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Bedaquiline Article Multidrug-Resistant Tuberculosis
Bedaquiline Article Multidrug-Resistant Tuberculosis
Bedaquiline Article Multidrug-Resistant Tuberculosis
original article
Multidrug-Resistant Tuberculosis
and Culture Conversion with Bedaquiline
Andreas H. Diacon, M.D., Ph.D., Alexander Pym, M.D., Ph.D.,
Martin P. Grobusch, M.D., Ph.D., Jorge M. de los Rios, M.D.,
Eduardo Gotuzzo, M.D., Irina Vasilyeva, M.D., Ph.D., Vaira Leimane, M.D.,
Koen Andries, D.V.M., Ph.D., Nyasha Bakare, M.D., M.P.H., Tine De Marez, Ph.D.,
Myriam Haxaire-Theeuwes, D.D.S., Nacer Lounis, Ph.D., Paul Meyvisch, M.Sc.,
Els De Paepe, M.Sc., Rolf P.G. van Heeswijk, Pharm.D., Ph.D.,
and Brian Dannemann, M.D., for the TMC207-C208 Study Group*
A bs t r ac t
Background
Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP The authors’ affiliations are provided in
synthase, has been associated with accelerated sputum-culture conversion in pa- the Appendix. Address reprint requests
to Dr. Dannemann at Janssen Research
tients with multidrug-resistant tuberculosis, when added to a preferred background and Development, 1125 Trenton Har-
regimen for 8 weeks. bourton Rd., Titusville, NJ 08560, or at
bdannema@its.jnj.com.
Methods * A complete list of investigators in the
In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, TMC207-C208 Study Group is provided
smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of beda- in the Supplementary Appendix, avail-
able at NEJM.org.
quiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks,
or placebo, both in combination with a preferred background regimen. The pri- N Engl J Med 2014;371:723-32.
DOI: 10.1056/NEJMoa1313865
mary efficacy end point was the time to sputum-culture conversion in liquid broth. Copyright © 2014 Massachusetts Medical Society.
Patients were followed for 120 weeks from baseline.
Results
Bedaquiline reduced the median time to culture conversion, as compared with pla-
cebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95%
confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased
the rate of culture conversion at 24 weeks (79% vs. 58%, P = 0.008) and at 120 weeks
(62% vs. 44%, P = 0.04). On the basis of World Health Organization outcome defini-
tions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the
bedaquiline group and 32% in the placebo group (P = 0.003). The overall incidence
of adverse events was similar in the two groups. There were 10 deaths in the beda-
quiline group and 2 in the placebo group, with no causal pattern evident.
Conclusions
The addition of bedaquiline to a preferred background regimen for 24 weeks re-
sulted in faster culture conversion and significantly more culture conversions at 120
weeks, as compared with placebo. There were more deaths in the bedaquiline group
than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208
ClinicalTrials.gov number, NCT00449644.)
T
he World Health Organization positive, pulmonary, multidrug-resistant tubercu-
(WHO) estimates that the global incidence losis on the basis of proportion-method results,11,12
of tuberculosis in 2012 was 8.6 million positive rapid-screening tests (FASTPlaque-
cases, with 1.3 million deaths, predominantly Response assay [Biotec] and GenoType MTBDR
occurring in developing countries.1 Although there plus line-probe tests [Hain Lifescience]). Patients
has been some progress in reducing tuberculosis who had received previous treatment for multi-
cases and deaths in the past 20 years, multidrug- drug-resistant tuberculosis were excluded. Addi-
resistant tuberculosis (i.e., with resistance to at tional exclusion criteria were a positive test for the
least isoniazid and rifampin) remains a major human immunodeficiency virus (HIV) with a CD4+
challenge. The 2012 global incidence of multi- count of less than 300 cells per cubic millimeter,
drug-resistant tuberculosis was 450,000 cases.1 complicated or severe extrapulmonary or neuro-
Therapy for multidrug-resistant tuberculosis is a logic manifestations of tuberculosis, severe cardi-
long, arduous regimen of antiquated drugs that ac arrhythmia requiring medication, a corrected
are mainly bacteriostatic and have an unfavorable QT interval with the use of Fridericia’s formula
side-effect profile.2 The WHO reports that major (QTcF)13 of more than 450 msec, a history of risk
efforts are needed to improve the current average factors for torsades de pointes, concomitant seri-
rate of 48% for successful treatment of patients ous illness, alcohol or drug abuse, pregnancy or
with multidrug-resistant tuberculosis.1 By 2012, breast-feeding, and previous treatment with beda-
extensively drug-resistant tuberculosis (i.e., with quiline. According to the protocol, moxifloxacin,
additional resistance to injectable second-line gatifloxacin, and systemic use of cytochrome
drugs and fluoroquinolones) was reported in 92 P-450 3A4 inhibitors or inducers were prohibited
countries worldwide, with the presence of exten- during and for 1 month after completion of the
sively drug-resistant isolates reported in 9.6% of study treatment.
