Document 0001 DOCN CATI4901 TI ANTI-HIV AGENTS: AZT 100 mg/day? DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX STEADY DETAILS Even though thousands of patients have used AZT doctors do not yet know the minimum `effective' dose. Researchers in Hamburg, Germany, carried out a small study to find out what that dose might be. Eighteen men and 2 women were monitored by doctors for 12 weeks as part of this study while they were taking various doses of AZT. Before entering this study none of the subjects used AZT. Seven subjects had AIDS, 7 ARC and the remaining subjects were free from symptoms. For the first four weeks of the study subjects took AZT 100 mg/day. During weeks 4 through 8 they took 200 mg/day. For the last 4 weeks of the study subjects took 500 mg/day of AZT. RESULTS- RED BLOOD CELLS, PLATELETS There were no significant changes in red blood cell, platelet and certain white blood cell counts during the study. As well, blood levels of Beta2-microglobulin and weight did not change while subjects were in the study. Indirect measures of HIV production (called p24 antigen) suggested that the amount of virus produced fell during the study. This decrease was statistically significant, that is, not likely due to chance alone. RESULTS--CD4+ AND CD8+ CELLS After the fourth week of the study there was an average increase of 120 CD4+ cells in the blood of subjects. This increase continued during the next 8 weeks of the study and was statistically significant. There were no significant changes in the CD8+ cell counts during the study. TOXICITY There were no serious side effects detected by the study physicians. SUMMARY In this study, researchers found that 50 mg of AZT taken "twice daily [had] a statistically significant effect on [CD4+ cell counts] when given to [subjects who had never used the drug]." AZT had no effect on CD8+ cell counts. The doctors warned that further studies need to be done to find out the effect of low doses of AZT on the appearance of symptoms of HIV infection. REFERENCES: 1. Stellbrink HJ, Abrecht H, Plettenberg A, et al. Antiviral and immunologic effects of escalating low doses of Zidovudine in HIV-positive patients. European Journal of Clinical Microbiology and Infections Diseases 1993;12:618-621. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0002 DOCN CATI4902 TI ANTI-HIV AGENTS: AZT and ddI: Combinations Verses Alternating DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND A number of long-term studies have found that the benefit(s) of AZT treatment wanes. The loss of the beneficial effect(s) may be due to the increasing toxicity of the drug over time, the development of AZT-resistant virus or other factors. If AZT resistance is an issue then perhaps treatment with other a HIV drugs may be an option. Doctors in the USA are conducting a number of clinical trials using anti-HIV drugs to see if they can help protect the immune system from further damage by HIV. We now report on one of these trials. STUDY DETAILS Doctors in Bethesda, Maryland enrolled 41 subjects for this study. Subjects were supposed to have received only "3 months or less antiviral therapy" in the past. As well, the subjects had between 10 and 350 CD4+ cells and were also "free of life-threatening [infections]" at the time they entered the study. Doctors randomly assigned subjects into two groups or `arms'. In one arm of the study subjects received 150 mg of AZT taken every 8 hours and 250 mg of ddI taken once daily. Subjects took ddI "in the mornings between the two doses of [AZT]." In the other study arm subjects took "100 mg of AZT every four hours for 3 weeks." At the end of the 3 weeks doctors switched the subjects from AZT to "250 mg ddI every 12 hours for [another] 3 weeks." At the end of this period they then switched back to AZT taking it in the same dose and schedule as before. These subjects continued, every 3 weeks, to switch back and fort between the two regimens for the rest of the study. The doctors assigned 20 subjects to the alternating arm and 21 to the combination arm. The trial was not blinded; subjects and doctors knew which drugs subjects received. DROP-OUTS AND DEATHS At the time of data analysis doctors had monitored some subjects for up to 104 weeks. Two subjects in the "alternating arm died of [AIDS-related complications]." One subject in the combination arm died because of complications from an inflamed pancreas. The doctors suggested that ddI's toxicity to the pancreas may have been the cause of his death. Two other subjects in the alternating arm of the study withdrew from the trial. RESULTS CD4+ CELL COUNTS Subjects given both drugs at once (the combination arm) had greater increases in their CD4+ cell counts than subjects in te alternating arm. As well, the increase in CD4+ cells lasted for up to 45 weeks. These increases in CD4+ cells in subjects in the combination arm were statistically significant; that is, not likely due to chance alone. Although some subjects in the combination arm had increasing CD4+ cell counts (reaching as high as 108 more CD4+ cells), after the 9th week of the study these started to decline. Subjects in the alternating arm had a maximum increase of 40 CD4+ cells 