Subject: Treatment Issues Vol. 4 No. 8 Date: Nov 30 1990 (315 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES Volume 4 Number 8 -- November 30, 1990 Contents: [items are separated by "*****" for this display] Imuthiol Steroids to Treat PCP Commentary Dermatoses in HIV Infection In Brief New Studies ***** Imuthiol Licensed in New Zealand Jim Brudner Mike Barr On October 5, 1990, in a move that took activists and scientists in North America by surprise, New Zealand became the first country to grant regulatory approval for Imuthiol, also known as sodium ditiocarb or DTC. Licensing for Imuthiol includes an oral and an intravenous formulation of the drug. Indication is for the treatment of HIV-infected individuals 18 years and older with T4 cell counts below 200 or for symptomatic individuals who cannot tolerate AZT regardless of their T4 level. While so far defying classification as either an antiviral or an immunomodulator, Imuthiol/DTC has shown promise as an AIDS therapeutic in a number of human and animal studies. The drug's major effect seems to be a reduction in the number of opportunistic infections (OI's) experienced by persons with HIV infection. In two small efficacy studies conducted in Germany and France and published in The Lancet, 76 HIV-positive asymptomatic persons who received Imuthiol did not progress to an AIDS-defining OI. Notably, 6 of 32 placebo patients in one study, and 4 of 41 in the other, did progress to AIDS (,). Investigators of the studies also noted stabilization or improvement in T4 cell counts for those on Imuthiol. Other benefits of the drug are improvement in constitutional symptoms like swollen lymph nodes, enlarged spleen, weight loss, and improvements in other immunological parameters. Earlier this year, the U. S. Food and Drug Administration denied an application by the drug's French manufacturer, Pasteur Merieux, for a Treatment-IND (Investigational New Drug), an early release status that would make the drug available in the U. S. to patients who meet certain medical criteria. However, the FDA regulators did not see the European data, but instead reviewed the results of a larger American Study ("USA 87") and disputed the results. French health authorities have also been dragging their feet, hoping, we are told, that the Americans would take the lead in getting the drug approved. Despite the existence of over a thousand scientific papers describing the drug's effects, DTC's mechanism of action is not well understood. Pasteur Merieux scientists believe that Imuthiol works either by protecting cells from oxidation, (in which case it should be considered an immunomodulator), or by bonding with metals necessary for, and thus interfering with, HIV-related processes (in which case it is an antiviral). It may even do both. In any case, Imuthiol is almost certainly safe. Long-term administration of Imuthiol (up to 74 months) so far has not caused any significant toxicity. Imuthiol/DTC, after being tried and discarded several years ago by the "underground," probably because it failed to produce T-cell increases, is now enjoying a new vogue. The PWA Health Group in New York City (212/532-0280), for example, has made Imuthiol/DTC available for approximately $30 a month, as have buyers' clubs in other cities, including San Francisco and Washington D. C. A month's supply is twenty 125 mg enteric-coated capsules, or capsules which allow the drug to bypass the stomach's digestive acids. However, all the buyers' groups have recently had trouble securing supplies of the drug, and at present all are completely out of stock. Buyers' groups expect to get new shipments in early December. Until the buyers' groups resolve their supply problems, persons wishing to use DTC have two options. One is to obtain the drug in its raw form from a chemical supply house and administer it rectally. A Project Inform (1-800-822-7422) fact sheet contains information on correct procedures. A second alternative is to obtain an anti-alcohol agent called Antabuse. Believed to break down into an imperfect form of DTC in the body, Antabuse is available with prescription from any pharmacist. The dosage recommendations in New Zealand call for weekly oral Imuthiol administration at 10 mg/kg of body weight. (The average adult weighs between 60 and 70 kg). A typical regimen would therefore be five 125 mg capsules on a full stomach once a week for a weekly total dose of 625 mg. No products containing alcohol should be consumed during the period 12 hours before administration and 48 hours afterwards. Consumption of alcohol before the drug is fully metabolized can cause nausea, vomiting, accelerated breathing, unusual sensations, blurry vision, vertigo and a host of other very unpleasant temporary side effects. Some people have even reported side effects when using cologne or mouthwash containing alcohol while taking Imuthiol. Imuthiol is not yet in the pharmacy in New Zealand, but will be, pending packaging and assurance of supply. However, the drug has been available from Rhone-Poulenc, Pasteur Merieux's New Zealand affiliate (011-64-4-67-86-29; add 18 hours) on a "free of charge" basis for the past nine months -- similar to an American expanded access program. Alan Anderson, a Rhone-Poulenc representative, said that six to ten patients have been receiving the drug in New Zealand under this program. He expressed surprise upon hearing that no similar accessibility program was in effect in the U. S., as it was his impression that both French and U. S. authorities were making provisions for people who might benefit from the drug. Since several studies now show that long-term use of Imuthiol as a dose of 10 mg/kg/week is safe and possibly efficacious, and since results from another U. S. study may take up to two years to be released, no reasonable argument exists for the denial of a Treatment-IND for Imuthiol in this country. And yet the FDA has seen fit to decide differently. How Much Will It Cost? Anderson expects that Imuthiol will become commercially available in New Zealand in late November or early December. As that time draws near, pricing information will be more readily available. Sources close to the company have offered conflicting visions of Merieux's pricing strategy. The drug itself is fairly inexpensive to make, but it has been in development for a long time and the company will no doubt attempt to recoup development costs. The future for Imuthiol approval in the U. S. may not be entirely bleak. As Treatment Issues went to press, Pasteur Merieux was reportedly on the verge of resolving its dispute with the FDA on the interpretation of the American study. While we have not been privy to these discussions, we can reasonably speculate that Pasteur Merieux and the FDA will agree that the study demonstrated a 30-40% reduction in opportunistic infections for patients receiving Imuthiol. The FDA then must determine this reduction to be "statistically significant," in order to ensure licensing and early access programs like a Treatment-IND. The National Institutes of Health's AIDS Clinical Drug Development Committee (ACDDC) gave Imuthiol a "high priority" rating earlier this year and is recommending further study on how the body metabolizes the drug. In conversations and correspondence with ACT UP/New York's Treatment and Data Committee, Pasteur Merieux hinted at promising additional research, including a comparison of persons taking Imuthiol with a similar untreated group whose preliminary results look "favorable," and a possible new trial in the U. S. More will be known about this trial after Merieux and the FDA finalize their understanding of the U. S. study. The company has agreed to allow activists an opportunity to participate in the development of protocols for new studies. On a final note: Treatment Issues heard a rumor in September that Pasteur Merieux planned to withdraw Imuthiol from persons receiving the drug as a result of participation in clinical trials. In a letter to one of the authors of this article, Dr. Jean Caraus, the Medical Director of Pasteur Merieux's Immunology Division, emphatically denied this rumor. ***** Steroids for Pneumocystis Carinii Pneumonia Gabriel Torres, M. D. Corticosteroids are hormones with strong anti-inflammatory and immunosuppressive properties that are used in many medical conditions such as asthma and arthritis. Steroid use in the treatment of pneumocystis carinii pneumonia (PCP) has been controversial because steroids can further immunodeficiency associated with HIV infection and allow new opportunistic infections and malignancies to emerge. The mechanism of action of corticosteroids in PCP is unclear, but is thought to dampen the immune response and keep extra white blood cells and fluid out of the airsacs in the lungs, making it easier for patients to breath (). Since 10% of PCP episodes are still fatal, steroid use has been suggested as a mechanism for salvaging patients in danger of respiratory failure. Who should receive steroids and when are questions that clinical trials in both the U. S. and Europe have tried to answer. One retrospective study of 20 patients receiving steroids for salvage therapy had shown reversal of respiratory failure in 14 patients and recurrence of respiratory failure when steroids were withdrawn (). Five major studies comparing steroids to placebo as adjunctive therapy were analyzed by a consensus panel convened in May 1990 by the National Institutes of Allergy and Infectious Diseases (NIAID) and the University of San Diego, California. The first study by Montaner et al. from Vancouver, Canada was published in the Annals of Internal Medicine in July 1990 (). In this study 38 patients with mild PCP were randomly assigned to conventional therapy plus placebo or steroids (prednisone 60 mg/day for 7 days followed by a 14-day tapering off). Eight of 19 placebo patients exhibited early deterioration, compared to only 1 of 18 patients treated with steroids. A much larger study conducted by the California Collaborative Treatment group compared steroids to placebo in 25 patients with mild, moderate, or severe PCP (). In the group with moderate or severe disease, steroids reduced