Subject: GMHC Treatment Issues vol. 5 no. 8 Date: November 1991 (1113 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& GMHC Treatment Issues vol. 5 no. 8, November 1991 Contents: [items are separated by "*****" for this display] Mycobacterium Avium Complex How to Get Information about Experimental Drugs for MAC Treatment Briefs Peptide T Available in NY Antiviral Combinations: Part II New Studies Glossary Resources Miscellaneous Sidebars ***** "Mycobacterium Avium Complex" by Darren Britton Mycobacterium avium complex, or MAC, is a disease made up of different strains of mycobacteria found in AIDS patients, which together form a "complex." M. avium, the most common strain, and M. intracellulare, previously gave the disease its name, MAI (or Mycobacterium avium intracellulare). The new name, MAC, came about when researchers discovered that the illness is actually caused by up to ten different strains of bacteria, which makes the infection notably difficult to treat. The organisms which cause MAC occur naturally in food, water, and soil[1] -- as well as in hospital water supplies.[2] The most common strains found in PWA's are particularly associated with heated water supplies.[3] Avoiding exposure remains difficult at best. BACKGROUND Before the AIDS epidemic, illness caused by MAC was rare in humans. In fact, in 1980, only 24 cases had ever been reported in medical literature.[4] In 1982, however, reports of MAC infection increased dramatically, and the infection began to be recognized as an AIDS-related illness. In the early days of AIDS, MAC infection was usually identified only at autopsy. Most PWA's dies of other causes, such as PCP, which can now usually be prevented. At that time, doctors and researchers believed that MAC bacteria caused infection in the late stages of HIV disease, but did not cause serious illness, since the bacteria was found at autopsy in people who had dies of other causes. Since then, studies have shown that MAC infection, which spreads to numerous parts of the body (disseminated infection), can cause both illness and death in PWA's.[5] By December 31, 1990, 12,202 cases of disseminated MAC infection were reported in persons with AIDS. This number comprises 7.6% of all AIDS cases reported to the Centers for Disease Control (CDC). In clinical studies, 76% - 90% of MAC infections come late in the course of HIV, well after AIDS has first been diagnosed.[6] Current estimates indicate that between 15% - 24% of PWA's have symptomatic MAC disease.[7] Applying this ratio to the number of actual reported cases, disseminated MAC infection may affect between 30,000 - 49,000 people with AIDS in the U.S. According to a report from Florence, MAC and other atypical mycobacterial infections occur in women twice as often as they occur in men.[8] At the National Conference on Women and HIV Infection, similar studies were reported from the Bronx, New York, and Newark, New Jersey, which point to the possibility that MAC may have a different pattern in women than in men.[9] This possibility requires immediate investigation. SYMPTOMS Symptoms of MAC usually include fevers, chills, weakness, abdominal pains, night sweats, diarrhea, anemia, and weight loss. MAC is a major cause of "wasting syndrome." Though very uncommon, the infection can produce non-specific symptoms, making diagnosis difficult. As people with AIDS live longer, MAC illness continues to occur relatively late. Data indicate that it occurs on average 7 to 15 months after AIDS is diagnosed.[10] Additionally, MAC seems to be associated with advanced immune dysfunction. In fact, the majority of patients with MAC disease seem to have T4 cell counts below 60.[11] DIAGNOSIS MAC remains a challenge to diagnose in PWA's. As with most bacterial infections, people with immunosuppression are often not capable of producing antibody responses to MAC infection.[12] When MAC involves the lungs, pulmonary symptoms may appear, but new studies show that symptoms don't occur in about 4% of PWA's. Chest x-rays may be insufficient to diagnose the illness. Microscopic examination of phlegm with a special acid-fast method of detection is another way do diagnose MAC. However, a positive result could represent other types of mycobacteria and may not be conclusive. Additionally, although lungs may become infected, recent research shows that bacteria first enter the gastrointestinal (GI) tract.[14] In the GI tract, MAC invades the wall of the intestine, liver, and spleen, causing diarrhea and abdominal pain, swelling and often abnormal liver function tests. Since most PWA's have disseminated disease, it is best to diagnose MAC by blood cultures. Blood culture is a process by which blood is removed from the body and placed in an atmosphere where bacteria, if present, will grow in large numbers for easy detection. Two consecutive blood cultures are usually adequate to make a diagnosis.[15] New techniques are leading to faster blood culturing for MAC. For instance, a French group reported using a 2-step polymerase chain reaction (PCR) test to diagnose MAC in less than 4 hours.[16] Studies have also shown that liver biopsies and bone marrow examinations are rapid ways of diagnosing MAC; however, they are more invasive procedures. PROMISING MULTI-DRUG THERAPIES Early studies of therapies for disseminated MAC were discouraging. Recently, studies have shown relief of symptoms in most patients with some treatments. The most effective MAC therapies have been shown to be multiple drug combinations of 3-7 drugs.