Comment

Tuberculosis is a major health priority, with 9 million cases

and 15 million deaths in 2013, of which 360 000 deaths
were in people with HIV and 210 000 deaths were in
people with multidrug-resistant (MDR) tuberculosis.13 In
several countries of the former Soviet Union, one in three
new cases is caused by MDR tuberculosis. In response,
WHO have proposed and scaled up various innovative
global public health interventions over the past two
decades, from directly observed treatment, short-course
(DOTS) and the Stop TB Strategy, to the recently approved
End TB Strategy.1 These strategies and interventions
support the vision of a tuberculosis-free world with no
death, disease, or suering caused by tuberculosis.46
Rapid diagnosis and eective treatment of infectious
cases are the pillars of the programmatic approach
to tuberculosis control, although a more aggressive
approach based on diagnosis and treatment of latently
infected individuals has been proposed in the context
of tuberculosis elimination. A vaccine that is better than
BCG will be also needed. However, for the past 40 years,
no new drug since rifampicin has been developed to
ght tuberculosis, although substantial progress has
been achieved in diagnostics (eg, the development
of Xpert MTB/RIF).7 Nowadays, whether a strain of
Mycobacterium tuberculosis is resistant to rifampicin can
be established in less than 2 h; this rapid detection of
rifampicin resistance is regarded as a reasonable proxy
of MDR tuberculosis where prevalence is high.1
To understand how dicult these drug-resistant cases
are for physicians to treat, the denition of extensively
drug-resistant (XDR) tuberculosis should be considered;
these strains are MDR (ie, resistant at least to isoniazid
and rifampicin) and have acquired additional resistance to
uoroquinolones and injectable second-line drugs. In the
largest cohort of patients with MDR tuberculosis reported
(n=9153),2 the proportion of cases treated successfully was
62%, with treatment failure or relapse occurring for 7% of
patients, death in 9%, and defaulting (lost to follow-up)
in 17%. In the subgroup of patients with XDR tuberculosis,
treatment outcomes were even worse: treatment was
successful for 40% of patients, but treatment failure or
relapse occurred for 22%, 15% died, and 16% defaulted.3,8,9
In addition to being very long (20 months or more) and
very toxic, treatment of drug-resistant tuberculosis is also
very expensive: in Germany, the cost of treating a patient
www.thelancet.com Vol 385 May 2, 2015

with XDR tuberculosis exceeds 168 000 for drugs alone.10

As a result of a multistakeholder initiative, to begin to
address these issues, two new antituberculosis drugs have
been approved by the US Food and Drug Administration,
European Medicines Agency, or bothbedaquiline and
delamanid.11,12
In The Lancet, Rodney Dawson and colleagues13
investigate what regimens can be designed with
new antituberculosis drugs. Their phase 2b trial at
eight sites in South Africa and Tanzania compared
the bactericidal activity of 8 week regimens of
moxioxacin, pretomanid (previously known as PA-824;
100 mg or 200 mg, dependent on treatment group),
and pyrazinamide (MPa100Z or MPa200Z regimen,
as dened by pretomanid dose) with the existing
standard antituberculosis regimen for drug-susceptible
tuberculosisisoniazid, rifampicin, pyrazinamide, and
ethambutol (HRZE)for the treatment of patients
with sputum smear-positive, drug-susceptible, or MDR
tuberculosis. 60 patients were randomly assigned
to the MPa100Z group, 62 to the MPa200Z group,
and 59 to the HRZE group; 26 patients with MDR
tuberculosis were also given the MPa200Z regimen and
treated as a separate analysis group (DRMPa200Z).
By a Bayesian approach, Dawson and colleagues13
assessed the mean daily rate of reduction in M tuberculosis
colony forming units (CFUs) per mL, as a marker of
bactericidal activity. Bactericidal activity was signicantly
increased in patients with drug-susceptible tuberculosis
compared with the WHO-recommended regimen
(HRZE) after 8 weeks of treatment. For patients with
drug-susceptible tuberculosis, the mean change in daily
log10CFU count was 0155 (credibility interval 01330178)
for MPa200Z, as compared with 0112 (00930131)
for HRZE. Change in bactericidal activity was 0133
(01090155) for MPa100Z, and, for patients with MDR
tuberculosis given MPa200Z, 0117 (00700174).
The safety prole and protective eect towards
development of resistance was similar to that detected
in the control group. 59 (29%) of 207 patients had
hyperuricaemia (17 [28%] of 60 patients in the MPa100Z
group, 17 [27%] of 62 patients in the MPa200Z group,
17 [29%] of 59 patients in the HRZE group, and eight [31%]
of 26 patients in the DRMPa200Z group); 37 (18%) had
nausea (14 [23%] in the MPa100Z group, eight [13%] in

A Dowsett, Public Health England/Science Photo Library

New eective antituberculosis regimens

Published Online
March 18, 2015
http://dx.doi.org/10.1016/
S0140-6736(14)62303-5
See Articles page 1738

