Subject: AIDS Treatment News #129 Date: Jun 28 1991 (1092 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 #129, June 28, 1991 phone 800/TREAT-12, or 415/255-0588 CONTENTS: [items are separated by "*****" for this display] Florence Conference Overview Leading Physicians Review Florence Conference, San Francisco Monday July 8 Seventh International Conference on AIDS: Treatment for Opportunistic Infections Newly Recognized, Treatable Organism May Mimic KS -- or Other AIDS Diagnoses MAC (MAI) Clarithromycin Open Trial Announced Foscarnet Note: Controlling Calcium Depletion In Memoriam: Tom Hannan In Memoriam: Rene Lopez Your Help Needed: Travel/Immigration Letter Writing Campaign Update ***** Florence Conference Overview by John S. James Most news-media reports of the Seventh International Conference on AIDS, June 16-21 in Florence, Italy, emphasized the lack of useful clinical information. While these stories are largely true, they do do not give the whole picture. About three thousand scientific reports were presented, and these included background information on most of the drugs we have covered in AIDS TREATMENT NEWS -- and also some new potential treatments which were unfamiliar to us. The shortage of practical, definitive medical information is not the fault of the conference. Although this year's meeting emphasized basic science (the theme was "Science Challenging AIDS"), there was plenty of room for important medical reports. The problem is that many obstacles -- commercial, academic, political, and regulatory -- and the lack of both funding and of national leadership, have kept important research from being done. Studies duplicate each other, produce indecisive or unreliable results, or address questions which will be obsolete before the study is done, because researchers face an obstacle course in which it is hard to make anything happen. They do what research they can, since the alternative is to do nothing; there is often no option of doing what is needed. The past year has seen significant progress in making clinical research more productive -- although shortage of funds is increasingly impeding progress. Results of the new trials were not ready for this year's conference, although many believe that important new information should be available by next year's conference, planned for May 1992 in Boston. The single area of greatest interest at the Florence conference last week was vaccines, especially those designed for treating persons already infected with HIV. Important information was also presented on ddC/AZT combination therapy, the anti- angiogenesis approach to developing KS treatments, and the value of keeping T-helper counts above 50. In this issue and the next two, we will cover in depth some of the practical information from the Seventh International Conference on AIDS. This issue also has important non-conference information -- for example, an article on angiomatosis (a treatable opportunistic infection sometimes misdiagnosed as Kaposi's sarcoma, MAC, or other conditions), and an announcement on obtaining free access to clarithromycin for treatment of MAC (MAI). How to Obtain Conference Abstracts and Tapes * In our articles on the Florence conference, the references in parentheses are to the abstracts of the meeting, unless otherwise stated. The program and abstracts have been published as a set of three books, which includes subject and author indexes; these books were given to persons attending the conference. The easiest way to obtain this material is to convince a local AIDS organization to acquire a set -- which will probably cost about $100, unless someone who attended will donate theirs. Anyone interesting in buying the abstracts should send a fax, including their mailing address and return fax number, to the Seventh International Conference on AIDS, fax number 396.4453369 (in Rome); arrangements for the purchase, such as means of payment accepted, have not yet been made final. Note that this office for post-conference inquiries is scheduled to close on September 30. * Besides the abstracts, audio tapes of almost all the conference meetings are available. You can purchase the tapes at any time from InfoMedix, in Garden Grove, California; they can be reached at 800/367-9286 (U. S. and Canada), or at 714/530-3454; their fax number is 714/537-3244. It is helpful to have a conference program available, as well as the InfoMedix order form, to select the tapes desired; the 320-page program is included with the abstracts. The submissions considered most valuable by the official conference reviewers were assigned to oral sessions; therefore, they are usually available on tape. The referees usually judged by academic rather than practical standards, however, and as a result, the useful information which did appear at the conference was scattered throughout the presentations. ***** Leading Physicians Review Florence Conference, San Francisco July 8 On Monday, July 8, leading HIV clinicians will review the Florence conference, and answer questions on the management of HIV disease, at a free public meeting in San Francisco. Scheduled speakers are Marcus Conant, M. D. (moderator), Donald Francis, M. D., Leon McKusick, Ph.D., Robert Schooley, M. D., Paul Volberding, M. D., and Constance Wofsy, M. D. The meeting will be from 7:00 p.m. to 9:00 p.m. at the San Francisco Marriott, 55 Fourth Street, San Francisco. We plan to report on this meeting in a later issue of AIDS TREATMENT NEWS, for those unable to attend. ***** Seventh International Conference on AIDS: Treatments for Opportunistic Infections by Michelle Roland There was little truly new, practical treatment information presented in Florence at the Seventh International Conference on AIDS. The bulk of the research on opportunistic infections focused on the incidence and diagnosis of these diseases; most of the clinical information came from relatively small confirmatory studies of treatments already in use. An occasional poster presentation discussed the use of a new drug, or a new use for an old drug, but these were all very small studies from which confident conclusions cannot easily be drawn. We present in this article a synopsis of the potentially relevant opportunistic infection treatment and prophylaxis news from Florence. The pneumocystis, toxoplasmosis and cryptococcal meningitis prophylaxis information is important for everyone with advanced HIV. (A comprehensive review of pneumocystis prophylaxis can be found in