[17] Fever, night sweats, and malaise may respond to combination therapies within two to eight weeks. Diarrhea and weight loss are still difficult to control, and improvement in survival has been modest. Several studies have demonstrated that combinations of three or more antibiotics can be effective in improving symptoms and clearing bacteria from the blood, although many patients still display MAC in tissue at autopsy. One study, reported in San Francisco last year by Dr. Potage and others, evaluated the response of 20 AIDS patients with disseminated MAC.[18] Patients were treated with a regimen consisting of intravenous amikacin, oral clofazimine, firampin, and ethambutol. Amikacin was given intravenously for 30 days or until a dose-limiting toxicity occurred. Nineteen of the 20 patients had a favorable response with lab blood tests showing clearance of mycobacteria from tissue. One patient's bacterial recurred when amikacin was stopped. Amikacin caused hearing loss in some patients who had been taking it for more than 60 days. The frequency of such hearing loss is significantly diminished when amikacin is used for no longer than 4 weeks. Irreversible ear damage may occur with longer-term use. In Florence, a study from Sweden was presented in which 31 patients with MAC were treated with the combination therapy: amikacin, ethambutol, and rifabutin. After an average of 14 days of therapy, 71% of patients had improvement in symptoms, including fever, diarrhea and a new sense of well-being.[19] Two other published studies have reported similar successes with combination therapies.[20] AZITHROMYCIN Azithromycin, an antibiotic made by Pfizer, is an experimental option for toxoplasmosis and MAC. The drug penetrates well into tissues with very little toxicity in both animals and humans. A four-week azithromycin study using mice resulted in 95% survival and a significant decrease in bacteria in the blood, liver, and spleen.[21] A phase I human pilot study treated 16 patients with AIDS and MAC bacteria with azithromycin (500 mg per day).[22] Of the 16 patients treated for 20 or 30 days, 14 had improvement of such symptoms as fever, night sweats, fatigue, and weight loss. Blood tests showed a reduction of bacteria. The main side effect was diarrhea. Azithromycin is available under compassionate use from Pfizer as treatment for toxoplasmosis and MAC. Unfortunately, according to Pfizer, only 20 patients have used the drug through compassionate use for MAC, since advertisement efforts have been minimal. A representative from the company did reveal that plans to get the word out are under way. Additionally, the PWA Health Group sells the drug for $43.00 per six pills at 250 mg. each. RIFABUTIN Rifabutin, an antibiotic similar to rifampin (used to treat tuberculosis), has been studied as a treatment for MAC for several years. It was originally available from the CDC and from Adria Pharmaceuticals for compassionate use. One study presented in San Francisco by Dr. Fred Siegal from New York, assessed rifabutin (300-900 mg/day) in 20 PWA's. Compared to an historical control group of 184 patients who did not receive rifabutin, the patients taking the drug for less than 30 days had an improvement in MAC-free survival.[23] In Florence, investigators from Adria Pharmaceuticals presented data on 90 patients with AIDS and MAC treated with rifabutin in a combination regimen.[24] Fever and night sweats resolved in 72% of patients, although there was a minimal decrease in diarrhea. Average survival time was 207 days. Side effects of Rifabutin include low white blood cell counts, low platelet counts, and rashes. Rifabutin is presently being studied in a large placebo-controlled trial sponsored by Adria for treatment of MAC in combination with ethambutol and clofazimine. In addition, it is being studied for preventing initial MAC infection in patients with T4 cell counts under 200. For more information on these trials in the New York area, patients can call 1-800-TRIALS-A. CLARITHROMYCIN Clarithromycin is a broad-spectrum antibiotic approved for use in 20 countries to treat respiratory, skin, and gastrointestinal infections. Until now, the drug has been imported from Europe, and costs about $600-$750 per month for six weeks of acute treatment. for maintenance therapy, it costs about $200 per month. It continues to be a hot item at buyers' clubs, such as the PWA Health Group. Experience using clarithromycin in AIDS patients is limited. One recent study compared a group of patients taking clarithromycin, isoniazid, ethambutol, and clofazimine to a group of patients taking placebo, isoniazid, ethambutol, and clofazimine for six weeks. Then all patients received clarithromycin and combination therapy with rifabutin for an additional six months and finally received clarithromycin alone as therapy to prevent relapse.[25] All patients receiving clarithromycin in combination showed that bacteria cleared from the blood, compared to only two patients of the five receiving placebo and combination therapy. Of six patients receiving clarithromycin alone to prevent recurrence of disease, only 1 in 5 had a relapse. Early data from Abbott Laboratories, developer of clarithromycin, indicate that the drug reduces blood levels of AZT by 15%-25%, but the significance of this reduction is not yet known. CLARITHROMYCIN PROPHYLAXIS The prevention of MAC with clarithromycin is controversial. Abbott Laboratories has put on hold until early 1992 a prophylaxis study using clarithromycin. The company claims to be uncertain as to the dose that should be used for prophylaxis. Since prophylaxis usually employs a lower dose than the dose used for treatment of disease, some physicians are recommending clarithromycin for prophylaxis, using doses in a lower range: 250 or 500 mg/day.