[Electronic distribution for GayCom by the Backroom 718 951-8256] Volume 7 no. 1 January, 1993 Gay Men's Health Crisis: Treatment Issues > Kaposi's Sarcoma (KS) Treatment Overview > Highlights from the AIDS Clinical Trials Group Meeting > Treatment Briefs >> gp 120 Vaccine Therapy Trials >> Nystatin: an Anti-HIV compound? >> Herpes Ulceration and Low CD4 counts >> TB Meds Hard to Swallow >> Keystone Joins Colorado Boycott >> Interim Results in on Thymopoentin Trial >> Staff Departure >> Corrections >> Biochem Announces 3TC trials for Hepatitis B >> VIMRx Develops Oral Hypericin Formulation >> Boehringer Begins New Nevirapine Trial >> Merck Meets with Activists >> Burroughs Wellcome Prices Mepron (566C80), Caps Acyclovir (sort of) ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Kaposi's Sarcoma (KS) Treatment Overview by John Chism It is a simple but persistent question that seems to have no definite answers at this time: What causes Kaposi's sarcoma? Is it an environmental agent, a virus, a growth factor, a sexually transmitted organism? Whatever the answer, it is clear that AIDS- related KS can be a life-threatening illness for people with AIDS. This article will give an overview of KS -- the theories of its origins, how people with HIV disease experience it, and an outline of several new treatment options which have developed in the last few years. Background KS occurs in about 20% of people with AIDS.[1] AIDS-associated KS is observed mainly in young homosexual and bisexual men. It can also occur in intravenous drug users and individuals with transfusion- related HIV infection.[2] KS remains rare in women with AIDS[3] but should not be ruled out until a diagnosis can be made. It is thought that KS, when it does occur in women, is more aggressive than KS in men.[4] Patients with HIV-related KS usually do not die of the disease itself. In fact, in a study of the cause of death in 174 patients with AIDS-associated KS, death was due to KS in only 22 patients.[5] Another report found that people presenting with KS as an AIDS- defining illness had a better prognosis than those who had other opportunistic infections first.[6] What Exactly is KS? KS is a malignancy of the cells which line blood vessels (called endothelial cells). In AIDS, KS lesions are characterized by an abnormally fast growth of spindle-shaped cells, whose origins are still a mystery. What happens is this: lesions form when capillaries (fine, thread-like vessels that carry blood) begin to grow irregularly and rapidly. The capillaries often become leaky, resulting in an accumulation of red blood cells that give the lesions their reddish- purple color. Over the past two years, researchers have speculated that KS may not be a cancer at all. Several claims have been made that certain cytokines (naturally-occurring proteins) induce the growth of AIDS- associated KS in the test tube. These have included interleukin-6 (IL-6),[7] the HIV-protein called TAT,[8] interleukin-1B (IL-1B), tumor necrosis factor-alpha (TNF), gamma-interferon, and platelet factor 4.[9] Some say the disease is caused by an infectious agent -- cytomegalovirus (CMV) has been named as a suspect,[1]0 as has the human papilloma virus (HPV).[11] Some data suggest that contact with feces in anal-oral sex may be a primary mode of transmission if KS is indeed caused by an infectious agent.[12] Dr. Robert Gallo and colleagues at the National Cancer Institute (NCI) and Dr. Steven Miles and colleagues at the University of California have found evidence that a natural body protein called Oncostatin M may be a growth factor in the development of KS cells.[13] Clinical KS KS is well-known for its appearance. It appears most often as reddish or purple raised lesions on the skin. In black or dark-skinned people, lesions can appear as dark spots which are often mistaken for other skin disorders. These lesions are usually not painful or tender. But while non-AIDS KS occurs commonly on the skin of the feet or legs (and can be painful), AIDS-associated KS can occur at almost any site, including the mouth, the gastrointestinal tract, and the eyes. The disease may also occur in the lymph nodes and occasionally in the liver and lungs. KS of the lungs can be particularly serious and, if left untreated, can lead to severe problems with breathing. Lesions can also occur in the rectum, stomach, lungs, testicles, and, in a few rare cases, the brain. Treatment for KS Lesions At its earliest stage, AIDS-related KS often does not require therapy, except to clear up disfiguring lesions, usually accomplished by exposing the site of the lesion to an anti-tumor therapy. Radiation therapy has been a common type of local therapy, although intralesional injections (administered at the site of the lesion) have been moderately effective. For example, injections of a well-known chemotherapeutic agent, vinblastine, is a standard approach. Local radiation has been reported to be effective as a therapy to reduce pain and swelling.[14] It has been used as well to clear up lesions on the skin, in the mouth, and the lining of the eyelids. Freezing lesions with liquid nitrogen, a procedure known as "cryotherapy," and laser surgery are also local treatments for lesions. Cryotherapy has been shown to be 85% effective in achieving partial or complete responses in skin KS lesions of people with AIDS.[15] Lesions that appear in the lymph system -- the network that carries blood products throughout the body -- may need more immediate, aggressive treatment, depending on the stage of disease. At an early stage, KS of the lymph nodes can cause swelling in the limbs (especially the legs) that can be painful and severely limit mobility, in which case local radiation may be administered. Alpha interferon Treatment Alpha interferon is a drug for KS which is sometimes used to treat individual lesions and sometimes used to treat the whole body (systemic treatment). Interferons are natural proteins occurring in the body that can prevent or fight cell infection. Through scientific technology, interferons have been synthesized into an injectable drug that can be used to treat many different diseases. Alpha interferon (6 MU per week for ten weeks), for instance, was shown to be effective when injected into the lesions of ten Canadian trial participants.