Download Compassionate Use of Bedaquiline for the Treatment

MAJOR ARTICLE
Compassionate Use of Bedaquiline for the
Treatment of Multidrug-Resistant and
Extensively Drug-Resistant Tuberculosis: Interim
Analysis of a French Cohort
Lorenzo Guglielmetti,1,2 Damien Le Dû,3,4 Mathilde Jachym,3 Benoît Henry,5 Diane Martin,1,2 Eric Caumes,5
Nicolas Veziris,1,2,6 Nathalie Métivier,3,a and Jérôme Robert1,2,6,a; for the MDR-TB Management Group of the French
National Reference Center for Mycobacteria and the Physicians of the French MDR-TB Cohortb
1
Background. Bedaquiline is a new antibiotic that was approved for the treatment of multidrug-resistant
(MDR) tuberculosis. We aimed to evaluate the short-term microbiological efficacy and the tolerability profile of
bedaquiline.
Methods. We performed a retrospective cohort study among patients with MDR tuberculosis receiving bedaquiline
for compassionate use between January 2010 and July 2013 and evaluated at 6 months of bedaquiline treatment.
Results. A total of 35 patients with MDR tuberculosis were included in the study. Nineteen (54%) had extensively
drug-resistant (XDR) tuberculosis, and 14 (40%) had isolates resistant to fluoroquinolones (Fqs) or second-line injectables. Bedaquiline was associated with a median of 4 (range, 2–5) other drugs, including linezolid in 33 (94%) cases. At 6
months of bedaquiline treatment, culture conversion was achieved in 28 of 29 (97%) cases with culture-positive pulmonary tuberculosis at bedaquiline initiation. Median time to culture conversion was 85 days (range, 8–235 days). Variables
independently associated with culture conversion were treatment with a Fq (P = .01), absence of lung cavities (P < .001),
and absence of hepatitis C virus infection (P = .001). A total of 7 patients (20%) experienced a ≥60-ms increase in QT
interval, leading to bedaquiline discontinuation in 2 (6%) cases. Severe liver enzyme elevation occurred in 2 patients
(6%). During the study period, 1 death (3%) occurred and was reported as unrelated to tuberculosis or antituberculosis
treatment.
Conclusions. The use of bedaquiline combined with other active drugs has the potential to achieve high culture conversion rates in complicated MDR and XDR tuberculosis cases, with a reassuring safety profile at 6 months of treatment.
Keywords. TMC207; bedaquiline; safety; multidrug-resistant tuberculosis; extensively drug-resistant tuberculosis.
Received 20 May 2014; accepted 27 September 2014; electronically published 15
October 2014.
a
N. M. and J. R. contributed equally to this work.
b
Members of the MDR-TB Management Group of the French National Reference
Center for Mycobacteria and the Physicians of the French MDR-TB Cohort are listed
in the Appendix.
Correspondence: Jérôme Robert, MD, PhD, Laboratoire de Bactériologie-Hygiène,
Faculté de Médecine Pierre et Marie Curie (UPMC Paris 6), 91 Boulevard de l’hôpital, 75634 Paris Cedex 13, France ( [email protected]).
Clinical Infectious Diseases® 2015;60(2):188–94
© The Author 2014. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/ciu786
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Despite recent achievements in reducing its global incidence, tuberculosis remains a major cause of death
worldwide. The efforts to grant effective tuberculosis
control have been impaired by the emergence of multidrug-resistant (MDR) strains and by the human immunodeficiency virus (HIV) epidemic. The World Health
Organization estimated that approximately 450 000
new MDR tuberculosis cases, defined as resistant to isoniazid and rifampicin, occurred in 2012 [1]. In addition,
extensively drug-resistant (XDR) tuberculosis, which is
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Sorbonne Universités, Université P. & M. Curie, Paris 06, CR7, 2Institut national de la santé et de la recherche médicale, U1135, Centre d’Immunologie
et des Maladies Infectieuses, Team E13 (Bactériologie), 3Sanatorium, Centre Hospitalier de Bligny, Briis-sous-Forges, 4Assistance publique—Hôpitaux de
Paris (AP-HP), CHU Raymond Poincaré, Garches, 5AP-HP, Service des Maladies Infectieuses et Tropicales, and 6AP-HP, Centre National de Référence des
Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux, Bactériologie-Hygiène, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix,
Paris, France
MATERIALS AND METHODS
The temporary authorization for use of Bdq was granted by the
French National Agency for the Safety of Medicine and Health
Products. The Bdq expanded-access use started in 2011. All MDR
tuberculosis patients managed at the sanatorium of Bligny
Hospital, in the Paris area, France, and treated by Bdq for at
least 1 month between January 2011 and July 2013 were included in the retrospective analysis. Considering that Bdq administration is currently recommended for a maximum of 6 months
[18], data for this interim analysis were collected for up to 6
months of Bdq treatment except for patients remaining culture
or smear positive, who were followed until culture and smear
conversion or until data censoring (February 2014).
