Subject: AIDS Treatment News #138 Date: Nov 01 1991 (552 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& J O H N J A M E S writes on A I D S &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Copyright 1991 by John S. James; permission granted for non-commercial use. AIDS TREATMENT NEWS Issue #138, November 1, 1991 phone 800/TREAT-12, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Foscarnet: Study Finds Increased Survival Hypericin Trial Begins in New York, Boston, Minneapolis NAC: Important Study Needs Volunteers Poll Shows Americans Support Experimental Treatment Access Announcements: Flu Shots Recommended Sarasota, Florida: AIDS Treatment Conference, November 15 and 16 Secret Treatment in Switzerland: Investigative Article Published San Francisco: Early Intervention Center Opens ***** Foscarnet: Study Finds Increased Survival by John S. James On October 21, the U. S. Public Health Service (PHS) announced that a major clinical trial comparing foscarnet (brand name Foscavir) to ganciclovir for treatment of CMV retinitis was stopped early after an unexpected finding that patients randomly assigned to foscarnet lived for an average of 12 months, four months longer than those randomly assigned to ganciclovir. Shortly before that date, the Public Health Service sent a clinical alert to 40,000 physicians and others caring for persons with AIDS, to inform them of the results. But the study is hard to interpret because it was not designed to measure survival differences, and it may be impossible to tell why the difference occurred. (The data showed that both drugs were equally effective in treating CMV retinitis.) The October 21 PHS press release quoted the study's chairman, Douglas Jabs, M. D., associate professor of ophthalmology at The Johns Hopkins School of Medicine, as noting that, "These results suggest that, for many patients with AIDS and CMV retinitis, foscarnet may be a better initial treatment than ganciclovir." The press release also noted that those who entered the study with decreased kidney function lived longer if assigned to ganciclovir. (Kidney toxicity is the most serious side effect of foscarnet.) On October 28 we interviewed Mark Jacobson, M. D., of San Francisco General Hospital, an expert in CMV retinitis who has much experience with both drugs; we had planned the interview even before the new study results were known, in order to ask about foscarnet, since it was recently approved by the FDA for marketing in the U. S. Dr. Jacobson made the following points: * The drugs were completely equivalent in controlling CMV retinitis. But beyond that, it is difficult to come up with a take-home message from the study. The observation that made the news is that those assigned to foscarnet lived an average of 50 percent longer than those assigned to ganciclovir. This observation seems to be real, not a random fluke; the data from the study is consistent and credible. * But it is hard to interpret what the data means, because the trial was not designed to compare survival -- only to compare the two treatments of CMV retinitis. A survival study would need to control or randomly assign the antiretroviral therapy and prophylaxis for opportunistic infections. There were major differences between the groups in the treatment which patients received; for example, more people in the foscarnet group than in the ganciclovir group used AZT. [Note: this difference is not surprising, since AZT and ganciclovir have similar toxicities and therefore it is hard to use them together.] * What cannot be answered from this study is whether the survival difference was due to the antiretroviral effect of foscarnet (the drug is known to have some degree of anti-HIV effect), or due to the suboptimal antiretroviral therapy of patients receiving ganciclovir, who often cannot use AZT. * Few of the patients in this study used ddI (which could probably be combined with ganciclovir better than AZT could be). And almost none received G-CSF or GM-CSF, which would allow many patients to combine ganciclovir and AZT. While the data has not yet been fully analyzed, these figures suggest that those in the ganciclovir group may have had too little anti-HIV therapy. * What does this mean for clinical management? If all things are equal, these results would probably favor foscarnet as the first choice for treating CMV retinitis. But for many patients, all things are not equal. Most importantly, those with any kidney abnormalities had worse survival with foscarnet than with ganciclovir. * Also, foscarnet is more expensive than ganciclovir, and more cumbersome to administer. It takes two hours daily for maintenance therapy, compared to one hour with ganciclovir; and you need an IV pump for foscarnet, but not for ganciclovir. * If you eliminate the practical differences, patients with normal kidney function may lean toward choosing foscarnet. But when patients in this study who were taking ganciclovir