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Tuberculosis

Article  in  Nature Reviews Disease Primers · October 2016

DOI: 10.1038/nrdp.2016.76

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 PRIMER
Tuberculosis
Madhukar Pai1, Marcel A. Behr1, David Dowdy2, Keertan Dheda3, Maziar Divangahi1,
Catharina C. Boehme4, Ann Ginsberg5, Soumya Swaminathan6, Melvin Spigelman7,
Haileyesus Getahun8, Dick Menzies1 and Mario Raviglione8
Abstract | Tuberculosis (TB) is an airborne infectious disease caused by organisms of the
Mycobacterium tuberculosis complex. Although primarily a pulmonary pathogen, M. tuberculosis can
cause disease in almost any part of the body. Infection with M. tuberculosis can evolve from
containment in the host, in which the bacteria are isolated within granulomas (latent TB infection), to a
contagious state, in which the patient will show symptoms that can include cough, fever, night sweats
and weight loss. Only active pulmonary TB is contagious. In many low-income and middle-income
countries, TB continues to be a major cause of morbidity and mortality, and drug-resistant TB is a
major concern in many settings. Although several new TB diagnostics have been developed, including
rapid molecular tests, there is a need for simpler point‑of‑care tests. Treatment usually requires a
prolonged course of multiple antibiotics, stimulating efforts to develop shorter drug regimens.
Although the Bacillus Calmette–Guérin (BCG) vaccine is used worldwide, mainly to prevent
life-threatening TB in infants and young children, it has been ineffective in controlling the global TB
epidemic. Thus, efforts are underway to develop newer vaccines with improved efficacy. However, the
development of new tools has been hampered by scientific and economic challenges.

In 1882, Robert Koch discovered the causative agent as M. tuberculosis resistance to at least isoniazid and
of tuberculosis (TB), an airborne infectious disease rifampicin — is a well-recognized entity that has been
caused by organisms of the Mycobacterium tuberculosis reported in virtually all countries1. Extensively drug-re-
complex. In 2016, TB continues to be a major cause of sistant TB disease, which causes even more-severe dis-
morbidity and mortality, primarily in low-income and ease manifestations, is not only resistant to isoniazid
middle-income countries1. and rifampicin but also to any fluoroquinolone and any
Although primarily a pulmonary pathogen, of the three injectable second-line aminoglycosides.
M. tuberculosis can cause disease throughout the body. Diagnostic and therapeutic options vary for LTBI and
Furthermore, TB can present as a dynamic spectrum, active TB disease, and for drug-sensitive and drug-re-
from asymptomatic infection to a life-threatening dis- sistant TB disease.
ease2,3 (FIG. 1). From a clinical and public health perspec- In this Primer, we discuss the epidemiology, micro­
tive, patients with TB are pragmatically classified as biology, immunology, pathogenesis, diagnosis, treat-
having latent TB infection (LTBI), which is an asympto- ment and prevention of M. tuberculosis infection and TB,
matic and non-transmissible state, or active TB disease, including drug-resistant TB, childhood TB and HIV-
which is transmissible (in active pulmonary TB) and for associated TB. We also review the pipeline of novel diag-
which culture-based or molecular diagnostics can be nostics, vaccines and drugs, provide an overview of the
used. Patients with active TB disease experience general End TB Strategy and summarize key research priorities.
symptoms, such as fever, fatigue, lack of appetite and
Correspondence to M.P.
weight loss, and those with pulmonary disease can have Epidemiology
McGill International TB persistent cough and haemoptysis (coughing up blood) According to the WHO, in 2014, an estimated 9.6 mil-
Centre, McGill University, in advanced disease. However, some patients with active, lion people developed active TB disease, of whom
1020 Pine Avenue West, culture-positive disease may be asymptomatic and are 1.5 million died1. The burden of TB is heterogene-
Montreal, Quebec,
best described as having subclinical TB2,3 (FIG. 1). ously distributed (FIG. 2). For example, TB incidence is
Quebec H3A 1A2, Canada.
[email protected] Standard treatment for TB comprises four first- >250‑fold higher in South Africa (834 cases per 100,000
line antibiotics: isoniazid, rifampicin, pyrazinamide population per year) than in the United States (3 cases
Article number: 16076
doi:10.1038/nrdp.2016.76 and ethambutol. Resistance to all drugs can occur. per 100,000 population per year)1. Rates of developing
Published online DD Mmm 2016 Indeed, multidrug-resistant TB (MDR-TB) — defined active TB disease are very high in exposed infants, but

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1

PRIMER

Author addresses a prolonged productive (phlegm or mucus-producing)

cough, and at least 25% have no symptoms whatsoever 19.
1
McGill International TB Centre, McGill University, 1020 Pine Avenue West, Montreal, Thus, the progression from LTBI to active TB disease can
Quebec, Quebec H3A 1A2, Canada. be clinically subtle, despite the fact that individuals with
2
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. subclinical TB can transmit the organism to others20.
3
Division of Pulmonology and UCT Lung Institute, Department of Medicine, University of
Trends in the epidemiology of TB reveal marked dis-
Cape Town, Cape Town, South Africa.
4
Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland. parities. From 1900 to 1980, TB‑related deaths in west-
5
Aeras, Rockville, Maryland, USA. ern Europe and the United States fell by >100‑fold21. As
6
Indian Council of Medical Research, New Delhi, India. much of this decline occurred before the discovery of
7
Global Alliance for TB Drug Development, New York, New York, USA. effective anti‑TB drugs, it is generally thought that much
8
Global TB Programme, WHO, Geneva, Switzerland. of this decrease resulted from general improvements
in hygiene and socioeconomic conditions. However,
progress in most high-burden settings has been much
much lower in children 2–10 years of age; risk then rises slower. The current worldwide rate of decline in inci-
during adolescence and plateaus around 25 years of age, dence is only about 1.5% per year 1. More-rapid pro-
remaining high throughout adult life4. The incidence of gress has been seen in certain areas; for example, China
active TB disease is approximately twofold higher in men halved its prevalence of active TB disease and reduced
than in women5, and approximately 10% of all new cases TB‑related mortality by an estimated 80% over a period
worldwide occur in children6. of 20 years (1990–2010)22. By contrast, the incidence of
Among major known risk factors for TB, HIV infec- active TB disease increased during the same time period
tion is the strongest 7; 12% of all new active TB dis- in Africa, primarily because of the effect of the HIV
ease cases and 25% of all TB‑related deaths occur in epidemic1. Treatments for TB have saved an estimated
HIV-positive individuals. The majority (75%) of HIV- >43 million lives between 2000 and 2014; nevertheless,
associated active TB disease cases and deaths occur in the WHO estimates that over one-third of all individuals
Africa8. Indeed, a systematic review showed that active who develop active TB disease are never diagnosed or
TB disease was the leading cause of hospitalization notified to public health authorities, based on the dif-
among HIV-infected adults (18%) and children (10%)9. ference between estimated and notified cases — these
TB‑related in‑hospital mortality was 25% among ‘missing 3.6 million’ constitute a major challenge in
adults and 30% among children with HIV infection9. ongoing efforts to control TB1.
Nevertheless, as HIV-positive individuals make up only The emergence of drug resistance is a major con-
0.5% of the world’s population, other risk factors are cern, and its distribution is particularly heterogeneous.
responsible for the remaining fraction of TB cases in the Globally, the prevalence of MDR‑TB is estimated at
general population. For example, with all due limitations 5% (3.5% in new cases of active TB disease and 20.5%
of such analyses, including the need to assume a causal in previously treated cases), but this prevalence varies
relationship and lack of precision, an estimated 27% of TB from approximately 1% in many countries in sub-Sa-
cases worldwide are attributable to undernutrition and haran Africa, western Europe and North America
22% to indoor air pollution10. Other risk factors for TB to >20% in areas of the former Soviet Union, such as
include type 2 diabetes mellitus11, excessive alcohol use12 Azerbaijan, Belarus, Kyrgyzstan and Moldova23. Of par-
(both of which roughly triple the risk of TB) and smoking ticular concern in recent years has been the problem of
(which doubles the risk)13. Thus, addressing these social drug-resistant TB in China (where one-quarter of all
and behavioural determinants could help to expand the active TB disease cases are resistant to either isoniazid
current biomedical paradigm for TB control10. or rifampicin)24 and India (which has witnessed the
The natural history of TB is defined by its airborne emergence of so‑called totally drug-resistant strains)25.
route of transmission and the diversity of its clinical Within individual countries, the prevalence of MDR‑TB
manifestations (FIG. 1). Compared with infectious agents can vary by a factor of ≥10 (REF. 26) at the sub-district
such as measles virus and varicella zoster virus, M. tuber- level; within cities, the per-capita incidence of MDR‑TB
culosis is not highly infectious (an average infectious can vary almost 100‑fold27 from one health centre to the
individual may infect 3–10 people per year 14, of whom next. Most cases of MDR‑TB are estimated to reflect
only a minority will progress to TB disease). However, transmission rather than initial acquisition28. Thus, a
among those with active TB disease, the average dura- high priority for the response to drug-resistant TB is to
tion of infectiousness — as inferred from the incidence identify and target ‘hotspots’ of MDR‑TB transmission29.
to prevalence ratio — is >1 year in many high-burden
settings15. TB is also frequently fatal; in the absence Mechanisms/pathophysiology
of treatment, approximately 50% of individuals who Microbiology
develop active TB disease will succumb to the disease16. Ongoing transmission of M. tuberculosis infection30 and
Between 5% and 15% of individuals infected with LTBI reactivation31 are globally responsible for TB dis-
M. tuberculosis will progress (over months to a few years) ease. The majority of TB cases are attributed to M. tuber-
to active TB disease17, whereas the remainder retain a culosis (sensu stricto) or the closely related organism
persistent risk of developing active TB disease through- Mycobacterium africanum; a minority of cases are due
out their lifetime18. In many settings, up to 50% of all peo- to zoonotic members of the M. tuberculosis complex,
ple with culture-positive active TB disease do not have such as Mycobacterium bovis or Mycobacterium caprae32.

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 PRIMER

M. tuberculosis has no known environmental reservoir; strains, findings were inconsistent between studies,
humans are its only known host reservoir 33. Thus, challenging their immediate translation into clinical
M. tuberculosis is both a pathogen and a symbiont, which care. Furthermore, the interactions between host and
has implications for our understanding of host–patho- M. tuberculosis are complex. Thus, studying M. tubercu-
gen interactions. losis virulence factors in the absence of host determinants
of susceptibility can obscure synergistic interactions. For
Host–pathogen interactions. Genomic studies have instance, a specific host–pathogen interaction might
shown substantial genetic variability among isolates explain why strains of the East-Asian lineage are highly
from around the world (several thousand single-nu- infective and pathogenic in Asian populations36 but have
cleotide polymorphisms across a genome of 4.4 million a normal clinical and epidemiological presentation when
base pairs), which reflects either accumulated genetic imported into Canada37 or Switzerland38. Conversely,
drift associated with patterns of human migration or strains that are otherwise unremarkable, according to
variable pathogenicity of different lineages34. It has genomic and laboratory characterization, can be asso-
been proposed that hypervirulent strains exist, based ciated with outbreaks, given the appropriate social and
on epidemiological studies. If true, genomic study of epidemiological setting 39.
such strains could uncover lineage-specific virulence
factors35 that can ultimately be used to prioritize patient Virulence. Given that the risk of progression from LTBI
care and infection control decisions. Although several to active TB disease is many orders of magnitude higher
attributes of M. tuberculosis, including increased trans- than the risk of developing disease from the live vaccine
missibility in humans, drug resistance and mortality in strain, M. bovis Bacillus Calmette–Guérin (BCG), it fol-
an experimental model34, have been linked with specific lows that genomic differences between M. tuberculosis

Infection eliminated Latent TB Subclinical Active

infection TB disease TB disease
With innate or With acquired
immune response* immune response
Mycobacterium
tuberculosis

Granuloma
Lung

Heart

TST Negative Positive Positive Positive Usually positive

IGRA Negative Positive Positive Positive Usually positive

Culture Negative Negative Negative Intermittently positive Positive

Smear Negative Negative Negative Usually negative Positive or negative

Infectious No No No Sporadically Yes

Symptoms None None None Mild or none Mild to severe

Preferred treatment None None Preventive therapy Multidrug therapy Multidrug therapy

Figure 1 | The spectrum of TB — from Mycobacterium tuberculosis a quiescent or latent state that can be detected as positive TST or IGRA
Nature Reviews | Disease Primers
infection to active (pulmonary) TB disease. Although tuberculosis (TB) results; these tests elicit T cell responses against M. tuberculosis antigens.
disease can be viewed as a dynamic continuum from Mycobacterium These patients would benefit from receiving one of the recommended
tuberculosis infection to active infectious disease, patients are LTBI preventive therapy regimens (mostly 6–9 months of isoniazid).
categorized as having either latent TB infection (LTBI) or active TB disease Patients with subclinical TB might not report symptoms, but will be
for simplicity in clinical and public health settings. Individuals can advance culture-positive (but generally smear-negative because of the low
or reverse positions, depending on changes in the host immunity and bacillary load). Patients with active TB disease experience symptoms such
comorbidities. Exposure to M. tuberculosis can result in the elimination of as cough, fever and weight loss, and the diagnosis can usually be
the pathogen, either because of innate immune response or because of confirmed with smear, culture and molecular tests. Patients with active TB
acquired T cell immunity. Individuals who have eliminated the infection disease might sometimes be negative on the TST or the IGRA because of
via innate immune responses or acquired immune response without T cell anergy that is induced by the disease itself or immune suppression caused
priming or memory (denoted by *) can have negative tuberculin skin test by comorbid conditions, such as HIV infection or malnutrition. Individuals
(TST) or interferon-γ release assay (IGRA) results. Some individuals will with subclinical or active TB disease should receive one of the
eliminate the pathogen, but retain a strong memory T cell response and recommended treatment regimens for active TB disease, which consist of
will be positive on the TST or the IGRA. These individuals will not benefit an intensive phase with four drugs, followed by a longer continuation
from LTBI treatment. If the pathogen is not eliminated, bacteria persist in phase with two drugs.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3

