From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: VA Summary 8/14/92
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6093
Organization: unspecified
Date: Sat, 5 Sep 92 22:45:26 PDT

                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                         August 14, 1992 
   FDA MAKES NEW DRUG AVAILABLE TO PHYSICIANS FOR TREATING MAC 
     The Food and Drug Administration has issued pre-approved distribution of 
rifabutin, an experimental drug for preventing or delaying the onset of life-
threating Mycobacterium avium complex (MAC).
     The drug will be made available under a treatment IND (investigational 
new drug) protocol.  Physicians can obtain rifabutin free of charge for HIV-
infected patients who have CD4 counts of 200 or less.
     The treatment IND was based on two recently completed, unpublished 
studies indicating the drug may be effective in preventing or delaying MAC 
infection in AIDS patients with CD4 counts of 200 or less, according to a 
statement issued by FDA. 
     The drug is adminstered orally at doses of 300 mg. a day.  The most 
serious adverse effect of the drug appears to be decreases in various types of 
blood cells.  Other side effects include flu-like symptoms--such as fever, 
headaches, and joint and muscle pain-- gastrointestinal disorders, and rash.
     The treatment IND for rifabutin is sponsored by the drug's developer, 
Adria Laboratories of Dublin, Ohio.  Physicians interested in enrolling 
patients should call (800) 552-7228. (AIDS ALERT. 1992 May;7(5):80). 
               RIFABUTIN AVAILABLE TO PREVENT MAC 
Under a "Treatment IND" approved by the U.S. Food and Drug Administration, 
Adria Laboratories will provide rifabutin to certain patients for prevention 
of MAC (mycobacterium avium complex), before the drug is regularly approved 
for U.S. marketing. In a major controlled trial with over 500 patients, 
rifabutin  reduced the incidence of MAC to about half that of the placebo 
group. A separate, similar trial is now being analyzed.  
This program is only for prevention, not treatment; patients must have no 
history of MAC. They must also have a T-helper count under 200, and meet 
certain other criteria.  
Physicians who have patients who might benefit from this program should call 
the PACT Rifabutin Treatment IND Study Center, 800/552-7228, between 8 a.m. 
and 5 p.m. Eastern time, for more information. (AIDS Treatment News Issue 
#149, April 17, 1992).  
RIFABUTIN THERAPY FOR THE PREVENTION OF MAC BACTEREMIA IN HIV POSITIVE 
PATIENTS WITH CD4 COUNTS <= 200: TREATMENT IND STUDY  
The Rifabutin Treatment IND study is designed to provide expanded access to 
rifabutin for AIDS patients with CD4 counts <= 200 for the PREVENTION of 
Mycobacterium-avium Complex (MAC). It IS NOT a treatment study. Patients must 
meet certain inclusion and exclusion criteria in order to be eligible to 
receive rifabutin. 
1.0  STUDY MANAGEMENT  
Adria Laboratories has assigned to PACT, Inc., a subsidiary of G.H. Besselar 
Associates, 150 Radnor-Chestor Road, Suite D200, St. Davids, PA 19087 (PACT), 
the management of this study, and all associated activities.  Sponsor, as used 
in this protocol, refers to Adria Laboratories.  
2.0  INTRODUCTION  
Mycobacterium avium-complex (MAC) organisms are ubiquitous environmental 
contaminants that may cause disseminated disease in patients with Acquired 
Immunodeficiency Syndrome (AIDS). Disseminated disease due to MAC occurs in up 
to 40% of patients with AIDS who have large numbers of mycobacteria in their 
tissues or blood.  However, the attack rate is probably higher, as 42 to 79 
cases (535) showed evidence of disseminated MAC.  
MAC is the most common disseminated bacterial infection in patients with AIDS 
and the prevalence reportedly increases with duration of HIV infection.  This 
infection usually presents with progressive weight loss, intermittent fevers, 
chills, night sweats and diarrhea.  It is associated with, and is a major 
cause of, the "wasting syndrome" in patients with AIDS to which they commonly  
succumb, if they have not developed Pneumocystis carinii pneumonia. In those 
patients who were successfully treated with antimycobacterial agents, culture 
conversion to negative was associated with defervescence, weight gain, 
cessation of sweats and a dramatic decrease in fatigue.  