[16] Nine of the ten participants showed partial remission, and one experienced a complete remission. Interferon seems to work best against KS when a person's immune system is still fairly functional (over 400 T4 cells). The main side effect of the drug is a flu-like illness. Treatment for Disseminated KS Disseminated (also known as widespread or advanced) KS may occur when the disease appears with one of the following characteristics: 25 or more lesions; a formation of ten new lesions per month; disease when T4 counts are under 200; or spread of lesions to the lungs or stomach.[17] Chemotherapy is currently the most standard treatment for disseminated KS. In the past, chemo regimens often used single agents. Of these, vinblastine, vincristine, and etoposide had the highest response rates (sometimes up to 70%).[18] These regimens can cause hair loss, neutropenia (lowered number of neutrophil cells), and severe gastrointestinal difficulties. Other chemotherapeutic single agents include bleomycin, doxorubicin, and mitoxantrone. Combinations of these agents, often referred to as "cocktails," are commonly used. In such cocktails two to three agents are used. A commonly used chemotherapeutic regimen is adriamycin, bleomycin and vincristine (A-B-V). Drawbacks to standard chemotherapy include possible suppression of the bone marrow, nausea, vomiting, fever, diarrhea and hair loss. To keep the immune system protected, colony stimulating factor drugs may be prescribed. These drugs -- GM-CSF and G-CSF -- are manufactured versions of naturally-occurring hormones that are known to stimulate the bone marrow. More specifically, they increase white blood cells. However, GM-CSF may stimulate the growth of HIV, since it stimulates macrophages which can harbor HIV in large quantities.[19] Some professionals, however, dispute the claim as theoretical, and the actual value of GM-CSF and G-CSF has yet to be determined. DaunoXome Liposomal technology may be the answer to some of the problems associated with chemotherapy and its side effects. A liposome is a fatty substance that can be used to encapsulate a drug. The process makes the chemotherapeutic drug less toxic and more target- specific to cancer cells, while bypassing the healthy ones. Vestar, Inc. has developed a liposomal version of a classic chemotherapy drug, daunorubicin. Vestar's liposomal drug, DaunoXome, is being studied in multicenter phase II trials in Los Angeles, San Francisco, London, Paris and Berlin. Dr. Michael Ross presented results at the VIIIth International Conference on AIDS of 87 patients who have received the drug for treatment of KS.[20] Doses used were up to 60 mg every two weeks, substantially higher than the usual doses of daunorubicin. Of 56 patients evaluated in the phase II trials, 95% have demonstrated a clinical benefit; more than 60% showed a complete or partial response, and 35% had a stabilization of disease. No evidence of toxicity to the heart (a common side effect of long-term daunorubicin therapy) was experienced. Side effects such as nausea, vomiting, and fatigue were mild and occurred in less than 10% of patients. No patient experienced severe hair loss due to the drug. Another study compared liposomal daunorubicin with standard combination chemotherapy (adriamycin, bleomycin, and vincristine) in patients with KS.[21] Combination chemotherapy induced a complete remission in two patients and partial remission in four patients, compared to DaunoXome which induced complete remission in none and partial remission in six patients. However, drug-related side effects were severe and common in all patients receiving chemotherapy, but mild and rare in patients receiving liposomal daunorubicin (colitis and leukopenia occurred in a few patients.) Phase III trials will compare DaunoXome (40 mg) to the standard chemotherapeutic "cocktail" (adriamycin, bleomycin and vincristine, or ABV) in a larger cohort of participants. For more information about enrolling in clinical trials, call 1-800-TRIALS-A. In New York, call New York University, (212) 263 - 6485. Doxil (Liposomal Doxorubicin) Another liposomal drug, called Doxil, manufactured by Liposome Technology, was reported to produce a greater than 50% decrease in the size of KS lesions within two to four weeks of therapy.[22] This open study enrolled 30 patients who were randomized to take the drug in different doses (10 mg, 20 mg, and 40 mg). Twenty-five percent of patients reported a flattening of skin lesions, and no patients developed new lesions. Improvements were also observed in limb and facial swelling, difficulty with swallowing, and gastrointestinal bleeding. All patients with KS of the lungs experienced partial remission and improved breathing. Only participants taking 40 mg of the drug experienced hair loss and leukopenia and had to be switched to a lower dose. This drug also seems to be superior and less toxic than doxirubicin without liposomal encasement. It is designed, in fact, to prevent liposomal particles from being stopped in the bloodstream, liver, and spleen by the body's own natural defenses. The drug is able to be released directly to the tissue through the abnormally leaky walls of the capillaries. Biopsies show that the liposomes deliver four to ten times more drug to lesion-tissue than (non-liposomal) doxirubicin is able to do. However, Doxil needs further investigation in combination with other therapies for KS. A representative of Liposome Technology told Treatment Issues that two phase III trials are currently in development. One trial, scheduled to take place in England, Germany, and Holland, will compare Doxil to the standard regimen of bleomycin and vincristine. In the U.S. Doxil will be compared to a standard chemotherapeutic regimen (ABV) in early 1993. Both phase III trials will enroll 200 patients. For more information, contact the drug company at (415) 323-9011. Purified CD8 Cell Infusions An innovative device, called the Cellector, manufactured by Applied Immune Sciences, Inc. (AIS) is the focus of a new therapy for KS. CD8 cells were taken from six patients using the Cellector, a plastic box that removes only CD8 cells from the subjects and then treats them with Interleukin-2 (IL-2).