AIDS TREATMENT NEWS #114.) Unfortunately, providing a complete overview of the status of treatments for each opportunistic infection would require several issues of the newsletter. Instead, we hope this article will be of use to individuals who are already dealing with a given infection, and are familiar with the basic treatment information, but would like to know about potentially important treatment advances presented at the conference. [Unless otherwise stated, the references in parenthesis (for example, "W. B. 2245") refer to the abstracts of the Seventh International Conference on AIDS; these abstracts, together with the program of the conference and subject and author indices, have been published as a set of three books. Four-digit numbers refer to poster presentations; smaller numbers refer to oral talks. The first letters (M, TU, W, TH, or F) refer to the day of the week; the second letter (A, B, C, or D) refers to one of four "tracks" of the conference: Track A, Basic Science; Track B, Clinical Science and Trials; Track C, Epidemiology and Prevention; or Track D, Social and Behavioral Science. A note earlier in this issue tells how to purchase a copy of the conference abstracts, as well as tapes of the oral sessions.] Pneumocystis Prophylaxis Over fifteen studies compared two or more of the common drugs used for pneumocystis (PCP) prophylaxis, including aerosolized pentamidine, Septra (also called Bactrim, co- trimoxazole, or trimethoprim-sulfamethoxazole), and dapsone with or without pyrimethamine. Figuring out which of these drugs is the most effective for preventing pneumocystis is extremely important. However, none of the small studies presented at the conference will truly answer that question because of their design (chart reviews as opposed to controlled clinical trials) and/or the relatively small numbers of patients studied. Hopefully, the two large, on-going ACTG pneumocystis prophylaxis studies will provide reliable answers within the next year. (The ACTG, or AIDS Clinical Trials Group, is the primary AIDS research arm of the Federal government's National Institutes of Health). In the meantime, some useful information can be gleaned from the conference presentations. Of the two studies which compared aerosolized pentamidine, Septra and dapsone, one found that Septra was the most effective in preventing pneumocystis, in spite of frequent side effects (M. B. 160); the second concluded that all three were equally effective, but that aerosolized pentamidine was more easily tolerated (W. B. 2245). Five studies compared aerosolized pentamidine with Septra. Four found no significant difference in the occurrence of pneumocystis (W. B. 2236, W. B. 2247, W. B. 2251, W. B. 2224) while one concluded that Septra was a more effective prophylaxis (W. B. 2246). One study looked at the occurrence of both pneumocystis and cerebral toxoplasmosis and found two cases of each in the aerosolized pentamidine group and none in the Septra group (W. B. 2224). A larger study of over one thousand people appeared to show that although both aerosolized pentamidine and Septra were effective in preventing pneumocystis, only aerosolized pentamidine was associated with a statistically significant increase in over-all survival time (W. B. 2236). We spoke with Richard Chaisson, M. D., the principal investigator from Johns Hopkins University. He explained that because the study was conducted before Septra was in common use, only a small percentage of the patients were taking it, possibly explaining the failure to achieve statistical difference in survival rates. Although Dr. Chaisson believes that Septra is a better first choice for pneumocystis prophylaxis in patients who can tolerate it, he feels that his study is important in demonstrating that aerosolized pentamidine remains a very useful drug for patients who cannot tolerate Septra or other systemic drugs. Dr. Chaisson emphasized that comparisons of the two drugs cannot be made from a study designed as this one was; such comparisons must await the large, randomized ACTG trials. Two studies compared aerosolized pentamidine with dapsone (W. B. 2228 and W. B. 2248). Neither showed a statistically significant difference in the occurrence of pneumocystis. However, one of the studies also looked at the occurrence of toxoplasmosis and found five cases in the aerosolized pentamidine group and none in the dapsone group (W. B. 2248). The authors of this study concluded that as a dual prophylactic regimen, dapsone may be superior. A small study compared patients receiving sulfadiazine and pyrimethamine as standard maintenance treatment for toxoplasmosis with a placebo control group from a recently completed study; they found that the toxoplasmosis maintenance treatment also prevented pneumocystis in these patients, again suggesting a possible dual prophylactic approach (W. B. 2218). Different dosage schedules of Septra were compared in a study which looked at twice daily vs. three times weekly dosing. Both regimens were equally effective, but the thrice weekly dosing appeared to be more easily tolerated (W. B. 2199). Another group administered pentamidine by monthly intramuscular injections in a group of 89 patients; there were three cases of pneumocystis (W. B. 2227). Although there was no control group, this method of administering the drug appears to be approximately as effective as the other regimens currently in use. Important side effects included abscess formation at the injection site, glucose intolerance similar to diabetes and low blood pressure when standing up. We spoke with Sam Bozzette, M. D., one of the leading pneumocystis researchers working with the ACTG, about this approach. In his experience, the occurrence of the sterile abscesses, which often require surgical intervention, makes intramuscular injections of pentamidine an unattractive alternative. In addition, the diabetes-like side effects of systemic pentamidine therapy can be quite serious. For rare patients who are unable or unwilling to regularly take pills or use aerosolized pentamidine, intramuscular injections may be a less than ideal but reasonable alternative. What is the bottom line about pneumocystis prophylaxis? All the treatments currently in widespread use seem to have approximately the same effectiveness in preventing the disease. The systemic treatments like Septra and dapsone may well have the added advantage of preventing toxoplasmosis, as well as pneumocystis infections in organs other than the lungs. Even if the large ACTG studies do confirm that the systemic treatments are a superior first choice, aerosolized pentamidine will remain an important second-line prophylaxis with equal or slightly less effectiveness in preventing pneumocystis, but fewer side effects. Pneumocystis Treatment The usual treatments for acute pneumocystis include intravenous Septra or pentamidine. Alternatives to these drugs are important because serious side effects often limit their use. One regimen being tested is oral clindamycin plus primaquine. Two small studies using this combination confirm its usefulness and tolerability in mild to moderate pneumocystis, either as the initial therapy (TH. B. 42) or as salvage in patients who have failed or are intolerant of the other drugs (W. B. 2229). 