Download Use of Rifabutin in the Treatment of Pulmonary Tuberculosis

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Use of Rifabutin in the Treatment of Pulmonary Tuberculosis
Carlo Grassi and Vittoria Peona
From the Respiratory Diseases Clinic, Pavia, Italy
This article reviews recent studies conducted outside the United States assessing the efficacy and
safety of rifabutin in the treatment of tuberculosis (TB) in HIV-infected patients, in patients with
newly diagnosed TB, and in patients with multidrug-resistant TB. A 6-month pilot study of 50
Ugandan patients with TB associated with HIV infection showed that rifabutin and rifampin were
similarly effective with regard to conversion of sputum-smear findings (sputum conversion) and in
bringing about clinical and radiologic improvement. Compared with rifampin, rifabutin showed
potential for reducing the time to sputum conversion for these patients. Multicenter studies in five
countries compared two rifabutin dosages (150 mg/d and 300 mg/d) with rifampin as part of a
combination regimen for treatment of newly diagnosed TB in 935 patients. Rifabutin compared
favorably with rifampin in sputum conversion; administration of 150 mg/d of rifabutin yielded good
results and the fewest adverse effects. The use of rifabutin by 270 patients in five countries who
had multidrug-resistant TB (...... 90% of isolates tested were resistant to rifampin and isoniazid) was
assessed in another study. For the majority of these patients, signs and symptoms diminished; onethird had bacteriologic conversions.
Major factors contributing to the resurgence of tuberculosis
(TB) include the growing rate of HIV infection, poor housing,
overcrowding, and migration [1]. Of these factors, HIV infection is the most potent risk factor for the development of active TB.
Because HIV destroys CD4 T lymphocytes and macrophages, cells that play a central role in antimycobacterial defenses, people with HIV infection are more vulnerable than
the general population to reactivation of latent Mycobacterium
tuberculosis infection [2]; clinical disease follows quickly after
infection. This problem is especially prevalent in developing
countries. Since the late 1980s, the annual number of patients
with both TB and HIV infection has nearly tripled in Zambia
and more than doubled in Malawi and Uganda [3].
Diagnosis of TB in patients with HIV infection may be
delayed because of atypical presentation or poor management.
Such delays in treatment may lead to an increased period of
infectivity and transmission to other susceptible persons [4].
Drug resistance may also play a role. Patients who have been
treated with a first-line agent that proves to be ineffective only
after several weeks have elapsed [5] may have infected other
susceptible individuals during that period.
Managing the TB epidemic depends not only on preventing
reactivation of latent infection but also on preventing primary
transmission of TB [6]. The aims of treatment of active disease
are to eliminate M tuberculosis from sputum cultures in the
shortest time, to prevent the emergence of drug resistance, and
to prevent relapse.
The dramatic increase in single drug-resistant and multidrug-resistant strains of M. tuberculosis has raised concern
throughout the medical community. From January to March
1991, 10% of all culture-positive cases of TB in the United
States were found to be resistant to isoniazid and/or rifampin
[7]. The overall rate of resistance of M. tuberculosis to one or
more drugs was found to be 14.2% [7]. Noncompliance is
probably the major factor associated with the increased incidence of drug-resistant strains: nearly 95% oftreatment failures
are due to this cause [8].
Standard treatment regimens for drug-susceptible TB, such
as administration of isoniazid/rifampin/pyrazinamide for 2
months and then isoniazid/rifampin for 4 months, yield cure
rates of >95% [9]. Even for isoniazid-resistant organisms, cure
rates of >90% are achievable by addition of ethambutol or
streptomycin to the regimen [9-11]. However, resistance to
both isoniazid and rifampin markedly reduces the efficacy of
treatment and is associated with failure rates of 40%-70%
[10-12].
Rifabutin is active against a variety of mycobacteria, including M. tuberculosis and atypical strains such as Mycobacterium
intracellulare and Mycobacterium avium [13, 14]. It has greater
activity than rifampin against M. tuberculosis and, more important, is active against . . . . 35% of strains that are resistant to
rifampin [15, 16].