Rifabutin is a spiro-piperidyl-rifamycin derived from rifamycin-S. The 
chemical name is 4-deoxo-3, 4 - [2-spiro - (N-isobutyl - 4-piperidyl) - 2,5-
dihydro - 1H - imidazo] - rifamycin - S.  It has a broad spectrum of 
antibacterial activity against gram-positive and gram-negative organisms 
including mycobacteria.  In vitro activity has been demonstrated against 
Mycobacterium avium intracellular and the data indicated that approximately 
90% of the strains were susceptible to concentrations of <= 1.0 ug/ml. The 
primary mechanism of action of rifabutin is through inhibition of  DNA-
dependent RNA-polymerase.  In animals, rifabutin is well tolerated and has no 
immunodepressant activity in humoral immunity tests.  
A summary of the preclinical pharmacology, toxicology, and pharmacokinetic 
data is provided in the rifabutin Investigator's Brochure.  
Rifabutin was provided by the Centers for Disease Control for the treatment of 
patients with life threatening mycobacterial infections between February, 1983 
and January, 1988.  This investigational drug has been made available for the 
treatment of approximately 3,000 patients, the majority of whom had AIDS and  
disseminated MAC disease.  
Daily rifabutin doses of 150, 300 and 450 mg were generally well tolerated. 
Rates of suspected adverse experiences requiring discontinuation have been 
similar to those seen for rifampin in the treatment of tuberculosis.  The 
types of adverse experiences have also been similar to those reported for 
rifampin. These included decreases in peripheral blood leukocyte count and 
increases in AST, BUN and serum creatinine.  The most common signs and 
symptoms listed as adverse experiences are gastrointestinal distress which 
include nausea, vomiting and diarrhea, and hypersensitivity reactions reported 
as rash, fever and "allergy".  
More than 1,100 patients have been entered in two double-blind, placebo 
controlled, multicenter trials for the prevention of MAC in AIDS patients. 
Also, approximately 300 patients have been treated in two double-blind, 
controlled trials for the treatment of MAC in AIDS patients.  
3.0   RATIONALE  
Results of a double-blind, randomized, placebo-control trial indicated that 
rifabutin may delay or prevent MAC bacteremia in patients with AIDS and CD4 
counts <= 200 when administered at a dose of 300 mg/day.  A second, identical, 
randomized, double-blind, placebo-controlled study remains active and as yet 
is incomplete.  
4.0  OBJECTIVES  
The primary objective of this trial is to provide rifabutin to HIV positive 
patients to attempt to prevent or delay MAC infection by a daily dose of 
rifabutin.  The secondary objective is to further characterize the safety of 
rifabutin monotherapy in preventing or delaying MAC bacteremia in HIV positive 
patients with CD4 counts <= 200.  
5.0  STUDY DESIGN  
This is an open-label, non-blinded multicenter trial in which HIV positive 
patients with CD4 cell counts <= 200 will receive rifabutin at a dose of 300 
mg/day.  
Patients who develop MAC while on this therapy will be removed from the study 
and treated at the discretion of their physician.   
STUDY POPULATION  
Patients  
HIV positive patients with CD4 counts <= 200 may receive rifabutin for the 
prevention of MAC, if they satisfy the study entry criteria and adequate drug 
supplies are available. Physicians may request an enrollment package by 
calling 1-800-552-7228.  
ELIGIBILITY CRITERIA  
Inclusion Criteria  
Patients must meet all of the following criteria.  
Age, 12 years or older.  
Positive serology test for HIV by Elisa confirmed by another Method (e.g., 
Western Blot).  
Pregnant females may be included, but nursing mothers must be excluded. 
