Subject: GMHC Treatment Issues vol. 5 no. 9 Date: December 1991 (1023 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& GMHC Treatment Issues vol. 5 no. 9 December 1991 Contents: [items are separated by "*****" for this display] ddI Update Hypericin Trial in New York Underground Buyers Club List Photopheresis Update Surrogate Markers in Photopheresis Trials Treatment Briefs Megace Update Glossary Miscellaneous ***** "Life After FDA Approval: ddI Update" by Gabriel Torres, M. D. Didanosine (ddI) is now available by prescription, under the brand name Videx, as a treatment for adult and pediatric patients with advanced HIV infection. These patients must demonstrate AZT intolerance or significant deterioration while on AZT therapy.[1] The FDA approval was based primarily on the results of non- randomized phase I studies in which increases in T4 cell counts were observed for many patients taking ddI. These results were compared with data from historical controls. In addition, an interim analysis of T4 cell data from an ongoing federally-funded study was considered.[2] This article will summarize the data which led to the approval of ddI and present some unanswered questions regarding its use and toxicities. EARLY STUDY RESULTS Four phase I trials have been conducted, enrolling a total of 170 patients, 75% of whom had previously been treated with AZT. Most of the patients in these trials were white, homosexual, or bisexual men. The mean T4 cell count was 62 at study entry. ddI was administered in different doses and by different routes (orally or intravenously) for a median duration of 38 weeks. The average daily dose was 10.3 mg/kg. The historical control groups consisted of patients from placebo groups of three randomized, blinded studies which compared AZT to placebo and patients from a dextran sulfate study. Response definitions included a 50 T4 cell rise or 50% rise from baseline in T4 cells (50:50 response), maintained for 4 weeks or longer, or a 10 T4 cell rise or 10% rise over baseline (10:10 response). Results were as follows: - 22% of patients receiving ddI had a 50:50 response compared to 28 -- 12% of the patients in the historical control groups. - 50% of patients receiving ddI had a 10:10 response in T4 cell counts compared to 17%-31% of the historical control group. Pancreatitis occurred in 9% of patients who received ddI at a dose less than 12.5 mg/kg, and in 27% of patients who received a dose greater than 12.5 mg/kg. Peripheral neuropathy occurred in 34% of patients treated with less than 12.5 mg/kg of ddI and in 51% of those treated with greater 12.5 mg/kg. It occurred more frequently in patients with a history of previous neuropathy or those taking other drugs which can cause neuropathy. DATA FROM LARGE HUMAN TRIALS ACTG study #116 compares ddI to AZT in patients previously treated with AZT. Data available from the first 12 weeks of the study included information on 412 patients who had received an average of 13 months of AZT therapy and had an average T4 cell counts of 83 at study entry. The group who received ddI had an 11% increase in T4 cells from baseline compared to a decrease of 3.2% in patients who remained on AZT. No data on clinical outcomes in this study are currently available. EXPANDED ACCESS While the package insert for ddI reports an overall low incidence of toxic side effects for the first 7,806 patients in expanded access programs, various smaller studies presented at the VIIth International Conference on AIDS in Florence, and at the 31st Interscience Conference on Antimicrobials Agents and Chemotherapy (ICAAC), report a considerably higher rate of toxicities. A study of 166 patients with AIDS or ARC was presented at ICAAC by Dr. James Steinberg from Emory University in Atlanta, Georgia.[3] After an average of 31 weeks of follow-up, fewer than 30% were still receiving ddI. Thirty-one patients became too sick to continue the drug or died. In 76 patients the drug had to be stopped because of pancreatitis, peripheral neuropathy, diarrhea or abdominal pain. The incidence of pancreatitis was 13.8% (including two deaths), which is higher than the 5% reported by Bristol-Meyers in the package insert. Because there was no control group it cannot be determined whether patients in this study benefited from ddI. Another study presented at Florence compared patients in the expanded access protocols who received ddI to a matched control group who received AZT or no anti-HIV therapy.[4] No difference in survival was seen for the ddI group, yet patients _maintained_on_one_ [italics] of the anti-HIV drugs developed opportunistic infections less frequently. However, ddI had a beneficial effect on the majority of patients in this study with dementia. A London study showed that patients who are intolerant of AZT and who switched to ddI are more likely to have T4 cell rises if their baseline T4 cell count is greater than 100.[5] The authors of this study also reported several new side effects of ddI, including diabetes (elevated blood sugar) and Raynaud's phenomenon (pain and cold feeling in the fingertips resulting from constriction of the blood vessels in the fingers).