Subject: GMHC Treatment Issues Vol. 6 No. 1 Date: Jan 1992 (1375 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& GMHC Treatment Issues, Volume 6, Number 1 January 1992 Contents: [items are separated by "*****" for this display] 566c80: New Weapon Against PCP and Toxoplasmosis Surrogate Markers: Overview and Update More Information About Surrogate Marker Tests [Side bar] Treatment Briefs: Azithromycin, Proposed AIDS Definition, Dronabinol, Vitamin B-12 Trials, Roka Substance Tested, Fauci on AIDS Funding, Notes Cimetidine Protease Inhibitors: Development Glossary Miscellaneous ***** 566c80: New Weapon Against PCP and Toxoplasmosis by Gabriel Torres, M.D. 566c80, originally manufactured by Burroughs Wellcome to treat malaria, is a new oral drug that also works against Pneumocystis carinii and Toxoplasma gondii. These two parasites commonly cause opportunistic infections in persons with advanced HIV disease. Initial research with mice has shown 566c80 to be 100% effective in preventing and treating PCP.[1] Unlike other anti-PCP drugs, 566c80 seems to kill the disease-causing organisms, rather than just halt their growth. HUMAN STUDIES FOR PCP An early human study showed that 566c80 was safe and tolerable in doses up to 3000 mg/day in HIV infected patients.[2] The study included 24 HIV-positive volunteers who took different doses for several weeks under close observation. It was found that the drug requires food intake in order to be absorbed in the body. The most significant side-effect was a rash that developed in one patient, but it resolved without stopping drug therapy. A follow-up study of 566c80, conducted by Dr. Judith Falloon and co-workers at the National Institutes of Health, was recently published in the New England Journal of Medicine.[3] In this trial, 34 AIDS patients with mild-to-moderate PCP took three different doses of the drug. All patients survived the illness. Twenty-seven patients (79%) were successfully treated with 566c80 alone. The drug was stopped in five patients who did not respond to treatment. Two patients developed a rash and two a fever, which caused them to stop taking the drug. Nine patients had rises in liver enzymes, but none of these participants needed to stop therapy. In this study, several patients were also taking AZT or ganciclovir for CMV; none seemed to react adversely to the combination. All patients received some other form of PCP prophylaxis after treatment with 566c80. Of the 27 involved, 7 (26%) had recurrences of PCP within six months. Some of these recurrences may have been due to a failure of the drug aerosolized pentamidine (AP), since AP was the prophylactic drug administered to 65% of the group. Most of the participants were treated as outpatients and therefore avoided hospitalization. All of the doses seemed to be effective in treating PCP. The dose that was chosen for further testing was 750 mg taken three times daily with food. RESULTS OF A LARGE-SCALE HUMAN TRIAL Burroughs Wellcome has just completed the first large-scale human trial of 566c80, and the data are being analyzed. This trial compared 566c80 to trimethoprim/sulfamethoxazole (TMP/SMX, brands are Septra and Bactrim). More than 400 patients with mild-to-moderate PCP participated at 39 sites throughout the U.S., Canada, and Europe. Early analysis of the data suggests that patients treated with 566c80 have nearly as good a response as patients treated with TMP/SMX. Twenty-five percent of Bactrim/Septra patients stopped therapy due to side-effects, compared to only 10% of 566c80 patients. However, it seems that slightly more patients had no response at all to 566c80 than had no response at all to Bactrim/Septra. 566c80 EXPANDED ACCESS Currently there are two different expanded access plans for 566c80. In mid-November, Burroughs Wellcome made the drug available to patients with mild-to-moderate PCP. These patients must be intolerant of, or non-responsive to, Bactrim/Septra, which is standard therapy for PCP. The most common ways people show intolerance of Bactrim/Septra are skin rashes, bone marrow toxicity (lowering of the white blood cell counts or platelet counts), hepatitis, kidney dysfunction, nausea, vomiting, diarrhea and hallucinations. The second program is available for patients with severe PCP who are intolerant of Bactrim/Septra and pentamidine. In order to access 566c80, physicians must call 1-800-755- 2020 and request the drug, which will be shipped within 24 hours. The amount of paperwork required in these expanded access protocols is minimal; thus Burroughs Wellcome should be commended for providing very easy access to the drug. Excessive paperwork is usually the limiting factor in the success of expanded access programs. The 566c80 programs are sure to attract many physicians and patients since they are easy to use. The programs may well prove to be life-saving for many people who can not tolerate or who deteriorate on standard therapy. So far, reported side-effects of 566c80 include rashes, headaches, diarrhea, fever, elevated liver enzymes, and nausea. These side-effects are seen in 10% - 25% of patients, but for the most part they are mild and generally do not require that therapy be stopped. 566c80 FOR TOXOPLASMOSIS Animal studies show that 566c80 works well against toxoplasma gondii, the parasite which causes toxoplasmosis, a serious brain infection common in people with AIDS.[4] At the VIIth International Conference on AIDS in Florence, Italy, Dr. Henry Masur presented the results of the first 566c80 study in patients with toxoplasmosis of the brain who were intolerant of or failing standard therapy (sulfadiazine/pyrimethamine or clindamycin/pyrimethamine). Of eight patients treated, six improved. Brain scans showed that one patient remained stable and one deteriorated due to HIV dementia. Only one patient on 566c80 had a recurrence of toxoplasmosis, apparently because the drug was not well absorbed in this patient. Burroughs Wellcome is sponsoring an open clinical trial for patients with intolerance or failure of standard toxoplasmosis therapies. In New York trials are open at St. Vincent's Hospital (contact Michael Thorn, R.N. tel: 790-8319) and at Harlem Hospital (contact: Wafaa El-Sadr, M.D. tel: 694-4034). It is anticipated that, if the results of this trial are positive, 566c80 may also be made available under expanded access for patients with toxoplasmosis. PROPHYLAXIS WITH 566c80 566c80 seems to be one of the most promising agents for preventing the onset of PCP. The drug is oral, which means patients using it may well avoid hospitalization. It is also well tolerated with few side-effects and may prevent multiple opportunistic infections. A prophylaxis trial comparing 566c80 and TMP/SMX in adults with PCP has been discussed for several months and should be available in the near future. A pediatric prophylaxis trial is open at Duke University in NC (Contact: Ross McKinnney at 919- 684-6335) and at St. Jude's Children's Hospital in Memphis TN (Contact: Walter Hages at 901-522-0485). Burroughs Wellcome is trying different new oral formulations, so that absorption is less dependent on food intake. If all goes well, the new formulation will allow the company to proceed with the prophylaxis trial, perhaps by the summer of 1992. REFERENCES 1 Hughes WT et al. Efficacy of a hydroxynapthoquinone, 566c80. in experimental Pneumocystis carinii pneumonitis. Antimicrob Agents Chemother 34: 225-8,1990. 