patients with multidrug-resistant tuberculosis.1
Bedaquiline (Sirturo, TMC207), a diarylquino- Study Design
line that inhibits mycobacterial ATP synthase,3 is
In this randomized, double-blind, placebo-con-
the first antituberculosis drug with a new mecha-trolled study, patients were stratified according
nism of action to be approved for use in multi- to study site and radiographic assessment of lung
drug-resistant tuberculosis in 40 years.4 Beda- cavitation (≥2 cm bilaterally, ≥2 cm unilaterally,
quiline has shown bactericidal activity in vitro,or <2 cm). Trial sites were located in Brazil, India,
in murine models of tuberculosis,3,5-7 and in a Latvia, Peru, the Philippines, Russia, South Africa,
7-day proof-of-concept study involving patients and Thailand. Patients received either bedaqui-
with drug-sensitive tuberculosis.8 In stage 1 of an
line (400 mg once daily for 2 weeks, followed by
exploratory phase 2b randomized trial, called 200 mg three times a week for 22 weeks, admin-
TMC207-C208, involving patients with newly diag- istered as 100-mg tablets) or placebo, plus a pre-
nosed, smear-positive, multidrug-resistant tuber-ferred five-drug, second-line antituberculosis
culosis, 8 weeks of bedaquiline treatment had background regimen (Fig. 1). Patients were in-
better antibacterial activity than placebo when structed to take bedaquiline or placebo with wa-
added to a preferred five-drug, second-line back-ter after breakfast. National treatment-program
ground regimen.9,10 In stage 2 of the TMC207- regimens were respected, although the preferred
C208 study, a phase 2b study in which bedaqui- five-drug background regimen was ethionamide,
line was administered for 24 weeks to a larger pyrazinamide, ofloxacin, kanamycin, and cyclo-
number of patients, we evaluated the time to serine. Changes in the background regimen were
sputum-culture conversion, the rates of culture permitted on the basis of the results of drug-
conversion and drug resistance, pharmacokinetics,susceptibility testing, side effects, or unavailabil-
and safety over a 120-week period in patients re-ity of drugs on site.
ceiving a preferred five-drug background regimen. After the 24-week treatment period, there was
a 96-week period during which patients were
Me thods instructed to complete their background regi-
men (Fig. 1). Patients who prematurely discon-
Patients tinued the trial were followed for collection of
We recruited patients between the ages of 18 and survival data until trial completion unless they
65 years with newly diagnosed, sputum smear– withdrew consent.
24 Wk 96 Wk
24 Wk 96 Wk
Each site obtained approval of the study pro- isolates. Isolates for which the MIC was increased
tocol from at least one (or more, if required by by a factor of 4 or more, as compared with the
local regulations) independent ethics committee baseline value, were considered to have decreased
or institutional review board. The trial was con- susceptibility to bedaquiline.