Comparison of Rifabutin and Rifampin in the Treatment
of TB in HIV-Infected Patients
Study Design
Reprints or correspondence: Professor Carlo Grassi, Respiratory Diseases
Clinic, via Taramelli 5, 27100 Pavia, Italy.
Clinical Infectious Diseases 1996;22(Suppll):S50-4
© 1996 by The University of Chicago. All rights reserved.
1058-4838/96/2201-0052$02.00
The first direct comparison of rifabutin and rifampin in the
treatment of HIV-I-associated TB was conducted by
Schwander et al. [17], who studied 50 Ugandan patients with
HIV-1 infection and culture-positive pulmonary TB. The pilot
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Treatment of Pulmonary TB with Rifabutin
study was designed to evaluate the feasibility of a larger, phase
III trial using a four-drug regimen with rifabutin instead of
rifampin.
A 2-month initiation phase of treatment consisted of the
administration of isoniazid (300 mg/d), ethambutol (800 or
1,200 mg/d), pyrazinamide (1,500 or 2,000 mg/d), and either
rifampin (450 or 600 mg/d) or rifabutin (150 or 300 mg/d).
The lower dosages were used for patients with body weights
of <50 kg. After the initial phase, ethambutol and pyrazinamide were withdrawn, and patients received daily treatment
with isoniazid and either rifampin or rifabutin for an additional
4 months.
To improve compliance, patients received their medication
at the Joint Clinical Research Centre in Kampala twice weekly
during the initiation phase and once weekly during the continuation phase.
Results
Forty-one patients (82%) completed the 6-month treatment
course, and their conditions improved. Six patients, 4 treated
with the rifabutin regimen and 2 with the rifampin regimen,
died during the study period (5 died of nonmycobacterial HIVassociated complications and 1 of a multidrug-resistant M. fortuitum infection). Three patients were withdrawn because of
protocol violations.
Clinical improvement was assessed by the decrease in mean
body temperature and mean respiration rate, the decrease in
frequency of productive cough and night sweats, and the increase in Kamofsky performance score and body weight. None
ofthese parameters differed significantly between the treatment
regimens.
Radiologically evident improvement was seen in 95% of
patients receiving the rifabutin regimen and in 100% of patients
receiving the rifampin regimen.
Microbiological efficacy was assessed by measuring the time
from the first day of therapy to (1) the first of three consecutive
negative sputum smears and cultures or (2) a negative sputum
smear followed by consistent absence of sputum production.
Sputum conversion (i.e., conversion of sputum smear findings
to negative) occurred in 42 patients, 21 in each treatment group.
However, patients receiving the rifabutin regimen had a significantly lower number of positive smears during the first 8
weeks of treatment than did patients receiving the rifampin
regimen (P < .05, log rank test). The number of patients was
too small to show a statistically significant difference between
the two groups in terms of the mean time to sputum conversion.
More than half of the patients in each treatment group reported mild, moderate, or (rarely) severe episodes of arthralgia
up to week 8. Other, less frequently reported symptoms were
myalgia, nausea, vomiting, gastrointestinal discomfort, and loss
of appetite. After week 8, the frequency and grade of these
symptoms decreased when the amount of study medication
was decreased. No major differences in frequency or grade of
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severity of any of the reported side effects were observed between the two groups.
Conclusions
In this pilot study of patients with TB and HIV infection,
both rifampin and rifabutin regimens were effective in inducing
clinical and radiological improvement. Both regimens were
well tolerated. However, the sputum of patients treated with
the rifabutin regimen was significantly more rapidly cleared of
acid-fast bacilli than was that of patients treated with the rifampin regimen. A larger study is warranted to confirm this observation. An earlier sputum conversion time may have important
implications for shortening the infectious period of pulmonary
TB and reducing further spread of M. tuberculosis.
Treatment of Newly Diagnosed Pulmonary TB in HIVNegative Patients
Study Design
To assess the efficacy and safety of rifabutin in the treatment
of newly diagnosed TB, five multicenter, randomized, open,
controlled studies were conducted. An identical protocol was
used in studies originating in Argentina, Brazil, and Thailand.
Data from these studies were combined for analysis [18]. Two
additional protocols were used in studies conducted in South
Africa and Spain [19, 20].
