Civ 609

SUPPLEMENT ARTICLE
Perspectives on Advances in Tuberculosis

Diagnostics, Drugs, and Vaccines
Marco Schito,1 Giovanni Battista Migliori,2 Helen A. Fletcher,3 Ruth McNerney,4 Rosella Centis,2 Lia D’Ambrosio,2
Matthew Bates,5 Gibson Kibiki,6 Nathan Kapata,5 Tumena Corrah,7 Jamshed Bomanji,8 Cris Vilaplana,9 Daniel Johnson,10
Peter Mwaba,5 Markus Maeurer,11 and Alimuddin Zumla12
Downloaded from https://academic.oup.com/cid/article/61/suppl_3/S102/356054 by guest on 12 March 2024

1
Critical Path to TB Drug Regimens, Critical Path Institute, Tucson, Arizona; 2World Health Organization Collaborating Centre for Tuberculosis and Lung
Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy; 3Department of Immunology and Infection, London School of Hygiene and
Tropical Medicine, and 4TB Alert, Brighton, United Kingdom; 5University of Zambia—University College London Medical School Research and Training
Project, University Teaching Hospital, Lusaka, Zambia; 6Kilimanjaro Clinical Research Institute, Moshi, Tanzania; 7Department of Infectious Diseases and
Tropical Medicine, Northwick Park Hospital, and 8Department of Nuclear Imaging, University College London Hospitals NHS Foundation Trust, United
Kingdom; 9Unitat de Tuberculosi Experimental, Fundació Institut d’Investigació en Ciències de la Salut Germans Trias i Pujol, Ctra. de Can Ruti, Camí de les
Escoles, Barcelona, Spain; 10Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland;
11
Therapeutic Immunology, Departments of Laboratory Medicine and Microbiology, Tumour and Cell Biology, Karolinska Institute, Stockholm, Sweden; and
12
Division of Infection and Immunity, University College London and National Institute for Health Research Biomedical Research Centre, UCL Hospitals
NHS Foundation Trust, United Kingdom
Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with ex-
panding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise
of better point-of-care rapid tests for tuberculosis including nucleic acid–based amplification tests, imaging,
and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multi-
drug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several
new drug regimens and their evaluation in clinical trials and now influence World Health Organization guide-
lines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candi-
dates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment
outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immuno-
deficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder com-
mitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and
prevention are urgently required.
Keywords. tuberculosis; diagnostics; drugs; vaccines; management.
Tuberculosis remains a leading infectious disease cause confirm the large load of undiagnosed tuberculosis,
of death globally, and an estimated 3 million cases of subclinical tuberculosis, and tuberculosis comorbidity
tuberculosis remained undiagnosed and untreated in with HIV, pyogenic pneumonia, and other infectious
2013 [1, 2]. Early-stage disease, extrapulmonary tuber- and noncommunicable diseases [3–5]. This unaccept-
culosis, tuberculosis/human immunodeficiency virus able status quo indicates that prevailing approaches to
(HIV) coinfection, childhood tuberculosis, and multi- diagnosing, treating, managing, and preventing tuber-
drug-resistant tuberculosis are particularly problematic culosis are inadequate and require critical appraisal.
to diagnose and treat. Autopsy studies from Africa We discuss the current and developmental landscape
of diagnostics, drugs, and vaccines.
All authors contributed equally to this work.

Correspondence: Marco Schito, PhD, Critical Path to TB Drug Regimens, Critical
Path Institute, 1730 E River Rd, Ste 200, Tucson, AZ 85718 ([email protected]). TUBERCULOSIS DIAGNOSTICS
®
Clinical Infectious Diseases 2015;61(S3):S102–18
© The Author 2015. Published by Oxford University Press on behalf of the Infectious The definitive test for tuberculosis disease is detection
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
of Mycobacterium tuberculosis complex bacilli (Mtb)
DOI: 10.1093/cid/civ609 in clinical specimens from a symptomatic patient [6].
S102 • CID 2015:61 (Suppl 3) • Schito et al

Sputum is the specimen of choice for diagnosing pulmonary dis- requires some technical training and equipment maintenance.
ease, but the mucoid and viscous nature of the sample makes it When used at the point of care, it also cannot perform in settings
difficult to manipulate and often interferes with test performance. requiring high throughput.
Sample processing is usually necessary before diagnostic tests are Two tuberculosis tests recently released to the market are descri-
applied, resulting in increasing complexity and cost. For extrap- bed in Table 1. Evaluation of these devices is ongoing, and there is
ulmonary tuberculosis, sampling is dependent on the suspected as yet little published data regarding their clinical performance.
site of disease and requires invasive procedures. Attempts to de- Studies on the Truenat MTB test (Molbio Diagnostics, India)
velop blood, urine, and breath-based tests have met with limited [19] undertaken in India found sensitivity and specificity to be
success, as they are lacking in sensitivity and specificity [7]. In similar to that of the Xpert MTB/RIF assay [20, 21], whereas a
2010, the World Health Organization issued a recommendation study using EasyNAT in Tanzania reported high specificity
against the use of serological tests [8]. Several novel diagnostic (100%) and a sensitivity compared with culture of 66.7%,
technologies are being explored with the aim of providing better with 10% of smear-negative cases found to be positive [22]. A
point-of-care rapid tests for tuberculosis. They include nucleic study from China on the EasyNAT Diagnostic Kit (Ustar Bio-

acid amplification tests (NAATs), imaging, and the analysis of technologies, China) [23] using processed sputum reported sen-
volatile organic compounds. sitivity and specificity of 84% and 98%, respectively. The
sensitivity in smear-negative cases was 60% [24]. There are sev-
Nucleic Acid Amplification Tests eral tests ready for evaluation, but not yet released into the mar-
The most advanced of the new tests, and first to the market, were ket, and a fuller description of the tuberculosis NAAT product
simple methods for amplifying and detecting nucleic acids that development pipeline may be found in the 2014 UNITAID Tu-
do not need laboratory facilities or specialist technical skills. berculosis Diagnostics Technology and Market Landscape Re-
They have the potential advantage of incorporating detection port [25].
of mutations predictive of drug resistance. The Xpert MTB/RIF
assay (Cepheid Inc) is an automated polymerase chain reaction– Imaging
based test that can identify Mtb DNA in clinical specimens and A number of imaging techniques can be used to gauge the ex-
detect rifampicin resistance. It has been widely rolled out globally tent of disease and to monitor treatment, and imaging remains
and evaluated extensively at all points of healthcare [9–17]. The a first-line tool for investigating extrapulmonary manifestations
current assay might miss up to 15%–30% of rifampicin rpoB of the disease [26]. Chest radiography played a major role in re-
gene mutations that confer resistance. An optimized version of ducing the prevalence of tuberculosis in Europe and North
the Xpert MTB/RIF is being developed, and preliminary data America in the 1950s and 1960s, with mobile radiograph units
suggest 10-fold higher sensitivity than the standard Xpert assay used for mass screening of communities. The introduction of
[18]. The optimized version has improved the performance both digital radiography has improved image quality and facilitates
in terms of sensitivity for detection of Mtb and for the detection the storage and sharing of images and, if required, a second
of rifampicin resistance mutations that are missed by the current opinion may be sought by remote (electronic) access. Compared
assay. However, this optimized assay at this point has not been to film-based radiographs, running costs are reduced and
tested in any human clinical context. In addition, the GeneXpert reagent stockouts avoided, but the cost of buying/leasing and
technology is not really an optimized point-of-care assay and maintaining the equipment remains high. A further development
Table 1. Commercially Available Nucleic Acid Amplification Tests for Tuberculosis Intended for Use at the Point of Care
Drug Time to
Device Manufacturer Technology Target Power Source Resistance Sample Extraction Result
Expert MTB/RIF Cepheid, USA Real-time PCR rpoB Mains Rifampicin Automated 90 min
Truenat MTB Molbio Diagnostics, Miniaturized Ribonucleoside- Mains or None Semiautomated 60 min
India chip-based diphosphate battery using separate
real-time PCR reductase gene device
EasyNAT CPA Ustar Isothermal IS6110 Mains: Heating None Manual extraction 90 min,
diagnostic kit for Biotechnologies, cross-priming block or excluding
Mycobacterium China amplification water bath sample
tuberculosis and vortex extraction
DNA required (not
supplied)
Abbreviations: CPA, cross priming amplification; PCR, polymerase chain reaction.
Advances in Clinical Tuberculosis Research • CID 2015:61 (Suppl 3) • S103