2 Hughes WT et al. Safety and Pharmakokinetics of 566c80, a hydroxynapthoquinone with anti-Pneumocystis carinii activity: A Phase I study in HIV-infected men. J Infec Dis 163: 843-48, 1991. 3 Falloon J et al. A Preliminary Evaluation of 566c80 for the treatment of PCP in patients with AIDS. N Engl J Med 325: 1534- 1538, 1991. 4 Araujo FG et al. Remarkable in vitro and in vivo activities of the hydroxynapthoquinone 566 against tachyzoites and tissue cysts of Toxoplasma gondii. Antimicrob Agents Chemother 35:293-99, 1991. ***** Surrogate Markers: Overview and Update by Kevin Armington INTRODUCTION Ever since AIDS was recognized in 1981, the medical establishment has grappled with how exactly to describe the disease and monitor its progression. A major obstacle to monitoring the disease is that measuring the amount of HIV in the human body is extremely difficult. HIV is notoriously difficult to track, since it mutates rapidly, and is difficult to grow in the test tube. No reliable, standardized lab test that measures HIV accurately is yet available. However, many health care workers have been monitoring disease progression of HIV by measuring quantities other than virus levels. Measurements that reflect HIV activity, such as T4 cells, are referred to as "surrogate markers." These are "surrogate" because they do not report the absolute amount of HIV, but the secondary effects of the virus on the immune system. The information provided by surrogate markers is very useful and can guide treatment decisions, as well as monitor the efficacy of experimental treatments in human research. Researchers and activists are constantly engaged in debates about which markers are the most reliable, practical, and predictive of HIV progression. As with most aspects of AIDS, the dialogue about surrogate markers resonates with political implications. for instance, the use of surrogate markers to measure a drug's efficacy may significantly shorten human trials and make experimental drugs available more expediently. Additionally, the use of surrogate markers as a way of defining AIDS will directly determine who receives a diagnosis of AIDS or ARC, who receives financial entitlements, who receives medical treatment, how research efforts are conducted, and how the full scope of the epidemic is understood. IMMUNOLOGIC MARKERS Most surrogate markers are components of the immune system. These include different types of cells, such as T4 and T8 cells. In addition, proteins secreted by immune system cells, like neopterin and beta-2 microglobulin, are used as surrogate markers. It is important to keep in mind that these markers are indirect measurements of HIV. Nonetheless, clinicians have been following some of these markers for years, and using the information, to help decide if and when patients are to begin treatment. The current community trend, according to physicians interviewed for this article, is to consider several of the following markers together, as a way of accurately monitoring HIV progression. A fluctuation in one single marker may not call for drastic action, especially when a number of other markers remain steady. It is therefore important to try to draw a complete picture of the impact of HIV on the immune system in order to make informed treatment decisions. Beta-2 Microglobulin Early in the AIDS epidemic, physicians noticed that people with AIDS tended to have unusually high levels of a protein called beta-2 microglobulin (beta-2) in the blood. Beta-2's function is not well understood, but it is probably linked to the immune response. Increased levels of beta-2 may be due to sustained activity of certain white blood cells called lymphocytes, which help the immune system fight infections of all kinds. (The T4 cell is a kind of lymphocyte cell.) Another possibility is that beta-2 is released when T4 cells are destroyed.[1] Since T4 cells are a major target for HIV, a high level of beta-2 may indicate that HIV is actively reproducing and killing T4 cells. Much has been written about beta-2 and HIV infection. Many studies have found that elevated levels of beta-2 in HIV-infected persons predict the progression of HIV disease.[2] However, two small European studies conclude that beta-2 is not a good marker in people with a history of injecting drug use because it seems not to correlate with disease progression.[3] One study, from the medical journal AIDS, enrolled and observed 50 people from the time of sero-conversion. Data showed that during the first year of observation, a higher percentage of people experienced increases in beta-2 than experienced decreases in T4 counts.[4] This study raises the possibility that beta-2, rather than T4 counts, might better mark early disease progression. Dr. Bo Hofmann and colleagues found that those who had high levels of beta-2 in the year following seroconversion had a worse prognosis. The authors suggest that combining T4 and beta-2 levels provides a more powerful disease-predicting tool than either alone. An important question is whether changes in beta-2 levels can be interpreted as an indication that an experimental therapy is working. Here, the data are more sketchy. An article in The British Medical Journal reports that beta-2 levels changed significantly in the blood of participants taking AZT. This suggests that beta-2 may act as a marker for a drug's anti-HIV efficacy.[5] Interestingly, an Italian study of 403 participants found that beta-2 and neopterin (discussed below) were more sensitive markers of AZT's effects than T4 cell counts. They also found that changes in these markers persisted longer than did the increased T4 levels in patients on AZT.[6] According to a study at City Hospital in Edinburgh, beta-2 levels are elevated in children with HIV infection.[7] However, a group of Italian researchers reports that beta-2 levels are not responsive to AZT therapy in children.[8] Neopterin Neopterin is a protein produced by macrophages (white blood cells that act as reservoirs for HIV), which are activated by certain immune responses.[9] Elevated neopterin levels are common in viral infections, because the macrophage cell is usually in high gear when the body must fight infection. Plenty of evidence links an increase in neopterin levels to HIV disease progression.[10] A number of physicians assert that neopterin and beta-2 levels can be used interchangeably and that monitoring both is redundant and expensive. Studies which examine both markers usually find that they are about equally predictive of disease progression. As with beta-2, there is some evidence that neopterin levels may not be useful in predicting progression in people with a history of injecting drug use.[11] A study in Austria, however, measured urine levels with neopterin in 38 asymptomatic HIV- positive participants with a history of injecting drugs for over one year.