---------------------------------------- Subject: AIDS Treatment News #145 Date: Feb 21 1992 (641 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 #145, February 21, 1992 phone 800/TREAT-1-2, or 415/255-0588 Contents: [items are separated by "*****" for this display] ddC: Buyers' Clubs Discontinue Sales After Potency Variations Found ddC Background AZT: Doubts on New Survival Paper Cancer Funding: Breast Cancer Action Seeks AIDS Activists' Help Announcements: FLT: New York Trial of Antiviral Pentoxifylline: AmFAR Supports CRIA Trial in New York Early Intervention Guidelines: Public Testimony Sought ***** ddC: Buyers' Clubs Discontinue Sales After Potency Variations Found by John S. James On January 24, 1992, the U. S. Food and Drug Administration visited three buyers' clubs -- PWA Health Group in New York, Healing Alternatives Foundation in San Francisco, and PWA Fight for Life in Fort Lauderdale, Florida -- and took samples of ddC for analysis, after unconfirmed reports of variations in dosage between capsules. On February 5 the FDA notified the New York and San Francisco clubs that significant variations in potency had been found, in lots number 119153 (New York) and 119153 and 1291125 (San Francisco). An independent test run by the distributor also found unacceptable potency variations. Both clubs stopped selling the ddC, sent their customers warning letters as the FDA had suggested, and offered refunds. The ddC in Fort Lauderdale, supplied by a different distributor in the form of tablets, not capsules, had much less variation. PWA Fight for Life (PWA Health Alliance) has only limited supplies of this product, but is still making it available. Among persons with HIV, the greatest fear by far has been that the treatment may become unavailable. There is also a demand that better quality-assurance testing be in place in the future, with test results made available to clients. The FDA asked buyers' clubs to "strongly encourage your customers who wish to take ddC to explore the options for obtaining legally produced ddC through the existing expanded access program or on-going controlled clinical trials." However, these options have not been available in the recent past; the expanded access program referred to, for example, has not allowed ddC to be combined with AZT, although almost all the current interest in ddC is in its use as part of this combination, not in single therapy with ddC alone. And of the two clinical trials testing the ddC plus AZT combination in comparison with other treatments, one (ACTG 155) is already full, and another (ACTG 175) is only beginning now. The FDA is working with the drug's developer, Hoffmann-La Roche, to liberalize the company's existing expanded access program to provide an alternative to buyers' club ddC to some of the patients who are not eligible to receive the drug in trials. We do not know how inclusive a program, if any, will be worked out. Future availability of combination treatment with ddC plus AZT is not guaranteed; the AIDS community may need to defend this treatment access in the future. ddC Quality-Control Problem: What Was Found? A recent letter from the PWA Health Group, the buyers' club in New York, to its clients summarized the test results on that group's ddC: "The results of FDA laboratory testing indicated that ddC obtained through the PWA Health Group varied in potency from 64-188 percent of declared value. That means that the capsules tested (they tested 10), which should have contained 0.25 mg of ddC, were found to contain between 0.16 and 0.47 mg of ddC. The average potency was found to be 129 percent of declared value, or approximately 0.32 mg." In San Francisco, of ten individual capsules tested from each of the two lots (20 capsules altogether), the FDA found no ddC in one capsule, and 2.3 times the stated amount in another; the other 18 varied between .25 and 1.28 times the stated amount. In Fort Lauderdale, the ddC was provided in 0.50 mg tablets (instead of 0.25 mg capsules); the tablets were made by a different manufacturer. These tablets were found to contain from 86-91 percent of their declared value. There is no evidence of any problem with the ddC itself, although FDA tests are continuing; the variation seems to have been in mixing it with an inert ingredient for filling the capsules. (In any case, the danger of impurities from the manufacture of the chemical would be less with ddC than with most other drugs, because ddC is used in very small doses; one gram is enough to treat an adult for well over a year.) The dosage problem appears to be new, apparently brought on by an attempt to improve the inert ingredient used as filler in the capsules (by using a hypoallergenic filler). Earlier tests on capsules from the same distributor, in December 1990, March 1991, and December 1991, showed much better product consistency. Where Do We Go from Here? The big fear in the AIDS community now is that ddC may be unavailable, with people unable to get the treatment which they and their