is application of computer-aided image analysis to provide an Mtb-infected sputum [36]. When samples were exposed to ten
automated imaging service. Studies suggest that sensitivities different rats, 91% of Mtb smear-positive samples were detected
from automated readers can be similar to those obtained by [37]. Attempts to mimic the rats using electronic and chromato-
eye but that specificity is reduced [27], a finding confirmed by graphic methods have so far been disappointing. E-nose techno-
studies in Africa [28, 29]. Alternative imaging technologies such logies that showed early promise were found to be unreliable
as magnetic resonance imaging, computed tomography, and [38]. Developers of a chromatographic-based breath test have
positron emission tomography–computed tomography (PET- reported sensitivities and specificities of 71% and 72%, respec-
CT) may eventually find utility in the investigation of extrapul- tively, when comparing untreated tuberculosis patients against
monary disease [26]. nonsymptomatic individuals [38].
PET-CT is another modality that is being explored for tuber-
culosis [19]. Fluorodeoxyglucose (FDG) accumulates in metabo- E-health
lically active immune system cells and can serve as a marker A feature shared by many of the new diagnostic devices is the
of tuberculosis-associated inflammation. FDG PET-CT at 2 capacity to transmit data via wireless or cell phone technology

months has been shown in pilot studies to correlate with out- to an external database. The ability to store, retrieve, and share
come in patients with confirmed MDR tuberculosis [30]. How- data in a central repository offers considerable logistic advan-
ever, as FDG accumulates in all metabolically active cells, it has tages for health providers and may facilitate an improved ser-
low specificity as a diagnostic and is unable to distinguish be- vice for patients. However, as presented in Table 2, there are a
tween tuberculosis and other metabolically active lung processes number of concerns to be addressed about this new and cur-
such as malignancy. New radioprobes for PET and single- rently unregulated technology. It is as yet unclear who shall
proton emission computed tomography are being developed own the data, and for what purposes it would be used. A second,
that target not glucose metabolism but markers of tuberculo- and pressing issue, is compatibility and standardization of data
sis-specific pathology including tissue pH, hypoxia, tissue calci- handling storage and systems, because if manufacturers choose
fication [31], and inflammation [32, 33]. to adopt different systems, the potential benefits of e-health to
the patient and the health provider will be diluted.
Breath Tests
Volatile organic compounds (VOC) and gases are produced by NEW TUBERCULOSIS DRUGS, REPURPOSED
Mtb as byproducts of their metabolic processes, and their detec- DRUGS, AND TREATMENT REGIMENS
tion by analysis of breath or volatile compounds [34] emanating
from clinical specimens is being exploited for development of Advances in new and repurposed drugs continuously update
breath-based tests. The most sensitive detectors and those best World Health Organization (WHO) guidelines for use in de-
suited to differentiating complex mixtures are olfactory systems signing treatment regimens for MDR and XDR tuberculosis.
of mammals and insects [35]. Giant African pouched rats (Cri- Figure 1 illustrates tuberculosis drug development over time.
cetomys gambianus) have been trained to recognize the smell of Recent attention has focused on development of the new
Table 2. Potential Advantage and Pitfalls of eHealth and Transfer of Information From In Vitro Diagnostics Devices to External Data
Handling and Storage Facilities
Advantages Beneficiaries Risks Victims

1. Access to online expert Patients, health professionals 1. Breaches of confidentiality Patients
opinion
2. Improved record keeping Health providers, patients 2. Exclusion of patients with poor access to the Patients
technology
3. Improved stock Health providers, manufacturers, 3. Exclusion of sites/communities with poor access to Patients and health
management distributors the technology providers
4. Improved quality control Health providers 4. Lack of access to information during equipment Health providers,
data failure or power outages patients
5. Improved epidemiological Control program, policy makers 5. Data used for inappropriate purposes (eg, unsolicited Health providers,
data collection marketing of products, insurance policies) patients
6. Monitoring device Manufacturers, distributors 6. Failure to integrate leading to multiple systems, Health providers,
performance resulting in chaos patients
7. Improved market Manufacturers, distributors, 7. Increased suspicion and mistrust of health providers Patients
intelligence private health providers promotes delayed health seeking

Advances in Clinical Tuberculosis Research
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CID 2015:61 (Suppl 3)
Figure 1. Historical timelines of discovery of tuberculosis drugs and introduction of tuberculosis treatment regimens used at programmatic level. Abbreviations: DOTS, directly observed treatment, short-course;
MMR, mass miniature radiograph; Mtb, Mycobacterium tuberculosis; PAS, para-aminosalicylic acid; TB, tuberculosis; WHO, World Health Organization.
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drugs bedaquiline, delamanid, pretomanid (PA-824), sutezolid, In a recent phase 2b trial, the bactericidal activity of a new
and SQ109 and their evaluation in clinical trials (Table 3). 8-week regimen including moxifloxacin, pretomanid, and pyra-
zinamide was compared to that of the standard antituberculosis
Diarylquinolones regimen for drug-susceptible and drug-resistant tuberculosis.
Bedaquiline selectively targets the proton pump of adenosine tri- The new regimen yielded higher bactericidal activity in liquid
phosphate (ATP) synthesis, leading to inadequate ATP [48]. culture than the current WHO-recommended regimen after 2
Bedaquiline’s bactericidal activity is superior to that of isoniazid months of treatment [43].
and rifampicin [48]. The results of phase 2 trials suggest that a Tuberculosis-354 is a second-generation nitroimidazole and
standard 2-month treatment regimen with bedaquiline can have the first tuberculosis drug to enter phase 1 trials since 2009 [57].
high culture conversion rates, rapid sputum culture conversion,
and low acquired resistance to companion drugs in newly diag- Oxazolidinones
nosed MDR tuberculosis cases [39, 49]. Both WHO [50] and Sutezolid (PNU-100480) has potent anti-Mtb activity and acts
the US Centers for Disease Control and Prevention [51] issued by binding to 23S RNA and 50S ribosomal subunits [58], pre-