were told that they could switch to foscarnet, the majority did not want to do so. Anti-HIV effect of foscarnet: We also asked Dr. Jacobson what was known about the anti-HIV effect of foscarnet: * Dr. Jacobson and others published two papers showing that p24 antigen (an indication of HIV activity) went down with foscarnet treatment -- even in people who had been on AZT but still had p24 antigen. However, we know that p24 changes do not correlate well with survival. There is no question that foscarnet has biologic activity against HIV -- that is almost indisputable. But whether that is beneficial clinically is unknown. Perhaps a trial will be done to see if the drug is beneficial, now that the new survival result (from the CMV retinitis trial) has raised the issue. Safety Concerns: We also asked about how physicians can use foscarnet safely. We particularly asked if the package insert that comes with the drug included all the information required: * The package insert has the information, but it's long; the physician must pay close attention and become familiar with it in order to safely give this drug. It is very important to monitor serum creatinine and and adjust doses accordingly, at least weekly during maintenance therapy, and more often during induction, in order to avoid toxicity. * Problems are manageable if physicians are monitoring patients. But what happens if people travel or otherwise are not monitored and continue to take their drug? With foscarnet it is possible to go into renal failure over a four-day period; that is unusual, but it can happen. If patients have been on therapy for some time and are known to be stable, we (Dr. Jacobson's unit) have had some be away for as long as two weeks, but that is the outside limit with which we would be comfortable. With ganciclovir, it is less serious to not be monitored. If the neutrophil count goes low and the patient does not get an infection, all that is necessary is to stop the drug, and the count will recover. (We asked about hydration -- making sure patients have enough water, usually by giving intravenous fluids -- which is often emphasized by European physicians who are familiar with the drug.) * The hydration data comes from a small French study. Patients given saline seemed to have less kidney dysfunction than controls; this study was not randomized. Hydration does make sense, and it is what people have done, although there is no controlled-study data showing that you have to do it. It is generally easy to do, since you need to give the foscarnet intravenously over two hours anyway, and the saline can be given during that time. Other Uses of Foscarnet (We asked Dr. Jacobson about "unlabeled" uses of foscarnet -- those not included in the official approval -- such as for treatment of CMV colitis.) * For other CMV diseases, there is very little data, mostly anecdotal reports that it might be beneficial. Patients with gastrointestinal disease might have more problems than others with foscarnet toxicity; they might be at more risk with this drug than with ganciclovir, but there is very little data. If people have not responded to ganciclovir, then foscarnet might be worth a try for gastrointestinal CMV disease. * For acyclovir-resistant herpes simplex, however, there is plenty of data to support use of foscarnet. A recent article (1) gives very convincing data that foscarnet works better than any other available therapy for acyclovir-resistant herpes. Foscarnet is clearly the therapy of choice for this condition. References 1. Safrin S, Crumpacker C, Chatis P, and others. A controlled trial comparing foscarnet with vidarabine for acyclovir- resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. New England Journal of Medicine. August 22, 1991; volume 325, number 8, pages 551-555. ***** Hypericin Trial Begins in New York, Boston, Minneapolis by John S. James The long-delayed phase I/II trial of synthetic hypericin has begun in New York; the fourth volunteer received the drug on October 28. The two other trial sites, in Boston and Minneapolis, are expected to begin soon. Volunteers are needed at the Boston, Minneapolis, and possibly New York sites. Hypericin is an antiviral which has been extensively covered in AIDS TREATMENT NEWS for over three years (starting with issue #63, August 26, 1988). This potential drug is important because it has shown quite promising results in laboratory tests with HIV, including "wild" strains directly taken from patients; in the laboratory, it suppresses HIV infection in freshly-drawn human blood. And in animal tests, it has been found effective in treating diseases caused by other retroviruses (other than HIV, which is difficult to study in animals). In addition, hypericin has long been in human use as low- dose herbal extracts of the St. John's wort plant; this experience, as well an animal tests with larger doses, suggest that it might be nontoxic in doses large enough to be useful. And