Subject: GMHC Treatment Issues Vol. 6 No. 3 Date: Mar 1992 (1240 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& && T R E A T M E N T I S S U E S && &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES The Gay Men's Health Crisis Newsletter of Experimental Therapies Vol. 6, No. 3 March, 1992 CONTENTS: [items are separated by "*****" for this display] Cryptosporidiosis Microsporidiosis PML Treatment Briefs TAT-Inhibitor Update Resources Glossary ****** Cryptosporidiosis: Treatment Update by Gregg Gonsalves Cryptosporidiosis is a common opportunistic intestinal disease found in persons with AIDS. The first cases of cryptosporidial infection in humans were reported in 1976.[1] Caused by the parasite Cryptosporidium parvum, cryptosporidiosis is usually characterized by profuse watery diarrhea. Apparently due to weakened immune systems, people with AIDS contract cryptosporidiosis at an increased rate. The parasite has been found in 15% of AIDS patients in the United States, 30% in Europe, and 50% in Africa and Haiti. Cryptosporidiosis is contagious and spread from animal to person and from person to person, as well as through contaminated water and food. Transmission can also occur by oral anal contact, so a latex barrier should be used for all forms of anal sex. This article is mainly concerned with the latest information about potential treatments for cryptosporidiosis. SYMPTOMS The severity of diarrhea caused by cryptosporidiosis varies. The amount of diarrhea daily in volumes can range from 1 to 17 liters. Bowel movements may occur as frequently as 6 to 26 times per day.[2] Other symptoms of cryptosporidial infection in AIDS can include weight loss, nausea, vomiting, cramping, abdominal pain, and fever. The infection by the parasite usually occurs in the small intestine, but infection of the colon and other areas of the gastrointestinal tract have been observed.[3] In the case of cryptosporidial infection of the bile duct, nausea and vomiting may be more severe. Finally, several cases of respiratory cryptosporidiosis have been documented in immunocompromised individuals.[4] In the lungs, cryptosporidiosis resembles PCP. Cryptosporidiosis is highly contagious and has an incubation period of 5 to 14 days. It is difficult to avoid exposure. The prevention of transmission rests on good hygiene, hand washing, and avoidance of direct oral fecal contact. THE DIFFICULTY WITH TREATMENT Since cryptosporidiosis was first identified in people with AIDS in 1982, over 70 therapeutic agents have been tested against the infection without success.[5] Cryptosporidium was originally classified as a veterinary pathogen, or an organism that affects and causes disease in animals only. Recently recognized as a common cause of diarrhea in humans, Cryptosporidium parvum is poorly understood. Without a clear understanding of the biology of the parasite, attempts to design rational therapy for the disease are nearly impossible. In addition, using animals as models for human cryptosporidiosis has largely been unsuccessful. Another unfortunate situation is that the organism does not grow well in the test tube, making it difficult to determine a drug s potential for animal and human testing. The presence of multiple disease-causing organisms in the gastrointestinal tract of PWAs also often confounds efforts to assess the efficacy of anti- cryptosporidial drugs. Lastly, severe immune dysfunction may also contribute to the stubborn nature of cryptosporidial infections in people with AIDS. [6] Two recent experimental therapies for cryptosporidiosis -- namely spiramycin and diclazuril -- have been proven ineffective against the disease in human trials.[7] Other treatments, such as hyperimmune bovine colostrum and oral bovine transfer factor, have shown varying degrees of success.[8] Unfortunately, these particular treatments are largely impractical because they are difficult to obtain in adequate supplies. Currently, three experimental drugs are being tested in humans with cryptosporidiosis. A description of each one follows. 566c80 566c80, produced by Burroughs Wellcome, is a novel drug which potentially works against a number of diseases caused by protozoal parasites. The drug is also being studied for the treatment of PCP and toxoplasmosis (see Treatment Issues, Vol., 6, No. 1). 566c80 is currently being tested at the NIH in Bethesda, Maryland to see if it is effective against cryptosporidial infection. Interestingly, there is no supporting evidence that the drug will work against cryptosporidiosis. However, Cryptosporidium parvum is very closely related to Toxoplasma gondii, the parasite which causes toxoplasmosis, and researchers believe the drug may also prove effective for cryptosporidiosis. Because 566c80 is best absorbed with a high fat diet, there is reason to suspect that the drug may not be suitable or effective against cryptosporidiosis.[9] People with cryptosporidiosis often cannot tolerate fatty foods. LETRAZURIL A human, placebo-controlled trial of letrazuril, manufactured by Janssen Pharmaceuticals, has begun in three locations in New York City. Trial sites include Cornell Medical Center (contact Rosemary Soave at 212-746-6320); New York University Medical Center (contact Douglas Dieterich at 212-986- 3330); and St. Lukes/ Roosevelt Hospital (contact Donald Kotler at 212-523-3671). Letrazuril is a derivative of diclazuril, but has been shown to be better absorbed than its parent drug. People wishing to enter the trial must have had chronic diarrhea for at least two weeks. No one will know who of the 25 participants enrolled is taking placebo and which is taking letrazuril. AZITHROMYCIN The oral antibiotic, azithromycin, made by Pfizer, is being studied against cryptosporidiosis at Cornell Medical Center (contact Rosemary Soave at 212-746-6320) and at the Regional Medical Center in Memphis, TN, (901-575- 7100). A pilot study in England has shown encouraging results, although the investigation was not a controlled study.[10] Azithromycin is available from Pfizer on a compassionate use basis for the treatment of cryptosporidiosis, MAC and toxoplasmosis. The drug can be obtained for any of these purposes by calling this new toll free number: 1-800-742-3029. PAROMOMYCIN Finally, a trial of paromomycin, a drug manufactured by Parke-Davis, is slated to begin sometime this spring through NIAID's AIDS Clinical Trials Group. Paromomycin, (brand name Humatin) has long been discussed as a treatment for cryptosporidiosis. Anecdotal reports and the results of several clinical studies of the drug have pointed to its effectiveness, but a definitive, randomized, controlled trial of the drug has yet to be conducted. A study of 22 AIDS patients with cryptosporidiosis was reported at the International AIDS Conference in June, 1991.