BACKGROUND
Patients with highly drug-resistant forms of tuberculosis have limited treatment
options and historically have had poor outcomes.
METHODS
In an open-label, single-group study in which follow-up is ongoing at three South
African sites, we investigated treatment with three oral drugs — bedaquiline,
pretomanid, and linezolid — that have bactericidal activity against tuberculosis and
to which there is little preexisting resistance. We evaluated the safety and efficacy
of the drug combination for 26 weeks in patients with extensively drug-resistant
tuberculosis and patients with multidrug-resistant tuberculosis that was not respon-
sive to treatment or for which a second-line regimen had been discontinued because
of side effects. The primary end point was the incidence of an unfavorable outcome,
defined as treatment failure (bacteriologic or clinical) or relapse during follow-up,
which continued until 6 months after the end of treatment. Patients were classified
as having a favorable outcome at 6 months if they had resolution of clinical disease,
a negative culture status, and had not already been classified as having had an un-
favorable outcome. Other efficacy end points and safety were also evaluated.
RESULTS
A total of 109 patients were enrolled in the study and were included in the evalu-
ation of efficacy and safety end points. At 6 months after the end of treatment in
the intention-to-treat analysis, 11 patients (10%) had an unfavorable outcome and
98 patients (90%; 95% confidence interval, 83 to 95) had a favorable outcome. The
11 unfavorable outcomes were 7 deaths (6 during treatment and 1 from an un-
known cause during follow-up), 1 withdrawal of consent during treatment, 2 re-
lapses during follow-up, and 1 loss to follow-up. The expected linezolid toxic ef-
fects of peripheral neuropathy (occurring in 81% of patients) and myelosuppression
(48%), although common, were manageable, often leading to dose reductions or
interruptions in treatment with linezolid.
CONCLUSIONS
The combination of bedaquiline, pretomanid, and linezolid led to a favorable outcome
at 6 months after the end of therapy in a high percentage of patients with highly drug-
resistant forms of tuberculosis; some associated toxic effects were observed.
(Funded by the TB Alliance and others; ClinicalTrials.gov number, NCT02333799.)
Since the discovery of the first antituberculosis
drugs 75 years ago, the pursuit of a short, effec-
tive, and affordable regimen that has acceptable
side effects and is capable of curing most pa-
tients most of the time has been a major public
health priority. Such a “pan-tuberculosis” regi-
men is seen by many as essential in reducing the
global tuberculosis burden.1
The successful development of two new anti-
tuberculosis drugs — bedaquiline and pretoma-
nid — represents an important step forward in
the pursuit of pan-tuberculosis regimens fit for the
21st century. Conradie and colleagues now report
in the Journal that when this all-oral regimen was
combined with a third drug — linezolid, repur-
posed from its licensed indication for gram-
positive bacterial infections — and given for 26
to 39 weeks to patients with extensively drug-
resistant or complicated multidrug-resistant tu-
berculosis, it produced a favorable outcome in 98
of 109 patients (90%) at 6 months after the end
of treatment.2
Cure rates for extensively drug-
resistant tuberculosis were less than 50% before
the advent of new drugs.3
Therefore, this is a
triumph, and the authors are to be congratulated
for their vision and courage in tackling the most
difficult-to-treat forms of tuberculosis.
The tragedy being confronted, however, is the
overlapping realities of the persisting need for
new regimens and the spectacular inadequacy of
support for their development and the tools
needed for their effective use in the field. Our
current tuberculosis regimen was the product of
a remarkable series of global, iterative, random-
ized, controlled trials conducted between 1947
and 1980.4
The resulting “short-course chemo-
therapy” was an oral regimen, containing rifam-
pin, isoniazid, and pyrazinamide, that cured the
large majority of people with tuberculosis if it
was taken for 6 months. This regimen, despite
known toxicities, has produced extraordinary
gains, curing approximately 58 million people
since the year 2000.5
However, 30 years of its
global use has revealed the serious limitations of
depending on a single, one-size-fits-all regimen
to treat a challenging infectious disease.6
Pre-
dictable toxicities and the development of resis-
tance are directly relevant to ongoing efforts to
develop other regimens,7
including the new
regimen studied by Conradie et al.
During the early global adoption of rifampin-
based short-course chemotherapy, the possibility
that resistance would become a barrier to ending
the epidemic was considered unlikely. As a result,
the development of accessible and affordable
laboratory tools for the detection of drug resis-
tance was not prioritized. Thus, when resistance
did inevitably emerge, the tools to detect and
manage it were too inefficient, too costly, and too
far from the clinic to halt the spread of rifampin
resistance. The acquisition of resistance is also a
risk for the bedaquiline–pretomanid–linezolid
regimen. Conradie reports one patient who had
a relapse caused by bacteria with reduced sus-
ceptibility to bedaquiline. When this evidence is
considered together with other reports of pri-
mary resistance to bedaquiline,8
along with the
described toxicities of linezolid, the need for
monitoring of the QT interval, and the residual
uncertainty about hepatotoxicity of pretomanid,9
it suggests a risk of going back to where we
started: a situation in which a pan-tuberculosis
regimen with known toxicities that are likely to
result in pauses in or discontinuation of treat-
ment is sent to the field without adequate tools
for monitoring resistance.
The other major tragedy is that every year
tuberculosis still affects approximately 10 million people and kills 1.5 million.5
In light of
these figures, we should not be dependent on
one small, single-group, single-country study for
evidence of the efficacy of the newest tuberculo-
sis regimen. The study was rigorously conducted
and laudably designed to report on definitive
outcomes of durable cure and relapse; however,
such approaches for the development of tubercu-
losis regimens do not correspond with the mag-
nitude of the problem. Tuberculosis does not
present insurmountable hurdles for the conduct
of clinical trials. Even the creation of multidrug
regimens with new agents from different devel-
opers is feasible, as evidenced by the recent his-
tory of treatment for human immunodeficiency
virus infection and hepatitis C, both of which
have new regimens developed and defined
through multiple large trials. In contrast and
tragically, the majority of evidence available to
the World Health Organization in 2020 as it
formulates treatment guidelines for drug-resis-
tant tuberculosis comes from noncomparative
or observational studies.10,11 Such studies should
serve as the adjunct to an evidence base of robust
randomized, controlled clinical trials, rather than
as its leading edge.
A rejuvenated program of innovative phase 2
and phase 3 clinical trials of new drugs and
regimens, in conjunction with continued invest-
ment in tools for detecting and monitoring resis-
tance, is required worldwide. It will take substan-
tially greater investment and coordinated forms
of collaboration among sponsors, industry, aca-
demic partners, and policy decision makers to
develop and implement new evidence-based regi-
mens that are fitting for a disease that has killed
hundreds of millions of people. Until that hap-
pens, if the current inadequate investment path
is held, history is bound to repeat itself — and
for all the jubilation that comes with developing
a new effective regimen, there will be more trag-
edy yet to come.
Disclosure forms provided by the authors are available with
the full text of this editorial at NEJM.org.
From the Oxford University Clinical Research Unit, Ho Chi
Minh City, Vietnam (G.T.); the Centre for Tropical Medicine and
Global Health, Nuffield Department of Medicine, University of
Oxford, Oxford, United Kingdom (G.T.); and the UCSF Center
for Tuberculosis and Division of Pulmonary and Critical Care
Medicine, University of California, San Francisco (P.N.).