[23] In this process, blood is removed from the individual and CD8 cells are isolated and stimulated with IL-2, a genetically manufactured protein found naturally in the body that is believed to stimulate rapid growth and activity of CD8 cells. The process itself is referred to as "CD-8 expansion," and phase I trials in AIDS patients in Miami and Pittsburgh showed enough promise that the company has moved forward with phase II trials for participants with KS. In the study with six patients, conducted at the VA Medical Center of the University of Miami, cells were expanded for 14-21 days and infused with IL-2 in the Cellector and then reinfused into the patients, followed by five days of IL-2 infused into the bloodstream. One patient with extensive KS had a 70% regression of tumor size, a decrease in the number of lesions, and a resolution of swollen lymph nodes. Another patient with KS had partial resolution of lesions on the skin in the mouth and on the head and neck, but no change in arm and chest lesions. Several patients with oral hairy leukoplakia had resolution of their lesions as well. Phase II clinical trials are underway at San Francisco General Hospital. PROSORBA Column Another device, approved as a treatment for a blood disorder involving low platelet counts called idiopathic thrombocytopenic purpura (ITP), is being investigated as a treatment for KS. The device, called Prosorba column, is manufactured by IMRE Corporation and removes molecules that block immune function. During the procedure a patient is connected to the PROSORBA column, and his or her blood is filtered through the machine. Plasma is extracted from the blood, and circulating immune complexes that block immune function are removed, before being reintroduced into the patient. The process lasts about three hours, and can be done on an outpatient basis. Side effects are transient and include fever, chills, nausea, vomiting, and pain during the procedure. Tumor shrinkage and arrested disease have been observed in patients who have had at least 12 treatments. Researchers are yet unsure of the agent that is being removed, or how and why its removal alleviates KS disease. The question is currently under review. Interested parties can call (206) 298-9400 for more information. Anti-Angiogenesis Drugs Angiogenesis is derived from a Greek word meaning the creation of blood vessels. The term refers to a normal body process that can be abnormally stimulated. Cancer tumors, in general, seem to secrete factors that can switch on the body's angiogenesis function, so that the tumor can induce the growth of capillaries that will then sustain it with a supply of blood. Inhibiting angiogenesis, some theorize, may inhibit the growth of tumors. Over the past two years, the following four anti-angiogenic drugs have attracted attention: - Fumagillin: A natural substance, secreted by a fungus, this drug can inhibit capillary growth in the test tube with little drug resistance. It is very toxic and so may not be useful in humans. A genetically engineered version of fumagillin, called AGM-1470, is being tested by Takeda, the Japanese pharmaceutical company. AGM- 1470 (or TNP-470) has been shown to successfully stop the growth of many different kinds of solid tumors. A mild risk of uncontrolled bleeding may accompany use of this drug, although researchers have made some headway in lessening this risk. A trial is now underway. For more information call (301) 496-8398 or (301) 496-8959. - SP-PG: This compound, sulfated polysaccharide peptidoglycan, is produced by soil bacteria and has blocked tumor growth in mice and other animals. It received public attention when Dr. Robert Gallo said that KS tumors "melt away" at the introduction of the drug. However, in truth, tumors are halted, not dissolved, and their purplish color does fade some. After much pressure from AIDS activists Daiichi Pharmaceuticals has submitted preliminary material to the FDA for approval to use the drug in human trials. - Platelet 4 Factor: This compound is polypeptide naturally found in the granules of platelets, and is made by Repligen Corporation of Massachusetts. A phase I study is being conducted in San Francisco for local treatment of lesions, in which each patient will undergo therapy for about three weeks, receiving several injections per week. The drug halts tumor growth but also may complicate the natural healing process in humans. Time off the drug will probably be needed in order to let wounds heal. Shark Cartilage A few months ago, AIDS activist, author, and long-term survivor Michael Callen published an article describing his remission from pulmonary KS after starting therapy with a drug made of shark cartilage along with radiation treatments.[24] He had enrolled in a trial through Search Alliance in Los Angeles. While one person's experience hardly makes scientific news, Mr. Callen's report has caused quite a stir. Principal investigator Dr. Fleishman "believes shark cartilage may prove to be the long-sought-after radiation potentiator." In 1983, a group of scientists at MIT found that shark cartilage contained an agent that inhibits the growth of new blood vessels that make solid tumors.[25] When injected into rabbits or mice, no toxic side effects were observed, and the growth of new blood vessels toward tumor growth stopped. The product (brand name Cartilade) is being used by a group of PWAs in Boston and New York. It is sold for $108.00 per bottle in health food stores, a supply that lasts for about two weeks. The Boston group uses this therapy in combination with Immulin, the plant and herb extracts that made a splash earlier this year when Dr. Jozsef Roka of Switzerland offered it to Americans travelling abroad. A clinical trial in California conducted by Search Alliance uses the drug in combination with radiation therapy. Treatment Issues could not get through to Dr. Fleishman, but will report further on the trial in upcoming issues. Retinoic Acid Retinoic acid, a derivative of vitamin A, is a common anti-acne medication, produced as a gel or a cream by Johnson & Johnson. The familiar brand name is Retin-A. The drug, manufactured by Hoffmann-La Roche as a pill, is being investigated against AIDS- associated KS in phase II trials at the University of Southern California. It is a year-long study with a range of different doses. Twenty of 30 patients have so far been enrolled in this trial, and researchers have shared some early impressions. For instance, there seems to be a 50% - 60% stabilization of disease and a 20% - 30% rate of tumor regression in patients.