[11] The participants in this study were treated with paromomycin at a dose of 500 mg four times daily for 4-30 days. Most episodes of diarrhea lessened with treatments after about four weeks. Three months after completing therapy, five patients had relapsed, but all responded to repeat treatment with paromomycin. The dose of maintenance therapy used was 250 mg twice daily. Humatin is available by prescription and should be tried in all cases of cryptosporidiosis as a first-line therapy. CONCLUSION Without an effective treatment for cryptosporidiosis, the care of PWAs with this opportunistic infection largely involves attempts to control and minimize diarrhea, while maintaining fluid and electrolyte balance and nutritional status.[12] Total parenteral nutrition (TPN) is an intravenous therapy that provides nutrition to people with wasting. It is commonly required to provide sufficient calories and hydration to persons with cryptosporidiosis. Solutions of concentrated glucose protein and fat emulsions are used to provide between 2000-3000 calories per day. Unfortunately, to receive TPN, a person usually needs a permanent catheter, such as a Hickman or Mediport. Clinical research on cryptosporidiosis is largely hampered by the scientific obstacles discussed above. In the absence of a useful animal model or successful test tube testing for screening drugs, many agents have been tried with little pre-clinical justification. Some of these agents have entered a lengthy clinical trials process, only to be proven quite ineffective in the end. References: 1. Nine FA et al. Acute enterocolitis in a human being infected with the protozoan cryptosporidium. Gastroenterol 70:592-598, 1976. 2. Wofsy C. Cryptospondiosis. AIDS Clin Care, 3(4):25- 27,1991. 3. 5th Int'l Conf on AIDS, Abstract #P. 358, Montreal, 1989. 4. Ma P et al, JAMA, 252:1298-1301,1984; and Soave R. Treatment strategies for cryptosporidiosis. Ann NY Acad Sci, 616:442- 51,1990. 5. Fayer RL et al. Cryptosporidium, SPP, and Cryptosporidiosis. Microbio Rev, 50:458-483, 1986. 6. Soave R. Treatment strategies for cryptosporidiosis. Ann NY Acad Sci, 616:442-51, 1990. 7. Soave R. Treatment strategies for cryptosporidiosis. Ann NY Acad Sci, 616:442-51,1990 and Soave R. Personal Communication, January, 1992. 8. Soave R. Treatment strategies for cryptosporidiosis. Ann NY Acad Sci, 616:442-51,1990. 9. Soave R. Personal Communication, January, 1992. 10. Hopkins S. Personal Communication, January, 1992. 11. VIIth Int'l Conf on AIDS, Abstract #2270, Florence, June 1991. 12. Soave R. Treatment strategies for cryptosporidiosis. Ann NY Acad Sci, 616:442-51, 1990. ---------------------------------------------------- OTHER COMMON CAUSES OF DIARRHEA IN PEOPLE WITH AIDS GIARDIA: a non-opportunistic illness caused by the parasite Giardia lamblia. It is a cause of acute diarrhea in 4%-25% of people with AIDS. CMV: a virus of the herpes family, which is commonly reactivated in people with weak immune systems and causes a disease of the colon, called colitis. Colitis causes mild to severe persistent diarrhea with abdominal pains. ISOSPORA BELLI: is a parasite common in tropical and subtropical climates. It causes diarrhea in ten percent of PWAs in Haiti but is less of a problem in the U. S. Profuse, watery, non-bloody diarrhea with weight loss and notable stomach pains are symptoms. MAC: a complicated illness caused by a microorganism that is found everywhere in soil air, water, and food. In people with AIDS, MAC can cause serious disseminated infection, including chronic diarrhea and abdominal pain. SHIGELLA AND SALMONELLA: Two bacterial organisms transmitted primarily by anal-oral contact or through contaminated foods. This kind of infection occurs regularly in people without immune suppression, but may cause severe bacterial diarrhea in people with AIDS. LESS COMMON CAUSES OF DIARRHEA IN PEOPLE WITH HIV/AIDS INCLUDE THE FOLLOWING: Herpes Simplex Virus; Amebiasis; Chlamydia; Strongyloides; Candida albicans; Microsporidia; and Tuberculosis. --------------------------------------------------------- ***** Microsporidiosis by Laura Morrison Diarrhea accompanied by wasting is often one of the first manifestations of HIV infection. It is certainly a frequent and debilitating problem in persons with AIDS. Unfortunately, the exact cause of chronic diarrheal illnesses in persons with HIV is often very difficult to determine. Studies show, though, that examination of diarrhea in AIDS patients leads to the identification of disease-causing organisms in 45%-85% of the cases. Moreover, 50% to 70% of these are treatable.[1] Microsporidiosis, another infection in HIV/AIDS, also causes diarrhea. It is caused by newly discovered spore-forming parasites called microspora. Although very small and difficult to detect, a variety of microspora exists widely in animals and humans. The most common type of microspora, which has been found in about 10% - 30% of people with AIDS, was a recent discovery, called Enterocytozon bieneusi.[2] This particular type of microspora invades the small intestine and seems to cause severe chronic diarrhea.[3] In fact, at the Academic Medical Centre in Amsterdam, infection with E. bieneusi was found in 15 of 55 (27%) of a group of AIDS patients with persistent diarrhea and no other known cause.[4] Prior to the HIV/AIDS epidemic, only eleven cases of microsporidiosis had been reported in world literature. It is conjectured that there are many different species and classes of microspora, which can cause a variety of problems in people with HIV. However, these are very difficult to detect by the current available diagnostic tests. Although best known as a cause of chronic diarrhea, microspora can also cause infections of the eye, kidney, liver, muscles, brain, and several other tissues. Dr. Ralph Bryan of the U. S. Centers for Disease Control (CDC), for instance, reported to Treatment Issues that the agency has documented up to eight cases of microsporidial infection of the eye.