Subject: GMHC Treatment Issues Vol. 6 No. 6 Date: July 1992 (1085 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& GMHC Treatment Issues, Volume 6, Number 6 July 1992 CONTENTS: [items are separated by "*****" for this display] Thymic Peptides: An Introduction and Overview The Thymus The Thymus and AIDS Thymus Peptides Thymomodulin Thymostimulin Thymopentin Thymosin Alpha 1 Thymic Humoral Factor (THF) "Thymo-Ripoffs" Conclusion United for AIDS Action Rally: July 14, 1992, New York City Opportunistic Infections: European Conference Update Toxoplasmosis Prophylaxis for PCP and Toxoplasmosis Cryptococcal Meningitis Mycobacterium avium complex (MAC) Microsporidiosis and Cryptosporidiois Conclusion Astra Boycott Begins Treatment Briefs Immune restoration think tank After needless FDA delays, new hepatitis C test approved The grapevine Approval for KS study New Drugs added to ADAP program AIDS Treatment Politics Clinical trials Imumuno RGP 160 vaccine trial begins HIV standard of care Treatment & Data Committee Toxoplasmosis prophylaxis study cancelled ddC approved! Correction Glossary ***** Thymic Peptides: An Introduction and Overview by Derek Link It is now obvious to researchers, doctors, and people with AIDS that antiretroviral therapies like AZT, ddI and ddC may do little to repair immunity. Community interests have consequentially turned toward therapies that may restore immunity in people with damaged immune systems. "Immune Reconstitution" have become buzz words in many AIDS circles. However, reconstitution depends on a substantial understanding of the immune system, and immunology, the branch of medicine that studies the immune system, is an infant science. While some progress has been made recently, little is actually known about the basic elements which regulate and control the normal functioning of the human immune system. The Thymus The thymus was not a well understood organ until the early 1960's, when pioneering studies showed that infant animals, whose thymus organs were removed, developed profound immune deficiencies and died. It was then discovered that these immuno-deficiencies could be partially corrected when thymic tissue was reimplanted.[1] As early as 1968, fetal thymic tissue transplantations in human infants with defective thymuses resulted in partial correction of immunodeficiencies and in clinical improvement.[2] Since those experiments, the thymus has been identified as a key immune system organ. It is thought to be responsible for the development and regulation of T cell immunity in both infants and adults. The thymus seems to exert its regulatory functions through the secretion of various noncellular, hormonelike products, called thymic peptides.[3] Thymic peptides are reported to have many effects on T cells. Several studies have reported that thymic peptides can assist development of immature, precursor cells into fully competent T cells. Thymic peptides seem to regulate the expression of various cytokine and monokine receptors on T cells and induce secretion of IL-2, interferon alpha, and interferon gamma (disease-fighting substances) when the immune system is challenged.[4] There are reports that the use of thymic hormones in children with immuno-deficiencies caused by chemotherapy has resulted in an increase in circulating T cells, normalization of T cell subsets, and restoration of delayed hypersensitivity reactions.[5] Nevertheless, the full extent of the effects of thymic peptides is still not known. For instance, do they affect cells that are not T cells? Do they regulate mature T cells? Are they involved with the neuro-endocrine system? Despite these unanswered questions, it is clear that thymic peptides are critical to the development of T cell immunity. The Thymus and AIDS From the beginning of the AIDS epidemic, research has been directed at the effect of HIV on the thymus. However, none of the reports appears to offer a consistent understanding. Some researchers report that the thymus in HIV-infected people is significantly destroyed. In particular, Dr. Grody and colleagues reported that the parts of the thymus most responsible for the secretion of thymic peptides -- epithelium and Hassall's corpuscles -- are impaired.[6] Savino and colleagues reported that the thymus glands of 13 AIDS patients studied demonstrated consistent thymus abnormalities.[7] This was not seen in any of the non-HIV-infected controls. The authors suggest that the thymus is a direct target tissue in HIV infection. Other research groups offer the exact opposite analysis. According to Dr. Schuurman and colleagues, there is no evidence of HIV infection in the thymus or signs of HIV-specific destruction.[8] It is difficult, therefore, to have a clear understanding of the role of the thymus in AIDS from published reports at this time. Thymus Peptides Although much interest has focused on thymic peptides as immune-restoring drugs, studies designed to generate data to support this claim have yet to be performed. In the best case, there is a slight hint that thymic peptides might be of some benefit. In most cases, however, data is either nonexistent or uninterpretable. It is encouraging, though, that, unlike other immune products, such as alpha interferon or interleukin-2, these agents have yet to demonstrate any significant toxicities. The various thymic peptide drugs given to HIV-infected people have produced ambiguous and, in some cases, contradictory results. Since most reports of thymic peptides in AIDS appear to be in obscure medical journals, this information remains out of reach to most physicians treating people with HIV. To understand the bewildering array of thymic peptides, the following is an overview of the most widely discussed and used thymic preparations. Thymomodulin Thymomodulin is the natural extract of calf thymus which was approved in Italy as Leucotrofina. It is used to treat bacterial and viral infections, food allergies in children, and immunodeficiencies in the elderly. Unlike most of the synthetic peptides, thymomodulin is an oral drug. It is made into syrup from filtered freeze-dried calf thymus extract. The drug's manufacturer, Ellen Pharmaceuticals, has sponsored one small, uncontrolled study in people with HIV in Rome in 1987.