[12] Comparing urine neopterin levels to beta-2 levels, the former was found to predict progression to advanced disease more accurately. The authors of this study assert that measuring neopterin levels in urine may be beneficial and practical, since it is often difficult to draw blood from injecting drug users. Conflicting opinions abound about the ability of neopterin to assess a drug's anti-HIV activity. The study in The British Medical Journal states that, in contrast to beta-2, neopterin did not change when patients began taking AZT. However, a much larger study, reported in Florence, claimed that both neopterin and beta-2 are more sensitive markers of AZT activity than T4 counts.[13] There is also some suggestion from a small trial that neopterin reflects AZT's anti-HIV effect in children while beta-2 does not.[14] T4 Cells as Surrogate Markers T4 counts are the best known and most widely used surrogate markers. T4 cells are a kind of lymphocyte cell, which, along with B-cells and T8 suppressor cells, regulate the immune system to fight infection. Since HIV attacks the T4 cell, comparing the numbers of existing T4 cells to a "normal" range is commonly used to predict progression of disease. A normal range is anywhere from 400-1500. T4 levels can be reported in the following ways: * absolute number of T4 cells (per cubic centimeter of blood) * percent of T4 cells compared to all lymphocyte cells * ratio of T4 to T8 cells (see below under T8 cells) Evidence supports each of these three measurements as the most accurate predictor. When pressed to pick one marker as the most reliable, Dr. Howard Grossman, an internist with a large practice in New York City, chooses the percentage of T4 cell to total number of lymphocyte cells.[15] In particular, Dr. Grossman feels that T4 percent values are safer to use when deciding when to begin PCP prophylaxis. T4 Cell Counts and Human Trials There is an emerging concensus that absolute T4 levels are the most powerful surrogate marker for HIV disease. The FDA hosted a major conference last spring on the use of surrogate markers in human research with anti-HIV drugs, like AZT and ddI. Until now, the researchers conducting trials relied upon two drastic events: death and disease progression. Most would agree that using an absolute T4 count is not an ideal marker (see side bar) [below], but is better than allowing trial participants to progress significantly and possibly die. The FDA's new investment in absolute T4 counts was put to the test recently when the agency approved ddI for prescription use. The drug was approved because it seemed to increase absolute T4 counts in people who were intolerant or resistant to AZT. Some researchers who participated in the deliberations over Bristol Myers' application for ddI approval made no secret of their discomfort in using absolute T4 counts as the only deciding criteria. Nonetheless, it is encouraging that the FDA is becoming flexible about surrogate markers in an effort to make potentially useful treatments available to HIV-infected people as rapidly as possible. T4 Counts and Predicting Survival At the International AIDS conference in Florence, Dr. Robert Yarchoan, Director of the National Cancer Institute, presented a strong case for correlating T4 counts with survival. Looking back at three small trials between 1987 and 1990, Dr. Yarchoan reported that death was unlikely when T4 counts were above 50. All but one of the 41 evaluable patients who died during the followup period had T4 counts below 50. These results were recently published, and Dr. Yarchoan states that they demonstrate the need to follow T4 counts even when they fall below 200.[16] In fact, the study suggests that all possible steps should be taken to raise T4 cell counts above 50. The use of multiple prophylaxes (against CMV, MAI, candidiasis, etc.) may also be indicated when T4 counts reach 50. Dr. Yarchoan is careful to point out that the prognosis for individuals with counts under 50 is not necessarily bleak. And anecdotal experience certainly allows for exceptions to this trend. T4 Counts and Women Most research exploring T4 cells as surrogate markers for HIV disease has enrolled only gay and bisexual men. For example, the data from the Multi-Center AIDS cohort study (MAC), which enrolled over 1,600 men, was used to determine that a 200 T4 cell count indicates the need for PCP prophylaxis. This information has been applied to women, though no study or direct knowledge of surrogate markers in women is available. Such extrapolation is unfortunately common in HIV and many other research areas. Research of surrogate markers in women is desperately needed to confirm treatment recommendations such as PCP prophylaxis and anti-HIV therapies, such as AZT and ddI. T4 Cells As Surrogate Markers T8 cells Q- also known as CD8 or "suppressor" cells -Q play an important role in a healthy immune response. Among other things, these white blood cells "turn off" the immune system when an infection has been suppressed. Without T8 cells, our immune systems would remain activated and might attack the healthy parts of our bodies. According to Dr. Luc Montagnier of the Pasteur Institute in Paris, T8 cells have been "ignored" in HIV infection.[17] Dr. Montagnier says his lab has shown that certain T8 cells attack an enzyme on HIV called protease. Protease is responsible for tailoring new HIV to attack certain.cells of the body. Dr. Montagnier has noted a rise in T8 levels in late infection. Much emphasis has been placed on the ratio of T8 cells to T4 cells. Normally, a person should have twice as many T4 cells as T8 cells, a ratio of 2:1. However, during HIV progression, T4 cells decrease dramatically, and a person may have twice as many T8 cells as T4 cells. This inversion has been interpreted as a bad sign, and some people advocate tracking the ratio of these cells. Absolute T8 counts -Q although not altogether well understood -Q have also been endorsed as a good surrogate marker by Dr. Barbara Starrett, a well-known AIDS clinician in New York City. Dr. Starrett noticed that her patients with low T4 cells but high T8 cells remain stable and do not progress rapidly.[18] Antibodies The body attempts to rid itself of HIV infection in part by producing antibodies (proteins which destroy or neutralize harmful invaders). The test used to diagnose HIV infection relies on the presence or absence of these antibodies. Most of the research concerning antibodies has used a specific protein called the p24 antibody. Low levels of p24 antibodies are associated with disease progression.[19] A group of Dutch researchers hypothesizes that a reduction in p24 antibody levels may also be linked to a decline in the number of B cells that produce p24 antibodies.[20] Researchers have documented that people have extremely high levels of virus in the body after exposure, and may experience a brief flu-like illness. Then the amount of virus decreases, allowing a long asymptomatic phase to occur.