Review

New antituberculosis drugs, regimens, and adjunct

therapies: needs, advances, and future prospects
Alimuddin I Zumla, Stephen H Gillespie, Michael Hoelscher, Patrick P J Philips, Stewart T Cole, Ibrahim Abubakar, Timothy D McHugh,
Marco Schito, Markus Maeurer, Andrew J Nunn

About 1·3 million people died of tuberculosis in 2012, despite availability of effective drug treatment. Barriers to Lancet Infect Dis 2014;
improvements in outcomes include long treatment duration (resulting in poor patient adherence and loss of patients 14: 327–40

to follow-up), complex regimens that involve expensive and toxic drugs, toxic effects when given with antiretroviral Published Online
March 24, 2014
therapy, and multidrug resistance. After 50 years of no antituberculosis drug development, a promising pipeline is
http://dx.doi.org/10.1016/
emerging through the repurposing of old drugs, re-engineering of existing antibacterial compounds, and discovery of S1473-3099(13)70328-1
new compounds. A range of novel antituberculosis drugs are in preclinical development, several phase 2 and 3 trials Centre for Clinical
are underway, and use of adjunct therapies is being explored for drug-sensitive and drug-resistant tuberculosis. Microbiology, Division of
Historical advances include approval of two new drugs, delamanid and bedaquiline. Combinations of new and Infection and Immunity,
University College London,
existing drugs are being assessed to shorten the duration of therapy and to treat multidrug-resistant tuberculosis.
London, UK
There has also been progress in development of new antituberculosis drugs that are active against dormant or (Prof A I Zumla FRCP,
persister populations of Mycobacterium tuberculosis. In this Review, we discuss recent advances in antituberculosis Prof T D McHugh PhD);
drug discovery and development, clinical trial designs, laboratory methods, and adjunct host-directed therapies, and University College London
Hospitals NHS Foundation
we provide an update of phase 3 trials of various fluoroquinolones (RIFAQUIN, NIRT, OFLOTUB, and REMoxTB).
Trust, London, UK
We also emphasise the need to engage the community in design, implementation, and uptake of research, to increase (Prof A I Zumla); School of
international cooperation between drug developers and health-care providers adopting new regimens. Medicine, University of
St Andrews, St Andrews, UK
(Prof S H Gillespie DSc);
Introduction provided the first hope for tuberculosis drug treatment.6 Department for Infectious
In 1993, WHO declared tuberculosis a global public Results of small observational studies of streptomycin in Diseases and Tropical Medicine,
health emergency.1 Authors of the 18th WHO Global human tuberculosis infections were promising, but its University of Munich, Munich,
Tuberculosis Report2 estimated that the number of ability to consistently cure patients and to combat Germany
(Prof M Hoelscher FRCP);
incident cases of tuberculosis worldwide in 2012 was tuberculosis was unknown. The UK Medical Research German Centre for Infection
8·6 million, including 2·9 million cases in women and Council Tuberculosis Unit led the way for the first Research, Munich, Germany
530 000 in children. Tuberculosis caused 1·3 million investigation of its kind (the randomised controlled trial) (Prof M Hoelscher); Medical
deaths, including 320 000 deaths in people with HIV. for assessment of new antituberculosis drugs7,8 and Research Council Clinical Trials
Unit at University College
About 170 000 deaths were caused by multidrug-resistant showed that drug resistance develops rapidly when one London, London, UK
tuberculosis, a relatively high total when compared with drug is used for treatment. Findings showed efficacy of (P P J Phillips PhD,
the estimated 450 000 global incident cases of multidrug- streptomycin at 6 months (27% of patients receiving Prof I Abubakar FRCP,
resistant tuberculosis. Only about a fifth of the bedrest died compared with 7% who received Prof A J Nunn MSc); Global
Health Institute, Ecole
450 000 people estimated to have developed multidrug- streptomycin), although the 5 year follow-up data showed Polytechnique Fédérale de
resistant tuberculosis in 2012 were actually detected, no benefit since death rates (58% death rate in those Lausanne, EPFLSV/GHI/UPCOL,
raising major issues about the quality of laboratory and given streptomycin vs 76% in controls) were effectively Lausanne, Switzerland
tuberculosis services. Moreover, of the 94 000 people who the same and almost all patients acquired streptomycin (Prof S T Cole FRS); Henry M
Jackson Foundation-Division of
were detected as eligible for treatment for multidrug- resistance.7,8 Several other antituberculosis drugs were AIDS, TB Clinical Research
resistant tuberculosis in 2012, only 77 000 patients were discovered and developed in the 1950s, including Branch, National Institute of
actually started on treatment2 because second-line aminosalicylic acid, isoniazid, pyrazinamide, cycloserine, Allergy and Infectious Diseases,
National Institutes of Health,
antituberculosis drugs were not available.3,4 In this and kanamycin. These discoveries paved the way for
Bethesda, MD, USA
Review, we assess advances in antituberculosis drug combination therapy, which generally lasted 18 months (M Schito PhD); and Centre for
discovery and development, explore the results of or longer and evolved from the results of a series of Allogeneic Stem Cell
continuing and recently completed phase 2 and 3 trials, clinical trials. A major breakthrough came in the 1960s Transplantation, Therapeutic
Immunology Division,
and present an overview of new clinical trial designs, with the introduction of rifampicin because this allowed
Department of Laboratory
laboratory methods, and adjunct host-directed therapies. treatment duration to be shortened to 9 months. The Medicine, Karolinska Institutet,
reintroduction of pyrazinamide at a lower dose than was Stockholm, Sweden
Historical perspective previously used enabled the creation of the widely used (Prof M Maeurer MD)
Aug 23, 2013, marked the 70th anniversary of current regimen. Researchers also discovered the weaker Correspondence to:
Prof Alimuddin I Zumla, Centre
experiment 11, “Antagonistic Actinomycetes” done by drug ethambutol in the 1960s.8
for Clinical Microbiology,
Albert Schatz at Rutgers University, part of a series of Division of Infection and
experiments that led to the discovery of streptomycin, an Need for new antituberculosis drugs and Immunity, Royal Free Campus,
antibiotic purified from Streptomyces griseus and the first regimens University College London,
London W1T 4JF, UK
substance with an effective bactericidal action against Although current treatment regimens for drug-sensitive a.zumla@ucl.ac.uk
M tuberculosis.5 Within 1 year of its discovery, streptomycin tuberculosis are highly effective when adherence of

www.thelancet.com/infection Vol 14 April 2014 327

 Review
patients is optimum and under trial conditions,9–11
outcomes are far from ideal when given in the realities of
real-life tuberculosis programmatic conditions. WHO-
recommended treatment regimens for drug-sensitive12
and drug-resistant tuberculosis13 have several inherent
problems, making new antituberculosis drugs and
treatment regimens a clinical and public health priority.
The first problem is that treatment of drug-sensitive
disease is long—lasting at least 6 months.12 Furthermore,
all four of the most effective first-line oral drugs
(rifampicin, isoniazid, pyrazinamide, and ethambutol)
must be taken together during the first 2 months of
treatment, and two (rifampicin and isoniazid) for a
subsequent 4 months in the continuation phase, causing
issues with patient adherence. When given in
suboptimum programmatic conditions, these regimens
are associated with high rates of non-adherence and
increased mortality, and can create chronic cases of
infectious drug-resistant tuberculosis.14 Thus, a priority
for drug development has been for new tuberculosis
drugs that will shorten regimens. Potent sterilising drugs
that can shorten treatment duration to 2 months or less
would improve adherence, and reduce programme
supervision and distribution costs. Furthermore, drugs
that would reduce both total length of treatment and
frequency of drug intake would be ideal. Studies of the
lifecycle of M tuberculosis have shown that mycobacteria
develop a dormancy phenotype under conditions of
anaerobiosis and nutrient depletion.15–18 Bacterial
populations of persisters can last for up to 100 days after
the start of antituberculosis treatment16 and need
resuscitation promotion factor for replication to trigger
rapid multiplication of dormant bacilli.19 These dormant
bacteria are tolerant to many antituberculosis drugs,
which is one reason why a lengthy duration of
antituberculosis treatment is required.20 Thus, new drugs
and regimens are needed so that all persisters can be
killed, whatever the stage of development M tuberculosis
bacilli have reached.20
Second, new drugs are needed to tackle the growing
global problem of multidrug-resistant and extensively
drug-resistant tuberculosis.21 Multidrug-resistant tuber-
culosis, caused by M tuberculosis bacilli resistant to at least
isoniazid and rifampicin, is now widespread throughout
the world, with about half a million cases reported in
2012.2 Extensively drug-resistant tuberculosis (resistance
to rifampicin, isoniazid, plus any fluoroquinolone, and at
least one of three injectable second-line drugs: amikacin,
kanamycin, or capreomycin) has been reported in
92 countries.2 Patients with multidrug-resistant tuber-
culosis need a combination of second-line and third-line
antituberculosis drugs,22,23 which are much more
expensive, more toxic, and less effective than are standard
treatments. WHO recommendations for the treatment of
multidrug-resistant or extensively drug-resistant tuber-
culosis include second-line drugs and a treatment duration
of 18–24 months or longer.13,14 These guidelines are based
328
on low-grade evidence, expert opinion, and little
observational data, and do not have the rigour of
evidence based on data from randomised controlled
trials. Implementation of these guidelines results in a
wide range of treatment regimens that are dependent on
the availability of drug-susceptibility testing, cost,
physician preference, and drug availability in developing
countries. Thus, new regimens for multidrug-resistant
or extensively drug-resistant tuberculosis that are
shorter, more tolerable, and more effective, and have
been trialled under programmatic conditions, are
urgently needed.21
Third, antituberculosis drugs can interact with
antiretroviral therapy (ART), which poses an enormous
management problem in sub-Saharan Africa where
tuberculosis cases are driven mainly by the HIV
epidemic.24 Fourth, new therapies are needed for
improved treatment of persons with latent tuberculosis
infection from both drug-sensitive and drug-resistant
strains of M tuberculosis before it converts into active
disease. WHO estimates that about 2 billion people have
latent tuberculosis infection,25,26 and more than
100 million people with latent tuberculosis infection will
develop active disease during their lifetime. Although
the incidence of tuberculosis is relatively low in
developed countries, reactivation of latent tuberculosis
infection in local and migrant communities account for
a large tuberculosis burden.27 New antituberculosis
drugs and other intervention strategies28–30 to improve
treatment of latent tuberculosis infection are seen as the
way forward for elimination of tuberculosis.
Therefore, new antituberculosis drugs should have a
good safety profile, be more potent than existing drugs,
be able to reduce the duration of therapy, be effective to
treat multidrug-resistant and extensively drug-resistant
tuberculosis, be compatible with concomitant ART, and
have no antagonistic activity against other tuberculosis
drugs in the treatment regimen. For treatment of latent
tuberculosis infection, drugs should be effective against
the various replication and physiological states of
M tuberculosis.20,26,29
Discovery of new tuberculosis drugs
In February, 2000, representatives from academia,
industry, major government agencies, non-govern-
mental organisations, and donors met in South Africa to
discuss the crises facing antituberculosis treatment; the
drug development landscape looked bleak. Nowadays,
the landscape is being revitalised with a range of novel
drugs in preclinical development and several new
compounds being assessed at all stages of clinical
trials.22,23,28 After several decades of near inactivity in
antituberculosis drug development, the pipeline has
increased in the past 5 years (figure 1). Increases in the
tuberculosis drugs portfolio are being achieved through
repurposing of old drugs, re-engineering of existing
antibacterial compounds, and discovery of new
www.thelancet.com/infection Vol 14 April 2014