[6] Though the expanded access protocols were not designed to produce data on efficacy, the experience from these patients is very valuable since the final results of comparative trials are still not available, and physicians and patients must make treatment decisions in the interim. Since the drug is approved for patients who have experienced AZT intolerance or failure, it behooves us all to become aware of the toxicities, drug interactions, and clinical outcomes of patients in the expanded access protocols, since they may predict the similar outcomes in patients who will now receive the drug by prescription. DOSE AND ADMINISTRATION ddI (Videx) is available as a mint-flavored, buffered, cheweable tablet of 25, 50, 100 or 150 mgs. It is also available to children or adults as a buffered powder to be added to water for easy drinking. Two tablets at each dose every 12 hours is recommended. The exact dose depends on body weight, but should approximate 10 mg/kg. Some professionals recommend lower doses for patients with underlying opportunistic diseases such as CMV or MAC, which may predispose patients to pancreatitis or neuropathy. DRUG INTERACTIONS Drugs whose absorption can be affected by the amount of acidity in the stomach (such as ketoconazole and dapsone) should be taken at least two hours prior to ddI. Since ddI tablets contain a buffer (magnesium hydroxide, sodium carbonate and sodium citrate), they should not be taken with the antibiotic tetracycline or any of its derivatives. Since the absorption of quinolone antibiotics (Cipro, Noroxin, and Floxin) are decreased by antacids, ddI should be administered at least 2 hours after these antibiotics are given. No drug interactions have been noted between ddI and ganciclovir, although this combination has been in widespread use. RESISTANCE HIV strains taken from five AIDS patients were shown to have developed ddI resistance by researchers from Burroughs Wellcome.[7] These particular patients received AZT for longer than 12 months and were switched to ddI after appearing to deteriorate clinically. The viral strains seemed to have recovered their sensitivity to AZT in test tube experiments. The mechanism for ddI resistance was traced to a mutation in the gene, called reverse transcriptase (RT). RT is the enzyme which copies the HIV blueprint inside newly infected cells. The ddI mutation apparently eliminates one of the mutations responsible for AZT resistance, allowing the virus to once again be inhibited by AZT. The mutation responsible for ddI resistance also causes ddC resistance. This test tube work suggests that patients who receive ddI after receiving AZT may be able to derive benefit from AZT once again. How well clinical deterioration correlates with test tube resistance is yet to be determined. Combinations of ddI and AZT may prevent the development of resistance since the mutation sites are different. CONCLUSION Videx is now approved for use in HIV-infected patients who are intolerant or failing AZT. Unfortunately, relatively little data is available on patients who have never taken AZT, or on long-term effects and toxicities. Definitively, use of the drug among asymptomatic patients cannot be recommended until more information on long-term effects is available. Toxicities in advanced or late-stage disease are significant, and dose modifications may be appropriate. Combinations of AZT and ddI are just now receiving adequate attention and may become widely used before formal studies are available. REFERENCES 1. Bristol Laboratories, VIDEX package insert. 2. AIDS Clinical Trial Group ACTG Trial #116. 3. Steinberg JP et al. Outcome and Toxicities on DDI in the Expanded Access Program (abstract), 31st ICAAC, 1991, Chicago, Illinois. 4. VII Int'l Conf on AIDS. Abstract #W. B. 2113, Florence, June, 1991. 5. VII Int'l Conf on AIDS. Abstract #W. B. 2090, Florence, June, 1991. 6. VII Int'l Conf on AIDS. Abstract #W. B. 2111, Florence, June, 1991. 7. St. Clair MH. et al. Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase. Science 253:1557-1559, 1991. ***** Hypericin Trial in New York: At Last! by Anna Blume Hypericin is a natural pigment found in stems and petals of plants in the genus hypericum. The compound hypericin has been of interest to scientists for many years, as a natural antiviral and antidepressant, and was first described as a plant extract in 1830. In August, 1991 a form of hypericin was successfully synthesized and FDA-approved for testing in humans as an AIDS therapy. DATA LEADING TO HUMAN TESTING In test tube studies, hypericin hardens the outer surface of HIV, inhibiting the virus from infecting cells. Hypericin also inhibits the replication of cells already infected with HIV and is able to enter both lymphocytes and macrophages.[1] These functions, if indeed they occur in the human body, could slow the progression of HIV disease. Based on the potential of this drug, testing in humans has long been recommended and will soon begin. One recent dose-ranging, observational, phase I/II study from Australia found that hypericin at a dose of 2.0 mg/day appears to be safe in the majority of subjects observed so far. Participants in this study were gay and bisexual men visiting an AIDS clinic in Australia. They were followed, while taking hypericin, for 12 weeks. No specific T4 cell count criteria were required for entry. Side effects included diarrhea, indigestion, infrequent rash, and fatigue or depression. Monitoring of blood and liver tests is recommended.