[26] Toxicities noted at higher doses seem to be headaches and dry skin. TAT Inhibitor Finally, Hoffmann-La Roche has designed a trial for a phase II study to examine the effect of their anti-HIV drug, the TAT inhibitor, in patients with early-stage KS. The trial will probably involve 18 patients. Enrollment will increase if early responses seem promising. Activists have been working to get the drug company to initiate other TAT-inhibitor trials. Until recently, the company seemed reluctant to test the drug against KS. The KS trial of TAT is still in the early planning stage, although according to activists, the trial may begin sometime in 1993. Conclusion Much activity in the research and activist communities has focused on new KS therapies, including liposomal drugs, anti-angiogenesis agents, and immune modulating devices. However, many activists, clinicians and people with AIDS/ HIV believe that even this level of activity is insufficient to guarantee substantial progress toward effective KS therapy. 1. Ziegler JL et al. Kaposi's sarcoma: a comparison of classical, endemic and epidemic forms. Seminars in Oncology 11:47-52, 1984 and Krown SE. AIDS-associated Kaposi's sarcoma: pathogenesis, clinical course and treatment. AIDS 2:71-80, 1988. 2. Beral V et al. KS among persons with AIDS: a sexually transmitted infection. Lancet 335:123-128, 1990. 3. Beral V et al. KS among persons with AIDS: a sexually transmitted infection. Lancet 335:123-128, 1990 and V Int'l Conf on AIDS. Abstract # MBP 297, Montreal June 1989. 4. Kaiss L et al. AIDS-associated Kaposi's sarcoma in female patients. AIDS 5:877-880, 1991. 5. Chachoua A et al. Prognostic factors and staging classification of patients with epidemic KS. J Clin Oncol 7:774-780, 1989. 6. Rothenberg R et al. Survival with AIDS: Experience with 5,833 cases in New York City. N Engl J Med 317:1297, 1987. 7. Miles SA et al. AIDS KS-derived cells produce and respond to IL-6. Proc Natl Acad Sci 87 4068, 1990. 8. Ensoli B et al. Nature 345:84, 1990. 9. Ensoli B et al. Science 243:233, 1989. 10. Giraldo G et al. Antibody patterns to herpes virus in KS: Seriological association of American Association of American KS with CMV. Int J Cancer 22:126-131, 1978. 11. Huang YQ et al. HPV-16-related DNA sequences in KS. Lancet 339:515-518, 1992. 12. Beral V et al. Risk of KS and sexual practices associated with fecal contact in homosexual or bisexual men with AIDS. Lancet 339:632-635, 1992. 13. Nair BC et al. Identification of a major growth factor for AIDS- KS cells as Oncostatin M. Science 255:1430-1432, 1992 and Miles SA. Oncostatin M as potent mitogen for AIDS-KS-derived cells. Science 255:1432-1444, 1992. 14. Hill DR. The role of radiotherapy for epidemic KS. Semin Oncol 14 (suppl 3):19-22, 1987. 15. Tappero JW et al. Cryotherapy for cutaneous KS associated with AIDS: A phase II trial. J AIDS 4:839-846, 1991. 16. VIII Int'l Conf on AIDS, Abstract # PoB 3361, Amsterdam, July, 1992. 17. Northfelt DW. Clinical presentation and treatment of AIDS- related KS. AIDS Medical Report 3(9):99-114, 1990. 18. Ibid. 19. Roland, M. KS Treatment Overview. AIDS Treatment News 122:2, 1991. 20. VIII Int'l Conf on AIDS, Abstract # PoB. 3123, Amsterdam, July, 1992. 21. VIII Int'l Conf on AIDS, Abstract # PoB. 3123, Amsterdam, July, 1992. 22. Liposome Technology. Press release, July 20, 1990. 23. VIII Int'l Conf on AIDS, Abstract # PoB 3444, Amsterdam, July, 1992. 24. Callen M. A Miracle Cure? Michael Callen Reports on the remarkable remission from KS after shark-cartilage treatments. QW November 15, 1992, p.35. 25. Langer R et al. Shark cartilage contains inhibitors of tumor angiogenesis.Science 221: 1185-1187, 1983. 26. Personal communication, Gill Parkash, October, 1992. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Highlights from the AIDS Clinical Trials Group Meeting by Gabriel Torres, M.D. The 15th AIDS Clinical Trials Group (ACTG) meeting in Washington, November 3 - 6, 1992, was attended by hundreds of researchers, scientists, activists, community physicians and persons with HIV. The ACTG is the largest body responsible for federally-funded HIV- related clinical trials. The meeting was most notable for the discussions surrounding upcoming clinical trials for new antiviral and anti-infective therapies. Since the restructuring of the ACTG, which is comprised of about fifty institutions across the country, officials claim to be enrolling a greater number of women and minority patients into AIDS clinical trials. Researchers asserted that of the latest enrollees, 76% were male, 24% female, 59% white, 24% black, 17% latino. However, many participants and activists were able to demonstrate that the percentages, at least for women, were highly inflated. The 24%, in fact, was pumped up by including female children. In fact only about 7% of clinical trial participants were women. ACTG officials publicly admitted to trumping up the numbers by adding female children. Nonetheless, this article will review a few of the new trials under development by the ACTG and some new information which came out of this meeting. Acyclovir Controversy Three large trials from the U.S. and Europe testing acyclovir were reviewed by principal investigators. These included the large multi- center European-Australian trial (H56-002), headed by Dr. David Cooper, which showed that the combination of high-dose acyclovir (800 mg four times daily) and zidovudine (AZT) was associated with a longer survival time for patients with AIDS or ARC. More deaths occurred in participants taking only AZT, as compared to participants taking the combination of AZT and acyclovir. No significant differences in the distribution of opportunistic infections was noted between the two groups. No differences in blood side effects, changes in T4 cells, or changes in p24 antigen levels were observed between the two treatment groups. The second European study, headed by Dr. Michael Youle, also showed a longer survival time for HIV-positive patients with T4 cell counts under 150 receiving high-dose acyclovir as compared to placebo. No preventive effect on CMV was seen in this trial. Survival benefit was not associated with differences in the use of ddI and