compounds. The most rapid progress has been made
by researchers repurposing or redosing known anti-
tuberculosis drugs such as rifamycins (rifampicin,
rifapentine), fluoroquinolones (moxifloxacin, gatifloxacin),
and riminophenazines (clofazimine). These drugs have all
entered advanced phase 3 studies. Other non-
antibiotic drugs such as efflux-pump inhibitors31–33 show
antimycobacterial potency in preclinical studies,
although proof of concept in human beings needs to be
established.
Advances in preclinical development
The discovery of entirely new and novel compounds
remains challenging. After whole-genome sequencing of
M tuberculosis, much effort was put into genome-derived,
targeted approaches, which have yet to realise their
potential.28 A major advance in the screening efficacy for
novel targets was achieved by researchers shifting from
single-enzyme targets to phenotypic screening of the
whole bacterial cell.49 In this method, libraries of small
molecules are added to replicating and non-replicating
cultures of M tuberculosis and tested for growth inhibition.
This approach incorporates cell permeability and solubility
in the primary screen, but does not lead to knowledge of
the addressed target, which needs to be identified later.
Whole bacteria cell screening identified diarylquinolines
(bedaquiline),34 benzothiazines (BTZ-043 and PBTZ-169),35
and imidazopyridine amide (Q-203).36 Although many
novel compounds are in the preclinical-hit-to-lead-
optimisation phase, the pipeline for the early clinical
development phase is very small. To our knowledge, no
tuberculosis-specific drugs are in phase 1 studies. Of the
eight compounds that are in the preclinical development
stage (figure 2), only four are scheduled to advance to
clinical assessment in the next 24 months.
TBA-354, a second-generation nitroimidazole that was
identified from more than 1000 analogues, shows similar
in-vitro anti-M-tuberculosis activity as did delamanid, but
better activity than PA-824, and shows slightly improved
Discovery Preclinical
Lead optimisation Preclinical development
Cyclopeptides CPZEN-45
Diarylquinolines DC-159a
DprE inhibitors Q203
InhA inhibitor SQ609
LeuRS inhibitor SQ641
Macrolides TBI-166
Mycobacterial gyrase inhibitors BTZ-043
Pyrazinamide analogues PBTZ-169
Riminophenazines TBA-354
Ruthenium(II) complexes
Spectinamides
Translocase-1 inhibitors
Chemical classes: fluoroquinolone, rifamycin, oxazolidinone, nitroimidazole, diarylquinoline, benzothiazinone
Figure 1: Global pipeline of new tuberculosis drugs2,22–24,31–48
Used with permission of the Stop TB Partnership Working Group on New Drugs.
www.thelancet.com/infection Vol 14 April 2014
Review
activity at higher doses in a mouse model of tuberculosis
(1000-fold reduction in colony forming unit). The major
improvement compared with the first-generation
nitroimidazoles is a better bioavailability in animals,
suggesting a longer exposure to the drug than with PA-824
or delamanid.37
Riminophenazines—exemplified by clofazimine,
originally a dye—show potential to shorten treatment of
multidrug-resistant tuberculosis, but skin colouration due
to accumulation in fatty tissue and organs is a major side-
effect. To reduce discoloration, TBI-166 was selected from
69 riminophenazine derivatives and first preclinical data
suggests that it has retained the same antimycobacterial
properties.50
Q203 is an optimised compound made from
imidazopyridines, a new class of drugs36 that inhibit
mycobacterial growth by blocking the respiratory
cytochrome bc1 complex—essential to maintain the
proton gradient and ATP synthesis. Although the drug has
a similar target as bedaquiline, it inhibits ATP synthesis
more potently in both aerobic and hypoxic conditions. It is
active against multidrug-resistant and extensively drug-
resistant isolates of M tuberculosis from human beings,
and data from mice models show a 100–1000-fold
reduction of colony-forming units and a blocking of
granuloma formation.36
Two benzothiazinones, PBTZ-169 and BTZ-043, are in
late stage clinical development. Both drugs use a novel
mechanism of action that inhibits the enzyme
decaprenylphosphoryl-β-D-ribose 2´epimerase (DprE1) in
M tuberculosis.48 Inhibition of this enzyme prevents the
formation of decaprenylphosphoryl arabinose (a key
precursor in the biosynthesis of the cell wall arabinans),
which results in cell lysis and bacterial death.48 Both
compounds show a 100–1000-fold reduction of colony-
forming units in a chronic mouse model and in-vitro
experiments suggest synergy with bedaquiline. By
targeting the mycobacterial cell wall, benzothiazinones
affect replicating bacilli more than dormant bacilli.
Clinical
Phase 1 Phase 2 Phase 3
AZD-5847 Gatifloxacin
Linezolid Moxifloxacin
Sutezolid Rifapentine
SQ109
Novel regimens
Bedaquiline
Delamanid
PA-824
329
 Review

Multiple targets: nitroimidazoles Multiple targets: pyrazinamide Multiple targets: riminophenazines

Inhibit cell wall synthesis and Including intracellular acidification, Targeting the outer membrane and
cell respiration disrupts plasma membrane possibly bacterial respiratory chain
• Delamanid • Pyrazinamide and ion transporters
• PA-824 • Clofazimine
• TBA-354 • TBI-166

Arabinosyl transferase: ethambutol

Inhibit cell wall synthesis
• Ethambutol DNA gyrase: quinolones
Inhibit DNA synthesis
InhA: isoniazid • Moxifloxacin
Inhibit cell wall synthesis • Gatifloxacin
• Isoniazid
DNA RNA polymerase: rifamycins
DprE1: benzothiazinone Inhibit transcription
Inhibit cell wall synthesis Cell wall
• Rifampicin
• BTZ-043 • Rifapentine
• PBTZ-169 • Rifabutin
mRNA
Transpeptidase + β-lactamase–carbapenems
+ clavulanic acid
Inhibit cell wall synthesis Respiratory chain
• Faropenem H+ Peptide
ADP ATP ½ O2 H2O
Cell wall synthesis: dimethlyamine
Inhibit cell wall synthesis (transport and processing)
• SQ109
ATP–synthase: diarylquinolines Cytochrome bc complex: Ribosome: oxazolidinones
Inhibit ATP synthesis imidazopyridines Inhibit protein synthesis
• Bedaquiline Essential for proton gradient • Linezolid
2 H+
and ATP synthesis • Sutezolid
• Q203 • AZD-5847
• Radezolid
• Tedizolid

Figure 2: Mechanisms of action of tuberculosis drugs in preclinical development

Phase 2a early bactericidal studies aspartate aminotransferase.53 A similar phase 2a early

The most successful approach to yield novel drugs has
been to re-engineer old antibacterial drug classes and
improve their antimycobacterial potencies.23,28 Examples of
such redesigned scaffolds are the nitroimidazoles
(delamanid, PA-824, and TBA-354) and 1,2-ethylenediamine
(SQ109). Oxazolidinones such as linezolid were developed
for Gram-positive bacterial infections and were later
shown to have anti-M-tuberculosis activity. Four modified
versions of oxazolidinone derivatives (sutezolid, AZD-
5847, radezolid, and tedizolid) might have improved
activity against M tuberculosis and avoid myelo-
suppression—a problem with linezolid.38,51 These
oxazolidinones are being studied in a head-to-head
comparison in marmosets to help to select the best
candidate for phase 2b studies in people. This study is
complemented by studies in the hollow-fibre model to
determine the degree of inhibition of mitochondrial
protein synthesis.52 The development of sutezolid is the
most advanced so far.53 In a phase 1, 14 day, early
bactericidal study, reductions in bacterial load (measured
in decline in colony forming units) were slightly more
pronounced in the 600 mg twice a day regimen than in the
group given 1200 mg four times a day (−0·09 log per day
vs 0·07 log per day). 14% of patients had transiently
increased liver enzyme alanine transaminase and
bactericidal study in South Africa used different doses of
AZD-5847 (clinicaltrials.gov identifier: NCT01516203).
Combination of carbapenems with clavulanic acid (a
β-lactamase inhibitor) has shown promising bactericidal
activity against replicating and non-replicating isolates of
M tuberculosis.54 Faropenem, an orally active carbapenem,
is in a phase 2a early bactericidal study.55 Although the
drug’s oral bioavailability is better than is that for other
carbapenems, its short half-life requires patients to take
several doses per day, which makes it impractical for use
in individuals with drug-sensitive tuberculosis.
Advances in phase 2b and phase 3 trials
Recent advances in tuberculosis treatment include
submissions to regulatory agencies for approval of two
new drugs, bedaquiline and delamanid. The US Food and
Drug Administration (FDA) used its regulatory path for
accelerated approval after review of scarce efficacy data to
approve bedaquiline as part of combination treatment for
adults with multidrug-resistant tuberculosis when other
alternatives are not available.40 European Medicines
Agency have recently approved delamanid.41 Combinations
between these new drugs with existing antituberculosis
therapies could lead to regimens that are better tolerated,
shorter, and have fewer drug–drug interactions compared