Standard definitions were used for MDR and XDR tuberculosis. Bedaquiline was used as part of an individualized antituberculosis regimen, which was tailored to drug susceptibility
testing (DST) results by a group of multidisciplinary experts
(MDR Tuberculosis Management Group of the French National Reference Centre for Mycobacteria [NRC-MyRMA]), implemented after surveys on the MDR tuberculosis management
in France [19, 20]. All drugs were administered as directly
observed treatment during hospitalization. Bedaquiline was administered as recommended by the manufacturer: 400 mg once
daily for 2 weeks, followed by 200 mg thrice weekly. Patients
with pulmonary tuberculosis repeated smear and culture examinations every 2 weeks up to culture conversion, and monthly
thereafter. Safety and tolerability of treatment were monitored
through serial complete blood counts and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) measurements. An electrocardiogram was requested at baseline, and
after 2, 4, 8, 12, and 24 weeks of Bdq treatment. QT interval
was corrected for heart rate using Bazett formula (QTcB) [21]:
corrected QT interval = QT/(RR interval)1/2. A prolongation of
the QT interval was defined as ≥60 ms increase.
DST for first- and second-line drugs was conducted at
the NRC-MyRMA by the proportion method on LöwensteinJensen medium [22].
Sputum smear and culture conversion were defined as 2 consecutive negative exams at least 2 weeks apart, in a patient with a
positive specimen at baseline. Time to conversion was measured
from the beginning of Bdq treatment to the time of the first of
the 2 negative exams. Adverse events were considered as related
to Bdq if that was the opinion of the treating physician.
Data were retrospectively extracted from medical records.
Statistical analysis was performed using Stata software, version
11.1 (StataCorp). The χ2 test or Fisher exact test was used to
compare categorical variables. Continuous variables were compared by the 2-sample Wilcoxon–Mann–Whitney test. Kaplan–
Meier analysis was used to evaluate the time to smear and
culture conversion. A Cox proportional hazards model with robust estimation of confidence interval (CI) was used to assess
the association between time to culture conversion and explanatory variables. Variables associated with the time-to-event outcomes in univariate analysis (P < .20) were introduced into a
multivariate model following a forward stepwise strategy. The
test of the proportional hazards assumption and Cox-Snell
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defined as MDR tuberculosis with additional resistance to any
fluoroquinolone (Fq) and at least 1 second-line injectable (2LI)
antibiotic [2], has been estimated to account for almost 10% of
all MDR cases in 2012 [1].
Dealing with MDR and XDR tuberculosis cases requires burdensome, poorly tolerated treatment regimens, which can last up
to 24 months [3]. A large meta-analysis has shown an overall
success rate of 54% in MDR tuberculosis patients [4]. When
only subjects with available data on Fq and/or 2LI resistance
were included, pooled treatment success rates for MDR and
XDR tuberculosis cases were 64% and 40%, respectively [5].
In the last 12 months, 2 new molecules have been approved for
the treatment of MDR tuberculosis: bedaquiline (Bdq) by the US
Food and Drug Administration (FDA) and delamanid by the European Medicines Agency. Bedaquiline, developed as TMC207,
belongs to a new class of antituberculosis drugs, the diarylquinolines, which inhibit the mycobacterial adenosine triphosphate synthase [6]. Bedaquiline has shown in vitro activity against both
drug-sensitive and MDR Mycobacterium tuberculosis strains [7].