PRIMER

Estimated new
TB cases (pulmonary
and extrapulmonary)
per 100,000 population
per year
0–9.9
10–19
20–49
50–124
125–299
300–499
≥500
Not applicable
Figure 2 | Global incidence of active TB disease (pulmonary and extrapulmonary). High-income countries — including
most countries in western Europe, Canada, the United States, Australia and New Zealand Nature
— haveReviews
the lowest rates of active
| Disease Primers
tuberculosis (TB) disease, typically <10 cases per 100,000 population per year. By contrast, lower-income countries have
higher rates of TB. The data to base these estimates were acquired by a combination of case notifications with expert
opinion, prevalence surveys, case notifications with standard adjustment and capture–recapture methodologies.
Reprinted from Global Tuberculosis Report 2015, World Health Organization, 18, figure 2.6, Copyright (2015).

and BCG can be used to search for the basis of attenuated Mycobacterium kansasii and Mycobacterium marinum)
virulence40. Indeed, genomic comparisons uncovered has prompted a reconsideration of the primacy of ESX‑1
several differences, most notably the region of difference in M. tuberculosis virulence. That is, ESX‑1 is thought
1 (RD1)40–42, that help to explain why the vaccine can be to be necessary, but not solely responsible, for the full
given to millions of newborn infants each year with a low virulence of M. tuberculosis 47. A better understanding of
risk of progression to disease. what sets M. tuberculosis apart from other mycobacteria
RD1 contains genes that encode a bacterial secretion might provide insights into the pathogenic mechanisms
system (the early secreted antigen 6 secretion system 1 of active TB disease and targets for new diagnostics and
(ESX‑1) [Au:OK?] secretion system43). Once the bacte- vaccines.
ria have been internalized in a phagosome by the host
macrophages, the ESX‑1 secretion system mediates the LTBI
delivery of bacterial products into the macrophage cyto- Exposure to M. tuberculosis leads to two broad out-
plasm (see below, Pathogenesis)44. [Au: Which section comes: elimination of the pathogen or persistence of the
specifically? There isn’t a ‘Pathogenesis’ heading. pathogen. In the first case, the pathogen is eliminated,
Should this just read (see below)?]On a translational either because of innate immune responses (in this
level, the absence of RD1 in the BCG strains enabled case, tuberculin skin tests (TSTs) or interferon-γ (IFNγ)
the development of immunological assays to distin- release assays (IGRAs) might be negative) or because of
guish the host response to M. tuberculosis infection adaptive immune responses (in which case, TSTs and
from the response caused by the BCG vaccine (BCG- IGRAs might be positive or negative, depending on
osis)45. Because many non-tuberculous mycobacteria whether memory T cell responses have been primed)2,3
also lack RD1, these assays also help to distinguish (FIG. 1). Regardless of how the pathogen is eliminated, this
infection with M. tuberculosis from infection by com- individual will not benefit from LTBI therapy. It has long
monly encountered environmental mycobacteria, such been recognized that, even among close household con-
as Mycobacterium avium45. tacts of TB cases, nearly half of exposed individuals have
Although the ESX‑1 secretion system plays a major negative TST results48. The finding that there is a genetic
part in the pathogenesis of active TB disease, the predisposition to remaining persistently TST negative
demonstration that ESX‑1 antigens are conserved in despite ample exposure provides one potential explana-
a few non-tuberculous mycobacteria46 (for example, tion for why some people are naturally resistant to TB49.

4 | 2016 | VOLUME 2 www.nature.com/nrdp

 PRIMER

However, if M. tuberculosis infection is not elimi- tract, where it encounters alveolar macrophages, which
nated, the pathogen can persist in a quiescent or latent are the dominant cell type that M. tuberculosis infects
state and, typically, the individual will develop posi- (FIG. 3). These cells internalize the bacteria by recep-
tive TST and IGRA results (but no symptoms). This tor-mediated phagocytosis, with numerous different
individual would probably benefit from LTBI therapy. receptors contributing to this process. This process
Unfortunately, a positive TST or IGRA result does not had long been studied without taking into account
automatically imply LTBI, as individuals who eliminate the microenvironment that is present in the alveolus.
the infection successfully might still be TST or IGRA Surfactants, which are abundant in the fluid that lines
positive because of memory T cell responses2,3. This the epithelium, might have an important role in this
partly explains the low predictive (prognostic) value of initial host–pathogen interaction52. Surfactant protein
TSTs and IGRAs50. D can prevent M. tuberculosis phagocytosis by alveolar
Our understanding of the early phase of M. tubercu- macrophages53.
losis infection in humans is very limited, but experimen- Once internalized, M.  tuberculosis actively
tal studies in small mammals (such as mice, guinea pigs blocks phagosome fusion with the lysosome, ensur-
and rabbits) and non-human primates have substantially ing its survival 54 . Then, through the activity of
helped to identify the importance of early events during RD1‑encoded[Au:OK?] proteins of the ESX‑1 secre-
primary infection51. The route of entry of M. tubercu- tion system, M. tuberculosis can disrupt the phagosomal
losis is via the respiratory tract; following inhalation, membrane, causing the release of bacterial products,
M. tuberculosis is translocated to the lower respiratory including mycobacteria DNA, into the macrophage

a Latent infection Alveolar Lung

space parenchyma
Interstitial
Alveolus macrophage T cell
B cell
Mycobacterium
tuberculosis
Phagosome

Dendritic
cell Granuloma
Alveolar Migrating to the
macrophage lymph nodes for Epithelial
Monocyte T cell priming cell

b Active disease

Granuloma

Lymph
node

Infected
lymph node
Figure 3 | Mycobacterium tuberculosis infection. a | Infection begins priming. This leads to the recruitment of immune cells, including T cells and
Nature Reviews | Disease Primers
when Mycobacterium tuberculosis enters the lungs via inhalation, reaches B cells, to the lung parenchyma to form a granuloma. b | The bacteria
the alveolar space and encounters the resident alveolar macrophages. If this replicate within the growing granuloma. If the bacterial load becomes too
first line of defence fails to eliminate the bacteria, M. tuberculosis invades great, the granuloma will fail to contain the infection75 and bacteria will
the lung interstitial tissue, either by the bacteria directly infecting the disseminate to the local lymph nodes and eventually to other organs,
alveolar epithelium or the infected alveolar macrophages migrating to the including the brain. At this phase, the bacteria can enter the bloodstream
lung parenchyma. Subsequently, either dendritic cells or inflammatory or re‑enter the respiratory tract to be released — the infected host is now
monocytes transport M. tuberculosis to pulmonary lymph nodes for T cell infectious and symptomatic and is said to have active TB disease.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 5

PRIMER

cytosol; a few bacteria might also be found in the cyto- infection: from the host’s perspective, the granuloma
sol in the ensuing days55,56. The advantages of delivering is a bacterial ‘prison’ with the potential to ‘wall off ’
bacterial products into the cytosol are an active area of infection from the rest of the body; however, from the
investigation57,58; one possibility is that the activation bacterial perspective, it is a growing collection of phago-
of the cytosolic surveillance pathway, resulting in the cytic cells to infect and replicate within. For instance,
induction of a type I IFN response, can promote the M. tuberculosis ESX‑1 can initiate a type I IFN response,
growth of intracellular bacterial pathogens, such as which has been directly linked to the recruitment of a
M. tuberculosis 59–63. Furthermore, experimental studies unique myeloid population (CD11b+F4/80+Gr1int) to
have shown that the type of cell death (apoptosis ver- the nascent granuloma that is highly permissive to
sus necrosis) experienced by infected macrophages is M. tuberculosis infection76. Interestingly, a study has
crucial, not only for the innate response to infection demonstrated that immune responses are geographi-
but also for the ensuing adaptive immune response64–66. cally segregated around the granuloma, with its centre
In addition, studies suggest that the ontogeny of mac- containing pro-inflammatory components, whereas
rophages markedly affects the function and fate of the surrounding tissue has anti-inflammatory ones77.
these cells 67,68. Further investigation is required to [Au:OK?] It has also been proposed that the granu-
determine the importance of residential alveolar mac- loma might have a maximal bacterial burden (or carry-
rophages versus bone marrow-derived macrophages ing capacity), beyond which the infection will continue
that are recruited to the lung in the outcome of to progress75. If the granuloma contains the infection
M. tuberculosis infection. without inducing substantial tissue pathology, then the
After infecting the alveolar macrophages in the air- person has LTBI and could be a candidate for preventive
ways, M. tuberculosis gains access to the lung interstit- treatment (see below).
ium, where the process of infection evolves. However,
how M.  tuberculosis accesses the parenchyma is Progression to active TB disease
unknown. There are two possible mechanisms: one In most individuals with LTBI, the combination of mac-
involving M. tuberculosis directly infecting epithelial rophages, dendritic cells and T cells is sufficient to main-
cells and the second via transmigration of M. tubercu- tain a controlled, asymptomatic infection. However, in a
losis-infected macrophages across the epithelium (FIG. 3). subset of hosts, for reasons that are not completely clear,
Regardless of the route, M. tuberculosis access the paren- infection can progress to clinical disease, in as early as
chyma, which leads to the recruitment of an increasing weeks or as long as decades. Certain natural experiments
number of cells to the site of infection, ­generating a in human immunology provide clues as to the reasons
multicellular host response called a granuloma. why some individuals with LTBI are unable to contain
As the primary infection is established, either the infection and progress to active TB disease.
infected dendritic cells69 or inflammatory monocytes70 From a bacteriological vantage, it seems that an
transport M. tuberculosis to pulmonary lymph nodes important contributor to the progression to disease is
for T cell priming. M. tuberculosis has been shown to presenting intact antigenic proteins. Genomic studies of
actively delay initial T cell priming as well as their traf- clinical isolates have shown that M. tuberculosis genes
ficking into the lung 69,71. HIV infection substantially that are predicted to be involved in the production of
reduces the number of CD4+ T cells and is therefore a immunodominant CD4+ T cell antigens do not vary
risk factor for progression from M. tuberculosis infec- across strains and lineages, suggesting the possibility
tion to active disease. However, some studies indicate that M. tuberculosis might benefit from antigen-specific
that the risk of active TB disease is enhanced during CD4+ T cell activation in humans78. This hypothesis
the early stage of HIV infection — when the number derives further indirect support from the HIV-TB syn-
of CD4+ T cells is normal — suggesting that other, T demic; although HIV is clearly a risk factor for progres-
cell-independent immune responses are also impaired72. sion from LTBI to active TB disease in an individual,
In addition, for the purposes of vaccination, it is unclear HIV/AIDS is negatively associated with contagion79.
whether enhanced T cell responses provide better pro- The importance of immunodominant antigens extends
tection. In fact, studies in an experimental mouse model beyond understanding the pathogenesis of disease to
of TB have shown that increasing the total CD4+ T cell the translational goal of defining a strategy for vaccina-
responses in a programmed death 1 (PD1)-dependent tion. Traditionally, identification of immunodominant
manner led to reduced protection and enhanced mor- M. tuberculosis antigens for generating a repertoire of
tality 73,74. Thus, understanding the regulatory mecha- M. tuberculosis-specific T cells was considered the foun-
nisms involved in immunity to TB is fundamental for dation for T cell-mediated protective immunity and,
generating a strong host defence that hinders bacterial therefore, an effective vaccine-based strategy. However,
growth while maintaining host tolerance. despite inducing a modest level of enhanced T cell-me-
diated responses, a vaccine that was generated using an
The granuloma. An important research priority is immunodominant M. tuberculosis antigen has failed to
decoding the underlying mechanisms that are involved improve protection in a human trial80. After nearly a cen-
in the initiation and maintenance of the granulomas, tury of BCG vaccination, we still do not know exactly the
as they are involved in both the control of the infection basis for BCG protection and to what extent this pro-
and, in some cases, the persistence of the pathogen75. tection is mediated by CD4+ T cells or through innate
The granuloma illustrates the duality of M. tuberculosis immune pathways81.

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 PRIMER

From a host vantage, three natural epidemiological The understanding of resistance mechanisms is
experiments have informed on the risk of TB disease, hampered by limitations in both the phenotypic and the
and hence on crucial pathways in controlling infection: genotypic drug susceptibility tests88. The result of phe-
HIV (discussed above), tumour necrosis factor (TNF) notypic tests is dichotomous (the M. tuberculosis strain
neutralizing antibodies and inborn errors in immunity. is either susceptible or resistant to a set drug dose), and
The role of TNF in containing M. tuberculosis infec- these tests are best standardized for only some drugs (for
tion was experimentally demonstrated in mice in the example, isoniazid, rifampicin, ethambutol and pyrazi-
early 1990s and confirmed in observational studies namide). Furthermore, genotypic drug susceptibility
that showed an increased risk of active TB disease in tests could fail to identify a mutation in a phenotypically
patients receiving TNF. However, further investigation resistant isolate. Finally, finding a mutation in a pheno-
has shown that TNF mechanisms are complex. Rather typically resistant isolate using a genotypic drug sus-
than TNF simply being protective, with anti-TNF ther- ceptibility test does not equate [Au:OK?]to finding the
apy being a risk factor for disease, an emerging interpre- causal mutation of the resistance. The observed muta-
tation suggests that there is an ideal set point for TNF in tion could be any of these kinds of mutations: causal,
controlling M. tuberculosis infection; excessive activation stepping-stone, compensatory or companion (that is,
worsens the existing immunopathology and insufficient merely a marker of the strain circulating in that par-
activation leads to lack of immune containment 82,83. This ticular setting). In other words, the identified mutation
model is supported by the adjunctive use of anti-inflam- might not cause drug resistance on its own. Diagnostic
matory agents, such as steroids, to address the inflam- assays designed to detect drug resistance should be based
matory pathology of TB in confined anatomical spaces only on causal mutation. Thus, understanding the type
(for example, the brain)84. of the identified mutation is crucial.
Inborn errors in immunity can shed light on the To this end, several groups have begun to perform
mechanisms of the immune response to TB85. Over whole-genome sequencing on clinical isolates, with the
100 million infants are vaccinated with BCG each year, short-term goal of identifying novel resistance-associ-
and only a small number develop disseminated BCG dis- ated mutations and the long-term goal of developing a
ease; thus, it has been possible to map mutations in genes test that could detect resistance faster than culture-based
encoding proteins that are crucial for mycobacterial drug susceptibility tests and replace them89,90. Studies
containment. Many of these proteins are involved in the show the feasibility of this approach; however, this
IL‑12–IFNγ [Au:OK or just IFN?] axis. Although these approach suffers from imperfect sensitivity (there are
defects were originally identified in patients with disease still phenotypically resistant isolates in which the causal
due to BCG vaccine or non-tuberculous mycobacteria, mutation cannot be identified91) and high costs, so cul-
in some cases, the identified mutations have also been ture-based tests remain a cornerstone of clinical care92.
linked to TB disease85. Several other genes have been
linked to experimental TB in animal models, some of Diagnosis, screening and prevention
which were subsequently linked to TB and/or leprosy in Diagnosis
human genetic studies. In conclusion, a genetic suscep- The choice of a diagnostic tool for TB depends on the
tibility is likely to explain in part why some people with purpose of testing (detecting LTBI, active TB disease or
LTBI progress to active TB disease; however, the precise drug resistance). [Au:OK?]
immunological pathways that are crucial for control of
mycobacterial infection require further investigation81. LTBI. Two tests are available for the identification of
LTBI: the TST and the IGRA. The IGRA can also distin-
Mechanisms of drug resistance guish between BCG-induced and M. tuberculosis infec-
TB is the infectious disease in which the phenomenon tion-induced positive TST responses45.
of drug resistance was first described in 1948, during The TST, performed using the Mantoux technique,
the very first human trial of TB therapy 86. As each new consists of an intradermal injection of 5 tuberculin units
anti-TB drug has been introduced into clinical practice, (5‑TU) of purified protein derivative (PPD) S or 2 TU of
widespread emergence of resistant strains has been PPD RT23. In a person who has cell-mediated immunity
described, usually within a decade. to these antigens, a delayed-type hypersensitivity reac-
M. tuberculosis develops drug resistance through tion will occur within 48–72 hours. Interpretation of the
genetic mutations (there are no reports of resistance TST takes into account the size of induration, the pre-
developed by the acquisition of new DNA). Although test probability of M. tuberculosis infection and the risk
there is an ever-expanding list of genes that have been of developing active TB disease if the person was truly
linked to resistance, allelic exchange experiments have infected. A simple, web-based, interactive algorithm —
confirmed the causality between mutation and drug the Online TST/IGRA Interpreter (www.tstin3d.com) —
resistance for only a subset of mutated genes87. In these incorporates all these parameters and also computes the
genes, the two mechanisms of drug resistance are tar- risk of serious adverse events due to LTBI treatment 93.
get modification (for example, a mutant bacterial RNA Although the TST has several advantages, particu-
polymerase that eludes the action of rifampicin) or a larly in low-resource settings, including low reagent
defective enzyme that converts a pro-drug into an active and equipment costs and limited skill and laboratory
drug (for example, a mutant bacterial catalase that fails requirements, it has two major limitations: first, its spec-
to activate isoniazid). ificity is compromised by late (that is, post-infancy) or