566C80 is an experimental drug being studied as a treatment for pneumocystis and toxoplasmosis. A small pilot study reported on its effectiveness in the initial treatment of mild to moderate pneumocystis (W. B. 2239). 79% of the patients were successfully treated with 566C80. Side effects included rash, drug related fever, and an increased liver enzyme (alanine aminotransferase) in some patients. Six of the 34 patients experienced a recurrence of their pneumocystis within 6 months of completing treatment. The abstract does not state what kind of prophylaxis they were using. ACT UP/Boston has been working with Burroughs Wellcome, the developers of 566C80, to make this unapproved compound available to patients who have failed or are intolerant of standard pneumocystis treatments. Burroughs Wellcome confirmed that the drug is available on a case-by-case basis for patients who are intolerant of all other treatment options and do not qualify for an existing study of 566C80. Although Burroughs Wellcome has not yet formalized an expanded access program, physicians may call the medical department at 800/722-9292 for information on compassionate access to 566C80 for the treatment of pneumocystis. For information on clinical trials of 566C80, call 1-800/TRIALS- A. Finally, a Canadian study raised questions about the usefulness of adding steroids to standard treatment of moderate to severe pneumocystis. A consensus statement published in the New England Journal of Medicine in November 1990 recommends routine use of corticosteroids in certain cases of acute pneumocystis, based on the consensus panel's analysis of five studies (NEJM, November 22, 1990; volume 323, number 21, pages 1500-1504). The randomized, placebo controlled study of 78 patients presented at the Florence conference found no statistically significant difference in survival between the steroid treated and untreated groups. Dr. Bozzette raised several issues to consider when interpreting the data from this study. First, although there was no statistically significant difference between the treated and untreated groups, there was a trend toward better survival in the treated group. Second, individuals who were not treated with steroids on the study, but became sicker, were eligible for steroid treatment off the study. Ten of the thirty-eight placebo patients did in fact receive steroids. Finally, the study was too small to detect a significant difference since the death rate even without steroids was low. When the data from this study are added to those from the other studies on which the consensus statement were based, the conclusion remains valid that steroid therapy improves survival in very sick patients. In an article published in the daily conference newspaper, Sharon Walmsley, the principal investigator of the steroid study from the University of Toronto, warns that steroid therapy could worsen the course of lung disease which is misdiagnosed as pneumocystis but is actually tuberculosis or another viral or bacterial infection. Dr. Bozette agrees that patients should only be treated with steroids after a complete and definitive diagnostic work-up because of the dangers of steroid use with diseases other than pneumocystis. Although this particular study found no statistically significant benefit with the use of steroids, when the study is interpreted in the context of all the available data about steroid use in severe pneumocystis, use of the steroids appears to remain an important recommendation. CMV Infections Intravenous ganciclovir (DHPG) is the only FDA-approved treatment for CMV infections. Foscarnet, manufactured by Astra Pharmaceuticals, is an experimental treatment in the United States which is available on expanded access to patients who have failed or are intolerant of ganciclovir; Foscarnet is also an intravenous drug. Information was presented at the conference about both of these drugs, used separately and in combination, and on various methods of administering them (for example, orally, directly into the eye using an implant, or three times weekly rather than daily). In addition, minimal information on other experimental compounds such as oral FIAU and the monoclonal antibody TI-23 was also presented. Unfortunately, there were no clinical studies of compounds which we have not already discussed in past issues of AIDS TREATMENT NEWS. There were, however, two studies on the treatment of CMV colitis and esophagitis, problems which have been inadequately studied in the past. Treatment of CMV esophagitis was effective in approximately 80 percent of the patients using foscarnet in two separate studies (W. B. 2262 and W. B. 2293), with resolution of symptoms and clearing of CMV organisms in biopsy tissue. In one study, patients were only treated for three weeks; three of the fifteen participants experienced a recurrence of their CMV within seven months. Two of these three were successfully retreated and remained asymptomatic after nine months (W. B. 2262). The second study utilized on-going maintenance treatment, with a 79% success rate, although three of the seven patients experienced complications of their esophagitis (strictures) and survival did not seem to be greatly improved with treatment. The rate of improvement of CMV colitis symptoms and biopsies was similar to the esophageal improvements in the maintenance study, but less successful in the three week only treatment study. Only eleven of 22 patients experienced biopsy clearance of CMV after the three week treatment, and most continued to have diarrhea. The authors of the presentation attributed the diarrhea to the presence of other organisms in addition to the CMV. An encouraging