ducted in accordance with the principles of
Good Clinical Practice and the Declaration of Safety Assessments
Helsinki. All patients provided written informed Safety assessments included monitoring for ad-
consent before trial entry. Details regarding the verse events, clinical laboratory testing, and elec-
study design are provided in the protocol, avail- trocardiography at predefined intervals through-
able with the full text of this article at NEJM.org. out the study. Toxicity was graded on the basis of
the Division of Microbiology and Infectious Dis-
Microbiologic Assessments eases (DMID) adult toxicity tables.14
Triplicate spot sputum samples were collected at
every visit (except on the day of the first adminis- Study End Points
tration of the study drug) and at the time of with- The primary end point was the time to sputum-
drawal, for patients who did not complete the culture conversion, which was defined as two
study, for culture of Mycobacterium tuberculosis in consecutive negative liquid cultures from sputum
liquid medium (Mycobacteria Growth Indicator samples that were collected at least 25 days apart
Tube, Becton Dickinson). Drug-susceptibility test- and were not followed by confirmed positive cul-
ing was performed at a central laboratory (Insti- tures. The primary analysis was performed on
tute of Tropical Medicine, Antwerp, Belgium) at the basis of data at 24 weeks. Secondary efficacy
baseline and at 8, 24, and 72 weeks in all patients measurements were the rates of culture conver-
and in those with reversion to a positive culture sion after 24 weeks and after 120 weeks. We also
after initial culture conversion. The minimal in- performed 11 subgroup efficacy analyses of the
hibitory concentration (MIC) of bedaquiline on rate of culture conversion, including in patients
7H11 agar was defined as the lowest concentra- with M. tuberculosis isolates that were resistant
tion (measured in micrograms per milliliter) that only to isoniazid and rifampin and in those with
prevented the growth of 99% of M. tuberculosis isolates that also were resistant to any second-
line injectable drug or any fluoroquinolone patients were considered to have had no response.
(which were categorized as having pre-extensive We used a Cox proportional-hazards model with
drug resistance) and in patients with isolates that adjustment for stratification variables to com-
were susceptible or resistant to pyrazinamide. pare the time to culture conversion in the two
(For details regarding all 11 subgroups, see the study groups.
Methods section in the Supplementary Appendix, For the 11 prespecified subgroup analyses, no
available at NEJM.org.) formal adjustments for multiple comparisons
were made. With this number of subgroups, there
Study Oversight is a probability of 43% that at least one test would
The study was funded by Janssen Pharmaceuti- be significant (P<0.05) on the basis of chance
cals. Medical-writing support (funded by Janssen) alone. A post hoc analysis was performed to as-
was provided by an employee of Gardiner- sess treatment outcomes on the basis of WHO
Caldwell Communications, who wrote the initial definitions for multidrug-resistant tuberculosis.15
draft of the manuscript and incorporated com-
ments from the authors. The data were collected R e sult s
by the investigators and analyzed by the sponsor.
All the authors made the decision to submit the Study Population
manuscript for publication and vouch for the Of 282 patients who were screened, 160 under-
accuracy and completeness of the data reported went randomization and received at least one
and the fidelity of the study to the protocol. dose of the assigned study drug (the intention-to-
treat population, comprising 79 patients in the
Statistical Analysis bedaquiline group and 81 in the placebo group).
We determined that enrollment of 75 patients in The modified intention-to-treat population con-
each study group would provide a power of 80% sisted of 132 patients (Fig. 2). In the intention-to-
to detect a difference of 22 percentage points in treat population, 60 patients (38%) discontinued
the 6-month rate of culture conversion between the trial prematurely, with no relevant differences
the placebo group (estimated at 50%) and the between the two study groups in the reasons for
bedaquiline group (estimated at 72%) at a two- discontinuation (Fig. 2, and Fig. S1 in the Supple-
sided significance level of 0.05. The safety analy- mentary Appendix). The most common reasons
sis was conducted in the intention-to-treat pop- for discontinuation were withdrawal of consent
ulation and included all patients who had and adverse events.