[9] The study, conducted by Dr. Valesini and colleagues, enrolled 15 people with HIV. All participants received 60 mg of the drug twice daily for 50 days. Two patients, those with the worst clinical condition at entry, died during the study. The other patients were all reported to have improvements in their condition and surrogate markers. No side- effects were observed. Despite these encouraging reports, the study had serious flaws. It was not randomized, double-blinded, or placebo- controlled. Additionally, there was no report of other medications used by trial participants. At the time of writing, the authors promised results of future, larger studies. No sub- sequent reports have been found in any medical literature. However, there are reports of ongoing community trials of thymomodulin in San Francisco. Thymostimulin Thymostimulin, also known as TP-1, is another natural extract from a calf thymus. No evidence indicates how it differs from thymomodulin. This drug is made by Serono Pharmaceuticals in Italy and is available only as an injectable drug. An initial study, reported by Dr. Lazzarin and colleagues in Milan, enrolled nine HIV-infected IV drug users with persistent generalized lymphadenopathy (PGL -- an AIDS-related condition consisting of swollen lymph glands).[10] Participants were given 1 mg / kg of thymostimulin each day and all were reported to have increases in T cells. Like the thymomodulin study, this study was flawed. It had a very high rate of patient dropouts who were not included in the final analysis. Additionally, several subgroup analyses were performed which were not accounted for in the original study design. A follow-up, double-blinded, randomized, placebo-controlled study using the same dose in 50 individuals with ARC failed to duplicate the results. The followup study, reported by Dr. Beall and colleagues at the University of California at Los Angeles, showed no difference in progression of disease, mean T4 and T8 numbers, or body weight in patients treated with thymostimulin or placebo.[11] The most recent study from Italy, released as an abstract at the VII International Conference, compared a combination of thymostimulin (70 mg three times a week) and AZT (500 mg daily) versus AZT alone.[12] Participants included 30 individuals (men) with asymptomatic HIV infection and T4 counts of over 400. The study suggests that the combination arm did much better than AZT alone. The authors, Dr. Barbarini and colleagues, claimed that the combination had significantly greater increases in T4 cells, improved "nutritional status," and slowed disease progression. The authors did not provide any specific information, such as actual T cell number, or baseline characteristics of the patients. This data, therefore, remains difficult to interpret. Thymopentin Thymopentin is a small, synthesized thymic peptide drug, also known as TP-5 or Timunox. In the U.S. it is being developed as an AIDS therapy by the Immunobiology Research Institute. Thymopentin has been studied more extensively than most other thymic peptide drugs. However, the results of these studies remain ambiguous due to their small size and flawed design. Nevertheless, several community physicians, including Dr. Howard Grossman in New York and Dr. Marcus Conant of San Francisco, are evaluating thymopentin through clinical trials in their own practices. Dr. Grossman reports that 52 HIV-infected participants have completed a randomized, blinded study of 300- 500 mg of AZT daily plus 50 mg of thymopentin, 3 times per week versus AZT plus placebo.[13] As of this date, the results have not been released. The initial report of thymopentin in AIDS came from Dr. Barcellini and colleagues in a small study of IV drug users with PGL in Milan.[14] The study noted improved surrogate markers in some patients who had taken 50 mg thymopentin three times a week. However, no clinical improvement was noted. Notably, many patients dropped out, and analysis of the study results is difficult. Follow-up studies by Dr. Silvestris and colleagues and Dr. Costigliola and colleagues have offered some confirmation of the original report. Silvestris conducted a year-long study following 21 patients.[15] The study claimed a significant rise in T cells and slight clinical improvement in those patients who received 50 mg of thymopentin three times a week, compared to untreated control participants. Dr. Costigliola conducted a trial of 12 patients treated with the same dose of thymopentin. Compared to the 14 untreated control participants, those taking the drug showed greater "immunologic stability" and some clinical improvement. Reported side effects of thymopentin have been limited to local pain and swelling at the site of the subcutaneous injections. Thymosin Alpha 1 Thymosin is a small synthetic peptide first characterized in the 1970's. It has just been licensed in Italy for the treatment of primary immunodeficiencies and as a booster for influenza vaccine in renal dialysis patients. The drug is being developed by Alpha One Biomedicals and is being tested in ongoing clinical trials for activity against chronic hepatitis B and C, HIV infection, and certain forms of cancer. It is by far the most thoroughly studied of all the thymic peptide drugs. However, the published results from ongoing trials remain indeterminate. The initial report of thymosin in AIDS was made by Dr. Schulof and colleagues in Washington, D. C. [16] In this phase I/II study of 42 HIV-infected men, no immunological effects, as measured by T cell increases, natural killer cell activity, HIV antibody levels, or clinical improvements were noted in patients taking 600 ug of