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repeated BCG vaccination (booster vaccinations) and, to Although sputum smear microscopy has many lim-
a limited extent, by exposure to non-tuberculous myco- itations, it continues to be the most widely used active
bacteria94. Second, it has limited predictive value45. Most TB disease test in low-income and middle-income coun-
individuals with positive TST results do not progress to tries102. However, the ongoing roll-out of Xpert MTB/RIF
active TB disease. Currently, efforts are underway to (Cepheid Inc., Sunnyvale, California, USA), a molecu-
develop or validate new skin tests that can replace PPD lar assay based on the automated GeneXpert technology
with more-specific RD1 antigens95. (Cepheid Inc.), is measurably shifting the TB diagnos-
In the early 2000s, IGRAs were introduced, with the tics landscape, with >17 million cartridges procured via
hope to replace TSTs96. IGRAs are in vitro blood tests of subsidized pricing programmes since its introduction in
cell-mediated immune response: they measure T cell 2010 (REFS 103,104). Owing to superior accuracy than
release of IFNγ following stimulation by RD1‑encoded sputum smear microscopy 105–108, the WHO now recom-
antigens (namely, early secreted antigenic target 6 and mends Xpert MTB/RIF as the first-line diagnostic test in
culture filtrate protein 10)42,97. RD1 antigens are more all adults or children who are suspected of having active
specific for M. tuberculosis than PPD antigens because TB disease109.
they are not encoded in the genome of any BCG vac- Furthermore, in HIV-positive individuals, sputum
cine strains or of most species of non-tuberculous smear microscopy detects only 22–43% of active TB dis-
mycobacteria (exceptions are M. marinum, M. kansasii, ease110. Thus, the WHO also recommends Xpert MTB/
Mycobacterium szulgai and Mycobacterium flavescens)98. RIF as an initial diagnostic test in these patients109. In
However, like TSTs, IGRAs have poor predictive value45,50. addition, the detection of lipoarabinomannan (LAM)
After hundreds of research studies, it is clear that antigen in urine has emerged as a potential point-
both the TST and the IGRA are acceptable but imper- of-care test to detect HIV-associated active TB dis-
fect tests for LTBI45,95. They have reduced sensitivity in ease, with a modest reduction in mortality in a highly
immunocompromised patients45 and neither test is able selected group of hospitalized HIV-positive patients111.
to accurately differentiate between LTBI and active TB A LAM rapid test is now recommended by the WHO to
disease45,99 nor to distinguish between new infections assist and expedite the diagnosis of active TB disease in
and re‑infection events, a distinction that could be rel- two specific populations: in HIV-positive adult in‑pa-
evant in settings in which individuals who had previ- tients with signs and symptoms of pulmonary and/or
ously received preventive therapy are at risk of becoming extrapulmonary TB who have a CD4+ T cell count of
re‑infected45. In summary, none of the currently avail- ≤100 cells per μl, or HIV-positive patients who are seri-
able LTBI tests meets the need for a highly predictive ously ill regardless of their CD4+ T cell count or with an
test that can help to identify the individuals who are at unknown CD4+ T cell count 112.
increased risk for the development of active TB disease Diagnosing paediatric TB and monitoring treatment
and would therefore benefit most from LTBI therapy response are challenging, as collecting respiratory spec-
(preventive therapy). imens is difficult (young children are unable to produce
Notably, because all LTBI tests have low predictive sputum) and the disease might be extrapulmonary 113.
value, widespread screening of low-risk populations is Children with active TB disease often present with non-
counterproductive. North American occupational health specific symptoms (for example, failure to thrive), so
programmes are an example, in which repeated IGRA history of contact with an adult with active TB disease
testing in health care workers has shown high rates of should be considered. There is no adequate gold-stand-
test conversions and reversions, raising concerns about ard test for childhood TB, and diagnosis requires an
test reproducibility 45. Thus, LTBI screening should be algorithm. Sputum smear microscopy is often negative
done only if it is supported by a serious intent to fol- because of the low number of bacilli in children with TB.
low‑up with therapy if the test is positive. Thus, the diagnostic algorithm relies on signs, symptoms,
evidence of M. tuberculosis infection (a positive TST or
Active TB disease. For detection of active TB disease, IGRA), history of contact with active TB disease and the
four main technologies are used: imaging techniques results of chest X‑ray (for example, showing hilar ade-
(chest X‑rays and PET-CT), microscopy (sputum nopathy), liquid culture and molecular tests (Xpert MTB/
smears), culture-based methods and molecular tests. RIF). If sputum can be collected (from older children and
Whereas imaging tests are used for screening, active TB adolescents), at least two specimens must be submitted
disease requires a microbiological diagnosis. TABLE 1 pro- for microscopic examination, Xpert MTB/RIF testing
vides an overview of the various diagnostic technologies and culture. In young children (<7–8 years of age), two
that have been reviewed and endorsed by the WHO. to three fasting gastric aspirates can also be collected.
Chest radiography is an established triage or screen- A meta-analysis showed that, when used to detect
ing test (FIG. 4a), and the emergence of digital radiology active TB disease in children, Xpert MTB/RIF has a
and computer-aided diagnostic software are impor- sensitivity that is 36–44% higher than sputum smear
tant recent advances100. Because X‑rays lack specific- microscopy 108. Compared with cultures of expectorated
ity, abnormal chest X‑rays need to be followed up with or induced sputum samples or gastric aspirate samples,
microbiological tests. Advanced imaging modalities Xpert MTB/RIF has a sensitivity of 62–66% and a spec-
are providing new insights into the diversity of lung ificity of 98%108. Because Xpert MTB/RIF is superior to
lesions, although they are too expensive for routine use101 sputum smear microscopy, the WHO has recommended
(FIG. 4b). it as a routine front-line test in children (and adults) with

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 PRIMER

Table 1 | Technologies reviewed by the WHO for the diagnosis of active TB disease and the detection of drug resistance
Test Assay Use Sensitivity Specificity TAT* Target Year endorsed Refs
principle setting‡
Imaging techniques
Chest X‑ray Imaging of the Screening for 87% (using TB 89% (using TB Same Secondary Included in the 217
lungs active TB disease abnormality as a abnormality as a day and tertiary WHO guidelines
threshold) threshold) centres for many years
Microscopy
Conventional Direct Active TB disease 32–94% 50–99% Same Peripheral Included in the 218
sputum smear visualization of diagnosis day and WHO guidelines
microscopy mycobacteria reference for many years
using light laboratories
microscopy
LED Direct Active TB disease 52–97% 94–100% Same Peripheral 2011 218
fluorescence visualization of diagnosis day and
smear mycobacteria reference
microscopy§ using laboratories
fluorescence
microscopy
Culture-based techniques
Liquid culture Mycobacterial • Active TB • 89% (among >99% 10–21 Reference 2007 219
with DST culture on disease smear-positive days laboratory
liquid media diagnosis and
• Drug resistance culture-positive)
• 73% (among
smear-
negative and
culture-positive)
Antigen detection techniques
LAM lateral Antigen Active TB disease • 44% (all) • 92% (all) Same Peripheral 2015 (conditional 112
flow assay§ detection diagnosis in • 54% (in • 90% (in day laboratory recommendations
HIV-positive HIV-positive HIV-positive in selected
individuals individuals) individuals) groups)
Molecular techniques (nucleic acid amplification tests)
Xpert MTB/ NAAT (qPCR) • Active TB • 98% • 99% (smear- Same District or 2010 105
RIF‡,§ disease (smear-positive negative and day sub-district
diagnosis and culture- culture-negative) laboratory
• Drug resistance positive) • 98% (rifampicin
(rifampicin) • 67% (smear- resistance)
negative and
culture-positive)
• 95% (rifampicin
resistance)
First-line LPA NAAT (LPA) • Active TB • 98% (rifampicin • 99% (rifampicin 1–2 days Reference 2008 220
(GenoType disease resistance) resistance) laboratory
MTBDRplus|| diagnosis • 84% (isoniazid • >99% (isoniazid
and NIPRO¶) • Drug resistance resistance) resistance)
(isoniazid and
rifampicin)
Second-line NAAT (LPA) Drug resistance • 86% • 98% 1–2 days Reference 2016 121
LPA (GenoType (fluoroquinolones (fluoroquinolone (fluoroquinolone laboratory
MTBDRsl||) and second-line resistance) resistace)
injectable drugs) • 87% (second-line • 99% (second-line
injectable drugs) injectable drugs)
Loopamp NAAT (LAMP) Active TB disease 76–80% 97–98% Same Peripheral 2016 120
Mycobacterium diagnosis day laboratory
tuberculosis
complex
assay§,#
Peripheral laboratories (basic microscopy centres) are typically located at the primary-care level. District-level laboratories are the next level of referral and have
better infrastructure. The tertiary hospital or a reference laboratory that offers the most sophisticated infrastructure are the highest and final [Au:OK?] level of
referral. DST, drug susceptibility testing; LAM, lipoarabinomannan; LAMP, loop-mediated isothermal amplification; LED, light-emitting diode; LPA, line probe assay;
NAAT, nucleic acid amplification test; qPCR: quantitative PCR; TAT, turnaround time; TB, tuberculosis. *May require longer TAT owing to batching of specimens.
‡
Newer versions of GeneXpert (Cepheid Inc., Sunnyvale, California, USA) instrument (OMNI) and cartridge (Xpert Ultra MTB/RIF) are currently under development
and yet to be reviewed by the WHO. §Amenable to rapid test and treat. ||Hain Lifescience GmbH, Nehren, Germany. ¶NIPRO Corporation, Osaka, Japan. #Eiken
Chemical, Tokyo, Japan.

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PRIMER

suspected active TB disease, TB lymphadenitis and TB products are designed for laboratory settings, making
meningitis109. In some settings, upfront testing with use of the only proven TB biomarker: bacterial nucleic
Xpert MTB/RIF has also helped to identify substantially acid sequences. Such molecular tests might not meet
larger numbers of children with MDR‑TB114. affordability and ease‑of‑use requirements for integra-
tion into primary care. To meet these needs, short-term,
Drug resistance. For the detection of drug resistance, medium-term and longer-term approaches are required.
there are phenotypic, culture-based (that is, testing the In the short term, the goal is to expand the range
ability of bacteria to grow in the presence of anti‑TB of molecular technologies that could replace sputum
drugs) and molecular-based (based on the detection of smear microscopy 117. The decentralized deployment of
genetic mutations in M. tuberculosis that confer drug such techniques in low-income countries is challenging
resistance) methods (TABLE 1). In many settings, the because of technical and infrastructure issues, as the
implementation of Xpert MTB/RIF as a diagnostic tool GeneXpert technology experience shows124–127. However,
for active TB disease has greatly increased the upfront rugged systems such as the GeneXpert OMNI system (a
detection of MDR‑TB115,116. The Xpert MTB/RIF roll-out portable, battery-operated platform intended for periph-
has paved the way for universal drug susceptibility test- eral microscopy centres) might help to overcome this
ing and has attracted new product developers to the TB issue. Aligned with this device, two new diagnostic test
field104,117. However, pragmatic trials of Xpert MTB/RIF cartridges are in development: the Xpert MTB/RIF Ultra
have shown that the clinical impact of this new technol- and the Xpert XDR. The Xpert MTB/RIF Ultra cartridge
ogy might be blunted in weak health systems, with gaps is expected to have a higher sensitivity than the existing
in the TB care cascade104,118,119. Xpert MTB/RIF assay and will soon be commercialized;
Besides Xpert MTB/RIF, the WHO has endorsed the its use will be reviewed by the WHO in 2017. The Xpert
use of loop-mediated isothermal amplification for the XDR cartridge will provide information on drug resist-
diagnosis of pulmonary TB120 and molecular line probe ance for additional key drugs (isoniazid, fluoroquinolo-
assays for rapid drug susceptibility testing of first-line nes and aminoglycosides).
drugs (such as isoniazid and rifampicin) as well as Besides their diagnostic application, new molecular
selected second-line drugs (such as fluoroquinolones tools can identify drug resistance mutations and help
and injectable second-line drugs)121,122. reach the post‑2015 target of a universal drug suscep-
tibility test for all individuals with active TB disease at
New diagnostics. Given the limitations of the available the time of diagnosis. New forthcoming drug regimens
diagnostics, the development of new diagnostic tools is a will require adequate companion diagnostics to ensure
priority. Several diagnostic tools are in the pipeline117,123. rapid completion of the ‘test and treat’ approach128. To
Although the pipeline appears robust at first glance, most this end, next-generation sequencing tools are showing

a b

Right Left Right Left

Figure 4 | Imaging tools for active TB disease. a | Conventional chest X‑ray. The imageNatureshows typical
Reviewsfeatures of active
| Disease Primers
pulmonary tuberculosis (TB) disease: a large cavity in the right upper lobe of the lung (arrow) with surrounding infiltrates
or consolidation (due to inflammation and oedema). An abnormal chest X‑ray is suggestive of TB, but not confirmatory.
b | High-resolution CT scan. Three-dimensional rendering using 18F-fluorodeoxyglucose (FDG) PET-CT scan of the
posterior half of the thoracic cavity of a person who was newly diagnosed with bilateral pulmonary TB. The orange colour
depicts FDG uptake in regions with abnormalities with standardized uptake values ranging from 5 to 9. A 1–2 cm air-filled
cavity in the right upper lobe (arrow) is embedded within an area of nodular disease with intense uptake, whereas an area
of ground glass opacity located below this feature (arrowhead) shows only modest uptake of the tracer. Image in part a
courtesy of B. Rabinovitch, Montreal Chest Institute, Montreal, Canada. Image in part b courtesy of C. E. Barry 3rd,
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