deterioration in respiratory function, need for mechanical ventilation (respirator) and death by about 50% within the first 36 hours of treatment. Two other studies, one from the University of Miami and a European study, also showed a statistically significant survival advantage (fewer deaths) in groups of patients receiving steroids compared to placebo. A fifth study by Clement et al. from San Francisco did not show a survival advantage, but steroids were added much later in the course of therapy. Six serious infections occurred in the steroid group compared to none in the placebo group. Yet none of these infections were life-threatening. The final analysis of the consensus panel was in favor of using steroids early in the therapy of PCP (within 36 hours) for those with moderate to severe PCP and blood oxygen concentration of 70 mm Hg or less. The dosage regimen recommended is oral prednisone (40 mg twice daily) for the first five days, followed by a two-to-three week tapering off period (). The complications to be aware of include resurgence of oral thrush, herpes simplex infections, herpes zoster and in some cases elevations in blood sugar, high blood pressure and gastrointestinal ulcerations. In conclusion, corticosteroids appear to be beneficial, if used early in the course of moderate to severe PCP, and should be used routinely. In patients with milder disease, steroids are presently not recommended, and require further study. For a discussion of the controversial aspects surrounding release of this information, see the following article. ***** Withholding Medical Findings: Who's to Blame? Kevin Armington How long should it take for important medical findings to be reported? This question has generated controversy within the medical community for many years. It recently became the subject of public debate when The New York Times charged that The New England Journal of Medicine (NEJM) withheld a report for five months about the benefits of adding steroids to standard therapy for PCP. Long publication delays are common in medical literature, but this particular story is not a strong example of what is wrong with the system. The issue as framed by the Times is not as simple as it seems. After a medical journal receives a paper for publication, a certain amount of time is necessary to evaluate the study and to verify the conclusions. To do this, journals have established a practice known as the "peer review" system. In this system, the results of a group of researchers are held up to the scrutiny of peers before publication. The intent is to catch errors in trial design, statistical analysis or interpretation of the data. Researchers sometimes try to put the best "spin" on their results or try to avoid inconvenient questions that may put their findings in a less favorable light. Objective reviewers who have no stake in the paper are supposed to catch errors and ask difficult questions. The peer review system is not perfect, however, and it is still possible for bad papers to get through the system. How long should peer review take? According to Dr. Arnold Relman, editor of NEJM, "a few weeks" is sufficient time to shepherd a paper through the peer review system. If important revisions are necessary, it takes more time. Dr. Relman publicly stated at the Sixth International Conference on AIDS in San Francisco that the journal's policy is to speed most papers dealing with AIDS through the normal schedule. In addition, Dr. Relman asserted that the journal allows public disclosure of new medical information that has been critically reviewed by experts and is considered urgent for the public health. Therefore, in some instances, researchers are allowed to reveal their results to the press after peer review but before the paper is published in NEJM. Public disclosure might take the form of a press release mailed out by the National Institutes of Health (NIH). In the case of the steroids story, Dr. Relman stated that the two papers in question had been received by August 15, 1990. After the papers had been reviewed, a telephone call was placed to NIH on September 10 to grant permission for public disclosure of the results. In this case, peer review took a little over three weeks. It still took over two additional months to get the articles into print, but the information was no longer embargoed after September 10. Other groundbreaking papers have taken much longer to get through the system. The paper proving that aerosolized pentamidine can prevent PCP, for instance, was not published in NEJM until September 1990, more than one year after the results of the study were made public. Many community physicians had been using aerosolized pentamidine for two years when the article was published. If all physicians had waited until this fall to prescribe aerosolized pentamidine, how many more thousands would have died needlessly? Fortunately, the Centers for Disease Control (CDC) issued guidelines recommending prophylaxis for PCP, including aerosolized pentamidine, in June, 1989. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display