physicians want, and which in many cases has worked well for them. The best way to prevent this from happening would be for the FDA to approve ddC -- and in the meantime for developer Hoffmann-La Roche to liberalize its current "expanded access" program to make ddC available to those who want to use it in combination with AZT. In addition, the buyers' clubs must tighten their quality assurance procedures. A simple requirement that a report of the results of quality-assurance testing be on file for every lot before that lot is sold -- with copies available for any customer who wants one -- would have prevented the current situation from happening. In some cases, the clubs should do their own quality control, independent of that of the distributor. Buyers' clubs from across the country were already developing such guidelines and standards, even before the ddC problem was suspected. Because of the strong emotions raised by the fear that ddC will be cut off, there have been suspicions that the timing of this issue was part of a plot, by pharmaceutical companies, the FDA, or others, to discredit and ultimately destroy the buyers' clubs. We have found no evidence, or even any reason to believe, that this is the case. Since thousands of people have been using the buyers' club ddC (some for well over a year), usually on the recommendation of their physician, the quality-assurance problem would have come to light on its own, without any conspiracy. This is because many physicians have naturally been concerned that the drug their patients were using was of good quality; during the last year physicians have tried to get samples analyzed, either by Hoffmann-La Roche or by the FDA. We do not know what tests were done. But once a problem was found, it would have been grossly improper to conceal it and not give a warning. So far at least it appears that the FDA, and Hoffmann- La Roche (if it has been involved at all), have acted properly. Among those close to the buyers' clubs, many believe that private conflicts among a few AIDS activists have complicated the handling of this situation, and also complicated other aspects of the relationship between the clubs and the FDA. These disputes would not have affected the quality-control problem itself, however, or the timing of its discovery. There is also a concern that the current, easily correctable ddC dosage problem may later be used, by the FDA and/or pharmaceutical companies, as an occasion to shut down access to treatments which should be available. The AIDS community may need to fight for ddC access in the future -- either for FDA approval as soon as possible (the best option), a liberalized expanded-access program (second best), and/or for reliable buyers' club access. If all of these channels are blocked, then the drug will be available in the least desirable way -- through a traditional black market, where money talks and the community has little control. Those with financial means and/or connections will continue to get treatment, but access could become difficult and burdensome for others. ***** ddC Background by John S. James ddC has become part of a de facto standard of care for thousands of people, before being officially approved for any human use. How did this situation come about? ddC (2',3'-dideoxycytidine), an experimental antiretroviral, is a nucleoside analog (in the same class of drug as AZT). ddC, which has been available from chemical supply houses for years (it is used in DNA experiments in laboratories) was one of the first drugs tried as an anti-HIV treatment. But nobody knew that the appropriate dose was very small -- a hundred times or more less than the dose of AZT or ddI. Therefore the first trials used doses which were far too large, which caused serious, crippling neuropathy. As a result, researchers largely lost interest in the drug for about two years. When it was learned that lower doses might be tolerable and effective, interest revived; there have now been over 20 human trials of ddC that are either finished or ongoing. The most scientifically definitive trial of ddC as a single- drug treatment for patients without prior AZT therapy recently ended in failure. The trial, known as ACTG 114, tested ddC alone vs. AZT alone in patients with AIDS or advanced ARC. This national study, with more than 600 volunteers, was stopped a year earlier than planned, by the study's Data Safety Monitoring Board, or DSMB (which periodically meets and secretly "unblinds" the trial, to see if the results are so extreme that it would be unethical to continue). The DSMB found that there were 59 deaths in the 320 patients assigned to ddC, compared to 33 deaths in the 315 assigned to AZT -- meaning that AZT clearly worked better when used as a single drug, at least at the doses being tested. (ddC might still be used for patients who cannot tolerate or no longer respond to AZT and have no other choice; trials to test this use are continuing.) Even before this result came out, almost all of the interest in