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 PRIMER

great promise89,90, but translational work is required to New vaccines

make them affordable and deployable in low-income, Despite the variability in its efficacy, the BCG vaccine
high-burden countries.
In the medium term, the priority has proven that protective immunity against TB can be
is to develop a rapid, low-cost, non-sputum-based test induced by a vaccine, even though the protective mech-
to be used at the primary-care level, where the major- anism is not well elucidated. Indeed, the main goal of
ity of people first seek care117. Such a test requires the current vaccination research is to help prevent active
identification of a suitable biomarker signature (primar- TB disease from developing in the 10% of infected indi-
ily antigens, antibodies, volatile organic compounds or viduals who cannot contain the infection on their own
enzymatic markers). Although several promising bio- as LTBI. Ideally, a vaccine might prevent the establish-
markers have been identified129–131, validation is ongoing ment of M. tuberculosis infection entirely (for example,
and no tests are likely to be submitted for policy endorse- as measured by prevention of conversion of an IGRA).
ment until 2019 (REF. 132). Novel trial designs can be used to assess the ability of
In the longer term, the main goal is to identify a a vaccine to achieve these goals142. To maximize the
biomarker that can reliably predict which individu- efficacy of vaccination on morbidity and mortality,
als with LTBI are at the highest risk of progressing to transmissible active TB disease must be prevented in
active TB disease, so that these individuals can receive the populations most at risk. Because M. tuberculosis
preventive treatment and the vast LTBI ‘pool’ can be infection is mostly spread by adolescents and adults with
successfully reduced117,133. Another goal is to develop a pulmonary active TB disease, much of the new vaccine
biomarker-based test to monitor treatment efficacy, as development focuses on vaccines that are designed for
current molecular tests are not suitable for this purpose. these age groups. However, as the BCG vaccine is only
The pipeline for such tests is currently weak. Increased partially effective even in infants and not recommended
investments are necessary to support biomarker discov- for HIV-exposed infants, an improved vaccine for new-
ery, validation and translation into clinical tools133. borns is also desirable.
Modelling has shown that a vaccine with 60% effi-
BCG vaccine cacy delivered to 20% of adolescents and adults could
Globally, >90% of newborns are vaccinated annually with avert 30 million cases of active TB disease in the first
BCG, the only currently licensed vaccine to prevent the 20 years (a total of 35 million cases could be averted
development of active TB disease134,135. The BCG vaccine if also administered to 90% of newborns)143. Another
was first used in humans in 1921 and has been evaluated modelling study also concluded that vaccines targeted
in numerous interventional trials and observational stud- at adolescents and adults could have a much greater
ies looking at less-common manifestations of active TB effect on the global TB burden over the 2024–2050 time
disease. In clinical trials, the efficacy of the BCG vaccine horizon than vaccines targeted at infants, and that such
against pulmonary TB in adults has been reported to be vaccines could be relatively cost-effective144.
0–80%136,137. The reasons for this observed variability in The development of TB vaccines faces numerous
BCG vaccine efficacy are unknown. It has been noted challenges (BOX 1). Despite these limitations, at least 13
that BCG vaccine efficacy varies with distance from vaccine candidates are currently being tested clinically
the equator 136, but it is unclear whether greater efficacy (TABLE 2), which are classified into three platform types:
at greater latitude depends on the force of exposure to whole-cell or lysates of mycobacteria, viral-vector vac-
selected non-tuberculous mycobacteria, to all non-tuber- cines and adjuvanted recombinant protein vaccines. The
culous mycobacteria, to M. tuberculosis itself or on other, M. tuberculosis-specific antigenic make-up ranges from
still undefined causative factors. [Au:OK?] Case–control several thousand antigens in mycobacterial vaccines to
studies in infants and children <5 years of age have found four or fewer in the viral-vector and recombinant pro-
the efficacy of the BCG vaccine in protecting from severe, tein vaccines.
extrapulmonary forms of active TB disease to be between
50% and 80%138. [Au:OK?]In children, the BCG vaccine Management
has also been associated with protection from M. tuber- The WHO has estimated that 80% of all patients diag-
culosis infection137. nosed with active TB disease each year are infected
TB morbidity and mortality can be high in children with M. tuberculosis strains that are fully susceptible
<5 years of age, so the BCG vaccine is invaluable in pre- to all available antibiotics and the remaining 20% with
venting active TB disease in this age group. However, drug-resistant strains (13.3% isoniazid mono-resistant
most cases of transmissible, pulmonary active TB dis- and 5.3% MDR)1,23. Extrapolating from these estimates,
ease occur in adolescents and adults, in whom the effi- approximately 1.9 million people developed active
cacy of the BCG vaccine is uncertain139,140. Moreover, drug-resistant TB disease in 2014 — a major burden.
a meta-analysis of paediatric BCG vaccine efficacy Drug resistance accordingly requires longer and more-
has indicated that the duration of protection is gener- toxic treatment regimens for patients.
ally up to 10 years, with vaccine efficacy waning over
time141. Thus, it is unlikely that the current BCG regi- LTBI
mens substantially contribute to the control of the global In 2014, the WHO published its first comprehensive
TB epidemic, as in most countries, the BCG vaccine is guideline on LTBI management 145, recommending that
administered once, at birth, and its protection is unlikely only selected risk groups should undergo LTBI screen-
to extend consistently into adolescence135. ing 145: HIV-positive individuals; adults and children who

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PRIMER

Box 1 | Hurdles for TB vaccine development of therapy, with rifampicin, isoniazid, pyrazinamide
and ethambutol during the first 2 months (the inten-
Many countries with a high tuberculosis (TB) burden are also confronted with the sive phase of treatment), followed by isoniazid and
emergence and spread of drug-resistant TB. An efficacious vaccine should work equally rifampicin for 4 months (the continuation phase)147,148.
well against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis, as
Treatment efficacy and progress are usually monitored
vaccine targets are likely to be completely independent of drug targets. Thus, a new TB
with repeat smears, cultures and chest X‑rays.
vaccine could help to preserve the therapeutic efficacy of TB antibiotics and overcome
the crucial drug-resistance challenge. However, the development of TB vaccines has Although the standard 6‑month regimen has a
only limited support from private sector biopharmaceutical companies because of high success rate (approximately 86% under routine,
scientific and economic barriers. Key scientific challenges include the lack of a programmatic field conditions1; the regimen itself has
validated, predictive animal model or correlate of protection. As a result, vaccine higher efficacy), it also has several limitations. In part
efficacy trials, which are costly, time-consuming and can only be carried out relatively because of the long duration of the treatment, a certain
late in development, have been the first opportunity to understand the promise of a proportion of patients will develop toxicity 149. The com-
vaccine candidate. Thus, TB vaccine development has been highly inefficient without mon adverse events are mild increases in the level of liver
an easy way to triage candidates early in development. Current approaches to improve enzymes, skin rash, gastrointestinal intolerance, neurop-
efficiency focus on implementing novel pre-proof-of-concept trials that look for a
athy and arthralgia and can be managed symptomatically
meaningful biological effect, including ‘prevention of (established) infection’ and
without discontinuation of the offending drugs. Serious
‘prevention of recurrence’ in high-risk populations, and on optimizing and validating a
non-human primate or another animal model as a safe, predictive model of the human adverse events are severe hepatitis, immune thrombo-
disease142,215. All designs of vaccine efficacy trials should also include sample collection, cytopaenia, agranulocytosis, haemolysis, renal failure,
to support discovery and validation of correlates of protection216. optic neuritis and ototoxicity. Furthermore, prolonged
Another challenge is that assessment of any candidate vaccine for infants must be therapy undermines patient compliance. As a result,
compared against the licensed vaccine (Bacillus Calmette–Guérin (BCG)), which not supportive measures are necessary to ensure optimal
only protects (at least partially) against TB in infants but also protects against leprosy. adherence, as lack of treatment completion contributes
This increases the number of requirements for any vaccine that attempts to replace the to treatment failure, relapse and the emergence of drug
BCG vaccine in infants. resistance.
Despite TB globally being the leading cause of death due to a single pathogen, the
The most common adherence monitoring approach
market is limited for TB vaccines143. Most cases of active TB disease, even in
is directly observed therapy (DOT), in which every
high-income countries, occur among the poor who are living in crowded conditions.
This reality affects the market forecast for a new vaccine and therefore limits dose of treatment is directly supervised by a health pro-
investment in TB vaccine research and development by the for-profit sector. fessional, although the effectiveness of this measure is
controversial150. Although DOT continues to be valu-
able in many settings, various alternative methods are
had contact with patients with active pulmonary TB; and now being tried out to improve adherence, including
patients initiating anti-TNF treatment, on dialysis with mobile phone reminders, smart pill boxes, video DOT
end-stage renal disease, preparing for organ or haema- and the use of call centres to follow‑up with patients.
tological transplantation or with silicosis. The rationale Regardless of the method, it is crucial to use a team-
for giving these subgroups priority is that they are at based, patient-centric approach that incorporates edu-
very high risk of progressing from LTBI to active TB cation, counselling and patient empowerment 151.
disease, and receiving LTBI treatment could prevent it.
Treatment of LBTI in individuals who have had contact Active drug-resistant TB disease
with patients with active MDR‑TB disease is controver- Early and rapid diagnosis and timely initiation of an
sial. The WHO recommends close monitoring of these effective regimen against active drug-resistant TB dis-
individuals, preferably for at least 2 years. Clinicians ease is essential for optimizing treatment outcomes,
could consider individually tailored treatment regimens minimizing disease transmission and reducing further
(based on the drug susceptibility profile of the patient drug resistance152,153. Designing an appropriate regimen
with active MDR‑TB disease that the individual had is a complex task as it depends on the characteristics of
been exposed to) when benefits would outweigh harms, the patient and the specific drug susceptibility profile of
particularly for children <5 years of age145. the organism152–154 (BOX 2).
LTBI treatment regimens recommended by the Currently, therapies for active drug-resistant TB dis-
WHO include 6–9 months of isoniazid, 3 months of ease have a poor evidence base, are lengthy, use drugs of
rifapentine plus isoniazid, 3–4 months of isoniazid plus uncertain efficacy and are characterized by high toxicity
rifampicin or 3–4 months of rifampicin alone145. All (TABLE 4). Indeed, adherence rates are poor in TB endemic
regimens are known to be efficacious8,145, but patient countries and so are the outcomes (approximately 50%
compliance can be poor with the longer regimens146. treatment success for active MDR‑TB disease in most
Rifampicin-containing regimens are shorter and might TB endemic countries)1. Furthermore, several toxici-
be more suitable in populations with a high prevalence ty-related parameters require close monitoring during
of isoniazid mono-resistant strains. Regardless of the therapy 155, in addition to regular medical examinations,
regimen, it is important to ensure adherence and provide placing an extra burden on health care systems. On the
patients with adequate counselling. basis of promising results of a seven-drug regimen that is
being used in numerous countries, the WHO updated its
Active drug-sensitive TB disease treatment guidelines for active drug-resistant TB disease
The current preferred regimen (TABLE  3) for active in May 2016. The recommendation calls for using this
drug-sensitive TB disease is a minimum of 6 months shorter regimen under specific conditions156. Although

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expected to benefit the majority of patients with active with either bedaquiline or delamanid means that such
MDR‑TB disease, worsening resistance is possible if the patients might remain therapeutically destitute. Thus,
regimen is used inappropriately or without appropriate there is a pool of essentially incurable patients with
drug sensitivity testing. active drug-resistant TB disease. This phenomenon is
In an increasing number of patients, appropri- well documented in many countries, including India
ate effective regimens cannot be devised or fail. Such and countries in eastern Europe and sub-Saharan Africa,
cases of extensively drug-resistant TB (BOX 3) have been where community-based transmission of untreatable
reported in several countries, including India, China, strains has been demonstrated157. This finding has raised
South Africa, Russia and other countries in eastern numerous legal, ethical and logistical dilemmas about
Europe153. New agents such as bedaquiline or delamanid long-term accommodation, access to palliative care and
might be beneficial for these patients, even though an individual rights to unrestricted work and travel for
effective regimen could still be challenging to construct. these patients153. Transmission of such untreatable exten-
However, lack of or limited access to these drugs or the sively drug-resistant strains poses a major challenge for
absence of available drugs to be used in conjunction global TB control.