[2] No marked anti-HIV activity was discovered in this early trial data. It should be noted, though, that this was a relatively relaxed, uncontrolled trial, using the street-version, rather than the synthetic, of hypericin. BACKGROUND ON DRUG DEVELOPMENT Hypericin was given "ACTG status" over a year ago. This means that a specific protocol and a series of sites were chosen to carry out government-funded clinical trials of the drug in order to study the compound's effect in people living with HIV/AIDS. It took the small pharmaceutical company VIMRX over 17 months to formulate a drug which met FDA standards of quality for testing in human beings. In May, 1991, members of ACT UP/NY waged a concentrated campaign aimed at VIMRX, NIAID and the FDA to accelerate development. On August 20, 1991, the compound was approved for testing in human beings, and a few days later the IRB (Internal Review Board) at New York University (NYU) approved the final protocol. These were the last major obstacles to setting up a trial. The hypericin trial has now begun and is recruiting 32 participants with T4 counts under 300. To enroll, or obtain more information, call Kate Krikorian, R. N. or Janet Vaccariello, R. N. at (212) 263-6565. The trial will try to determine possible toxicities and appropriate dose ranges of synthetic hypericin in people. Shortly after the commencement of this trial, similar trials are scheduled to begin in Boston and Minneapolis. The principal investigator for the protocol is Dr. Fred Valentine of NYU. The first segment of the trial will last for eight weeks. To enter the trial, patients must stop taking AZT, ddI or ddC for four weeks and must stop taking therapies against CMV and other OI's. Hypericin will be administered intravenously (IV) two times a week, and a hospital stay is required for the first infusion. If safety and signs of efficacy are evident, the trial will continue for a total of 24 weeks. If safety and efficacy markers continue to be reached, NIAID and the sponsoring pharmaceutical company VIMRX, will immediately design phase II trials to test rigorously the possible use of hypericin as an anti-HIV drug. By February of 1992, it is hoped that sufficient evidence of safety and efficacy will allow hypericin to proceed into phase II trials. CURRENT AVAILABILITY In the phase I trial, researchers will use a synthetic hypericin that is not available on the market at this time, and that is said to be a more pure form of the drug. Hypericin is available in health food stores in a form called St. John's Wort, either as a pill or tincture (liquid extract), and it is also available in multiple pill forms from the different buyers clubs throughout the country. To date there have been no evaluations about which available form of the drug is most effective. It is possible that the market formulations of hypericin may have enough active drug to be effective against HIV, but such an assertion has yet to be confirmed. Anecdotal reports suggest that people with HIV/AIDS do benefit from the hypericin on the market in the following ways: increase in energy; decrease in depression; and, for some, an increase in T4 cell counts. Hypericin has been used as a natural anti-depressant and antiviral for centuries. In the test tube the drug has been shown to be effective against CMV and Sindbis virus[3], and other retroviruses such as equine infectious anemia virus (EIAV).[4] We look forward to evidence determining whether this drug will be effective against HIV. References 1. VIIth Int'l Conf on AIDS. Abstract #A. 1022, Florence. June 1991. 2. VIIth Int'I Conf on AIDS. Abstract #W. B. 2071, Florence, June 1991. 3. Hudson JB et al. Antiviral properties of hypericin. Antiviral Research 15(2):101-12, 1991. 4 Kraus GA et al. Antiretroviral activity of synthetic hypericin and related analogs. Biochemical & Biophysical Research Communications 172(1):149-53, 1990. ***** "Underground Buyers Club List" The following is a list of the eight largest buyers' clubs in the country. Many underground groups, both unapproved and approved abroad, carry nutritional supplements and vitamins, as well as minerals, enzymes and herbal or Chinese therapies. It is important to ask questions and explore the standards and procedures of any group offering unapproved therapies before buying a drug from them. Also remember to consult with your doctor. Alliance 7 Buyers' Club San Diego, CA (619) 281-5360 AIDS Action Baltimore Baltimore, MD (301) 837-2437 Carl Vogel Foundation Washington, DC (202) 289-4898 Dallas Buyers' Club Dallas, TX (214) 826-7455 DC Buyers' Club Washington, DC (202) 232-5494 Healing Alternatives Foundation San Francisco, CA (415) 626-2316 Los Angeles Buyers' Club Los Angeles, CA (213) 748-1295 PACT Buyers' Club Tuscon, AZ (602) 322-9808 PWA Health Alliance Oakland Park, Florida (305) 568-3001 PWA Health Group New York, NY (212) 532-0280 ***** "What Ever Happened to Photopheresis? An Update" by Mike Barr A little over a year ago, Treatment Issues reported preliminary results from a five-patient pilot study of a treatment, called photopheresis, for HIV-positive people with ARC.