[5] The eye infection results in a itchy cornea and abnormal sensitivity to light. Dr. Bryan requests that people with AIDS and with ocular microsporidiosis notify him at (404) 488-4437 so he can add to his data base. TRANSMISSION The mode of transmission of microsporidiosis is unknown, though many patients with it have a history of extensive foreign travel or residence.[6] Other proposed forms of transmission may include unprotected sexual activity and eating food contaminated with microspora. Symptoms, such as diarrhea, abdominal cramps, fever and weight loss, do not always occur immediately after exposure. DIAGNOSIS Small obscure microspora are thought to exist in the intestine, liver, muscles, cornea and other tissues in human beings. However, they rarely show up with routine methods of detection that use stool samples. In fact, microspora often evoke little or no response, and examining stool with an electron-microscope may be the only means for classification, and, sometimes, even recognition. In most cases, diagnosis of microsporidiosis requires a biopsy. Because there is not yet an accepted technique for the detection of microspora in the human stool, diagnosis of intestinal microsporidiosis must be done by small bowel biopsy. It should be noted that the small bowel is relatively slow to heal. Examining urine under an electron microscope may lead to detection of microsporidiosis of the kidney.[7] However, there seem to be no symptoms of microsporidiosis with kidney infection that would lead a doctor to make such a diagnosis. It is important to note, though, that the parasite seems to be shed through the system. So patients with diarrhea caused by microspora may have the organism elsewhere in the body, as well. In fact, it was in treating intestinal microsporidiosis that doctors at St. Luke's Hospital were first led to look for the organism in urine. Presumptive diagnosis of microspora of the eye can be made by examining a scraping of the cornea (swabbing a numbed eye) under an electron microscope. Diagnostic confirmation still requires biopsy. TREATMENT Presently, there is no known effective therapy for microsporidiosis. A variety of old and new agents are currently under investigation and a few scattered reports have shown partial success with the following drugs: o Metronidazole (Flagyl): was the subject of a scientific study from the Netherlands.[8] In the study, 19 HIV-positive patients with microsporidiosis were treated with Flagyl at doses of 500 mg three times a day or 250 mg twice a day. In five patients the diarrhea disappeared. Ten patients had improvement demonstrated by a lessening of diarrhea. Three of the 15 patients had a relapse within one year, and 12 patients had a relapse within four weeks after stopping therapy. In nine of these patients, the diarrhea improved after restarting therapy and the response was maintained when patients took the drug at 500 mg a day. Although patients responded and had less diarrhea, a biopsy of the small bowel of all of these patients showed microspora were still present. o Albendazole: A promising report was made this summer about a drug made by Smith Kline Beecham called albendazole.[9] Six patients treated twice a day with 400 mg of albendazole showed signs of improvement and a reduced number of parasites in the body while they were taking the drug. The federally-funded group that conducts trials (the ACTG) is planning to sponsor a large-scale study of albendazole for intestinal microsporidiosis. Initial designs for the trial have been submitted. Dr. Douglas Dieterich of New York University Medical Center, who designed the trial, is currently treating microsporidiosis patients with albendazole through a compassionate use trial. He has so far treated eight patients with albendazole and reports that all but one have had less diarrhea. One patient's small bowel biopsy no longer shows microspora in the blood. One patient with very advanced AIDS died early on. Treatment with albendazole has been continuous, since patients taken off the drug tend to relapse. The only requirement for enrollment is a positive biopsy for microspora. To enroll call Dr. Dieterich at (212) 986-3330. o 566c80: This Burroughs Wellcome drug has activity against PCP and Toxoplasmosis. Currently, 566c80 is being investigated as a treatment for microsporidiosis and cryptosporidiosis. The NIH is sponsoring a phase I trail for people with these infections. As with cryptosporidiosis, anecdotal reports from the trial indicate that the agent does not I seem to be effective against i microsporidiosis, but it may be too premature to expect results or to extrapolate conclusions. ITRACONAZOLE FOR MICROSPORIDIOSIS OF THE EYE It has been noted that some people with microsporidiosis of the eye get better on their own. Additionally, in at least two cases, people with persistent ocular microsporidiosis were successfully treated with itraconazole, a drug made by Janssen Pharmaceuticals. In other cases, however, itraconazole has been tried with no success. One published account showed that itraconazole works for ocular microsporidiosis.[10] Doctors at the University of Texas Health Science Center treated a person with AIDS who had ocular microsporidiosis and cryptococcal meningitis. However, it cannot be definitively concluded from this case whether it was the itraconazole that worked, or another agent, or if the patient got better on his own. Additionally, Dr. George Corrent at the Cleveland Clinic in Florida observed improvement in a person with microsporidiosis of the eye who was treated with 200 mg of IV Itraconazole daily for 2-3 weeks.[11] The patient was then maintained on 100 mg of the drug daily. Dr. Corrent is willing to talk to doctors of people with ocular microsporidiosis. He can be reached at (305) 978-5082. CONCLUSION Perhaps because microsporidiosis has been considered a rare opportunistic infection, treatment advances, until recently, have been few. Only now with the 566c80 trial at the NIH and the slated ACTG albendazole trial has our federal research establishment taken an interest in this infection. And although albendazole shows promise for intestinal microsporidiosis and itraconazole for ocular microsporidiosis, well designed trials for these and other promising therapies must begin as soon as possible. Increased awareness of the possibility of this infection is necessary, and aggressive investigation of new drugs which may be effective in treating this parasite must be pursued. References: 1. Gerberding JL. Diagnosis and management of HIV infected patients with diarrhea. J Antimicrob Chmother 23 (suppl):83-87, 1989; and Smith PD et al. Intestinal infections in patients with AIDS. Ann Intern Med 108:328-333, 1988. 