[2l] As virus levels drop, antibody levels rise, suggesting that antibodies may temporarily control the infection. Antibody levels, then, may seem like a logical marker for disease progression. (see chart on page 7) [Graphic omitted] At least two groups of researchers have documented that, in early infection, Africans and African-Americans have higher levels of p24 antibodies.[22] These findings hint that there may be racial differences in disease progression, a theory that needs to be investigated. In addition, one study has found that p24 antibody levels decline in saliva before they decline in blood. It is possible, therefore, that p24 antibody levels reflect progression earlier.[23] A study published last year demonstrates a link between declining levels of p7, another protein from HIV's core, and progression.[24] VIROLOGIC MARKERS Direct measurements of the amount of HIV are called "virologic markers". As previously mentioned these tests are difficult to perfect and most are not currently available to the public at large. Some virologic tests are not sensitive enough and others are too labor-intensive to be practical for everyday use. Recently, however, a few tests have moved forward, and are being used in human research to measure the anti-HIV effects of experimental drugs directly on HIV quantity. p24 Antigen One of the first virologic markers to receive serious attention was a protein from HIV's core called p24 antigen. The presence of p24 is linked directly to the reproduction of HIV. p24 levels do not fluctuate as dramatically as do T4 counts. At most, they may change by 10% over several days.[25] Tests that detect p24 antigen have been in use for several years now. But most HIV-infected people test p24 antigen negative. This may be because p24 antibodies bind up levels of p24 antigen, rendering levels unmeasureable. Although many asymptomatic people are p24 antigen-negative, it does not mean that they will not progress to AIDS or ARC. However, someone who tests p24 antigen positive, even with T4 counts above 500, may be well advised to start antiviral therapy.[26] p24 is not a practical marker of disease progression, especially in newly infected individuals. The best use of the p24 antigen test is to monitor the effects of experimental anti- HIV drugs in human trials. Many trials seek to enroll only individuals who are p24-positive, which is one reason why recruitment for some trials has been painstakingly slow. An innovation for p24 sensitivity is accomplished by first mixing blood samples with acid. Acid breaks the bond between antibody and antigen, so that p24 becomes measurable again. Dr. Ed Winger, Medical Director of Immunodiagnostic Laboratories in San Leandro, CA, for example, is developing a more sensitive p24 antigen test. Dr. Winger's lab also pre-treats blood samples with acid. This method has yielded positive p24 results in 85%- 90% of blood samples tested in Dr. Winger's lab.[27] Since the new test is still experimental, his lab will perform it at no additional charge on samples sent for standard p24 tests. Polymerase Chain Reaction (PCR) PCR is a test that amplifies and measures a minuscule amount of DNA or RNA from HIV. DNA and RNA are the gene particles which carry instructions for making more HIV. The PCR test is extremely sensitive and is able to detect viruses where other tests may report false negative. PCR might have a role as a staging test. Another possible use is for diagnosing HIV. Some people with persistently low T4 counts who are HIV antibody negative may still worry about their HIV status if other causes of immunodeficiency are ruled out. PCR could be used to confirm the presence or absence of HIV itself. In addition, PCR may be quite useful for early diagnosis of infants born to HIV-infected mothers. But the test has a long way to go before it is widely available. Many labs are developing direct methods to quantify HIV. Some labs, working independently on the same methods, came up with strikingly different results. The need for standardization of lab methods is great. Dr. David Ho, Medical Director of the Aaron Diamond AIDS Research Center in New York City, is trying to organize a conference for researchers in this field. Conclusion In the absence of readily available direct-virus tests, people with HIV and their physicians are using other lab tests to decide the best course of action. When possible, it is preferable to monitor more than one marker. Several other markers are being investigated in addition to the ones mentioned here. For example, levels of alpha interferon, interleukin-II receptors, tryptophan, glutathione, and DHEA have been proposed as surrogate markers. Relentless search for a good marker has yielded clues about how HIV causes disease, and this information will undoubtedly help in the design of new antiviral drugs and other treatment approaches. REFERENCES 1 Hoffman B et al. Serum beta-2 microglobulin level increases in HIV infection: relation to seroconversion. CD4 T-cell fall and prognosis. AIDS 4:207-14, 1990. 2 Fahey JL et al. The prognostic value of cellular and serologic markers in infection with HIV type 1. NEJM 322(3):155-172, 1990; and Moss AR et al. Natural history of HIV infection. AIDS 3:55-61, 1989; and Anderson RE et al. Use of beta-2 microglobulin level and CD4 lymphocyte count to predict development of AIDS in persons with HIV infection. Arch Int Med 150:73-77, 1990. 3 VIIth Intl Conf on AIDS. Abstracts #W.A. 1180 and W.B. 2444, Florence, June, 1991. 4 Op. Cit. Hoffman et al. 5 Jacobson MA et al. Surrogate markers for survival in patients with AIDS and AIDS-related complex treated with zidovudine. BMJ 302(6768):73-78, 1991. 6 VIIth Intl Conf on AIDS. Abstract #W B. 2436, Florence, June, 1991. 7 VIIth Intl Conf on AIDS. Abstract #W.B. 2026, Florence, June, 1991 8 VIIth Intl Conf on AIDS. Abstract #W.B 2024 Florence, June, 1991. 9 VIIth Intl Conf on AIDS. Abstract #W.A. 1270, Florence, June, l99l. 10 Prince HE et al. Interrelationships between serologic markers of immune activation and T lymphocyte subsets in HIV infection. J AIDS 3:525-530, 1990; and Fahey JL et al. The prognostic value of cellular and serologic markers in infection with HIV type 1. NEJM 322(3):155-172, 1990; and Moss AR et al. Natural history of HIV infection. AIDS 3:55-61,1989. 11 VIIth Intl Conf on AIDS. Abstract # W.A. 1180, Florence, June, 1991. 12 Zangerle R et al. Markers for disease progression in IVDU's infected with HIV. AIDS 5:985-991, 1991. 13 VIIth Intl Conf on AIDS. Abstract # W.B. 2436, Florence, June, 1991. 14 VIIth Intl Conf on AIDS. Abstract # W.B..2024, Florence, June, 1991. 15 Grossman, H. Personal Communication. 16 Yarchoan R et al. CD4 count and the risk for death in patients infected with HIV receiving antiretroviral therapy. Ann Int Med ll5(3):184-189, 1991. 17 Montagnier L. Oral presentation, VIIth Int'l Conf on AIDS, Florence, June, 1991. 18 Starrett B. Personal Communication, December 1991. 19 McHugh T et al. Relations of circulating levels of HIV-l antigens, antibody to P-24 and HIV-l containing immune complexes on HIV-l infected patients. J INFECT DIS 158:1088-91, 1988. 20 VIIth Intl Conf on AIDS. Abstract # W.A. 1333, Florence, June, 1991. 21 Daar ES et al. Transient high levels of viremia in patients with primary HIV type 1 infection. NEJM 324:961-64 1991. 