buyers' club ddC concerned its use in combination with AZT, not its use as a single drug. ddC and AZT In Combination A small clinical trial of HIV treatment with a combination of AZT and ddC was finished in November 1990, but not formally published for over a year (TC Meng and others, Combination Therapy with Zidovudine and Dideoxycytidine in Patients with Advanced Human Immunodeficiency Virus Infection: A Phase I/II Study, Annals of Internal Medicine, January 1, 1992, pages 13-20; also see accompanying editorial by Anthony S. Fauci, M. D., pages 85-86). Project Inform and AIDS TREATMENT NEWS published the major results of this study in November 1990 (see "ddC/AZT Combination: Promising Early Results," AIDS TREATMENT NEWS #115, November 23, 1990). In June 1991 the results were presented at satellite seminars at the VII International Conference on AIDS in Florence. In any event, long before the scientific paper was published, the results of this study had established a de facto standard of care among many of the best-informed patients and physicians -- a standard which includes a drug not officially approved for any medical use. While exact figures are not available, low estimates are that several thousand patients -- most at the suggestion of their physicians -- are obtaining ddC at buyers' clubs to use in combination with AZT, which they obtain by prescription. But this major growth of combination anti-HIV therapy also took place largely outside of public view, as AIDS activists (including this newsletter) were concerned that too much attention could pressure the FDA to crack down, cutting off a lifeline on which thousands depended. Now the attention has come anyway -- even before the recent quality-control issue. Behind the delay in releasing the scientific results was an intense but quiet controversy in the AIDS research community. Our best understanding of this controversy (and we cannot claim objectivity) is that the study in question, officially called ACTG 106, with principal investigators Margaret Fischl, M. D., and Douglas Richman, M. D., was designed as a small trial (with 56 patients total) to test the safety of using various doses of ddC and AZT in combination. To everyone's surprise, not only did the combination seem safe, it also appeared to work much better than any other anti- HIV treatment known. All volunteers had AIDS or advanced ARC, with average T-cells counts under 100 at the start of treatment, but these averages went up with peak increases of at least 70 to 120 above the starting count, depending on dosage group. These T-cell rises lasted about twice as long as would have been expected with either drug alone, and over two thirds of the patients on the four appropriate combination doses had T-helper rises of at least 50 on two consecutive monthly measurements. Very few opportunistic infections occurred after the first five weeks of the study; several occurred in the first five weeks, presumably before the treatment had time to be fully effective. Before this study, the "conventional wisdom" had been that persons with T-cell counts below 100 would not recover even if the AIDS virus could be entirely stopped, because the immune system had been too badly damaged. This small trial showed how much could be done with improved antiviral treatments alone, even without any immune-based treatment to help repair damage which had already occurred. But this study was not designed or intended to test the efficacy of the combination treatment -- only to test its safety. The number of patients was small. The study was unblinded, and patients were not fully randomized in their assignment to treatment groups. New patients were added to the treatment groups to replace those who left, for various reasons, in the first eight weeks. The treatment groups were not always well balanced, with one dosage group having a median T-helper count as high as 103 at baseline, another a median as low as 35. (But the group which did best also started with a low median T-helper count, of 47.) And no patients received standard treatment for comparison; one group received AZT alone, but only 150 mg per day -- a dose which this study showed is too low. These issues would not make much difference for a preliminary safety trial, but they would have been avoided in a study designed to collect definitive efficacy information. ACTG 106 was intended as a preliminary study; if results were good, it would be followed by a much larger efficacy trial. (That larger study, called ACTG 155, is now under way. It includes over 1,000 volunteers randomly assigned to one of three groups: AZT alone, ddC alone, or the combination). What happened with ACTG 106 is that scientists and people with HIV drew different practical conclusions from it. Scientists who run clinical trials are interested in maintaining scientific standards, in doing studies correctly so that they get solid, trustworthy results. People with life-threatening illnesses, on the other hand, are interested in using