In the mouse model, Bdq was associated with an effective
sterilizing activity [8, 9]. The combination of Bdq and pyrazinamide has been shown to have bactericidal and sterilizing efficacy
[10–12].
A clinical trial (C208 study) comparing a second-line background regimen with or without 8 weeks of Bdq demonstrated a
higher proportion of culture conversion at 6 months (81.0% vs
62.5%) in the Bdq arm [13, 14]. In the second stage of the study
(C208-2), Bdq together with background regimen led to faster
culture conversion and higher rates of culture conversion at 6
months of treatment than in the background regimen plus placebo arm [15]. Efficacy results in the open-label C209 study
were consistent with those of the C208-2 trial [16]. Finally,
pooled data from all studies conducted in humans showed a
similar rate of mild-to-moderate adverse effects in Bdq and placebo-treated patients [16]. These promising results were counterbalanced by a worrying imbalance in the number of deaths
found between the 2 treatment arms in the C208-2 trial, with
10 vs 2 deaths occurring in Bdq-treated patients [15].
The objective of our study is to evaluate the microbiological
efficacy of Bdq-containing regimens, as well as the safety and
tolerability profile of Bdq in patients treated under compassionate use in a MDR tuberculosis cohort in France, where a marked
increase in the number of MDR tuberculosis cases has been observed since 2011 [17].
residuals were used to assess the model validity. Patients with
missing information were censored at the date of the last available microbiological result. P values < .05 were considered statistically significant.
All patients included were treated according to Good Clinical
Practice, and were informed about expected benefits and potential side effects of each drug including Bdq and its compassionate use, but were not asked to sign a consent form. Ethical
approval was obtained from the institutional review board of
the Bligny Hospital for the retrospective chart review.
RESULTS
sputum-smear positivity at hospital admission (Table 2). The
remaining patient had Pott disease.
A majority of patients (n = 24 [69%]) had a history of previous tuberculosis treatment, of whom 7 (20%) received only firstline drugs and 17 (49%) were treated with second-line drugs.
A total of 19 patients (54.3%) had XDR tuberculosis. Among
the 16 (45.7%) others, 10 (28.6%) had isolates resistant to at
least 1 Fq and 4 (11.4%) to at least 1 2LI. Two (5.7%) patients
had strains susceptible to Fq and 2LI, but had medical contraindications to their use. Isolates were resistant to a median number of 9 drugs (range, 5–12), including pyrazinamide (n = 25
[71.4%]), ethambutol (n = 28 [80%]), streptomycin (n = 32
[91.4%]), ofloxacin (n = 29 [82.9%]), moxifloxacin (n = 21
Patient Characteristics
Table 2. Clinical and Therapeutic Characteristics of the 35
Patients With Multidrug-Resistant or Extensively Drug-Resistant
Tuberculosis
Variable
No. (%) or Median
(IQR)
Categorical variables
Disease Status on Admission
All patients but 1 (n = 34 [97%]) had pulmonary tuberculosis,
including 5 (14%) with extrapulmonary involvement (2 genital
tuberculosis, 1 osteoarticular and intra-abdominal tuberculosis,
1 myocardial tuberculosis, and 1 laryngeal tuberculosis). Among
the 34 patients with pulmonary tuberculosis, 26 (77%) had bilateral lung involvement, and 29 (85%) at least 1 lung cavity and
Table 1. Demographic Characteristics of the 35 Patients With
Multidrug-Resistant or Extensively Drug-Resistant Tuberculosis
Disease localization
Pulmonary only
Pulmonary + extrapulmonary
29 (82.8)
5 (14.3)
Extrapulmonary only
Bilateral lung involvement (n = 34)
1 (2.9)
26 (76.5)
Cavities on chest radiography (n = 34)
29 (85.3)
Sputum-smear positive (n = 34)
Previous tuberculosis treatment on admission
29 (85.3)
None
11 (31.4)
First-line drugs only
Second-line drugs
7 (20)
17 (48.6)
Resistance pattern
Variables
No. (%) or Median (IQR)
Categorical variables
Sex, male
Place of birth
28 (80)
Eastern Europe
27 (77.1)
Africa
Asia
5 (14.3)
2 (5.7)
France
1 (2.9)
HIV coinfected
HCV coinfected
0
18 (51.4)
Alcohol abuse
7 (20)
Intravenous drug use
Presence of comorbidities
13 (37.4)
8 (23)
Continuous variables
Age at admission, y
Serum albumin, g/dL
39 (31–41)
32 (26.2–34.9)
Body mass index, kg/m2
19.4 (17.4–22)
Abbreviations: HCV, hepatitis C virus; HIV, human immunodeficiency virus;
IQR, interquartile range.