thymosin, injected under the skin every day (4.2 mg per week). These results have led some believers in thymosin to speculate that, since the drug is an immunomodulator, it needs to be combined with an antiretroviral agent. Subsequent studies of thymosin have been performed by Dr. Garaci and colleagues at the University of Rome. Garaci's study reported that the combination of thymosin (1 mg twice weekly, subcutaneously), AZT (500 mg/day), and alpha interferon (2 million units, twice weekly, injected under the skin), resulted in increased T4 counts for a longer duration than either AZT alone or AZT with alpha interferon. During the first six months of this study, both the thymosin / AZT / interferon group and the AZT/interferon group had similar increases in T4 counts, which were both superior to the AZT-alone arm. However, after six months T4 counts in the AZT/interferon group peaked while those in the three-drug regimen continued to increase through the one-year period. This study is still underway with anecdotal reports of continued benefits seen in the thymosin/AZT/interferon group. No adverse effects or major toxicities have been observed in any patients. However, this study should be viewed with caution in light of the fact that there were only 25 people in the entire three-arm study and that reported results represent only one year of follow-up. Dr. Alan Goldstein, who first developed thymosin, disclosed to Treatment Issues that a multicenter trial is being planned for the U.S. using the same combination regimen that was used by Dr. Garaci.[17] Promising results using thymosin as a treatment for chronic hepatitis have also been reported. This may provide significant hope for the large number of HIV-infected individuals with chronic hepatitis. In a pilot study of 12 people with chronic hepatitis B infection, Dr. Mutchnik and colleagues compared seven patients treated with thymosin with five individuals who were given placebo.[18] After one year, the authors reported significantly improved liver function tests in all of the treatment group but not in the placebo groups. Loss of hepatitis B DNA was observed in six of the seven patients in the treatment group compared to one in five patients of the placebo. No significant side effects were observed. Dr. Mutchnick reports that a multicenter chronic hepatitis B trial has begun and that a trial for HIV-infected individuals with chronic hepatitis C is also being planned. Thymic Humoral Factor (THF) THF is a synthetic thymic peptide being examined as an anti-HIV treatment by researchers in France, Israel, and the U.S. Although this compound has generated considerable interest among some people with HIV, there is no clinical data at this time to support its efficacy. However, in preclinical studies in rats with CMV-related immunosuppression, THF restored immune competence through modulation of T cells.[19] In studies in humans, Dr. Handzel and colleagues in Israel evaluated THF in "asymptomatic" homosexual men.[20] Strangely enough, participants in the study were not HIV-infected; therefore, this data has limited usefulness in evaluating THF's role as an AIDS treatment. Nevertheless, Israeli researchers also report that when individuals with severe herpes virus infections were treated with THF intramuscularly, the viral infections "regressed rapidly and T-cell populations increased remarkably.[21] Treatment consisted of 2 ng/kg of THF, six days per week for four weeks. While no other clinical data has been published on the use of THF for HIV, clinical trials are presently under way at Brown University, the University of Arizona, and in France. The U.S. sites are using daily intramuscular doses of THF (from 5ng/kg to 50 ng/kg) for two weeks on, one week off, in combination with AZT. Participants in this open-label, dose-ranging study are HIV-infected and have T4 counts between 100-500. The French studies, conducted by Dr. Jean-Claude Chermann, have been the subject of rumors and hope within the community. It is believed that Dr. Chermann is using significantly higher doses of THF than that being used in the U.S. However, Dr. Chermann has not published any efficacy data at this point. Therefore, we must wait until the ongoing studies begin to yield data before this agent can be considered a truly promising therapy. "Thymo-Ripoffs" Responding to the recent surge of interest in thymic peptide drugs, several groups have made various thymic products available through underground channels. Many of the AIDS buyers' clubs are ethical and responsible community organizations helping thousands of people obtain lifesaving medication. However, there are always some blatant profiteers. We advise readers to watch out for exaggerated claims of efficacy and high prices for any underground drugs. When buying an underground drug, remember that you have a right to know who is selling the medication, how it has been priced, and who is ultimately accountable for any problems with the drug. Conclusion Presently, there is little clear scientific data to support claims that thymic peptides are effective treatments for HIV infection. Of course, they may ultimately prove to be valuable therapies, particularly since preclinical models and certain clinical reports suggest some promise. At this point, the thymic peptides have demonstrated no evidence of any systemic toxicities. With the widespread interest in these compounds and the lack of truly promising immunorestorative agents in development, it is disappointing, to say the least, that neither the National Institute of Allergies and Infectious Diseases (NIAID) nor the National Cancer Institute has initiated clinical trials designed to provide reliable information about these therapies. Moreover, few of the ongoing trials of the various thymic peptides appear to be designed to provide convincing evidence of efficacy in the treatment of HIV infection. Without well-designed clinical trials for these therapies, we will probably be dealing with ambiguous data and anecdotal reports for the foreseeable future. References: 1. Levy RH et al. Evidence for function of thymic tissue in diffusion chambers implanted in neonatally thymectomized mice. Preliminary report. J Natl Cancer Inst. 31:199-217,1963. 