Subject: AIDS Treatment News #96 Date: Feb 11 1990 (545 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 # 96, February 2, 1990 CONTENTS: [items are separated by "*****" for this display] Fluconazole: Important Antifungal Approved AZT: FDA Committee Recommends Early Use Hypericin Results: Community Research Alliance Study CMV Update San Francisco, San Diego: Oral Ganciclovir Study Seeks Volunteers Sixth International Conference: Free Registration for Persons With AIDS or HIV, Mar. 15 AIDS TREATMENT NEWS Issues 1-75 Now Available in Book Form ***** FLUCONAZOLE: IMPORTANT ANTIFUNGAL APPROVED by John S. James On January 29, the U. S. Food and Drug Administration (FDA) approved fluconazole (brand name Diflucan), a major broad- spectrum antifungal especially important for treating cryptococcal meningitis. Fluconazole, which has long been approved in England, is about equally effective as amphotericin B, but has much less toxicity. Also, fluconazole can be taken by mouth, while amphotericin requires intravenous infusions, often every day in a hospital. Fluconazole should be available to pharmacies by late February. If local pharmacies cannot get it quickly, patients or physicians could check availability with a mail-order pharmacy such as American Preferred Plan, 800/227-1195 (in New York State the number is 800/445-4519). Until the drug is actually delivered, the PWA Health Group in New York will continue importing it from England, which takes about a week. We do not know the price, but fluconazole will be very expensive. If price is an obstacle, people should know that another drug itraconazole (brand name Sporanox) may be almost as good as fluconazole and is available in Mexico at a fraction of the fluconazole price (see AIDS TREATMENT NEWS #80, June 2, 1989). History and Comment Physicians familiar with fluconazole agree that it should have been approved long ago, probably well over a year ago. No one seems to know why it took so long for this drug to become widely available in the United States. AIDS TREATMENT NEWS published an in-depth article on fluconazole over two years ago ("Fluconazole: A Major Advance for Cryptococcal Meningitis and Other Systemic Fungal Infections? " issue #41, September 25, 1987). At that time the drug was already in widespread use in Europe, where over a thousand people had taken it, mostly for relatively minor infections. In addition, about 150 persons with AIDS had been treated with fluconazole for serious or life-threatening fungal infections. But few U. S. physicians knew about the drug at that time; one leading AIDS specialist told us he had heard about fluconazole but could not follow up because he did not know how to get more information about it. (AIDS TREATMENT NEWS had also given up on an earlier attempt to cover fluconazole, because we could not find information.) The fluconazole history illustrates once again how much U. S. medicine could improve if it could take advantage of important treatment successes in common use elsewhere in the world. In this age of rapid globalization of business and communication, why is medicine such a major exception to the trend? The answer is that the corporate/regulatory dynamic creates business, regulatory, professional, political, and media empires which are threatened by the free flow of medical practice into the United States from other countries. Medicine will be the last refuge of protectionism, to the great detriment of the health of the American people. Progress in solving this problem could make solid contributions to better quality, less costly health care. While fluconazole was unapproved in the United States, it was made available through studies and/or compassionate use in life-threatening emergencies for people who could not tolerate amphotericin and had no other alternative. We do not know how many fell through the cracks of this system. For example, although the drug was free, did grotesquely underfunded public clinics have the physician time to do the paperwork required? What happened when their clients needed the drug to save their lives? Of all drugs in history, fluconazole may be the most precisely targeted to matter least to those who in the United States matter most -- HIV negative white men. For aside from AIDS, the drug will be especially important to Blacks and members of some other races for treatment of valley fever (coccidioidomycosis), a disease much more serious for them than for whites. (Valley fever is endemic in certain geographical areas, including parts of the Southwestern United States, and the San Joaquin Valley in California.) And in Europe, fluconazole has been used primarily for treating women with vaginal candidiasis. We do not know whether this demographic profile of the drug allowed it to remain unavailable for so long. AIDS TREATMENT NEWS did not investigate these particular questions about fluconazole because of repeated rumors that approval was imminent. And after mailing our 1987 article to thousands of people, we thought that followup could be left to others. In retrospect, we made a mistake in not pursuing this drug aggressively. The shallow press coverage of this shameful chapter in U. S. medicine shows that history laundering is well advanced. ***** AZT: FDA COMMITTEE RECOMMENDS EARLY USE On January 30, an advisory committee of the FDA unanimously recommended that AZT be officially approved for treating persons with T-helper counts of 500 or less, even if they have few or no symptoms. Approval is not yet official, but the agency almost always follows such recommendations of its advisory committees. Physicians already can legally prescribe AZT for any patient, without specific FDA approval. But more physicians will prescribe it for early HIV infection when the drug's official "labeling" suggests that they do so. And when the new recommendation becomes official, it will be much easier than