22 ibid, Abstracts # M.C. 3258 and W.A. 1345. 23 Sun D et al. Variations of secretory antibodies in parotid saliva to HIV type 1 with HIV-1 disease stage. AIDS Research and Retrov 6(7):933-41, 1990. 24 Mehta SU et al. Prevalence of antibodies to core protein pl7, a serologic marker during HIV infection. AIDS Research and Retrov 6(4):443-53, 1990. 25 Personal Communication, Winger E., December 1991. 26 Personal Communication, Torres G., December, 1991. 27 VIIth Int'l Conf on AIDS. Oral Presentation, Abstract # M.B. 38, Florence, June, 1991. ***** More Information About Surrogate Marker Tests [Side bar] Beta-2 tests have some practical advantages. They seem to fluctuate less than T4 cell counts, thus their measurement may be mare reliable. They are also cheap, costing approximately $35- $40, compared to $100-150 for T cell tests. Beta-2 levels can be checked in the blood or the urine. Same have suggested that the inexpensive beta-2 test may be a good option for widespread use in countries where health care budgets will not absorb the cost of T4 tests. T4 Cell tests are significantly limited. First, T4 counts may include non-functioning cells, since the mechanism that counts the cells does not distinguish between healthy T4 cells and HIV-impairedness. Second, it is well known that T4 caunts can fluctuate dramatically in the course of one day, and different labs may well report different counts for the same blood sample. It is important to have blood drawn at approximately the same time of day if possible and to be sure that samples are sent to the same lab. The trend in T4 counts over time is more meaningful that any single T4 value. p24 Antigen tests are not commercially available in New York State, but are to appear on the market soon. The tests are available free from the New York Department of Health, and from Wadsworth lab, if requested along with an HIV antibody test. Antigen tests hold promise for earlier diagnosis of infants. All infants born to HIV-positive women, inherit their mothers' antibodies. It is therefore difficult to determine the actual HIV-status af children until the age of 18 months, when the baby sheds his or her mother's antibodies and -Q if actually infected -Q begins to make his or her own antibodies. In particular, p24 antigen tests, with acid pre-treatment of blood samples, seem to show a high degree of sensitivity in early testing in infants. ***** TREATMENT BRIEFS AZITHRO FOR CRYPTOSPORIDIOSIS & MAC Pfizer has instituted two new Compassionate Use Programs with the antibiotic azithromycin. This program allows individuals, meeting certain health criteria, to obtain the drug free. The FDA approves such use on a case by case basis. Physicians can obtain the drug for patients with cryptosporidiosis by calling (203) 441-6148. For patients with MAC who are failing existing therapy, the phone number is (203)441-5941. On a related note, a recent study in the November 2nd issue af Lancet found that the drug was safe and effective in treating MAC at 500 mg per day. Dr. Lowell Young, the investigator of the trials, told Treatment Issues that the most effective dose might be 1000 mg per day for treatment of infection and 500 mg per day thereafter to prevent recurrence of infection. PROBLEMS WITH THE NEW AIDS DEFINITION Finally acknowledging major limitations in the definition for AIDS, the Centers for Disease Control (CDC) yielded to pressure from AIDS community activists and organizations and agreed to change it. The new proposal will give an AIDS diagnosis to everyone with T4 count under 200. However, there is no evidence that such a change will improve tracking of persons previously undercounted -Q namely, women, drug users, and people of color. In fact, the new definition will do little to enhance a doctor's ability to diagnose HIV infection in people who are consistently undercounted and underdiagnosed. The same people without access to health care, who are consistently missed by the current definition, will be no better able to afford T4 tests. Undoubtedly they will go without a diagnosis, without financial entitlements, and without being counted. Confidentiality will be threatened when such proposed diagnosing of AIDS becomes reportable under public health laws. Confidentiality must be upheld. Write or fax the CDC to register your opposition to the new proposal which does not promote accurate surveillance, confidentiality, better health care and benefits for more people. Let the CDC know that again they have missed the mark: Technical Information Activity Division of HIV/AIDS (E49) Centers for Disease Control Atlanta, GA 30333 PHONE: (404) 639-2077 FAX (404)639-2029. DRONABINOL TRIALS FOR WEIGHT LOSS The newly reborn Community Research Initiative on AIDS (CRIA) is enrolling patients with AIDS for a trial using Marinol (dronabinol). The drug has been approved by the FDA for chemotherapy-associated nausea. It has recently been found to stimulate appetite and weight gain in HIV-positive patients, according to a study by Dr. Marcus Conant at San Francisco General Hospital. CRIA study is enrolling people who have lost at least five pounds from normal body weight. Call (212) 889- 1958 for more information. VITAMIN B-12, C TRIALS The Treatment Alternatives Committee of ACT UP/NY is working to persuade the National Institute of Mental Health (NIMH) to begin a trial of injectable B-12 vitamin for HIV-related neurological problems. Treatment Alternatives also reports that test tube work at the Pauling Institute shows N-acetylcysteine (NAC), a drug thought to inhibit HIV, increases nine-fold when used with vitamin C. Contact Chris Freiman at (212) 255-2982 for more information. ROKA SUBSTANCE TESTED The testing of Dr. Roka's compounds has been completed at the National Cancer Institute. Early test tube studies have been conducted with the much-hyped Swiss extracts (Carciviren and Rovital), promoted by the Hungarian physician. The plant extracts have received widespread attention among U.S. AIDS patients, leading many to travel abroad, stop anti-HIV and anti- CMV therapies, and pay large sums of money for the Swiss drugs, touted as cures. A researcher from the National Institutes of Health has tested both substances in the test tube and found that neither extract shows anti-HIV activity. The anti-HIV drug, ddI, was tested in the same experiment, as a control, and demonstrated significant activity against the virus being tested. Studies to determine whether these plant extracts have immune-boosting properties have yet to be conducted. Anecdotal reports from persons receiving the therapies indicate subjective responses (patients taking the drugs felt much better). Some doctors have conjectured that the method of administration -- ozone therapy (adding oxygen to the blood stream) -- may result in temporary relief of symptoms without actual therapeutic benefit. Persons wishing to pursue the Roka treatments should first consult with personal doctors and are advised _not_ to stop antiviral therapies. FAUCI DROPS THE BALL ON AIDS FUNDING Dr. Anthony Fauci, who directs federal AIDS research efforts, was recently asked his opinion on AIDS funding. "...Compared.to