Table 2 | Global pipeline of TB vaccine candidates listed [Au:OK?] by indication

Vaccine candidate Development partners [Au: Country of Description Current
companies/institutions below OK?] phase
Prevention of active TB disease in infants (BCG replacement)
VPM 1002* Serum Institute of India (India), Max Planck Recombinant BCG Phase IIb
Institute (Germany), Vakzine Projekt
Management GmbH (Germany) and TuBerculosis
Vaccine Initiative (The Netherlands)
MTBVAC‡ Biofabri (Spain), TuBerculosis Vaccine Initiative Live attenuated Mycobacterium tuberculosis Phase I
and University of Zaragoza (Spain)
Prevention of active TB disease in individuals with LTBI
Vaccae Anhui Zhifei Longcom (China) Heat-inactivated, whole-cell Mycobacterium vaccae Phase III
Adjunctive immunotherapy in individuals with LTBI
RUTI Archivel Farma (Spain) Detoxified, fragmented M. tuberculosis Phase II
Prevention of active TB disease recurrence in recently cured patients
ID93 plus GLA‑SE Infectious Disease Research Institute (United Adjuvanted recombinant protein expressing Phase IIb
[Au:OK?] States) and the Wellcome Trust (United Kingdom) M. tuberculosis antigens Rv3619, Rv3620, Rv1813 and
Rv2608
Prevention of active TB disease in uninfected individuals and in those with LTBI [Au: would “Prevention of M. tuberculosis infection in
uninfected individuals and active TB disease in individuals with LTBI” be OK?]
H1or H56:IC31 Statens Serum Institut (Denmark), Valneva Adjuvanted recombinant protein expressing Phase II
(United Kingdom) and Aeras (South Africa) M. tuberculosis antigens Ag85B, ESAT‑6 [H1]; or [Au:OK?]
Ag85B, ESAT‑6, Rv2660c [H56]
M72/ASO1E GlaxoSmithKline (GSK) Vaccines (United Adjuvanted recombinant protein expressing Phase IIb
Kingdom) and Aeras M. tuberculosis antigens 32A and 39A
DAR‑901 Dartmouth College (United States) Whole-cell, inactivated non-tuberculous mycobacterium Phase II
(Mycobacterium obuense)
H4:IC31 Sanofi Pasteur (United Kingdom), Statens Serum Adjuvanted recombinant protein expressing Phase II
Institut and Aeras M. tuberculosis antigens Ag85B and TB10.4
Ad5 Ag85A McMaster University (Canada) and CanSino Viral vector (human adenovirus 5) expressing Phase II
(China) M. tuberculosis antigen Ag85A
ChAdOx1‑85A/MVA85A Oxford University (United Kingdom) Viral vectors (Chimp adenovirus/modified Vaccinia Phase I
Virus Ankara) heterologous prime–boost expressing
M. tuberculosis antigen Ag85A
MVA85A/MVA85A Oxford University Viral vector (modified Vaccinia Virus Ankara) intradermal Phase I
[Au:OK?] or aerosol prime–boost vaccine [Au:OK?]
TB/FLU‑04L Research Institute for Biological Safety Problems Viral vector (influenza A virus) Phase I
(Republic of Kazakhstan)
Information as reported by the vaccine sponsors to Aeras. [Au:OK?] To date, tuberculosis (TB) vaccine candidates have been designed predominantly to stimulate a
T helper 1‑type CD4+ T cell response. The viral vector candidates alone or in combination typically also stimulate a robust CD8+ T cell response. The whole-cell and
lysate mycobacteria-based candidates have the greatest potential to stimulate other aspects of the host innate and adaptive immune system, including, for
example, donor unrestricted T cells (such as γδ-cells, mucosal-associated invariant T cells, CD1-restricted T cells and natural killer T cells), as they present the
broadest array of antigens. All candidates tested stimulate antigen-specific antibody responses. The contribution of these various responses to protection is not yet
clear. BCG, Bacillus Calmette–Guérin; ESAT‑6, early secreted antigenic target 6; LTBI, latent TB infection. *Also for the prevention of active TB disease recurrence in
recently cured patients. ‡Also for the prevention of active TB disease in adolescents and adults.

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PRIMER

Table 3 | Drug regimens for drug-sensitive pulmonary TB

Intensive phase Continuation phase
Drugs* Interval and Drugs Interval and Total Important practice
dose‡ dose‡,§ doses points§,||[Au:OK?]
• Isoniazid Daily for 8 weeks • Isoniazid Daily for 18 weeks 182 Preferred regimen for patients
• Rifampicin or 5 days • Rifampicin or 5 days or 130 with newly diagnosed pulmonary
• Pyrazinamide per week for per week for TB
• Ethambutol 8 weeks 18 weeks
• Isoniazid Daily for 8 weeks • Isoniazid 3 days per week 110 Preferred alternative regimen
• Rifampicin or 5 days • Rifampicin for 18 weeks or 94 when more-frequent DOT during
• Pyrazinamide per week for the continuation phase is difficult
• Ethambutol 8 weeks to achieve
• Isoniazid 3 days per week • Isoniazid 3 days per week 78 Use with caution in HIV-positive
• Rifampicin for 8 weeks • Rifampicin for 18 weeks patients and/or cavitary disease.
• Pyrazinamide Missed doses can lead to
• Ethambutol treatment failure, relapse and
acquired drug resistance
• Isoniazid Daily for • Isoniazid 2 days per week 62 Do not use 2 days per week
• Rifampicin 2 weeks, then • Rifampicin for 18 weeks regimens in HIV-positive patients
• Pyrazinamide 2 days per week and/or patients with cavitary
• Ethambutol for 6 weeks¶ disease or who are smear-positive.
Missed doses lead to inferior
efficacy of the therapy
DOT, directly observed therapy; TB, tuberculosis. *Other combinations might be appropriate in certain circumstances. ‡Minimum
duration; when DOT is used, drugs might be given 5 days per week and the necessary number of doses adjusted accordingly. DOT
should be used when drugs are administered <7 days per week. §Based on expert opinion, patients with cavitation on initial chest
X‑ray and with a positive culture test result [Au:OK?] at completion of 8 weeks of therapy should receive a 31‑week continuation
phase. ||Vitamin B6 (25–50 mg per day) is given with isoniazid to individuals who are at risk of neuropathy (for example, pregnant
women; breastfeeding infants; HIV-positive individuals; or patients with diabetes, alcoholism, malnutrition, chronic renal failure or
advanced age). For patients with peripheral neuropathy, experts recommend increasing the vitamin B6 dose to 100 mg per day.
¶
Alternatively, some US TB control programmes consist of intensive-phase regimens of 5 days per week for 3 weeks, then 2 days per
week for 6 weeks. Adapted from REF. 148.

Reports of possible totally drug-resistant strains higher doses of currently used anti-TB drugs159,160 and
highlight two key issues153,158. First, the development ‘re‑purposed’ drugs (drugs that were originally designed
and introduction of new drugs have not kept pace with for other diseases that could prove effective against
the emergence of drug-resistant strains. This failure drug-resistant TB). For example, rifapentine has simi-
reflects a lack of public and private investments since lar in vitro anti-mycobacterial activity as rifampicin but
the 1970s, when TB incidence fell in most high-income with a fivefold longer half-life. When substituting for
countries and the need for new drugs was perceived rifampicin, it has been shown to be effective when given
as less pressing. Second, by introducing new drugs in once or twice a week160, thereby facilitating treatment
settings with a high prevalence of drug-resistant strains adherence.
without correcting one of the fundamental causes of the Furthermore, fluoroquinolones are a class of antibi-
emergence of such strains (such as weak health care sys- otics that are widely used for the treatment of infections
tems with poor management of patients with TB), the of the lower respiratory tract. They have excellent in vitro
risk of amplifying anti-TB [Au:OK?] drug resistance is activity against M. tuberculosis, are as effective as isoni-
considerable. azid in the initial phase of treatment of drug-sensitive
Beyond drug therapy, there is a role for surgery in TB161 and are essential drugs in drug-resistant TB treat-
the management of drug-resistant TB. In patients with ment 162. However, three large trials have demonstrated
unilateral disease (or apical bilateral disease in selected that short (4 months) fluoroquinolone-based regimens
cases) with adequate lung function in whom medi- could not achieve similar cure rates of drug-resistant
cal treatment has failed, surgical treatment to remove [Au:OK?] TB as the standard 6‑month regimen160,163,164.
the entire affected area of the lung can be effective. Another possible re‑purposed drug is linezolid,
However, in patients with rifampicin-resistant TB or which has been used most successfully in patients with
MDR‑TB, elective partial lung resection (lobectomy or strains that are resistant to isoniazid, rifampicin or fluo-
wedge resection) is associated with improved treatment roquinolones165. However, experience with linezolid is
success154. limited because of its high cost and toxicity. Similarly,
carbapenems have been beneficial in patients with
Treatment solutions to drug resistance highly resistant strains166, but are expensive and, with
Optimizing existing drugs. Because the need for new some exceptions (such as faropenem), they need par-
regimens is urgent and new drug development is long, enteral administration. To improve the treatment of TB
expensive and with uncertain results, attempted interim (all types), the most promising approaches remain the
solutions include using highly intermittent regimens, discovery of novel compounds and the development of
existing anti-TB drugs that were never widely prescribed, new regimens.

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Newly approved drugs and the current pipeline. At HIV-associated TB

the end of 2012, the US FDA approved bedaquiline HIV poses a challenge for global TB control174. Worldwide
(a diarylquinoline), the first truly new anti-TB drug in 2014, 12% of all new cases of active TB disease occurred
in approximately 40 years167. In 2014, the European in HIV-positive individuals (1.2 million people) 1.
Commission authorized bedaquiline and another new Although there is geographical variation, it is estimated
compound, delamanid (a nitroimidazo-oxazole deriv- that HIV-positive individuals are 26‑fold more likely to
ative), for the treatment of adults with pulmonary develop active TB disease than HIV-negative individuals1.
MDR‑TB168. Bedaquiline has now been approved in This increased risk is observable as early as HIV sero-
many other countries. Both bedaquiline and delamanid conversion and further exacerbates as CD4+ T cell counts
work through novel mechanisms, bedaquiline through decrease7. Thus, HIV-positive individuals have a very
inhibition of ATP synthase and delamanid through inhi- high risk of progressing to active TB disease, although
bition of mycolic acid synthesis, and there is no known they are not necessarily more infectious to others.
cross-resistance with other approved anti-TB drugs. Antiretroviral therapy (ART) has been demonstrated
In addition, in preclinical models, both drugs seem to to reduce active TB disease incidence by providing
have very good ‘sterilizing’ properties, which measure immune reconstitution; the lower the CD4+ T cell count,
their ability to kill tuberculous organisms when there the higher the ART-associated protection175. The com-
are very few left in the body or when they are growing bined use of ART and isoniazid preventive treatment has
or reproducing very slowly; this ability might translate also been shown to reduce active TB disease incidence
into a shorter duration of TB therapy 169,170. and severe illnesses among HIV-positive individuals176,177.
However, these new drugs were approved based on Nevertheless, the risk of developing active TB disease
very limited evidence. Hence, well-designed and well-ex- remains twofold higher in HIV-positive individuals even
ecuted randomized trials will be needed to determine if their CD4+ T cell count is within normal range178 and
whether these two drugs can be administered together, they can still develop active TB disease even if they are
the optimal treatment duration, their actual ability to receiving ART179. The proportion of patients diagnosed
contribute to treatment shortening and the optimal with TB at the start of ART in sub-Saharan Africa ranges
companion drugs. The ultimate goals are shortening and between 5% and 40%180.
simplifying TB therapy while also increasing the cure HIV changes the presentation of active TB disease:
rates and developing regimens that cause fewer adverse it generally reduces pulmonary cavity formation and
effects, especially in treating drug-resistant TB171. sputum bacillary load and more frequently involves the
In terms of drug development, the TB drug pipeline lower lobes110. All HIV-positive individuals should be
is now the largest it has ever been172 (FIG. 5), with mul- regularly screened for active TB disease, particularly if
tiple early TB drug discovery projects, the majority of they experience the following symptoms: cough, fever,
which are incorporated into the TB Drug Accelerator, weight loss and night sweats110,181,182. Individuals who
a programme sponsored by the Bill and Melinda Gates report any one of these symptoms might have active TB
Foundation for collaborative TB drug discovery 173. disease and require immediate evaluation and treatment.
Individuals who report no symptoms should be provided
with preventive LTBI treatment, after ruling out active TB
Box 2 | Principles of managing MDR-TB
disease, depending on TB epidemiology and burden in
• A 9–12‑month regimen (conditional WHO recommendation with very-low-quality the area8,145,183.
evidence) might be used in selected patients, in appropriate settings, taking into In settings where diagnostic tools might not be avail­
account previous treatment and local resistance profiles able, TB treatment should then be empirically provided to
• If patients are not eligible for the shorter regimen, a longer treatment regimen is used. HIV-positive individuals with suspected active TB disease
The composition of the regimen includes pyrazinamide in addition to at least four who are seriously ill and in life-threatening conditions. In
second-line drugs to which the organism is likely or proven to be susceptible for a these settings, the WHO algorithms recommend starting
duration of ≥20 months treatment for suspected active TB disease in HIV-positive
• The second-line drugs should include a later-generation fluoroquinolone (such as patients who are in serious respiratory distress based only
moxifloxacin, levofloxacin or gatifloxacin), an injectable agent (such as amikacin, on the clinician’s judgement184.
kanamycin or capreomycin*) and two or more core second-line agents (such as
HIV-positive individuals, particularly if they have low
ethionamide, prothionamide, cycloserine, terizidone, clofazimine or linezolid)
CD4+ T cell counts, have a higher risk of extrapulmonary
• First-line drugs (such as isoniazid or ethambutol) could be added to strengthen the
TB, which could result in rapid clinical deterioration
regimen
and death. The most common forms of extrapulmonary
• When toxicity or resistance occurs, additional agents can be added, including
TB include lymph node, pleural and disseminated TB.
bedaquiline and delamanid, such that four drugs that are likely to be effective are
being used
Pericardial and meningeal TB are less frequent but dead-
lier. Diagnosing extrapulmonary TB is difficult; the WHO
• A single new drug should not be added to a failing regimen
recommends Xpert MTB/RIF to detect TB lymphadenitis
• Adherence and psychosocial support measures and, if necessary, counselling against
and TB meningitis109,185. Patients diagnosed with active TB
substance abuse are essential
disease who are HIV-positive or live in an HIV-prevalent
• Patients should be monitored for adverse drug reactions, which occur commonly setting should receive daily isoniazid and rifampicin for
MDR-TB, multidrug-resistant tuberculosis. *Capreomycin cross-resistance with aminoglycosides 6 months and also [Au:OK?] pyrazinamide and ethambu-
is not complete and it might be a therapeutic option in specific and appropriate contexts, and in tol for the first 2 months147. Treatment for TB meningitis
light of aminoglycoside resistance if no safe or effective alternatives are available.
should last 9–12 months given the serious risk of disability