if it does prove feasible as a treatment, hypericin might be especially valuable since its mechanism of action appears to be entirely different from that of AZT, ddI, ddC, or any other treatment available, meaning that the drug might provide a new kind of therapeutic option. Animal studies indicate that hypericin can be used orally (although the new trial will administer it intravenously in order to obtain the most precise data), and that it does cross the blood-brain barrier. Hypericin might also be useful against certain other viruses, possibly including cytomegalovirus (CMV) and hepatitis B. Previous trials of hypericin have only used the crude St. John's wort preparations which were available, but which contain much less than one percent of the active drug; the results of these trials have been modest at best, and laboratory studies suggest that the doses obtainable this way may be much too low to be effective against HIV. In the animal studies, best results have been obtained with pure hypericin chemically extracted from the plants. But chemically synthesized hypericin, not the plant extract, was chosen for development as a human drug. Synthetic hypericin is being developed by VIMRx Pharmaceuticals Inc., located in Stamford, Connecticut. In September 1991 U. S. patents were issued to New York University and to Yeda Research and Development Company Ltd., which commercializes inventions from The Weizmann Institute of Science, which in turn has worked with New York University and VIMRx on antiviral uses of hypericin; previous European and U. S. patents had been issued to Yeda. The clinical trial is being supported by the AIDS Clinical Trials Group (ACTG) of the U. S. National Institute of Allergy and Infectious Diseases. The principal investigator is Fred Valentine, M. D., of New York University. The Trial The new trial is designed primarily as a safety study, but will also look for evidence of anti-HIV activity. It will test four escalating doses of hypericin, ranging from 0.25 mg per kg of body weight, to 2.0 mg per kg; all doses will be given intravenously, twice per week. Volunteers must have a T-helper count under 300, and five of the eight patients at each dose level must have positive p24 antigen (by the conventional tests). Volunteers cannot use AZT, ddI, or any other retroviral during the trial, or within one month of starting; also, they cannot use any form of oral hypericin within one month of starting the trial. They cannot have an active opportunistic infection nor require continuous medication (other than pneumocystis prophylaxis) when they enter the trial. Short courses of most medicines are OK; but those which cause photosensitivity (increased sensitivity to sunlight) will not be allowed, because of the possibility that hypericin itself may cause photosensitivity. For information about volunteering for this trial, contact the AIDS Clinical Trials Unit near you and ask for information about the hypericin trial (protocol #150). Note that the trial is being conducted only at the following three centers; and the waiting list in New York may be full. You can talk with any of the research nurses at the following numbers: Boston: Beth Israel Hospital, ACTU Clinic, 617/735-4103. Minneapolis: University of Minnesota, ACTU Clinic, 612/625- 1462. New York: New York University Medical Center, ACTU Clinic, 212/263-6565. ***** NAC: Important Study Needs Volunteers by John S. James A small but important 15-week study of the experimental HIV treatment N-acetylcysteine (NAC) has been delayed because of lack of volunteers. The reasons few people have volunteered have been (1) this trial was not widely known, although it was listed in some directories; (2) until recently it was only open to residents of the Washington, DC area (since no travel funds were available); and (3) there is some discomfort involved, as the drug is given intravenously for part of the time, and one lumbar puncture is required. On the other hand, NAC is much safer than most experimental drugs, and the trial will give participants the best blood work available anywhere, including repeated plasma viremia tests, at no cost. No hospitalization is required. The entry criteria are easy to meet. Since travel expenses can now be paid, persons from anywhere in the U. S. can volunteer. And it is important for the AIDS community that this study be completed. The trial is being run by the U. S. National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health campus near Washington, D. C. ; it is sponsored in part by Zambon Corporation of East Rutherford, New Jersey, a subsidiary of the Italian pharmaceutical company which is developing NAC as a potential HIV treatment. A total of 16 volunteers are needed; seven are already in the trial, and three others are waiting to start. NAC has long been used in Europe as a bronchitis treatment. In the U. S., it is approved for aerosol use in treating bronchial mucous associated