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 Review

with existing regimens. Since antituberculosis drugs need
to be given in combination to prevent drug resistance,
trials are underway with companion drugs to simplify,
improve, or shorten treatment regimens for drug-sensitive
and multidrug-resistant tuberculosis (table 1, table 2).
Assessment of new drugs and doses in phase 2
trials
Phase 2 trials allow generation of important data for safety,
dosing, and efficacy, which guide the planning of phase 3
studies. This approach is being used to test novel drugs,
especially those for multidrug-resistant tuberculosis. A
phase 2 study of bedaquiline42 added to a background
regimen for 2 months significantly reduced time to culture
conversion in 24 weeks and was well tolerated by patients.56
Moreover, fewer patients developed resistance to the
companion drugs in the bedaquiline treatment group than
in the control group.43,57 A phase 3 trial is now planned.
Since phase 2 data show a significantly increased mortality
in users, its use in drug-sensitive patients is not indicated
until more safety data are available.
Delamanid, developed mainly for multidrug-resistant
tuberculosis, has early bactericidal activity and researchers
have defined an optimum dose.44,58 The addition of
delamanid to standard-of-care chemotherapy in patients
with multidrug-resistant tuberculosis was associated with
a significantly higher proportion of sputum culture
conversion at 2 months—ie, 45·4% versus 29·6%.59,60 In
November, 2013, the Committee for Medicinal Products
for Human Use of the European Medicines Agency
granted a marketing authorisation for delamanid as part
of an appropriate combination regimen for multidrug-
resistant tuberculosis in adults, which was conditional on
the inavailability of an otherwise effective regimen due to
tolerability or resistance issues.41 A phase 3 trial is
underway (table 2).
Recognition is increasing that the currently
recommended dose of rifampicin (450–600 mg) was
chosen without investigators doing studies of multiple
ascending doses or pharmacokinetics.61,62 Some have called
for evaluation and definition of the effect of higher doses
of rifampicin.61,62 A 2013 study (HIGHRIF2) assessed the
safety, tolerability, and pharmacokinetics of 900 mg and
1200 mg doses of rifampicin in combination with the
standard regimen components over 2 months. Results of
these trials are expected soon. Results from a phase 2a
study have shown that use of up to 35 mg/kg of rifampicin
over 14 days is safe and well tolerated.62

Trial registration Study groups Phase† Status

number*
Rifampicin
HIGHRIF1 NCT01392911 Rifampicin (10 mg/kg vs 20 mg/kg vs 25 mg/kg vs 30 mg/kg vs 35 mg/kg); dose-escalation 2a Results
study expected 2014
RIFATOX ISRCTN55670677 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (20 mg/kg vs 15 mg/kg vs 2b Results
10 mg/kg of rifampicin) expected 2014
HIGHRIF2 NCT00760149 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (1200 mg vs 900 mg vs 2b Results
600 mg of rifampicin) expected 2014
HIRIF NCT01408914 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (20 mg/kg vs 15 mg/kg vs 2b Recruiting
10 mg/kg of rifampicin)
PanACEA NCT01785186 Isoniazid, rifampicin (35 mg/kg), pyrazinamide, and ethambutol vs isoniazid, rifampicin (10 2b Recruiting
MAMS-TB-01 mg/kg), pyrazinamide, and SQ109 vs isoniazid, rifampicin (20 mg/kg), pyrazinamide, and
SQ109 vs isoniazid, rifampicin (20 mg/kg) pyrazinamide, and moxifloxacin vs isoniazid,
rifampicin (10 mg/kg), pyrazinamide, and ethambutol
Isoniazid
A5312 NCT01936831 Isoniazid (15 mg/kg vs 10 mg/kg vs 5 mg/kg); includes patients with INHA mutation 2a In
development
Rifapentine
TBTC 29X NCT00694629 Isoniazid, rifapentine (20 mg/kg vs 15 mg/kg vs 10 mg/kg of rifapentine), and ethambutol vs 2b Results
isoniazid, rifampicin, pyrazinamide, and ethambutol expected 2014
RPT study NCT00814671 Isoniazid, rifapentine, pyrazinamide, and ethambutol (600 mg vs 450 mg of rifapentine) vs 2b Results
isoniazid, rifampicin, pyrazinamide, and ethambutol; uses Simon’s two-stage design expected 2014
RioMAR NCT00728507 Isoniazid, rifapentine, pyrazinamide, and moxifloxacin (7·5 mg/kg of rifapentine) vs 2b Results
isoniazid, rifampicin, pyrazinamide, and ethambutol expected 2014
RIFAQUIN ISRCTN44153044 2 months of moxifloxacin, rifampicin, pyrazinamide, and ethambutol, and then 2 months of 3 Results
moxifloxacin and rifapentine (900 mg) twice a week vs 2 months of moxifloxacin, rifampicin, expected 2014
pyrazinamide, and ethambutol, and then 4 months of moxifloxacin and rifapentine
(1200 mg) once a week vs 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol,
and then 4 months of isoniazid and rifampicin
TBTC S31 ·· 4 months of isoniazid and rifapentine supplemented by pyrazinamide and ethambutol in the 3 In
first 2 months (1200 mg of rifapentine) vs 6 months of isoniazid and rifampicin development
supplemented by pyrazinamide and ethambutol in the first 2 months
(Table 1 continues on next page)

www.thelancet.com/infection Vol 14 April 2014 331

 Review

Trial registration Study groups Phase† Status

number*
(Continued from previous page)
Fluoroquinolones
A5307 NCT01589497 Moxifloxacin, rifampicin, pyrazinamide, and ethambutol vs rifampicin, pyrazinamide, and 2a Recruiting
ethambutol vs isoniazid, rifampicin, pyrazinamide, and ethambutol (after 2 days of
isoniazid, rifampicin, pyrazinamide, and ethambutol)
NIRT CTRI/2012 4 months of isoniazid, rifampicin, and gatifloxacin supplemented by pyrazinamide in the first 3 Results
3-weekly46 /10/003060 2 months vs 4 months of isoniazid, rifampicin, and moxifloxacin supplemented by pyrazinamide expected 2014
in the first 2 months vs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and
ethambutol in the first 2 months; all regimens given three times a week
OFLOTUB NCT00216385 4 months of isoniazid, rifampicin, and gatifloxacin supplemented by pyrazinamide in the 3 Results
first 2 months vs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and expected 2014
ethambutol in the first 2 months
REMoxTB NCT00864383 4 months of isoniazid, rifampicin, and moxifloxacin supplemented by pyrazinamide in the first 3 Results
2 months vs 4 months of rifampicin and moxifloxacin supplemented by pyrazinamide and expected 2014
ethambutol in the first 2 months vs 6 months of isoniazid and rifampicin supplemented by
pyrazinamide and ethambutol in the first 2 months
NIRT daily CTRI/2008 3 months of isoniazid, rifampicin, pyrazinamide, ethambutol, and moxifloxacin vs 4 months of 3 Recruiting
/091/000024 isoniazid, rifampicin, and moxifloxacin supplemented by pyrazinamide and ethambutol for the
first 2 months vs 4 months of isoniazid, rifampicin, and moxifloxacin supplemented by
pyrazinamide and ethambutol for the first 2 months and given three times a week in the last
2 months vs 4 months of isoniazid, rifampicin, moxifloxacin, and ethambutol supplemented by
pyrazinamide for the first 2 months and given three times a week in the last 2 months
vs 6 months of isoniazid and rifampicin supplemented by pyrazinamide and ethambutol in the
first 2 months given three times a week throughout
SQ109
SQ109 EBA NCT01218217 SQ109 75 mg vs SQ109 150 mg vs SQ109 300 mg vs SQ109 150mg and rifampicin vs SQ109 2a Results
300 mg and rifampicin vs rifampicin expected 2014
Sutezolid
Sutezolid EBA NCT01225640 Sutezolid 600 mg twice a day vs 1200 mg four times a day vs isoniazid, rifampicin, 2a Results
pyrazinamide, and ethambutol expected 2014
AZD-5847
AZD-5847 NCT01516203 500 mg four times a day vs 500 mg twice a day vs 1200 mg four times a day vs 800 mg twice 2a Results
EBA a day vs isoniazid, rifampicin, pyrazinamide, and ethambutol expected 2014
PA-824
NC-003 NCT01691534 Bedaquiline, PA-824, pyrazinamide, and clofazimine vs bedaquiline, PA-824, and 2a Results
pyrazinamide vs bedaquiline, PA-824, and clofazimine vs bedaquiline, pyrazinamide, and expected 2014
clofazimine vs pyrazinamide vs clofazimine vs isoniazid, rifampicin, pyrazinamide, and
ethambutol
NC-002 NCT01498419 PA-824 (100 vs 200 mg), moxifloxacin, and pyrazinamide vs 2 months of isoniazid, 2b Results
rifampicin, pyrazinamide, and ethambutol (includes cohort with multidrug resistance given expected 2014
PA-824 [200 mg], moxifloxacin, and pyrazinamide)
Paediatric tuberculosis
SHINE ·· 2 months of isoniazid, rifampicin, and pyrazinamide (ethambutol in some settings), and 3 In
then 4 months of isoniazid and rifampicin vs 2 months of isoniazid, rifampicin, development
pyrazinamide, and ethambutol, and then 2 months of isoniazid and rifampicin; population
included children aged younger than 16 years with minimal disease

If dose is not indicated, drugs given once a day. *Trial registration numbers from the following sources: NCT from ClinicalTrials.gov, ISRCTN from Current Controlled Trials,
and CTRI from Clinical Trials Registry of India. †Trial phases are as follows: phase 2a indicates a 7 or 14 day early bactericidal activity study; phase 2b indicates a study of
microbiological endpoints over 8–12 weeks of treatment; phase 3 is a confirmatory efficacy trial with 18–24 months of follow-up.