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Table 4 | First-line and second-line drugs used for the treatment of drug-resistant TB (WHO classification)
Class Mechanism of Drugs Key adverse events Important practice points[Au:OK?]
action
Group A
Fluoroquinolones Inhibition of • Levofloxacin QTc prolongation (levofloxacin less • Monitor QTc when fluoroquinolones are
DNA gyrase • Moxifloxacin so than moxifloxacin) combined with other QTc-prolonging agents,
• Gatifloxacin* for example, bedaquiline or clofazimine
• Levofloxacin is the fluoroquinolone of choice
in bedaquiline-containing regimens
Group B: second-line injectable anti-TB drugs [Au:OK?]
Aminoglycosides Inhibition • Kanamycin • Nephrotoxicity (all) • Avoid combination of aminoglycosides with
of protein • Amikacin • Ototoxicity (all) other potentially nephrotoxic agents, for
synthesis • Capreomycin • Electrolyte derangement (all) example, tenofovir or amphotericin B
• (Streptomycin)‡ • Use with caution in patients with diabetes
mellitus or renal disease
Group C: core second-line agents
Thioamides Inhibition of cell • Ethionamide • Nausea and vomiting (all) • If nausea and vomiting persist, consider
wall synthesis • Prothionamide • Hypothyroidism (all) drug-induced hepatitis or pancreatitis
• Monitor thyroid-stimulating hormone levels
in patients receiving ethionamide
Oxazolidinones Inhibition • Cycloserine • CNS effects, including psychosis, • Avoid concomitant use of linezolid with
of protein • Terizidone confusion and depression zidovudine, stavudine or didanosine; if
synthesis • Linezolid (terizidone and cycloserine) myelosuppression occurs, stop linezolid use
• Clofazimine • Peripheral neuropathy (linezolid) and transfuse as appropriate
• Myelosuppression (linezolid) • Monitor QTc when using clofazimine,
• Ocular toxicity (linezolid) especially when combined with
• QTc prolongation (clofazimine) QTc-prolonging agents
• Skin and conjunctival pigmentation
(clofazimine)
Group D: add‑on agents
D1, various classes: Inhibition of High-dose • Hepatotoxicity Use with pyridoxine to prevent peripheral
isonicotinic acid mycolic acid isoniazid • Peripheral neuropathy neuropathy
hydrazide (high-dose synthesis • CNS toxicity
isoniazid);
nicotinamide Disruption Pyrazinamide • Hepatotoxicity –
analogue of plasma • Gout
(pyrazinamide); membranes
aminoalcohols Inhibition of cell Ethambutol Ocular toxicity –
(ethambutol) wall synthesis
D2, various classes: Inhibition of Bedaquiline • QTc prolongation • Close monitoring of QTc is recommended
diarylquinoline mitochondrial • Arthralgia • Efavirenz should be changed to nevirapine
(bedaquiline); ATP synthase • Hepatitis or a protease inhibitor because of reduced
nitro-dihydro-­ • Headache bedaquiline exposure. Alternatively, an
imidazooxazole integrase inhibitor can be used
(delamanid)
Inhibition of Delamanid • Nausea • Close monitoring of QTc is recommended
mycolic acid • Vomiting • No significant anticipated drug–drug
synthesis • Dizziness interactions with antiretroviral drugs
• QTc prolongation
D3, various classes: Inhibition of Para- Gastrointestinal toxicity Monitor thyroid-stimulating hormone levels in
amino-phenol (para- DNA precursor aminosalicylic patients receiving para-aminosalicylic acid
aminosalicylic acid); synthesis acid
carbapenems; [Au:OK?]
thiosemicarbazone
(thiocetazone) Inhibition of Imipenem Seizures Monitor for CNS adverse events
peptidoglycan plus [Au:OK?]
synthesis cilastatin or
meropenem
plus clavulanate
(available orally
with amoxicillin)
Inhibition of Thiocetazone§ Severe skin reactions (for example, Close monitoring for severe skin reactions;
mycolic acid Stevens–Johnson syndrome and toxic avoid use if the patient is HIV-positive
synthesis epidermal necrolysis), especially in
patients with HIV infection
CNS, central nervous system; QTc, corrected QT interval; TB, tuberculosis. *This drug is being assessed for inclusion in the 2017 Essential Medicines List.
‡
Streptomycin can be used when the isolate is susceptible and none of the other injectable drugs are available. §Only use in HIV-negative individuals.

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 PRIMER

Box 3 | Principles of managing extensively drug-resistant TB estimates194,195. Active TB disease typically causes pul-
monary disease in adults, but the spectrum of disease is
• Regimens should be constructed using similar principles as outlined for multidrug- different in children, ranging from paucibacillary lym-
resistant tuberculosis (MDR‑TB) (BOX 2) phadenitis to severe disseminated (miliary) disease6,113,196.
• Drugs such as linezolid, bedaquiline and delamanid (if available) often need to be Children who have had contact with adult patients
used, such that at least four drugs that are likely to be effective are used concurrently with active TB disease are at high risk of M. tuberculosis
• Lack of access to newer and repurposed drugs means that, in reality, patients often infection and developing active TB disease, so they are
only receive one or two effective drugs, resulting in poor treatment outcomes prioritized for LTBI testing and treatment 145. The prin-
• Additional drugs, including meropenem and clavulanate, are used, but their role and ciples of LTBI treatment in adults also apply to children.
effectiveness are unclear In general, children tolerate anti‑TB drugs well with low
• As cross-resistance across different fluoroquinolones is not complete, moxifloxacin risk of toxicity. However, developmental differences in
can still be used in the presence of fluoroquinolone (for example, ofloxacin) resistance pharmacokinetics and pharmacodynamics require that
drug dosages in children be adjusted for body weight and
age. History of drug resistance among adult patients with
and mortality, and treatment for TB of the bones or joints active TB disease with whom children have had contact
should last 9 months because of the difficulties of assess- might be helpful in regimen selection.
ing treatment response. The basic principles and recommended standard
The WHO recommends that all HIV-positive indi- regimens for the treatment of active TB disease in chil-
viduals with drug-sensitive and drug-resistant active TB dren are similar to those applied to adults197. Treatment
disease should also begin ART within the first 2 months should be given daily at least in the intensive phase, and
of TB treatment, regardless of their CD4+ T cell count. might be extended up to 9–12 months in severe forms
Randomized controlled trials186–190, systematic review of active disease197. Management of HIV infection in
and meta-analyses191,192 have confirmed the benefit of children with active TB disease is described in the WHO
combined TB and HIV treatment in reducing mortality guidelines184,197. Treatment of MDR-TB in HIV-positive
rates. Preferred ART regimens are described in the 2016 children follows the same principles as treatment of HIV-
WHO guidelines184; in adults, first-line treatment consists negative children.
of a combination of two nucleoside reverse-transcriptase
inhibitors and a non-nucleoside reverse-transcriptase Quality of life
inhibitor or an integrase inhibitor. Several studies have documented lower self-reported
TB is the leading cause of death among people with health-related quality of life among patients with active
HIV infection, accounting for one in five HIV-related TB disease198. [Au: lower self-reported health-related
deaths1. The management of HIV‑TB is complicated by quality of life than whom? Or should ‘lower’ be changed
several factors. First, drug–drug interactions between to ‘low’?] Impairment of lung function with chronic
antitubercular and antiretroviral agents make it difficult pulmonary disability, bronchiectasis, aspergillomas and
to design an effective and safe treatment regimen and can chronic pulmonary aspergillosis are known complica-
cause severe adverse effects, such as hepatotoxicity and tions and are more frequent in patients with drug-resist-
neurotoxicity. Second, by restoring the immune system, ant TB than in patients with drug-sensitive TB199. Patients
ART can trigger immune reconstitution inflammatory with impaired lung function might require long-term
syndrome (IRIS), a condition in which the host’s inflam- ­pulmonary ­rehabilitation and chest physiotherapy.
matory response to an infection (in this case, M. tuber- If patients are untreated, the prognosis for individu-
culosis infection) is disproportionate and worsens the als affected by drug-resistant TB is similar to the prog-
patient’s status. Whereas the incidence of severe (grade 3 nosis for individuals with drug-sensitive TB (10‑year
or grade 4) non-IRIS adverse events was similar whether case fatality rates of approximately 70%)16. The current
the patients had started ART early or late during TB treat- WHO-recommended MDR‑TB regimen has an approx-
ment, there was a significantly higher incidence of IRIS- imate 50% cure rate, whereas the cure rate in endemic
related adverse effects in the early ART group. Similarly, settings of extensively drug-resistant TB in the absence
a small but significant increased risk of IRIS-related mor- of drugs such as bedaquiline, delamanid and linezolid
tality has been reported186,189,190. Patients with HIV infec- is approximately 20%157,200. Thus, TB (and drug-resistant
tion with drug-sensitive and drug-resistant active TB TB in particular) poses a grave threat to human health
disease and profound immunosuppression (CD4+ T cell and quality of life. High-quality patient care, consistent
counts of <50 cells per ml) should receive ART within with the International Standards for TB Care201, is cru-
the first 2 weeks of initiating TB treatment 184, [Au:OK?] cial to ensure good outcomes and preserve quality of
unless the patients are diagnosed with TB meningitis. life. Unfortunately, international standards are often not
In these patients, ART should be delayed to 2 months met in many low-income, high TB burden countries,
after the start of TB treatment to reduce the risk of severe particularly in the private health sector, which is a major
adverse effects193. provider of health care in many countries with a high
TB prevalence202–206. Poor quality of care is therefore a
Childhood TB key driver of TB mortality in high-burden countries, and
Models suggest that childhood active TB disease might explain the persistently high TB incidence in some
is more frequent than official reports indicate, and settings. Whereas national programmes are accountable
cases of MDR‑TB are far more numerous than prior to national and international authorities regarding their

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 17

PRIMER

implementation of proper standards of care, one of the ending the epidemic, increased awareness of the hetero-
greatest challenges in TB control is still engaging and geneities in transmission dynamics and catalysts of local
regulating the private sector 206. Innovative public–private epidemics will be essential to success.
mix approaches are required to overcome this challenge, In May 2014, the World Health Assembly approved
including social franchising, insurance-based initiatives, a new strategy for the modern era to reach the ambi-
intermediary agencies and provider consolidation, with tious target of ending the global TB epidemic by 2035
a heavy emphasis on the use of information and commu- (REFS 211,212): the End TB Strategy. The goal will be met
nication technologies206. when TB‑related deaths and active TB disease incidence
are reduced by 95% and 90%, respectively, compared with
Outlook­­­­­­ the 2015 values, which would mean that global active TB
The global TB epidemic is not a homogeneous entity that disease incidence is lower than 10 per 100,000 population.
is characterized by a gradual decline in incidence, but The End TB Strategy builds on four principles: stew-
rather a heterogeneous collection of local microepidem- ardship and accountability of governments; engagement
ics, in which transmission in each setting is driven by of civil society; respect of human rights, ethics and
different catalysts: from HIV-induced immune defects equity; and adaptation to local conditions. These prin-
to inadequate diagnosis and treatment 207. In regions ciples are structured in three pillars.[Au:OK?] The first
[Au:OK?] where increased attention and resources have pillar (‘integrated, patient-centred care and prevention’)
been devoted to fighting TB (for example, New York considers interventions for diagnosis, treatment, man-
City 208, Peru209, Alaska210 and China22), remarkable suc- agement and prevention, promoting all available tech-
cess has been achieved. By contrast, in regions where nological advances. The second pillar (‘bold policies and
catalysts of transmission have been left unaddressed supportive systems’) focuses on broad health systems and
(for example, economic collapse and incarceration in policies, including universal health coverage, social and
some eastern European countries and HIV in countries financial protection, and the engagement of all health
in sub-Saharan Africa before the widespread availabil- care providers. The third pillar (‘intensified research and
ity of ART), [Au:OK?] TB has resurged. As the goal of innovation’) is devoted to research and development of
the global response to TB transitions from controlling to new tools.

Discovery Preclinical development Clinical development

Presumed Early-stage Toxicity

Phase I Phase II Phase III
novel targets development assessment

• Rifapentine#–moxifloxacin||||
for drug-sensitive TB
• Delamanid‡‡ with OBR
for MDR-TB
• Pretomanid‡‡–moxifloxacin||||
• Sutezolid¶ –Pyrazinamide§§ regimen
• Linezolid¶ (STAND trial)
• High-dose rifampicin# • Bedaquiline**–pretomanid‡‡
for drug-sensitive TB –Linezolid¶ regimen (Nix-TB trial)
• Bedaquiline** • Bedaquiline**–STREAM regimen
• DprE inhibitors • TBI-166* –Pretomanid‡‡ with OBR with oral drugs
• InhA inhibitors • CPZEN-45‡ • BTZ-043§ –Pyrazinamide§§ (9 months) or with OBR with
• LeuRS inhibitors • SQ609‡ • PBTZ169§ regimen injectable drugs (6 months)
• Mycobacterial gyrase inhibitors • 1599‡ • TBA-7371‡ • Levofloxacin|||| with • Bedaquiline**–linezolid¶ with
• Translocase 1 inhibitors • SEQ-9‡ • GSK-070‡ • Q203|| OBR for MDR-TB OBR for MDR-TB (NExT trial)

Figure 5 | The global TB drug pipeline. The pipeline is based on data similar efficacy to the present standardNature
of careReviews
and decreased orPrimers
| Disease similar
compiled by the New Drugs Working Group of the Stop TB Partnership172 and associated toxicity. Most TB treatment-shortening trials are targeted at
based on voluntary reporting by drug developers. As a result, the compounds individuals with TB that is resistant to standard first-line therapy, and some
and regimens listed, especially under ‘Discovery’ and ‘Preclinical trials have the goal of discovering universal regimens that are equally
development’, are likely to be under-reported. Most compounds listed in effective against drug-sensitive and drug-resistant TB, which would
‘Discovery’ are derived from whole-cell screening, and true target eliminate the need for drug sensitivity testing. *Riminophenazine. ‡New
identification and validation is still ongoing. Among products under clinical chemical class. §Benzothiazinone. ||Imidazopyridine amide. #Rifamycin.
development, ten compounds (either new or repurposed) are currently **Diarylquinoline. §§Pyrazine (pyrazinoic acid amide). DprE, decaprenylphos-
being evaluated either in phase I trials or as part of anti-tuberculosis (TB) phoryl-β-d-ribose 2ʹ-epimerase; InhA, enoyl acyl carrier protein reductase;
[Au:OK?] drug regimens. Most of these compounds belong to three LeuRS, leucyl-tRNA synthetase; MDR, multidrug resistant; Nix‑TB, New
chemical classes — oxazolidinones (denoted as ¶), nitroimidazoles (denoted Investigational Drugs for Extensively Drug-Resistant TB; [Au:OK?]OBR,
as ‡‡) or fluoroquinolones (denoted as ||||). The main goal of many phase II and optimized background regimen; STAND, Shortening Treatment by
phase III trials is to combine new or repurposed compounds in treatment Advancing Novel Drugs; STREAM, Standard Treatment Regimen of
regimens that would be drastically shorter and simplified, have increased or Anti-tuberculosis Drugs for Patients With MDR‑TB.