[26] It should be noted that mycobacteria are known to develop resistance quite easily. Therefore, there is concern that an inadequate dose might promote resistance, making the drug useless for prophylaxis and treatment. The problem is that if MAC becomes resistant to clarithromycin, it may well become resistant to other similar antibiotics, thus erasing treatment options. Since there is much at risk, it is important to consult with physicians and other experts before deciding to prophylax against MAC. CLARITHROMYCIN EXPANDED ACCESS Abbott Laboratories announced in April the establishment of an expanded access study of clarithromycin for disseminated MAC infection. This study does not enroll patients who have previously used clarithromycin. However, a second expanded access study was recently announced for patients who have taken clarithromycin before. These patients do not have to test positive for MAC. One obstacle to both of these programs is the amount of paperwork required, which inhibits many physicians from obtaining the drug for patients. Another problem may be single-agent therapy. Despite the fact that there are more data supporting combination therapy, the Abbott-sponsored expanded access studies use clarithromycin alone. Patients with acute MAC are taking the drug for 12 weeks, and are randomized to receive either 500 mg or 1000 mg, each twice per day. Upon the first follow-up visit in the fourth week of using clarithromycin alone, a physician can add additional drugs if the patient is declining. All additional drugs used thereafter must be reported to Abbott with rationale. Expanded access is intended to offer earlier treatment to those patients without other options while at the same time collecting data that reflect "real world" use. Current trends indicate that clarithromycin in combination with other drugs is akin to "real world" use and, most importantly, is more beneficial for the patient. A formal clinical study with a control group, rather than an expanded access program, may be a better option for collecting complex data about such use of clarithromycin. SPARFLOXACIN A new antibiotic called sparfloxacin is about to be tested at 12 sites nationwide.[27] Sparfloxacin is more active in the test tube against MAC than older drugs of its class (called quinolones), including ciprofloxacin. The new studies, to be headed by Dr. Lowell Young, will determine the safety of the drug and, to a lesser degree, its efficacy. Sparfloxacin has been tested extensively in Japan to treat gynecological skin, respiratory, and urinary tract infections. The major side effect associated with the drug is skin sensitivity to sun or ultraviolet light. Five sites in Denver, CO; Irvine, CA; Orange, CA; Portland, OR, and San Francisco, CA are ready to enroll. Other sites will be announced. Parke-Davis is the only U.S. commercial developer of sparfloxacin for the Japanese pharmaceutical company, Dainippon. CONCLUSION Disseminated MAC infection is increasingly recognized as a significant illness in PWA's. Combined drug therapies can now lead to symptomatic improvement and are becoming more widely used. As always, there is much yet to learn about optimal therapies for treatment and prevention of MAC. Optimal study designs continue to be explored, since studying combination therapy is more complex than studying single agent therapy. Current experimental studies offer eligible patients some, though not many, alternatives to the handful of drugs currently available. REFERENCES 1. Wolinsky E. Non-tuberculous mycobacteria and associated diseases. Am Rev Respir Dis: 119:107-59, 1979; and Horsburgh C.R., Jr; Mason U.G., III; et al. Disseminated infection with MAI. Medicine (Baltimore) 64:36-48, 1985. 2. Stine TM et al. A pseudoepidemic due to atypical mycobacteria in a hospital hot water supply. JAMA 258:809-11, 1987. 3. Okello DO et al. Absence of bacteremia with MAI in Ugandan patients with AIDS. J. Infect Dis 162:208-10, 1990. 4. Horsburgh CR, Jr et al. Disseminated infection with MAI. Medicine (Baltimore) 64:36-48, 1985. 5. Horsburgh CR, Jr et al. The epidemiology of disseminated nontuberculous mycobacteria in AIDS. Am Rev Respir Dis 139:4-7, 1989. 6. Chiu J et al. Treatment of disseminated MAC in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. Ann Intern Med 113:358-61, 1990 and Hoy J et al. Quadruple drug therapy for MAI bacterium in AIDS patients. J Infect Dis 161:801-5, 1990. 7. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), abstract #297, Atlanta, October, 1990. 8. VII Internat Conf on AIDS, Abstract #M.C. 3115, Florence, June, 1991. 9. Freidland, G. Opportunistic infections in women. Nat Conf on Women and HIV Infection. Washington, D.C., 1990; and Kloser P. Opportunistic infections in women. Nat Conf on Women and HIV Infection, Washington, D.C., 1990. 10. VI Internat Conf on AIDS, Abstract #251. San Francisco, June, 1990. 11. Metroka C. Prophylaxis for Pneumocystis carinii pneumonia and other opportunistic infections. AIDS Targ Inf News 4(6) 1-2, 1990; VII Internat Conf on AIDS, Abstract #M.B. 2365, Florence, June, 1991. 12. Wayne WG et al. Absence of mycobacterial antibody in patients with AIDS. Eur J Clin Microbiol 5:363-5, 1986. 13. Ruf B et al. Pulmonary manifestations due to MAI in AIDS patients. Am Rev Respir Dis 141 (Supp): A611, 1990. 14. Klatt E.C.; Jensen D.F. et al. Pathology of MAI infection in AIDS. Hum Pathol 18:709-14, 1987. 15. Yagipsky P et al. Cumulative positivity rates of multiple blood cultures for MAI and Cryptococcus neoformans in patients with AIDS. Arch Pathol Lab Med; 114:923-5, 1990. 16. VII Internat Conf on AIDS, Abstract #M.B. 2405, Florence, June, 1991. 17. Horsburgh, C.R., Jr. Mycobacterium avium complex infection in AIDS. NEJM 324 (19):1332-7, 1991. 18. VI Internat Conf on AIDS, Abstract #Th.B. 517, San Francisco, June, 1990. 19. VII Internat Conf on AIDS, Abstract #M.B. 2365, Florence, June, 1991. 20. Hoy J. et al. Quadruple drug therapy for MAI bacteremia in AIDS patients, J Infec Dis 161:801, 1990. 