undergone randomization and received at least In the modified intention-to-treat population
one dose of the assigned study drug. Safety data (protocol-defined efficacy population), there were
are presented for the 120-week treatment period. more men (64%) than women, and more black
The efficacy analyses were performed in the patients (37%) than any other racial or ethnic
modified intention-to-treat population, which group (Table 1, and Table S3 in the Supplemen-
excluded patients who had no positive mycobac- tary Appendix). Baseline demographic and dis-
terial cultures from sputum samples obtained ease characteristics were similar in the two study
before administration of the first dose of the groups except that the proportion of patients
study drug or a positive culture up to week 8 in who had isolates with resistance to pyrazin-
cases in which baseline cultures were negative, amide and the proportion classified as having
those for whom susceptibility to rifampin and isolates with pre-extensive drug resistance were
isoniazid was shown or resistance could not be nonsignificantly larger in the bedaquiline group,
confirmed, those with extensively drug-resistant and the proportions of HIV-positive patients and
tuberculosis, and those who had not undergone patients with abnormally low albumin levels
assessment after baseline. were significantly larger in the placebo group
The primary end point was analyzed in the (Table 1). The median overall treatment phase
modified intention-to-treat population. In this was longer in the placebo group than in the
analysis, data for patients who discontinued treat- bedaquiline group (Table 2). A higher proportion
ment, died, or did not have sputum-culture con- of patients in the placebo group than in the
version before 24 weeks were censored at the last bedaquiline group (58% vs. 47%) had at least
assessment, regardless of the culture status at one new antituberculosis drug added to their
the time of study dropout or death, and these background regimen.
Table 1. Demographic and Clinical Characteristics in the Modified Intention-to-Treat Population at Baseline.*
* There were no significant differences between the two study groups except for the proportion of patients who were
HIV-positive (P = 0.04) and those who had a baseline albumin grade of 1 to 3 (P = 0.02). Fisher’s exact test was used
for the categorical measures, and an asymptotic Wilcoxon test for the continuous measures.
† Race was reported by the investigators.
‡ Albumin was graded according to the Division of Microbiology and Infectious Diseases criteria14 as follows: grade 1,
less than the lower limit of the normal range to 3 g per deciliter; grade 2, less than 3 g per deciliter to 2 g per decili-
ter; and grade 3, less than 2 g per deciliter.
§ For 12 patients in the bedaquiline group and 8 patients in the placebo group, no confirmation of isoniazid and ri-
fampin resistance was available from the central laboratory.
¶ Pre-extensively drug-resistant tuberculosis is defined as multidrug-resistant tuberculosis with resistance to either any
second-line injectable drug (amikacin, kanamycin, or capreomycin) or any fluoroquinolone.
∥ Some isolates did not grow for resistance testing.
** Other agents included aminosalicylic acid, capreomycin, amoxicillin plus clavulanic acid, and streptomycin.
(44%), respectively, at 120 weeks (P = 0.04) (Fig. 4). conversion or conversion status (Fig. S3 in the
At 120 weeks, of the 25 patients in the bedaqui- Supplementary Appendix).
line group who did not have a response, 8 did
not have culture conversion, 6 had subsequent Subgroup Analyses
reversion, and 11 discontinued the study after In subgroup analyses at 120 weeks, sputum-cul-
culture conversion. Of the 37 patients in the ture conversion occurred in more patients in the
placebo group who did not have a response, 15 bedaquiline group than in the placebo group
did not have culture conversion, 10 had subse- among those who had isolates with resistance
quent reversion, and 12 discontinued the study only to isoniazid and rifampin (27 of 39 patients
after culture conversion. In the bedaquiline [69%] and 20 of 46 patients [43%], respectively)
group, there was no relationship between the and among those who had isolates with pre-
area under the plasma concentration–time curve extensive drug resistance (9 of 15 patients [60%]
over a 24-hour period at week 2 and the time to and 5 of 12 patients [42%], respectively). In addi-
Bedaquiline Placebo
Variable (N = 79) (N = 81)
Median duration of overall treatment phase (range) — wk 91.7 (2.0–120.0) 94.1 (2.0–137.3)
Adverse event — no. (%)
Any 78 (99) 79 (98)
Related to treatment 55 (70) 56 (69)
Grade 3 or 4† 34 (43) 29 (36)
Leading to discontinuation of treatment 4 (5) 5 (6)
Serious adverse events — no. (%)‡ 18 (23) 15 (19)
Adverse event occurring in ≥20% of patients — no. (%)
Nausea 32 (41) 30 (37)
Arthralgia 29 (37) 22 (27)
Vomiting 23 (29) 22 (27)
Headache 23 (29) 18 (22)
Hyperuricemia 20 (25) 27 (33)
Hemoptysis 16 (20) 14 (17)
* There were no significant differences between the two groups in any category as calculated by means of Fisher’s exact
test in a post hoc analysis.