1703

Comment

the MPa200Z group, seven [12%] in the HRZE group, and

eight [31%] in the DRMPa200Z group); and 25 (13%)
had vomiting (seven [12%] in the MPa100Z group,
seven [11%] in the MPa200Z group, seven [12%] in the
HRZE group, and four [15%] in the DRMPa200Z group).
Importantly, no episodes of QT interval in excess of
500 ms were identied.
Dawson and colleagues results13 are encouraging for
several reasons. First, the investigators have shown the
ecacy of a rifampicin-sparing regimen, which has the
potential to improve the ease and safety of treatment
of patients with HIV taking protease inhibitors. Second,
the 8 week period needed to achieve sputum culture
conversion might benet the individual patient (ie, rapid
recovery) and the community (ie, reduced M tuberculosis
transmission). The potential exists to shorten treatment
duration and thereby improve adherence. As the
investigators note,13 the ecacy of the rifampicin-sparing
regimen in patients with MDR tuberculosis needs further
investigation, since the study was not powered to detect
an eect in the small subgroup of patients with MDR
disease. Furthermore, the positive protective eect on
the emergence of phenotypic drug resistance identied in
this study needs to be further assessed in the longer term,
especially during the continuation phase of treatment.
Much work still needs to be done to improve the present
approach to clinical trials of antituberculosis drugs. The
surrogate markers adopted to measure ecacy are old
and need complex statistical approaches. Furthermore,
the time needed to assess the pharmacological prole of
a new drug is still very long, and the diculty of enrolling
susceptible individuals into trials is a further barrier.9 The
new WHO End TB Strategy aims to support these eorts
needed for research on new antituberculosis drugs.

Giovanni Sotgiu, *Giovanni Battista Migliori

Clinical Epidemiology and Medical Statistics Unit, Department of
Biomedical Sciences, University of Sassari, Sassari, Italy (GS); and
WHO Collaborating Centre for TB and Lung Diseases,
Fondazione S Maugeri, Care and Research Institute,
Tradate 21049, Italy (GBM)
giovannibattista.migliori@fsm.it
We declare no competing interests.
1
2

4
5
6

8
9

10
11

12

13

WHO. Global tuberculosis report 2014. Geneva: World Health

Organization, 2014.
Falzon D, Gandhi N, Migliori GB, et al, on behalf of the Collaborative Group
for Meta-Analysis of Individual Patient Data in MDR-TB. Resistance to
uoroquinolones and second-line injectable drugs: impact on MDR-TB
outcomes. Eur Respir J 2013; 42: 15668.
Migliori GB, Sotgiu G, Gandhi NR; 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: 16979.
Sotgiu G, Migliori GB. Is tuberculosis elimination a reality?
Lancet Infect Dis 2014; 14: 36465.
Migliori GB, Sotgiu G. Measuring the eect of tuberculosis control: a step
forward. Lancet 2014; 383: 202628.
Tanimura T, Jaramillo E, Weil D, Raviglione M, Lnnroth K. Financial burden
for tuberculosis patients in low- and middle-income countries: a systematic
review. Eur Respir J 2014; 43: 176375.
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: 25271.
Raviglione M, Uplekar M, Vincent C, Pablos-Mndez A. Rebalancing the
global battle against tuberculosis. Lancet Glob Health 2014; 2: e7172.
Zumla AI, Schito M, Maeurer M. Advancing the portfolio of tuberculosis
diagnostics, drugs, biomarkers, and vaccines. Lancet Infect Dis 2014;
14: 26769.
Diel R, Rutz S, Castell S, Schaberg T. Tuberculosis: cost of illness in Germany.
Eur Respir J 2012; 40: 14351.
Skripconoka V, Danilovits M, Pehme L. Delamanid improves outcomes and
reduces mortality in multidrug-resistant tuberculosis. Eur Respir J 2013;
41: 1393400.
Diacon AH, Pym A, Grobusch MP, et al, for the TMC207-C208 Study Group.
Multidrug-resistant tuberculosis and culture conversion with bedaquiline.
N Engl J Med 2014; 371: 72332.
Dawson R, Diacon AH, Everitt D, et al. Eciency and safety of the
combination of moxioxacin, pretomanid (PA-824), and pyrazinamide
during the rst 8 weeks of antituberculosis treatment: a phase 2b,
open-label, partly randomised trial in patients with drug-susceptible or
drug-resistant pulmonary tuberculosis. Lancet 2015; published online
March 18. http://dx.doi.org/10.1016/S0140-6736(14)62002-X.

Ecacy of idebenone in Duchenne muscular dystrophy

Published Online
April 21, 2015
http://dx.doi.org/10.1016/
S0140-6736(15)60758-9
See Articles page 1748

1704

In The Lancet, Gunnar Buyse and colleagues1 report

the results of DELOS, a double-masked, randomised,
placebo-controlled, multicentre, phase 3 trial
investigating the ecacy of idebenone on respiratory
outcomes in patients with Duchenne muscular
dystrophy. The authors report for the rst time the
possible ecacy of a non-steroidal drug in a cohort of
patients with Duchenne muscular dystrophy, most of
whom were non-ambulant. The results are promising

because of the favourable safety prole of idebenone,

but also show that challenges exist for studies in people
with this disease, especially non-ambulant patients, and
raise questions about the choice of outcome measures
and inclusion criteria for this population.
In the past few years, several experimental therapies
have been studied in patients with Duchenne muscular
dystrophy2 and this research has strongly encouraged
international collaboration to identify suitable outcome
www.thelancet.com Vol 385 May 2, 2015