21. Young, L et al. In vitro and in vivo activity of azithromycin against MAC. J. Infec Dis 159:994, 1989. 22. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), abstract #294, Chicago, October, 1991. 23. VI Internat Conf on AIDS, Abstract #Th.B. 518. San Francisco, June, 1990. 24. VII Internat Conf on AIDS, Abstract #W.B. 2300, Florence, June, 1991. 25. VII Internat Conf on AIDS, Abstract #W.B. 2358, Florence, June, 1991. 26. Franke-Ruta G. Clarithromycin Confusion Notes From the Underground. July/August, 1991. 27. Smith D. MAC: new drug, sparfloxacin, enters trials. AIDS Treat News 132:5, 1991. ***** "How to Get Information about Experimental Drugs for MAC" 1. Clarithromycin: Expanded Access: Have your physician call: 800-688-9118. The Underground: Drug is expensive ($27 for 14 pills at 250 mg.). Call (212) 532-0280. Clinical Trial: Must meet specific entry criteria/entry limited. Call (800) TRIAL[S]-A and consult with a doctor. 2. Sparfloxacin: Clinical Trials: On West coast only. Call Parke-Davis at (800) 521-3084, ext. 7297. 3. Azithromycin: Compassionate Use Program: Have your physician call (203) 441- 5701. The Underground: Drug is expensive ($43 for 7 pills at 250 mg). Call (212) 532-0280. Clinical Trials: Must meet specific entry criteria/entry limited. Call (800) TRIALS-A. 4. Rifabutin: Compassionate Use Program: Have your physician call (614) 764- 8159. ***** Treatment Briefs CALRITHROMYCIN Abbott Laboratories recently reported that more than 500 people with MAC are taking clarithromycin through its expanded access program -- quite an accomplishment considering the program's enormous paperwork requirements. The company additionally agreed to test clarithromycin as a prophylaxis for MAC by the end of 1991. Abbott claims it is still awaiting data from the MAC treatment trial to determine adequate prophylaxis dosing. Call (800) 688-9118 for more information. On a related note, Abbott disclosed plans to start human trials for its Protease Inhibitor drugs in June 1992. The trials will probably begin in Paris and Amsterdam. The company is still working out some problems with the compound. Apparently, the drugs seem to cause the tails of some rats to fall off. EXPANDED ACCESS FOR 566C80 AIDS activists from ACT UP/Boston and New York have succeeded in pressuring Burroughs Wellcome, the manufacturer of the drug 566C80, to agree to a widespread expanded access program for those who have failed standard therapy for PCP or Toxoplasmosis. The announcement is expected to be made sometime in October. In the meantime, 566C80 is provided by the company on a individual case basis. Call Dr. Michael Rogers at (800) 722-9292 for more information. FOSCARNET The good news is that the FDA has approved foscarnet for treatment of cytomegalovirus (CMV) retinitis in PWA's. CMV retinitis is an eye infection which can lead to blindness. Standard therapy for this condition is gancyclovir; however, many patients are intolerant of the drug's toxicities and many develop gancyclovir-resistant CMV. Foscarnet also shows efficacy against acyclovir-resistant herpes, but has not, as of now, been approved for this condition. The bad news is the price of Foscavir (brand name for foscarnet). Astra Pharmaceuticals has priced the drug at $22,200.00 per year, wholesale. This excludes the cost of infusion. While many pharmaceutical companies have priced their AIDS drugs at unreasonable cost, the price of foscarnet stands out as particularly obscene. Astra is, however, taking great pride in the fact that it has set up a FOSCAVIR Assistance & Information Program (FAIR), which can be reached by calling (800) 488-FAIR (we're not joking). ddI APPROVED FDA approval of ddI is ground-breaking in many areas: ddI is the first drug to be approved solely on the basis of T4 counts; the first drug to be approved for both adults and children at the same time, and the first anti-HIV drug since AZT's approval in 1987. Videx, ddI's brand-name, is for adult and pediatric patients with advanced HIV infection who are intolerant of AZT or have demonstrated deterioration on AZT. Since "advanced HIV," "intolerant," and "deterioration" are loosely defined, patients and their physicians will have freer reign over choosing and accessing this therapy. The price of ddI will be less than the price of AZT, costing approximately $1,745.00 per year, wholesale. The manufacturer of ddI, Bristol Meyers, deserves significant credit for agreeing to an expanded access program for ddI, which provided the drug free of charge to over 22,000 PWA's, and for pricing ddI, at a less expensive cost than other treatments such as AZT. For information regarding reimbursement, call Bristol Meyers's VIDEX HelpLine at (800) 788-0123, 8 am - 8 pm, M-F. GP-160 VACCINE Additional data were released on recombinant gp160, the vaccine that made a splash earlier this year. Initial reports from June showed that 19 of 30 HIV-positive, asymptomatic individuals in the trial developed an increased antibody and cellular immunity to HIV. Dr. Redfield, principal investigator of gp-160 trial, confirms that the remaining 10 individuals (one died in a car accident) experienced immune responses when given higher gp160 doses. Immunization appears to be safe. Patients receiving gp160 experienced T4 count declines of 6% compared to an historicals group not receiving the vaccine, whose T4 counts dropped by 23%. A placebo-controlled phase II trial began in November 1990 at Walter Reed Research Center, and preliminary analysis of that trial should be ready by March 1992. FDA TO INSPECT BUYER'S CLUBS In a meeting with AIDS activists, FDA officials disclosed that they would inspect buyer's clubs, which sell unapproved AIDS treatments. The FDA claims the reason