Table 1: Randomised clinical trials for drug-sensitive tuberculosis

Drugs to eradicate persister populations of effective eradication of persister populations. Up to 90%

M tuberculosis
Investigators have described mechanisms and pathways
for the formation of persister and dormant M tuberculosis
populations,16–20 which are being used to guide targeted
drug development and treatment regimens for latent
tuberculosis infection. Combinations of drugs with
adjunct immunotherapy might be needed for more
of M tuberculosis isolates from untreated patients have
evidence of lipid bodies—apparent in mycobacterial cells
in a dormant state and an important target for drug
development,19 in-vitro studies,16,17,63,64 and animal studies.65
A reduced, but still substantial, pool of ATP is maintained
during dormancy in persister mycobacteria.66 Targeting
of this pool has led to identification of 32 clusters of

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 Review

Trial registration Study groups Phase† Status

number*
C208 NCT00449644 2 weeks of bedaquiline 400 mg, plus 22 weeks of bedaquiline three times a week 2b Results 2014
200 mg vs placebo plus background regimen
MARVEL ·· Bedaquiline, PA824, pyrazinamide, and sutezolid (1200 mg, four times a day) vs 2b In development
bedaquiline, PA824, pyrazinamide, and sutezolid (600mg twice a day) vs bedaquiline,
PA824, pyrazinamide, and levofloxacin (600 mg) vs standard of care
Trial 204 NCT00685360 8 weeks of delamanid 200 mg twice a day vs 8 weeks of delamanid 100 mg twice a 2b Results 2014
day vs placebo added to optimised background regimen
Trial 213 NCT01424670 2 months of delamanid (100 mg twice a day) and then 4 months of delamanid 3 Recruiting
(200 mg four times a day) vs placebo added to optimised background regimen
STREAM ISRCTN78372190 9 months of moxifloxacin, clofazimine, ethambutol, and pyrazinamide, 3 Recruiting
supplemented with kanamycin, isoniazid, and prothionamide for the first 4 months
vs local WHO-recommended regimen
OPTI-Q NCT01918397 8 weeks of levofloxacin (20 mg/kg vs 17 mg/kg vs 14 mg/kg vs 11 mg/kg), plus 2b In development
optimised background regimen

If dose is not indicated, drugs given once a day. *Trial registration numbers from the following sources: NCT from ClinicalTrials.gov, ISRCTN from Current Controlled Trials. †Trial
phases are as follows: phase 2a indicates a 7 or 14 day early bactericidal activity study; phase 2b indicates a study of microbiological endpoints over 8–12 weeks of treatment;
phase 3 is a confirmatory efficacy trial with 18–24 months of follow-up.

Table 2: Randomised clinical trials for drug-resistant tuberculosis

compounds that reduce ATP concentrations and thus are
active against non-replicating M tuberculosis.66 Bryk and
colleagues67 screened for inhibitors of dihydrolipoamide
acyltransferase, an enzyme used by the bacterium to
resist host-derived nitric oxide reactive oxygen
intermediates. The search for inhibitors of M tuberculosis
dihydrolipoamide acyltransferase to kill almost
exclusively non-replicating mycobacteria led to identi-
fication of the rhodanines. The nitroimidazoles,
(delamanid and PA-824) and benzothiazinones (BTZ-043)
also have some activity against persister mycobacteria.
PA-824 was originally developed as an analogue of
metronidazole, which kills organisms that had become
dormant through anaerobiasis,68 yet this drug is being
assessed successfully according to a standard develop-
ment pathway.43 Pyrazinamide can be used to kill
persisters.69 Furthermore, several drugs are now
predicted to have activity against persister populations—
namely, clofazimine, bedaquiline, and the oxazolidonones
(sutezolid and AZD-5847). Clinical data are needed to
confirm these preclinical data. How a persister-directed
or dormancy-directed drug might be assessed in clinical
practice is not known.
Advances towards simpler and shorter
tuberculosis treatments
The need to simplify and shorten treatment for tuberculosis
is a long-standing priority. Initial Medical Research
Council trials showed that treatment regimens that last
18 months or more were highly effective when done in
randomised trial conditions, but all too often had poor
adherence and resulting unfavourable outcomes when
applied in programme conditions.11 Trial results for a short-
course chemotherapy first presented in 1972 showed that a
6 month regimen of isoniazid, rifampicin, and
streptomycin gave excellent results with respect to
relapse,10,11 which were comparable to or even better than
those after an 18 month regimen. The authors emphasised
the need to find short-course regimens that readily lent
themselves to practical application in routine treatment
services.70
After this trial, researchers made several attempts to
simplify the 6 month regimen, particularly to reduce the
amount of rifampicin needed because of both its cost and
their concern about the development of multidrug-
resistant tuberculosis. One option adopted by WHO in
their guidelines was to limit the use of rifampicin to the
first 2 months, but to extend the total treatment duration to
8 months by giving thioacetazone and isoniazid in the
continuation phase, later changed to ethambutol and
isoniazid. Each of these alternative regimens were inferior
to the 6 month regimen,71 leading to WHO revising their
guidelines in 2010,12 stating that “new patients with
pulmonary tuberculosis should receive a regimen
containing 6 months of rifampicin”.12 Expect for in patients
with smear-negative disease,71 attempts to shorten duration
to less than 6 months for some groups who might have
needed less treatment (eg, those without cavitation and
with culture conversion by 2 months) did not succeed.72
Internationally, people recognise that 6 months treatment
is still too long and there is a need for new drugs to shorten
duration.
Since 2000, results from several studies in mice, and
later phase 2 trials in human beings, suggested that
quinolones could shorten treatment duration.73 Several
phase 3 trials were done to assess the role of various
fluoroquinolones (table 1). Results from three of these
trials became available in 2013. The INTERTB
consortium in southern Africa presented the results of
the RIFAQUIN45 trial in March, 2013. Investigators
showed that the 6 month regimen with a once-weekly
continuation phase of moxifloxacin and high-dose

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 Review
rifapentine was as effective as the standard 6 month
control regimen of daily rifampicin and isoniazid,
whereas a 4 month regimen with twice-weekly
moxifloxacin and high-dose rifapentine was significantly
inferior. Although the 6 month regimen does not
shorten treatment duration, once-weekly dosage
provides the opportunity to simplify treatment and
lower the cost of treatment supervision for both patients
and health systems.
Two studies were done of whether substitution of a
fluoroquinolone for ethambutol in the initial intensive
phase of the standard 6 month regimen and continuation
of a fluoroquinolone through the continuation phase
could result in a successful, non-inferior, 4 month
regimen.46,47 The National Institute for Tuberculosis
Research (NIRT) in Chennai did the first study,46 with
investigators comparing one regimen using gatifloxacin
with one using moxifloxacin, both given for 4 months
and, similar to the control regimen, given three times a
week. The data and safety monitoring board stopped the
trial prematurely, and the authors concluded that the
groups given fluoroquinolone for 4 months had higher
recurrence rates than had controls, although data for
the groups given moxifloxacin were not significantly
inferior in the final published results. Because of the
early termination (and delayed start of the moxifloxacin
group), results of the study are difficult to interpret, as
readers’ comments show. The second, the OFLOTUB
study,47 is similar in some respects to the REMoxTB trial
because it tested a 4 month regimen that substituted
gatifloxacin for ethambutol in the first 2 months
compared with the standard tuberculosis treatment.47
In the study, 1836 patients in five African countries
(Benin, Guinea, Kenya, South Africa, and Senegal) were
randomly allocated to the treatments. The study finished
in 2011 and had very good patient retention, and the
investigators reported the results at the World Lung
Conference in Paris in November, 2013.48 The
intervention did not show non-inferiority to controls
based on a prespecified margin, but there was
substantial heterogeneity between trial sites in different
countries that needs further exploration.
At this stage, it would be premature to conclude that
fluoroquinolones cannot help to shorten treatment since
results are still awaited from the REMoxTB trial (expected
early 2014). REMoxTB74 is the first regulatory phase 3
clinical trial of a treatment-shortening regimen. The
investigators aim to find out whether substitution of
moxifloxacin for isoniazid or ethambutol could allow
reductions in the duration of tuberculosis chemotherapy
to only 4 months and whether this regimen is not inferior
to that of the standard 6 month regimen. The primary
endpoint is bacteriological failure and relapse. The trial is
now completed and researchers report recruiting
1932 patients from Kenya, South Africa, Tanzania, and
Zambia, and China, India, Malaysia, Mexico, and
Thailand.
334
Analysis of the results of non-inferiority trials is
challenging, particularly those that use composite
endpoints.75 The full reports of the RIFAQUIN45 and
OFLOTUB47 trials are expected to be published in early
2014, and these will provide more complete information to
help interpretation of their results. However, it is important
to consider the extent to which the results obtained so far
confirm the predictions of what might have been expected
to happen from earlier mouse and phase 2 trials. For
example, studies in mice of intermittent rifapentine and
moxifloxacin had particularly impressive results.76 Phase 2
studies with gatifloxacin substituted for ethambutol
suggested some evidence for a more rapid culture
conversion, although the difference in culture conversion
rates between the gatifloxacin and control regimens was
much less in the OFLOTUB47 study than in the NIRT trial.46
Wallis and colleagues77 used a meta-regression model
to predict that a new 4 month regimen would need to
have 2 month culture positivity rates of only 1–2% of
treated individuals to yield relapse rates of no more than
5% of patients, although few studies of duration less
than 6 months in this model have been done, and culture
positivity at 2 months is not a fully reliable surrogate.68
Although public funders of trials usually do not like
dose-ranging studies and prefer rapidly successful
phase 3 trials, analyses are needed for whether some of
the continuing or completed phase 3 trials have used
novel drugs without researchers establishing the
appropriate and most efficient dose. Furthermore,
potentially useful drugs or entire drug classes should
not be dysregarded solely because they had been initially
used in very low concentrations.
Combination evaluation
PA-824 has now entered phase 2 trials, but as part of a
regimen development programme. This scheme has the
advantage that patients with multidrug-resistant
tuberculosis can be included into the same recruitment
process as those with treatment-sensitive tuberculosis.
The regimen of PA-824 plus moxifloxacin and
pyrazinamide was assessed successfully in an early
bactericidal activity study43,44 and a larger trial of this
regimen for 8 weeks has now completed. If results are
promising, this combination might lead to the
development of a phase 3 pivotal trial.
Phase 3 selection
The novel multiarm multistage (MAMS) trial design
compares several regimens simultaneously.78–80 Planned
interim analyses act as intermediate checkpoints and
are used to compare the experimental groups with
common controls. Treatment groups that do not show
sufficient evidence of benefit are dropped on the basis
of previously prespecified values because weak
regimens are unlikely to succeed in phase 3. This
approach addresses the most relevant public health
question: not which regimen can be used to treat
www.thelancet.com/infection Vol 14 April 2014