NOTICE: There are no studies of the safety or efficacy of rifabutin in 
pregnant women. Rifabutin should be used during pregnancy only if the 
potential benefit justifies the potential risk to the fetus. Please refer to 
the investigator's brochure (Section 6.7) for a discussion of the effects of 
rifabutin in pregnant animals. In addition, a risk/benefit decision should 
consider the likelihood of a woman's developing MAC if she does not receive 
prophylaxis. The risk of developing MAC rises substantially for women with CD4 
counts less that 100, although it can also develop in women with higher CD4 
counts.  
Women who are not pregnant but are of child-bearing potential must utilize 
contraception. They are encouraged to use means other than oral 
contraceptives. Although the interaction of rifabutin with oral contraceptives 
is unknown, it has been reported that the reliability of oral contraceptives  
may be affected by rifampin.  
Patients must have a CD4 count of <= 200 and have a diagnosis of AIDS as 
defined by the Centers for Disease Control Case Definition for Acquired 
Immunodeficiency Syndrome.  
Serum liver function tests as follows: SGOT/AST < five times the upper limit 
of normal and alkaline phosphatase < three times the upper limit of normal.  
Serum creatinine <= 2.0 mg percent.  
Hematologic tests as follows: Absolute neutrophil count >= 1,000/mm(3), 
hemoglobin >= 9.5 gm/dl, hematocrit >= 29 percent, platelet count >= 
75,000/mm(3).  
No evidence of disseminated MAC disease as evaluated by a blood culture, taken 
within 21 days pretreatment. Since the pretreatmnent culture results will be 
pending, patients may be entered in the study based on presumptive negative 
clinical evaluation. Written informed consent obtained. Patients between 12 
and less than 18 years of age require informed consent from a parent or legal  
guardian.  
Exclusion Criteria  
One or more of the following will exclude a patient from study enrollment:  
Eligibility for any ongoing rifabutin controlled study.  
Known hypersensitivity to rifabutin, rifampin, or other rifamycins. 
Previous (or current) infection due to MAC, or other mycobacterial disease, or 
complaints consistent with tuberculosis.  
Administration of other investigational drugs with the exception of 
investigational drugs with expanded access programs.  
Nursing mothers.  
TREATMENT  
Study Drug/Packaging  
Rifabutin will be supplied by Adria as dark orange capsules each containing 
150 mg of active drug. The capsules will be packaged in labeled bottles 
containing 60 capsules and stored at room temperature.  
Administration of Rifabutin  
Rifabutin will be administered as a single dose of two 150 mg capsules with 
breakfast, or, if not tolerated, in two divided doses of 150 mg each with 
morning and evening meals.  
Patient Registration  
To register a patient the physician must call PACT at 1-800-552-7228 between 
8:00 a.m. and 5:00 p.m. Eastern Time, to determine if the patient is eligible 
to receive rifabutin. If the patient meets the entry criteria a study document 
package will be sent to the site. Upon return of the completed documents, 
rifabutin will then be sent to the physician for administration to the 
patient. 
  Other Concomitant Therapy  
Generally, concomitant therapy will not be restricted. The exception is any 
investigational drugs without expanded access programs. It is recommended that 
antimycobacterial therapy, e.g., ethambutol, clofazimine, amikacin, 
streptomycin, ciprofloxacin, clarithromycin, or azithromycin for a period 
greater than 15 days, be reserved for the management of MAC or other 
mycobacterial infection, should it develop. (Philadelphia Association of 
Clinical Trials (PACT). January 20, 1992. 800-552-7228). 