is to determine if the drugs are being sold for profit and if they are safe. However, some activists believe this "crackdown" was precipitated by the widespread availability of bootleg ddC through buyer's clubs across the country. The underground price for a six-to-eight week supply of ddC is about $68.00. The New York City-based non-profit PWA Health Group, for instance, maintains the highest standards of quality, responsibility, and accountability. Perhaps rather than FDA- orchestrated inspections, community-generated standards for operating procedures and accountability of buyer's clubs would benefit all involved. SWISS THERAPY STILL UNDER QUESTION Anecdotal reports of an effective Swiss herbal extract continues to capture the attention of PWAs. The treatment is available only from Hungarian physician Dr. Roka. Several patients stopped conventional therapies for HIV, herpes and CMV in order to receive this unproven therapy. A sample of the extract is being tested at New York University Medical Center by Dr. Charles Farthing to assess its activity in the test tube against HIV. Treatment Issues awaits results. In the meantime, use caution regarding this therapy and/or the discontinuation of other life-saving antiviral treatments. ***** "Peptide T Available in New York" by Anna Blume Peptide T was invented as a potential AIDS therapy in 1986 by a group of scientists, including Dr. Candace Pert at the NIMH. The drug is a string of eight amino acids configured to prevent HIV from attaching to and thus infecting cells. Cells that have already been infected by HIV, prior to therapy with Peptide T, will remain infected until the cell dies. The body, however, less vulnerable to HIV, should have a dramatically enhanced ability to ward off the effects of the virus. In addition to this, Peptide T is a neuronal stimulant which is potentially therapeutic for people with HIV/AIDS. Several phase I clinical trials suggest that Peptide T stabilizes T4-cell counts and improves HIV-related diarrhea, dermatitis, and neuro-cognitive disorders, such as memory or concentration loss, fatigue, and depression. UPDATE FROM FLORENCE Results from a federally-funded, double-blind, placebo- controlled trial of Peptide T were reported at the international conference in Florence.[1] Dr. Peter Bridge and others studied intranasal doses of drug at 1.2 mg/day, 6 mg/day, and 30 mg/day of Peptide T in 32 patients with AIDS. Trial patients did not take any antiviral drug, but continued pentamidine to prevent PCP. Evaluations of improvement were based on neuropsychologic tests. No toxicity was observed, and the greatest improvement in neuropsychologic function and symptom report was seen in patients taking the lowest dose of intranasal drug; that is, 1.2 mg/day. Another study from Canada found that injected Peptide T is an effective, non-toxic, pain reliever for HIV-related peripheral neuropathy. Dr. MacFadden, and others, studied the effects of drug in 27 PWA's, nine of whom had peripheral neuropathies.[2] Injections of Peptide T were self-administered at 10 mg/day, and two patients were tapered to 2.5 mg/day in order to determine minimal effective dose. All patients experienced either complete or subjectively significant resolution of lower limb pain, with effects noticed as early as two days after treatment began. Pain recurred gradually within one week of stopping the drug, and began to resolve with reinstitution of treatment. Two patients with sensory loss or numbness did not have improvement from treatment. In this study, no change in immune function could be attributed to Peptide T. Finally news from Florence evidenced that Peptide T given intravenously, helps nerve cells survive, according to results of 15 AIDS and ARC patients receiving the drug.[3] AVAILABILITY OF DRUG Peptide T is available through two clinical trials: one in Los Angeles for intranasal use, and one in Connecticut for people on methadone and AZT. Additionally, the drug can be bought through buyer's clubs. At the L.A. Buyer's club, the cost of Peptide T at 50 ml is $200.00, a supply that lasts about 40 days at 6 mg/day. (Prices may fluctuate). For more information call (213) 748-1143. The PWA Health Group in New York has also recently received the drug. The cost is $95.00 per 125 mg, a supply which lasts about 21.8 days. For more information call (212) 532-0820. DOSING AND ADMINISTRATION Peptide T can be administered intravenously (IV -- into the vein), intramuscularly (IM -- into a muscle), or intranasally. IV administration is tricky, requires a block of time for infusion, and must be done under medical supervision. The absorption rate and appropriate dose of IM administration are not yet confirmed. Intranasal administration is the least complicated, although it requires a dose five times as high to achieve the same concentration as IV administration. Intranasal Peptide T contains benzyl alcohol as a preservative and should not be used for IV or IM injection. In current clinical trials, dosing for intranasal application is 6 mg/day, administered with a pump-like apparatus. Two squirts (1 mg) per nostril, three times per day for a total of 12 squirts/day is necessary to achieve a 6 mg daily dose. LICENSING AND EXPANDED ACCESS In June 1991 Peptide T was licensed to two companies for further development. Integra Institute and Reed MacFadden, both small companies, hope to conduct phase II trials in New York, Boston, Baltimore, Minneapolis, Seattle, and Portland within three months of receiving their license. Reed MacFadden is planning two trials at this time. One study is for people with advanced AIDS who have failed other therapies for general HIV infection, and the second is planned as a larger trial for people with 150 T cells or less, with symptomatic