with cystic fibrosis and other lung conditions, and also as an antidote for poisoning due to acetaminophen (e.g. Tylenol) overdose. Laboratory studies by several different research groups have built a strong case that the drug should be tested as a treatment for AIDS or HIV; we hope to review these studies in a future issue of AIDS TREATMENT NEWS. NAC is widely available in buyers' clubs and health-food stores, and is already in wide use as one of the most common "alternative" treatments. But until trials are done we cannot know for sure that it is working, or (if it is) how to use it best. There are anecdotal reports of cases of significant benefit, but there are also people NAC seems not to help. And the theory and laboratory data suggests that in many cases benefit might be long-term, with no way to tell quickly if the treatment is working -- especially for those who are healthy to begin with and have no obvious illness to indicate possible benefit from the drug. The NIAID trial will not by itself tell if NAC is useful, but it will provide data to improve the design of larger studies, which will soon be ready to begin. This early trial will determine how well the drug is absorbed, and how well it crosses the blood-brain barrier, in persons with AIDS or HIV. It will also test if there is any drug interaction between NAC and AZT, ddC, or ddI. And it will obtain preliminary data on whether NAC reduces viremia, or improves T-helper counts or other measures of immune functioning. Although no surprises are expected, it is good practice to do a small, rapid test like this to to help assure that later studies are optimally designed. Volunteers must be HIV positive and have T-helper counts less than 500 (there is no lower limit). They can be using AZT, ddI, or ddC (through the expanded-access program), but must not use experimental drugs except ddC during the study; those with T-helper count under 200 should also be on pneumocystis prophylaxis, either by aerosol pentamidine or by oral drugs. They cannot have a serious infection when they begin the study; those with KS are eligible, but must not have received systemic therapy for KS (other than alpha interferon) within two months of starting the NAC study. There are also various medical exclusion conditions, including certain abnormal blood counts and blood- chemistry tests. Potential volunteers should call Ms. Chris Boenning, RN, MSN, 800/772-5464 ext. 401. ***** Poll Shows Americans Support Experimental Treatment Access by John S. James A September 1991 poll by The Wirthlin Group, a polling company, found that 79 percent of Americans agreed that persons with a fatal illness should be allowed to use promising experimental drugs even if they have not been approved by the U. S. Food and Drug Administration. Nineteen percent disagreed, and two percent did not answer. Of those who agreed, 88 percent would still leave the decision to patients and their physicians even if the drug had a serious but reversible side effect. And 97 percent would give patients the choice in case of AIDS; the percentages for other diseases were cancer (96 percent) Alzheimer's disease (91 percent), heart disease (84 percent), diabetes (84 percent), and arthritis (78 percent). These questions were included in the company's monthly "omnibus" poll of about one thousand adult Americans; the margin of sampling error is plus or minus three percent. The wording of the key question was: "If an individual has a fatal disease, for which there is no cure, and a drug that has been tested and shows promise in treating that disease is under review by the Food and Drug Administration, do you think ... patients, in consultation with their doctors, should be allowed to make the decision about whether or not to try the drug before the FDA makes a decision about whether or not the approve it ..... (79 percent) or patients should not be allowed to use the drug unless it has been approved by the Food and Drug Administration .... (19 percent) Don't know/refused ..... (2 percent)" This poll was not paid for by industrial or other groups. Instead, The Wirthlin Group added these questions to its own monthly survey because of public interest in the issue. ***** Announcements: ** Flu Shots Recommended The flu season may be more severe than usual this year (although no one knows for sure), and the U. S. Department of Health and Human Services has recommended that "everyone at particular risk...should get vaccinated soon." We called the office of Marcus Conant, M. D., who has a large AIDS practice in San Francisco, and learned that physicians are recommending flu shots for patients with AIDS or HIV, except for those allergic to eggs, or who are pregnant, or who have some special medical reason for not receiving the shot. Most physicians in San Francisco at least are providing the shots to their patients for a nominal charge to cover the cost of the syringe, since physicians get the vaccine free