AZT, but survival was most evident in those on AZT with T4 cell counts under 50. Finally, Dr. Michael Saag from the University of Alabama presented the results of the Burroughs-Wellcome trial (BWP5329) studying acyclovir versus the combination of acyclovir and AZT. They enrolled early symptomatic HIV-positive participants with T4 cell counts between 200-500. No differences in progression to AIDS or death were noted, although the group in the combination arm had a larger and more sustained rise in percentage of T4 cells than the AZT group. Despite the fact that these three trials demonstrated a clear benefit of high-dose acyclovir, researchers regarded the data with some skepticism. Acyclovir's benefit does not seem to be related to a suppressive effect on CMV. Potential mechanisms for the drug's activity includes synergy with the nucleoside analogues (AZT, ddI, ddC), delay in the development of nucleoside resistance, inhibition of herpes viruses which could suppress HIV, and reduction of susceptibility of herpes-infected cells to HIV. Most people seem to agree that these studies have shown that high dose acyclovir is safe, well-tolerated and possibly beneficial, most notably in patients with low T4 cell counts and those taking AZT therapy. Concern was expressed about the high cost of the 800 mg acyclovir dose and the fact that many do not have access to the drug since the drug- assistance programs in many states do not cover it. (See Drug Company Watch) 256U87 For Herpes Plans for an upcoming large international multicenter trial of the acyclovir prodrug, made by Burroughs Wellcome, called BW256U87, were presented by Dr. Judith Feinberg from John's Hopkins University.[1] This trial will be a randomized, double-blind trial comparing the drug to two doses of acyclovir in patients with T4 cell counts less than 100. Its primary objective is to determine whether 256U87 can prevent CMV infections. The drug has been shown in an open label phase I study to be well tolerated at doses of 1-2 grams four times daily. Major side effects include nausea, vomiting, diarrhea and abdominal pain. Data shows that 256U87 produces blood levels of acyclovir which are three to four times greater than its parent drug, acyclovir, and may be better able to suppress CMV at such a level. Histoplasmosis Dr. Joseph Wheat presented the preliminary results of ACTG #120 which evaluated itraconazole (licensed under the brand name Sporonox) as acute and maintenance treatment for histoplasmosis. Histoplasmosis can be a life-threatening fungal infection and commonly occurs in the Southwestern U.S. Out of 58 participants with disseminated (widespread) or pulmonary (in the lungs) histoplasmosis, 51 (88%) responded to oral itraconazole, thus showing that the drug is highly effective for this infection. In the past, histoplasmosis was treatable only with intravenous amphotericin. Itraconazole may not be effective in histoplasmosis involving the central nervous system and brain, since it does not penetrate well into the cerebrospinal fluid (the fluid that surrounds the spinal cord and brain). In addition, drugs such as dilantin, phenobarbital, and rifampin lower blood levels of itraconazole and may result in therapeutic failures. A new trial (ACTG #174) is evaluating high-dose fluconazole (800 mg/day) for histoplasmosis; early data on fluconazole (600 mg/day) showed that eight of 25 (32%) failed at this drug at this dose. Candidal Infections (Thrush) & Resistance Various studies were reviewed which confirm that fluconazole can lead to the development of resistant candidal species in patients on long-term fluconazole for prophylaxis (preventive medication). Resistance occurs when an organism, such as a Candida albicans, is able to mutate and become untreatable by a certain medication. Candida can occur in the mouth, esophagus or vagina of people with HIV disease. Two studies presented at a conference earlier this year[2] showed that patients who have recurrent candidiasis and do not respond to fluconazole often have lower T4 cell counts and more advanced HIV disease than patients who do respond to the drug. Another study is comparing fluconazole to clotrimazole troches (throat lozenges for local therapy of oral thrush) as candida prophylaxis in patients with T4 cell counts under 200.2 Results should be available soon. Cytomegalovirus Preliminary results of a trial comparing ganciclovir and foscarnet in combined and alternating ganciclovir regimens for maintenance therapy for CMV retinitis were presented.[3] Maintenance therapy is treatment given after an initial case of disease has been treated. In this trial, initial treatment of CMV retinitis was with ganciclovir. In the 27 evaluable patients (12 on combined therapy and 15 on alternating therapy), no difference in progression of disease was noted. The combined regimen had more neutropenia (lowered neutrophil cells) than the alternating regimen. Another study will be evaluating ganciclovir, foscarnet and the combination of both in patients with CMV retinitis, needing retreatment due to progressive disease.[4] HPMPC, a nucleoside analogue which inhibits CMV and has a very long intracellular half-life, was also reviewed at the ACTG meeting. This may mean the drug can be taken less frequently than other anti-CMV medication and may not require a catheter. HPMPC seems to be active against ganciclovir-resistant strains of CMV, and therefore may be useful for patients who have failed ganciclovir. Trials with this drug are being developed by the ACTG. Mycobacterium Avium Complex (MAC) ACTG #157 is a phase II, double-blinded, dose-ranging trial of clarithromycin as a treatment for MAC disease. The study suggested that the optimal dose appears to be 1 gram twice daily. This dose achieved a decline in MAC bacteria with few toxicities. However, after twelve weeks, 20% of the patients developed resistance to clarithromycin, and, after one year, 40% developed resistance. Microsporidiosis Dr. Douglas Dieterich from NYU presented some preliminary results of albendazole in patients in the compassionate use protocol for microsporidiosis. In the study, 20 patients were evaluated who had experienced a weight loss of about 30 lbs. each, six to eight bowel movements per day and an average T4 cell count of 15. Albendazole was given at a dose of 400 mg twice daily for 28 days. Diarrhea stopped in half of the patients by the end of the study period and the group gained an average of eight lbs. each within 3 months. In two patients the disease-causing organism was eradicated as demonstrated by repeat biopsies of the small bowel. A new placebo- controlled study will evaluate 800 mg twice daily of albendazole in patients with intestinal microsporidiosis.