recommendations that support the use of bedaquiline, at the venting the initiation of protein synthesis. It is safe and well tol-
dose of 400 mg daily for 2 weeks, then 200 mg 3 times a week erated [59, 60]. Recent phase 2 clinical trials of sutezolid
for 22 weeks, added to an optimized background regimen to (NCT01225640) assessing safety and efficacy using early bacter-
treat MDR tuberculosis in adults when the following conditions icidal activity (EBA) and whole-blood bactericidal activity were
are met: pharmacovigilance is in place, informed consent is completed [45] (Table 3). Tedizolid, recently approved by the
ensured and QT monitoring is possible [50, 51]. Due to an US Food and Drug Administration for skin and skin structure
increased risk of QT prolongation and death, simultaneous use infections, has shown activity in vitro against Mtb [61], but no
of bedaquiline and delamanid is not recommended [50, 51]. studies in Mtb-infected humans has been performed. AZD5847,
Phase 3 trials of the use of bedaquiline for shortening duration another new oxazolidinone, has been shown to have activity in
of therapy are under way. mice [62], and human studies are ongoing.
Nitroimidazoles Ethylenediamines
Delamanid (OPC-67683) and pretomanid (PA-824) inhibit the SQ109 is an analogue of ethambutol active against both drug-
synthesis of mycolic acids and are active against both replicating susceptible and drug-resistant Mtb by targeting MmpL3 and in-
and anaerobic, nonreplicating Mtb persisters and have shown hibiting the protein synthesis [63]. In a 2-week phase 2 EBA
potential for improving treatment outcomes for MDR tubercu- trial, SQ109, although safe, did not appear to be active alone or
losis [40–44, 52–56]. They are currently in phase 2 and phase 3 to enhance the activity of rifampicin [46]. Similarly, in a recent
clinical trials (Table 3) [40–44]. Based on the available evidence, trial that compared ethambutol with SQ109 for drug-susceptible
WHO [54] recommends the use of delamanid at the dose of tuberculosis in a 12-week intensive phase regimen including ri-
100 mg twice daily for 6 months, added to optimized back- fampicin, isoniazid, and pyrazinamide, no difference was seen in
ground regimen in adults, when pharmacovigilance is in place 12-week culture conversion [64].
and informed consent ensured. Although anecdotal evidence
suggests that delamanid is effective and safe in children [55], Benzothiazinones
2 clinical trials (NCT01859923 and NCT01856634) are study- These new classes of antituberculosis drugs, in preclinical devel-
ing delamanid in the treatment of pediatric MDR tuberculosis. opment phase, are able to inhibit the synthesis of decaprenyl-
Diacon et al assessed the 14-day early bactericidal activity of a phospho-arabinose, the precursor of the arabinans in the
regimen composed of pretomanid, moxifloxacin, and pyrazina- mycobacterial cell wall [23]. Preliminary evidence suggests the
mide, which proved to be significantly higher than that of beda- BTZ043 is potent, with activity against 240 clinical isolates of
quiline alone, bedaquiline plus pyrazinamide, and bedaquiline Mtb, including drug-susceptible, MDR, and XDR tuberculosis.
plus pretomanid (but not to pretomanid plus pyrazinamide), Additive interactions and no antagonism were found between
and comparable to that of the standard treatment regimen (iso- BTZ043 and rifampicin, isoniazid, ethambutol, pretomanid,
niazid, rifampicin, and pyrazinamide with streptomycin or eth- moxifloxacin, meropenem with or without clavulanate, and
ambutol). Interestingly, the addition of pyrazinamide increased SQ109, whereas synergic effects were found combining BTZ043
the activity of both bedaquiline and pretomanid [39, 42, 44, 56]. and bedaquiline (Table 3) [47].
Pharmacokinetic/pharmacodynamic and safety studies are In addition, some repurposed drugs for treatment of MDR/
under way combining bedaquiline and delamanid and, al- XDR tuberculosis (linezolid, clofazimine, moxifloxacin and lev-
though the combination of these is not currently recommended, ofloxacin, meropenem, rifapentine) are summarized in Table 4
outcomes from these studies may change that. [65–83].

REMOX, OFLOTUB, AND RIFAQUIN tuberculosis vaccine efficacy trials, and the effectiveness of
FLUOROQUINOLONE TRIALS other vaccines in clinical development has been brought
under close scrutiny [91, 92]. The post-2015 strategy of the
Recently, 3 trials failed to demonstrate noninferiority of Stop TB Partnership is more ambitious, aiming for a 90% re-
4-month fluoroquinolone-containing regimens compared with duction in tuberculosis incidence by 2035 [1]. Mathematical
standard 6-month therapy. The Rapid Evaluation of Moxiflox- modeling highlights the contribution that an effective vaccine
acin in Tuberculosis (REMoxTB) study was a randomized, dou- could make toward achievement of this goal [93]. Given the cur-
ble-blind, placebo-controlled trial evaluating 2 regimens in rent uncertainty in the field, there is a high risk of failure in the
which either ethambutol or isoniazid was substituted by moxi- development and testing of a new tuberculosis vaccine; howev-
floxacin in a single 4-month combination therapy [84]. The er, as the potential gains in terms of reduced global mortality
Ofloxacine-Containing, Short-Course Regimen for the Treat- and morbidity are also high, clinical development of tuberculo-
ment of Pulmonary Tuberculosis trial [85, 86] evaluated a stan- sis vaccine candidates must continue.
dard 6-month regimen that included ethambutol during the Following the failure of MVA85A, there has been no new,