tuberculosis, but which is the best regimen that
clinicians can use to treat tuberculosis? The scale of
the barrier is dependent on how much improvement is
sought in the trial. As the study progresses, the hurdles
are progressively raised for the subsequent interim
analysis. This progression means that the analysis
done at the end of the trial is based on the trial
endpoints that would be used in a pivotal study.
Through a series of increasing hurdles, investigators
will only choose the best groups (treatments) for
phase 3 trials.78–80 The MAMS trial being done by the
Pan African Consortium for Evaluation of Anti-
tuberculosis Antibiotics (PanACEA) is currently
recruiting in South Africa and Tanzania and should
report results towards the end of 2014. The results of
continuing trials will inform the next steps for the
development of shorter regimens and the simplification
of treatment. Approaches should include investigators
revisiting the doses of existing drugs such as
rifampicin, and carefully considering the use of new
drugs such as bedaquiline and delamanid.
Advances in biomarker development for clinical
trials
At present, the endpoints of phase 3 clinical trials are
combined failure and relapse. The lack of accurate
surrogate biomarkers for trial endpoints necessitates that
phase 3 trials involve large numbers of people, and are
lengthy and invariably expensive. Because current
treatment is 95% curative in trial conditions, non-
inferiority designs are required.44 An effect of using this
trial type is that sample sizes are very large.47 Through
quantification of sequential viable count, it is possible to
distinguish between the killing efficacy of regimens,81 but
whether these methods can predict success in the
registered endpoint is not known. There is a widespread
belief that culture conversion at 8 weeks predicts
treatment failure and relapse.82 Yet, this relation is
dependent on the sterilising efficacy of the regimen after
8 weeks, as was shown in study A in which all regimens
were similar at 8 weeks, but the 8 month isoniazid and
ethambutol continuation-phase regimen was significantly
inferior.9
Clinicians can infer a decrease in viable organisms with
a rise in the time to positivity using methods for automated
mycobacterial culture such as mycobacteria growth
indicator tube, which can be used in phase 2 studies.83,84
Detection of M tuberculosis viability by molecular means
might make this process more rapid and allow results to
be available in clinical real time.85 Investigators must
choose the marker carefully because DNA-based tests,
including the GeneXpert MTB-RIF assay, remain positive
after an extended period,86 and mRNA tests revert to
negativity rapidly.87,88 A marker based on rRNA seems to
overcome several of these problems and follows viable
counts closely; this method is now in assessment in a
phase 2b study (MAMS-TB 001).89
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Review
Advances in laboratory methods to support
tuberculosis trials
Since the original series of clinical trials, there has been a
transformation in methods available.44 The importance of
microbiological results for the outcome of trial endpoints
and treatment has led to better standardisation of
laboratory methods. The standard laboratory manual for
the REMoxTB trial has been used as a basis of commercial For the REMoxTB trial see
and other academic trials57 and MAMS-TB.90 A template http://www.ucl.ac.uk/infection-
immunity/research/res_ccm/
laboratory manual for general use in antituberculosis ccm_files/CCM_REMox
drug trials is nearing completion and will soon be made
available through the Global Alliance. Such an approach
must be incorporated widely to allow maximum For more on the Pan African
comparability for phase 2 and 3 clinical trials done by Consortium for Evaluation of
Anti-tuberculosis Antibiotics
different groups in different settings. (PanACEA) see http://panacea-
Automated liquid culture is not only more rapid, but tb.net/
more sensitive, changing the proportion of patients who
are culture negative. The GeneXpert MTB-RIF assay is
becoming widely adopted and might become the
standard screening method for trial entry, as was tested
in the MAMS-TB trial.91 Use of Xpert will reduce the risk
of patients with multidrug-resistant tuberculosis being
recruited because it is more sensitive than smear
methods, but some patients will be recruited who are not
culture positive. Other molecular susceptibility tests
such as GenoType MTBC have helped to exclude patients
with multidrug-resistant and extensively drug-resistant
tuberculosis at sites in which drug resistance is
common.57,91
Molecular technology has also affected the use of
relapse endpoints, with methods such as variable
number of tandem repeats able to distinguish between
relapse and reinfection.92,93 In a 2013 study, Bryant and
colleagues94 did next-generation whole-genome
sequencing of patients involved in a phase 3 trial and
showed that the patients identified as relapsed had fewer
than six single-nucleotide polymorphisms between the
initial and recurrent M tuberculosis strains, whereas
reinfection strains had many hundred single-nucleotide
polymorphisms. They also showed that mixed infection
was common (six of 47 patients), and that variable
number of tandem repeats miscalled six relapse cases. In
the future, the implications of these technologies will
substantially change clinical trial design.94
Optimum timing of ART in patients with HIV
infection who have newly diagnosed
tuberculosis
The treatment of patients with HIV who have newly
diagnosed tuberculosis is complicated by toxic effects
and pharmacokinetic interactions of tuberculosis and
ART.28 Thus, time to initiation of ART is dependent on
balance between the risk of HIV disease progression and
the risk of having to discontinue treatment because of
drug toxic effects, ART and antituberculosis drug
interactions, or high pill burden.95 Immune reconstitution
inflammatory syndrome occurs in up to 45% of patients
335
 Review
with HIV who start ART while receiving tuberculosis
treatment.96 Delay of initiation of ART until after
completion of tuberculosis treatment in people with HIV
who have active tuberculosis is generally considered to
be associated with increased mortality across a spectrum
of immunodeficiency. Three open-label clinical trials
(SAPIT, CAMELIA, and STRIDE96–98) assessed the timing
of ART, showing that initiation of ART shortly after the
start of antituberculosis therapy is associated with lower
mortality, especially among people with HIV who have
low baseline CD4 cell counts. Results of the TIME99
clinical trial in Thailand showed that, although early ART
was not associated with survival advantage, there were
trends towards this effect in those with very low baseline
CD4 T cell counts. Although WHO recommendations
are that ART100 should be started as soon as possible in
the first 8 weeks of tuberculosis treatment, and that those
with CD4 cell counts less than 50 cells per μL should
receive ART within the first 2 weeks, the WHO guidelines
also state that there is low quality of evidence for
optimum timing of ART initiation in patient with HIV
and tuberculosis who present with CD4 cell counts
greater than 350 cells per μL. The effect of early or
delayed initiation of ART on tuberculosis treatment
outcomes in people with HIV with newly diagnosed,
culture-confirmed tuberculosis is being assessed by
investigators in a large phase 4, prospective, multicentre,
multicountry (South Africa, Tanzania, Uganda, and
Zambia), randomised, placebo-controlled trial (ISRCTN
77861053; results expected March, 2014).101
Adjunct treatments and host-directed therapies
Adjunct immunotherapies
Results of a phase 1 trial of autologous bone-marrow-
derived stromal-cell infusions for adjunct treatment of
terminally ill patients with multidrug-resistant
tuberculosis and extensively drug-resistant tuberculosis
in Belarus show that the procedure is safe.102 Phase 2
trials are now planned to assess the effect of adjunct
therapy with mesenchymal stromal cells on
microbiological, immunological, and clinical outcomes.
Several other adjunct immunotherapy approaches that
use a range of cytokines or their inhibitors, or chemical
and biological immunomodulatory compounds, are
being developed as an adjunct to drugs to improve
treatment outcomes for multidrug-resistant tuberculosis,
shorten duration of treatment, and prevent relapse.103
These treatments involve use of mycobacterial antigens
or inactivated whole-cell environmental mycobacterial
preparations to enhance cellular immune responses.
Increases in anti-M-tuberculosis immune responses,
which reduce collateral damage in inflammatory
responses when given with antituberculosis drug
regimens, tend to overlook the nutritional status of
patients with tuberculosis. Malnutrition is associated
with a deficient T-helper-1-type response, resulting in
decreased ability to contain M tuberculosis.104 Vitamin D
336
receptor genotypes, and variations in the LTA4H locus
affect treatment outcomes and the responses to anti-
inflammatory therapy in patients with tuberculosis
meningitis.105 Various cytokine regimens, including
interferon γ or interleukin 2, have been assessed with
variable responses,79 underlining the need for clinically
relevant biomarkers to define the best timepoint at
which patients with tuberculosis are most likely to
benefit from adjunct therapies. Reinfections, different
exposures to M tuberculosis, infection with several
M-tuberculosis strains, and the bimodal distribution of
latent and active tuberculosis might occur in a
patient,106,107 underlying the need to find the optimum
timing for adjunct therapies in the course of
antituberculosis therapy.
The effect of antituberculosis drugs on the immune
system has not yet been sufficiently addressed;
uncertainty about this effect has also challenged
treatment of patients with several drugs simultaneously.
The anti-inflammatory effects of macrolide antibiotics
are well known.108 Similar or other effects mediated by
antituberculosis drugs on complex cellular interactions
need systematic study. Use of systems immunology in
preclinical research and during drug development could
help to improve clinical outcomes through personalised
medicine and help to define clinically relevant patterns of
immune reactivity.109 The future of personalised medicine
for tuberculosis might also benefit from the use of whole-
genome sequencing110 to show the patterns of antibiotic
resistance in M tuberculosis strains isolated from patients,
enabling highly individual-specific treatment regimens.
Repurposing of drugs for tuberculosis
Non-steroidal anti-inflammatory drugs (NSAIDs) can
reduce M tuberculosis load and alleviate lung damage in
mice,111 and they show anti-M-tuberculosis activity in
phenotypical assays.112 Efflux-pump inhibitors such as
verapamil and reserpine can reduce macrophage-
induced drug tolerance and their addition to standard
tuberculosis therapy could potentially shorten the
duration of curative treatment.113,114 Phosphodiesterase
inhibitors cilostazol and sildenafil, when added to the
standard treatment, reduced tissue damage, quickened
mycobacterial clearance, and shortened time to lung
sterilisation by 1 month.115
Need for international cooperation and
coordination
The importance of enhanced communication,
coordination, and when appropriate, collaboration,
among researchers, funding agencies, governments, and
communities cannot be overstated.21,116–118 The ultimate
therapeutic research goal is not development of single
drugs or combinations, but to know which of several
combinations, including at least two or three new drugs,
will be the best to advance to phase 3. A phase 2 and 3
trial planning-coordination forum of non-commercial
www.thelancet.com/infection Vol 14 April 2014