[1] Photopheresis is a process by which a light-sensitive drug, called psoralen, is injected into the body. Blood is then removed from the body and exposed to ultraviolet light, thus activating the psoralen in white blood cells. Finally, the blood is returned to the body by reinfusion. The whole procedure is usually performed on two consecutive days at monthly intervals and takes about four hours per session. Photopheresis has been used to treat various autoimmune diseases and is an approved therapy for a specific skin cancer that is called cutaneous T-cell lymphoma. In the test tube photopheresis works to inhibit viruses which involve RNA and DNA, including HIV. [2] The company developing this potential treatment is Philadelphia-based Therakos, a subsidiary of the Johnson & Johnson Company of Raritan, NJ. The small pilot study was conducted at Memorial Hospital in Morristown, New Jersey, under the direction of Dr. Emil Bisaccia. DATA FROM A FIVE-PERSON STUDY As was reported last year, four of the five participants in the Morristown pilot study were said to have experienced either a stabilization" or an "encouraging response" to the photopheresis treatment. Swollen lymph nodes resolved in all five patients by the third month of therapy and have not since recurred, three years later. None of the five patients has taken AZT or any other antiviral or immune modulating therapies. Two participants, however, are taking medication to prevent PCP. After three years of photopheresis treatment, skin reactions returned to normal in all four patients, and no toxicity was observed. Additionally, on average T4 cell counts rose from 251-486. T4 cell percentages rose on average from 19%-30%. Beta-2 microglobulin decreased on average from 5 mg/L to 3 mg/L. However, neopterin levels increased from approximately 14 to 20. DATA FROM A FIFTEEN-PERSON STUDY A second, slightly larger group of 15 participants entered into photopheresis treatment at Morristown Memorial Hospital in May, 1990. While, once again, swollen lymph nodes resolved in all trial participants, neither the average T4 cell count nor the average T4 percentage increased during the period of treatment. In fact, results conflicted with the original smaller group of participants and were somewhat discouraging. For example, T4 counts fell from 401 to 325 and percentages dropped from 30% to 27%, while beta-microglobulin rose from about 2.10 to 2.83. Ability to respond to skin tests did return to normal in eight participants, as in the original study group of five, and improved in others. As was the case m the initial pilot study, none of the trial participants was taking AZT or other antiviral/immune modulating substances. Again no toxicity was observed. WHAT DOES IT MEAN? When asked to comment on the inconsistent study results, Dr. Bisaccia stated that the data indicated a need for further study of the treatment in HIV infection. The question of an application for photopheresis as a treatment for HIV is "clearly not a concluded story," he added.[3] And at a recent Columbia University-sponsored medical symposium in New York where he presented the most recent data, Dr. Bisaccia seemed undaunted but unable to conceal completely his disappointment with the results so far. "If this therapy is ever to prove efficacious in the treatment of HIV disease," he noted, "it will take us a long time to gain such approval. Clinically, patients look very good. And at the very least this procedure appears to be safe. But we cannot say that we have data showing evidence of efficacy."[4] WHAT'S THE HOLD UP? At the time of this report, Therakos is in the process of designing a phase II study with the FDA for people with HIV. According to FDA sources, the trial is pending Therakos' next move, since regulators have asked the company to elaborate on various microbiological and virological aspects of the treatment. Therakos has not yet produced the information. There may also be some concern on the part of the FDA over the inconsistency of T4 changes between the two groups participating in the Morristown studies. Apparently, several different labs were used during the study, and so results may include muddy" data. Finally, Therakos' parent company, Johnson & Johnson, filed a New Drug Application (NDA) back in January, 1991, to use this method of photopheresis in the treatment of scleroderma, an autoimmune disease of the skin. Treatment activists monitoring the progress of photopheresis research for HIV infection speculate that Therakos will be reluctant to pursue the HIV angle any further until the FDA has taken action -- either licensing or rejecting -- the 2-year-old NDA for scleroderma. When asked about future plans for HIV-related research, a spokesperson for Therakos said that the company needed to review data from the Morristown study before deciding to proceed in other treatment areas. REFERENCES 1. Torres G. Photopheresis. Treatment Issues (4) 7:5, 1990. 2. Bisaccia Emil et al. Extracorporeal photopheresis in the treatment of AIDS-related complex: A pilot study. Ann Int Med 113(4):270-275, 1991. 3. Bisaccia E. Personal Communication, October, 1991. 