2. Peacock CS et al. The histological diagnosis of intestinal microsporidiosis in AIDS patient. J Clin Path 1991; and Orenstein JM et al. Intestinal microsporidiosis as a cause of diarrhea in HIV-infected patients: a report of 20 cases. Hum Pathol 21:475-81,1990. Desportes I et al. Occurrence of a new microsporidian: Enterocytozoon bieneusi in the enterocytes of a human patients with AIDS. J Protozoal 32:250-54,1985; and Kotler DP et al. Small intestinal injury and parasitic diseases in AIDS. Ann Intern Med 113:444-49,1990. 4. van Gool T et al. Diagnosis of Enterocytozoon bieneusi microsporidiosis in AIDS patients by recovery of spores from feces. Lancet 336:697-680,1990. 5. Personal Communication, R. Bryan, January 1992. 6. Rene E et al. Diagnosis and treatment of gastrointestinal infection in AIDS in Gastrointestinal and Nutritional Manifestations of AIDS. ed Kotler DP (New York: Raven Press, 1991) pp. 65-93. 7. Personal Communication, Dr. Kotler, January 1992. 8. VIIth Int'l Conf on AIDS, Abstract #W. B. 2267, Florence, June 1991. 9. VIIth Int 'l Conf on AIDS, Abstract #W. B. 2265, Florence, June 1991. 10. R Yee et al. Ophthalmology 98(2):196-201,1991. 11. Personal Communication, Dr. Corrent, January, 1992. ***** PML Treatment Update by Carole Lemens PML stands for progressive multifocal leukoencephalopathy. It is a disease of the central nervous system which results in the destruction of the sheath that covers the nerves. PML can cause a series of symptoms related to mental functioning, including confusion, disorientation, lack of energy, loss of balance, weakness in the arms or legs, blurred or double vision, and blindness. PML is thought to develop in up to 4% of persons with AIDS. [1] The condition results in HIV infected persons due to the reaction of a virus called the Jacob Creutzfeld (JC) virus. It is believed that up to 80% of the general population has asymptomatic JC virus in the kidney. Most people contract JC virus in childhood. In a person with a weak immune system, the virus is reactivated and spread to the brain by white blood cells from the bone marrow.[2] Once in the brain, the virus infects the brain cells responsible for producing the protective sheath around the nerves. Without this protection on the nerves, nerve cells die and cause lesions in the brain. Neurologic dysfunction may follow quickly. Prolonged survival and spontaneous partial recovery has been described in AIDS-associated PML. [3] However, for the most part, PML is a serious condition which can progress somewhat rapidly to serious disease and death. CT or MRI scans may reveal focal or diffuse lesions in the white matter of the brain. A brain biopsy is needed for a definitive diagnosis, since PML is often mistaken for other common AIDS-related infections, like toxo- plasmosis or AIDS dementia complex. There has been little information regarding the treatment of PML, but recent case reports offer hope. CASE REPORTS OF TREATMENT SUCCESS Cytarabine, a drug used to treat leukemia and lymphoma, has had remarkable results in eight patients with AIDS-related PML, according to several recent reports.[4] Positive results when using cytarabine have been reported previously in non-AIDS patients,[5] but previous reports of cytarabine in some patients with AIDS-related PML indicated a lack of response.[6] Three people with AIDS-related PML improved while taking 2 mg/kg of cytarabine administered intravenously every 4 weeks for 5 days, according to a study by Dr. Peter Portegies. It is notable that in all cases, the response was slow, taking anywhere from three weeks to two months. The first patient observed was taking AZT prior to the development of neurological symptoms and continued the anti-HIV drug throughout the course of treatment with cytarabine. No adverse effects were reported. After two weeks of continued symptoms, improvement was seen. The patient was able to resume normal speech and experienced increasing strength in his right arm and leg. The second patient was started on 1000 mg of AZT, when PML was diagnosed, due to weakness in the left side of his body. Deterioration continued with AZT therapy, and the patient was started on a cytarabine regimen. This patient interrupted AZT therapy due to bone marrow toxicity after the first cycle of cytarabine treatment. Improvement was noted after three cycles of cytarabine. After six months an MRI scan showed lesions were much improved and the patient was able to walk with a cane. The third patient complained of muscle pain and had tests revealing an abnormal level of muscle enzymes. He stopped AZT, but two months later developed aphasia, which is the absence of comprehension and the inability to communicate. The patient was diagnosed as having a progressive stroke, but standard therapy with heparin showed no improvement. Later he was started on cytarabine and after three cycles of treatment, his aphasia was slightly improved. MORE CASE STUDIES Another group of researchers, led by Dr. Lidman, reported cytarabine results in one patient, who received the drug intrathecally, or directly into the brain. This patient was diagnosed with PML following an abnormal MRI scan and a biopsy. The patient received 2 mg/kg of cytarabine intravenously on a daily basis for five days. This regimen was repeated every 15 days. The patient was also taking 1000 mg of AZT per day, which he started three months prior to the PML diagnosis. He continued with AZT therapy, except during the five days of intravenous cytarabine in order to prevent bone marrow suppression. Side effects observed included nausea and a slight decrease in white blood cells, which occurred during intravenous therapy. After four months (12 administrations of cytarabine), a good response was noted, and therapy was stopped. Two final patients responding well to cytarabine treatment were reported in Lancet, February 1992. The first patient, experiencing motor deficiency in his face and right hand, was confirmed as having PML by a brain biopsy. Cytarabine treatment was administered monthly; after three cycles of treatment the patient improved. Five months later, improvement continued. The last patient was taking AZT at 600 mg daily, when he started experiencing word-finding difficulties, confusion, and time disorientation. Treatment for toxoplasmosis was tried for three weeks unsuccessfully. During this time, symptoms worsened and changed, leading to a presumptive diagnosis of PML. He was treated with cytarabine, and AZT therapy eventually needed to be stopped due to side effects. The patient began to improve after the fifth cycle of therapy. CYTARABINE AND AZT There are conflicting views as to the benefit of AZT in the treatment of PML. A recent report of one person with AIDS-related PML responding to AZT therapy was published in the Review of Infectious Diseases.