3 weeks after entering the study. RESULTS--IMMUNE SYSTEM TESTS During the study some subjects had an improvement in tests of immune system function (called delayed type hypersensitivity). But a year later only 1 subject who improved during the study "preserved [this improvement]". VIRUS PRODUCTION One indirect but cheap and quick way to find out if HIV production is changing is to measure an HIV protein called p24 antigen, or simply `p24'. Overall it appeared that subjects on the combination arm had reduced viral production compared to subjects in the alternating arm. Only in the 27th week of the study were there any statistically significant differences between the arms of the study. WEIGHT Subjects in both arms of the study gained weight. The largest average increase happened in the 27th week. In the combination arm that average increase was 6 kg and in the alternating arm it was 2 kg. This difference was statistically significant. After te 27th week the average weight of subjects began to decline in both arms of the study. LIFE-THREATENING INFECTIONS At the time of data analysis 3 subjects in the combination arm had 4 life-threatening infections and 6 subjects in the alternating arm had 10 life-threatening infections. This difference was not statistically significant. TOXICITY The researchers think that at least 1 subject died because of the toxicity of AZT and ddI. Some subjects also had bone marrow and liver damage which may have been caused by AZT, ddI or both drugs. SUMMARY In this study, a combination of AZT and ddI seemed to be tolerated and caused an increase in weight and CD4+ cell counts compared to a regimen of alternating AZT and ddI. Whether the increased weight and CD4+ cell counts resulted in improved quality of life, survival and/or delayed the decline of the immune system is not at all clear. Larger, controlled studies may be able to answer these questions. REFERENCES: 1. Yarchoan R. Lietzau JA, Nguyen B-Y. et at. A randomized pilot study of alternating or simultaneous Zidovudine and Didanosine therapy in patients with symptomatic Human Immunodeficiency Virus infection. Journal of Infectious Diseases 1994;169:9-17. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0003 DOCN CATI4903 TI ANTI-HIV AGENTS: AZT--How Many Times A Day? DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND Although some doctors have gained experience using AZT they are not sure which schedule is best; that is, how many times a day patients should take the drug. We now present some research that might affect decisions about AZT schedules. AZT INSIDE THE CELL By itself, in its ordinary form, AZT is not an antiviral. When swallowed, a capsule of AZT eventually breaks open and the drug is absorbed into the blood. From the blood AZT has to enter T-cells. Once inside a cell AZT then has to be converted into its "active" or antiviral form (called AZT triphosphate). To study this processing of AZT, researchers in the USA have been conducting sophisticated analyses of blood cells from 12 people with HIV infection who used AZT. STUDY DETAILS The subjects were male and free from symptoms. The doctors gave the subjects 100 ma of AZT to take orally. Technicians then took blood samples from the subjects over the next 6 hours. RESULTS * the researchers found a wide range of AZT levels in the blood cells of subjects taking the same oral dose. * the level of activated AZT (AZT-triphosphate) increased in all subjects during the first and second hour after swallowing a dose of the drug. After the second hour the concentration of processed AZT remained the same for at least the next 4 hours. The amount of AZT processed during this time varied from one subject to another. However, the doctors found the general pattern of increasing concentrations of activated AZT during the first 2 hours, and a stable concentration after that time, in all subjects. These results raise questions about current schedules for taking AZT. In this study it seems that taking the drug every 6 hours might be one possible schedule. Further experiments need to be done to Confirm and explore the issue of AZT schedules. REFERENCES: 1. Robbins BL, Rodman J. McDonald C et al. Enzymatic assay for the measurement of Zidovudine triphosphate in peripheral blood mononuclear cells. Antimicrobial Agents and Chemotherapy 1994;38(1): 1 15-121 DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0004 DOCN CATI4904 TI IMMUNOMODULATORS: AZT, Pentoxifylline and TNF DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND The body produces a number of chemical messengers that help the immune system coordinate, focus and withstand attacks by invading microorganisms as well as tumours. One of these chemicals is TNF (tumour necrosis factor). Researchers do not fully understand the effects of TNF and much work on it continues. We now present results from a short trial in the USA. STUDY DETAILS Researchers reported results on 32 HIV-infected subjects (28 men and 4 women). The average CD4+ cell count of subjects was about 300 cells and the average CD8+ cell count was almost 900 cells. Subjects were divided into 3 groups; group 1 received 400 to 500 mg/day of AZT; group 2 received pentoxifylline 400 