now to get insurance companies to pay for AZT for those patients. Hundreds of thousands of patients could be affected by the new recommendation -- but probably most of them do not know that they are HIV positive and will not be receiving medical care. In the past, the main arguments against early AZT use have been fear of side effects, and fear that the virus might become resistant to the drug. But now it is clear that side effects are much less of a problem if patients are healthier when they start AZT -- especially with the lower doses which are increasingly being used. There seems to be less concern about early use causing viral resistance, and more thinking that the drug might be even more effective at slowing the development of the disease if given early than if given late. Much is still unknown about long-term effects of AZT. The advisory panel decided that it was better to take the risks of using it earlier in HIV infection, than to take the risks of leaving the infection untreated. ***** HYPERICIN RESULTS: COMMUNITY RESEARCH ALLIANCE STUDY by John S. James Background Hypericin is an antiviral found in St. John's wort, a plant long used as a medicinal herb. AIDS researchers at New York University have studied hypericin's activity against HIV, and also against other retroviruses in animals (Lavie and others, 1989; Meruelo and others, 1988). Hypericin works in an entirely different way than AZT, and was better than AZT against the retroviral infections in animals. The researchers have now developed methods for synthesizing large amounts of hypericin; with luck they will begin early "phase I" human trials next summer. Meanwhile the Community Research Alliance, a San Francisco research organization started by San Francisco's PWA Coalition, began its own observational study of hypericin herbal extracts as an AIDS/HIV treatment last summer. Because the study volunteers obtained their own extracts from buyers' clubs or health-food stores, the Community Research Alliance did not administer any drug and therefore did not need to go through the FDA to obtain an "IND" (Investigational New Drug approval), which for various reasons would have been impossible in this case. The study complied with legal and ethical requirements by being approved by an Institutional Review Board, which the Community Research Alliance had previously organized in accordance with Federal regulations. The organization's Scientific Advisory Committee had also approved the study. For more information on the Community Research Alliance, see AIDS TREATMENT NEWS #85, August 11, 1989. This writer is a co- founder of the Community Research Alliance, and co-author of the formal report of the study, which has been submitted to the Sixth International Conference on AIDS. The study's principal investigator, and principal author of the report, is William C. Cooper, M. D. Methods The Community Research Alliance study lasted four months; a total of 33 volunteers were enrolled. The only entry criteria was to be HIV positive, and not to have used hypericin extracts within the last six months (so that baseline data could be obtained). Extensive blood tests were given at baseline and at four additional monthly visits; other data collected included medical history, physical examinations before and after the four-month test period, and the Merieux Multitest of skin immune response. All testing and other expenses (except for the cost of the herbal extracts, which the research organization could not legally provide) were paid by the Community Research Alliance, which financed the study primarily through donations from individuals; a grant from the American Foundation for AIDS Research (AmFAR) paid salary for a medical director. While four months of data were collected, the study actually ran six months, as resource limitations prevented enrollment of all the volunteers at once. There was no problem recruiting people to join the study. Volunteers were not asked to use any particular brand or dose of hypericin extracts, and they were not asked to make any changes in the treatments they would have used anyway, for the sake of the study. They were, of course, asked to report all treatments they used. All volunteers kept daily logs, and compliance with the protocol is believed to have been very good. A separate treatment database now being developed may be able to collect long-term followup information from the volunteers in the future. Results Of the 33 patients enrolled, 26 completed the four months. Of the seven who did not complete the study, six were hospitalized for AIDS complications and had to drop out; one was dropped for non-compliance with the protocol. A first look at the data showed no clear trends. About as many of the volunteers had T-helper decreases as increases. But a closer look showed a pattern which had not been expected. Of the 26 volunteers who completed the study, ten had never used any AZT, while ten others had been on AZT throughout (the remaining six had either started or stopped AZT during the four months). Of the ten "AZT virgins," eight had T-helper increases; the mean increase for the ten was 12 percent, which occurred in the first month and was sustained for the four months for which data are available. But of the ten on AZT throughout the study, eight had T-helper decreases, with the mean decrease for the ten of 13 percent. (The mean T-helper count increased nine percent in the first month, then declined.) These results do not show that AZT worked poorly with hypericin. Those who were on AZT were more seriously ill, with mean T-helper count of 189 at baseline (before they started hypericin) than those who had never used AZT (mean T-helper count 558 at baseline). The difference in outcome is not surprising, since other anti-HIV treatments, such as AZT and ddI, are known to work better in patients who begin with higher T-helper counts. The 