2. Cleveland WW et al. Fetal thymic transplantation in a case of DiGeorge Syndrome. The Lancet 2:1211-4,1963 3. Fried man H et al. Thymic Hormones. In Goldstein. Thymic Hormones and Lymphokines. Plenum Press, New York, 1984. 4. Garaci E. Enhanced immune response and antitumour immunity with combinations of biological response modifiers. Bulletin of NY Academy of Science. 65:111-119, 1989 and Werner GH et al. Immunomodulating peptides. Experientia 42:521-531,1986. 5. Trainin N. Prospects of AIDS therapy by thymic humoral factor, a thymic hormone. Nat Immun Cell Growth Regul 9:155- 159,1990 6. Grody Wet al. Thymus involution in AIDS. Amer J Clin Pathol 84:85-95,1985. 7. Savino W et al. Thymic epithelium in AIDS, an immunohistologic study. Am J Pathol. 122:302-307,1986. 8. Schuurman, Hl. The thymus in AIDS. Amer J Pathol 134:1329- 1338,1989. 9. Valesini G. A calf thymus acid lysate improves clinical symptoms and T-cell defects in early stages of HIV infection: second report. European J Cancer and Clin Oncol 23:521-531,1987. 10. Lazarrin A et al. Increase of OK-T4 positive cells during treatment with thymostimulin in parenteral drug addicts with PGL. J Clin Lab Immunol 20:57-61,1986. 11. Beall G. A double-blinded, placebo-controlled trial of thymostimulin in symptomatic HIV-infected patients. AIDS 4:679- 681,1990. 12. VII Int'l Conf on AIDS, Abstract #WB2130, Florence, June, 1991. 13. Personal communication, H. Grossman 14. Barcellini Wet al. Effect of subcutaneous thymopentin treatment in drug addicts with PGL. Clin Exper Immunol 67:537- 543, 1987. 15. Silvestris F et al. Immunologic effects of long-term thymopentin treatment in patients with HIV-induced lymphadenopathy syndrome. J Lab and Clin Med 113:139-144.1 989. 16. Schulof RS. Phase I/II trial of thymosin fraction 5 and thymosin alpha-one in HTLV-III seropositive subjects. J Biol Response Mod 5:429-443, 1986.443, 1986. 17. Personal communication, A. Goldstein, June, 1992. 18. Mutchnick M et al. Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial. Hepatology 14:409- 415,1991. 19. Katorza R et al. Restoration of immunological responses by THF, a thymic hormone, in rats inflected with murine CMV. Clin Exp. Immunol. 70:268-275, 1897. 20. Handzel ZT et al. Immuno-reconstitution of T-cell impairments in asymptomatic male homosexuals by thymic humoral factor. Intern J Immunopharmacol 9:165-173, 1987. 21. Trainin N et al. Thymic function. Lancet 338:1533,1991 ***** United for AIDS Action Rally July 14, 1992, New York City On Tuesday, July 14, 1992, United for AIDS Action (UAA) will assemble at Columbus Circle at 1 PM. The coalition is a diverse congregation of over 500 service organizations, health care providers, church communities, women's groups, unions, community organizers, volunteers, and activists. A rally will follow at 3 PM in Times Square to support a five-point program to end the AIDS crisis. This platform calls for the U.S. government to provide sufficient leadership, AIDS care, research, education, and an end to AIDS-related discrimination. Just last week, a Harvard University research group released the projection that by the year 2000, 110 million people may be infected with HIV worldwide. The need for safe, effective, and affordable treatments for AIDS is undeniable, but the U.S. government's real dollar budget for the AIDS research effort has been reduced. President Bush's 1993 budget calls for only a 3% increase in the AIDS research budget of the National Institutes of Health, while the biomedical inflation rate is greater than 12%. In order to insure adequate AIDS research, leadership, care, education, and an end to discrimination, the staff of Treatment Issues urges readers to attend and spread the word about this important event. ***** Opportunistic Infections: European Conference Update by Gabriel Torres, M. D. Much of the Third European Conference on AIDS focused on the management and prophylaxis of opportunistic infections (OI). OI management has been a high priority research focus for European scientists over the past several years. This article will focus on some of the highlights of the conference regarding innovative treatment and preventive strategies for AIDS-related infections. Toxoplasmosis The treatment and prevention of toxoplasmosis, a serious infection of the brain, has received much more attention abroad than it has in the U.S. As PCP rates declined in Europe, toxoplasmosis cases sky rocketed, especially in the southern European countries, such as Spain, France, and Italy. Therefore, large clinical trials have been conducted, seeking convenient, effective strategies against the parasite that causes the infection, Toxoplasma gondii. The European Network for the Treatment of AIDS (ENTA) conducted a multicenter trial comparing the standard treatment for toxoplasmosis, sulfadiazine and pyrimethamine, to a treatment alternative used in people with sulfa allergies, pyrimethamine and clindamycin.