       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.