Patients with previously untreated TB were eligible for the
studies in all five countries. They were required to have two
sputum cultures positive for M. tuberculosis plus clinical signs
and symptoms and radiological evidence of disease. Patients
included in these studies were HIV-negative. A total of 520
patients were enrolled in the three studies with the identical
protocol. In the Spanish and South African studies, 415 patients
were enrolled. There were no significant differences between
the treatment groups regarding demographics and baseline
findings.
In the three combined studies, patients were randomly assigned to an 8-week multidrug regimen of rifabutin (150
mg/d or 300 mg/d) or rifampin (600 mg/d) plus isoniazid (300
mg/d), ethambutol (25 mg/[kg' dD, and pyrazinamide (30
mg/[kg' dD. Treatment with the same dosages ofrifampin or
rifabutin plus isoniazid was then continued for an additional
16 weeks.
In the South African study, patients received either rifabutin
(300 mg/d) or rifampin (600 mg/d) plus isoniazid (400 mg/d),
ethambutol (1,200 mg/d), and pyrazinamide (2,000 mg/d) for
8 weeks, followed by 16 weeks of triple-drug therapy (administered twice weekly) with rifabutin (300 mg/d) or rifampin (600
mg/d) plus isoniazid (600 mg/d) and ethambutol (2,400
mg/d).
Patients in the Spanish study received daily doses of either
rifabutin (300 mg/d) or rifampin (600 mg/d) plus isoniazid
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Grassi and Peona
Table 1. Rifabutin vs. rifampin in the treatment of newly diagnosed
tuberculosis: rates of success (bacteriologic conversion noted at last
valid observation), per data combined from several studies [18].
Success rate (percent of patients)
Rifabutin
Study site
Rifampin
600 mgld
Argentina
Brazil
Thailand
All sites
87
82
97
89
150 mgld
300 mgld
100
94
92
89
92
81
99
94
(300 mg/d) for 36 weeks; ethambutol (25 mg/[kg . d]) was
added to the regimen during the first 8 weeks of treatment.
Efficacy
The criteria used to assess efficacy were the same for all
five studies. Sputum samples were collected prior to initiation
of drug therapy, fortnightly for the first 2 months of therapy,
and then at weeks 12, 16, and 24 (and 36 in the Spanish
study). Therapeutic efficacy was evaluated by assessment of
bacteriologic conversion of sputum cultures from positive to
negative. Conversion was considered to have occurred if two
successive sputum cultures were negative at the end of the
treatment or at the last valid observation (the last visit at which
the patient had a recorded value on the case record form while
receiving treatment; patients with missing data on cultures or
who had withdrawn from the study for any reason were considered treatment failures). If conversion occurred by week 12, it
was not necessary to have two successive negative cultures for
conversion to be considered valid.
Clinical efficacy was assessed by the monitoring of the occurrence of fever, dyspnea, cough, and anorexia and by performance of clinical laboratory tests and regular chest roentgenography.
In the combined studies, patients who were successfully
treated were followed up by means of cultures performed every
6 months for up to 2 years after therapy was completed. If two
successive cultures were positive during this follow-up period,
after culture negativity had been achieved during treatment,
then the patient was considered to have had a relapse.
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1996; 22 (Suppl 1)
also comparable among the treatment groups: 34 days for rifampin and 37 days for each of the rifabutin groups.
Follow-up data for patients in the combined studies show a
low relapse rate. A total of 5 patients (1 %) relapsed, of whom
2 were in the 300-mg rifabutin group, 1 was in the rifampin
group, and 2 were in the 150-mg rifabutin group.
Symptoms of fever, cough, and anorexia, which had been
reported by more than half of the patients at the time of enrollment, diminished dramatically during treatment in all three
groups. At the end of treatment, .improvement was evident on
the chest roentgenograms of 97%-100% of all patients.
In the South African and Spanish studies, the rate ofbacteriologic conversion among patients treated with rifabutin was similar to that among those treated with rifampin. In the Spanish
study, 80% of patients in the rifampin group and 87% of patients treated with rifabutin had negative cultures at week 36.