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MDR (FQ-S and 2LI-S)
MDR (FQ-R and 2LI-S)
MDR (FQ-S and 2LI-R)
XDR
Surgical treatment
2 (5.7)
10 (28.6)
4 (11.4)
19 (54.3)
9 (25.7)
Patients with culture conversion
At 3 mo (n = 29)
At 6 mo (n = 29)
21 (72.4)
28 (96.6)
Patients with smear conversion
At 3 mo (n = 29)
At 6 mo (n = 29)
14 (48.3)
20 (69)
Continuous variables
No. of molecules to which the isolate was
resistant on phenotypic DST
9 (7–10)
Time to culture conversion
85 (42–101)
Time to smear conversion
No. of active drugs associated with bedaquiline
92 (28–191)
4 (3–5)
Abbreviations: 2LI, second-line injectable drugs; DST, drug susceptibility
testing; FQ, fluoroquinolone; IQR, interquartile range; MDR, multidrugresistant; R, resistant; S, susceptible; XDR, extensively drug resistant.
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From 2010 to 2013, 35 patients with MDR tuberculosis received
Bdq for at least 1 month. The median age was 39 years (range,
18–70 years), and 28 (80%) were male (Table 1). Most of them
(n = 34 [97%]) were foreign-born. None were HIV-coinfected,
18 (51%) had hepatitis C virus (HCV) infection, and 8 (23%)
had at least 1 more comorbid condition, mainly diabetes (5 patients [14%]) and renal failure (2 patients [6%]).
[60%]), amikacin (n = 11 [31.4%]), capreomycin (n = 14 [40%]),
kanamycin (n = 21 [60%]), ethionamide (n = 28 [80%]), cycloserine (n = 21 [60%]), and para-aminosalicylic acid (PAS)
(n = 11 [31.4%]). None were resistant to linezolid.
Treatment
Efficacy
Of the 29 patients with culture-positive pulmonary tuberculosis
at Bdq initiation, 21 (72%) achieved culture conversion after 3
months and 28 (97%) after 6 months of Bdq. At 3 and 6 months
of Bdq treatment, sputum-smear conversion occurred in 14
(48%) and 20 (69%) of the 29 initially smear-positive patients.
Median time to culture and sputum-smear conversion was 85
Table 3. Univariate and Multivariate Cox Proportional Hazards
Models Assessing the Association of Factors With Time From
Bedaquiline Treatment Start to Culture Conversion
Univariate HR
(95% CI)
Variable
Figure 1. Kaplan–Meier analysis of time to smear and culture conversion
of patients with positive smear and culture exams at the beginning of treatment with bedaquiline (N = 29). Median time to conversion is shown for
both smear (solid vertical line) and culture (dashed vertical line). The vertical bar between 120 and 150 on the smear curve indicates censoring.
Multivariate
HR (95% CI)
Treatment with any
fluoroquinolone
2.59* (1.07–6.22) 3.28* (1.30–8.27)
HCV coinfected
Presence of lung cavities
0.24* (.10–.56)
0.08* (.02–.36)
0.21* (.08–.54)
0.04* (.01–.20)
Treatment with imipenem/
co-amoxiclav
Bilateral lung involvement
0.39* (.15–1.00)
0.32 (.09–1.08)
0.27* (.09–.80)
0.59 (.14–2.51)
Treatment with pyrazinamide
0.47 (.20–1.12)
0.87 (.39–1.94)
Treatment with ethambutol
Treatment with any secondline injectable drug
0.77 (.35–1.70)
0.68 (.28–1.65)
Treatment with ethionamide
1.29 (.54–3.08)
Treatment with cycloserine
Treatment with paraaminosalicylic acid
0.87 (.40–1.91)
1.21 (.45–3.22)
Age ≥40 y
1.21 (.56–2.61)
Body mass index <18.5 kg/m2 1.01 (.45–2.25)
Any surgical intervention
0.71 (.30–1.69)
Abbreviations: CI, confidence interval; HCV, hepatitis C virus; HR, hazard ratio.