[1] In this randomized, open study, 342 people with an initial episode of toxoplasmosic encephalitis (inflammation of the brain) were assigned to one or the other of the treatment regimens. Of those participating, 77% had either a complete or partial response to sulfadiazine / pyrimethamine, compared to 68% who responded to pyrimethamine / clindamycin. This difference was not statistically significant; therefore, both treatments appear to be equally effective in treating toxoplasmosis. The most common side effects of sulfadiazine/ pyrimethamine were rashes and fever. These side effects caused 31% of participants taking sulfadiazine / pyrimethamine to switch to the other treatment. An equivalent percentage of participants taking pyrimethamine/ clindamycin switched over to the other treatment due to side effects, the most common of which were diarrhea and fever. Only one patient in the sulfadiazine/ pyrimethamine group had to switch over to the other treatment due to a lack of response and a worsening condition. However, 20 of the 37 participants taking pyrimethamine / clindamycin had worsening conditions due to failure of the treatment, and had to switch over to the other regimen. A second study investigated azithromycin and pyrimethamine as a combination therapy against toxoplasmosis. Azithromycin is a fairly new antibiotic from the macrolide family, which has shown activity against Toxoplasma gondii in experiments with mice. Dr. Joseph Saba of France investigated the use of 500 mg/day of azithromycin and 75 mg/day of pyrimethamine in patients with toxoplasmosis. Fourteen patients were enrolled, but four had to discontinue the treatment after three weeks due to side effects. The response was evaluated in ten patients who completed 21 days of therapy. Five had better than 50% improvement in symptoms and a reduction in the size of toxoplasmic brain lesions. One patient had a partial response. Two patients had worsened conditions or no change in their condition. Two patients were not able to be evaluated. The most ~t*m~side effects were fever and rash, vomiting, elevated liver enzymes, and hearing impairment. The overall feeling was that the combination of azithromycin and pyrimethamine was slightly inferior to the response rates which have been demonstrated with sulfadiazine and pyrimethamine, but that further studies were required using participants who could not tolerate other drugs. Finally, 566C80, an antimalarial drug, was found to be effective in a small group of participants with toxoplasmic encephalitis who failed or were intolerant of standard therapy. The original study was conducted in the U.S. at the National Institutes of Health. Burroughs Wellcome is developing a larger open trial of 566C80 as salvage therapy, but the final results are not available yet. In the meantime, a group of investigators from Belgium and France used the drug as a first choice therapy in 28 patients.2 Of the 28 participants, 23 completed six weeks of treatment at a dose of 750 mg four times daily. Thirteen patients (56%) saw a disappearance of their brain lesions or a significant decrease in the size of their lesions. Only two patients saw no change in their condition after 42 days of treatment, although they remained in stable condition. Side effects included elevated liver enzymes in ten patients, rash in six patients, and gastrointestinal problems in four. The response rate of 566C80 was slightly inferior to that of the standard therapy, but 566C80 remains a promising agent as an alternative treatment for people who fail standard therapy. Because the drug is also active against the organism that causes PCP, further investigation of this concerning prophylaxis against both infections is urgently needed. A new oral formulation of 566C80 which is thought to be absorbed better should be available soon for future trials. Prophylaxis for PCP and Toxoplasmosis Various European studies evaluated trimethoprim / sulfamethoxazole (Bactrim/Septra), dapsone/pyrimethamine and aerosolized pentamidine (AP) as a prophylaxis against PCP and/or toxoplasmosis. One large Swiss study compared a weekly dose of dapsone (200 mg)/pyrimethamine (75 mg) to aerosolized pentamidine once monthly in 364 patients with T4 cell counts under 200.[3] Five cases of toxoplasmosis occurred in these participants (one in the dapsone/pyrimethamine group and four in the AP group). One case of PCP occurred in the AP group. Unfortunately, 26% of the participants in the dapsone/pyrimethamine group had to discontinue the drugs due to side effects (fever and rashes) compared to only 2% of participants taking aerosolized pentamidine. Another Spanish group of investigators compared Bactrim/Septra three times weekly, AP (300 mg once monthly) and dapsone (100 mg)/ pyrimethamine (25 mg once weekly).[4] All three treatments were effective in preventing a first episode of PCP, but pentamidine was the best tolerated. A similar comparative trial of dapsone (50 mg/day) versus fansidar (1 tablet per week) showed similar effects in preventing both PCP and toxoplasmosis.[5] A poster presentation compared Bactrim to dapsone and found that Bactrim tended to be better in preventing bacterial infections and PCP in injection drug users (IDUs).[6] One study of AP in children (ages 5 months - 7 years) showed that the drug was not as effective as Bactrim.[7] The overall European experience demonstrates that Bactrim and the combination of dapsone and pyrimethamine can prevent both PCP and toxoplasmosis. Therefore, they may be the preferred prophylaxis regimens since they can prevent both infections, whereas AP has no activity against toxoplasmosis. Cryptococcal Meningitis Cryptococcal meningitis is a fungal infection that causes serious brain disease. Standard medicine is with intravenous amphotericin, a highly toxic drug. At the European conference, an Italian group studied a different version of the same drug which is coated with a fatty covering, making the drug less toxic to the body.[8] The drug is called liposomal amphotericin, and its brand name is Ambisome. Seven patients with cryptococcal meningitis were treated with the drug. Within two weeks, four participants responded with a decrease in the number of cryptococcal organisms in the cerebrospinal fluid (CSF) and an improvement of symptoms. Two participants remained completely free from infections for six months, although two had a recurrence of infection in the prostate gland. Two patients had a moderate response to the treatment, and one failed. The only side effect was nausea in one participant. This is a dramatic divergence from the usual side effects of amphotericin B, which are fever, chills, and kidney dysfunction. Such side effects, in fact, have been reported to occur in 100% of patients. Liposomal amphotericin is a welcome addition to fungal treatment. A French study compared fluconazole to amphotericin B in the treatment of cryptococcal meningitis.