2-month intensive phase against a 4-month regimen in which high-profile tuberculosis vaccine candidate entering clinical test-
ethambutol was substituted with gatifloxacin during the inten- ing in the last 2 years. The number of candidates in clinical test-
sive phase and continued, along with rifampicin and isoniazid, ing remains at 16 and can be divided into priming vaccines
during the continuation phase. The High-Dose Rifapentine (VPM1002, MTBVAC), prime-boost vaccines (M72 + AS0,
with Moxifloxacin for Pulmonary Tuberculosis trial [87] evalu- MVA85A, Crucell Ad35, Hybrid 1 + IC31, Hybrid 4 + IC31, Hy-
ated 2 regimens in which moxifloxacin replaced isoniazid in an brid 56 + IC31, Ad5Ag85A, ChAdOx1 85A + MVA85A, Combi-
intensive phase. Although these results have been disappoint- nation Crucell Ad35 + MVA85A, DAR-901, ID93 + GLA-SE),
ing, ongoing combination regimens in phase 3 clinical trials and immunotherapeutic vaccines (Mycobacterium indicus pranii,
using existing, repurposed, and new drugs, together with devel- Mycobacterium vaccae, RUTI) [89]. As BCG confers some pro-
opments in adjunct host-directed therapies, provide hope for tection in childhood, the optimum strategy is believed to be a
increasing therapeutic efficacy; shortening treatment duration prime-boost strategy in adolescents or young adults that would
and improving treatment outcomes for drug-susceptible and prevent progression to pulmonary tuberculosis disease. However,
drug-resistant tuberculosis remain global priorities. Rifapentine the incidence of disease in adolescents is lower than that of in-
and clofazimine and high-dose rifampicin are under investiga- fants, and efficacy trials in adolescents would be substantially
tion for treatment-shortening regimens of drug-susceptible tu- larger than the MVA85A infant efficacy trial, which recruited
berculosis, not just for MDR and XDR tuberculosis. 2797 infants and had follow-up for a median of 24.6 months.
Design and selection of future experimental regimens will need to In addition, with a large proportion of the population in tuber-
incorporate a triage process so that accelerated evaluation of treat- culosis-endemic countries already latently infected with tubercu-
ment-shortening regimens can be achieved. Whereas the recent losis, the vaccine candidate likely to have the greatest impact on
phase 3 fluoroquinolone trials have pointed to the difficulty of pre- transmission would be one that worked both before and follow-
dicting successful 4-month regimens using existing biomarkers, an ing latent tuberculosis infection [91].
alternative strategy uses novel trial designs looking at clinically rele- Since 2013, attention has been focused on strategies for re-
vant outcomes as an alternative to biomarkers for screening new ducing the risk of failure in tuberculosis vaccine efficacy trials
drugs or drug combinations. Viable approaches include the multi- with a disease endpoint. Such strategies include improving an-
arm, multistage trial design and other adaptive trial designs [88]. imal models, human challenge models, and prevention of infec-
While optimal drug treatment regimens are developed, even if tion trials. Identifying vaccine failure in preclinical development
they are made up of fewer drugs and are for a shorter duration, it or early clinical development is critical if scarce resources avail-
will be critical that adherence to full-course chemotherapy is mon- able for clinical vaccine testing are to be used most effectively.
itored to minimize the generation of drug resistance. However, uncertainty in how to identify early success or failure
of a tuberculosis vaccine candidate and lack of a correlate of
TUBERCULOSIS VACCINE DEVELOPMENT protection has led to a situation of status quo in the field.
The universal hope that by 2015 a candidate vaccine that would Future Tuberculosis Vaccine Prospects
be able, at least partially, to boost protection induced by BCG Following the recent launch of 2 major tuberculosis vaccine con-
alone would become available from the existing pipeline [89] sortiums funded through the Horizon 2020 European Union
has not materialized. The failure of the MVA85A vaccine to Framework Programme for Research and Innovation, reinvigora-
demonstrate any improvement over BCG in an infant efficacy tion of tuberculosis vaccine development programs is anticipated.
trial [90] has led to reluctance by funders to invest in further The Tuberculosis Vaccine Initiative Consortium (TBVI) was

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Table 3. Summary of the Main New Antituberculosis Drugs With the Most Relevant Studies and Related Findings

Study ID Registration
Drug Class Number Clinical Trial Phase Number Main Findings Reference
Bedaquiline (TMC207) Diarylquinoline TMC207- Phase 2 NCT00449644 The addition of delamanid (TMC207) to OBR reduced the time to C [39]
•
TIDP13- conversion, compared with OBR (HR, 11.8; 95% CI, 2.3–61.3;
P = .003) and increased the proportion of C converters (48% vs
Schito et al
C208
9%). The mean log(10) count of CFU in SS declined more rapidly in
the TMC207 group than in OBR group. No significant differences in
average plasma TMC207 concentrations were noted between
patients with and those without C conversion. Most AE were mild
to moderate.
Delamanid Trial 204 Nitroimidazole 242–07-204 Phase 2 NCT00685360 Among patients who received OBR plus 100 mg of delamanid BID, [40]
(OPC 67 683) 45.4% had C conversion at 2 mo, as compared with 29.6% of
patients receiving OBR (P = .008). As compared with OBR, the
group receiving OBR plus delamanid 200 mg BID had a higher
proportion of SS and C conversion (41.9%, P = .04. Most AEs were
mild to moderate and evenly distributed across groups. Although no
clinical events due to QT prolongation on ECG were observed, QT
prolongation was reported significantly more frequently in the
delamanid groups.
Delamanid Trial 208 Nitroimidazole 242-09-213 Phase 3 NCT01424670 Patients who participated in the previously reported controlled trial of [41]
(OPC 67 683) delamanid and the subsequent open-label extension trial were
eligible to participate in a 24-month observational study designed to
capture treatment outcomes. Favorable outcomes were observed
in 143/192 (74.5%) patients receiving delamanid for ≥6 mo, vs 126/
229 (55%) patients who received delamanid for ≤2 mo. Mortality
was reduced to 1.0% among those receiving long-term delamanid
vs short-term/no delamanid (8.3%; P < .001). Treatment benefit
was also seen among XDR-TB patients.
Pretomanid Trial NC-001 Nitroimidazole NC-001-(J-M- Phase 2 NCT01215851 The mean 14-d EBA of pretomanid (PA-824) -moxifloxacin- [42]
(PA-824) Pa-Z) pyrazinamide (n = 13; 0.233 [SD, 0.128]) was significantly higher
than that of bedaquiline (n = 14; 0.061 [SD, 0.068]), bedaquiline-
pyrazinamide (n = 15; 0.131 [SD, 0.102]), bedaquiline-PA-824
(n = 14; 0.114 [SD, 0.050]), but not PA-824-pyrazinamide (n = 14;
0.154 [SD, 0.040]), and comparable with that of standard treatment
(n = 10; 0.140 [SD, 0.094]). Treatments were well tolerated and
appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide
was withdrawn because of corrected QT interval changes
exceeding prespecified criteria.
Table 3 continued.

Pretomanid Trial NC-002 Nitroimidazole NC-002-(M- Phase 2 NCT01498419 The study evaluated a novel regimen for efficacy and safety in DS and [43]
(PA-824) Pa-Z) MDR-TB during the first 8 wk of treatment. Smear-positive DS,
treatment-naive PTB patients randomized were enrolled to receive
8 wk of moxifloxacin, pretomanid (100 mg) and pyrazinamide
(MPa100Z – regimen 1) or moxifloxacin, pretomanid (200 mg), and
pyrazinamide (MPa200Z- regimen 2) or the current standard
regimen for DS-PTB, (isoniazid, rifampicin, PZA, and ethambutol,
HRZE) as positive control]). A group of MDR participants received
moxifloxacin 400 mg, pretomanid 200 mg, and pyrazinamide 1500
mg (DRMPa200Z). The regimen 1 BA days 0–56 (n = 54; 0.155
[95% BCI, .133–.178]) in DS patients was significantly greater than
for standard regimen (n = 54; 0.112 [95% BCI, .093–.131]).
Regimen 2 had similar BA to regimen standard. The BA days 7–14
was well correlated with BA days 7–56. AEs were equally
distributed among group and control subjects. The most common
AE was hyperuricemia in 59 (28.5%) patients spread similarly
across treatment groups. Other common AEs were nausea in 37
(17.9%) and vomiting in 25 (12.1%) patients. No patient had
corrected QT interval exceeding 500 msec. No phenotypic
resistance developed . The MPaZ combination, previously found to
have promising activity over 14 d in DS-TB, was safe, well tolerated,

and demonstrated superior BA in DS-TB during 8 wk of treatment.
Results were consistent between DS-TB and MDR-TB.
Pretomanid Trial NC-003 Nitroimidazole NC-003-(C-J- Phase 2 NCT01691534 Experimental and clinical evidence suggests that the new drugs [44]
(PA-824) Pa-Z) bedaquiline (Bdq) and pretomanid (Pto), combined with an existing
drug, pyrazinamide (Z), and a repurposed drug, clofazimine (Cfz),
may assist treatment shortening of both DS-TB and DR-TB. The
study evaluated the 14-d early BA of Cfz and Z in monotherapy and
in combinations with Pto and Bdq. Groups of 15 treatment-naive,
SS-positive pulmonary TB patients were randomized to receive
combinations of Bdq with Z-Cfz, Pto-Z, Pto-Z-Cfz and Pto-Cfz, or Cfz
or Z alone, or standard combination treatment for 14 d. The primary
endpoint was the mean daily fall in log10 M. tuberculosis CFU/mL
SS estimated by joint nonlinear mixed effects Bayesian regression
modeling. Results: estimated activities were 0.167 (95% CI,
•
.075–.257) for Bdq-Pto-Z, 0.151 (95% CI, .071–.232) for standard