* P < .05.
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Bedaquiline was included in the initial MDR tuberculosis treatment regimen for 26 (74.3%) patients, while 9 (25.7%) were
already treated for MDR tuberculosis for a median of 85 days
(range, 47–171) prior to Bdq initiation.
Patients who received Bdq received a median of 4 additional
antibiotics (range, 2–5), including linezolid (n = 33 [94.3%]),
PAS (n = 26 [74.3%]), amikacin (n = 25 [71.4%]), imipenem
combined with co-amoxiclav (amoxicillin/clavulanic acid; n = 23
[65.7%]), cycloserine (n = 19 [54.3%]), Fq (n = 16 [45.7%]), ethambutol (n = 11 [31.4%]), pyrazinamide (n = 10 [28.6%]), ethionamide (n = 8 [22.9%]), and clofazimine (n = 5 [14.3%]). Of
note, 31 (89%) received at least Fq or 2LI, including 15 XDR
patients and 16 non-XDR patients.
Nine (25.7%) patients had pulmonary surgery (5 lobectomies, 2 bilobectomies, and 2 pneumonectomies), which
occurred after a median of 111 days of Bdq treatment.
days (range, 8–235 days) and 103 days (range, 12–252 days),
respectively (Figure 1).
An Fq (ofloxacin or moxifloxacin)–containing regimen was
significantly associated with culture (P = .03) and sputumsmear conversion (P = .02) after 3 months of treatment and
with a shorter time to culture conversion (P = .02). No similar
association was found with 2LI-containing regimens, nor with
the number of drugs with documented susceptibility at DST
and number of active compounds administered in association
with Bdq.
At 6 months of Bdq treatment, all patients but 1 had culture
conversion; this patient was infected by a MDR tuberculosis
strain that was resistant to both ofloxacin and moxifloxacin,
but maintained susceptibility to all 2LIs. In this case, culture
conversion was successively achieved after 235 days of Bdq
treatment.
In a multivariable Cox proportional hazards model (Table 3),
presence of lung cavities and HCV infection were associated
with a slower time to culture conversion (hazard ratio [HR],
0.04 [95% CI, .01–.20], P < .001 and HR, 0.21 [95% CI,
.08–.54], P = .001, respectively), while treatment for ≥30 days
with any Fq was associated with a faster time to culture conversion (HR, 3.28 [95% CI, 1.30–8.27], P = .01). After introduction
in the above model, treatment with imipenem/co-amoxiclav
was associated with a slower time to culture conversion (Table 3)
but was at the limit of statistical significance (P = .06). The other
variables with P < .20 in univariate analysis (ie, treatment with
pyrazinamide and bilateral lung involvement), did not reach
statistical significance. The other factors were not tested in the
multivariate model because they did not reach the P level of <.20
in univariate analysis.
Safety and Tolerability
DISCUSSION
Following the recent “fast-track” approval of Bdq by the FDA, it
is crucial to increase the amount of clinical evidence on this
compound. The aim of this interim analysis at 6 months of
treatment was to assess data on Bdq efficacy and tolerability
in a cohort of patients treated for MDR and XDR tuberculosis.
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Mean QTcB values increased by a median of 1.96 ms (range,
−64 to 71 ms) during Bdq treatment. The increase was greater,
although not statistically significant, in patients receiving Bdq
combined with Fq (median, 4.9 ms) or clofazimine (median,
7.3 ms) than in those not treated with any of these 2 QTprolonging drug classes (median, −5.3 ms).
Overall, 7 (20%) patients had an increase of QTcB ≥60 ms
from baseline and 3 (9%) had a QTcB value >500 ms. None of
these events was found to be significantly associated with Fq or
clofazimine administration. Bedaquiline was discontinued in 2
(6%) patients due to persistent QTcB prolongation: 1 receiving
moxifloxacin, and the other clofazimine and amiodarone. No
cardiac arrhythmia was recorded.