report on the treatment of a five year old girl who had failed sequential ganciclovir and foscarnet therapies described success using a combination of the two drugs (W. B. 2286). There was no significant toxicity with this combination, and it was effective in preserving her vision. The ACTG is currently implementing a study to compare the use of ganciclovir and foscarnet concurrently, as in this case, or on an alternating basis. There are theoretical advantages and disadvantages to each approach, including the hope for decreased toxicity and increased effectiveness. One of the disadvantages of concurrent therapy is the need to use two intravenous infusions each day. However, until effective oral drugs are readily available, we consider the development of creative uses of ganciclovir and foscarnet together and/or in alternation to be important. An alternative approach to oral or intravenous therapy is the deposition of the drug directly into the eye. Ganciclovir can be administered by intravitreal injection to patients who cannot tolerate systemic therapy. Initial animal studies of intravitreal foscarnet have suggested a dose which is expected to be effective and minimally toxic (W. A. 66). This approach is obviously not an attractive one, but may be an important option for those who cannot tolerate systemic therapy. An intraocular device which contains ganciclovir was placed in the eyes of eight patients with CMV retinitis (W. B. 2255). The device releases ganciclovir over 120 days and is placed surgically, using local anesthesia. This approach was effective, with stabilization or regression of the retinitis in all of the treated eyes. There were some complications, however, including two retinal detachments and a change in the ability to focus (astigmatism) in one patient. It is unclear from this small number of people whether the rate of retinal detachments was similar to, or higher than, the usual detachments seen with CMV retinitis (approximately 15-20%). This approach may offer an alternative to intravitreal injections for people who cannot tolerate systemic therapy. One serious concern in the case of CMV, however, is that it often causes disease in multiple organs, making systemic therapy preferable in those who can tolerate it. We reported from last year's Sixth International Conference on AIDS in San Francisco on a small series of patients from Australia who used ganciclovir three times a week (see AIDS TREATMENT NEWS #108). This year, there was another report using the same regimen, i.e. 30 mg/kg/week divided into three doses, in contrast to the standard 5 to 6 mg/kg/day, five or seven days per week (W. B. 2354). This approach would be more convenient than a daily intravenous infusion. We spoke with Stephen Follansbee, M. D., an Infectious Disease consultant in San Francisco, who said that he would be uncomfortable using this regimen. He explained that early pharmacokinetic studies with the 6 mg/kg dose demonstrated that there was no drug in the bloodstream at the end of 24 hours. Although he was unsure of similar data with the larger dose, from his experience he feels that it is necessary to use the drug seven days per week in order to adequately control CMV progression. In addition, the U. K. study showed an unexpectedly high rate of thrombocytopenia (decreased number of platelets, a type of blood cell), which Dr. Follansbee believes might indicate a toxicity from the higher dose. William Buhles, D. V. M., Ph.D., from Syntex, the manufacturers of ganciclovir, explained that Syntex has never directly compared daily vs. thrice weekly ganciclovir therapy. He did express concern about the potential danger of infusing this higher dose, since some central nervous system toxicity has been seen with high plasma levels and rapid infusion of the drug. (Dr. Follansbee does not feel that central nervous system toxicity is a significant concern.) However, the retinitis progression rates seem similar to those seen with daily therapy. Dr. Buhles believes a controlled trial would be warranted if it was believed that enough benefit would be gained by patients with this dosing schedule. Syntex does not plan to run such a trial, however, because they are focusing on developing oral ganciclovir, about which they are very optimistic. CMV cultures were shown to clear in the majority of patients treated with oral ganciclovir (W. B. 2309), suggesting that enough of the drug is being absorbed to be effective, and studies of this compound are ongoing for CMV retinitis (see AIDS TREATMENT NEWS #124). Syntex is also planning an important CMV prophylaxis study with oral ganciclovir. Unfortunately, a small study of oral foscarnet suggested that it is not adequately absorbed to treat CMV infections; adjusting the acidity of the stomach did not improve absorption (W. B. 2115). FIAU is an oral compound which is being studied at increasing doses for safety and tolerance. Nausea and vomiting seem to be common side effects. Only a single study was presented on this compound, and no efficacy information was included (W. B. 2290). The drugs discussed above are all antivirals with activity against CMV. Another approach to treating CMV involves the use of a concentrated solution of antibodies, similar to the antibodies produced by the healthy immune system to fight disease. Several studies have been conducted in other immunosuppressed patients, including bone marrow and renal transplant recipients, with a mixture that is rich in CMV antibodies. These studies suggest a positive prophylactic and treatment effect in these HIV negative patients. (For a good review article, refer to Snydman, D. R., Cytomegalovirus immunoglobulins in the prevention and treatment of cytomegalovirus disease. Reviews of Infectious Diseases, September-October 1990; volume 12, supplement 7.) A more specific approach is to make a monoclonal antibody, i.e. many copies of a single antibody which is believed to be effective in neutralizing the virus. For the past two years, small studies of a monoclonal antibody called TI-23 have been reported on at the International Conference. Last year, an initial safety study suggested that TI-23 was safe. This year, there was a report of a study in 13 patients, eight with CMV retinitis and four with gastrointestinal CMV disease (W. B. 2291). Patients were treated with the intravenous formulation weekly for eleven weeks, and then continued treatment on a compassionate access basis if the treatment was effective, for