other diseases," stated Fauci, "look at what is being done for AIDS! Ten percent of the entire NIH budget is spent on AIDS research even though cancer and heart disease patients far outstrip the number of AIDS patients." Dr. Fauci went on to defend George Bush's efforts on AIDS, claiming, "When you look at what he's done, it's been substantial." (AIDS Weekly 11/18/91) The damaging effect of Dr. Fauci's playing one disease against another and implying that too much funding goes to AIDS research is enormous. Let Fauci know what you think by calling his office at (301) 496-2263 or FAX (301) 446-4409. NOTES * For a copy of the New York State Directory of AIDS Trials, call AmFAR at (212) 719-0033. * For an informative, yet somewhat self-promoting report on AIDS drugs under development call the Pharmaceutical Manufacturers Association (PMA) at (202) 835-3400. * The New York State Drug Assistance Program (ADAP) has added medications for Kaposi's Sarcoma, toxo, Cryptococcal meningitis, and PCP prophylaxis for under 300 T cells to the reimbursement plans. Call (800)542-243.[sic] ***** Cimetidine by Douglas G. Brust, Ph.D Cimetidine (brand name Tagamet), a drug designed to treat ulcers, has demonstrated some potential for boosting the immune system. A few physicians regularly prescribe a regimen of drugs including cimetidine.[l] And in a few small human trials, researchers are exploring the drug's potential as a treatment for people with HIV infection. A QUICK LOOK AT HISTAMINE ANTAGONISTS Cimetidine, made by Smith, Kline & French, belongs to a class of drugs called histamine antagonists. Histamine is a substance secreted by white blood cells in the stomach or in response to an allergic reaction. For example, when pollen enters the respiratory system through the nose and mouth of someone who has hay fever, irritation occurs at the nasal and bronchial passageways. In response to such irritation, specialized body cells, called mast cells and basophils, produce histamine. Histamine travels to the sites of irritation and binds to cells in the tissue lining along the respiratory tract in order to cause increased secretions in the nasal passages, producing the characteristic congestion associated with pollen allergies. As a remedy, allergy sufferers take antihistamines to combat symptoms like a runny nose or congested breathing. An antihistamine is a drug that prevents histamines from binding to cells at the site of irritation. This "antagonistic" property is what limits histamines from causing allergic responses in the body. Cimetidine, which blocks histamines in the stomach, was originally licensed in 1977 to control peptic ulcer disease by reducing the amount of hydrochloric acid (HCl) in the stomach. HCl helps digest food. An overproduction of HCl can lead to erosion of the protective lining of the stomach and can therefore cause ulceration. Similar to the antagonistic action of the allergy medicine described above, cimetidine binds to specialized cells in the stomach cavity that produce HCl.[2] CIMETIDINE AND THE IMMUNE SYSTEM Unexpected findings were noted during studies to determine cimetidine's efficacy in treating peptic ulcers, including the drug's apparent action as an immune modulator. The immune system has a set of histamine receptors of its own, called H2-receptors, which contribute significantly to healthy immune function. Because cimetidine is able to attach to these receptors on many immune cells, it theoretically functions to block the ill effects that histamine may have on immune function.[3] Some small studies confirm the theory that cimetidine does indeed have a positive effect on the immune system.[4] The drug has been used experimentally to treat conditions related to a suppressed immune system, such as rashes,[5] herpes simplex virus[6], candidiasis,[7] and an underproduction of gamma globulins.[8] HUMAN STUDY RESULTS To date, only one published study has focused on cimetidine as a treatment for HIV infection.[9] Brockmeyer, and others, administered 1200 mg of cimetidine daily to 33 people with ARC (25 male and 8 female) for five months. Therapy was interrupted after the first three months for an interval of three weeks. All enrolled participants had swollen lymph nodes, or oral thrush, and T4 counts under 400. They were receiving no other therapy. Cimetidine treatment significantly increased the levels of cells which measure immunity, such as immunoglobulins, T4 cells, and B-lymphocytes. In fact, after three months of treatment T4 counts doubled (from 385 to 779). After cimetidine therapy was discontinued, T4 counts dropped to 511, but rebounded to 693 after six more weeks of treatment. Skin tests, also used to measure the immune response, improved significantly with cimetidine treatment, indicating a partial restoration of immune function. The authors of the study concluded that the immune modulating effects of the drug were "both reversible with discontinuation" and "reproducible with repeated administration." Perhaps the most encouraging finding of this initial study was the clinical improvement of ARC patients treated with cimetidine. Upon entering the study, 74% of the participants reported night sweats, and 71% complained of diarrhea. After treatment with cimetidine, none reported diarrhea or night sweats. The size of enlarged lymph nodes decreased by at least 50%. The authors also noted improvement in body weight and temperature with cimetidine use. It should be noted that this was not a formal study designed to produce specific, precise data which can be compared to a control. Therefore, the results described herein may not be completely reliable. However, some health care providers feel that cimetidine is significantly non-toxic enough to warrant adding the drug to an immune boosting regimen. SIDE EFFECTS Because of its extensive use in the treatment of ulcers, the side effects of cimetidine are well-documented in non-HIV- infected individuals. The most frequent adverse reactions encountered include diarrhea, nausea, vomiting, and muscular pain. Cimetidine is also known to increase prolactin (a hormone which increases breast growth), decrease sexual drive, and cause impotence in a small percentage of men.[10] Reactions of the drug in women have not been reported. Brockmeyer stated that cimetidine was well-tolerated in HIV-infected participants, and no toxic side effects were reported in this study. SIMILAR DRUGS Recently, Nielson and others reported that ranitidine (Zantac, made by Glaxo Pharmaceuticals), another histamine antagonist, improves natural killer cell activity in the test tube.