† Events were graded according to the Division of Microbiology and Infectious Diseases criteria.14
‡ Two serious adverse events were considered by the investigator to be possibly related to a study drug, including 2 events
of acute pancreatitis in 1 patient in the bedaquiline group and spontaneous abortion in 1 patient in the placebo group.
tion, there were more culture conversions in the (extensive drug resistance, observed in 1 patient);
bedaquiline group than in the placebo group the 1 patient in the bedaquiline group did not
among patients with isolates that were suscepti- have either pre-extensive or extensive drug resis-
ble to pyrazinamide (13 of 18 patients [72%] and tance. Though the number of paired isolates (10)
14 of 26 patients [54%], respectively) and among is limited, the isolate from 1 patient in the beda-
those with isolates that were resistant to pyrazin- quiline group who had pre-extensive drug resis-
amide (23 of 38 patients [61%] and 11 of 33 pa- tance at baseline had an increase by a factor of
tients [33%], respectively). 4 in the bedaquiline MIC at the end of the study,
On the basis of the WHO definition of cure,15 as compared with baseline. No mutations were
in the modified intention-to-treat population at observed in the ATP synthase operon.
120 weeks, more patients in the bedaquiline
group than in the placebo group were cured (38 Safety
of 66 patients [58%] and 21 of 66 patients [32%], During 120 weeks in the intention-to-treat popu-
respectively; P = 0.003) (Fig. 4). lation, there were similar rates of adverse events,
treatment-related adverse events, and adverse
Drug Resistance events leading to study discontinuation in the
New resistance to at least one antituberculosis two study groups (Table 2). The most frequent
drug developed in isolates from 2 patients in the adverse events were nausea, arthralgia, and vom-
bedaquiline group and in 16 patients in the pla- iting. The severity of most adverse events was
cebo group; 1 of the 2 patients in the bedaquiline grade 1 or 2.14
group (50%) and 9 of the 16 in the placebo group Overall, 10 of 79 patients (13%) in the beda-
(56%) did not have a response to treatment. Of quiline group and 2 of 81 patients (2%) in the
the latter patients, 6 of the 9 patients (67%) in the placebo group died (P = 0.02). (Detailed case re-
placebo group were found to have isolates with ports on all deaths are provided in Table S5 in
resistance either to injectable second-line drugs the Supplementary Appendix.) In the bedaqui-
or fluoroquinolones (pre-extensive drug resis- line group, deaths occurred during study-drug
tance, observed in 5 patients) or to both inject- treatment in 1 patient and after study week 24 in
able second-line drugs and fluoroquinolones 9 patients (median time after receipt of the last
70
60
Placebo plus absolute QTcF values or changes in the QTcF.
background
50 regimen
There were no reports of clinically significant
40 dysrhythmia during the trial.
30 Bedaquiline plus
background
20 regimen Discussion
10
0 In this study, we found that 24 weeks of treat-
0 4 8 12 16 20 24
ment with bedaquiline in combination with a
Weeks
five-drug, second-line background regimen (con-
No. at Risk sistent with WHO recommendations for the
Bedaquiline 58 37 25 12 7 3
Placebo 61 53 40 30 22 5 treatment of multidrug-resistant tuberculosis at
that time15) significantly shortened the time to
Figure 3. Time to Sputum-Culture Conversion in the Modified Intention-to- culture conversion and increased the rate of cul-
Treat Population.
ture conversion at 24 weeks, as compared with
Shown is the proportion of patients in each study group who had positive
results on Mycobacterium tuberculosis culture during the 24-week investiga-
placebo plus the background regimen. These re-
tional treatment phase of the study. Patients who withdrew from the study, sults confirm the faster culture conversion re-
who died, or who did not have sputum-culture conversion by week 24 were ported in a previous phase 2b trial of 8 weeks of
considered to have had treatment failure in the primary analysis, regardless bedaquiline.9 The treatment benefit of adding
of their culture status at the time of dropout or death. For these patients, bedaquiline to the background regimen that was
data were censored at their last assessment, so the proportion of patients
who had culture conversion cannot be derived from the data in the figure.
seen at 24 weeks in terms of the proportion of
Analysis based on a Cox proportional-hazards model with adjustment for patients with a response was durable and of sim-
study center and degree of radiographic lung cavitation showed significant- ilar magnitude at the end of the 120-week trial.