up to 350 days. Unfortunately, retinitis progressed in four of the eight patients; gastrointestinal symptoms were reduced in two of the three who were treated on the extended compassionate basis. While TI-23 does not yet seem to be more effective than ganciclovir or foscarnet, it may prove to be useful in combination with these other drugs. It may be possible to identify more effective antibodies than TI-23. Monoclonal antibody technology is important for AIDS treatment activists with an interest in CMV to follow closely. Two case reports described patients with symptoms of chronic sinusitis who were found to have CMV infections of their sinuses (M. B. 2182). These patients responded to ganciclovir therapy and surgical drainage. Sinus cultures, unfortunately, were negative, and diagnosis required microscopic examination of biopsy tissue. It is important to consider that CMV may be a treatable cause of chronic sinus symptoms in some patients. Toxoplasmosis Common treatments for toxoplasmosis include pyrimethamine plus sulfadiazine or pyrimethamine plus clindamycin. An oral presentation of a study in 216 people with toxoplasmosis found no statistically significant difference in the effectiveness of these two combinations, although there was a trend towards fewer treatment failures with the sulfadiazine-pyrimethamine combination (W. B. 30). The types of side effects were different with the two regimens, occurring slightly more often with sulfadiazine. A trial of 566C80 in eight patients who had failed or were intolerant of standard therapy showed improvement in 6 patients, stable disease in one, and progressive symptoms but a stable MRI in one (W. B. 31). See AIDS TREATMENT NEWS #123 for information on ongoing clinical trials with 566C80 for people with toxoplasmosis or call 1-800/TRIALSA. Two very small studies of FDA-approved drugs which are not normally used for the treatment of toxoplasmosis, including doxycycline (M. B. 2027) and a combination of clindamycin and 5- fluorouricil (5-FU; M. B. 2003) were also presented. 5-FU is a cancer chemotherapy drug with significant side effects. In combination with clindamycin, it was claimed to be effective in nine out of ten cases of toxoplasmosis in eight patients who had failed or were intolerant of standard therapy. Doxycycline is an antibiotic which was associated with clinical and radiologic improvement in two patients. Several studies of pyrimethamine for the prevention of toxoplasmosis are currently ongoing. Clindamycin was also being studied but has been dropped from the protocol because of an unexpectedly high rate of side effects. A study using twice weekly dapsone (100 mg) plus pyrimethamine (25 mg) for the prevention of pneumocystis and toxoplasmosis was presented (W. B. 2185). Two of 109 patients developed pneumocystis. Twenty-six individuals were antibody positive for toxoplasmosis, indicating that they have been exposed to the organism and are at risk of developing disease; none developed toxoplasmosis with a mean follow up of 16 months. The incidence of toxoplasmosis will also be assessed in the on-going ACTG pneumocystis prophylaxis trials. The development of agents which are effective in preventing both infections must be a high priority in current and future prophylaxis trials. MAC (or MAI) Rifabutin is currently being tested in clinical trials for the prevention of MAC and for treatment in combination with a multi-drug regimen. Results from a study of 90 patients who received rifabutin under a compassionate access program showed an over-all symptom improvement rate of 72% (W. B. 2300). Most of these people used rifabutin in combination with one or more other anti-mycobacterial drugs. Treatment and prophylaxis studies using rifabutin are on-going (800/TRIALSA). According to Beverly Wynne, Ph.D., rifabutin project leader and associate director of anti-infectives from Adria Labs, compassionate access to rifabutin will only be granted by Adria on a case by case basis. Physicians can call Dr. Wynne at 614/764-8307. Clarithromycin, a new macrolide antibiotic, is also being studied as a treatment for MAC. A very small study tested combination therapy with INH, ethambutol and clofazimine plus placebo or clarithromycin for six weeks, followed by twenty-four weeks of clarithromycin plus rifabutin, followed by clarithromycin alone (W. B. 2358). Although there appeared to be a greater response in the clarithromycin group as opposed to the placebo group, a total of only nine patients were studied, so definitive conclusions cannot be drawn. Finally, a test-tube study suggested that an experimental antibiotic called sparfloxacin may be as active against MAC as clarithromycin and azithromycin (W. A. 1051). Cryptococcal Meningitis Standard treatments for cryptococcal meningitis include amphotericin B and fluconazole. Small studies presented at the conference confirmed the utility of high dose fluconazole (800 mgs; W. B. 2287) and suggested that the addition of flucytosine to 400 mg fluconazole might increase it's effectiveness, in spite of some gastrointestinal and bone marrow toxicity (W. B. 2337). A new form of amphotericin B, liposomal amphotericin, was discussed in two small studies (W. B. 2305 and W. B. 2177). As expected, this formulation was effective and more tolerable than standard amphotericin. A prophylaxis study of cryptococcal meningitis using 100 mg fluconazole daily, compared to a historical control group, suggested that fluconazole is effective in preventing crypotococcal meningitis. One case of meningitis developed in 329 treated patients with fewer than 68 T-cells, whereas sixteen cases developed in 337 untreated historical controls (W. B. 2279). Unfortunately, there was no significant difference in the number of patients who developed histoplasmosis, indicating that fluconazole is not effective in preventing this fungal infection. Cryptosporidiosis Several agents have been proposed as treatments for cryptosporidiosis, and some patients have been reported in small studies and case reports to respond to each, although none has been found effective in all patients. Paromomycin (Humatin) was reported to improve the symptoms of cryptosporidiosis in 30 of 31 episodes in 22 patients (M. B. 2270). Five individuals experienced a relapse of symptoms; all five improved when retreated with paromomycin. An unconventional approach, using fluconazole, was reported to be effective in four patients. All four improved clinically, with some reduction