[9] The effectiveness of amphotericin B was 80%, compared to 76% with fluconazole. Amphotericin B remains the treatment of choice for cryptococcal meningitis in the U.S., although fluconazole can be used for mild episodes of disease. Mycobacterium avium complex (MAC) Several posters described small trials of clarithromycin in combination with either clofazimine or ciprofloxacin/amikacin in patients with disseminated MAC. This AIDS-defining illness is a complicated grouping of bacteria that causes severe disease late in the course of HIV disease. In a small French study, clarithromycin (2 gms/day) and clofazimine (200 mg/day) were used for two months and then the doses were reduced by 50%.[10] In 14 of 17 patients, blood samples showed that no MAC bacteria remained after only one week of therapy, and, after four months of therapy, the 14 patients were still on treatment and surviving. Only one patient stopped treatment due to liver toxicity. No relapses or resistance developed. In the second study from Italy, clarithromycin was used in combination with amikacin and ciprofloxacin in ten patients.[11] In all cases, fever disappeared within one week and blood samples tested negative for MAC bacteria in six of the seven cases. No patient had to stop treatment due to toxicity. These two small trials are very encouraging and provide some groundwork for the use of combination clarithromycin regimens in the treatment of MAC infection. It is still unclear whether the same results can be obtained using clarithromycin as a single-agent treatment. Microsporidiosis and Cryptosporidiosis Various European researchers have investigated new ways of diagnosing microsporidiosis, a severe diarrhea-causing infection that is prevalent in many AIDS patients with gastrointestinal symptoms. A group from France has developed a method of diagnosing microsporidiosis by direct microscopic examination of stool.[12] This method seems to be as effective as microscopic examination of biopsy tissue from the small bowel, which requires an endoscopy, a procedure that is invasive and uncomfortable. Other researchers reported that microsporidia in the biliary tree (passages for bile to flow in the liver) and the gall bladder may be the cause of common biliary obstruction that often leads to infection (cholangitis) in people with AIDS.[13] Another interesting study compared azithromycin, letrazuril, and paromomycin (Humatin) as treatments for people with cryptosporidial diarrhea.[14] Azithromycin (500 mg/daily) was determined to be completely ineffective in the treatment of cryptosporidiosis. Letrazuril (50 mg/day) seemed to kill the disease-causing organisms in the stool, but did not reduce the amount of diarrhea. Paromomycin (500 mg daily) improved symptoms in the majority of patients, but did not remove the organisms from stool or biopsy. Another new drug called aminoside sulfate, which had previously demonstrated anticryptosporidial activity in the test tube, was tested in five French patients with cryptosporidiosis.[15] Four of the five patients had a resolution of diarrhea and the number of organisms in the stool was reduced, making the drug a promising potential treatment for cryptosporidiosis. Conclusion European scientists seem to be quite advanced in the treatment and research of AIDS-related opportunistic infections. These results are all promising, in that they offer people with HIV and AIDS some new understanding, hope, and clarity about treatment. The ACTG and other U.S. research forces must follow suit in prioritizing research efforts that contribute to the enhancement and quality of life for people with HIV/AIDS. The prevention of OIs must become a priority for U.S. researchers. References: 1. III European Conf on AIDS, Abstract #019, Paris, March, 1992. 2. III European Conf on AIDS, Abstract #048, Paris, March, 1992. 3. III European Conf on AIDS, Abstract #034, Paris, March, 1992. 4. III European Conf on AIDS, Abstract #035, Paris, March, 1992. 5. III European Conf on AIDS, Abstract #036, Paris, March, 1992. 6. III European Conf on AIDS, Abstract #P99, Paris, March, 1992. 7. III European Conf on AIDS, Abstract #044, Paris, March, 1992. 8. III European Conf on AIDS, Abstract #027, Paris, March, 1992. 9. III European Conf on AIDS, Abstract #P182, Paris, March, 1992. 10. III European Conf on AIDS, Abstract #243, Paris, March, 1992. 11. III European Conf on AIDS, Abstract #P41, Paris, March, 1992. 12. III European Conf on AIDS, Abstract #030, Paris, March, 1992. 13. III European Conf on AIDS, Abstract #031, Paris, March, 1992 14. III European Conf on AIDS, Abstract #P28, Paris, March, 1992. 15. III European Conf on AIDS, Abstract #P175, Paris, March, 1992. ***** ASTRA BOYCOTT BEGINS by David Rephun Six months ago, Astra Pharmaceutical Products, Inc. announced that the wholesale price of their recently approved drug foscarnet (Foscavir(R)) would cost $21,500 per year. Foscarnet is one of two drugs, along with Ganciclovir (Cytovene(R)) that are approved for the treatment of Cytomegalovirus (CMV), a life-threatening disease in people with AIDS (see Treatment Issues, Vol. 6 No. 4, CMV Treatment Update). Ganciclovir costs $9,000 per year; however, there are many PWAs for whom ganciclovir is too toxic or ineffective. Thus, for many foscarnet is the only alternative, but because of its price many PWAs will be left without an option. AIDS activists have tried to convince Astra to reduce the price of foscarnet by 50% by negotiating and meeting with company representatives. But the company has refused all such requests, claiming that it has invested over $100 million into developing the drug. Activists believe that this figure is enormously inflated, particularly since only five small