Search strategy and selection criteria
We searched English-language publications using PubMed and
Google Scholar (articles published from Jan 1, 1940, to Jan 8,
2014), the Cochrane Library (published from Jan 1, 2001, to Dec
31, 2013), and Embase (published from Jan 1, 2001, to Dec 31,
2013) with the terms “tuberculosis”, “TB”, “mycobacterium
tuberculosis”, “drugs”, “new drugs”, “repurposed drugs”, “re-
engineering and drugs”, “treatment”, “regimens”, “treatment
regimens”, “trials”, “clinical trials”, “EBA”, and “adjunct therapy”.
We complemented this search by searching for publications on
tuberculosis by WHO, Global Tuberculosis Department, and the
International Union Against Tuberculosis and Lung Disease,
websites of tuberculosis drugs manufacturers, and the
Tuberculosis Alliance. We also included data from abstracts
presented at conferences in 2010–13. We reviewed studies
cited in articles that were identified with use of this search
strategy and selected those that were relevant. Some review
articles are cited to provide readers with more details and
references than this Review could accommodate.
clinical research sponsors and trial groups was formed in
2012 with the aim of meeting this goal. For the past
2 years, the forum has discussed which combinations will
be studied in phase 2 trials to be done by each partner and
allows its participating research programmes to benefit
from each other’s experience and to share study results as
early as possible. Coordinated study planning avoids
redundant projects and helps to achieve synergistic study
outcomes, as well as optimum resource use in the era of
scarce funding. Barriers to timely implementation of
phase 2b trials are also addressed, including leads for
studies of drug–drug interactions among tuberculosis
drugs and with ART. This coordination allows more
efficient discussions with pharmaceutical developers and
regulatory authorities for the planning and im-
plementation of trials. Furthermore, lack of regulatory
capacity stops many countries from rapidly reviewing the
new treatment regimens and doing post-marketing and
pharmacovigilance surveillance.
The sponsors and research groups in the forum include
the Global Alliance for Tuberculosis Drug Development,
the National Institute of Allergy and Infectious Diseases
and its AIDS Clinical Trials Group Network and
Tuberculosis Research Unit, the US Centers for Disease
Control and Prevention and its Tuberculosis Research
Unit, the European and Developing Countries Clinical
Trials Partnership and PanACEA, and the UK Medical
Research Council and its funded investigators. The forum
presently focused mainly on phase 2 studies and
complements the objectives of the Critical Path to
Tuberculosis Regimens (CPTR) to bring new
combinations into phase 3 trials and gain regulatory
approvals as soon as possible. A global trial outcomes
registry would confirm safety and effectiveness of new
drugs and treatment regimens.117 There is also a need for
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Review
producers, purchasers, and providers to cooperate, and
for governments to become more flexible116 in adopting
new regimens, so that all patients with multidrug-
resistant tuberculosis can get second-line treatments
without stock-outs of drugs. Achievement of this aim will
require more community engagement in design,
implementation, and uptake of research.
Conclusion and perspectives
In the past decade, substantial progress has been made
in tuberculosis drug development. Several compounds
are in late clinical development and there have been
innovative approaches to trials and laboratory methods.
However, the pipeline remains inadequate and the
specialty cannot be complacent since many more
compounds and approaches will be needed to achieve
shorter and more effective regimens that will banish the
scourge of tuberculosis worldwide.
Contributors
AIZ, MM, and MS initiated the idea of the Review as a follow-up of
The Lancet Infectious Diseases 2013 Tuberculosis Series, which they
coordinated as guest editors. AIZ coordinated the Review and wrote the
first, subsequent, and final drafts of the Review. All authors contributed
their respective expertise to the text, figures, and references. All authors
contributed to the revision and approved the final version.
Declaration of interests
STC is a named inventor on patents relevant to this Review
(WO2012/066518, WO2009/010163). All other authors declare that they
have no competing interests.
Acknowledgments
For development of table 1, we thank Michael J Vjecha, from the Institute
for Clinical Research, Washington, DC, USA, and Executive Coordinator
for US Centers for Disease Control and Prevention Tuberculosis Trials
Consortium. We thank Adam Zumla (UCL School of Pharmacy, University
College London, London, UK) for technical and administrative assistance.
AIZ is supported by UK European Union FP7Rid-RTI programme grant;
European Developing Countries Clinical Trials Partnership TB NEAT,
PanACEA, and REMox grants; and grants from UBS Optimus Foundation,
Switzerland, and National Institute for Health Research Biomedical
Research Centre, University College London Hospitals, London, UK. STC
is supported by European Community’s Seventh Framework Programme
(FP7/2007–13) under grant agreement number 260872. MH is supported
by BmBF grants, European Developing Countries Clinical Trials
Partnership PanACEA 2007.32011.013, TB NEAT, PanACEA, and REMox
grants. SHG and TDMH are supported by Global Alliance for Tuberculosis
Drug Development; and European and Developing Country Clinical Trials
Partnership (grants IP.2007.32011.011, IP.2007.32011.012, and
IP.2007.32011.013), including TB NEAT, PanACEA, and REMox grants; and
Innovative Medicines Initiative Joint Undertaking grant 115337. MM is
supported by the European Developing Countries Clinical Trials
Partnership, TB NEAT, Vetenskapsrådet, VINNOVA, and HLF (Heart and
Lung foundation) Sweden. MS is supported by National Institute of
Allergies and Infectious Diseases, National Institutes of Health,
Department of Health and Human Services under contract number
HHSN272200800014C.
References
1 WHO. TB–a global emergency. WHO Press Release: WHO/31.
Geneva: World Health Organization, 1993.
2 WHO. Global Tuberculosis report 2013. WHO/HTM/TB/2013. For the Critical Path to
http://www.who.int/tb/publications/global_report/en (accessed Tuberculosis Regimens see
Nov 12, 2013). http://new.tballiance.org/cptr/
3 Migliori GB, Sotgiu G, Gandhi NR, et al, for the Collaborative
Group for Meta-Analysis of Individual Patient Data in MDR-TB.
Drug resistance beyond extensively drug-resistant tuberculosis:
individual patient data meta-analysis. Eur Respir J 2013; 42: 169–79.
337
 Review
4 Falzon D, Gandhi N, Migliori GB, et al, for the Collaborative Group
for Meta-Analysis of Individual Patient Data in MDR-TB.
Resistance to fluoroquinolones and second-line injectable drugs:
impact on multidrug-resistant TB outcomes. Eur Respir J 2013;
42: 156–68.
5 Schatz A, Bugie E, Waksman SA. Streptomycin, a substance
exhibiting antibiotic activity against Gram-positive and Gram-
negative bacteria. Proc Soc Exp Biol Med 1944; 55: 66–69.
6 Wassersug JD. Pulmonary tuberculosis. N Engl J Med 1946;
235: 220–29.
7 Medical Research Council. Streptomycin treatment of pulmonary
tuberculosis: a Medical Research Council investigation. BMJ 1948;
2: 769–82.
8 Fox W, Sutherland I, Daniels M. A five-year assessment of patients
in a controlled trial of streptomycin in pulmonary tuberculosis;
report to the Tuberculosis Chemotherapy Trials Committee of the
Medical Research Council. Q J Med 1954; 23: 347–66.
9 Nunn AJ, Jindani A, Enarson DA, for the Study A investigators.
Results at 30 months of a randomised trial of two 8-month
regimens for the treatment of tuberculosis. Int J Tuberc Lung Dis
2011; 15: 741–45.
10 East African/British Medical Research Councils. Controlled clinical
trial of four short-course (6-month) regimens of chemotherapy for
treatment of pulmonary tuberculosis. Third report. Lancet 1974;
2: 237–40.
11 East African/British Medical Research Councils. Controlled clinical
trial of short-course (6-month) regimens of chemotherapy for
treatment of pulmonary tuberculosis. Lancet 1972; 1: 1079–85.
12 WHO. Treatment of tuberculosis guidelines. 4th edition. Geneva:
World Health Organization, 2010. http://whqlibdoc.who.int/
publications/2010/9789241547833_eng.pdf (accessed Dec 18, 2013).
13 WHO. Guidelines for the programmatic management of drug-
resistant tuberculosis: 2011 update. Geneva: World Health
Organization, 2011 http://www.ncbi.nlm.nih.gov/books/
NBK148644/ (accessed Jan 12, 2014).
14 Falzon D, Jaramillo E, Schünemann HJ, et al. WHO guidelines for
the programmatic management of drug-resistant tuberculosis: 2011
update. Eur Respir J 2011; 38: 516–28.
15 Garton NJ, Christensen H, Minnikin DE, Adegbola RA, Barer MR.
Intracellular lipophilic inclusions of mycobacteria in vitro and in
sputum. Microbiology 2002; 148: 2951–58.
16 Wayne LG, Hayes LG. An in vitro model for sequential study of
shiftdown of Mycobacterium tuberculosis through two stages of
nonreplicating persistence. Infect Immun 1996; 64: 2062–69.
17 Loebel RO, Shorr E, Richardson HB. The influence of adverse
conditions upon the respiratory metabolism and growth of human
tubercle bacilli. J Bacteriol 1933; 26: 167–200.
18 Shleeva MO, Kudykina YK, Vostroknutova GN, Suzina NE,
Mulyukin AL, Kaprelyants AS. Dormant ovoid cells of
Mycobacterium tuberculosis are formed in response to gradual
external acidification. Tuberculosis (Edinb) 2011; 91: 146–54.
19 Mukamolova GV, Turapov O, Malkin J, Woltmann G, Barer MR.
Resuscitation-promoting factors reveal an occult population of
tubercle bacilli in sputum. Am J Respir Crit Care Med 2010;
181: 174–80.
20 Zhang Y, Yew WW, Barer MR. Targeting persisters for tuberculosis
control. Antimicrob Agents Chemother 2012; 56: 2223–30.
21 Abubakar I, Zignol M, Falzon D, et al. Drug-resistant tuberculosis:
time for visionary political leadership. Lancet Infect Dis 2013;
13: 529–39.
22 Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis.
N Engl J Med 2013; 368: 745–55.
23 Zumla A, Nahid P, Cole ST. Advances in the development of new
tuberculosis drugs and treatment regimens. Nat Rev Drug Discov
2013; 12: 388–404.
24 McIlleron H, Meintjes G, Burman WJ, Maartens G. Complications
of antiretroviral therapy in patients with tuberculosis:
drug interactions, toxicity, and immune reconstitution
inflammatory syndrome. J Infect Dis 2007; 196 (suppl): S63–75.
25 Sudre P, ten Dam G, Kochi A. Tuberculosis: a global overview of the
situation today. Bull World Health Organ 1992; 70: 149–59.
26 Zumla A, Atun R, Maeurer M, et al. Viewpoint: scientific dogmas,
paradoxes and mysteries of latent Mycobacterium tuberculosis
infection. Trop Med Int Health 2011; 16: 79–83.
338
27 Walter ND, Painter J, Parker M, et al, for the TB Epidemiologic
Studies Consortium. Persistent latent tuberculosis reactivation risk
in us immigrants. Am J Respir Crit Care Med 2014; 189: 88–95.
28 Lechartier B, Rybniker J, Zumla A, Cole S. Tuberculosis drug
discovery in the post-post-genomic era. EMBO Mol Med 2014;
published online Jan 8. DOI: 10.1002/emmm.201201772.
29 Barry CE 3rd, Boshoff HI, Dartois V, et al. The spectrum of latent
tuberculosis: rethinking the biology and intervention strategies.
Nat Rev Microbiol 2009; 7: 845–55.
30 Diel R, Loddenkemper R, Zellweger JP, et al, for the European
Forum for TB Innovation. Old ideas to innovate tuberculosis
control: preventive treatment to achieve elimination. Eur Respir J
2013; 42: 785–801.
31 Amaral L, Udwadia Z, Abbate E, van Soolingen D. The added effect
of thioridazine in the treatment of drug-resistant tuberculosis.
Int J Tuberc Lung Dis 2012; 16: 1706–08.
32 Musuka S, Srivastava S, Siyambalapitiyage Dona CW, et al.
Thioridazine pharmacokinetic-pharmacodynamic parameters
“Wobble” during treatment of tuberculosis: a theoretical basis for
shorter-duration curative monotherapy with congeners.
Antimicrob Agents Chemother 2013; 57: 5870–77.
33 Mullin S, Mani N, Grossman TH. Inhibition of antibiotic efflux in
bacteria by the novel multidrug resistance inhibitors biricodar
(VX-710) and timcodar (VX-853). Antimicrob Agents Chemother 2004;
48: 4171–76.
34 Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug
active on the ATP synthase of Mycobacterium tuberculosis. Science
2005; 307: 223–27.
35 Makarov V, Manina G, Mikusova K, et al. Benzothiazinones kill
Mycobacterium tuberculosis by blocking arabinan synthesis. Science
2009; 324: 801–04.
36 Pethe K, Bifani P, Jang J, et al. Discovery of Q203, a potent clinical
candidate for the treatment of tuberculosis. Nat Med 2013;
19: 1157–60.
37 Upton AM. TBA-354: a next generation nitroimidazole for
treatment of drug sensitive and drug-resistant tuberculosis.
52nd Interscience Conference on Antimicrobial Agents and
Chemotherapy: San Francisco, CA, USA; Sept 9–12, 2012. 438.
38 Lechartier B, Hartkoorn RC, Cole ST. In vitro combination
studies of benzothiazinone lead compound BTZ043 against
Mycobacterium tuberculosis. Antimicrob Agents Chemother 2012;
56: 5790–93.
39 Fortún J, Martín-Dávila P, Navas E, et al. Linezolid for the treatment
of multidrug-resistant tuberculosis. J Antimicrob Chemother 2005;
56: 180–85.
40 CDC. Provisional CDC guidelines for the use and safety
monitoring of bedaquiline fumarate (Sirturo) for the treatment
of multidrug-resistant tuberculosis. MMWR Recomm Rep 2013;
62: 1–12.
41 EMA. European Medicines Agency positive opinion granting a
conditional marketing authorisation for Deltyba. http://www.ema.
europa.eu/ema/index.jsp?curl=pages/medicines/human/
medicines/002552/smops/Positive/human_smop_000572.
jsp&mid=WC0b01ac058001d127 (accessed Jan 12, 2014).
42 Andries K, Verhasselt P, Guillemont J, et al. A diarylquinoline drug
active on the ATP synthase of Mycobacterium tuberculosis. Science
307: 223–27.
43 Diacon AH, Dawson R, von Groote-Bidlingmaier F, et al. 14-day
bactericidal activity of PA-824, bedaquiline, pyrazinamide, and
moxifloxacin combinations: a randomised trial. Lancet 2012;
380: 986–93.
44 Diacon AH, Dawson R, Hanekom M, et al. Early bactericidal
activity and pharmacokinetics of PA-824 in smear-positive
tuberculosis patients. Antimicrob Agents Chemother 2010;
54: 3402–07.
45 Jindani A, Hatherill M, Charalambous S, et al. A multicentre
randomized clinical trial to evaluate high-dose rifapentine with a
quinolone for treatment of pulmonary TB: The RIFAQUIN Trial.
20th Conference on Retroviruses and Opportunistic Infections:
Atlanta, GA, USA; March 3–6, 2013. 48012.
46 Jawahar MS, Banurekha VV, Paramasivan CN, et al. Randomized
clinical trial of thrice-weekly 4-month moxifloxacin or gatifloxacin
containing regimens in the treatment of new sputum positive
pulmonary tuberculosis patients. PLoS One 2013; 8: e67030.
www.thelancet.com/infection Vol 14 April 2014