CID 2015:61 (Suppl 3)
treatment, 0.124 (95% CI, .035–.214) for Bdq-Z-Cfz, 0.115 (95% CI,
.039–.189) for Bdq-Pto-Z-Cfz, and 0.076 (95% CI, .005–.145) for
Bdq-Pto-Cfz. Z alone had modest activity (0.036; 95% CI,
−.026–.099). Cfz had no activity alone (−.017; 95% CI, −.085 to
.053) or in combinations. Treatments were well tolerated and safe.
Bdq-Pto-Z, including 2 novel agents without resistance in prevalent
M. tuberculosis strains, is a potential new TB treatment regimen.
Cfz had no measurable activity in the first 14 d of treatment.
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CID 2015:61 (Suppl 3)

Table 3 continued.
Sutezolid Trial Sutezolid Oxazolidinone B1171003 Phase 2 NCT01225640 All patients completed assigned treatments and began subsequent [45]
•
EBA and WBA (PNU- standard TB treatment according to protocol. The 90% CI for BA in
Schito et al
100480) sputum over the 14-d interval excluded zero for all treatments and
both monitoring methods, as did those for cumulative WBA. There
were no treatment-related serious AEs, premature
discontinuations, or dose reductions due to laboratory
abnormalities. There was no effect on the QT interval. Seven
sutezolid-treated patients (14%) had transient, asymptomatic ALT
elevations to 173 ± 34 U/L on day 14 that subsequently normalized
promptly; none met Hy’s criteria for serious liver injury. The BA of
sutezolid 600 mg BID or 1200 mg OB was readily detected in
sputum and blood. Both schedules were generally safe and well
tolerated.
SQ109 Trial SQ109-01 Ethylenediamine LMU-IMPH- Phase 2 NCT01218217 This first study in patients was done to determine safety, tolerability, [46]
SQ109-01 pharmacokinetics, and bacteriological effect of different doses of
SQ109 alone and in combination with rifampicin when
administered over 14 d. SQ109 was safe and generally well
tolerated. Mild to moderate dose-dependent gastrointestinal
complaints were the most frequent adverse events. No relevant QT
prolongation was noted. Maximum SQ109 plasma concentrations
were lower than MICs. Exposure to SQ109 (AUC0-24) increased by
drug accumulation upon repeated administration in the SQ109
monotherapy groups. Coadministration of SQ109 150 mg with
rifampicin resulted in decreasing SQ109 exposures from day 1 to
day 14. A higher (300 mg) dose of SQ109 largely outweighed the
evolving inductive effect of rifampicin. The daily fall in log CFU/mL
of sputum was 0.093 (95% CI, .126–.059) with rifampicin, 0.133
(95% CI, .166–.100) with rifampicin plus 150 mg of SQ109 and
0.089 (95% CI, .121–.057) with rifampicin plus 300 mg of SQ109.
Treatments with SQ109 alone showed no significant activity.
SQ109 alone or with rifampicin was safe over 14 d. Upon
coadministration with rifampicin, 300 mg of SQ109 yielded a higher
exposure than the 150-mg dose. SQ109 did not appear to be active
alone or to enhance the activity of rifampicin during the 14 d of
treatment.
Table 3 continued.
Benzothiazinones (BTZ043) 2-[(2S)-2-methyl-1,4- Preclinical The authors studied the interaction profiles of BTZ043, the current [47]
dioxa-8-azaspiro development lead compound, with several anti-TB drugs or drug candidates
[4.5]dec-8-yl]-8- phases against M. tuberculosis strain H37Rv, namely, rifampicin, isoniazid,
nitro-6- ethambutol, delamanid, pretomanid (PA-824), moxifloxacin,
trifluoromethyl- meropenem with or without clavulanate, and SQ-109. No
4H-1,3- antagonism was found between BTZ043 and the tested
benzothiazin-4- compounds, and most of the interactions were purely additive.
one/Rv3790 - BTZ043 acts synergistically with delamanid, with a fractional
inhibitory concentration index of 0.5. TMC207 at a quarter of the
MIC (20 ng/mL) used in combination with BTZ043 (1/4 MIC, 0.375
ng/mL) had a stronger bactericidal effect on M. tuberculosis than

delamanid alone at a concentration of 80 ng/mL. This synergy was
not observed when the combination was tested on a BTZ-resistant
M. tuberculosis mutant, suggesting that DprE1 inhibition is the
basis for the interaction. This finding excludes the possibility of
synergy occurring through an off-target mechanism. The authors
hypothesize that sub-MICs of BTZ043 weaken the bacterial cell wall
and allow improved penetration of delamanid to its target. Synergy
between 2 new antimycobacterial compounds, (delamanid and
BTZ043), with novel targets, offers an attractive foundation for a
new anti-TB regimen.
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; BA, bactericidal activity; BCI, Bayesian credibility interval; BID, twice daily; BTZ, benzothiazinone; C, culture; CFU, colony-forming unit; CI, confidence
interval; DR-TB, drug-resistant tuberculosis; DS-TB, drug-susceptible tuberculosis; EBA, early bactericidal activity; ECG, electrocardiogram; HR, hazard ratio; HRZE, isoniazid rifampin pyrazinamide ethambutol; MDR-TB,
multidrug-resistant tuberculosis; MIC, minimum inhibitory concentration; MPaZ, moxifloxacin Pa824 pyrazinamide; OB, once daily; OBR, optimized background regimen; PTB, pulmonary tuberculosis; PZA,
pyrazinamide; QT, QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle; SS, sputum smear; TB, tuberculosis; WBA, whole-blood
•
bactericidal activity; XDR-TB, extensively drug-resistant tuberculosis.

CID 2015:61 (Suppl 3)
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Table 4. Summary of the Main Reproposed Antituberculosis Drugs With the Most Relevant Studies and Related Findings
CID 2015:61 (Suppl 3)
Drug Class Main Findings Reference

