phase of treatment, this lab work is required approximately three times per week. It is required approximately every two weeks during maintenance therapy. In the case of CMV retinitis, routine monitoring includes eye exams. Photography is not required, but is requested by Astra for both retinitis and herpes. Note ACT UP/Boston (617/492-2887) and AIDS activists elsewhere have worked for 18 months to make compassionate access to foscarnet available. This drug was first proposed as an AIDS treatment many years ago. It has suffered a long and tortuous history on its way to acceptance. ***** STATEMENT OF PURPOSE AIDS TREATMENT NEWS reports on experimental and complementary treatments, especially those available now. It collects information from medical journals, and from interviews with scientists, physicians, and other health practitioners, and persons with AIDS or ARC. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS TREATMENT NEWS does not recommend particular therapies, but seeks to increase the options available. We also examine the ethical and public-policy issues around AIDS treatment research and treatment access. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display