18 | 2016 | VOLUME 2 www.nature.com/nrdp

 PRIMER

Reaching the targets set for 2035 will not be possible mutations are ongoing, using epidemiologically repre-
unless a substantial decrease in TB incidence occurs. sentative strain collections coupled with patient outcome
Currently, TB incidence declines by 1.5% annually, but data88. Genome sequencing and molecular platforms
the gains in reducing TB incidence could still be lost that detect mutations that confer drug resistance also
if the rising threat of MDR‑TB is not adequately tack- need to be developed to support the introduction of new
led212. The model projecting a further reduction in TB drug regimens for active TB disease128. Current regimens
incidence is built on two basic assumptions. First, that are long, cumbersome and toxic. New medicines and
implementation of current (or soon‑to‑be available) universal regimens (that can be used in both drug-sen-
interventions and tools are optimized, enabling a 10% sitive TB and MDR‑TB) are being studied to shorten
annual reduction by 2025 (the highest ever reached at duration, facilitate administration and enable safe use
national scale). Achieving this result will require effec- in people with comorbidities. However, the development
tive rapid molecular diagnostics, universal drug sus- pipeline remains very limited. Regimens that simplify
ceptibility testing and systematic screening of high-risk and shorten LTBI treatment are also a priority, as any
populations (which also implies providing curative or attempt to eradicate TB needs to address the huge pool
preventive treatment to individuals who test positive), as of individuals with LTBI.
well as bolder policies on universal coverage and social The current vaccine development pipeline includes
protection, which would alleviate the socioeconomic 13 different candidates aiming at preventing both the
causes of disease. The second assumption is that research establishment of LTBI and the progression from LTBI to
efforts deliver new revolutionizing transformational active disease, but they represent limited diversity in the
tools and interventions. immune responses they induce. Increasing the under-
standing of the protective human immune response,
Research needs and priorities identifying animal models that predict vaccine efficacy
Effective TB research must span from basic to transla- in humans, discovering a correlate of protection and
tional and clinical213. The pathogenesis and immunology developing a controlled human infection model would
of M. tuberculosis infection and active disease remain each, if successful, represent a game-changer in acceler-
only partly understood. For instance, the ontogeny of ating vaccine development.
macrophages markedly affects their function and fate67,68, Finally, it is important to optimize delivery of exist-
but current primary cell line models are not derived ing or new tools and rapid transfer of innovations to
from the alveolar tissue. The dynamics that regulate high-burden settings through well-planned implemen-
progression from exposure to M. tuberculosis to LTBI tation research projects, taking into account that these
and from LTBI to active TB disease need to be clarified tools might have to be adapted to different conditions.
to develop new rapid, simple diagnostic tools, which This strategy will require, in turn, socio-anthropologi-
need to be available at the point of care. To develop tests cal, epidemiological, health system and policy research.
with reliable predictive value, it is crucial to identify It is also clear that strengthening of health systems is
biomarkers or bio-signatures that can resolve the LTBI crucial for successful introduction of new technologies.
spectrum2, so that individuals who are at highest risk Ultimately, global targets will be reached only when
of progressing from LTBI to active disease can be rec- governments and their partners decide to invest inten-
ognized and treated133. Preliminary research has shown sively in both research and implementation efforts. In
promising results for a blood RNA signature214. High- this context, lack of adequate financing of national TB
resolution lung imaging might also be able to separate programmes is a major challenge in many low-income
phenotypes within the TB spectrum101. countries. Thus, high-income countries must continue
A complete understanding of how M. tuberculosis investing in TB research and, via multi-lateral or bi‑lat-
develops resistance has the potential to revolutionize eral financial mechanisms, support the efforts of low-in-
TB care, so efforts to catalogue resistance-associated come settings.

1. World Health Organization. Global Tuberculosis overlapping HIV and TB epidemics. JAMA 300, 423– 13. Bates, M. N. et al. Risk of tuberculosis from exposure
Report 2015 (WHO, 2015). 430 (2008). to tobacco smoke: a systematic review and meta-
2. Barry, C. E. 3rd et al. The spectrum of latent 8. Getahun, H. et al. Management of latent analysis. Arch. Intern. Med. 167, 335–342 (2007).
tuberculosis: rethinking the biology and intervention Mycobacterium tuberculosis infection: WHO 14. van Leth, F., van der Werf, M. J. & Borgdorff, M. W.
strategies. Nat. Rev. Microbiol. 7, 845–855 (2009). guidelines for low tuberculosis burden countries. Eur. Prevalence of tuberculous infection and incidence of
This paper provides an overview of the spectrum of Respir. J. 46, 1563–1576 (2015). tuberculosis: a re‑assessment of the Styblo rule. Bull.
TB. 9. Ford, N. et al. Causes of hospital admission among World Health Organ. 86, 20–26 (2008).
3. Esmail, H., Barry, C. E. 3rd, Young, D. B. & people living with HIV worldwide: a systematic review 15. Onozaki, I. et al. National tuberculosis prevalence
Wilkinson, R. J. The ongoing challenge of latent and meta-analysis. Lancet HIV 2, e438–e444 surveys in Asia, 1990–2012: an overview of results
tuberculosis. Phil. Trans. R. Soc. B 369, 20130437 (2015). and lessons learned. Trop. Med. Int. Health 20,
(2014). 10. Lonnroth, K. et al. Tuberculosis control and 1128–1145 (2015).
4. Marais, B. J. et al. Childhood pulmonary tuberculosis: elimination 2010‑50: cure, care, and social 16. Tiemersma, E. W., van der Werf, M. J.,
old wisdom and new challenges. Am. J. Respir. Crit. development. Lancet 375, 1814–1829 (2010). Borgdorff, M. W., Williams, B. G. & Nagelkerke, N. J.
Care Med. 173, 1078–1090 (2006). 11. Jeon, C. Y. & Murray, M. B. Diabetes mellitus Natural history of tuberculosis: duration and fatality of
5. Dye, C. Global epidemiology of tuberculosis. Lancet increases the risk of active tuberculosis: a systematic untreated pulmonary tuberculosis in HIV negative
367, 938–940 (2006). review of 13 observational studies. PLoS Med. 5, patients: a systematic review. PLoS ONE 6, e17601
6. Swaminathan, S. & Rekha, B. Pediatric tuberculosis: e152 (2008). (2011).
global overview and challenges. Clin. Infect. Dis. 50, 12. Rehm, J. et al. The association between alcohol use, 17. Vynnycky, E. & Fine, P. E. The natural history of
S184–S194 (2010). alcohol use disorders and tuberculosis (TB). tuberculosis: the implications of age-dependent risks
7. Havlir, D. V., Getahun, H., Sanne, I. & Nunn, P. A systematic review. BMC Public Health 9, 450 of disease and the role of reinfection. Epidemiol.
Opportunities and challenges for HIV care in (2009). Infect. 119, 183–201 (1997).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 19

PRIMER

18. Andrews, J. R. et al. Risk of progression to active 43. Abdallah, A. M. et al. Type VII secretion — 65. Schaible, U. E. et al. Apoptosis facilitates antigen
tuberculosis following reinfection with mycobacteria show the way. Nat. Rev. Microbiol. 5, presentation to T lymphocytes through MHC‑I and
Mycobacterium tuberculosis. Clin. Infect. Dis. 54, 883–891 (2007). CD1 in tuberculosis. Nat. Med. 9, 1039–1046
784–791 (2012). 44. Simeone, R. et al. Phagosomal rupture by (2003).
19. Hoa, N. B. et al. National survey of tuberculosis Mycobacterium tuberculosis results in toxicity and 66. Behar, S. M., Divangahi, M. & Remold, H. G. Evasion
prevalence in Vietnam. Bull. World Health Organ. 88, host cell death. PLoS Pathog. 8, e1002507 (2012). of innate immunity by Mycobacterium tuberculosis:
273–280 (2010). 45. Pai, M. et al. Gamma interferon release assays for is death an exit strategy? Nat. Rev. Microbiol. 8,
20. Dowdy, D. W., Basu, S. & Andrews, J. R. Is passive detection of Mycobacterium tuberculosis infection. 668–674 (2010).
diagnosis enough? The impact of subclinical disease Clin. Microbiol. Rev. 27, 3–20 (2014). 67. Divangahi, M., King, I. L. & Pernet, E. Alveolar
on diagnostic strategies for tuberculosis. Am. This is a comprehensive review of the literature on macrophages and type I IFN in airway homeostasis
J. Respir. Crit. Care Med. 187, 543–551 (2013). IGRAs for LTBI diagnosis. and immunity. Trends Immunol. 36, 307–314
21. Lienhardt, C. et al. Global tuberculosis control: 46. Arend, S. M. et al. Tuberculin skin testing and in vitro (2015).
lessons learnt and future prospects. Nat. Rev. T cell responses to ESAT‑6 and culture filtrate 68. Janssen, W. J. et al. Fas determines differential fates
Microbiol. 10, 407–416 (2012). protein 10 after infection with Mycobacterium of resident and recruited macrophages during
22. Wang, L. et al. Tuberculosis prevalence in China, marinum or M. kansasii. J. Infect. Dis. 186, 1797– resolution of acute lung injury. Am. J. Respir. Crit.
1990–2010; a longitudinal analysis of national 1807 (2002). Care Med. 184, 547–560 (2011).
survey data. Lancet 383, 2057–2064 (2014). 47. Wang, J. et al. Insights on the emergence of 69. Wolf, A. J. et al. Initiation of the adaptive immune
23. World Health Organization. Drug-Resistant TB Mycobacterium tuberculosis from the analysis of response to Mycobacterium tuberculosis depends on
Surveillance and Response. Supplement to Global TB Mycobacterium kansasii. Genome Biol. Evol. 7, antigen production in the local lymph node, not the
Report 2014 (WHO, 2014). 856–870 (2015). lungs. J. Exp. Med. 205, 105–115 (2008).
24. Zhao, Y. et al. National survey of drug-resistant 48. Morrison, J., Pai, M. & Hopewell, P. C. Tuberculosis 70. Samstein, M. et al. Essential yet limited role for
tuberculosis in China. N. Engl. J. Med. 366, 2161– and latent tuberculosis infection in close contacts of CCR2+ inflammatory monocytes during
2170 (2012). people with pulmonary tuberculosis in low-income Mycobacterium tuberculosis-specific T cell priming.
25. Udwadia, Z. F., Amale, R. A., Ajbani, K. K. & and middle-income countries: a systematic review eLife 2, e01086 (2013).
Rodrigues, C. Totally drug-resistant tuberculosis in and meta-analysis. Lancet Infect. Dis. 8, 359–368 71. Chackerian, A. A., Alt, J. M., Perera, T. V.,
India. Clin. Infect. Dis. 54, 579–581 (2012). (2008). Dascher, C. C. & Behar, S. M. Dissemination of
26. Jenkins, H. E. et al. Assessing spatial heterogeneity 49. Cobat, A. et al. Two loci control tuberculin skin test Mycobacterium tuberculosis is influenced by host
of multidrug-resistant tuberculosis in a high-burden reactivity in an area hyperendemic for tuberculosis. factors and precedes the initiation of T‑cell immunity.
country. Eur. Respir. J. 42, 1291–1301 (2013). J. Exp. Med. 206, 2583–2591 (2009). Infect. Immun. 70, 4501–4509 (2002).
27. Zelner, J. L. et al. Identifying hotspots of multidrug 50. Rangaka, M. X. et al. Predictive value of interferon-γ 72. Sonnenberg, P. et al. How soon after infection with
resistant tuberculosis transmission using spatial and release assays for incident active tuberculosis: HIV does the risk of tuberculosis start to increase?
molecular genetic data. J. Infect. Dis. 213, 287–294 a systematic review and meta-analysis. Lancet Infect. A retrospective cohort study in South African gold
(2016). Dis. 12, 45–55 (2012). miners. J. Infect. Dis. 191, 150–158 (2005).
28. Kendall, E. A., Fofana, M. O. & Dowdy, D. W. Burden This systematic review shows the limited predictive 73. Lazar‑Molnar, E. et al. Programmed death‑1 (PD‑1)-
of transmitted multidrug resistance in epidemics of value of all existing LTBI diagnostic tests. deficient mice are extraordinarily sensitive to
tuberculosis: a transmission modelling analysis. 51. Orme, I. M., Robinson, R. T. & Cooper, A. M. The tuberculosis. Proc. Natl Acad. Sci. USA 107, 13402–
Lancet Respir. Med. 3, 963–972 (2015). balance between protective and pathogenic immune 13407 (2010).
29. Dowdy, D. W., Golub, J. E., Chaisson, R. E. & responses in the TB‑infected lung. Nat. Immunol. 16, 74. Barber, D. L., Mayer‑Barber, K. D., Feng, C. G.,
Saraceni, V. Heterogeneity in tuberculosis 57–63 (2015). Sharpe, A. H. & Sher, A. CD4 T cells promote rather
transmission and the role of geographic hotspots in 52. Watford, W. T., Wright, J. R., Hester, C. G., Jiang, H. than control tuberculosis in the absence of
propagating epidemics. Proc. Natl Acad. Sci. USA & Frank, M. M. Surfactant protein A regulates PD‑1‑mediated inhibition. J. Immunol. 186, 1598–
109, 9557–9562 (2012). complement activation. J. Immunol. 167, 6593– 1607 (2011).
This study suggests that high-incidence hotspots 6600 (2001). 75. Lin, P. L. et al. Sterilization of granulomas is common
may have an important role in propagating TB 53. Ferguson, J. S., Voelker, D. R., McCormack, F. X. & in active and latent tuberculosis despite within-host
epidemics. Schlesinger, L. S. Surfactant protein D binds to variability in bacterial killing. Nat. Med. 20, 75–79
30. Firdessa, R. et al. Mycobacterial lineages causing Mycobacterium tuberculosis bacilli and (2014).
pulmonary and extrapulmonary tuberculosis, lipoarabinomannan via carbohydrate–lectin 76. Antonelli, L. R. et al. Intranasal poly‑IC treatment
Ethiopia. Emerg. Infect. Dis. 19, 460–463 (2013). interactions resulting in reduced phagocytosis of the exacerbates tuberculosis in mice through the
31. Reed, M. B. et al. Major Mycobacterium tuberculosis bacteria by macrophages. J. Immunol. 163, 312– pulmonary recruitment of a pathogen-permissive
lineages associate with patient country of origin. 321 (1999). monocyte/macrophage population. J. Clin. Invest.
J. Clin. Microbiol. 47, 1119–1128 (2009). 54. Russell, D. G. Mycobacterium tuberculosis and the 120, 1674–1682 (2010).
32. Bos, K. I. et al. Pre-Columbian mycobacterial intimate discourse of a chronic infection. Immunol. 77. Marakalala, M. J. et al. Inflammatory signaling in
genomes reveal seals as a source of New World Rev. 240, 252–268 (2011). human tuberculosis granulomas is spatially
human tuberculosis. Nature 514, 494–497 (2014). 55. Houben, D. et al. ESX‑1‑mediated translocation to organized. Nat. Med. 22, 531–538 (2016).
33. Comas, I. et al. Out‑of‑Africa migration and Neolithic the cytosol controls virulence of mycobacteria. Cell. 78. Comas, I. et al. Human T cell epitopes of
coexpansion of Mycobacterium tuberculosis with Microbiol. 14, 1287–1298 (2012). Mycobacterium tuberculosis are evolutionarily
modern humans. Nat. Genet. 45, 1176–1182 56. van der Wel, N. et al. M. tuberculosis and M. leprae hyperconserved. Nat. Genet. 42, 498–503 (2010).
(2013). translocate from the phagolysosome to the cytosol in 79. Corbett, E. L., Marston, B., Churchyard, G. J. &
34. Warner, D. F., Koch, A. & Mizrahi, V. Diversity and myeloid cells. Cell 129, 1287–1298 (2007). De Cock, K. M. Tuberculosis in sub-Saharan Africa:
disease pathogenesis in Mycobacterium 57. Simeone, R., Majlessi, L., Enninga, J. & Brosch, R. opportunities, challenges, and change in the era of
tuberculosis. Trends Microbiol. 23, 14–21 (2015). Perspectives on mycobacterial vacuole-to‑cytosol antiretroviral treatment. Lancet 367, 926–937
35. Reed, M. B. et al. A glycolipid of hypervirulent translocation: the importance of cytosolic access. (2006).
tuberculosis strains that inhibits the innate immune Cell. Microbiol. 18, 1070–1077 (2016). 80. Tameris, M. D. et al. Safety and efficacy of MVA85A,
response. Nature 431, 84–87 (2004). 58. Russell, D. G. The ins and outs of the Mycobacterium a new tuberculosis vaccine, in infants previously
36. Gagneux, S. et al. Variable host–pathogen tuberculosis-containing vacuole. Cell. Microbiol. 18, vaccinated with BCG: a randomised, placebo-
compatibility in Mycobacterium tuberculosis. Proc. 1065–1069 (2016). controlled phase 2b trial. Lancet 381, 1021–1028
Natl Acad. Sci. USA 103, 2869–2873 (2006). 59. Manca, C. et al. Virulence of a Mycobacterium (2013).
37. Albanna, A. S. et al. Reduced transmissibility of East tuberculosis clinical isolate in mice is determined by This large trial shows that MVA85A had no
African Indian strains of Mycobacterium failure to induce Th1 type immunity and is associated efficacy against TB or M. tuberculosis infection in
tuberculosis. PLoS ONE 6, e25075 (2011). with induction of IFN-α/β. Proc. Natl Acad. Sci. USA infants.
38. Fenner, L. et al. Mycobacterium tuberculosis 98, 5752–5757 (2001). 81. Abel, L., El‑Baghdadi, J., Bousfiha, A. A.,
transmission in a country with low tuberculosis 60. Mayer‑Barber, K. D. et al. Host-directed therapy of Casanova, J. L. & Schurr, E. Human genetics of
incidence: role of immigration and HIV infection. tuberculosis based on interleukin‑1 and type I tuberculosis: a long and winding road. Phil. Trans.
J. Clin. Microbiol. 50, 388–395 (2012). interferon crosstalk. Nature 511, 99–103 (2014). R. Soc. B 369, 20130428 (2014).
39. Lee, R. S. et al. Population genomics of 61. Stanley, S. A., Johndrow, J. E., Manzanillo, P. & This is a comprehensive review of host genetics of
Mycobacterium tuberculosis in the Inuit. Proc. Natl Cox, J. S. The type I IFN response to infection with TB.
Acad. Sci. USA 112, 13609–13614 (2015). Mycobacterium tuberculosis requires 82. Tobin, D. M. et al. Host genotype-specific therapies
40. Behr, M. A. et al. Comparative genomics of BCG ESX‑1‑mediated secretion and contributes to can optimize the inflammatory response to
vaccines by whole-genome DNA microarray. Science pathogenesis. J. Immunol. 178, 3143–3152 (2007). mycobacterial infections. Cell 148, 434–446 (2012).
284, 1520–1523 (1999). 62. Pandey, A. K. et al. NOD2, RIP2 and IRF5 play a 83. Lalvani, A., Behr, M. A. & Sridhar, S. Innate immunity
This study shows the ongoing evolution of BCG critical role in the type I interferon response to to TB: a druggable balancing act. Cell 148, 389–391
strains since their original derivation. Mycobacterium tuberculosis. PLoS Pathog. 5, (2012).
41. Lewis, K. N. et al. Deletion of RD1 from e1000500 (2009). 84. Thwaites, G. E. et al. Dexamethasone for the
Mycobacterium tuberculosis mimics bacille 63. Manzanillo, P. S., Shiloh, M. U., Portnoy, D. A. & treatment of tuberculous meningitis in adolescents
Calmette–Guerin attenuation. J. Infect. Dis. 187, Cox, J. S. Mycobacterium tuberculosis activates the and adults. N. Engl. J. Med. 351, 1741–1751
117–123 (2003). DNA-dependent cytosolic surveillance pathway within (2004).
42. Mahairas, G. G., Sabo, P. J., Hickey, M. J., macrophages. Cell Host Microbe 11, 469–480 85. Bustamante, J., Boisson‑Dupuis, S., Abel, L. &
Singh, D. C. & Stover, C. K. Molecular analysis of (2012). Casanova, J. L. Mendelian susceptibility to
genetic differences between Mycobacterium bovis 64. Kaufmann, S. H. & Dorhoi, A. Molecular mycobacterial disease: genetic, immunological, and
BCG and virulent M. bovis. J. Bacteriol. 178, 1274– determinants in phagocyte–bacteria interactions. clinical features of inborn errors of IFN-γ immunity.
1282 (1996). Immunity 44, 476–491 (2016). Semin. Immunol. 26, 454–470 (2014).