12 percent T-helper increase in the ten who had never used AZT may be a meaningful trend, since without any treatment the average T-helper count would tend to decrease. However the increase in this small group was not enough to be statistically significant, meaning that it might have occurred by chance. The fact that the increase occurred in the first month, and then was sustained for several months, is consistent with results of other antivirals. P24 antigen test results were inconclusive -- although they did show that there was no dramatic antiviral effect of the hypericin-extract treatment. Only six of the 26 who completed the study were p24 positive at the beginning. Two became p24 negative, but they were on AZT throughout the study, so the improvement might have been due to AZT. Of the other four, two went up and two went down. No one changed from negative to positive. What about safety? There have been several anecdotal reports that some people's liver enzyme values have risen after use of St. John's wort, suggesting possible toxicity. In this study, five of the 26 volunteers showed rises in liver-function test values, and were advised to discontinue the herbal extract. All returned to normal after 30 days off the treatment, except for one who had earlier liver problems and high liver-function values before starting the study. This effect (rise in liver function tests in some patients) is suspected to be due not to hypericin but to some other component in the herbal extract, since animal studies have shown no effect on liver enzymes even when very large doses of pure hypericin were given. Much other data was collected and has not yet been analyzed. But principal investigator Dr. William Cooper has not seen anything striking or unusual in a first look. Comments A small, uncontrolled observational study like this one is not designed to prove that a treatment does or does not work. This study provides no proof either way, although the trends observed were in the direction which would be expected if there was some effect. One reason for doing this study was the hope that there might have been benefits dramatic enough (for some groups of patients at least) that they would be unmistakable even in this limited trial. No such benefits were found. We should remember, however, that the available herbal extracts contain only small amounts of hypericin, and there have been doubts as to whether there is enough to be effective. It is still possible that pure hypericin, or perhaps better extracts, could be of major benefit. Even before this study began, it was clear that the chance was slight that the herbal extracts would have so dramatic an effect that a small observational study would show it unmistakably. But the chance was not zero; and a positive result would have been of such great importance that we believe the chance justified doing this study, and justifies future studies of other available treatments which have a good scientific rationale. References Lavie, G. and others. Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin. Proceedings of the National Academy of Sciences USA, volume 86, pages 5963- 5967, August 1989. Meruelo, D. and others. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: Aromatic polycyclic diones hypericin and pseudohypericin. Proceedings of the National Academy of Sciences USA, volume 85, pages 5230-5234, July 1988. ***** CMV UPDATE by Denny Smith and John S. James AIDS TREATMENT NEWS #94 carried of brief report on the latest developments in the treatment of herpes and CMV infections. Recently we spoke with knowledgeable people who had additional information. Our article had suggested that ganciclovir, approved last year by the FDA, may be at least as good a treatment as Foscarnet, which remains experimental. But some people cannot use ganciclovir because of its toxicity -- especially those who are also using AZT, which has similar toxicities -- and therefore they should have access to Foscarnet. Dale Henderly, M. D., who practices ophthalmology at Northwestern University and has treated many people with CMV retinitis, suggested some other approaches for these patients. He pointed out that the new anti-HIV drug ddI can be administered simultaneously with ganciclovir in many patients, since the drugs have different toxicities. He also feels that if neutrophil counts are within normal limits during treatment with ganciclovir, the patients may be able to tolerate the newly lowered dose of AZT, 500 mg a day. If ganciclovir cannot be used with either ddI or AZT, then theoretically no obstacles would prevent access to Foscarnet, through a clinical trial or compassionate use. But Dr. Henderly urged people newly diagnosed with CMV to seek the care of a physician experienced with AIDS treatment, so that all the options for dealing with both HIV and the opportunistic infection will be explored. One example is the possibility of entering a clinical trial of granulocyte macrophage-colony stimulating factor (GM-CSF), an agent which looks promising as a control for bone-marrow suppression induced by AZT or ganciclovir. An experimental use of ganciclovir which may avoid the systemic toxicities involves intraocular administration of the drug. This method uses a small needle to inject the ganciclovir directly into the eye, which delivers the treatment to the specific site of the infection. Although this mode appears to be successful for stabilizing the retinitis, it is not especially practical or safe, as the injections must be repeated twice a week indefinitely, and they risk introducing other eye infections. However, intraocular injections remain a potential "salvage" option if other attempts to treat CMV fail. Dr. Henderly also told us that laser therapy should not be construed as a treatment for retinitis. Rather, lasers have been used to correct a complication of treating retinitis -- the