[11] Natural killer cells are white blood cells that directly attack foreign invaders like viruses and bacteria. T4 cell counts did not change over the course of the 28-day study, in which 600 mg of ranitidine was administered daily. Although the authors concluded that "the improvement of immune function by ranitidine shown in the present study was quantitatively small and did not reverse immune function to normal," they called for further trials with ranitidine in HIV-infected persons. CONCLUSION Almost three years have passed since the original study documenting clinical and immunological effects of cimetidine on HIV-infected individuals was first reported. The drug is one of the safest agents being tested for HIV therapy. Although not specifically developed for immune modulation, cimetidine deserves an expanded and prolonged investigation, possibly in combination with antiviral drugs, such as ddI, AZT and ddC. A FINAL WORD OF CAUTION Cimetidine reverses the acidic environment of the stomach -- an effect which has serious implications for drugs that must be absorbed in an acidic environment, like Dapsone (Jacobus) and ketoconazole (Nizoral, Janssen). Patients on these and other medications may be able to use cimetidine if ingestion of the other drugs is delayed long enough for the stomach to return to its normal acid balance. REFERENCES 1 Bihari B. Ambulatory management of HIV-related immune suppression & AIDS. The Body Positive 4(7), 1991. 2 Brockmeyer NH et al. Immunomodulatory properties of cimetidine in ARC patients. Clinical Immun and Immunopathol 48:50-60, 1988. 3 Ibid. 4 Brockmeyer NH et al. Simulating potency of cimetidine on the immune system in man. British J Clinical Pharmacol 21:567-569, 1986. 5 Efremidis AP et al. Correspondence. NEJM 313:265, 1985. 6 Cohen PR et al. Herpes simplex virus infections and cimetidine therapy. J Amer Acad Dermatol 19:762-763, 1988; and Kurzrock R et al. Cimetidine therapy of herpes simplex virus infections in immunocompromised patients. Clinical and Exper Dermatol l2:326- 331,1987. 7 Kumar A. Cimetidine: an Immunomodulator. DICP 24(3):289-95 1990. 8 White WB and Ballow M. Modulation of suppressor-cell activity by cimetidine in patients with common variable hypogammaglobulinemia. NEJM 312:198-202, 1985. 9 Brockmeyer NH et al. Immunomodulatory properties of cimetidine in ARC patients. Clinical Immun and Immunopathol 48:50-60, 1988. 10 Freston JW. Cimetidine: II. adverse reactions and patterns of use. Annals of Intern Med 97:728-734, 1982. 11 Nielson HJ et al. Ranitidine improves certain cellular immune responses in asymptomatic HIV-infected individuals. J AIDS 4:577-584, 1991. ***** Protease Inhibitors: Push for Rapid Development by Michael Becker Most of us are now aware of the recent depressing news that promising new drugs by Merck, Sharpe, and Doehme, called the "L- Drugs," cause rapid resistance in humans. In all likelihood, this resistance problem will apply to the entire class of once promising compounds, affectionately known as "non-nucleoside reverse transcriptase inhibitors." These reverse transcriptase (RT) drugs include BI-RG-587 and TIBO derivatives. Although L697,661 and L697,639 are not the successes we hoped they would be, Merck developed the drugs in record time and disclosed results to the community as soon as they were available. The company created a superb model for future development of anti-HIV drugs. However, because of the limited usefulness of reverse transcriptase (RT) drugs and the lack of other truly effective anti-HIV therapies, a major concerted effort must be launched by the government, the pharmaceutical industry, and AIDS activists aimed at the rapid development of what is now the most promising class of anti-HIV drugs, the protease inhibitors. WHAT ARE PROTEASE INHIBITORS? Protease is an enzyme on HIV which is required for the virus to reproduce. The protease inhibitor, originally developed in England, was specifically designed to target the enzyme that is necessary for HIV to replicate. Many major pharmaceutical companies began programs designed to screen their drugs for activity against this important enzyme or to create new compounds designed to inhibit or disrupt HIV protease. Companies like Abbott, Hoffmann-La Roche, Merck, Smith Kline-Beecham, Upjohn, and Vertex Pharmaceuticals all have extensive protease inhibitor programs involving drugs that may do the trick. Unfortunately, only Hoffmann-La Roche has a compound that is near testing in human beings. Hoffmann-La Roche's lead protease inhibitor is known as RO 31895. The drug is actually related to a class of anti- hypertension medications. The first human research studied the drug in six groups of ten HIV-negative individualism [sic] who were given the drug orally (25 mg - 600 mg of drug). While the drug was found to have very low toxicity, it was not very well absorbed in the body. Roche has now begun larger human trials in three European cities. The trial in London began in August 1991 and is a 16 week study in individuals who have not taken anti-HIV medication before and who have T4 counts of less than 350. The dosage is 600 mg three times a day. The company has planned two other short-term European trials for early 1992, both as a single-drug therapy and in combination with AZT. In a recent meeting with activists, Roche disclosed plans to begin two protease trials in the U.S. One of the trials will test an intravenous administration of the drug and the other will be a dose-ranging study in pediatric patients. Both trials should begin in the first half 1992. OBSTACLES TO THE DEVELOPMENT OF PROTEASE Conversations with various scientists designing protease programs revealed the following significant stumbling blocks to the development of protease drugs: * Oral Drug vs. Intravenous Drug: Unfortunately the oral formulation of protease is poorly distributed within the body. Only an oral form of the drug will be useful to a wide range of people. Efforts must be focused on developing an easy-to-take, effective pill. * Surrogate Markers: Apparently protease inhibitors do not stop reproduction of HIV. The drug inhibits HIV protease so that it produces dysfunctional new virus, which cannot infect other cells. Traditional viral markers will not be useful in determining whether the drug is working. Affordable, less- complicated tests to detect if the drug is stopping protease must be developed, so that the effect of this new class of drug can be tested quickly and economically. * Production: According to Hofmmann La Roche, a protease drug is difficult to manufacture because it requires 24-26 steps. The company indicated recently that producing enough drug to start a clinical trial could take about one year -Q a long time to wait. These production problems must be solved, with governmental assistance, so that large-scale efficacy trials and expanded access programs can be supplied with drug. * Resistance: Resistance to RT inhibitor drugs must be explored in the test tube and in human beings as soon as possible to determine whether or not the drugs will be viable options. PUSH FOR DEVELOPMENT Because of the critical Importance of the protease class as perhaps the only promising alternative to anti-HIV drugs like AZT, ddI, and ddC, people with HIV/AIDS cannot afford to wait years for development and testing of these compounds. Development of protease, tat, and other HIV enzyme-inhibiting drugs must be expedited by the pharmaceutical industry, the NIH, and AIDS activists. In this regard, the Treatment and Data Committee of ACT UP New York, after having spoken to several pharmaceutical companies, has requested that Dr. Anthony Fauci of the NIAID call a working conference on protease