mg three times daily; and group 3 received a combination of regimens 1 and 2. The researchers monitored all groups for 3 months. RESULTS No life-threatening inactions appeared during the study. Blood levels of TNF and Beta2-microglobulin did not change significantly among the 3 groups. The average CD4+ and CD8+ cell counts did not change significantly among the 3 groups over the course of the study. The amount of virus produced in subjects given the combination of AZT and pentoxifylline was 4 times less than in subjects in the other 2 groups. This difference in viral production was statistically significant; that is, not likely due to chance alone. Pentoxifylline did not cause any bone marrow damage and was "well tolerated". It is interesting that the researchers used P24 antigen (an indirect way of measuring viral production). They found that results from P24 antigen tests were not reliable. The researchers suggested longer and larger studies of this combination of drugs may be needed to see if reducing HIV production can have an effect on quality of life and survival. OTHER STUDIES Researchers in Milan, Italy, have been studying nearly 200 subjects at various stages of HIV infection. They could not find a link between blood levels of TNF and decreasing CD4+ cell counts. In 25 subjects with high blood levels of TNF 500 mg of AZT every "48 hours" for 3 months caused TNF levels to fall. This change was statistically significant and had no effect on CD4+ cell counts. REFERENCES: 1. Luke DR, McCreedy BJ, Sarnoski TP, et al. Phase I/II study of pentoxifylline with Zidovudine on HIV-1 growth in AIDS patients. International Journal of Clinical Pharmacology, Therapy and Toxicology 1993;31(7):343-350. 2. Cremoni L, Vaira LL. Grassi MG and Millazzo F. Does Zidovudine reduce tumour necrosis factor-alpha in HIV-positive patients? AIDS 1993;7(1):128-129. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0005 DOCN CATI4905 TI IMMUNOMODULATORS: Pentoxifylline, TNF and the Immune System--A Delicate Balance DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND The body produces a number of chemical messengers that help the immune system coordinate, focus and withstand attacks by invading microorganisms as well as tumours. One of these chemicals is TNF (tumour necrosis factor). Researchers have limited information on the effects of TNF and much work on it continues. TNF INJECTIONS In the late 1980s one group of researchers in the USA tested the effect of injections of TNF (tumour necrosis factor) on the health of subjects with HIV infection. During the 4-month double-blind study some subjects received 10 ug per square mete of skin 3 times per week. When the researchers analysed the data they found that there was no short-term benefit or risk from the injections of TNF. Now other researchers are taking a different approach and are using the drug Trental(R)(pentoxifylline) to try and reduce blood levels of TNF in subjects with HIV/AIDS. DECREASING TNF In some laboratory experiments with HIV-infected cells, TNF seems to increase production of HIV by those cells. TNF may also cause weight loss in HIV-infected patients. Thus it seems reasonable to think that by reducing production of TNF some HIV-infected patients may regain or maintain their weight and/or reduce production of HIV. PENTOXIFYLLINE RISKS TNF plays a very important role as part of the immune system's defenses against tumours and infections. By severely reducing production of TNF pentoxifylline may make some patients more vulnerable to some infections. As well, some researchers have found that the interaction between pentoxifylline and the immune system is more complex and pentoxifylline may suppress more than just TNF. This could cause some HIV-infected patients to become at higher risk for certain infections. In patients whose immune systems are already damaged by HIV infection, adding yet another immunosuppressive drug may be risky. REFERENCES: 1. Agosti JM, Coombs REV, Collier AC, et al. A randomized, double-blind, phase I/II trial of tumour necrosis factor and interferon gamma for the treatment of AIDS-related complex (protocol 025 from the AIDS Clinical Trials Group). AIDS Research and Human Retroviruses 1992;8(5):581 2. Hilsh CS, Ellner JJ, Russell DG and Rich EA. Complement receptor-mediated uptake and tumour necrosis factor-alpha-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages. Journal of Immunology 1994;152:743. 3. Jewett A and Bonavida B . Pentoxifylline suppresses interleukin-2-mediated activation of immature human natural killer cells by inhibiting endogenous tumour necrosis factor-alpha secretion. Journal of Clinical Immunology 1994;14(1):31-38. 4. Thanhauser A, Roiling N. Bonhle A. Pentoxifylline: a potent inhibitor of IL-2 and INF-gamma biosynthesis and BCG-induced cytotoxicity. Immunology 1993;80:151-156. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0006 DOCN CATI4906 TI IMMUNOMODULATORS: Steroids DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND "Steroids" (corticosteroids) are drugs that suppress and reduce many of the activities of the immune system. Doctors sometimes find them useful in treating certain conditions such as arthritis and psoriasis. During some of the life-threatening infections seen in AIDS such as PCP, 'toxo' (toxoplasmosis) and 'crypto' (cryptococcal meningitis) the resulting inflammation and swelling can be dangerous. This is why doctors sometimes prescribe steroids to reduce the inflammation until the infection can be brought under control. As steroids can affect the immune system, bone marrow and brain, side effects can be expected. Last year doctors in England found that patients who had less than 50 CD4+ cells appeared to be at increased risk for developing te sight-threatening infection CMV retinitis as a result of using steroids. REFERENCES: 1. Chrousos GP, Wilder RL, Cupps TR and Balow JE. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates. Annals of Internal Medicine 1993:119(12):1198-1208. 2. Nelson MR, Erskine D, Hawkins DA and Gazzard BC. Treatment with corticosteroids a risk factor for the development of clinical cytomegalovirus disease in AIDS. AIDS 1993;7:375-378. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0007 DOCN CATI4907 TI IMMUNOMODULATORS: Steroids for MAC DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND Infection with MAC/MAI (Mycobacterium avium complex/Mycobacterium avium intracellulare, the two are interchangeable) can happen as the CD4+ cell count falls below 100 cells. The symptoms of MAC are not pleasant and may include fever, night sweats, persistently swollen lymph nodes, diarrhea weight loss and fatigue. MAC infection may also affect the bone marrow and cause reduced production of red blood cells resulting in anemia. Only in the 1990s did two powerful antibiotics such as azithromycin and clarithromycin become licensed in North America and the EU. Even so MAC can rapidly become resistant to the effects of either of these drugs when used alone. A number of trials are underway to test various combinations of antibiotics against MAC infection. ANTIBIOTICS Doctors in England have recently reported their experience with steroids to treat 2 patients with MAC infection. Both patients were male and had less than 40 CD4+ cells. Their symptoms included "fever, night sweats and weight loss." one patient "developed anemia". At first doctors gave these patients the antibiotics rifampin, isoniazid and pyrazinamide. These antibiotics were not effective. So the doctors then prescribed azithromycin 1 gram/day and clofazimine 100 mg/day for 1 patient while the other got Cipro(R)(ciprofloxacin) 1 gram/day, azithromycin 1 gram/day and clofazimine 100 mg/day. Lab tests on stool and blood samples, taken at the time they first developed symptoms detected MAC. RESULTS Within 2 weeks of starting the second antibiotic regimen both patients had diminished] fever and sweats." Despite this the anemic patient had to receive blood transfusions.. STEROIDS The doctors then prescribed 20 mg/day of the steroid Prednisone after which the fever and night sweats cleared (this steroid is different from the kind used by some athletes to increase muscle size). They also enjoyed "a feeling of well-being." The patients gained weight and, while continuing to take azithromycin and clofazimine or Cipro, have not developed sweats and fever. Five months later one patient has maintained his weight but developed a fungal infection in his mouth that was resistant to antifungal drugs. The doctors have reduced his dose of steroids to 10 mg/ day hoping to restore some immunity against the fungus. At 8 months after beginning his anti-MAC therapy the second patient is well enough to return to work (the doctors did not provide details about his job). HOW HAVE STEROIDS HELPED/HARMED? Steroids can block the production of chemicals called cytokines which are used by cells of the immune system to send-messages to each other. Cytokines affected by Prednisone include TNF (tumour necrosis factor) and interferon-gamma, among others. Suppressing production of excessive amounts of TNF may reduce fever and weight loss and production of HIV. Some researchers are concerned that steroids may speed up the decline of the immune system in people with HIV infection. Indeed, some studies have found tat steroids can increase the appearance of Kaposi's sarcoma, CMV retinitis and other herpes virus infections and perhaps fungal infections as well. Data from these two patients suggest that in the short term steroids may be useful and carry some risk. The appearance of drug-resistant fungus in one patient does raise concerns about the risks of steroid therapy. As well, there may be the overall impact on their survival in the long term. In a future issue of TreatmentUpdate we will report results from other studies where HIV-infected patients were also treated with steroids. REFERENCES: 1. Steven N. Pithie Ask Wood M and Innes J. Corticosteroid therapy for AIDS patients with Mycobacterium avium-intracellulare infection. AIDS 1994;8(1):136-138. 2. Shiratsuchi H. Johnson JL, Toosiz and Ellner JJ. Modulation of the effector function of human monocytes for Mycobacterium avium by Human Immunodeficiency Virus-1 envelope protein gp120. Journal of Clinical Investigation 1994;93:885. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0008 DOCN CATI4908 TI INFECTION FIGHTERS: Living longer but... DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND Compared to the early part of the 1980s some people with HIV/AIDS are living longer. One possible explanation is that doctors have gained more experience in treating many of the life-threatening infections that affect people with HIV/AIDS. New and better antimicrobial agents (antibiotics/antifungals/ antivirals) or combinations of these drugs may also have played a role. Unfortunately, most of the anti-HIV agents in use or being tested do not result in improved survival in the long term compared to placebo. This is because these drugs cannot help the immune system to repair the damage caused by years of HIV infection. Thus, although some patients are living longer thanks to antimicrobial drugs, their immune systems continue to degrade. One microorganism that causes serious problems for some patients with AIDS is MAC/MAI (Mycobacterium avium complex/Mycobacterium avium intracellulare; they cause the same symptoms, respond to the same drugs so for this article they can be considered the same). DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0009 DOCN CATI4909 TI INFECTION FIGHTERS: Signs/Symptoms of MAC infection DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX WHERE TO FIND MAC MAC/MAI are related to the bacteria that cause leprosy and tuberculosis. MAC is found in tap, river and sea water, soil, dairy products and animals, including insects. In North America the number of people becoming ill from serious MAC infection is increasing at the rate of about 20% per year. Signs/symptoms include: * night sweats * fevers * unintentional weight loss * diarrhea * unusually low levels of white and red blood cells * high blood levels of the liver enzyme alkaline phosphatase * painful intestines ANTIBIOTICS Some doctors in the USA think that MAC infection may eventually affect "most if not all" people with HIV infection. When MAC spreads to several sites in the body (bone marrow, blood, spleens liver and intestines) quality of life and survival decrease. Until the 1990s common antibiotic regimens were not effective and were toxic as well. The testing of new antibiotics such as azithromycin and clarithromycin and rifabutin has made treating and suppressing MAC infection much easier in the short term. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0010 DOCN CATI4910 TI INFECTION FIGHTERS: Rifabutin--results from placebo-controlled studies DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND Researchers in Canada and the USA have conducted two clinical trials (called 023 and 027) to test the ability of rifabutin to delay the appearance of MAC infection. That drug was released in the 1980s on a compassionate basis for people with MAC infection, see TreatmentUpdate 30 for details. Data collected from the 1980s suggested that 300 mg/day of rifabutin was more effective than 150 mg/day. For the purposes of this report data from the two studies (023 and 027) will be combined. TRIAL DETAILS All subjects enrolled had less than 201 CD4+ cells and had AIDS. Over 95% were male and over 1100 were randomly assigned to one of two arms or groups; either rifabutin 300 mg/day (566 subjects) or a dummy capsule or placebo (580 subjects). On average all subjects had high blood levels of the liver enzyme alkaline phosphatase. At the beginning of the study 10 subjects had MAC detected in their blood samples and they were not used in the data analysis. Subjects were not supposed to be using anti-MAC/TB drugs. Subjects continued to stay in the study until certain events or end points occurred. When one event or endpoint occurred the researchers unblinded the data on that subject to find out if he/she was on placebo or rifabutin. At that point subjects were allowed to receive rifabutin if they chose. End points in the trial included: * detectable MAC from bone marrow or blood samples * detectable TB from blood/bone or other samples * subjects became ill and had to receive anti-TB/ MAC therapy * "serious or life-threatening toxicity caused by study drugs or [some other] cause" RESULTS--MAC INFECTION On averages during the double-blind phase of the trial, the following became infected with MAC: * 17% of subjects given placebo * 8% given rifabutin These differences between placebo and rifabutin were statistically significant; that is, not likely due to chance alone. From this data it is clear that rifabutin can delay the appearance of MAC in some subjects. RESULTS--CD4+ CELL COUNTS At least half of the subjects had a CD4+ cell count between 12 and 15 cells when technicians detected MAC in blood/bone/tissue samples. The researchers did not provide data on CD8+ cell counts. RESULTS--TB Doctors diagnosed 7 of the 1146 subjects with having TB. Technicians could not find any TB-causing bacteria in blood/bone/tissue samples from these subjects. RESULTS--SIGNS/SYMPTOMS Rifabutin, compared to placebo reduced: * fever * fatigue * high blood levels of the liver enzyme alkaline phosphatase * anemia * the need for hospitalization This reduction in signs/symptoms between the subjects on rifabutin and others on placebo was statistically significant. Rifabutin did not affect: * weight loss * night sweats * diarrhea * intestinal pain RESULTS--SURVIVAL Roughly similar proportions of subjects died in each arm of the study; 200 on rifabutin and 226 on placebo. This difference between the two arms of the study was not statistically significant. TOXICITY A small proportion of subjects (16% on rifabutin and 8% on placebo) had to leave the study because of side effects. These adverse reactions included: * rash * gastrointestinal problems * low levels of a type of white blood cell called neutrophils. That these side effects were not reduced by rifabutin is not surprising as the drug can cause these effects. REFERENCES: 1. Nightingale SD, Cameron DW, Gordin FM. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. New England Journal of Medicine 1993;329(12):828-833. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0011 DOCN CATI4911 TI INFECTION FIGHTERS: Who benefits from rifabutin? DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX SUMMARY Data from trials 023 and 027 suggest that rifabutin 300 mg/day can: * reduce blood levels of MAC * reduce the intensity of some symptoms: fatigue and fever * reduce the need to put patients in hospital because of symptoms of MAC infection * reduce the incidence of red blood cell anemia DRUG RESISTANCE Technicians could not detect any rifabutin-resistant bacteria from subjects during the study. RISKS * no increase in survival in subjects given rifabutin compared to others given placebo during the double-blind phase of the study * some toxicity to the bone marrow and possibly the immune system * rash RIFABUTIN--WHO BENEFITS? In this study, during the double-blind period, roughly 8% of subjects on rifabutin and 17% on placebo developed MAC infection. This means that only 9% clearly had benefit and another 8% worsened despite being given rifabutin. For 83% of subjects there was no benefit to being given rifabutin. Based on the data provided by the manufacturer, Adria Laboratories, 100 people had to be given rifabutin for 9 to show benefit from the drug. These figures are not surprising; rifabutin is clearly a weak antibiotic and there was no statistically significant difference between the two groups when statisticians looked at survival. RIFABUTIN AND FLUCONAZOLE--WHICH DOSE? One prominent Canadian researcher told us privately that there may be other factors that need to be considered--the toxicity and the dose of rifabutin. At the International AIDS Conference in Berlin last year doctors presented an abstract on an interaction between rifabutin and fluconazole. They found that in 12 patients taking fluconazole 200 mg/day and 300 mg/day of rifabutin that blood levels of rifabutin increased between 2 and 3 times their normal levels. Some researchers think that taking 450 mg/day of rifabutin will make the antibiotic more effective. Others are not so sure, because at higher doses rifabutin becomes more toxic to patients with AIDS. As well, there are increasing reports of eye inflammation in patients using rifabutin. In one report, this condition resolves once the patient stops using rifabutin. WEIGHING RISK/BENEFIT These results do not mean that rifabutin should not be considered as preventative therapy against MAC. The real issue is how to get the greatest benefit from the drug. According to the company, subjects who may benefit the most from rifabutin are probably those with CD4+ counts of 75 cells or less. Some doctors who were not affiliated with Adria Laboratories or this study suggest that frequent monitoring of patients (including sending stool and blood samples for laboratory detection of MAC) and paying close attention to symptoms are important. They "save" rifabutin until it is clear that the patient's immune system cannot cope (symptoms become worse and lab tests detect MAC) with MAC infection and prescribe rifabutin in combination with a number of antibiotics. We have also heard anecdotal reports from doctors that some of their patients may develop symptoms of MAC which get confirmed by laboratory testing. By the time the test result returns to the doctor the patient has recovered, often without treatment. These courses of action are not recommended by the United States Public Health Service. REFERENCES: 1. Frank MO, Graham MB, Wispelway B. Rifabutin and uveitis. New England Journal of Medicine 1994;330(19):868. 2. Trapnel CB, Narang PK, Li R. et al. Fluconazole increases rifabutin absorption in HIV-positive patients on stable Zidovudine therapy. IX International Conference on AIDS Berlin 1993, abstract PO-B-31-2212, page 504. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0012 DOCN CATI4912 TI INFECTION FIGHTERS: Detecting and preventing MAC infection DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX WIDESPREAD (DISSEMINATED) INFECTION When technicians find a sample of blood containing MAC then the infection is no longer contained and doctors describe it as "disseminated". Some doctors also make the same diagnosis based on a sample of bone marrow or liver cells that test 'positive' for MAC. STANDARD PROCEDURES TO FIND MAC To detect MAC a small amount of blood (10 ml) is collected by a nurse or lab technician in a tube. They then put a small amount of an anti-clotting drug into the tube. This does not reduce the number of bacteria even if the blood is kept up to a week after being collected. Technicians later spread the blood on containers with nutrients that MAC needs in order to survive. In Bactec devices MAC can be grown in 1 to 2 weeks. In other systems it can take 2 to 3 weeks, sometimes even longer. In a future issue of TreatmentUpdate we will provide more details on using PCR (polymerase chain reaction) for detecting MAC. MAC PREVENTION RECOMMENDATIONS According to the US Public Health Service, patients with less tan 100 CD4+ cells should get preventative therapy for the rest of their lives. These patients should not have active TB or MAC infection. To confirm this, x-rays blood cultures and TB skin tests may be necessary. Preventative therapy against MAC should be 300 mg/day of rifabutin. DIFFICULT DECISIONS The US Public Health Service recommended that in reaching a decision about preventative MAC therapy, doctors should weigh the following carefully: * rifabutin toxicity * rifabutin's interaction with other drugs * the cost of rifabutin * the willingness of patients to take the drug as directed * drug resistance TREATMENT The US Public Health Service recommended the following when treating patients with MAC: * a minimum of 2 antibiotics should be prescribed * all regimens should include azithromycin or clarithromycin * ethambutol is probably a useful second drug For third or fourth drugs, they suggested the following options: * Cipro(R), rifabutin, rifampin and clofazimine * isoniazid and pyrazinamide should not be used * in cases where patients are using rifabutin as a preventative and they develop disseminated MAC infection, rifabutin can still be used as part of a treatment regimen. The task force stated that patients who "responder to therapy will improve during the "first 4 to 6 weeks of therapy." If patients do not improve after the "first 4 to 8 weeks of therapy they should be reevaluated." REFERENCES: 1. Nightingale SD, Cameron DW, Gordin FM. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. New England Journal of Medicine 1993;329(12):828-833. 2. Masur H. Public Health Service Task Force on Prophylaxis and Therapy for disseminated Mycobacterium avium complex disease in patients infected with human immunodeficiency virus. New England Journal of Medicine 1993;329:898-904. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0013 DOCN CATI4913 TI INFECTION FIGHTERS: Mepron as PCP prevention DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND Although there are several effective antibiotics with which to treat the life-threatening pneumonia PCP, many patients cannot tolerate them. This intolerance arises because patients become sensitive to sulfa drugs. This sensitivity is a problem because many of the drugs used to treat PCP are also taken in smaller doses as PCP prevention or prophylaxis. Patients may find themselves using aerosolized pentamidine which is not the best therapy. The new antiparasite drug Mepron(R)(atovaquone) works as a treatment for mild-to-moderate PCP. Mepron can be tolerated by many patients who are allergic to sulfa drugs. Some doctors are considering using Mepron as a prophylaxis for their patients allergic to sulfa. RESULTS FROM ENGLAND Doctors in England have reported their experience using Mepron as prophylaxis against PCP in 3 patients. All subjects had less than 10 CD4+ cells and had PCP 2 to 5 times. The patients could not tolerate Bactrim/Septra, dapsone, or aerosolized pentamidine. They received Mepron 750 mg three times daily. One patient has used it for 3 months, another 5 and the third 6 months. No patient has developed PCP while on this regimen. While more research on Mepron needs to be done, this report does offer some hope to patients allergic to sulfa drugs. REFERENCES: 1. Fisher MJ, Gazard BG, Hawkins DA and Nelson MR. Atovaquone as prophylaxis against Pneumocystis carinii pneumonia. Journal of Infection 1994;103-104. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0014 DOCN CATI4914 TI INFECTION FIGHTERS: Toxo with high CD4+ cell counts DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX The parasite T. gondii can infect the brain causing the life-threatening infection 'toxo' (toxoplasmosis). People can get infected with the parasite by eating raw or undercooked meat and also by accidentally eating cat feces. Most cases of toxo occur in patients when the CD4+ cell count falls below 200 cells. However, Italian researchers have found 4 cases of toxo in patients with more tan 600 CD4+ cells. These patients 2 males and 2 females, all adults, had symptoms such as seizures, worsening headache and sensitivity to light. As well, tests detected antibodies against the parasite in their blood. Treated with "50 to 75 mg/day of pyrimethamine and sulfadiazine 100 mg/kilogram of body weight/day" they recovered over the course of 6 weeks. No lesions appeared when doctors examined the X-ray scans of their brains. These patients are now on suppressive therapy: 25 mg/day of pyrimethamine and 2 grams/day of sulfadiazine, and remain healthy. Their CD4+ cell counts are still above 600 cells. The doctors suggest that HIV-infected patients who have relatively high CD4+ cell counts and who develop neurological problems should be investigated for toxo. REFERENCES: 1. Gervasoni C, Bini T. Franzetti F. et al. Central nervous system toxoplasmosis in HIV-1-infected patients with persistently normal CD4+ cell counts. European Journal of Infectious diseases 1993;12(10):787. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0015 DOCN CATI4915 TI TOXICITY: AZT toxicity may be linked to biorhythm DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND As plants and animals have a 24-hour cycle some researchers think that cycle might influence the effect of drugs inside the body. Researchers at the Comprehensive Cancer Center, Birmingham, Alabama, have been performing experiments on rats to find out if the toxicity of AZT may be linked to daily biorhythms. STUDY DETAILS In the first part of the experiments technicians placed the rats in cages (with food and water) and turned the lights off and on to produce the effect of night and day. The technicians maintained these conditions for 4 weeks to let the rats adjust. After this, in the second phase of the experiment, technicians gave most of the rats various doses of AZT at different times of day/night. The rats that did not get AZT were kept as a "control" for comparison. RESULT--NIGHT AND DAY All rats given AZT suffered from weight loss. The mice that experienced the greatest weight loss received AZT at 4 a.m. This finding was statistically significant; that is, not likely due to chance alone. Rats given AZT had bone marrow damage and reduced production of red and white blood cells. The rats suffered the least toxicity when they received AZT at 2 pm or 5 pm. These observations on toxicity and time of administration of AZT were statistically significant. RESULTS--DEATH Among the rats that died, the cause was usually bone marrow damage caused by AZT. The death rate was highest (80%) when rats received AZT at midnight. Only half the rats died when given the same dose of AZT at noon. These differences in the death-rates were statistically significant. SUMMARY Twenty-four-hour biorhythms can have an impact on how animals are affected by various drugs. In these experiments on rats with AZT, the timing of the dose clearly had different effects at different points in their day/night cycle. These results may not be exactly the same in humans who also have a 24-hour biorhythm. According to the researchers rats and mice are "more active in the [night] and less active in the light". Humans are generally more active in the light and less active at night. Experiments on human bone marrow cells also suggest that the cells are most active during the period when people are awake and least active during sleep; between midnight and 4 am. Further studies need to be done to find the time when humans are least affected by the toxicity of AZT and other, related drugs. Researchers in France have also reported results from a study on subjects with cancer who did not have HIV infection. The researchers also found that biorhythms affected the toxicity of interferon-alfa. REFERENCES: 1. Zhang R. Lu Z. Diasio CR, et al. The time of administration of 3'-azido-3'- deoxythymidine (AZT) determines its host toxicity with possible relevance to AZT chemotherapy. Antimicrobial Agents and Chemotherapy 1993;37(9):1771-1776. 2. Depres-Brummer, Levi F. Di Palma M, et al. A phase I trial of 91-day continuous venous infusion of alfa-interferon at circadian rhythm modulated rate in cancer patients. Journal of Immunotherapy) 1991;10:440-447. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged. Document 0016 DOCN CATI4916 TI TOXICITY: Foscarnet toxicity in women DT 9405 AU Sean Hosein, Editor SO Community AIDS Treatment Information Exchange (CATIE) - TreatmentUpdate No. 49: A Publication of the Community AIDS Treatment Information Exchange, Suite 324 - 517 College Street, Toronto, Ontario M6G 4A2 - (416) 944-1916. TX BACKGROUND Foscarnet (Foscavir(R) is a drug licensed for the treatment of the sight-threatening infection CMV retinitis. Foscarnet can also block the production of other herpes viruses HIV and the hepatitis B virus. Unlike another anti-CMV drug, DHPG (Cytovene(R), ganciclovir), foscarnet is not toxic to the bone marrow. Foscarnet can, however, cause kidney damage. In uncircumcised men treated with foscarnet, ulcers may develop on the penis. This happens because foscarnet is released in the urine at relatively high concentrations. Urine containing foscarnet may collect in the folds of skin where it can form ulcers. Doctors in England have reported that ulcers can also form in women who use foscarnet. In one woman, the ulcers appeared on the labia and healed once she stopped taking the drug. Just as cleaning the foreskin after urination may help reduce the appearance of ulcers in men, cleaning the external genitals after urination may also help women who use foscarnet. REFERENCES: 1. Lacey HB, Ness A, Mandal BK. Vulval ulceration associated with foscarnet. Genitourinary Medicine 1992;68: 182. DISTRIBUTED BY GENA/aegis (714.248.2836). Copyright (c) 1994. Community AIDS Treatment Information Exchange (CATIE). Noncommercial reproduction encouraged.