infection. General symptomology and especially neuropsychology will be monitored. In November, 1991, a conference on Peptide T at the National Institute of Child Health and Human Development (NICHD) will be held. At this conference, researchers will present papers about testing Peptide T in children with HIV. Due to the low toxicity of the compound, many parents hope that the conference will lead to phase I Peptide T trials in infants and children. It is hoped that such trials will be conducted through the pediatric ACTG Committee. In Spring, 1991, the Peptide T ATAC (AIDS Treatment Activist Committee) began to demand that the NIMH establish an Expanded Access program to make Peptide T available to all HIV-positive individuals with neuropathy or severe neuropsychological impairment and to persons with HIV/AIDS who have failed or declined treatment with AZT. Integra and Reed MacFadden are currently committing their resources to the phase II trials and have expressed a commitment to design these trials to include an open label access to Peptide T at the end of the study. This would ensure access to all in the trial, even after it is completed. However, there are no immediate plans for a formal expanded access program, which means that there may only be access for the 60 people entered in phase II trials. Persons with severe cases are encouraged to plead for an Individual Treatment IND by calling Integra at (301) 294-0343; Reed MacFadden at (416) 941-9739 / (301) 653-3990, or FDA officer Paul Richman at (301) 295-8419. There is no guarantee that such an IND will be granted, but the effort may convince officials that people with HIV/AIDS should have access to potentially useful compound, as promising and non-toxic as Peptide T. REFERENCES 1. VII Internat Conf on AIDS, Abstract #TH.B. 90, Florence, June, 1991. 2. VII Internat Conf on AIDS, Abstract #W.B. 2173, Florence, June, 1991. 3. VII Internat Conf on AIDS, Abstract #M.B. 2049, Florence, June, 1991. ***** "Antiviral Combinations: Part II" by Kevin Armington Conventional wisdom indicates that the best approach for treating HIV infection is with a combination of antiviral drugs. In our coverage of the Seventh International Conference on AIDS in Florence, we have given special attention to clinical trials using antiviral combinations. In August, we covered three combinations that have been in clinical trials long enough to have generated significant data (AZT plus ddC, alpha interferon, or ddI). This article will focus more on novel regimens that may hold promise. We will also cover two antiviral / immunomodulator combinations. Since these combinations, for the most part, have not been in trials for very long, results reported here should be considered preliminary. AZT WITH CD4-IGG This alphabet soup combination employs standard antiviral therapy with a new version of the antiviral "decoy" drug, CD4. CD4, in theory, should block the CD4 receptor, which acts as an entry way for HIV into a cell. Early trials of CD4 were very disappointing, but the new modified version, CD4-IgG, was designed to eliminate one of the problems associated with using CD4 as a single-drug therapy: its half-life was much too short to allow the drug to work. Unfortunately, CD4-IgG did not perform any more impressively in this study, although it did stay in the bloodstream longer. In the study, 25 patients received varying doses of CD4-IgG three times a week through subcutaneous injections for at least 12 weeks.[1] p24 antigen levels declined only in the blood of patients who were administered concurrent AZT. Watch for results of a trial using even more drugs: AZT, CD4-IgG, and alpha interferon! AZT WITH ACYCLOVIR Studies to date have failed to demonstrate convincingly any anti-HIV benefit in combining AZT and acyclovir (ACV), the drug approved to treat herpes. No studies in Florence, however, directly compared AZT/ACV to other antivirals, and there are other reasons to continue taking the combination. One study took the novel approach of alternating three different antivirals in alternating weeks.[2] Participants took 600 mg AZT with 2400 mg ACV daily for the first week of the regimen. During the second week, participants took approximately 500 mg ddI/day, and during the third week, 3 mg of ddC/day. This three-week cycle was repeated throughout the trial. Twenty-one patients with an average T4 count of 181 were enrolled in the trial. Increases in counts were observed and sustained for 34 weeks. Researchers document that this alternating drug approach showed anti-HIV activity for at least nine months. This complicated therapy, however, may not be realistic in clinical practice, since the alternating schedule may be difficult to juggle. COMPOUND Q AND AZT OR DDI A joint effort between Cancer Research Campaign Labs in England and Immunology, Inc. in San Francisco studied the effects of combining Compound Q (Tricosanthin) and ddI or AZT in people with declining T4 counts. Participants had been on ddI or AZT for at least one year and had T4 counts under 500. They received 1.2 mg Compound Q weekly for two weeks, then monthly. The authors claim that this is considered a low dose. An unusual statistical analysis was performed, showing that patients gained an average of 1.61 T4 cells per week after therapy with Compound Q began. Before Q, the same people had been losing 1.47 T4 cells per week. Absolute T4 values are not reported. The combination produced no effect on p24 antigen levels.