[5] All participants will receive the drug after thirty days. The microsporidium which seems to respond to albendazole is a newly-discovered species that tends to cause disseminated disease. Toxoplasmosis One trial using azithromycin in combination with pyrimethamine and folinic acid for treatment of toxoplasmosis has demonstrated an unacceptable level of treatment failure at the first dose level (900 mg/daily for 6 weeks).[6] At the next dose level (1200 mg/day) azithromycin in combination with pyrimethamine (50 mg/day) achieved 20 complete or partial responses and five failures. Further studies using higher doses (1500 and 1800 mg/day) of azithromycin are ongoing. PCP Little new information on Pneumocystis carinii pneumonia (PCP) was available at the ACTG conference. ACTG study 081 comparing trimethoprim/sulfamethoxazole, dapsone, and aerosol pentamidine (AP) for primary prophylaxis of PCP is scheduled to terminate at the end of this year. ACTG study #108 comparing dapsone/trimethoprim, clindamycin/primaquine and trimethoprim/sulfamethoxazole in patients with mild-moderate PCP has enrolled 163 patients of which only 85 have completed 21 days of therapy. This study is important since it will determine which is the best oral regimen to use for outpatient therapy of PCP. Because of the widespread availability of the drugs, this trial has had difficulty in enrolling patients. Nucleoside Analogues Relatively little new information on AZT, ddI, or ddC monotherapy or combination therapy was presented at the ACTG conference. ACTG Study #143 evaluated the combination of AZT and ddI in asymptomatic HIV-positive patients with T4 cells between 200- 500. Three doses of AZT (150, 300 and 600 mg/day) are being studied in combination with one of three doses of ddI (134, 334 or 500 mg/day). A control arm uses 500 mg/day of ddI alone. Increases in T4 cells have been noted in all arms after one year of therapy, though the greatest changes have been seen in the arm using 300 mg of AZT and 334 mg of ddI. The hemophiliac participants enrolled in this study had lower T4 cell responses than the non-hemophiliac participants, possibly related to more severe immune suppression. ACTG # 076, which is evaluating the use of AZT versus placebo in pregnant women and their infants, has enrolled a total of 236 women as of October 1992. The controversial study is designed to determine whether or not AZT can stop the transmission of HIV to babies born to infected mothers. Sixty three percent have entry T4 cell counts over 500. Minimal toxicity has been noted in the women, whereas infants have been noted to develop anemia and neutropenia. Protease Inhibitor -- Ro-31-8959 This protease inhibitor manufactured by Hoffmann-La Roche has been shown to be active against AZT-resistant strains of HIV in acute- and chronically-infected cells. In initial phase I studies in humans the drug seems to have a low bioavailability (24%) when given orally, yet food seems to increase its absorption. Three on-going blinded studies are being conducted in the United Kingdom, France and Italy in groups of HIV-seropositive patients with and without prior AZT therapy. The ACTG study will be a 300-patient double- blind comparative study of the combination of AZT and ddC compared to R0-31-8959 with AZT or the combination of AZT and ddC.7 Patients must have four months or greater of AZT therapy and baseline T4 cell counts between 50-300. The study will be a collaboration between the drug company and the ACTG to evaluate the effect of the protease inhibitor in combination with these nucleoside analogues by measuring changes in T cell counts and HIV quantities within six months. Tat Antagonist (Ro-24-7429) The TAT antagonist is a protein which seems to inhibit HIV at a later stage than the nucleoside analogue. The drug RO-24-7429 is a TAT antagonist developed by Hoffmann-La Roche. It has been tested in a phase I study by Dr. Paul Leitman from Johns Hopkins University. The drug resembles Valium in its chemical structure. In the test tube, the TAT antagonist reduces cell-associated viral RNA in acute and chronically infected cells. Resistance still has not been observed. In various phase I studies performed by Dr. Richard Ginsburg from Hoffmann-La Roche 60, 200 and 600 mg single doses followed by multiple doses have been administered to HIV-positive patients. This has led to a fluorescent yellow discoloration of the urine and seems to be related to a metabolite. Other side effects, occurring in approximately half of the patients, were headaches and sleepiness. An ACTG study8 will evaluate the TAT antagonist at three different dose levels (25, 50 or 100 mg every 8 hours) in patients with entry T4 cells between 50-500. Patients in the control group will receive the TAT antagonist after 12 weeks of AZT or ddI monotherapy. Half of the patients must have p24 antigen detectable in the blood, and all must have had no antiretroviral therapy within 28 days of the study. The study will be conducted at Johns Hopkins University, Harvard University, Case Western Reserve University, and the University of California at San Diego. Conclusion The ACTG introduced trials on some newer anti-HIV drugs, such as TAT antagonist and the protease inhibitor. The key trials of AZT, ddI and ddC in various combinations and comparisons are still ongoing and results may not be available until mid-1993. The interaction between NIAID and ACTG researchers, AIDS activists, women's activists and persons with HIV seems to have improved recently. Many questions are still unanswered, and more creative trial designs that incorporate people of color, IDUs and women are still urgently needed. Alternative therapies were notably lacking among the priorities of the ACTG leaders. Some progress in the ACTG has been made, but frustration was clearly evident concerning the very few promising anti-HIV drugs in the pipeline. Almost all participants seemed to agree that the