In the South African study, treatment with rifampin resulted
in a 90% success rate at the last valid observation, vs. a 95%
success rate for treatment with rifabutin (data on file, Pharmacia, Milan, Italy).
Adverse Events
In the three combined studies, adverse events were reported
by 9% of patients receiving rifampin vs. 8% of patients receiving 150-mg doses of rifabutin and 17% of patients receiving
300-mg doses of rifabutin. Gastrointestinal symptoms were the
most common adverse effect in all three treatment groups. The
150-mg dose of rifabutin was associated with fewer musculoskeletal, hematologic, and lymphatic abnormalities and fewer
gastrointestinal complaints than were the 300-mg dose of rifabutin and rifampin.
Discontinuation of treatment due to an adverse event occurred for no patients in the 150-mg rifabutin group, one patient
in the rifampin group, and five in the 300-mg rifabutin group.
Of the adverse events reported, 26% in the rifampin group, 4%
in the 150-mg rifabutin group, and 8% in the 300-mg rifabutin
group were considered severe.
Three of 5 deaths that occurred were considered drug-related:
2 in the 300-mg rifabutin group (thrombocytopenia and cerebral
hemorrhage occurred in 1 patient and severe vomiting in the
other) and 1 in the rifampin group (severe gastrointestinal disease, purpura, and erythematous rash occurred).
Conclusions
Results
A total of 513 patients in the combined studies had positive
cultures at baseline and were included in the intent-to-treat
analysis. The rate at which bacteriologic conversion was noted
at each patient's last valid observation was 94% in the group
receiving 150-mg doses ofrifabutin, 92% in the group receiving
300-mg doses of rifabutin, and 89% in the group receiving
rifampin (table 1). The median time to culture conversion was
The results of these studies show that a 150-mg dose of
rifabutin, a 300-mg dose of rifabutin, and rifampin are all
effective in clearing sputum of M. tuberculosis. Rifabutin compared favorably with rifampin in terms of bacteriologic conversion and clinical improvement. Good results were achieved
with 150 mg of rifabutin, and this lower dosage was associated
with fewer adverse effects than the number occurring with
rifampin or 300 mg of rifabutin. The results suggest that rifa-
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1996;22 (Suppl 1)
Treatment of Pulmonary TB with Rifabutin
butin is well tolerated and is an effective alternative to rifampin
in multidrug regimens for the treatment of newly diagnosed
pulmonary TB.
Treatment of Chronic Multidrug-Resistant
Pulmonary TB
50
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E
CD
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c.
CD
The conditions of patients with chronic multidrug-resistant
pulmonary TB often fail to respond to anti-TB therapy with
rifampin and isoniazid, which are generally used in combination with other drugs. The safety and efficacy of rifabutin as
an alternative to rifampin in this patient population were assessed in five uncontrolled, open studies in centers in Algeria,
Argentina, France, South Africa, and Spain [21].
A total of 270 patients with confirmed pulmonary TB who
had failed to respond to previous standard therapy were enrolled. Nearly 60% of these patients were considered to have
severe advanced disease at baseline. Approximately 80% of
patients had previously completed a 12-week course of antiTB therapy; 70% had completed at least 6 months of treatment.
Patients were allocated to receive treatment with a 6- to 12month multidrug regimen including rifabutin (300 mg/d or 450
mg/d). The lower dosage was used if a patient weighed <50
kg. Nine patients in the French study weighing> 50 kg received
600 mg/d. Concomitant antimycobacterial medication was selected according to the results of in vitro susceptibility testing
of sputum isolates. Fifty-eight percent of patients received kanamycin; 50%, ethambutol; 48%, pyrazinamide; and 24.5%,
isoniazid.
Efficacy
Efficacy was assessed by the monitoring of conversion of
sputum cultures from positive to negative during the treatment
period. Conversion was considered to have occurred if two
successive cultures were negative at the end of treatment or at
the last valid observation (defined as the time when data were
last recorded for each patient, regardless of the length of treatment). If conversion occurred at week 12, only one negative
culture was considered necessary.