[7] Some researchers assert that spontaneous AZT-related recovery cannot be ruled out, but they also assert that cytarabine had a definite beneficial effect. AZT may stabilize the immune system, while cytarabine attacks the JC virus which causes PML. Combining AZT and cytarabine may be of general benefit, since it has been suggested that JC virus can enhance HIV-reproduction in the central nervous system by involving macrophages of the brain.[8] Further investigation of cytarabine and AZT in a controlled clinical trial is urgently needed. It is clear that Dr. Portegies, for one, believes that it may be unlikely that AZT therapy contributes to improvement.[9] CONCLUSION Longer-term cytarabine seems to be a good option for people with AIDS-related PML. Early lack of response to the drug in people with AIDS and PML has been attributed to a premature discontinuation of therapy.lo The drug takes time work, perhaps because it is slow to penetrate into the brain. But these recent encouraging reports offer hope for treatment. It is clear that a clinical trial should be started immediately to test the drug with and without AZT for treatment of this serious disease. References: 1. Berger JR et al. PML associated with HIV. Ann Intern Med 107:78-87,1987. 2. Houff SA et al. Involvement of JC infected mononuclear cells from bone marrow and spleen in the pathogenesis of PML. NEJM 318:301-301,1988. 3. Berger JR et al. Prolonged survival and partial recovery in AIDS-associated PML. Neurol 38:1060-65, 1988. 4. Portegies P et al. Response to cytarabine in PML in AIDS. Lancet 337:680-681, 1991; Lidman C et al. PML in AIDS. AIDS 5(8):1039-31 Z, 1991; and Nicoli F. Efficacy of cytarabine in PML in AIDS. Lancet 339:306, 1992. 5. Marriot PJ et al. PML remission with cytarabine. Neurol Neurosurg Psych 38:107-116,1975; and O'Riordan et al. PML- remission with cytarabine. J Infect 20:51-54, 1990. 6. Berger JR et al. PML associated with HIV. Ann Intern Med 107:78-87,1987; and Speelman JD et al. PML in a case of AIDS. Clin Neurol Neurosurgery 87:27-33,1985. 7. Conway et al. HIV-associated PML: apparent response to 3' -azido- 3'-deoxythymidine. Rev Infect Dis 12:479-82, 1990. 8. Vazeux R et al. Severe encephalitis resulting from coinfections with HIV and JC virus. Neurology 40:944-948, 1990. 9. Portegies P et al. Response to cytarabine in PML in AIDS. Lancet 337:680-681, 1991 10. Ibid. --------------------------------------------------------- The editors of Women's Treatment Issues are seeking Doctors, Researchers, Activist, Healthcare Providers, Women with HIV, or just plain Interested Parties to review and comment on the draft version of the special edition devoted solely to medical issues concerning women with HIV disease. Please send a postcard with your name, address, and organizational affiliation (if applicable) to: Mary Beth Caschetto, Women's Treatment Issues, GMHC, 129 W. 20th Street, NY, NY 10011 ----------------------------------------------- ***** TREATMENT BRIEFS ROCHE BEGINS NEW ACCESS PLAN Early in February the FDA strongly urged the PWA Health Group of New York City, and other buyers' clubs, to stop selling ddC. Buyers' clubs had long been selling a street, or non- pharmacy, version of the still experimental anti-HlV drug. The government agency, conducting a crackdown on buyers' clubs, tested ddC from the underground and found that the supply varied widely in potency -- anywhere from 0%-230% of the declared value of the drug existed in the tested capsules. The PWA Health Group stands behind its original policy that individuals should first try to obtain the drug from the manufacturer, in this case, Hoffmann-La Roche. For the most part, though, access to the drug is difficult. In fact, 8,000- 10,000 people in the U. S. obtained ddC for personal use through buyers' clubs. Those individuals are advised to stop taking underground ddC immediately, since consuming an unknown dose of the drug may present significant safety risks. Hoffmann-La Roche has responded by launching a new and definitely improved ddC access program for individuals with symptomatic HIV-infection and less than 300 T4 cells and for individuals with asymptomatic HlV-infection and less than 200 T4 cells. People can obtain ddC at either T4 cells. No lab reports are required for T4 counts, just verification by phone. The drug will be sent within two weeks. The program is designed for people who want to use the drug in combination with AZT. A second program for asymptomatic people with T4 counts from 300- 500 will offer randomized doses. More details will be forthcoming. For New Yorkers and others, please note that the PWA Health Group has moved. The new address is 150 W. 26th Street, Suite 201, New York, New York 10001, and the new phone is (212) 255- 0520. ACUPUNCTURE FOR HIV A University of Miami trial is studying acupuncture and Chinese herbs to determine whether the therapies relieve stress and improve the quality of life in HIV positive people. According to AIDS Weekly, initial results are promising. Patients report easier sleep and increased energy. The study has received no outside funding and relies on volunteer acupuncturists and herbal experts. It is hoped that government agencies will find the resources to begin a randomized trial to study the potential benefits of acupuncture and Chinese herbs for HIV disease. ANTIVIRAL DRUG SCREENING The National Cancer Institute operates an AIDS Antiviral Screening Program which determines anti-HlV efficacy of compounds in the test tube. Any group or individual can submit a potential anti-HlV compound for testing. It is requested that as much written information about the pure compound accompany the compound for