Linezolid Oxazolidinone Systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data [65]
analysis based on 12 studies (11 countries from 3 continents) reporting complete information on safety, tolerability, efficacy of
linezolid-containing regimes in treating MDR-TB cases. Most MDR-TB cases achieved SS (86/93 [92.5%]) and C (100/107
[93.5%]) conversion after treatment with individualized regimens containing linezolid (median [interquartile range] times for SS
and C conversions were 43.5 [21–90] and 61 [29–119] days, respectively), and 99/121 (81.8%) patients were successfully
treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 mg vs >600
•
mg). AEs were observed in 63/107 (58.9%) patients, of which 54/79 (68.4%) were major AEs that included anemia (38.1%),
Schito et al
peripheral neuropathy (47.1%), gastrointestinal disorders (16.7%), optic neuritis (13.2%), and thrombocytopenia (11.8%). The
proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results
suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.
Retrospective, nonrandomized, unblinded observational study evaluating safety and tolerability of linezolid (600 mg OD or BID). [66]
in MDR/XDR-TB treatment in 4 European countries. Out of 195 MDR/XDR-TB patients, 85 were treated with linezolid for a
mean of 221 d. Of these, 35/85 (41.2%) experienced major AEs attributed to linezolid (anaemia, thrombocytopenia and/or
polyneuropathy), requiring discontinuation in 27 (77%) cases. Most AEs occurred after 60 d of treatment. Twice-daily
administration produced more major AE than once-daily dosing (P = .0004), with no difference in efficacy found. Outcomes
were similar in patients treated with/without linezolid (P = .8), although linezolid-treated cases had more first-line (P = .002) and
second-line (P = .02) drug resistance and a higher number of previous treatment regimens (4.5 vs 2.3; P = .07). Linezolid 600
mg OD added to an individualized multidrug regimen may improve the chance of bacteriological conversion, providing a better
chance of treatment success in only the most complicated MDR/XDR-TB cases. Its safety profile does not warrant use in
cases for which there are other, safer, alternatives.
Forty-one patients were enrolled, who had C-positive XDR-TB and who had not had a response to any available [67]
chemotherapeutic option during the previous 6 mo. Patients were randomly assigned to linezolid therapy that started
immediately or after 2 mo, at a dose of 600 mg per day, without a change in their OBR. The primary endpoint was the time to
SS/C conversion on solid medium, with data censored 4 mo after study entry. By 4 mo, 15/19 patients (79%) in the immediate-
start group and 7/20 (35%) in the delayed-start group had C conversion (P = .001). In addition, 34/39 patients (87%) had a
negative C within 6 mo after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31
(82%) had clinically significant AEs that were possibly or probably related to linezolid, including 3 patients who discontinued
therapy. Patients who received 300 mg per day after the second randomization had fewer AEs than those who continued
taking 600 mg per day. 13 patients completed therapy and have not had a relapse. 4 cases of acquired resistance to linezolid
have been observed. Linezolid is effective at achieving C conversion among patients with treatment-refractory pulmonary
XDR-TB, but patients must be monitored carefully for AEs.
The authors evaluated treatment with linezolid (800 mg once daily for 1 to 4 mo as guided by SS/C status and tolerance and then [68]
at 1200 mg thrice weekly until ≥1 y after C conversion), in addition to OBD among 10 consecutive patients with XDR-TB or
fluoroquinolone-resistant MDR-TB. All achieved stable cure, with anemia corrected and neuropathy stabilized, ameliorated, or
avoided after switching to intermittent dosing. Serum linezolid profiles appeared better optimized.
Prospective pharmacokinetic study aimed at quantifying the effect of clarithromycin on the exposure of linezolid. All subjects [69]
received 300 mg linezolid twice daily during the entire study, consecutively coadministered with 250 mg and 500 mg
clarithromycin once daily. Linezolid exposure increased by a median of 44% (interquartile range, 23%–102%, P = .043) after
coadministration of 500 mg clarithromycin (n = 5) vs baseline, whereas 250 mg clarithromycin had no statistically significant
effect. Coadministration was well tolerated by most patients; none experienced severe AE. One patient reported common
toxicity criteria grade 2 gastrointestinal AE. Clarithromycin significantly increased linezolid serum exposure after combining
clarithromycin with linezolid in MDR-TB patients. The drug–drug interaction is possibly P-glycoprotein-mediated. Due to large
interpatient variability, TDM is advisable to determine individual effect size.
Table 4 continued.

Clofazimine Riminophenazine A systematic review of studies reporting on the efficacy and safety of clofazimine as part of combination therapy for DR-TB (12 [70]
studies, comprising 3489 patients across 10 countries). Treatment success ranged from 16.5% (95% CI, 2.7%–38.7%) to
87.8% (95% CI, 76.8%–95.6%), with an overall pooled proportion of 61.96% achieving treatment success (95% CI, 52.79%–
71.12%) (τ2 0.07). Mortality, treatment interruptions, defaulting, and AEs were all in line with DR-TB treatment outcomes
overall. The most commonly reported AEs were gastrointestinal disturbances and skin pigmentation. Clofazimine could be
considered as an additional therapeutic option in the treatment of DR-TB. The optimal dose of clofazimine and duration of use
require further investigation.
The authors searched multiple databases for studies published through February 2012 that reported use of Clofazimine in MDR- [71]
and XDR-TB treatment regimens. They identified 9 observational studies (6 MDR-TB and 3 XDR-TB) including patients with
MDR-TB treated with clofazimine. Overall, 65% (95% CI, 54–76) of the patients experienced favorable outcomes (cure or
treatment completion). Using random-effects meta-analysis, 65% (95% CI, 52–79) of those with MDR-TB and 66% (95% CI,
42–89) of those with XDR-TB experienced favorable treatment outcomes.
The authors reported the treatment outcome of all patients with MDR-TB enrolled from May 1997 to December 2007. The most [72]
effective treatment regimen (among 6 standardized treatment regimens) required a minimum of 9 mo of treatment with
gatifloxacin, clofazimine, ethambutol, and pyrazinamide throughout the treatment period supplemented by prothionamide,
kanamycin, and high-dose isoniazid during an intensive phase of a minimum of 4 mo, giving a relapse-free cure of 87.9% (95%
CI, 82.7–91.6) among 206 patients. Major AEs were infrequent and manageable. Compared with the 221 patients treated with
regimens based on ofloxacin and commonly prothionamide throughout, the HR of any adverse outcome was 0.39 (95% CI,
.26–.59). Serial regimen formulation guided by overall treatment effectiveness resulted in treatment outcomes comparable to
those obtained with first-line treatment.
The study was aimed to directly compare the activity of a standard second-line drug regimen with or without the addition of [73]
clofazimine in a mouse model of MDR-TB. Our comparative outcomes included time to C conversion in the mouse lungs and
the percentage of relapses after treatment cessation. After 2 mo, the bacillary load in lungs was reduced from 9.74 log10 at
baseline to 3.61 and 4.68 in mice treated with or without clofazimine, respectively (P < .001). Mice treated with clofazimine
were C-negative after 5 mo, whereas all mice treated without clofazimine remained heavily C-positive for the entire 9 mo of
the study. The relapse rate was 7% among mice treated with clofazimine for 8–9 mo. The clofazimine contribution was
substantial in these experimental conditions
Moxifloxacin Fluoroquinolone The study compared the efficacy of moxifloxacin (M) and high-dose levofloxacin (L) alone or in combination with ethionamide [74]
(Et), amikacin (A), and pyrazinamide (Z) given for 2 or 7 mo. After 2 mo of treatment, lung CFU counts were similar in mice
receiving either FQ alone, but, after 4 and 5 mo, CFU counts were 2 log10 lower in mice receiving moxifloxacin. Mice receiving
2MEtZA/3MEt and 2LEtZA/3LEt had 1.0 and 2.7 log10 lung CFUs, respectively. When Z was given throughout, both regimens
rendered mice culture negative by 5 mo, and most mice did not relapse after 7 mo of treatment, with fewer relapses observed
in the M group after 6 and 7 mo of treatment. In murine TB, M had superior efficacy compared with L despite lower serum drug
exposures and may remain the fluoroquinolone of choice for second-line regimens. Z contributed substantial sterilizing activity
beyond 2 mo in FQ-containing second-line regimens, largely compensating for L’s weaker activity.
•
CID 2015:61 (Suppl 3)
The study was aimed to compare the antimicrobial activity and safety of MXF vs isoniazid during the first 8 wk of combination [75]
therapy for pulmonary TB. Of 433 participants enrolled, 328 were eligible for the primary efficacy analysis. Of these, 35 (11%)
were HIV positive, 248 (76%) had cavitation on baseline chest radiograph, and 213 (65%) were enrolled at African sites.
Negative C at week 8 were observed in 90/164 (54.9%) participants in the isoniazid arm, and 99/164 (60.4%) in the MXF arm
(P = .37). In multivariate analysis, cavitation and enrollment at an African site were associated with lower likelihood of week 8 C
negativity. The proportion of participants who discontinued assigned treatment was 31/214 (14.5%) for the MXF group vs 22/
205 (10.7%) for the isoniazid group (RR, 1.35; 95% CI, .81–2.25). Substitution of MXF for isoniazid resulted in a small but
statistically nonsignificant increase in week 8 C negativity.
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Table 4 continued.
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Levofloxacin Fluoroquinolone The study was aimed to compare the effectiveness of LFX and MXF in terms of C conversion after 3 mo of treatment for MDR- [76]