47 Merle CS, Sismanidis C, Bah Sow O, et al. A pivotal registration
phase III, multicenter, randomized tuberculosis controlled trial:
design issues and lessons learnt from the gatifloxacin for TB
(OFLOTUB) project. Trials 2012; 13: 61.
48 Merle C, Fielding K, Lapujade O, et al, for OFLOTUB/gatifloxacin
for TB Project. A randomised controlled trial of 4-month
gatifloxacin-containing regimen vs. standard 6-month regimen for
treating drug-susceptible pulmonary tuberculosis: main efficacy
and safety results of the OLFOTUB Trial. 44th World Conference on
Lung Health of the International Union Against Tuberculosis and
Lung Disease: Paris, France; Oct 30–Nov 3, 2013.
49 Koul A, Arnoult E, Lounis N, Guillemont J, Andries K.
The challenge of new drug discovery for tuberculosis. Nature 2011;
469: 483–90.
50 Zhang D, Lu Y, Liu K, et al. Identification of less lipophilic
riminophenazine derivatives for the treatment of drug-resistant
tuberculosis. J Med Chem 2012; 55: 8409–17.
51 Sotgiu G, Centis R, D’Ambrosio L, et al. Efficacy, safety and
tolerability of linezolid containing regimens in treating MDR-TB
and XDR-TB: systematic review and meta-analysis. Eur Respir J
2012; 40: 1430–42.
52 Drusano GL, Sgambati N, Eichas A, Brown DL, Kulawy R, Louie A.
The combination of rifampin plus moxifloxacin is synergistic for
suppression of resistance but antagonistic for cell kill of
Mycobacterium tuberculosis as determined in a hollow-fiber infection
model. MBio 2010; 1: e00139–10.
53 Wallis RS, Diacon AH, Dawson R, et al. Safety, tolerability and early
bactericidal activity in sputum of PNU-100480 (sutezolid) in patients
with pulmonary tuberculosis. XIX International AIDS Conference:
Washington, DC, USA; July 22–27, 2012. THLBB02.
54 Hugonnet JE, Tremblay LW, Boshoff HI, Barry CE 3rd,
Blanchard JS. Meropenem-clavulanate is effective against
extensively drug-resistant Mycobacterium tuberculosis. Science 2009;
323: 1215–18.
55 Faropenem medoxomil: A0026, BAY 56-6854, BAY 566854,
faropenem daloxate, SUN 208, SUN A0026. Drugs R D 2008;
9: 115–24.
56 Diacon AH, Pym A, Grobusch M, et al. The diarylquinoline
TMC207 for multidrug-resistant tuberculosis. N Engl J Med 2009;
360: 2397–05.
57 Diacon AH, Donald PR, Pym A, et al. Randomized pilot trial
of eight weeks of bedaquiline (TMC207) treatment for
multidrug-resistant tuberculosis: long-term outcome, tolerability,
and effect on emergence of drug resistance.
Antimicrob Agents Chemother 2012; 56: 3271–76.
58 Diacon AH, Dawson R, Hanekom M, et al. Early bactericidal activity
of delamanid (OPC-67683) in smear-positive pulmonary
tuberculosis patients. Int J Tuberc Lung Dis 2011; 15: 949–54.
59 Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid for
multidrug-resistant pulmonary tuberculosis. N Engl J Med 2012;
366: 2151–60.
60 Skripconoka V, Danilovits M, Pehme L, et al. Delamanid improves
outcomes and reduces mortality in multidrug-resistant
tuberculosis. Eur Respir J 2013; 41: 1393–400.
61 van Ingen J, Aarnoutse RE, Donald PR, et al. Why do we use
600 mg of rifampicin in tuberculosis treatment? Clin Infect Dis 2011;
52: e194–99.
62 Boeree M, Diacon A, Dawson R, et al. What is the “right” dose of
rifampin? 20th Conference on Retroviruses and Opportunistic
Infections; Atlanta, GA, USA; March 3–6, 2013. 148LB.
63 Fattorini L, Piccaro G, Mustazzolu A, Giannoni F. Targeting
dormant bacilli to fight tuberculosis. Mediterr J Hematol Infect Dis
2013; 5: e2013072.
64 Deb C, Lee C-M, Dubey VS, et al. A novel in vitro multiple-stress
dormancy model for Mycobacterium tuberculosis generates a lipid-
loaded, drug-tolerant, dormant pathogen. PLoS One 2009;
4: e6077.
65 Hu YM, Butcher PD, Sole K, Mitchison DA, Coates AR. Protein
synthesis is shutdown in dormant Mycobacterium tuberculosis and is
reversed by oxygen or heat shock. FEMS Microbiol Lett 1998;
158: 139–45.
66 Mak PA, Rao SP, Ping Tan M, et al. A high-throughput screen to
identify inhibitors of ATP homeostasis in non-replicating
Mycobacterium tuberculosis. ACS Chem Biol 2012; 7: 1190–97.
www.thelancet.com/infection Vol 14 April 2014
Review
67 Bryk R, Arango N, Maksymiuk C, et al. Lipoamide channel-binding
sulfonamides selectively inhibit mycobacterial lipoamide
dehydrogenase. Biochemistry 2013; 52: 9375–84.
68 Stover CK, Warrener P, VanDevanter DR, et al. A small-molecule
nitroimidazopyran drug candidate for the treatment of tuberculosis.
Nature 2000; 405: 962–66.
69 Manca C, Koo MS, Peixoto B, Fallows D, Kaplan G, Subbian S.
Host targeted activity of pyrazinamide in Mycobacterium tuberculosis
infection. PLoS One 2013; 8: e74082.
70 Jindani A, Nunn AJ, Enarson DA. Two 8-month regimens of
chemotherapy for treatment of newly diagnosed pulmonary
tuberculosis: international multicentre randomised trial. Lancet
2004; 364: 1244–51.
71 Hong Kong Chest Service, Tuberculosis Research Centre, Madras,
British Medical Research Council. A controlled trial of 3-month,
4-month, and 6-month regimens of chemotherapy for sputum-
smear-negative pulmonary tuberculosis. Results at 5 years.
Am Rev Respir Dis 1989; 139: 871–76.
72 Johnson JL, Hadad DJ, Dietze R, et al. Shortening treatment in
adults with noncavitary tuberculosis and 2-month culture
conversion. Am J Respir Crit Care Med 2009; 180: 558–63.
73 Ziganshina LE, Titarenko AF, Davies GR. Fluoroquinolones for
treating tuberculosis (presumed drug-sensitive).
Cochrane Database Syst Rev 2013; 6: CD004795.
74 REMox. Controlled comparison of two moxifloxacin containing
treatment shortening regimens in pulmonary tuberculosis
(REMoxTB). NCT00864383. http://clinicaltrials.gov/ct2/show/
NCT00864383 (accessed Dec 1, 2013).
75 Prieto-Merino D, Smeeth L, Staa TP, Roberts I. Dangers of
non-specific composite outcome measures in clinical trials. BMJ
2013; 347: f6782.
76 Lounis N, Bentoucha A, Truffot-Pernot C, et al. Effectiveness of
once-weekly rifapentine and moxifloxacin regimens against
Mycobacterium tuberculosis in mice. Antimicrob Agents Chemother
2001; 45: 3482–86.
77 Wallis RS, Wang C, Meyer D, Thomas N. Month 2 culture status
and treatment duration as predictors of tuberculosis relapse risk in
a meta-regression model. PLoS One 2013; 8: e71116.
78 Phillips PP, Fielding K, Nunn AJ. An evaluation of culture results
during treatment for tuberculosis as surrogate endpoints for
treatment failure and relapse. PLoS One 2013; 8: e63840.
79 Phillips PPJ, Gillespie SH, Boeree M, et al. Innovative trial designs
are practical solutions for improving the treatment of tuberculosis.
J Infect Dis 2012; 205 (suppl): S250–57.
80 Nunn AJ, Phillips PPJ, Gillespie SH. Design issues in pivotal drug
trials for drug sensitive tuberculosis (TB). Tuberculosis 2008;
88 (suppl): S85–92.
81 Rustomjee R, Lienhardt C, Kanyok, T, et al. A phase II study of the
sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in
pulmonary tuberculosis. Int J Tuberc Lung Dis 2008: 12: 128–38.
82 Aber VR, Nunn AJ. Short term chemotherapy of tuberculosis.