[3] AZT AND INTERLEUKIN-2 Interleukin-2 (IL-2) is a substance secreted by immune system cells and plays a role in the immune response. Because it may stimulate natural killer cells, complementing antiviral therapy with a synthetic version of the substance may be an attractive potential treatment. A small study of 15 patients at Duke University in Durham, NC administered escalating doses of IL-2 over one month. One of the concerns with IL-2 is the high degree of toxicity it has produced in trials so far; in this study, three patients became neutropenic, one developed thrombocytopenia, one experienced severe muscle aches and another developed labyrinthitis, an ear disorder which can lead to vertigo. On the positive side, the authors saw a transient rise in T4 counts while participants were receiving the drug, but levels tapered off after treatment was interrupted. The authors also claim that several other parameters that measure cellular immunity improved. IL-2, when administered with AZT, did not enhance HIV reproduction (it does in the test tube). No advantage to higher doses was noted.[4] THYMOSTIMULIN PLUS AZT A small Italian study divided two groups of 30 asymptomatic people (T4 counts under 400) into two arms. The first group received 500 mg AZT per day alone; the second, AZT plus 70 mg thymostimulin intravenously three times a week. Thymostimulin is a thymic hormone that stimulates production of thymocytes, cells that develop into T cells. In the first group, six patients had rises in T4 counts, while, in 14 of 30 patients receiving the combination, small T4 cell increases remained elevated for at least 8 months. Three patients on AZT alone progressed to AIDS compared to no patients receiving combination. This is a small sample, and it is not possible to state with certainty whether AZT or thymostimulin was responsible for the additional benefit seen in those on combination.[5] CONCLUSION Combinations have the obvious attraction of a multi-pronged attack on HIV. Use of them should also delay development of resistance to any single drug. The challenge is now up to the pharmaceutical companies and the federal agencies conducting AIDS clinical research to move these combinations rapidly through the remainder of the licensing process. REFERENCES 1. VIIth Internat Conf on AIDS, Abstract #W.B. 2123, Florence, June, 1991. 2. VIIth Internat Conf on AIDS, Abstract #TH.B. 84, Florence, June, 1991. 3. VIIth Internat Conf on AIDS, Abstract #W.B. 2171, Florence, June, 1991. 4. VIIth Internat Conf on AIDS, Abstract #W.B. 2154, Florence, June, 1991. 5. VIIth Internat Conf on AIDS, Abstract #W.B. 2130, Florence, June, 1991. ***** New Studies An alpha Interferon and AZT study for mildly symptomatic HIV-positive people is opening enrollment in many sites across the country. This open-label study will be randomized, so that for every two patients receiving injected alpha interferon and oral AZT, one patient will receive AZT alone. Participants must have T4 counts between 200-500 and have been taking AZT for less than six months. Persons taking AZT alone will be switched to the combination if T4 counts drop to 100 or by 50%. Persons with intolerance to AZT who are taking another antiretroviral drug (ddI or ddC) will still be considered for enrollment. For more information in Manhattan, call Noel George, RN, St. Vincent's Hospital at (212) 790-8319; or call Michael Mullen, MD, Cabrini Hospital, at (212) 725-7305. ***** Glossary Amino acids: Any of 20 or more natural acids, which are the building blocks for proteins and necessary for human growth. Anemia: A decrease in red blood cells. A condition which is often caused by AZT, as well as other drugs and conditions. Autopsy: The examination of a dead body to determine cause of death. Broad-spectrum antibiotic: A substance that kills or inhibits the growth of a range of different organisms and can be used to combat disease and infection. Buyers' group: A group that imports drugs that have been approved for use in other countries but have not yet been approved by the FDA for use in the United States. CD4 receptor: The notch on a human cell which allows HIV to attach, enter, and thus infect the cell. Clinical studies: Scientific studies of experimental medicine in human beings. Compassionate user: A program which makes an unapproved experimental drug available to some patients free of charge through their physicians. The process of collecting data is usually monitored by the drug's manufacturer. Special approval to enter such a program must be obtained from the FDA. Dermatitis: Inflammation of the skin. Disseminated: Scattered throughout the body. Efficacy: Effective at the dose tested and against the illness for which it is prescribed. Expanded access: An FDA-approved program which allows patients, who are not in trials, but who meet certain set criteria, to take an experimental drug. In the program, doctors monitor patients' response and report data to the pharmaceutical company sponsoring the drug and the program. Gastrointestinal: Of or pertaining to the stomach or intestines. Half-life: The time required for half of a substance to be excreted from the body. Herpes simplex virus (HSV): A virus causing painful sores of the mouth, eyes, anus, and genitals in men and women which may lie dormant in nerve tissue and later be activated to produce symptoms. Historical control group: A group of people used for comparison in a clinical trial, but which did not participate directly in that trial. Immunosuppression: Weakening of the immune response which occurs with HIV infection as well as with some antiviral or anticancer treatments. Investigational New Drug (IND): Name given to an experimental drug after the FDA approves an application for testing in people. Individual Treatment IND: A program by which a person can receive an experimental drug free from the maker of the drug through a personal physician. The FDA approves entry into this program on an individual basis. Labyrinthitis: An ear condition which can cause loss of balance or dizziness. Lymph node: Small bean-sized organs of the immune system, widely distributed throughout the body, containing white blood cells, lymphocytes and macrophages. Methadone: A synthetic narcotic drug which works like morphine and is used as a replacement for heroine during drug treatment. NIMH: National Institute of Mental Health, an agency of the federal government. Neuropathy: A syndrome of sensory, motor, and reflex symptoms. Sensory loss, muscle weakness, atrophy, as well as burning or tingling are hallmark symptoms reported by PWA's. Neuropsychologic tests: Specific tests designed to measure certain aspects of brain function. p24 antigen levels: A marker of HIV replication which can be measured in the blood and represents a core protein fragment (p24) on HIV. Placebo: An inactive substance against which experimental drugs are compared. In placebo-controlled trials the control group takes placebo, while the test group takes an experimental drug. Many such studies are also double-blinded, which means that neither doctors nor patients know who is receiving drug or placebo. Platelets: Fragments of blood cells which help the normal clotting of blood. Normally 200,000 to 300,000 platelets are found in one cubic centimeter of blood. Pneumocystis carinii pneumonia (PCP): A common parasite which 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). Polymerase chain reaction (PCR): A very sensitive test used in research to detect minute amounts of DNA from an organ. Prophylaxis: Treatment intended to prevent the onset of an infection of disease. Resistance: Diminished effectiveness of a drug on a certain infectious organisms that are able to change enough to avoid the drug's action against it. Survival: An evaluation of drug efficacy which measures the length of life of a person on an experimental drug. Symptomology: The science of symptoms of disease, their production, and the indications they furnish. T4 cell: A type of T-lymphocyte. The T4 cell enhances the immune response to an infection through a complex series of interactions with other types of lymphocytes (B cells, T8 cells), macrophages, antibody producing cells and infectious organisms. Thymic hormone: A hormone of the lymphoid organ. Toxic side effect: A range of many reactions by the body when a beneficial medicine is also poisonous to some part of 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: Wide spread infection of an organ or the whole body with the parasite Toxoplasma gondii. ***** Resources The AIDS Drug Assistance Program (ADAP) pays for several drugs commonly used by people who are HIV-infected. Eligible individuals must be New York State residents, who earn less than $44,000 annually and cannot have a health insurance plan that covers 100% of prescription costs. The program pays for AZT, Zovirax, fluconazole and Ganciclovir, among other drugs. For more information, call 1-800-542-2437. American Foundation for AIDS Research (AmFAR) publishes a catalog of trials involving experimental drugs. To order the AIDS/HIV Experimental Treatment Directory write or call AmFAR, 1515 Broadway, Suite 3601, New York, NY 10036, (212) 719-0033. AIDS Treatment News is a biweekly report which chronicles current developments in experimental and alternative treatments and deals with public policy issues. Contact John S. James at P.O. Box 411256, San Francisco, CA 94141, or call 1-800-TREAT-1-2. Project Inform publishes a newsletter called PI Perspective on experimental treatments with in-depth political analysis. Another excellent resource is their drug hotline, 1-800-822-7422. PWA Coalition Newsline, published by and for people with AIDS and AIDS related conditions, is a grassroots news magazine that appears monthly. Write PWA Coalition, Inc., 31 West 26th Street, New York, N.Y. 10010, or call (212) 532-0290. Notes from the Underground is a grassroots publication focusing on drugs available through the underground network. Write to: PWA Health Group, 31 West 26th Street, 4th floor, New York, NY 10010, or call (212) 532-0280. Body Positive is an organization for people who are HIV-positive. Body Positive publishes a monthly newsletter called The Body Positive. For more information or a subscription, write to 2095 Broadway, Suite 306, New York, NY 10023, or call (212) 633-1782. Also providing services to seropositives is an organization called Positive Action. For more information, call (212) 727- 7768. Critical Path AIDS Project is a newsletter created by and for people with AIDS/ARC/HIV, affiliated with the AIDS Library of Philadelphia. The publication includes an excellent resource directory, medical updates, and clinical trials information, as well as articles about public policy. Write to: 2062 Lombard Street, Philadelphia, PA 19146, or call (215) 545-2212. Treatment and Data Digest, a publication of ACT UP/New York's review of important drug treatment issues addressed the the T + D Committee. To subscribe, write to ACT UP/NY, 155 E. 31 Street, Suite 20-L, New York, NY 10016. ***** Miscellaneous Sidebars (separated by "=====" for this display) ===== "Treatment Issues Compilation Price Lowered" Treatment Issues Compilation is now available; the price has been lowered from $30 to $12. 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 national 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 Accounting Dept. 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. ===== Interested in writing for Treatment Issues? Have story suggestions? Let us know. ===== LIVING WITH AIDS, GMHC produced Cable TV Program. The only show in the country made specifically for people with HIV, now includes a treatment segment. Every Thursday, 10:30 p.m., Manhattan Cablevision, Channel 35/V [New York City]. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display