testing. Submit drugs to the Acquisitions Input Committee, Drug Synthesis and Chemistry Branch, National Cancer Institute, Executive Plaza North, Room 835, Bethesda, MD 20892 FLUCONAZOLE, LIPOSOMAL AMPHOTERICIN B FOR CRYPTO An ACTG study (#059) showed that the oral drug fluconazole is as effective in treating cryptococcal meningitis as the standard intravenous treatment, amphotericin B. Cryptococcal meningitis is the most common life-threatening fungal infection in people with AIDS. It accounts for 5% - 8% of all AIDS-related opportunistic infections. Of the 194 patients studied, 131 received fluconazole (200 mg/day) and 63 received amphotericin B (0.4-0.5 mg/kg/day) Fluconazole was far better tolerated and the rate of successful treatment and survival was similar for both drugs. A letter to the Lancet (2/8/92) reports the use of liposomal amphotericin B to treat fungal infections in 144 immune- compromised patients (12 of whom had AIDS). The authors report that this formulation of the drug appears to allow for a higher dose to be administered without any increased toxicity and for smaller infusion volumes and shorter infusion times. NYS HOME HEALTH CARE REIMBURSEMENT New York State has launched a program to fund home health care for uninsured or under-insured persons with HIV/AIDS. The program will pay for personal care, homemaker, and home health aide services, intravenous medications, laboratory services and medical equipment. For more information call (518) 474-3293. MOTHERS PRESSURE BUSH FOR AIDS FUNDING Mothers' Voices, a campaign to enlist mothers of people with HIV, their friends, and families, in the fight against AIDS, is planning to send tens of thousands of Mother's Day cards to President Bush and Congress. These "greetings" will demand increased funding for AIDs research and education. Organizations and individuals who can distribute at least 25 cards are encouraged to call (212) 366-9217. Happy Mother's Day, George. PHARMACEUTICAL FUNDS FOR COMMUNITY RESEARCH AIDS activists organized a meeting with representatives of ten major pharmaceutical companies involved in AIDS drug development to discuss funding for community-based research. The companies have expressed interest in committing funds for such research. AmFAR's Community Based Clinical Trials Network (CBCT) is a possible administrator for such grants. This is an important effort which could provide much needed funds for community-based HIV research. TREATMENT ISSUES SPECIAL EDITIONS Two special editions of Treatment Issues are under development. The first edition, to be published later this spring, focuses on treatment information for HIV-positive women. A second special edition is slated for the fall of 1992 and will focus on alternative therapies for HIV. Individuals interested in writing concept sheets or articles about vitamins C and E, garlic, barley green, acupuncture, refined sugar in disease progression, Iscador (mistletoe), glycyrrhizin (licorice), micro-nutrient therapy, Selenium, beta-carotene, zinc, and other alternative therapies should call Jon Greenberg at (212) 673- 0491. ***** The Status of Tat by Karl Owens Tat inhibitors, also referred to as tat antagonists or anti-tat compounds, are one of several new antiviral drugs that will soon move into widespread testing in people with HIV. Since early 1990, a close eye has been kept on these and other new drugs, namely the protease inhibitor drugs (see Treatment Issues, Vol. 6, No. 1) and the less-promising reverse transcriptase compounds. Each of these drugs attacks HIV differently than the standard therapy nucleoside analogues (AZT, ddI, ddC). Unfortunately, researchers of the compounds can draw little useful information from data derived from studies with nucleoside analogues. Additionally, the role of tat in HIV infection is only partially understood, and a theory of the gene and its inhibitor needs to be devised and substantiated in order to further the development of this compound. TAT -- WHAT IS IT? HIV has a complicated life cycle. Many factors contribute to the virus' ability to replicate. HIV is composed of a number of genes, each with a distinct function in producing new virus.[1] Some genes on HIV facilitate the release of new virus, while others prepare target cells for infection. Unfortunately, the purpose of many HIV genes is still unknown. One group of genes crucial to HIV reproduction is called "the regulators." There are two regulator genes -- one called tat and one called rev. These are called regulator genes because they do not themselves cause HIV to reproduce, but they promote or regulate the conditions necessary for other genes to make more HIV. The role of tat is essential in regulating such conditions. In fact, researchers theorize that if tat can be stopped, all the other HIV genes will also be stopped. Therefore, HIV will be unable to produce more virus to invade the body and infect immune cells. HISTORY Tat antagonists are a group of compounds that interfere with HIV reproduction by eliminating or disabling the tat gene. Tat has been implicated in a number of serious infections and conditions, including various cancers and infections. The agency of the government involved in funding AIDS research, NIAID, has provided $700,000 this year to researcher groups headed by Hoffmann-La Roche for research into tat and HIV. Hoffmann-La Roche is the maker of a specific tat antagonist called RO 5-3335 (recently reformulated as RO 247429, which it identified in 1987). Though other pharmaceutical companies have anti-tat compounds, Hoffmann-La Roche is thought to be the furthest along in research on tat since RO 5-3335 is the only such compound to be tested in humans. CURRENT RESEARCH A team of researchers headed by Hoffmann-La Roche virologists recently reported the results of test tube data in Science.