4. Bisaccia E. Photopheresis in HIV disease. HIV & Skin Disease: Issues in Diagnosis & Management. Columbia University College of Physicians & Surgeons, New York City, October, 1991. ***** "Surrogate Markers in Photopheresis Trials" - Beta-2 Microglobulin is a type of protein found in human cells, including T4s. When these cells are destroyed by HIV, a beta-2 protein is released into the blood. Increased levels of beta-2 in the blood may indicate that T4 cells are being destoyed and the immune system damaged. - Skin Tests measure the body's immune reaction to certain proteins which are injected just below the surface of the skin. If the immune system is relatively intact, and able to mount a response against the injection of these proteins, a hardened red or inflamed area will appear within 48 hours at the site of injection. A negative reaction is when there is no response at all. This condition is called anergy. - T4 Cell Counts are the most popular means of measuring HIV progression, since HIV attacks the T4 cell. The test measures the number of T4 cells, which are white blood cells called lymphocytes. A normal range is anywhere from 500 to 1500 T4 cells. - T4 Cell Percentages show what percentage of the total numbger of lymphocytes are T4 cells. A normal range for percentages of T4 helper cells is between 32% to 50%. A change of 3 percentage points is considered a significant reduction, and may indicate HIV progression, even if T4 counts remain steady. - Neopterin is a protein released in large quantities by macrophage cells, which are reservoirs for HIV. It is thought that a rise in neopterin levels correlates with a drop in T4 cell counts. ***** Treatment Briefs PHONE ZAP FOR NEW KS DRUG AIDS and Breast Cancer activists are demanding that The Japanese company, Daiichi Pharmaceuticals, initiate human testing af a new drug called SP-PG. In 1990, researchers found that in animals SP-PG appeared "to melt Kaposi's sarcoma (KS) away." KS may not be a true cancer, but an infectious disease that stimulates growth factors in the body causing the purplish lesions known to signify he AIDS-defining condition. SP-PG may have an enormous impact on the whole field of cancer treatment, particularly cancers that begin in the breast or colon and then spread out. GMHC is leading a nationwide phone zap to pressure the Japanese Government to initiate human trials and a compassionate access program by January 1 1991. On November 25, treatment activists were urged to call Mr. Thomas Boersig at the office in Daiichi Pharmaceuticals at (201) 944-4333, and one af the following Japanese Consulate offices: Mr. Hanabusa Masamichi in New York City at (212) 371-8222; Mr. Atsushi Tokinoya in San Francisco at (415) 777-3633; and Mr. Tateshi Natamura in Chicago at (312) 280-0400. Treatment Issues readers are urged to make follow up holiday calls to the same people throughout the month. Please call and tell them that Daiichi must act quickly in providing human trials and access to SP-PG. Call collect if needed. FOSCARNET RECOMMENDED FOR CMV RETINITIS A preliminary report revealed the first trial results comparing newly-approved foscarnet (brand name Foscavir) to the standard therapy drug ganciclovir (Cytovene). Both drugs are used to treat initial cases af CMV retinitis, an eye disease which can lead to blindness. Recently trials comparing the two drugs were suspended because patients treated with foscarnet, which costs $30,000 per year, lived an average of 4 months longer than those treated with ganciclovir (12 months vs. 8 months). Both drugs, however, seem equally effective in halting the progression of CMV retinitis and preserving vision. The results of this study have not been published, although a paper has been submitted to a major medical journal and awaits peer review. However, two significant features of the data should be noted: (1) It is unclear what causes foscarnet to improve survival rates. It may be that the drug has anti-HIV activity or that more patients taking Foscavir in this study were also taking AZT. Data from the study, however, were not statistically significant enough to offer a solid explanation of the results. And (2) a subgroup of patients with abnormal kidney function had better survival with ganciclovir, which may be because foscarnet is known to cause kidney damage. ddC READY FOR FDA-APPROVAL On Halloween, 1991, Hoffmann-LaRoche announced the completion of the New Drug Application filing process for ddC (trade name HIVID). The company is seeking approval for the treatment af HIV-infected persons who have failed or are intolerant to AZT. Additionally, the company is seeking approval of ddC as a first line therapy for HIV in combination with AZT. HEART FAILURE IN A FEW ddC PATIENTS Hoffmann-La Roche, manufacturer of ddC, reports seven cases of heart inflammation or failure in patients enrolled in the ddC Expanded Access Program. ddC is an antiretroviral drug which has been taken by about 8,000 persons in clinical trials or through the ddC expanded access program. Six af these seven patients died of heart failure. One patient who stopped taking ddC, is undergoing treatment for congestive heart failure. While such heart failure cannot be ascribed definitively to ddC, the drug cannot be ruled out as a contributing factor to the onset or worsening of heart problems in the seven patients. Persons with underlying heart trouble are advised to interrupt anti-HIV therapy for one month and take non-invasive tests for heart function. All Persons taking ddC need to be aware of, and to report to a doctor, the signs of heart failure which are low blood pressure and fluid in the lungs, liver or lower extremities, causing difficulty breathing, liver enlargement, stomach pain, or swelling in