clinical trials were needed for the drug's approval and one of them was paid for by the U.S. government. Activists have proposed that the company either disclose how it arrived at such a figure or, at the very least, agree to have an independent accountant review the figure and ascertain whether it is accurate. The company, which recently reported a 36% increase in profits, has refused each of these proposals. The pricing of this drug will cause severe hardship to many PWAs and drain state drug reimbursement programs of available funds. Therefore, ACT UP/New York and the Treatment Action Group (TAG) have launched an international boycott of one of Astra's most lucrative products, Xylocaine(R) (lidocaine HCL). Xylocaine(R) is an anesthetic, which is most commonly used in dental practices and often referred to as "novocain." ACT UP and TAG are asking that dentists, physicians, hospitals, and clinics agree to boycott Astra's Xylocaine(R) until the price of foscarnet is reduced substantially. A number of companies including Abbott, Elkins-Sinn, and Webcon manufacture lidocaine HCL. Individuals and health care providers are being asked to write to Lars Bildman, President, Astra Pharmaceuticals, 50 Otis St., Westborough, MA 01581 or FAX (508) 366-7406 to let him know of plans to support the boycott. Derek Link, of the PWA Health Group and TAG, has turned down Astra's request to serve on its Community Advisory Board as long as the current pricing structure remains in effect. ACT UP and TAG are requesting that any other individuals invited to serve on this board refuse to do so. For information on the Astra boycott, call David Rephun at (212) 9296143. ***** TREATMENT BRIEFS by David Gold Immune Restoration Think Tank In April, Project Inform sponsored a "think tank" in which many leading researchers from around the world were invited to Washington, D. C. to discuss various options and possibilities for restoring the immune system in people with HIV. Participating researchers from the U.S. included Jonas Salk, Anthony Fauci, and Robert Redfield. Perhaps the most valuable aspect of the meeting was the forum it provided for a relatively small group of researchers to discuss basic AIDS research, disease progression, and possible mechanisms to restore immune systems. Martin Delaney and Jesse Dobson of Project Inform deserve great credit for pulling this meeting together. For a summary, call Project Inform at (800) 822-7422 (National) and (800) 334-7422 (California). After Needless FDA Delays, New Hepatitis C Test Approved The FDA has approved a second generation Hepatitis C (HCV) antibody test that is significantly more accurate for diagnosing disease and screening blood. Over 170,000 new cases of HCV occur each year in the U.S., and over 50% of these cases result in chronic hepatitis. (For details see: CDC Morbidity and Mortality Weekly Report. 40:4, 4/19/91) Chronic HCV infection seems to be particularly damaging to HIV-infected individuals. Of hemophiliacs who are co-infected with HIV and HCV, approximately 15 % die of chronic liver disease. It is estimated that the new HCV test will prevent an additional 21,000 cases of HCV from blood screening each year in the U.S. alone. The application for FDA approval of this new screening test was made in May 1991. The test has long been approved in Europe. Experts estimate that each day an additional 60 transfusion recipients became infected before implementing the new screening test with HCV every day (30 of whom would go on to develop chronic hepatitis). Despite such compelling data, the FDA did not approve the new test until March of 1992. Clearly, not enough progress has been made in forcing the FDA to approve life saving therapies and diagnostics in as rapid a manner as possible. The Grapevine Stephan Korsia at AIDS Project LA publishes "I Heard it Through the Grapevine" (IHITTG) which is a very informative and "very subjective flyer about underground HIV and AIDS treatments." The publication, which deals primarily with "alternative" treatments for HIV, is available through IHITTG c/o Stephan Korsia, AIDS Project/LA 6721 Romaine St., Los Angeles, CA 90038 Approval For KS Study Repligen, a U.S. pharmaceutical company, has received approval from the FDA to begin a phase I trial of a new drug for Kaposi's sarcoma (KS). The trial, in which PF4 (Human Platelet Factor 4) will be administered directly into KS lesions, is slated to begin at San Francisco General Hospital. The company plans to move quickly toward testing the compound for systemic (throughout the body) use in KS. New Drugs Added To ADAP Program The New York State AIDS Drug Assistance Program (ADAP), the program which reimburses people with annual incomes under $44,0000 for AIDS drugs, has added ddI (for HIV), foscarnet (for CMV retinitis), intravenous immune globulin (for the prevention of bacterial infections in children), and ten drugs for the treatment of MAC and M. tuberculosis: isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin, clofazimine, cycloserine, ethionamide, capreomycin and kanamycin. Call (800) 542-2437 for more information and a complete list of ADAP drugs. AIDS Treatment Politics Terry Beswick of the Human Rights Campaign Fund publishes a newsletter called AIDS Treatment Politics, which covers developments in federal policies and practices relating to AIDS treatment research and access. Call (202) 628-4160 for a copy. The following clinical trials in the New York area are currently enrolling participants: o Depression in HIV-Positive individuals -- using three different forms of psychotherapy and one arm of psychotherapy and antidepressant drugs, Cornell Medical Center (212) 746-3921 o Peptide T as a treatment for painful peripheral neuropathy, Mount Sinai Medical Center (212) 241-8748, St. Lukes (212) 523-6722, Columbia Presbyterian (212) 305-8507-AZT/ ddI or AZT/ddC, Harlem Hospital (212) 694-4034. Immuno RGP 760 Vaccine Trial Begins A Phase I clinical trial