ly faster conversion in the bedaquiline group than in the placebo group at Evaluation of the study outcome on the basis
24 weeks (P<0.001). The number of patients at risk at each time point is of the modified WHO definitions for multidrug-
the number of patients who did not have culture conversion and who were
still participating in the study.
resistant tuberculosis supported our results at 24
weeks and 120 weeks. On the basis of the WHO
definition of cure, nearly twice as many patients
dose of study drug, 49.1 weeks; range 12.3 to in the bedaquiline group as in the placebo group
130.1), with 1 of these deaths occurring after were cured, a finding that addresses the unmet
study week 120. In 6 patients, the deaths were need for improved long-term treatment outcomes
attributed to tuberculosis (in 5 patients in the in patients with multidrug-resistant tuberculo-
bedaquiline group and 1 in the placebo group). sis. The treatment-success rate among patients
There was no difference in the duration of fol- in the placebo group in our trial was lower than
low-up between the two study groups. No deaths that reported in a recent meta-analysis (32% vs.
were considered to be related to the study drug 54%).16 This finding might be explained by the
by an investigator who was unaware of the higher proportions of patients in our study, as
group assignments, nor was there any associa- compared with the meta-analysis, who had iso-
tion between the deaths and bedaquiline plasma lates that were positive for acid-fast bacilli (100%
concentrations or a QTcF interval of 500 msec or vs. 66%), cavitary disease (83% vs. 52%), and
more during the trial. pyrazinamide resistance (62% vs. 26%). In addi-
At study week 24, the mean change from tion, we collected triplicate sputum samples and
baseline in the QTcF was an increase of 15.4 msec used liquid culture, which is more sensitive than
in the bedaquiline group and an increase of the solid medium used in the studies cited in the
3.3 msec in the placebo group (P<0.001). After meta-analysis.17
bedaquiline treatment ended, the QTcF gradu- The inclusion of bedaquiline in the regimen
ally decreased, and the mean value was similar was associated with a reduced risk of pre-exten-
to that in the placebo group by study week 60. sive drug resistance or extensive drug resistance
Only one patient in the bedaquiline group had a and a reduced risk of additional resistance to
which provides evidence of the potential useful- 120-week period, with more negative sputum
ness of this surrogate end point. The study did cultures, fewer culture reversions, and a reduced
not assess whether the use of bedaquiline can risk of evolution to a more resistant subtype.
simplify or shorten treatment. Supported by Janssen Pharmaceuticals.
In conclusion, the addition of bedaquiline to Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
a five-drug regimen for patients with multidrug- We thank the patients and their families, along with study-
resistant tuberculosis resulted in faster sputum- center staff and public health authorities, for their support; Jans-
culture conversion and a higher rate of culture sen study personnel, in particular Chrispin Kambili and Ross
Underwood for their critical review; David McNeeley, who previ-
conversion at 24 weeks, as compared with pla- ously worked for Janssen Pharmaceuticals; and Ian Woolveridge of
cebo. This effect remained significant during a Gardiner-Caldwell Communications for medical-writing support.
Appendix
The authors’ affiliations are as follows: the Division of Medical Physiology and the Department of Science and Technology/National
Research Foundation Centre of Excellence for Biomedical Tuberculosis Research and Medical Research Council Centre for Tuberculosis
Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town (A.H.D.), and the Medical Research Council
and Kwazulu Research Institute for Tuberculosis and HIV, Durban (A.P.) — both in South Africa; the Center for Tropical Medicine and
Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Academic Medical Center, University of Amsterdam,
Amsterdam (M.P.G.); Centro de Excelencia para el Control de la Tuberculosis Niño Jesús, Servicio de Neumología, Hospital María
Auxiliadora (J.M.R.), and Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia (E.G.) —
both in Lima, Peru; Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow (I.V.); Riga East University
Hospital–Center for Tuberculosis and Lung Diseases, Riga, Latvia (V.L.); Janssen Infectious Diseases, Beerse, Belgium (K.A., N.B.,
M.H.-T., N.L., P.M., E.D.P., R.P.G.H.); and Janssen Research and Development, Titusville, NJ (T.D.M., B.D.).
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