[2] The studies were designed to test the ability of RO 5-3335 to inhibit tat in various different strains of HIV. Data indicated that the compound was able to deactivate tat. The researchers also showed that viruses with a deactivated tat gene were unable to reproduce. Because HIV exists in different strains, an important observation noted by researchers was that viral reproduction was halted in various strains of HIV. RO 53335 was also effective against chronically- infected cells, such as macrophages and dendritic cells. These cells can become reservoirs for HIV and can produce substances toxic to the body. It is important to note that nucleoside analogues such as AZT and ddI have been unable to affect chronically-infected cells. The only toxic side effects so far reported from animal studies is damage to the kidney observed in rats. LIFE WITHOUT RESISTANCE? As with many compounds tested against HIV, resistance can be a problem and exists in two forms. First, a strain of HIV may be naturally resistant to a specific drug. For example, there are certain strains of virus which are resistant or not sensitive to AZT. This may or may not cause a treatment problem because most people with HIV-infection often have many different strains of virus in their body. Test tube studies showed that tat was equally effective against AZT-sensitive and AZT-resistant strains of the virus. The second type of resistance develops when a strain of virus which is initially sensitive to a drug, mutates and avoids the drug's action. It is theorized that the tat- antagonist will not encounter mutation, since it targets an actual regulator gene on HIV, which is unlikely to mutate. In fact, one study shows that after a year of exposure to RO 5-3335 in the test tube, the virus remained sensitive to the drug.[3] HUMAN TRIALS Hoffmann-La Roche sponsored two human trials of its tat inhibitor, now called RO 24-7429 at Johns Hopkins University. The first study was conducted last spring with a single dose of the drug injected into twelve participants. Sufficient levels of drug were maintained in the blood, and no major toxicities were observed. The second on-going study is a phase I placebo- controlled trial using three doses of drug (60 mg, 200 mg, 600 mg). Safety data, but not efficacy data, is being collected. As of November, 26 men and one woman were enrolled in the study. Each participant received a single dose of drug followed by two days of observation and then another five-and-one-half days of drug. An interim review of the patients taking 60 mg and 200 mg was scheduled for December 1991. There are reports that the drug is more easily absorbed than expected, which means that the highest dose of drug (600 mg) may be eliminated from testing. It is hoped that the drug will speed into the next phase of human testing, where efficacy data will be collected. CONCLUSION Finally, it was noted that KS-like lesions appear in mice when they are injected with the tat gene. This may suggest that tat plays an important role in the development or progression of KS in HIV-infected persons.[4] Therefore, anti-tat drugs may be useful in treating KS, the OI thought to be a cancer, which occurs in up to 30% of HIV-infected persons. The implications for anti-tat drugs are clearly important and wide ranging. For information on tat research programs at Hoffmann-La Roche, contact Paul Oestreicher, Ph.D. at (201) 235-3370. For information on the status of trials at Johns Hopkins, contact Linda Nerwood at (410) 955-7703. References: 1. Steffy K. Genetic regulation of HIV. Microbiol Reu 55(2):193-205, 1991. 2. Hsu M. Inhibition of HIV replication in acute and chronic infections in vitro by a tat antagonist. Science 254:1799-1802, 1991. 3. James J. Treatment to watch. AIDS Treatment News 141:1-3, December 20,1991. 4. Ensoli B. Tat protein of HIV-1 stimulates growth of cells derived from KS lesions of AIDS patients. Nature 345 (6270):84- 6, 1990. ***** Future and Related Research In the 1980s, hundreds of millions of dollars were sunk into researching the nucleoside drugs, AZT, ddl & ddC. The results, considering the investment, hove been modest. We have a few drugs which help certain individuals for a limited period during the progression of disease. Tat research is at a critical stage. Barring problems with toxicity, tat could move into large-scale human testing in the first half of 1992. Plans for this drug may shape HIV/AIDS research over the next five years. Two lessons from the history of AIDS drug research are therefore worth reiterating: 1) The FDA approves new anti-HIV drugs according to the following stipulations: the new drug must significantly extend life; create and sustain significant increases in T4 counts; or show a clinical benefit, such as weight gain or lower infections and cancers. Therefore, researchers must design and conduct studies that show the drug can perform in this manner. Studies designed to produce ambiguous results or results without clinical meaning are useless. 2) Studies must keep pace with state-of-the-art community use. For instance, combination therapy with AZT, ddI and ddC has long been the norm for some HIV-positive people. However, federally-funded trials continue to study the efficacy of these drugs used alone. Combination therapy has been in use for two years, and there has yet to be a large combination study to recommend, countermand, or revise such combination use. ***** AIDS Treatment 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 covering 100% of prescription costs. For more information and a list of drugs that are covered, call 1-800-542-2437. The AIDS Readers, an educational journal funded by Pfizer, is designed specifically to provide clinicians with practical, scientifically-sound information on the prevention, diagnosis, and treatment of HIV disease. For more information write to: SCP Communications, Inc, 134 West 29th Street, New York, NY 10001-5304, or call (212) 714-1740. AIDS Targeted Information Newsletter (ATIN) performs a monthly search of medical journals. Written for doctors and researchers, it is one of the best ongoing literature searches available. It is funded by AmFAR and published by Williams & Wilkins, P. O. Box 23291, Baltimore, MD 21203, or phone 1-800-638-6423. AIDS Treatment News is a biweekly report which chronicles current developments in experimental and alternative treatments. Contact John James at P. O. Box 411256, San Francisco, CA 94141, or call 1-800-TREAT1-2. American Foundation for AIDS Research (AmFAR) publishes two catalogs of clinic trials. To order AIDS/ HIV Experimental Treatment Directory or the New York State Directory of AIDS/HIV Clinical Trials, which is produced in conjunction with GMHC, write to 1515 Broadway, Suite 3601, New York, NY 10036-0033, or call (212) 719-0033. 