whatever knowledge is available to make the best treatment decisions they can. What has been most persuasive to us about ACTG 106 is that it is hard to interpret the outcome other than as showing that the combination treatment of ddC with AZT works much better than any conventional treatment. Because of the small number of patients, it could be argued that the benefits seen might conceivably have been due to chance. But both the size and the consistency of the results makes this possibility unlikely. Why doesn't the FDA just approve ddC? (Over a year ago, a formal petition to the FDA by organizations representing almost all HIV physicians in San Francisco urged that the available data for ddC (and ddI, since approved) both be evaluated for possible approval; see "ddC/ddI Approval Update," AIDS TREATMENT NEWS, January 4, 1991.) The reason for reluctance is that the FDA would have to base approval largely on ACTG 106 -- but the Agency wants much more data than that before approving a drug. The FDA usually demands more than one study, larger studies, and studies designed in advance to test drug efficacy. Expanded Access to ddC It would be possible to have a regulatory system designed to approve drugs as soon as there was a rational case for physicians and patients to use them. Unfortunately, that is not the system we have. Often there is a compelling medical case for a drug long before the data available meets FDA standards for approval. To relieve the resulting harshness, a long series of early-access ideas (with names like "compassionate use," "treatment IND," "parallel track," and currently "expanded access") have been tried. All these programs have been seriously limited by the reluctance of pharmaceutical companies to pay for them. Ideas for more basic reforms have been tied up in partisan politics, with Democrats and Republicans each apparently willing and able to block plans acceptable to the other. But expanded access is the option (other than the buyers' clubs) which is available now to provide ddC for combination therapy pending marketing approval by the FDA, for patients who cannot enter a clinical trial. Negotiations are underway at this time to liberalize the Hoffmann-La Roche program which is already supplying ddC to over 8,000 patients, to allow those receiving ddC in this program to combine it with AZT. Even if combination treatment is allowed, there is still the issue of who will qualify. The data on combination use is for patients with T-helper counts under 200. But many patients with higher T-helper counts have been using the combination (with buyers' club ddC), since it is likely, although not yet proven, that the combination will be a more effective and lasting antiviral than AZT alone at any stage of infection. Some patients with T-helper counts between 200 and 500 will be able to obtain treatment by volunteering for ACTG 175, a major new study which will compare four different treatment regimens: AZT alone, ddI alone, combination treatment with ddI plus AZT, and combination treatment with ddC plus AZT. ACTG 175 is now or soon will be recruiting in the following cities: Boston; Buffalo; Chicago; Los Angeles; Miami; New York City; Rochester; San Diego; San Francisco; Seattle; St. Louis; Stanford; Syracuse; and Torrance, CA; there might also be a site in Hawaii. For more information about this trial, call the AIDS Clinical Trials Information Service, 800/TRIALS-A. Note: As we went to press, Hoffmann-La Roche announced that two new expanded-access programs would provide ddC for combination use: "In order to make HIVID [ddC] available in the most efficient way possible, a simplified open-label program will be implemented within the next two weeks. Rapid enrollment will be enhanced through the use of streamlined entry criteria and limited data collection. Symptomatic HIV infected individuals with CD4 counts [T-helper cell counts] of 300 or less or asymptomatic individuals with CD4 cell counts of 200 or less who cannot participate in controlled clinical trials will be eligible to receive HIVID for combination use.... Physicians should call the ddC Coordinating Center at 800/ddC-21-HIV (800/332-2144) between 9 a.m. and 8 p.m. (EST) for enrollment information. Like all Roche investigational drug programs, HIVID will be provided free of charge. "In the second program, to be designed with input from the AIDS community and the government, Roche will provide HIVID for combination therapy in healthier HIV infected individuals -- those with CD4 cell counts up to 500. This will be the first time that a so-called Large Simple Trial will be implemented in the study of an experimental AIDS drug. Roche will work with several community research consortia to initiate a trial that could potentially involve thousands of patients." ***** AZT: Doubts on New Survival Paper by John S. James A study by the U. S. Veterans Administration on early vs. late treatment with AZT, published February 13 in the NEW ENGLAND JOURNAL OF MEDICINE and widely reported in the