most optimistic news at the November ACTG meeting was the election results on November 3. Glossary 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. Histoplasmosis: A fungal infection common in Western and Southwestern parts of the U.S. Human Papilloma Virus (HPV): a virus that causes anal and genital warts and may lead to cancerous cell growth. Also thought to be a possible co-factor to many diseases, including KS and HIV. MAC: Mycobacterium avium complex (MAC) is a serious opportunistic infection in HIV, which causes symptoms such as fevers, chills, abdominal pains, night sweats, diarrhea, anemia, and weight loss. Malignancy: A tumor which is not benign; a cancer. Microsporidiosis: An AIDS-defining illness that causes severe diarrhea. Nucleoside: A building block of DNA, the genetic material found in living organisms. Oral hairy leukoplakia (OHL): a white lesion appearing on the tongue in patients with HIV; the lesion appears raised with a corrugated or "hairy" surface. Oral thrush: A fungal condition in the mouth which commonly appears as creamy white or yellow patches, or red splotches on the roof or corners of the mouth. Prognosis: The predicted course of a disease. Toxoplasmosis: An AIDS-defining illness caused by the parasite Toxoplasm gondii that causes disease of the brain or internal organs. 1. AIDS Clinical Trials Group, ACTG #204. 2. AIDS Clinical Trials Group, ACTG #981. 3. AIDS Clinical Trials Group, ACTG #151. 4. AIDS Clinical Trials Group, ACTG #228. 5. AIDS Clinical Trials Group, ACTG #207. 6. AIDS Clinical Trials Group, ACTG #156. 7. AIDS Clinical Trials Group, ACTG #229. 8. AIDS Clinical Trials Group, ACTG #213. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ treatment briefs by David Gold gp 120 Vaccine Therapy Trials ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Activists have been working for additional HIV vaccine therapy trials to be initiated in New York, a city that has approximately 18% of all AIDS cases in the country. Genentech now has two New York City sites for its gp120 trials. Unfortunately, the company has insisted on requiring that participants have at least 600 T4 cells. Endpoints will include declines in T4 cell counts as well as progression to minor clinical illness, such as the development of oral thrush or oral hairy leukoplakia. There are approximately 12 sites nationwide. Individuals interested should call St. Vincent's Hospital at (212) 790 - 7625 or Cornell/New York Hospital at (212) 746 - 4177. For information on the sites outside of NYC, call Genentech at (800) 821- 8590. Nystatin: an Anti-HIV compound? ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Nystatin, used primarily as a topical agent for oral candidiasis (thrush), has demonstrated significant anti-HIV activity according to a study first released at the 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC abstract #324). The study found that in the test tube Nystatin inhibited HIV replication and lowered p24 levels in greater amounts than either foscarnet or amphotericin B, two anti-fungal drugs. When taken orally for thrush Nystatin is almost completely non-toxic. However, in intravenous administration the drug demonstrated significant toxicity. Recently, Argus Pharmaceuticals announced the development of a lipid encapsulated formulation of drug, AR-121. Phase II/III trials are planned for 1993. Herpes Ulceration and Low CD4 counts ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ A study reported in AIDS (November 1992, p.1317) found a sharp rise in the number of herpes-simplex ulcers in HIV-positive individuals with T4 counts under 50. In addition to a substantial increase in the number of lesions, approximately 60% of all ulcers were HSV- positive in people with under 50 T4, compared to 20% in people with more than 50 T4 cells. The study found that all ulcers responded to acyclovir therapy, although a high rate of recurrence was noted. The dramatic increase in activation of herpes simplex virus in people with low T4 cells may provide some clue to the apparent benefits seen in continuous acyclovir therapy. TB Meds Hard to Swallow ^^^^^^^^^^^^^^^^^^^^^^^ A report from the National Jewish Center for Immunology in Denver, Colorado, has demonstrated that TB recurred in a PWA, who had recovered from TB due to only partial absorption of the TB medications. The TB bacteria were resistant to two drugs (INH and streptomycin). The patient was able to recover with higher doses of drugs. This indicates that patients with AIDS with gastrointestinal tract disorders may not be absorbing TB medication. Higher doses to prevent recurrence of disease with resistant strains may be required. Keystone Joins Colorado Boycott ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ The 1993 Keystone Symposium, one of the most prestigious yearly science conferences about AIDS/HIV, has been moved from Keystone, Colorado to Albuquerque, New Mexico in response to the growing boycott of travel to Colorado. Gay, lesbian, and human rights groups have called for a boycott of all events in and travel to Colorado due to its enactment of "Amendment 2" which prohibits all gay rights ordinances in the state. The organizers of the two HIV-related symposia, Margaret Johnston and David Ho ("Frontiers in HIV Pathogenesis") and Arthur Amman ("HIV Pathogensis in Infants and Children") deserve credit for acting quickly and decisively to move the conferences out of Colorado. Unfortunately, at least 12 other non-AIDS related Keystone symposia are still scheduled to be held in Colorado. Call Dr. Darrell Doyle, Director of the Keystone Symposia, at (303) 262-1230 and let him know that all Keystone conferences must be moved out of Colorado until Amendment 2 is repealed. Interim Results in on Thymopoentin Trial ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Immunology Research Institute (IRI) has released information regarding the trial of its synthetic thymic hormone, thymopentin (see Treatment Issues, July 1992, Vol.6, No.6). The trial compared AZT and thymopentin to AZT alone. The company reports that interim results from the double-blinded phase III trial suggest that thymopentin and AZT "was more effective than AZT alone in slowing disease progression in asymptomatic patients." It was reported that three of 173 patients taking AZT and thymopentin