the legs. Clarithromycin & Azithromycin Approved Two antibiotics, clarithromycin and azithromycin, which ore promising prospects for the treatment of HIV-related MAC and toxoplasmosis, have at last been FDA-approved. Azithromycin (brand name Zithromax) made by Pfizer, is now licensed as treatment for certain respiratory and skin infections and for chlamydia. Clarithromycin (brand name Biaxin), made by Abbott Labs, is approved for upper and lower respiratory infections as well as uncomplicated skin infections. The good news is that the drugs will became more available for use in HIV-infection. The bad news is that they are expensive and when used for non-licensed conditions such as HIV- related MAC or toxo, ("off-label use") the cost of the drugs may not be reimbursed by third-party insurance or Medicaid/Medicare. 566C80 Expanded Access As reported earlier, activists succeeded in pressuring Burroughs Wellcome to develop an expanded access program for 566C80, a promising treatment for PCP and toxoplasmosis. Burroughs submitted an application for the access program to the FDA, with hopes that approval would be granted in mid-October. The FDA has finally completed its review (a month later) after several inexcusable delays, and approved a 566C80 expanded access program. To enroll, individuals must have PCP and a history of dose-limiting intolerance to TMP/SMX (Bactrim) or on inadequate response to TMP/SMX. Physicians should call 1-800-755-2020 to register patients. "L"-Drug Pulled from Trials Disappointing early data from human trials using L-697-661 led drug company Merck, Sharp & Dohme to halt federally-funded trials of the drug. L-697-661 is a reverse transcriptase inhibitor, a new class of anti-HIV drug which inhibits an important protein in HIV called reverse transcriptase (RT). The company reported that resistance developed within six weeks of therapy in study participants, making therapy with the L-drug an unlikely prospect for HIV treatment. These developments also throw a doubtful light on other RT inhibitors including BIRG (Nevirapine) and TIBO derivatives as single therapies. ***** "Megace to Stimulate Appetite" by Gabriel Torres, M. D. Megace is the brand name of megestrol acetate, a synthetic substance derived from the female hormone, progesterone. The drug is marketed by Bristol-Myers Company for the treatment of breast cancer which has spread to other parts of the body. Another possible use of Megace is to stimulate appetite in order to produce weight gain. The actual way Megace works in appetite stimulation is unclear. Some experiments seem to indicate that the drug plays a role in fat synthesis in the body.[l] MEGACE HELPS IN WEIGHT GAIN AND IMPROVED APPETITE Several reports now indicate that Megace can be used successfully in the treatment of anorexia (poor appetite) and cachexia (wasting syndrome) associated with HIV infection. One of the initial studies was conducted at the Northwestern University Medical School in Chicago by Dr. Von Roenn and colleagues.[2] In an open study, 14 HIV-positive patients who had lost more than 10% of their body weight were treated with 80 mg of oral Megace four times daily. All patients received AZT previously, but five discontinued AZT when toxicity occurred. All patients taking Megace gained weight at a rate of approximately 3.1 lbs. per week, with an average weight gain for the entire group of almost 14 lbs. Three patients returned to their original body weight. All patients reported a marked improvement in appetite, and seven had improved sense of well being. None of the common Megace-related side effects -- like swelling, low platelet counts, and impotence in men -- was noted. This study, however, was criticized for being uncontrolled, since many of the patients had recovered from opportunistic infections and thus were expected to gain weight. Additionally, others were on AZT, which may also account for some improvement in appetite.[3] UPDATED STUDY RESULTS At the VIIth International Conference on AIDS in Florence, Italy several placebo-controlled studies demonstrated that Megace is effective in producing weight gain in patients with advanced HIV disease.[4] The largest study was a multi-center trial sponsored by Bristol-Myers. Participating were 278 patients with more than 10% weight loss, anorexia, and absence of infections. Patients were randomized to receive either placebo or one of three doses of Megace (100 mg, 400 mg or 800 mg). Participants could not have initiated AZT within the 8 weeks prior to starting the study. Of the first 176 patients analyzed, 62.7% assigned to Megace at 800 mg/day gained more than 5 lbs. Only 16% of patients receiving placebo gained more than 5 lbs. The average weight gain for the group receiving Megace was 7.8 lbs. compared to an average loss of 1.5 lbs. for placebo recipients. In another study reported in Florence similar weight gains were noted with Megace at doses of 400 mg/day and 800 mg/day, but not at 100 mg/day. Side effects included gastrointestinal upset and impotence in a few patients. Similar results were obtained in a study conducted by the New York Community Research Initiative (CRl),[5] which showed that doses of Megace above 100 mg produced an increase in fat-free mass and body fat, as well as improvement in perceived quality of life. No evidence of a favorable effect on the immune status (T4 cells) or effects which may prevent weight loss during disease complication was noted in this study. Finally, a study about Megace, conducted at Brown University, was reported at the 31st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in October, 1991.