TB (182 patients with MDR-TB, sensitive to LFX and MXF). At 3 mo of treatment, 68 (88.3%) of the 77 patients in the LFX
group and 67 (90.5%) of the 74 in the MXF group showed conversion to negative C (OR for LFX compared with MXF, 0.78;
95%, CI, .27–2.20). AEs were reported in 6 patients (7.7%) in the LFX group and 4 (5.2%) in the MXF group (P = .75). The
choice of LFX or MXF for treatment of patients with MDR-TB may not affect sputum C conversion at 3 mo of treatment.
The use of FQs to treat lower LTRIs other than TB allows selection of FQ-resistant TB when TB is misdiagnosed. This study maps [77]
national guidelines on the use of FQs for LRTIs in Europe and determines the risk of FQ-resistant TB upon FQ treatment before
•
TB diagnosis. A questionnaire was developed to map existing national LRTI and CAP guidelines. A systematic review and
Schito et al
meta-analysis were performed to determine the risk of FQ-resistant TB if prescribed FQs prior to TB diagnosis. 15 of 24 (80%)
responding European Respiratory Society national delegates reported having national LRTI management guidelines, 7
including recommendations on FQ use and 1 recommending FQs as the first-choice drug. 18/24 countries had national CAP
management guidelines, 2 recommending FQ as the drug of choice. 6 studies investigating FQ exposure and the risk of FQ-
resistant TB were analyzed. TB patients had a 3-fold higher risk of having FQ-resistant TB when prescribed FQs before TB
diagnosis, compared to non-FQ-exposed patients (OR, 2.81, 95% CI, 1.47–5.39). Although the majority of European countries
hold national LRTI/CAP guidelines, the results suggest that a risk of developing FQ resistance exists.
Meropenem- Carbapenem- Clavulanic The study was aimed to evaluate the contribution of meropenem-clavulanate when added to linezolid-containing regimens in [78]
clavulanate acid terms of efficacy and safety/tolerability in treating MDR- and XDR- TB cases after 3 mo of second-line treatment. The clinical
severity of cases was worse than that of controls (drug susceptibility profile, proportion of SS positive and of re-treatment
cases). The group of cases yielded a higher proportion of SS converters (28/32 [87.5%] vs 9/16 [56.3%]; P = .02) and C
converters (31/37 [83.8%] vs 15 /24 [62.5%]; P = .06). Excluding XDR-TB patients (11/98 [11.2%]), cases scored a significantly
higher proportion of C converters than controls (P = .03). One case had to withdraw from meropenem-clavulanate due to
increased transaminase levels. The results of our study provide: (1) preliminary evidence on effectiveness and safety/
tolerability of meropenem-clavulanate; (2) reference to design further trials; and (3) a guide to clinicians for its rationale use
within salvage/compassionate regimens.
Rifapentine Rifamycins The study aimed to compare rifapentine and isoniazid once a week with rifampicin and isoniazid twice a week. 1004 patients [79]
were enrolled (502 per treatment group); 928 successfully completed treatment, and 803 completed the 28-mo study. Crude
rates of failure/relapse were 46/502 (9.2%) in those on rifapentine once a week, and 28/502 (5.6%) in those given rifampicin
twice a week (relative risk 1.64, 95% CI, 1.04–2.58, P = .04). By proportional hazards regression, 5 characteristics were
independently associated with increased risk of failure/relapse: C-positive at 2 mo (HR, 2.8; 95% CI, 1.7–4.6); cavitation on
chest radiography (HR, 3.0; 95% CI, 1.6–5.9); being underweight (HR, 3.0; 95% CI, 1.8–4.9); bilateral pulmonary involvement
(HR, 1.8; 95% CI, 1.0–3.1); and being a non-Hispanic white person (HR, 1.8; 95% CI, 1.1–3.0). Adjustment for imbalances in 2-
month C and cavitation diminished the association of treatment group with outcome (HR, 1.34; 95% CI, .83–2.18; P = .23). Of
participants without cavitation, rates of failure/relapse were 6/210 (2.9%) in the once a week group and 6/241 (2.5%) in the
twice a week group (RR, 1.15; 95% CI, .38–3.50; P = .81). Rates of AEs and death were similar in the 2 treatment groups.
Rifapentine once a week is safe and effective for treatment of pulmonary TB in HIV-negative people without cavitation on
chest radiography. Clinical, radiographic, and microbiological data help to identify TB patients at increased risk of failure or
relapse when treated with either regimen
The study compared the antimicrobial activity and safety of rifapentine vs rifampicin during the first 8 wks of pulmonary TB [80]
treatment (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Negative C on solid media occurred in 145/174
participants (83.3%) in the rifampicin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%;
95% CI, −4.3 to 10.5); negative C in liquid media occurred in 110/169 (65.1%) in the rifampicin group and 133/196 (67.9%) in
the rifapentine group (difference, 2.8%; 95% CI, −6.9 to 12.4). Among 529 participants who received study therapy, 40/254
participants (15.7%) in the rifampicin group and 40/275 participants (14.5%) in the rifapentine group prematurely discontinued
treatment (P = .79). The rifapentine regimen was safe but not significantly more active than a standard rifampicin regimen, by
the surrogate endpoint of C status at completion of intensive phase.
granted €24.6 million from the European Commission and other
Reference
Abbreviations: τ2, tau-squared statistic; AE, adverse events; BID, twice daily; C, culture; CAP, community-acquired pneumonia; CFU, colony-forming unit; CI, confidence interval; DR-TB, drug- resistant tuberculosis; FQ,
fluoroquinolone; HIV, human immunodeficiency virus; HR, hazard ratio; LFX, levofloxacin; LTRI, respiratory tract infections; MDR-TB, multidrug-resistant tuberculosis; MXF, moxifloxacin; OB, once daily; OBR, optimized
background regimen; OR, odds ratio; RR, relative risk; SS, sputum smear; SS/C, sputum smear and culture; TB, tuberculosis; TDM, therapeutic drug monitoring; XDR-TB, extensively drug-resistant tuberculosis.
[81]
government sources for TBVAC2020, which aims to discover
and develop new tuberculosis vaccines (www.TBVI.eu). The
EMI-TB Consortium (Eliciting Mucosal Immunity in Tubercu-
to prevent relapse in all mice. Rifapentine should no longer be viewed solely as a rifamycin for once-weekly administration. The
Bactericidal activity was assessed by lung CFU counts, and sterilizing activity was assessed by the proportion of mice with C-
and thrice-weekly administered rifapentine- and MXF-containing regimens, whereas the standard daily regimen required 6 mo
regimen still harbored 3.17 log10 CFU in the lungs (P < .01). No relapse was observed after just 3 mo of treatment with daily
rifapentine- and MXF-containing regimens with that of the standard daily short-course regimen based on rifampicin, isoniazid,
results suggest that treatment regimens based on daily and thrice-weekly administration of rifapentine and MXF may permit
positive relapse after 2, 3, 4, and 6 mo of treatment. The results demonstrate that replacing rifampicin with rifapentine and
losis), led by the Institute for Infection and Immunity, St Georg-
receiving rifapentine- and MXF-containing regimens were found to have negative lung C, while those given the standard
Using a mouse model with a high bacterial burden and human-equivalent drug dosing, the study compared the efficacy of
isoniazid with MXF dramatically increased the activity of the standard daily regimen. After just 2 mo of treatment, mice
e’s University, London, was awarded €8 million to establish
effective mucosal immunity against Mtb (http://www.emi-tb.
org/). Both consortiums will be generating vaccine candidates
for clinical testing, and with renewed activity in preclinical de-
velopment, there is a need to prepare for future screening and
testing of these candidates.
In addition, the Global Tuberculosis Vaccine Partnership
(GTBVP), a global initiative working on tuberculosis vaccines,