together progressed to ARC, or had a "worsening of the disease" (defined by the company as AIDS or death) compared to 16 out of 179 taking AZT alone. No additional toxicities were reported in the thymopentin arm. However, it should be noted that no significant differences in the two arms in T4 counts, p24 antigen levels, and progression to AIDS or death were observed. Nevertheless, Dr. Howard Grossman, a leading community physician in New York, whose office was a trial site, reported that he is encouraged by this drug, particularly given the lack of toxicity that was seen. Staff Departure ^^^^^^^^^^^^^^^ Mary Beth Caschetta will be leaving her position as Editor of Medical Information at GMHC to become Editor-in-Chief of the SIECUS Report, a journal about sex information and education. As Editor at GMHC, Mary Beth has made lasting contributions to Treatment Issues and AIDS treatment activism. She oversaw the development of Women's Treatment Issues and was instrumental in expanding the Medical Information Program. Mary Beth will be sorely missed by volunteers, staff, and clients. We wish her well in her new position. Corrections ^^^^^^^^^^^ In "More on Nutrition" (Treatment Issues, Vo.6. No. 11, December 1992) a Yale University study was cited which suggested that 60 mg of beta carotene, taken twice per day, showed significant increases in T4 counts in seven individuals. In fact, the correct dosage used was 100,000 IU per day (30 mg. of beta carotene, twice per day). The doses used in the study were incorrectly published in the VIII International Conference in Amsterdam abstracts. In "Desensitization to Sulfa Drugs" (Treatment Issues, Vol. 6, No. 10, November 1992) an editing error was made in the scheduling dose. Dapsone desensitization for the first three days is conducted initially at 0.01 mg twice daily, not four times daily as published. Postponements The date of the Forum on "Community Perspectives on a Manhattan Project for AIDS Research" cosponsored by GMHC and TAG has been changed from January 28, 1992 to February 25, 1993. drug company watch by Theo Smart and David Gold Biochem Announces 3TC trials for Hepatitis B ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Biochem Pharmaceuticals of Canada announced the initiation of phase II trials with 3TC (Lamivudine) in patients with Hepatitis B infection this month. Dose-ranging studies will be conducted in the U.S., Canada, and Europe. Research efforts will be sponsored by Glaxo, the company that has acquired worldwide rights to develop and market Lamivudine. VIMRx Develops Oral Hypericin Formulation ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ VIMRx announced that it has developed an oral formulation for its synthetic hypericin drug (VIMRx). The drug was administered to two HIV-positive patients in ongoing phase I trials. The company claims that early results suggest the potential for once-daily oral dosing. One patient in the original IV-administered phase I trial showed complete remission of anal warts in men, so the company opened a small study in Boston for patients with anal HPV. Because gynecologists were not on the site of this early trial (as is the usual case for most ACTG clinical trials), no data was collected about HPV injection of the vulva or vagina in women. As a result the small study in Boston excludes women and female-specific HPV. Letter and phone zaps from ACT UP/New York, led by Anna Blume, have convinced the FDA that the trial should include women. However, Richard Podell, president of VIMRx, refuses to budge on the issue. Boehringer Begins New Nevirapine Trial ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Boehringer Ingleheim announced that it has begun a trial with combination AZT, ddI and Nevirapine, its non-nucleoside reverse transcriptase inhibitor. The trial site is at the University of Alabama at Birmingham. Test-tube studies of the three-drug combination (using either Nevirapine or Merck's L697,661) showed virtually a complete halt in viral replication. More significantly, the virus was unable to mutate and resist the combination. A large ACTG trial is slated to begin in early 1993, using the combination in individuals with under 350 T4 cells and more than six months of nucleoside therapy. Despite the development of resistance, high doses of Nevirapine continue to suppress viral activity and appear to be well tolerated. Merck Meets with Activists ^^^^^^^^^^^^^^^^^^^^^^^^^^ On December 9, 1992 activists met with executives from Merck to discuss their HIV research program. A study of the company's L 697,661 (pyridinone), in combination with AZT, has been ongoing in Frankfurt. Low-level resistance was encountered, but Merck believes that it may be able to achieve plasma levels of pyridonone high enough to be active against resistant strains. The company plans a study in four U.S. sites comparing the combination of AZT and pyridinone against AZT alone. Merck also disclosed that its protease inhibitor drug is further along in development than had been thought. The company's lead protease compound is currently in animal safety and bioavailibility studies. Clinical trials are planned for the first quarter of 1993. Burroughs Wellcome Prices Mepron (566C80), Caps Acyclovir (sort of) ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Burroughs Wellcome has set the price for Mepron (566c80), its newly FDA-approved second-line PCP therapy. The drug will sell for $402 per treatment (750 mg/3X daily/3 weeks), slightly more than TMP/SMX (Bactrim/Septra), but much less than intravenous pentamidine. The company also placed a cap on the price of acyclovir, so that individuals who use over 730 grams ($2,500) per year and who are without insurance will be entitled to receive up to 730 grams free for the remainder of the 12 month period. Activists noted that the cap would apply only to doses that exceed the FDA's highest approved dose (2 grams per day) and that the higher doses are based on only a few studies (see ACTG highlights). They are suggesting that the cap be lowered to $2,000 per year and that it apply to government and third party insurers as well. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^ For a hard copy of Volume 7 #1 or subscription information write to: Paul Warren Medical Information, 2nd Floor 129 West 29th Street New York, NY 10011