Factors affecting relapse following short term chemotherapy.
Bull Int Union Tuberc 1978; 53: 276–80.
83 Kayigire XA, Friedrich SO, Venter A, et al. Direct comparison of
Xpert MTB/RIF with liquid and solid mycobacterial culture for the
quantification of early bactericidal activity. J Clin Microbiol 2013;
51: 1894–98.
84 Bark CM, Gitta P, Ogwang S, et al. Comparison of time to
positive and colony counting in an early bactericidal activity study
of anti-tuberculosis treatment. Int J Tuberc Lung Dis 2013;
17: 1448–51.
85 Wallis RS, Kim P, Cole S, et al. Tuberculosis biomarkers discovery:
developments, needs, and challenges. Lancet Infect Dis 2013;
13: 362–72.
86 Friedrich SO, Rachow A, Saathoff E, et al. Assessment of the
sensitivity and specificity of Xpert MTB/RIF assay as an early
sputum biomarker of response to tuberculosis treatment.
Lancet Resp Med 2013; 1: 462–70.
87 Hellyer TJ, DesJardin LE, Hehman GL, Cave MD, Eisenach KD.
Quantitative analysis of mRNA as a marker for viability of
Mycobacterium tuberculosis. J Clin Microbiol 1999; 37: 290–95.
88 Liu J-Y, Jin L, Zhao M-Y, et al. New serum biomarkers for detection of
tuberculosis using surface-enhanced laser desorption/ionization time-
of-flight mass spectrometry. Clin Chem Lab Med 2011; 49: 1727–33.
339
 Review
89 Honeyborne I, McHugh TD, Phillips PPJ, et al. Molecular bacterial
load assay, a culture-free biomarker for rapid and accurate
quantification of sputum Mycobacterium tuberculosis bacillary load
during treatment. J Clin Microbiol 2011; 49: 3905–11.
90 Bratton DJ, Phillips PP, Parmar MK. A multi-arm multi-stage
clinical trial design for binary outcomes with application to
tuberculosis. BMC Med Res Methodol 2013; 13: 139.
91 Weyer K, Mirzayev F, Migliori GB, et al. Rapid molecular TB
diagnosis: evidence, policy making and global implementation of
Xpert MTB/RIF. Eur Respir J 2013; 42: 252–71.
92 Charalambous S, Grant AD, Moloi V, et al. Contribution of
reinfection to recurrent tuberculosis in South African gold miners.
Int J Tuberc Lung Dis 2008; 12: 942–48.
93 Glynn JR, Murray J, Bester A, et al. High rates of recurrence in
HIV-infected and HIV-uninfected patients with tuberculosis.
J Infect Dis 2010; 201: 704–11.
94 Bryant JM, Harris SR, Parkhill J, et al. Whole-genome sequencing
to establish relapse or re-infection with Mycobacterium tuberculosis:
a retrospective observational study. Lancet Infect Dis 2013; 1: 786–92.
95 Lawn SD, Harries AD, Wood R. Strategies to reduce early
morbidity and mortality in adults receiving antiretroviral therapy
in resource-limited settings. Curr Opin HIV AIDS 2010; 5: 18–26.
96 Abdool Karim SS, Naidoo K, Grobler A, et al. Timing of initiation of
antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;
362: 697–706.
97 Blanc F-X, Sok T, Laureillard D, et al, for the CAMELIA (ANRS
1295–CIPRA KH001) Study Team. Earlier versus later start of
antiretroviral therapy in HIV-infected adults with tuberculosis.
N Engl J Med 2011; 365: 1471–81.
98 Havlir DV, Kendall MA, Ive P, et al, for the AIDS Clinical Trials
Group Study A5221. Timing of antiretroviral therapy for HIV-1
infection and tuberculosis. N Engl J Med 2011; 365: 1482–91.
99 Manosuthi W, Mankatitham W, Lueangniyomkul A, et al, for the
TIME Study Team. Time to initiate antiretroviral therapy between
4 weeks and 12 weeks of tuberculosis treatment in HIV-infected
patients: results from the TIME study. J Acquir Immune Defic Syndr
2012; 60: 377–83.
100 WHO. Antiretroviral therapy for HIV infection in adults and
adolescents 2010 revision. Geneva: World Health Organization,
2010. http://www.who.int/hiv/pub/arv/adult2010/ (accessed
Dec 8, 2013).
101 TB HAART. An evaluation of the impact of early initiation of highly
active anti-retroviral therapy (HAART) on tuberculosis (TB)
treatment outcomes for TB patients co-infected with human
immunodeficiency virus (HIV). ISRCTN77861053. http://www.
controlled-trials.com/ISRCTN77861053 (accessed Dec 8, 2013).
102 Skrahin A, Ahmed R, Ferrara G, et al. Autologous mesenchymal
stromal cell infusion as adjunct treatment in patients with
multidrug and extensively drug-resistant tuberculosis: an open-label
phase 1 safety trial. Lancet Resp Med 2014; 2: 108–22.
340
103 Zumla A, Maeurer M. Rational development of adjunct immune-
based therapies for drug-resistant tuberculosis: hypotheses and
experimental designs. J Infect Dis 2012; 205 (suppl): S335–39.
104 Upadhyay P. Tuberculosis vaccine trials. Lancet 2013; 381: 2253–54.
105 Tobin DM, Roca FJ, Oh SF, et al. Host genotype-specific therapies
can optimize the inflammatory response to mycobacterial
infections. Cell 2012; 148: 434–46.
106 Wallis RS. Biologics and infections: lessons from tumor necrosis
factor blocking agents. Infect Dis Clin North Am 2011; 25: 895–910.
107 Lin PL, Flynn JL. Understanding latent tuberculosis: a moving
target. J Immunol 2010; 185: 15–22.
108 Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of
macrolide antibiotics. J Pharmacol Exp Ther 2000; 292: 156–63.
109 Brodin P, Valentini D, Uhlin M, Mattsson J, Zumla A, Maeurer MJ.
Systems level immune response analysis and personalized
medicine. Expert Rev Clin Immunol 2013; 9: 307–17.
110 Casali N, Nikolayevskyy V, Balabanova Y, et al. Microevolution of
extensively drug-resistant tuberculosis in Russia. Genome Res 2012;
22: 735–45.
111 Vilaplana C, Marzo E, Tapia G, Diaz J, Garcia V, Cardona PJ.
Ibuprofen therapy resulted in significantly decreased tissue
bacillary loads and increased survival in a new murine experimental
model of active tuberculosis. J Infect Dis 2013; 208: 199–202.
112 Guzman JD, Evangelopoulos D, Gupta A, et al. Antitubercular
specific activity of ibuprofen and the other 2-arylpropanoic acids
using the HT-SPOTi whole-cell phenotypic assay. BMJ Open 2013;
3: e002672.
113 Gupta S, Cohen KA, Winglee K, Maiga M, Diarra B, Bishai WR.
Efflux inhibition with verapamil potentiates bedaquiline in
Mycobacterium tuberculosis. Antimicrob Agents Chemother 2014;
58: 574–76
114 Gupta S, Tyagi S, Almeida DV, Maiga MC, Ammerman NC,
Bishai WR. Acceleration of tuberculosis treatment by adjunctive
therapy with verapamil as an efflux inhibitor.
Am J Respir Crit Care Med 2013; 188: 600–07.
115 Maiga M, Ammerman NC, Maiga MC, et al. Adjuvant host-directed
therapy with types 3 and 5 but not type 4 phosphodiesterase
inhibitors shortens the duration of tuberculosis treatment.
J Infect Dis 2013; 208: 512–19.
116 Zumla A, Atun R, Maeurer M, et al. Eliminating tuberculosis and
tuberculosis–HIV co-disease in the 21st century: key perspectives,
controversies, unresolved issues, and needs. J Infect Dis 2012;
205 (suppl): S141–46.
117 Wallis RS. Sustainable tuberculosis drug development.
Clin Infect Dis 2013; 56: 106–13.
118 Zumla A, Abubakar I, Raviglione M, et al. Drug-resistant
tuberculosis—current dilemmas, unanswered questions,
challenges, and priority needs. J Infect Dis 2012;
205 (suppl): S228–40.
www.thelancet.com/infection Vol 14 April 2014