[6] Megestrol acetate was administered as a single oral dose of 800 mg/day for 21 days to 9 HIV-infected patients. All of the participants had suffered weight loss of 10% of their total body fat. All patients reported an increase in appetite and eight patients gained weight at varying degrees (between 4 to 6 lbs.) after three weeks of therapy. However, unlike the special single dose used in the Brown University study, Megace is available in pill form only at 40 mg per tablet. Therefore, to duplicate the above noted studies, using 800 mg/day, a person must take 20 pills per day. CONCLUSION Megace seems to be a reasonable therapy for persons with HIV-related weight loss, where the wasting is not the result of an infection, diarrhea, malabsorption, or cancer. The drug is expensive at $27 per day for an overall dose of 800 mg/day. The potential adverse effects (such as impotence) may make it unattractive to some men. The consumption of 20 pills a day may make it difficult for all patients. However, in most circumstances Megace is still considered a fairly viable option for increasing appetite. REFERENCES 1. Tchekmedyian NS, Hickman M, Heber D. Treament of Anorexia and weight loss with Megestrol acetate in Patients with anorexia and AIDS. Seminars in Oncology, 1991; 18:35-42. 2. Von Roenn JH, Murphy R, Weber KM, Williams LM, Weitzmen SA. Megestrol Acetate for treatment of cachexia associated with HIV infection. Annals of Internal Medicine, 1988; 109:840-841. 3. Furth PA. Megestrol acetate and cachexia associated with HIV infection. (letter) Annals of Internal Medicine 1989; 110:667. 4. VIIth Int'l Confer on AIDS. Abstracts #W. B. 2392, #M. B. 2198, #M. B. 2233, Florence, Italy, June 1991. 5. CRI Representative, Personal Communication, October, 1991. 6. ICAAC, Abstract #550, Chicago, October, 1991. ***** Glossary AIDS Clinical Trials Group (ACTG): A set of about 50 research centers around the country where federally-funded human trials are conducted. Anorexia: Diminished appetite, or inability to eat. Antiviral activity: The action of an agent that stops or suppresses the activity of a virus. Autoimmune disease: A disease which arises from and is directed against an individual's own tissues. Baseline: Laboratory measurement made when a person is first entering a trial; used as a companion drug trial. Buffered: Coated or encased in a special substance which allows easier absorption of a medication by neutralizing the acidic environment of the stomach. Cachexia: A general weight loss and wasting occurring in the course of a chronic disease or emotional disturbance. Candidiasis: A condition, also known as thrush, which is caused by a fungus called Candida albicans. It can appear in a variety of places in the body, including the mouth, the vagina, and the esophagus. Cytomegalovirus (CMV): A virus related to the herpes family that can cause fever, fatigue, enlarged lymph glands, aching, and mild sore throat. DNA (deoxyribonucleic acid): A complex protein that carries genetic information. HIV can insert itself into the DNA molecules, which reside inside human cells and establish dormant infection. Dose-ranging: A kind of human trial, usually phase I, in which participants receive a varying dose of experimental drug and are observed, in order to determine which dose is least toxic. Efficacy: Effective at the dose tested and against the illness for which it is prescribed. Gamma globulins: A type of immunoglobulin (see below) made by plasma cells, which is able to resist infection by viruses and bacteria. Herpes Simplex virus (HSV): A virus which causes painful sores of the mouth, eyes, anus, and genitals in men and women. Immunoglobulin (Ig): An antibody or protein which attacks invading organisms and allows the body to destroy them. IRB (Internal Review Board): A regulatory committee comprised of staff and community representatives that reviews and approves human trials in the institution. Kaposi's sarcoma: A rare form of skin cancer, recognized as raised non-tender red or purplish spots on the skin, or in the stomach or lungs Lymph node: Small bean-sized organs of the immune system, widely distributed throughout the body, containing white blood cells, lymphocytes and macrophages. MAC: Mycobacterium avium complex (MAC) is a serious opportunistic infection in HIV, which causes symptoms such as fevers, chills, abdominal pains, night sweats, diarrhea, anemia and weight loss in patients with HIV disease. Macrophage: A scavenger cell specializing in the ingestion and processing of large matter, especially harmful bacteria and viruses Neuropathy: A condition of inflammation of the nerve tissue usually affecting the hands or feet. Package insert: A form containing all relevant information known about a drug which can be found on the inside of any prescription drug container. Phase I: The category of a federally funded trial which tests experimental drugs in humans to determine the drug's safety and finds the most effective dose to use. Phase II: The category of a federally funded trial which tests