in the amount of cryptosporidium present in the stool (M. B. 2199). It is questionable, however, whether or not this approach will be useful, as several physicians with whom we have spoken know of patients who are using fluconazole for other reasons, yet still have cryptosporidiosis. Microsporidiosis A report about five patients from the U. K. treated with albendazole, a broad spectrum antiparasitic drug which is used for various worm infections, demonstrated clinical improvement in all of them (W. B. 2265). This drug is approved in the U. K. for cestode infections (a type of worm) and is available in some other European countries. It is still investigational in the U. S. and is manufactured by Smith Kline &French. Metronidazole (Flagyl) demonstrated symptomatic benefit in fifteen of twenty- two patients with microsporidium (W. B. 2267). Twelve of these patients relapsed; most responded to re-treatment. Neither of these studies was large or controlled, so it is difficult to assess the true usefulness of these compounds. However, these encouraging preliminary results should certainly be followed up. PML A report of three patients with PML who were treated with multiple courses of the cancer chemotherapy drug ARA-C (cytosine arabinoside) demonstrated improved symptoms and decreased lesion size on MRI exam, but only after a minimum of three courses of treatment (M. B. 2037). A controlled study is being planned by these investigators who believe that negative results with ARA-C reported in the past may have resulted from an inadequate course of treatment. Mycoplasma Finally, Dr. Luc Montagnier attracted a significant amount of attention at the Sixth International Conference on AIDS in San Francisco last year with his announcement that a mycoplasma was an important co-factor in the development of AIDS. His research team presented results of an antibiotic treatment study which attempted to eradicate mycoplasma with the experimental antibiotic sparfloxacin (W. B. 2176). Unfortunately, markers of mycoplasma presence were not reduced with this treatment, which was potent in test-tube studies, nor were there any improvements in clinical or laboratory markers of the progression of HIV disease. ***** Newly Recognized, Treatable Organism May Mimic KS -- or Other AIDS Diagnoses by Denny Smith A newly described micro-organism has been found to cause opportunistic infections in persons with HIV -- infections which can mimic symptoms of Kaposi's sarcoma (KS) and Mycobacterium avium complex (MAC, also called MAI). The infectious agent is a previously unknown bacillus which is believed to be related to Rochalimaea quintana. The bacillus was thoroughly discussed last December 6 in a group of reports in The New England Journal of Medicine. Infection with this organism can lead to bacillary angiomatosis, hepatic peliosis, bacteremia, and possibly cat- scratch disease. Last month, Colin Blakeney, a friend of AIDS TREATMENT NEWS and a member of ACT UP/San Francisco, called us to share first hand experience with this infection. We want in turn to share with readers what he learned, as well as some observations of a national expert on the new bacillus, Philip E. LeBoit, M. D., a pathologist at the University of California San Francisco School of Medicine. Since January of this year, Colin had been experiencing symptoms suggestive of infections of Mycobacterium avium complex (MAC, or MAI): intermittent chills, very high fevers, anemia and loss of appetite. Several months earlier he had been diagnosed with Kaposi's sarcoma, based on a biopsy of a single lesion. After more than 100 various tests failed to explain Colin's constitutional symptoms, doctors removed one of his lymph nodes. An analysis of the node revealed the same infection described above. He was started on 1500 mg daily doses of the antibiotic ciprofloxacin, and the symptoms responded within several days. Unfortunately, the ciprofloxacin seemed to stop working after two weeks, and he was switched to doxycycline, which has apparently worked for the last four weeks. His doctors are now suspicious of the lab report that identified the KS lesion. Because of the nature of angiomatosis, they are re-evaluating the biopsy to rule out the possibility that the lesion was misidentified as KS. Colin feels that it is now very important for everyone with HIV, and their primary physicians, to be aware of the possibility of this bacillus posing as other opportunistic infections or as KS. Although the particular species of this bacillus has not been named or categorized yet, its discovery might have some very important consequences. For example, how many people who have been diagnosed and treated for symptoms of KS, or MAC, actually are dealing with this bacillus? Could this explain why some people do not respond to the current KS and MAC therapies? Could this explain why the empirical use of antibiotics like doxycycline seems to help symptoms which have eluded diagnosis? What is the potential for this bacillus to operate as a cofactor in the progression of HIV, as mycoplasma and herpes infections have been alleged to do? We are eager for answers to such questions, answers which might go a long way toward solving the puzzle of HIV disease. Dr. LeBoit has been working toward those answers. He told us that this bacillus has no doubt existed since before the AIDS epidemic, but probably does not cause disease in persons without immune deficiency. Unfortunately, nearly all of the symptoms associated with the bacillus -- fevers, profound anemia, lymphadenopathy, splenomegaly and skin lesions -- can easily be attributed to other opportunistic conditions. In view of the skin lesions and the prevalence of KS in the epidemic, Dr. LeBoit estimates that potentially one of every fifty KS diagnoses is actually angiomas caused by this bacillus. This could explain why some people's lesions never respond to chemotherapeutic agents, as well as why some "MAC-type" symptoms persist during MAC treatment. However, the bacillus does respond effectively to some antibiotics; Dr. LeBoit's first choice is erythromycin, 2 grams daily. He feels that doxycycline is an effective choice as well, only more expensive. Treatment in this case is simpler than diagnosis, which must be done by a knowledgeable pathologist. Pathologists and clinicians alike who are interested in the criteria for identifying this infection, which may include a liver biopsy, can obtain them in an early article describing the bacillus -- volume 13 of the American Journal of Surgical Pathology, 1989, pages 909 to 920. Dr. LeBoit emphasized that non-dermatologists working without a biopsy cannot definitively diagnose the infection. ***** MAC (MAI) Clarithromycin "Open Trial" Announced Persons with mycobacterium avium complex (MAC, also called MAI) may now qualify for clarithromycin treatment through an "open trial" protocol being run by Abbott Laboratories. Clarithromycin, the most important new treatment for MAC, is also available by importation from countries where it has been approved. The advantage of the Abbott program is that there is no cost to the patient for the drug, or for the laboratory tests required for the protocol. The open trial also assures consistent medical monitoring. Who is Eligible? The entry criteria for this clarithromycin open trial are: * Patients must be HIV-positive; * They must have a lab slip documenting a positive MAC culture; * They must usually be age 12 years or older; however, younger children may be accepted after case-by-case medical review. * Women usually need a negative pregnancy test; pregnant women, however, might still be accepted after medical review. * Patients must give informed consent. Three visits are required in the first 12 weeks for laboratory tests: blood chemistry, and MAC culture. After 12 weeks, in the maintenance phase of the protocol, visits are required every three months. While Abbott provides the drug and tests for free, it will not reimburse for cost of the office visit or associated expenses such as transportation; these are the responsibility of the patient. Other treatments for MAC must be discontinued during the first 12 weeks; later, treatment can be adjusted under guidelines given to the physicians. Note that there are ongoing formal trials of clarithromycin for both pediatric and adult AIDS-associated MAC. Some patients asking to join the open-trial program may be referred to one of these. What Physicians Must Do While some paperwork is necessary to meet FDA requirements, Abbott Laboratories has done everything possible to minimize it -- running an information center staffed by people trained to help, and even filling out all except site-specific information in FDA forms. IRB (Institutional Review Board) approval is required. If the physician's institution does not have an IRB, Abbott has contracted with an independent IRB to meet the requirements. If the physician does have a regular IRB, it must be used; it cannot be circumvented by Abbott's. A minimum of five documents is required: * A curriculum vitae for the physician (or for the principal investigator and sub-investigators); * A one-page FDA form; * The informed consent form, including physician's name and phone number; * A letter from the IRB stating that it has reviewed and approved the protocol and informed consent; and * Two pages in the protocol signed by the physician and returned. Medicine is dispensed on a per-patient basis, within 48 hours when patient first enters the study, later within 24 hours. Abbott strongly encourages physicians to do the paperwork now, even before they have any patient who qualifies for the program. That way the drug can be available as soon as needed. (The potentially serious delay in this process is the need for IRB approval, which will require a scheduled meeting of the IRB.) Any physician interested in this program should call Abbott's Clarithromycin Information Center, which can be reached through 800/688-9118, Monday through Friday between 9 a.m. and 9 p.m. Eastern time; physicians will immediately be transferred to the correct desk. The Information Center will mail a packet containing instructions and all necessary forms to any physician who wants one. Patients also can call this toll-free number for more information about the program. Foscarnet Note: Controlling Calcium Depletion The antiviral foscarnet, used in Europe for several years, is coming into wider U. S. use to treat acyclovir-resistant herpes, and also to treat CMV retinitis when ganciclovir fails. The drug is given intravenously. A patient called our attention to certain side effects of the drug, and their successful management in several patients by his physicians at New York University. This information may not be widely known. Foscarnet can produce an abnormally low level of ionized calcium in the blood, which can cause symptoms including seizures, leg cramps, nausea, dizziness, and tingling in the feet and fingers. The standard blood test for calcium often gives a normal value; to diagnose the problem, it is necessary to test for ionized calcium, which most large medical laboratories can do. When this problem occurs, it has been managed successfully by giving intravenous calcium, before giving the foscarnet. It is very important to properly flush the catheter after giving the calcium -- which otherwise could harden and destroy the catheter. For more information, physicians administering foscarnet can call Douglas Dieterich, M. D., at New York University Medical Center, 212/986-3330. [Note: The most serious side effect of foscarnet is kidney toxicity. Certain precautions, such as making sure the patient has enough water, usually with intravenous hydration, are necessary to reduce this risk. Any problem which results in nausea, vomiting, or diarrhea can lead to dehydration and make people especially vulnerable to kidney toxicity.] ***** In Memoriam: Rene Lopez Our friend and former AIDS TREATMENT NEWS staff member Rene Lopez died on May 14. Rene came to San Francisco from El Salvador several years ago, and spent much of his time collecting treatment information for the newsletter and for Spanish-speaking friends. He was proud of the progress he had made in addiction recovery, and he often brought HIV treatment news to his recovery support groups. We will very much miss Rene's bravery and sincerity. ***** In Memoriam: Tom Hannan by John S. James Tom Hannan, age 40, one of the principal founders of the movement for community-based clinical trials, died of AIDS on June 4, 1991, at his home in Manhattan. Hannan was the volunteer administrator who worked with medical professionals and community leaders to put together New York's Community Research Initiative in 1987. He learned the complex Federal and other requirements for legally conducting treatment research with human volunteers, and showed that a community organization could sponsor such research in the offices of practicing physicians. As the