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 HIV-positive people is an organization called Positive Action. For more information, call (212) 727- 7768. Notes from the Underground is a grassroots publication focusing on drugs available through the underground network. Write to: PWA Health Group at 150 W. 26th Street, Suite 201, New York, NY 10001, or call (212) 255-0520. Project Inform has a newsletter called Pl Perspective on experimental treatments with in-depth political analysis and offers an excellent drug hotline, 1-800-822-7422. PWA Coalition Newline, published by and for people with AIDS and AIDS-related conditions, is a grassroots news magazine that appears monthly. Write PWA Coalition, Inc., 31 W. 26th Street, 4th Floor, New York, NY 10010, or call (212) 5320280. The NIH, CDC, and FDA operate a toll-free hotline to provide information on all HIV-related clinical trials in the U. S. Callers may request a Spanish speaking operator. Lines are open between Monday and Friday, 9:00 am to 7 pm, eastern time. The number is 1800-TRIALS-A. The Positive Woman is a bi-monthly newsletter by, for, and about HIV- positive women. The newsletter provides information on traditional medical and holistic practices, as well as articles concerning general coping, spiritual issues, and living-well with HIV. Write to The Positive Woman, Inc. P. O. 34372, Washington, DC 20043, or call (202) 898-0372. Glossary AIDS Clinical Trials Group (ACTG): A set of about 50 research centers around the country where federally-funded human trials are conducted. AIDS Dementia Complex: A somewhat common condition in people with AIDS that results in the chronic loss of mental capacity that affects a person's ability to function in a social or occupational setting. Asymptomatic infection: An infection, or phase of an infection, without symptoms (i.e.: carrying antibodies to HIV but not displaying any of the symptoms of HIV infection). Central Nervous System (CNS): The brain and spinal cord. Chronically-infected: Cells infected with HIV which carry the blue-prints of the virus in them, and therefore continually make new HIV. Clinical: Human; or having direct affects on the human body. Colitis: Inflammation of the colon; a condition which causes abdominal pain and diarrhea. CT Scan: Scan which uses special beams to produce detailed images of organs and structures inside the body. 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. Expanded access: Systems for distributing experimental drugs for free to patients who are unable to participate in human trials and have no other treatment options available. Also called "open label study." Gastrointestinal tract: The system which allows absorption and digestion of food and includes the mouth esophagus, stomach, small and large intestine, and rectum. Immunity: A natural or acquired resistance to a specific disease. Immunity may be partial or complete, long lasting or temporary. Immunocompromised: A state when the body's immune system defenses are lowered and the body is less able to resist infections and tumors. Latency: A period of time in which an organism is in the body but not producing any ill effects. Macrophages: A scavenger cell that specializes in the ingestion of harmful organisms. MRI: Magnetic Resonance Imaging (MRI) is an expensive, sensitive brain scan. Mycobacterium avium complex (MAC): A serious opportunistic infection, which causes symptoms including night sweats, high fevers, cough, weight loss, general fatigue, malabsorption of food, and diarrhea. Neurologic: Relating to the brain and spinal cord. p24 antigen levels: A level which can be measured in blood and other body fluids. The test used to measure p24 levels detects the presence of 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. Pathogen: Any microorganism or substance that produces disease. Pneumocystis carinii pneumonia (PCP): A common parasite which grows rapidly in the lungs of people with AIDS and is the leading cause of death in AIDS. Sometimes, PCP infections may occur elsewhere in the body (skin, eye, spleen, liver, or heart). Presumptive diagnosis: The presumption by a health care professional that a specific infection or disease is present, based on certain signs and symptoms. Not a definitive diagnosis based on tests. T4 counts: 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. Toxoplasmosis: Widespread infection of an organ or the whole body with the parasite Toxoplasma gondii. ***** The Community Forum on Vaccine Therapies for HIV was held on February 25 at the Marriott Marquis. More than 650 people attended the forum. Speakers included: o Margaret Johnston, Associate Director, Program Division of AIDS (oversees all federal AIDS vaccine efforts) o Robert Redfield, Chief of Department of Retrovirol Research, Walter Reed Army Institute of Research (oversees Department of Defense Vaccine Studies) o Martha Eibl, Director of AIDS Vaccine Research of Immuno AG o Alan Goldstein, Professor and Chair, George Washington University Medical Center o Arthur Ammann, Director of Clinical Research, Genetech o Fred Valentine, Investigator of Vaccine Trials, New York University Medical Center Audio Tapes of the forum will be available for $12.00. Send requests and checks to: Vaccine Forum Audio Tape c/o Medical Information, GMHC, 129 W. 20th Street, New York, NY 10011. Thanks to all the staff and volunteers at GMHC and CRIA for the hard work that made this first forum in a series on state-of-the-art treatments so successful. ***** 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 Gregg Gonsalves Carole Lemens Laura Morrison Karl Owens DESIGNER Stephen Louis de Francesco PRODUCTION MANAGER Valerie M. Hoskins PROOFREADER Sara Hertz OFFICE VOLUNTEERS Edward Friedel Eric Goldsborough Gary Schmidgall Frank Schramm 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 Copyright (c) 1992 Gay Men's Health Crisis, Inc. The staff of Treatment Issues would like to thank everyone who responded to our December Subscription Appeal. This appeal raised over $35,000 much-needed dollars to help us continue to provide the most up-to-date treatment information to all who need it. For those who have not yet had a chance to respond, please take the time now to fill out the coupon below. This will help us to update our files and keep better track of subscriptions both paid and complimentary. (We want to assure you that our intention is not to remove from our mailing list those who do not respond. We merely need to update our records.) Thank you for your continued support. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display