press, compared starting AZT immediately for persons who have T-helper counts between 200 and 500 and who have AIDS-related symptoms, with waiting and starting AZT only when the patients fall below T- helper counts of 200 or develop AIDS. The results reported were that the early treatment greatly reduced progression to AIDS during the follow-up period of more than two years, but that it did not improve survival, which was about the same in both groups. In this study, when opportunistic infections did develop, they were apparently more severe in the early-treatment group, so that the advantage of slower progression to AIDS did not translate into the expected advantage in survival. We have not been able to fully investigate this study before going to press, but we are finding widespread concern among AIDS experts that the widely-reported results may not correctly apply to current treatment choices. For example, this study used a dose of 1500 mg of AZT per day -- three times the currently- accepted dose of 500 to 600 per day. Leukopenia (low white-cell blood counts) occurred in over three quarters of the patients receiving this regimen, and it appeared to be drug related, since it occurred more often in the early-treatment group. Severe leukopenia (white-cell count under 2,000, neutrophil count under 1,000) and anemia also occurred more often in the early-treatment group. These conditions, evidently caused or exacerbated by the excessive dose of AZT, could have affected survival from opportunistic infections and made the study results unrepresentative of current treatment options. There is widespread concern that misinterpretation of this study may cause people to miss early treatment for HIV infection when such treatment is appropriate for them. ***** Cancer Funding: Breast Cancer Action Seeks AIDS Activists' Help by John S. James Breast Cancer Action in San Francisco has asked for our help in supporting the National Institutes of Health Revitalization Amendments (commonly called the NIH Reauthorization Act), which has been passed by the U. S. House of Representatives and is now pending in the Senate. For breast cancer research, this bill would authorize an additional $55 million for basic scientific research, and $25 million for SPORE centers (Specialized Programs of Research Excellence). The same bill has many important provisions for AIDS research, and for women's health. It is controversial, with a White House veto threatened because of an amendment to overturn the current ban on Federal funding of fetal-tissue research (an issue which is tied up in the abortion controversy). We expect to cover the bill's AIDS-related provisions in a future article. Breast cancer research is grossly underfunded in view of the size of the epidemic (breast cancer and certain other cancers are increasingly rapidly, and no one knows why). Current funding is $132 million per year. Yet breast cancer will kill over 40,000 Americans in 1992; a projected 181,000 new cases will be diagnosed this year. One American woman in nine will have the disease in her lifetime. Coalition building with cancer and other disease groups is perhaps the most important direction the AIDS movement can take at this time. No one group has the influence to make the changes in healthcare and research priorities which are necessary. But by working together, we can establish the principle -- especially now, after the Cold War has ended -- that diseases which threaten Americans' lives and health are major national priorities, not to be subordinated to pork-barrel spending for influential constituencies. To support the NIH Reauthorization Act, call the Capitol at 202/224-3121, ask for one of your Senators, then ask to speak to the legislative aide in charge of health issues. To write, address your letter to The Honorable ____, United States Senate, Washington, DC 20510 (Dear Senator). Ask for a YES vote on this bill. Remind them that President Bush might veto the bill, so a two-thirds "yes" vote is critical. To get involved on a continuing basis with building healthcare and health-research coalitions, you might work through AIDS organizations; this coalition movement is only beginning, however. You could also contact Breast Cancer Action, P. O. Box 460185, San Francisco, CA 94146, 415/922-8279; they can refer you to breast-cancer advocacy organizations in your vicinity. ***** Announcements ** FLT : New Trial in New York, Baltimore, Chapel Hill A 16-week trial of FLT (fluorothymidine), an antiviral in the same class as AZT but which might have advantages as a therapy, is beginning at the Sloan-Kettering Memorial Cancer Center in New York City, Johns Hopkins University in Balitmore, and the University of North Carolina in Chapel Hill. Volunteers must have AIDS or ARC, a T-helper count under 300, and no history of AZT intolerance. The first human trial of FLT, in 14 volunteers, was completed in September 1991. FLT has similar bone-marrow toxicity as AZT, but it might have a larger range between