organization proved itself, dozens of leading physicians joined. The Community Research Initiative served as a model for most of the similar groups which now exist across the United States. Tom's apartment, where this writer stayed during visits to New York, was filled with experimental AIDS treatments which he was using personally. Later, his openness to new treatments got Tom involved in the East Coast/West Coast treatment disputes, and fired from the organization he had started. This happened after the Community Research Initiative rejected Project Inform's proposal to conduct a trial of Compound Q. Tom, who strongly favored the proposal, quietly organized much of the CRI staff to conduct the trial outside of the organization -- one of the earliest studies of this potential treatment for AIDS. Findings were quickly presented to the FDA, and helped to speed the development of larger, formal trials of the drug. Hannan continued to serve on the IRB (Institutional Review Board) of the Community Research Initiative, until shortly before his death. As founding director of New York's PWA Health Group, Tom was also one of the pioneers of the non-profit buyers' club movement. At Tom's request, no memorial service was held. ***** Your Help Needed: Travel/Immigration Letter Writing Campaign Update by John S. James Our last issue (AIDS TREATMENT NEWS #128) included an action kit on how to write letters supporting the lifting of the ban on persons with HIV entering the United States, and a list of organizations you can contact; it also included an in-depth background article on the controversy. [If you need a copy, send a self-addressed, stamped envelope to: AIDS TREATMENT NEWS, P. O. Box 411256, San Francisco, CA 94141; ask for issue #128.] We will continue publishing updates urging people to write their own letters and to organize friends and associates to do so, and to institutionalize such grassroots lobbying as a permanent part of the AIDS community, even beyond this immediate issue. Some major points: * Not only does the current travel ban threaten to cancel next year's International Conference on AIDS in Boston, but if it is not changed, retaliation by other countries against U. S. travelers with HIV is likely -- further restricting scientific and public-health conferences and coordination, and treatment options for individuals, as well as the ordinary conduct of business. Also, such border restrictions give everyone in the world an incentive not to be tested for HIV, if they might ever have a need for international travel. (No one has proposed testing everyone at the border, which would be grossly impractical; rather, those already known to be HIV-positive are not allowed to pass.) * All we are asking for is the straightforward implementation of the Immigration Reform Act of 1990, which became law on June 1, 1991. This law clearly requires that the U. S. Public Health Department -- not the Department of Justice -- decide which diseases warrant exclusion because of the danger of contagion; the Public Health Service has determined that only active tuberculosis should be on that list. The law also allows exclusion of foreigners who are likely for any reason to cause a financial burden to the U. S. * Some people have asked why not separate short-term travel from permanent immigration -- especially since there is much concern about cost to the government of caring for foreigners with HIV. Unfortunately this issue has been widely misunderstood. The real HIV "immigration" issue concerns persons already here -- most of them here continuously for at least nine years (as required to qualify for the immigration "amnesty" program) and therefore almost certainly infected in the United States. They now face deportation to countries throughout the world, regardless of prevention or treatment programs available there. Even those who want to keep foreigners with HIV from coming to the United States often agree that deporting persons who were infected here is a reprehensible attempt to unload our own problem on others -- and an action likely to damage this country's reputation worldwide. What about intermediate cases, such as persons in the U. S. for a year or two who are found to be HIV-positive when they try to change their visa status due to marriage or a job? Decisions could be made on a case-by-case basis, using the "public charge" provision in the current law. There is no need to automatically exclude HIV-positive visitors at the border, or to deport persons who have lived in the United States for years. The Immigration Reform Act of 1990 only provides for one list of diseases for exclusion on public-health grounds. It does not allow two lists, one for visitors and the other for permanent immigrants -- a fact well known to the right-wing politicians and officials who are trying to use the image of the U. S. being overrun with HIV-positive immigrants to stop all international travel by persons with HIV. At the Seventh International Conference on AIDS last week in Florence, there was much pessimism about whether the Eighth International Conference would take place in Boston next May -- or take place at all. The general view was that the White House does not want an AIDS conference in the U. S. during an election year, since AIDS (and health care in general) is an embarrassment to the government, and a conference will generate unfavorable or disturbing publicity. If the White House is willing to sabotage next year's AIDS conference in pursuit of Republican political gains in the November election -- we do not know whether or not this is true -- then it may be impossible to remove the travel ban at this time, no matter how many letters are sent to Atlanta or Washington. This uncertainty illustrates the need for letter writing as a permanent institution in the AIDS community, whatever happens on this issue. The AIDS "corporate culture" so far has included Washington lobbying, has included high-profile demonstrations, and has included treatment information and activism. But now it must also include grassroots lobbying, such as mass letter writing to elected representatives and other public officials, in order to insure that AIDS policy reflects public-health expertise, not right-wing sabotage. Let us respond to the immediate travel/immigration issue in a way that builds the long-term strength we need. ***** 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 HIV. 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