                            RIFABUTIN 
Pharmacology: MODE OF ACTION: Rifabutin acts in bacteria by inhibiting DNA-
dependent DNA-polymerase [Intl Conf on AIDS April 14-17, 1985 Atlanta, 
Georgia] Rifabutin shows good in vitro activity against most mycobacterial 
species, including Mycobacterium avium complex. It has a long half-life (16 
hours) in humans and marked tissue tropism, with tissue levels 5 to 10 fold  
higher than that in the serum. [Rev Infect Dis 1987 May-Jun;9(3)] Rifabutin 
has been tested for its effect on the replication of HTLV III/LAV CDC 451 
isolate grown in fresh human lymphocytes. It has shown inhibitory effect both 
on the infectivity and on the replication of the virus at nontoxic 
concentrations which appear to be clinically attainable inhuman. [Intl Conf on 
AIDS April  14017, 1985 Atlanta, Georgia] The pharmacokinetics of Rifabutin 
was  investigated in 15 male patients as part of a phase I trial of the 
treatment of early symptomatic human immunodeficiency virus infection. Six or 
more patients were studied at each of four different oral dosage levels: 300, 
600, 900, and 1,200 mg/day. Twelve studies were also conducted with tracer 
doses of intravenous radiolabeled (14C) Rifabutin. Blood and urine samples 
were  collected for at least 72 hours after the first (day 1) and last (day 
29) doses of Rifabutin and analyzed by high-pressure liquid chromatography 
(HPLC). The plasma concentration data were best described by a two-compartment 
open model with a terminal half-life of 36 hours. Rifabutin was rapidly 
absorbed, reaching a peak concentration about 2-3 hours after an oral dose. 
Peak and trough  concentrations for the 1,200 mg dose were 907 and 194 ng/ml, 
respectively. Total body clearance was 10-18 liter/h. Oral bioavailability was 
12-20 percent. The drug was moderately bound to plasma proteins with a free 
fraction of 29 +/- 2 percent (mean +/- standard deviation). About 10 percent 
of an administered intravenous dose of Rifabutin is excreted into urine 
unchanged. Renal clearance was 1.5 +/- 0.2 liters/h. The volume of 
distribution was large (8-9 liters/kg), suggesting extensive distribution into 
the tissues. The area under the curve for the last dose was smaller than that 
of the first dose, suggesting possible induction of drug-metabolizing enzymes. 
[Antimicrob Agents Chemother 1989 Aug;33(8)] 
Diseases Studied: Mycobacterium avium intracellulare infection (MAI) [FDA 
048A] 
Other Major Uses: Treatment for tuberculosis and myocbacterial infections 
resistant to Rifamycin [Rev Mal Respir 1988;5(4)] 
Substance Interactions: Rifabutin is known to act synergistically against 
strains of Mycobacterium avium complex isolated from AIDS patients when given  
with Ethambutol or Ciprofloxacin or Erythromycin. [Antimicrob Agents Chemother 
1988 Sep;32(9)] Ethambutol, when combined with Rifampin or Rifabutin produced 
an additive inhibitory effect against most of the tested M avium complex 
strains (12 of 16 with Rifampin, 13 of 16 with Rifabutin). The inhibitory 
effect was synergistic for the remaining 4 of 16 and 3 of 16 strains. This  
relationship reduced the minimal inhibitory concentrations for each drug in 
combination. In addition, the minimal bactericidal concentrations of all 3 
drugs were reduced because of synergistic bactericidal activity in 6 of 6 
strains tested. [Am Rev Respir Dis 1988;173(3)] 
Adverse Effects: A large experience from the compassionate use of rifabutin 
for life-threatening mycobacterial infections in humans, most commonly 
disseminated Mycobacterium avium complex disease (MAI) in patients with AIDS, 
had indicated relative drug safety. [Rev Infect Dis 1987 May-Jun;9(3)] 
Chemical/Physical Data: DESCRIPTION: Rifabutin is a semisynthetic 
spiropiperidyl derivative of Rifamycin S [Rev Infect Dis 1987 May-
Jun;9(3):519-30] ; MOLECULAR WEIGHT: 847.02 [USAN 1990] ; MOLECULAR FORMULA: 
C46H62N4O11 [CHEMLINE 1990] 
Substance Delivery Date: MODE OF DELIVERY: Oral. [FDA 048A] 
REFERENCES: Perronne C, Gikas A, Truffot-Pernot C, Grosset J, Pocidalo JJ,  
Vilde JL. Activities of clarithromycin, sulfisoxazole, and rifabutin against 
Mycobacterium avium complex multiplication within human macrophages. 