therapeutic and toxic doses. It might also differ from AZT in viral resistance. Three different oral doses will be tested in the new study: 0.125, 0.063, and 0.031 mg/kg per day. Volunteers will be randomly assigned to one of these doses. Blood levels of FLT will be measured and doses adjusted accordingly. Antiviral activity will be measured by changes in T-helper count, free and immune complexed p24 antigen, and quantitative HIV cultures. All costs except transportation will be paid by Lederle Laboratories, the sponsor of this study. For more information or to volunteer for this trial, call Mark Dickmeyer, R. N., Infectious Disease Service, Memorial Sloan-Kettering Cancer Center, 212/639-8404; the Clinical Pharmacology Drug Development Unit at Johns Hopkins, 301/955- 3422; or Cherrie Robinson, R. N., University of North Carolina, 919/966-6712. Note: AIDS TREATMENT NEWS published a brief article on FLT over three years ago (issue #72, January 13, 1989); we listed the drug as one of the most important new treatments to watch in 1989. We also published a brief update in issue #119, January 18, 1991. ** Pentoxifylline: AmFAR Supports CRIA Trial in New York A pilot study at the Community Research Initiative on AIDS (CRIA) will test pentoxifylline (brand name Trental), a prescription drug usually used to treat a clotting disorder in the elderly, as a potential treatment for HIV infection. Volunteers must have a T-helper count under 300. They will be randomly assigned to receive either pentoxifylline or placebo for the 16-week trial. Volunteers will receive blood tests for TNF levels, and for alpha interferon levels. In early human studies, pentoxifylline reduced the level of tumor necrosis factor (TNF) in the blood, with apparent clinical benefit for persons with AIDS and with cancer. TNF levels are often abnormally high in people with AIDS. High TNF levels can cause wasting syndrome and anemia. In addition, in laboratory tests TNF has been shown to increase HIV replication. And two scientific teams have found anti-HIV activity of pentoxifylline in test-tube studies. Pentoxifylline is already in use as an HIV treatment by some physicians. The purpose of the CRIA study is to quickly provide safety and efficacy information to guide physicians in using this drug in AIDS treatment. The study is being supported by a $100,000 grant from the American Foundation for AIDS Research (AmFAR). The principal investigator is Joseph Sonnabend, M. D. For more information or to volunteer for this study, call CRIA at 212/889-1958. ** Early Intervention Guidelines: Public Testimony Sought by John S. James An expert panel sponsored by the Federal Government is developing guidelines for medical treatment of persons who are HIV positive but asymptomatic. Physicians, community representatives, and others who wish to comment on what these guidelines should be can either mail written comments before March 10 to the address below, or testify in person on March 10 at a public hearing in New York City. The panel, of 21 AIDS experts (physicians and other medical professionals, and community representatives) was set up by the Office of the Forum for Quality and Effectiveness in Health Care, which is part of the U. S. Agency for Health Care Policy and Research (AHCPR). It held its West Coast hearing in San Francisco on February 10, 1992, and will hold its East Coast hearing on Tuesday, March 10, 1992, from 8 a.m. to 12 noon and 1 p.m. to 5 p.m., at the St. Moritz on the Park Hotel, 50 Central Park South, New York. If you wish to speak at the meeting, you should register in advance at the address below. (At the San Francisco meeting, however, it was not necessary to register, as the event was not heavily publicized and few people showed up. This writer spoke, without having planned to do so, on the need for flexibility in early intervention standards, in view of the movement toward earlier treatment, and toward combination antiviral therapy.) Send written comments, or a letter stating your plan to testify at the March 10 meeting, to the panel's support contractor at the following address: Mikalix (M & C) Attn: Carol Delaney 950 Winter Street, Suite 2450 Waltham, MA 02154 Phone: 617/290-0090; fax: 617/290-0180. ***** ** Update: How to Order VIRAL QUANTITATION IN HIV INFECTION After our last issue went to press, we heard from the distributor in England (Faber and Faber Limited, misspelled in our review in issue #144) that they are out of stock of the book. At the same time, the publisher told us that people can order directly from them; the price is $44 plus $6 postage (we do not know if this is airmail, or if faster delivery is available). The address is: John Libbey Eurotext 6, rue Blanche 92120 Montrouge FRANCE Phone: 33.1.47.35.85.52; fax: 33.1.46.57.10.09. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display - - - - - - - - - - - - AIDS Info BBS, 001-415-626-1246 (free) 8-N-1 also visible by gopher at itsa.ucsf.edu (free) From: Ben Gardiner Return address: ben@maggadu.Queernet.ORG