Clinical improvement was assessed by the reduction of signs
and symptoms ofTB (i.e., cough, dyspnea, and anorexia) from
the baseline evaluation to the last valid observation. If a patient
had been observed at baseline only, this was considered the
last valid observation.
Drug Resistance
Different methods of assessing the drug susceptibility of M.
tuberculosis isolates were used in the various studies; thus,
different breakpoints were adopted for the definition of susceptibility and resistance. For this reason, comparison of suscepti-
40
30
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Q)
Study Design
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c:
E
:::J
20
'5
enc.
10
o
Argentina
(n=68)
Spain
(n=33)
Algeria
(n=46)
France
(n=35)
S. Africa Combined
(n=38)
(n=220)
Figure 1. Rifabutin in the treatment of multidrug-resistant tuberculosis: rates of bacteriologic conversion of sputum, as noted at the last
valid observation (intent-to-treat analysis).
bility data across studies cannot be regarded as accurate. Overall, 90% of strains tested were resistant to rifampin and
isoniazid, 75% were resistant to streptomycin, and 50% were
resistant to ethambutol.
Results
The percentage of patients for whom bacteriologic conversion was noted at the last valid observation (intent:.:to-treat
analysis) is presented in figure 1. Overall, at the last valid
observation, bacteriologic conversion had occurred for 34% of
all patients analyzed. The results appeared to be independent
of the concomitant medication administered.
Adverse Events
Eleven patients (4% of all patients treated) were prematurely
withdrawn from study because of an adverse event. Adverse
events that resulted in early discontinuation of therapy were
related primarily to the gastrointestinal system. Although a
number of patients' hematologic and biochemical values
changed during the study, none showed evidence of severe
hepatic, renal, or hematologic toxicity. Eighteen patients died
of TB during the study.
Conclusions
In these five studies, rifabutin proved beneficial for patients
with chronic drug-resistant pulmonary TB that had been unresponsive to previous therapies, including those with rifampin.
In the majority of patients, the signs and symptoms of disease
diminished during treatment; in one-third ofthe patients, mycobacteria were cleared from the sputum. The drug regimens used
in these studies were well tolerated, and the incidence of ad-
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Grassi and Peona
verse events was low. Few patients discontinued treatment as
a result of adverse effects oftherapy. Rifabutin, as a component
of combination drug therapy, is associated with a positive
risk:benefit ratio in the treatment ofpatients with chronic multidrug-resistant pulmonary TB.
Summary
The results of these studies, which explored the safety and
efficacy of the use of rifabutin in the treatment of patients with
TB and HIV, with newly diagnosed TB, and with multidrugresistant TB, suggest that rifabutin can play a role in therapy
for TB.
It is acknowledged, however, that many ofthe data contained
in this review have (to date) been published only in abstract
form and, as such, can best be described as preliminary. Nevertheless, some interesting findings have emerged from these
studies.
Although the pilot study of HIV-infected patients with TB
was too small to show a statistically significant difference between rifabutin and rifampin with regard to the mean time to
sputum conversion, the results for rifabutin were promising.
Rifabutin was associated with a lower number of positive
smears in the first 8 weeks of treatment; this finding, if confirmed by a large-scale clinical trial, could have important implications for shortening the infectious period of TB. This
would greatly reduce the transmission of this disease among
high-risk patients.
In the treatment of newly diagnosed TB in HIV-negative
patients, rifabutin was shown to be as effective as rifampin in
combination regimens. Particularly at a lower dosage of 150
mg/d, rifabutin showed good efficacy and had a favorable tolerability profile.
Predictably, higher doses of rifabutin were more effective
in patients with chronic multidrug-resistant TB. Rifabutin
clearly has considerable potential for use in the treatment of
multidrug-resistant TB, particularly when susceptibility to rifabutin and resistance to rifampin and other drugs have been
demonstrated.
The results of these studies await confirmation in larger,
well-controlled, comparative trials. Furthermore, in view of the
importance of compliance in preventing the development of
resistance, future studies should address this issue specifically.
Although several aspects of optimizing rifabutin therapy remain to be resolved, evidence to date clearly indicates that
rifabutin is an effective alternative to rifampin in the treatment
ofTB.
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