detachment of a retina which has become thin and fragile because of prolonged treatment. Even in this context, lasers have been only moderately useful, and only for detachments which were not severe. Dr. Henderly added that lasers have also been tried as attempts at "sealing off" the retina to prevent detachment, but results were unconvincing. For retinal detachments which are too severe to correct with laser surgery, Dr. Henderly suggests the use of silicone oil to replace the vitreous interior of the eye; this treatment usually works to hold the retina in place again. The silicone oil, like laser treatment, has no therapeutic effect on the CMV infection. Future Possibilities The antiviral HPMPC is looking especially promising in animal studies for treating CMV and perhaps other herpesvirus infections. But as far as we know, it has never yet been tried in humans; therefore it is too early to know whether it will ever be a useful drug. An early report on animal studies was published as an abstract at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 1989, abstract number 751; for other background see AIDS TREATMENT NEWS #76, March 24, 1989. Other potentially important CMV treatments are FIAC and oral ganciclovir, both now in small-scale clinical trials. For more information on FIAC, see AIDS TREATMENT NEWS # 94. We do not know how well this drug is working. For more information on oral ganciclovir trials, see "San Francisco, San Diego: Oral Ganciclovir Study Seeks Volunteers," below in this issue; also see AIDS TREATMENT NEWS #89. Oral ganciclovir has the same toxicity as the approved intravenous treatment; its advantage is avoiding the need for intravenous infusion. AIDS TREATMENT NEWS believes that the most important action to improve treatment for CMV and other herpesviruses would be to speed the development of HPMPC. Apparently this potential drug works very well in the well-established "animal model" for CMV infection; if it passes standard toxicity tests, there would be no shortage of volunteers willing to try it as a therapy. When a new drug is potentially so important to so many people, its development should be treated as an emergency, not business as usual. ***** SAN FRANCISCO, SAN DIEGO: ORAL GANCICLOVIR STUDY SEEKS VOLUNTEERS A study of oral ganciclovir seeks two groups of patients: those with CMV retinitis, and also those who are only HIV positive but are found to have CMV in their urine. (1) One portion of the trial seeks persons with CMV retinitis which has been stabilized with intravenous ganciclovir and is not immediately sight threatening. The study will last 35 days, and those who complete it and for whom the drug works should be eligible to continue receiving oral ganciclovir for free from Syntex Corp. (2) The other arm of the study seeks persons who are HIV positive, but do not have retinitis. These volunteers will be tested to find those who are excreting CMV in their urine. Those who are will be accepted for a 35-day study to test the effect of different doses of oral ganciclovir on the level of CMV excreted. Because these volunteers will receive little medical benefit from this trial, and need to come for several hospital visits for blood tests, those who complete this wing of the study will receive a stipend of $400. No placebos will be used. Volunteers will not be allowed to use AZT for the 35 days of this trial, because the two drugs can cause additive toxicities. To volunteer or to learn more about this study, call Karen Taylor at Mount Zion Hospital and Medical Center, 415/885- 7432. (Note: This study is also taking place at two other sites in San Francisco, and in San Diego. For more information, see previous announcement in AIDS TREATMENT NEWS #89, October 20, 1989. San Diego volunteers can call 619/543-8080; ask for the pre-screening nurse for oral ganciclovir.) ***** SIXTH INTERNATIONAL CONFERENCE: FREE REGISTRATION FOR PERSONS WITH AIDS OR HIV, DEADLINE MARCH 15 The Sixth International Conference on AIDS (June 20-24 in San Francisco) is making 325 delegate passes available without charge to persons with AIDS or HIV who could not otherwise afford to attend. (Full registration would cost $475.00, or more after May 11; a reduced student rate is available.) A January 31 news release from the Conference explained that the goals of this HIV Delegate Program are to allow people with AIDS or HIV "to gather current treatment information for dissemination throughout the community, and to facilitate an exchange between the scientific and HIV infected communities to assure a better understanding of the needs of HIV infected people." "Interested HIV infected individuals are asked to prepare a letter requesting an HIV Delegate Pass. In the letter, mention should be made of any affiliations with community based AIDS related activities, and organizations. Phone numbers should be included. The deadline for requests is Thursday, March 15, 1990. Requests should be sent to the Conference as follows: Dana Van Gorder Community Relations Sixth International Conference on AIDS P. O. Box 1505 San Francisco, CA 94143-1505 ***** AIDS TREATMENT NEWS ISSUES 1-75 NOWAVAILABLE IN BOOK FORM The first 75 issues of AIDS TREATMENT NEWS, April 1986 through April 1989, have been published by Celestial Arts of Berkeley, California. This paperback volume includes a new, professionally compiled index. It will be available in bookstores retailing at $12.95. The book can also be ordered by mail from our offices in San Francisco, but at a higher price ($18) to include first class (priority mail) postage and handling costs. (Outside North America, add $6 for airmail postage.) The editor and staff of AIDS TREATMENT NEWS wish to thank Paul Reed, co-editor at Celestial Arts Publishing, for his extensive work on this volume. We plan to offer issues 76 through 100 later. ***** 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