an experimental drug to see how well it works, and to study the drug's side effects. Phase II trials often involve several hundred people who are randomly assigned to take either the experimental drug or a "control" (the standard treatment for the disease or no treatment at all). Usually the trial is double- blinded, which means no one knows who is getting the drug until the trial is done. Protocol: The blueprint or design for a particular experimental drug trial. Reverse transcriptase (RT): A protein on HIV which is capable of copying RNA to DNA, which is an essential step in the life-cycle of the virus. RNA (ribonucleic acid): A complex protein responsible for the transmission of genetic information. Toxic side effect: A range of many reactions by the body when a beneficial medicine is also damaging to some part of the body. Virology: The study of viruses and viral diseases. ***** Miscellaneous To Treatment Issues Readers: All of us in the Medical Information program at GMHC would like to share our goals and priorities for the coming year with you, and to remind you to renew your subscription to Treatment Issues, if you are financially able. Your payments and donations enable us to continue to publish and distribute Treatment Issues to a growing audience. Treatment Issues is now the nation's largest community-based publication devoted to HIV/AIDS therapies. It provides life- saving information to tens of thousands of people around the world. Your subscription enables us to make Treament Issues available to men and women with HIV/AIDS, who are not currently able to make a financial contribution. GMHC's Medical Information program provides much needed, reliable information about experimental therapies for HIV, guides to accessing these therapies, and updates on treatment advocacy efforts. Listed below are some of our priorities and projects for the upcoming year: - Treatment Issues now reaches over 20,000 readers, including healthcare professionals, government decision-makers, patients in clinics, hospitals and prisons, pharmaceutical executives and people with HIV/AIDS from all walks of life. Treatment Issues is also distributed to over 500 AIDS service and advocacy organizations worldwide. Treatment Issues Bulletins, a new feature, was added this year to provide late-breaking medical information to readers. - Treatment Advocacy. Working together with GMHC's Public Policy department, we are able to demand more rapid development, testing, and access to promising HIV/AIDS treatments. In this issue, for example, Treatment Issues is leading a nationwide phone zap to persuade a pharmaceutical company to test a promising drug for Kaposi's Sarcoma and breast cancer. - Community-wide Treatment Forums. In January, Medical Information will initiate the first in a series of regularly scheduled forums designed to provide treatment information to people affected by HIV. The first forum is co-sponsored by the Minority Task Force on AIDS and is scheduled to take place in Upper Manhattan. The second forum will address recent developments in immune-boosting vaccines. - Medical Information Outreach. Medical Information also publishes AIDS Clinical Update, a quarterly packet of cutting- edge information to over 1,000 healthcare professionals. Our aim is to educate those who provide primary health care about AIDS and HIV. We are also developing HIV Fact Sheets, a series of one-page fact sheets detailing the latest medical information about opportunistic infections, T-cells and other markers, experimental and approved HIV therapies, and medical reimbursement plans. - AIDS Treatment Library. The Medical Information program is working to enable people with HIV/AIDS, GMHC clients, activists, care-givers, healthcare providers, and other interested parties to have access to the most up-to-date information regarding potential AIDS therapies. We hope to open the nation's first library devoted solely to HIV/AIDS treatment information. - Treatment Issues Special Editions. Medical Information is planning to publish the first in a series of newsletters devoted to specific, often neglected, topics. Our first edition will be "Women and HIV Treatment Issues." The number of requests for Treatment Issues has increased dramatically and we are now faced with difficult budgetary choices. Nevertheless, we are committed to distributing Treatment Issues to individuals with HIV/AIDS and to AIDS organizations, regardless of their ability to pay. Please remember that your subscription fees and contributions enable us to continue providing life-saving infrormation and advocating for promising HIV/AIDS treatments. Thank you in advance for completing the form below and returning it to us in the enclosed envelope. Best wishes for a happy, healthy, and meaningful New Year. David Gold, Executive Editor Mary Beth Caschetta, Editor Griffin Meyer, Technical Coordinator [Coupon omitted.] Subscription fees are: $30 Individuals, $50 Physicians/Institutions, $60 Foreign, or Sliding Scale for those able to contribute. Contributions of $50 or more will receive a copy of the Treatment Issues Compilation. Please make checks payable to GMHC. Mail to GMHC, Medical Information, 129 West 20th Street, New York, NY 10011. For more information, please call (212) 337-1950. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display