is now being established. The GTBVP includes the European
Commission, the European Investment Bank, the Bill & Melinda
Gates Foundation, and the Department of Science and Technol-
ogy South Africa in collaboration with Aeras, TBVI, the South
African Medical Research Council, and the European and De-
veloping Countries Clinical Trials Partnership. The aim of the
Main Findings
shortening the current 6 mo duration of treatment to 3 mo or less.
GTBVP is to mobilize and optimize use of globally available

funds to manage the global vaccine pipeline efficiently and ef-
fectively, to provide a rational process for selecting the best can-
didates and help them to move forward into the clinical
development, while ensuring they comply with established
and consensed criteria at the global level.
Preparation for clinical testing of a vaccine can substantially
accelerate the progression of a candidate. Recent studies have
shown that a subunit vaccine can be delivered safely to the
lung using an aerosol delivery device in both nonhuman primates
and humans Although these studies were performed with
MVA85A, the proof-of-concept safety and immunogenicity
data generated from this study [94, 95] will accelerate the clinical
and pyrazinamide.
testing of aerosol vaccines emerging from the TBVAC2020 and

EMI-TB consortiums.
CONCLUSIONS
The current status quo of the lengthy treatment duration and

poor treatment outcomes associated with MDR/XDR tuberculo-
sis, and with comorbidity of tuberculosis with HIV and noncom-
municable diseases, is unacceptable. New innovations for
Class
shortening duration of therapy and improving treatment out-

comes are urgently required. The tuberculosis drug pipeline re-
mains sparse. The tuberculosis drug pipeline remains thin [57].
A range of host-directed therapies, including cellular therapy, re-
purposed drugs, and immune-based therapies, are emerging [96–
Table 4 continued.
101] and provide hope for reducing duration of therapy and im-
proving treatment of MDR tuberculosis. These require evaluation
in randomized, placebo-controlled clinical trials as adjuncts to
current tuberculosis treatment regimens. Meanwhile, proactive
Drug
screening for tuberculosis using best available diagnostics, making

an accurate, early diagnosis of drug-sensitive or drug-resistant tu- 13. Theron G, Zijenah L, Chanda D, et al. Feasibility, accuracy, and clinical
effect of point-of-care Xpert MTB/RIF testing for tuberculosis in pri-
berculosis, and initiating the most appropriate tuberculosis treat-
mary-care settings in Africa: a multicentre, randomised, controlled
ment regimen is crucial in detecting missed cases of tuberculosis trial. Lancet 2014; 383:424–35.
and reducing morbidity, mortality, and further transmission 14. Durovni B, Saraceni V, van den Hof S, et al. Impact of replacing smear
within the community. New innovations for early, rapid diagnosis microscopy with Xpert MTB/RIF for diagnosing tuberculosis in Brazil: a
stepped-wedge cluster-randomized trial. PLoS Med 2014; 11:e1001766.
at points of care, for shortening duration of therapy and improv- 15. Raizada N, Sachdeva KS, Sreenivas A, et al. Feasibility of decentralised
ing treatment outcomes of MDR tuberculosis, and for prevention deployment of Xpert MTB/RIF test at lower level of health system in
are urgently required. India. PLoS One 2014; 9:e89301.
16. Creswell J, Codlin AJ, Andre E, et al. Results from early programmatic
implementation of Xpert MTB/RIF testing in nine countries. BMC In-
Notes
fect Dis 2014; 14:2.
Supplement sponsorship. This article appears as part of the supplement 17. McNerney R, Cunningham J, Hepple P, Zumla A. New tuberculosis
“Advances in Tuberculosis Research: A Blueprint for Opportunities.” This diagnostics and rollout. Int J Infect Dis 2015; 32:81–6.
article was sponsored by the Division of AIDS, National Institute of Allergy 18. Alland D, Rowneki M, Smith L, et al. Xpert MTB/RIF Ultra: a new
near-patient TB test with sensitivity equal to culture. In: Conference

and Infectious Diseases, National Institutes of Health.
Potential conflicts of interest. All authors: No potential conflicts of on Retroviral and Opportunistic Infections, Seattle, WA, 2015.
interest. 19. Molbio Diagnostics. Truenat MTB chip-based real time PCR test for
All authors have submitted the ICMJE Form for Disclosure of Potential Mycobacterium tuberculosis [ package insert], 2014.
Conflicts of Interest. Conflicts that the editors consider relevant to the con- 20. Nikam C, Jagannath M, Narayanan MM, et al. Rapid diagnosis of My-
tent of the manuscript have been disclosed. cobacterium tuberculosis with Truenat MTB: a near-care approach.
PLoS One 2013; 8:e51121.
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SUPPLEMENT ARTICLE

Perspectives on Advances in Tuberculosis

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All authors contributed equally to this work.

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Advantages Beneficiaries Risks Victims

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Advances in Clinical Tuberculosis Research • CID 2015:61 (Suppl 3) • S107

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have promising activity over 14 d in DS-TB, was safe, well tolerated,

.075–.257) for Bdq-Pto-Z, 0.151 (95% CI, .071–.232) for standard

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ng/mL) had a stronger bactericidal effect on M. tuberculosis than

bactericidal activity; XDR-TB, extensively drug-resistant tuberculosis.

Drug Class Main Findings Reference

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Drug Class Main Findings Reference

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Drug Class Main Findings Reference

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shortening the current 6 mo duration of treatment to 3 mo or less.

GTBVP is to mobilize and optimize use of globally available

testing of aerosol vaccines emerging from the TBVAC2020 and

The current status quo of the lengthy treatment duration and

shortening duration of therapy and improving treatment out-

screening for tuberculosis using best available diagnostics, making

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