Mild liver enzyme elevation (≥2-fold baseline) was reported
in 5 (14%) patients, and ≥5-fold increase occurred in 2 additional patients (6%). In the latter, elevation was confounded
by the concomitant intake of hepatotoxic compounds ( pyrazinamide, Fq, PAS). Liver enzymes elevations were asymptomatic
and did not lead to Bdq discontinuation. In both patients, AST
and ALT levels peaked after 3 months of Bdq treatment and reverted to normality during the subsequent month. In 1 case,
treatment with PAS was suspended following liver enzyme
elevation.
One death occurred during the surveillance period, in a patient affected by an advanced pharyngolaryngeal cancer, who
received Bdq for 31 days and subsequently stopped, following
QTcB prolongation. Early culture and sputum-smear conversion
were achieved and death occurred 4 months after Bdq discontinuation and 9 months after starting active antituberculosis
therapy. Therefore, death was considered to be related to the
malignancy.
One patient had coronary artery dissection during percutaneous coronary stenting. No other clinically relevant adverse
events were associated with Bdq use, and the total number of
non-Bdq-related adverse events was 80.
Our results show that Bdq-containing regimens used in accordance with provisional guidelines [18, 23] led to a high rate
(97%) of culture conversion after 6 months for these difficultto-treat patients. Faster culture conversion was associated with
Fq-containing regimens, whereas lung cavities and HCV infection were associated with slower time to conversion. Treatment
was overall well tolerated, despite the fact that QTcB prolongation was fairly common.
In our study, the culture conversion rate was 97% after 6
months of Bdq. This is higher than in the randomized trials performed so far [14–16]. Of interest, Bdq was combined with linezolid in 94% of our patients. The relevant role of linezolid in the
treatment of MDR tuberculosis and particularly of Fq-resistant
strains has been recently highlighted and could partially explain
our satisfactory results [24]. Indeed, a culture conversion rate of
87% has been reported in MDR tuberculosis patients treated
with linezolid [25]. Of note, the proportion of XDR patients
in the latter study and in most linezolid-treated cohorts is
around 10% [25–27]. In a Portuguese MDR tuberculosis cohort
with a high rate of XDR tuberculosis treated with linezolid, only
57% of subjects achieved culture conversion at 6 months [28]. In
our cohort, 66% of the patients received a carbapenem and coamoxiclav. This combination with linezolid-containing regimens
has also shown promising preliminary results [26]. The fact
that 89% of our patients received either Fq or 2LI must be
taken into account as well when evaluating the results observed
in our cohort. Indeed, the major role of the latter drug classes,
and especially Fq, has already been emphasized [5, 29–32]. This
is reinforced by the fact that Fq use was the only factor independently associated with faster culture conversion in our study.
This finding suggests that Bdq cannot replace the fast bactericidal activity of Fq. This is consistent with previous early bactericidal activity studies [33]. In contrast with existing data [9, 10,
34], pyrazinamide combined with Bdq had no effect on culture
conversion in our study. This finding may be related to the reduced number of patients harboring pyrazinamide-susceptible
strains. Moreover, the synergistic sterilizing effect of the Bdq/
pyrazinamide combination on the prevention of relapses is to
be appreciated during the follow-up after treatment end.
In our cohort, longer time to culture conversion was associated with the presence of lung cavitations and to HCV infection.
Although lung cavitations are well-known risk factors for treatment failure [31, 35], HCV infection has only been associated
with an increased risk of hepatitis during tuberculosis therapy
[36] but not with poor treatment outcomes [37].
Side effects were rather common in our study, which is typically the case in MDR tuberculosis treatment. Bdq-associated
adverse events were mostly mild or moderate and regressed
spontaneously. The proportion of patients who experienced a
≥60-ms QTcB increase during treatment (20%) was higher
than in previous studies and, as found in the C209 trial, more
Notes
Acknowledgments. The authors thank all physicians and microbiologists who provided data for the study.
Financial support. L. G. was supported by a research grant provided by
the Italian Society for Infectious and Tropical Diseases.
Potential conflicts of interest. B. H. received fees from Janssen Pharmaceutica for a roundtable on multidrug-resistant (MDR) tuberculosis. J. R.
belongs to a research team that received research grants from Janssen
Pharmaceutica. M. J. received payment for lectures related to MDR tuberculosis from AstraZeneca. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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pronounced in patients receiving Bdq in association with clofazimine [16]. Of note, QTcB values >500 ms were also more
frequent in our study (9%) and led to Bdq discontinuation in
2 patients. However, as previously reported, no arrhythmias
occurred. The incidence of liver enzyme elevation (14%) was
fairly comparable to previous trials, with severe (≥5-fold) increase reported in only 6% of patients [16].