Antimicrob Agents Chemother 1990 Aug;34(8): 1508-11  
Wells KH, Poiesz BJ. Biology of retroviruses: detection, molecular biology, 
and treatment of retroviral infection. J Am Acad Dermatol 1990 Jun;22(6 Pt 
2):1175-95 
Siegal FP, Eilbott D, Burger H, Gehan K, Davidson B, Kaell AT, Weiser B. Dose-
limiting toxicity of rifabutin in AIDS-related complex: syndrome of 
arthralgia/arthritis. AIDS 1990 May;4(5):433-41 
Hoy J, Mijch A, Sandland M, Grayson L, Lucas R, Dwyer B. Quadruple-drug 
therapy for Mycobacterium avium-intracellulare bacteremia in AIDS patients. J 
Infect Dis 1990 Apr;161(4):801-5 
Weiser B, Burger H, Eilbott DJ, Gehan K, Flaherty K, Gulla J, Neff S, Davidson 
B, Anand R, Siegal FP. Efficacy of rifabutin in the treatment of AIDS-related 
complex. AIDS 1989 Dec;3(12):823-7 ;  Skinner MH, Hsieh M, Torseth J, Pauloin 
D, Bhatia G, Harkonen S, Merigan TC, Blaschke TF. Pharmacokinetics of 
rifabutin. Antimicrob Agents Chemother 1989 Aug;33(8):1237-41 
Agins BD, Berman DS, Spicehandler D, el-Sadr W, Simberkoff MS, Rahal JJ. 
Effect of combined therapy with ansamycin, clofazimine, ethambutol, and 
isoniazid for Mycobacterium avium infection in patients with AIDS. J Infect 
Dis 1989 Apr;159(4):784-7 
(Rifabutine in the treatment of mycobacterial infections resistant to 
rifampicin. Preliminary results. Group for the Study and Treatment of 
Resistant Mycobacterial Infections (GETIM)). Rev Mal Respir 1989;6(4):335-42 
Torseth J, Bhatia G, Harkonen S, Child  C, Skinner M, Robinson WS, Blaschke 
TF, Merigan TC. Evaluation of the antiviral effect of rifabutin in AIDS-
related complex. J Infect Dis 1989;159(6):1115-8 
Anand R, Moore JL, Curran JW, Srinivasan A. Interaction between rifabutin and 
human immunodeficiency virus type 1: inhibition of replication, cytopathic 
effect, and reverse transcriptase in vitro. Antimicrob Agents Chemother 1988 
May;32(5):684-8. 
Editor's Note:  For more information about clinical trials being conducted 
with rifabutin, contact the AIDS Clinical Trials Information Service (800) 
874-2572 or library service in your medical center. 
                      ADDITIONAL REFERENCES 
O'Brien RJ.  Geiter LJ.  Lyle MA. Rifabutin (ansamycin LM427) for the 
treatment of pulmonary Mycobacterium avium complex. American Review of 
Respiratory Disease. 141(4 Pt 1):821-6, 1990 Apr. 
Saito H.  Sato K. Activity of rifabutin alone and in combination with 
clofazimine, kanamycin and ethambutol against Mycobacterium intracellulare 
infections in mice. Tubercle. 70(3):201-5, 1989 Sep. 
Tomioka H.  Sato K.  Saito H.  Yamada Y. Susceptibility of Mycobacterium avium 
and Mycobacterium intracellulare to various antibacterial drugs. Microbiology 
& Immunology. 33(6):509-14, 1989. 
Yajko DM.  Nassos PS.  Sanders CA.  Hadley WK. Killing by antimycobacterial 
agents of AIDS-derived strains of Mycobacterium avium complex inside cells of 
the mouse macrophage cell line J774. American Review of Respiratory Disease. 
140(5):1198-203, 1989 Nov. 
Yajko DM.  Kirihara J.  Sanders C.  Nassos P.  Hadley WK. Antimicrobial 
synergism against Mycobacterium avium complex strains isolated from patients 
with acquired immune deficiency syndrome. Antimicrobial Agents & Chemotherapy. 
32(9):1392-5, 1988 Sep.  
Saito H.  Sato K.  Tomioka H. Comparative in vitro and in vivo activity of 
rifabutin and rifampicin against Mycobacterium avium complex. Tubercle. 
[JC:wh9]  69(3):187-92, 1988 Sep.  

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