inhibitors to clarify their developmental activities as soon as possible. An important issue to explore is what the government can do to expedite development and testing of these compounds. Needless duplication and production problems must not be allowed to delay the development of protease inhibitors. ***** Glossary Antibodies: Proteins in the blood that tag, destroy, or neutralize bacteria, viruses, or other harmful toxins. Antigen: An invading substance which may be the target of antibodies. ARC (AIDS Related Complex): A stage of HIV infection which is now only sometimes used; a condition referring to symptoms such as thrush, night sweats, fevers, and weight loss. Asymptomatic: An infection, or phase of infection, without symptoms (i.e. carrying antibodies to HIV but not displaying any of the symptoms of HIV infection). B cells: Type of white blood cell throughout the body that is able to detect the presence of foreign agents. Once exposed to the foreign agent, cells differentiate into plasma cells to produce antibodies. Bone Marrow: Soft tissue located in the cavities of bones, responsible for producing blood cells. Cytomegalovirus (CMV): A virus related to the herpes family that can cause fever, fatigue, enlarged lymph glands, aching, and a mild sore throat. In AIDS, CMV infections can produce hepatitis, pneumonia, retinitis, and colitis. It can sometimes lead to blindness, chronic diarrhea, and death. Dapsone: A drug used to treat and prevent PCP. Diagnostic: Something which evaluates a patient's medical history. Efficacy: Effectiveness at the dose tested and against the illness for which it is prescribed. Esophageal candidiasis: Serious fungal infection in the conduit between the mouth and the stomach (the esophagus). Hepatitis: Inflammation or disease of the liver from any of a variety of causes. Immune boosting: A drug treatment that repairs or reconstitutes an impaired immune system. Intolerance: The state of being unable to take a drug because of adverse reaction. Kaposi's sarcoma: A form of skin cancer, recognized as raised non-tender red or purplish spots on the skin. It may also occur internally (in the stomach or lungs, etc.) in addition to, or independent of, skin lesions. Ketoconazole: An antibiotic drug used to treat fungal infections. Liver enzymes: Secretions by the liver, which can be measured to ensure that it is functioning normally. Lymph nodes: Small, bean-sized organs of the immune system, distributed widely throughout the body, which filter invading organisms for immune system cells to attack. Lymphocyte cells: A type of white blood cell responsible for normal immune function. Macrophages: A white blood cell which acts as a reservoir for HIV. MAC: Mycobacterium avium intracellulare is a serious opportunistic infection in HIV that causes symptoms such as fevers, chills, abdominal pains, and nightsweats. Mutates: Changes; transforms. Natural killer cells: White blood cells which attack and destroy tumor cells and infected body cells. NIH (National Institutes of Health): An agency of the government responsible for overseeing human research and experimental drugs. Nucleoside analogue: A type of antiviral drug, like AZT, ddI, or ddC. p24 antigen levels: A marker of HIV replication which can be measured in the blood and represents a core protein fragment (p24) on HIV. Parasite: A plant or animal that lives and feeds on or within another living organism, and may or may not cause disease. Peptic ulcer: A lesion or opening of the lining in the stomach, which is exposed to acid. Pneumocystis carinii pneumonia (PCP): An AIDS-related illness caused by a common parasite that infects the lungs of people with HIV infection and low T4 cell counts (usually under 200). Sometimes, PCP infections may occur elsewhere in the body (skin, eye, spleen, liver, or heart). Prognosis: A forecast of the probable course and/or outcome of a disease Prophylaxis: Treatment intended to prevent the onset of an infection or disease. Protease inhibitors: A hopeful new class of anti-HIV drugs, which do not stop production of the virus, but instead inhibit a certain HIV enzyme, thus making the virus harmless in the body. Resistance: Diminished effectiveness of a drug on certain infectious organisms, which are able to mutate and avoid the drug's action against them. Reverse transcriptase (RT): An enzyme produced by retroviruses which can copy RNA into DNA, an essential step in the life-cycle of HIV. Seroconversion: The time when a person, who has been exposed to HIV, has a change in antibodies and can be tested positive, rather than negative. Skin Tests: A test of the immune system involving injections of certain proteins just below the surface of the skin. If the immune system is intact, rash appears within 48 hours at the site of injection. Sputum test: A way to diagnose tuberculosis by analyzing the mucus matter which collects in the air passage and upper food passage and is expelled by coughing. T4 counts: A type of T-lymphocyte. The T4 cell enhances the immune response through a complex series of interactions with other types of lymphocytes (B cells, T8 cells), macrophages, antibody producing cells, and infectious organisms. T4/T8 ratios: The existence and complicated action of two types of white blood cell, one which naturally suppresses the immune system and the other which naturally mediates immune reaction. Together these T-cells keep the immune system in balance. Toxicity: A range of many reactions by the body when a beneficial medicine is also poisonous elsewhere in the body. For instance, while AZT is helpful in controlling HIV, it has a toxic side- effect on the blood and sometimes causes lowered red blood cell counts, or anemia. Toxoplasmosis: Widespread infection of an organ, usually the brain, or the whole body with the parasite Toxoplasma gondii. Viremia: The presence of a virus in the bloodstream. ***** TREATMENT ISSUES Executive Editor: David Gold EDITOR Mary Beth Caschetta MEDICAL CONSULTANT Gabriel Torres, M.D. TECHNICAL COORDINATOR Griffin Meyer COPY EDITOR Gary Schmidgall WRITERS Kevin Armington Michael Becker Douglas Brust, Ph.D. Mary Beth Caschetta David Gold Gabriel Torres, M.D. DESIGNER Stephen de Francesco PRODUCTION MANAGER Val Hoshns PROOFREADER Sara Hertz OEFICE VOLUNTEERS Eric Goldsborough Edward Friedel Frank Schramm Gary Schmidgall 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 1991 Gay Men's Health Crisis, Inc. ***** Treatment Issues compilation is now available: A concise edited version of TI back issues, from our inception in November 1987 through March 1991. This handsome volume includes a complete index and list of other natinal AIDS publications and resources. This special issue is costly to produce, and your tax-deductible contribution of $12.00 will help to make it available to all who need the information. PLEASE SEND A CHECK OR MONEY ORDER TO: GMHC Medical Information 129 West 20th Street, New York, NY 10011 Attn: Treatment Issues Compilation IF YOU CANNOT AFFORD TO CONTRIBUTE AT THIS TIME AND YOU ARE A PWA, OR ARE HIV-POSITIVE, A COPY WILL BE SENT FREE OF CHARGE. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display