In our study, the only death was recorded in a patient with a
severe underlying disease. It occurred following a surgical intervention, several months after having stopped Bdq, and was not
associated with >500-ms QTcB values.
This study has several limitations, which derive mostly from
its observational nature. The choice of evaluating the 6-month
rate of culture conversion and the time to culture conversion as
surrogate markers of treatment outcomes was justified by the
purpose of our interim analysis. Treatment outcome data are
not yet available. As late failure or relapse is a major problem
in MDR tuberculosis treatment, our interim results should be
interpreted with caution. The evaluation of the individual role
of Bdq in treatment efficacy and safety is also limited by the use
of a heterogeneous array of accompanying drugs as part of individualized treatment regimens. In addition, we did not compare our results in the Bdq cohort to a control arm. However, in
our cohort with a large number of XDR tuberculosis, very few
alternatives to Bdq were available. Finally, QT interval was corrected for heart rate using the Bazett instead of the Fridericia
formula, which is recommended by the Bdq manufacturer.
The Bazett formula is less accurate at higher and lower heart
rates, but it is arguably the most widely used correction and better reflects the daily clinical practice.
In conclusion, this study suggests that Bdq combined with
other active drugs has the potential to achieve high culture conversion rates in cases of advanced MDR and XDR tuberculosis
with additional resistance to multiple first- and second-line antituberculosis drugs. Although short-term safety data seem reassuring, it is crucial to follow carefully all patients for severe
adverse events even after Bdq discontinuation. This is of
major importance in the prospect of the combination of Bdq
with other innovative antituberculosis drugs [38].
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APPENDIX
Members of the MDR-TB Management Group of the French
National Reference Center for Mycobacteria. C. Andrejak, C.
Bernard, F. Brossier, K. Chadelat, B. Dautzenberg, V. Jarlier,
L. Raskine, B. Rivoire, N. Veziris.
Members of the Physicians of the French MDR-TB Cohort.
C. Appere (Argenteuil), P. Assouline (Longjumeau), R. Borie
(Paris-Bichat), L. Boukari (Bondy), M. Caseris (Paris-Bichat),
E. Caumes (Paris-Pitié-Salpêtrière), Y. Douadi, (Saint Quentin),
J. Dumoulin (Boulogne-Billancourt), C. Duval (Juvisy-surOrge), J. F. Faucher (Besançon), S. Gallien (Paris-Saint-Louis),
C. Godet (Poitiers), J. Le Grusse (Toulouse), A. Lopes (ParisLariboisière), J. L. Meynard (Paris-St-Antoine), J. M. Naccache
(Paris-Tenon), B. Philippe (Pontoise), C. Richaud (ParisNecker), H. Saad (Laon).
Downloaded from http://cid.oxfordjournals.org/ at INSERM on January 4, 2015
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assessment of linezolid safety, tolerability and efficacy in multidrugresistant tuberculosis. Eur Respir J 2009; 34:387–93.
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treatment of MDR-/XDR-TB. Eur Respir J 2012; 41:1386–92.
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efficacy to treat multidrug- and extensively drug-resistant tuberculosis.
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29. Anderson L, Tamne S, Watson J, et al. Treatment outcome of multidrug resistant tuberculosis in the United Kingdom: retrospectiveprospective cohort study from 2004 to 2007. Euro Surveill 2013; 18:
pii:20601.
30. Chiang CY, Enarson DA, Yu MC, et al. Outcome of pulmonary multidrug-resistant tuberculosis: a 6-yr follow-up study. Eur Respir J 2006;
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31. Balabanova Y, Radiulyte B, Davidaviciene E, et al. Survival of drug resistant tuberculosis patients in Lithuania: retrospective national cohort
study. BMJ Open 2011; 1:e000351.
32. Kim DH, Kim HJ, Park S-K, et al. Treatment outcomes and survival
based on drug resistance patterns in multidrug-resistant tuberculosis.
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