for recombinant gp160 vaccine in HIV-positive individuals with CD4 counts of over 600 has begun at three U.S. sites. Immuno AG's gp160 differs from the gp160 being developed by MicroGenesis in that it is produced in mammalian cells rather than insect cells. The company has assured activists that it would begin trials for individuals with CD4 counts of between 200-500 and also 50-300 in the near future. Trial sites are in Baltimore (301) 955-4345, Nashville (615) 343-2437, and St. Louis (314) 577-8648, and 454-0058. In a related matter, a trial for the MicroGeneSys version of gp160 is underway at St. Vincent's Hospital in New York City. Call (212) 79()-8319 for details. HIV Standard of Care ACT UP Philadelphia has published an informative paper suggesting important components of what may be considered the standard of care for HIV disease. Call (215) 731-1844 for a copy. Treatment & Data Committee For those in New York who are looking to get involved in treatment activities, the Treatment & Data Committee of ACT UP/NY meets every Wednesday evening at 8PM at the Gay and Lesbian Community Center, 208 W. 13th St, NYC. Toxoplasmosis Prophylaxis Study Cancelled One of the largest studies sponsored by the Community Program for Clinical Research on AIDS (CPCRA) comparing pyrimethamine (Daraprim) to placebo for primary prophylaxis of toxoplasmosis has been closed. The halted trial indicated that participants on placebo survived longer than participants taking the drug Pyrimethamine. Interestingly, the study also found that patients who were taking Bactrim/Septra (TMP/SMX) or dapsone to prevent PCP had lower incidences of toxoplasmosis. However, this finding is inconclusive because the trial was not designed to make recommendations about TMP/SMX. Nonetheless, many interpret the finding to mean that TMP/ SMX should be strongly considered for prevention of both toxoplasmosis and PCP in patients with under 200 T4 cells. The most effective, least toxic dose for toxoplasmosis prevention is unknown at this time. ddC APPROVED! Hoffmann-La Roche released news that in June the FDA approved its anti-HIV drug, ddC (brand name HIVID). The drug will soon be available by prescription in combination with AZT for adults with less than 300 T4 cells with demonstrated deterioration. The approval was based on two small studies in which people who had never taken AZT were given the combination therapy AZT and ddC, and compared to two groups who received AZT alone. The group receiving combination therapy had a higher and more sustained increase in T4 cells. The basis for the FDA approval, nonetheless, remains controversial since it relies on T4 counts alone. Correction The correct phone number for Alfonse D'Amato's Washington office is (202) 224-6542. Call and let the Senator know if you support fetal tissue research. ***** Glossary Cytokine: A hormone-like substance that is produced and released by lymphocytes. Double-blinded: A kind of trial in which neither the participants nor the doctors know who is receiving the experimental drug and who is receiving placebo or other treatments. Efficacy: Effectiveness at the dose tested and against the illness for which it is prescribed. Hepatitis B: A serious liver disease caused by a sexually transmitted virus, called hepatitis B virus (HBV). Tests and vaccines for Hepatitis B are widely available. Hepatitis C: A live disease that is similar but somewhat milder than hepatitis B. Sexual transmission does not appear to be a major route. IL-2: A substance made by the immune system to fight off viruses and bacteria, called interleukin-2. It has been manufactured as an immune-modulating drug. Immunity: A natural or acquired resistance to a specific disease; the general ability of a body to fight off disease. Interferon: A substance secreted by an infected cell which strengthens the defenses of nearby cells that are not yet infected. These substances are named differently according to their activity (interferon alpha, interferon gamma, etc.) and some have been manufacturered into immune-modulating drugs. Neuro-endocrine system: The hormone system that is related to the central nervous system, including the brain. Placebo-controlled: A kind of study in which the experimental treatment being tested is compared to no treatment at all. Randomized: A kind of trial in which participants randomly receive one of the treatments being studied or a placebo. Renal: Of or relating to the kidneys. Resistance: Diminished effectiveness of a drug against a disease-causing organism. Surbcutaneous: Injected directly under the skin. Surrogate markers: Levels of cells or proteins that indirectly indicate HIV activity and are used to mark disease progression. Toxic side effect: A range of many reactions by the body when a beneficial medicine is also poisonous to some part of the body. ***** TREATMENT ISSUES EXECUTIVE EDITOR David Gold EDITOR Mary Beth Caschetta MEDICAL CONSULTANT Gabriel Torres, M. D. TECHNICAL COORDINATOR Paul Warren COPY EDITOR Gary Schmidgall WRITERS Gabriel Torres, M. D. Derek Link David Rephun DESIGNER Stephen de Francesco PRODUCTION MANAGER Bill Boedeker PROOFREADER Steven Humes OFFICE VOLUNTEERS Joseph Evans David Feiden Edward Friedel Suzanne Gilman Eric Goldsborough Gary Schmidgall Frank Schhramm STUDENT INTERN Julie Francis Treatment Issues is GMHC's newsletter devoted to providing reliable information on experimental therapies. Describing an experimental therapy should not be construed as recommending it. All new treatments should be conducted under a physician's care. Treatment issues is published ten times yearly. All rights reserved. Non-commercial reproduction is encouraged. Subscription lists are kept confidential. Treatment Issues is supported in part by contributions made to the Richard Dunne Memorial Fund. Medical Information 129 West 20th Street New York, NY 10011 (c)1992 Gay Men's Health Crisis, Inc. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display