from the Health Department. If you cannot get the flu shot through your primary care physician, it is also available at public clinics in many areas. Note that the U. S. Centers for Disease Control also recommends that persons with HIV have an annual TB screening, and a one-time Pneumovax (pneumococcal vaccine) injection. ** Sarasota, Florida: AIDS Treatment Conference, November 15 and 16 Leading physicians and other AIDS experts will speak at the third annual "Until There Is a Cure" conference, sponsored by AIDS-MANASOTA (a coalition of people with AIDS) in Sarasota, Florida on November 15 and 16. Scheduled speakers include: Marcus Conant, M. D., and Larry Waites, M. D., both from San Francisco; Larry Bruni, M. D., from Washington, D. C.; Bernard Bihari, M. D., from New York; Paula Sparti, M. D., from Miami; Dr. June Osborne, chair of the National Commission on AIDS; nutritionist and author Dr. Lark Lands; and Martin Delaney of Project Inform. Chairman of the conference is Peter Uitdenbosch of AIDS-MANASOTA. The registration is $30 for persons with AIDS (many scholarships are available), and $75 for healthcare workers; this includes lunches on both days. Delta Airlines has special fares, and hotel rooms start at $25 per night. For more information, call AIDS-MANASOTA at 813/954-6011, or fax them at 813/951-1721. ** Secret Treatment in Switzerland: Investigative Article Published A number of people with AIDS have flown to Switzerland for an expensive (over $3,000) treatment by Dr. Josef Roka; the treatment consists of plant-extract products called Rovital and Carciviren, and also ozone infusions. The interest in this treatment seems mainly due to some very positive anecdotal reports. But there are also reasons to be suspicious -- especially the fact that the herbal formulas are secret, which largely removes this remedy from the scrutiny of the AIDS medical and research community. The information which people would need in order to evaluate this treatment has not been available. On October 24 the San Francisco Bay Times published an in- depth article on Dr. Roka's treatment by reporter Tim Kingston, who contacted AIDS experts throughout the United States and abroad (Dr. Roka himself refused to discuss the treatment with Mr. Kingston, or to answer questions faxed to his office). The article begins and ends without preconceived conclusions, but it raises many questions. We still do not have answers, but at least an overview of the little information which has reached the AIDS community is now available. For a copy of "Cure or Quackery? Dr. Roka's Secret Swiss HIV Treatment" send a self-addressed stamped envelope to: Tim Kingston, San Francisco Bay Times, 288 7th Street, San Francisco, CA 94103. ** San Francisco: Early Intervention Center Opens The Center for Positive Care, a collaborative effort of 16 different AIDS agencies, has opened an early-intervention resource center for anyone who is HIV-positive, but targeting especially those who have been under-served, including women, racial and ethnic minorities, those who do not speak English, injection drug users, youth, undocumented immigrants, those without health insurance, and the homeless. Funding is provided in part by the agencies and in part by the San Francisco Department of Health. Services include anonymous HIV testing, case management, client advocacy, benefits counseling, health and psychosocial counseling, crisis intervention, seminars and information workshops on early treatment, clinical trials, nutrition, etc., and referrals to medical, substance-abuse, and other services. The center includes a library, developed with assistance from AIDS TREATMENT NEWS. All services are multilingual. There has been some controversy about the center, since due to funding limitations it does not include medical treatment, but must refer clients to treatment elsewhere. The agencies providing services are: AIDS Benefits Counselors, AIDS Health Project of the University of California San Francisco, AIDS Indigent Direct Services, American Indian AIDS Institute, California Prostitutes Education Project, Community United in Response to AIDS/SIDA, Early Advocacy and Care for HIV (EACH), 18th Street Services, Filipino Task Force on AIDS, Gay Asian Pacific Alliance Community HIV Project, Glide- Goodlet AIDS Project, Haight-Ashbury Free Clinic, National Task Force on AIDS Prevention, Perinatal HIV Reduction & Education Demonstration Activity, Project AHEAD/Special Programs for Youth, and the San Francisco AIDS Foundation. For more information, call the Center for Positive Care at 415/476-3644, or visit the Center at 3180 18th Street (near Folsom) in San Francisco. Hours are 9 a.m. to 8 p.m. Monday, Wednesday, Thursday, and Friday, noon to 8 on Tuesday, and 9 to 5 on Saturday. [Obsolete subscription information has been removed. See the latest issues for up-to-date information. -- sysop] &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display