20 | 2016 | VOLUME 2 www.nature.com/nrdp

 PRIMER

86. Daniels, M. & Hill, A. B. Chemotherapy of pulmonary 107. Boehme, C. C. et al. Feasibility, diagnostic accuracy, for next generation molecular tuberculosis
tuberculosis in young adults; an analysis of the and effectiveness of decentralised use of the Xpert diagnostics? Eur. Respir. J. 42, 544–547 (2013).
combined results of three Medical Research Council MTB/RIF test for diagnosis of tuberculosis and 126. Creswell, J. et al. Results from early programmatic
trials. Br. Med. J. 1, 1162–1168 (1952). multidrug resistance: a multicentre implementation implementation of Xpert MTB/RIF testing in nine
87. Nebenzahl‑Guimaraes, H., Jacobson, K. R., study. Lancet 377, 1495–1505 (2011). countries. BMC Infect. Dis. 14, 2 (2014).
Farhat, M. R. & Murray, M. B. Systematic review of 108. Detjen, A. K. et al. Xpert MTB/RIF assay for the 127. Raizada, N. et al. Feasibility of decentralised
allelic exchange experiments aimed at identifying diagnosis of pulmonary tuberculosis in children: deployment of Xpert MTB/RIF test at lower level of
mutations that confer drug resistance in a systematic review and meta-analysis. Lancet Respir. health system in India. PLoS ONE 9, e89301 (2014).
Mycobacterium tuberculosis. J. Antimicrob. Med. 3, 451–461 (2015). 128. Wells, W. A. et al. Alignment of new tuberculosis drug
Chemother. 69, 331–342 (2014). 109. World Health Organization. Policy update: automated regimens and drug susceptibility testing:
88. Solomon, H. et al. Integration of published real-time nucleic acid amplification technology for a framework for action. Lancet Infect. Dis. 13, 449–
information into a resistance-associated mutation rapid and simultaneous detection of tuberculosis and 458 (2013).
database for Mycobacterium tuberculosis. J. Infect. rifampicin resistance: Xpert MTB/RIF system for the 129. Sweeney, T. E., Braviak, L., Tato, C. M. & Khatri, P.
Dis. 211, S50–S57 (2015). diagnosis of pulmonary and extrapulmonary TB in Genome-wide expression for diagnosis of pulmonary
89. Pankhurst, L. J. et al. Rapid, comprehensive, and adults and children. WHO http://www.stoptb.org/wg/ tuberculosis: a multicohort analysis. Lancet Respir.
affordable mycobacterial diagnosis with whole- gli/assets/documents/WHO%20Policy%20 Med. 4, 213–224 (2016).
genome sequencing: a prospective study. Lancet Statement%20on%20Xpert%20MTB-RIF%20 130. Berry, M. P. et al. An interferon-inducible neutrophil-
Respir. Med. 4, 49–58 (2016). 2013%20pre%20publication%2022102013.pdf driven blood transcriptional signature in human
90. Walker, T. M. et al. Whole-genome sequencing for (2013). tuberculosis. Nature 466, 973–977 (2010).
prediction of Mycobacterium tuberculosis drug 110. Getahun, H., Harrington, M., O’Brien, R. & Nunn, P. 131. Xie, H. et al. Rapid point‑of‑care detection of the
susceptibility and resistance: a retrospective cohort Diagnosis of smear-negative pulmonary tuberculosis tuberculosis pathogen using a BlaC-specific
study. Lancet Infect. Dis. 15, 1193–1202 (2015). in people with HIV infection or AIDS in resource- fluorogenic probe. Nat. Chem. 4, 802–809 (2012).
91. Bradley, P. et al. Rapid antibiotic-resistance constrained settings: informing urgent policy 132. Lessem, E. The tuberculosis diagnostics pipeline.
predictions from genome sequence data for changes. Lancet 369, 2042–2049 (2007). Pipeline Report http://pipelinereport.org/2016/
Staphylococcus aureus and Mycobacterium 111. Peter, J. G. et al. Effect on mortality of point‑of‑care, tb-diagnostics (2016).[Au:OK?]
tuberculosis. Nat. Commun. 6, 10063 (2015). urine-based lipoarabinomannan testing to guide 133. Gardiner, J. L. & Karp, C. L. Transformative tools for
92. Dominguez, J. et al. Clinical implications of molecular tuberculosis treatment initiation in HIV-positive tackling tuberculosis. J. Exp. Med. 212, 1759–1769
drug resistance testing for Mycobacterium hospital inpatients: a pragmatic, parallel-group, (2015).
tuberculosis: a TBNET/RESIST‑TB consensus multicountry, open-label, randomised controlled trial. 134. [No authors listed.] Global routine vaccination
statement. Int. J. Tuberc. Lung Dis. 20, 24–42 Lancet 387, 1187–1197 (2016). coverage, 2014. Wkly Epidemiol. Rec. 90, 617–623
(2016). 112. World Health Organization. The Use of Lateral Flow (2015).
93. Menzies, D., Gardiner, G., Farhat, M., Greenaway, C. Urine Lipoarabinomannan Assay (LF‑LAM) for the 135. Zwerling, A. et al. The BCG World Atlas: a database
& Pai, M. Thinking in three dimensions: a web-based Diagnosis and Screening of Active Tuberculosis in of global BCG vaccination policies and practices.
algorithm to aid the interpretation of tuberculin skin People Living with HIV: Policy Update (WHO, 2015). PLoS Med. 8, e1001012 (2011).
test results. Int. J. Tuberc. Lung Dis. 12, 498–505 113. Swaminathan, S. & Ramachandran, G. Challenges in 136. Mangtani, P. et al. Protection by BCG vaccine against
(2008). childhood tuberculosis. Clin. Pharmacol. Ther. 98, tuberculosis: a systematic review of randomized
94. Farhat, M., Greenaway, C., Pai, M. & Menzies, D. 240–244 (2015). controlled trials. Clin. Infect. Dis. 58, 470–480
False-positive tuberculin skin tests: what is the 114. Raizada, N. et al. Enhancing TB case detection: (2014).
absolute effect of BCG and non-tuberculous experience in offering upfront Xpert MTB/RIF testing 137. Roy, A. et al. Effect of BCG vaccination against
mycobacteria? Int. J. Tuberc. Lung Dis. 10, 1192– to pediatric presumptive TB and DR TB cases for Mycobacterium tuberculosis infection in children:
1204 (2006). early rapid diagnosis of drug sensitive and drug systematic review and meta-analysis. BMJ 349,
95. Pai, M. & Sotgiu, G. Diagnostics for latent resistant TB. PLoS ONE 9, e105346 (2014). g4643 (2014).
tuberculosis infection: incremental, not transformative 115. Sachdeva, K. S. et al. The potential impact of up‑front 138. Trunz, B. B., Fine, P. & Dye, C. Effect of BCG
progress. Eur. Respir. J. 47, 704–706 (2016). drug sensitivity testing on India’s epidemic of multi- vaccination on childhood tuberculous meningitis and
96. Pai, M., Riley, L. W. & Colford, J. M. Jr. Interferon-γ drug resistant tuberculosis. PLoS ONE 10, miliary tuberculosis worldwide: a meta-analysis and
assays in the immunodiagnosis of tuberculosis: e0131438 (2015). assessment of cost-effectiveness. Lancet 367, 1173–
a systematic review. Lancet Infect. Dis. 4, 761–776 116. Sachdeva, K. S. et al. Use of Xpert MTB/RIF in 1180 (2006).
(2004). decentralized public health settings and its effect on 139. Barreto, M. L. et al. Evidence of an effect of BCG
97. Sorensen, A. L., Nagai, S., Houen, G., Andersen, P. & pulmonary TB and DR‑TB case finding in India. PLoS revaccination on incidence of tuberculosis in school-
Andersen, A. B. Purification and characterization of a ONE 10, e0126065 (2015). aged children in Brazil: second report of the BCG-
low-molecular-mass T‑cell antigen secreted by 117. UNITAID. Tuberculosis: Diagnostics Technology and REVAC cluster-randomised trial. Vaccine 29, 4875–
Mycobacterium tuberculosis. Infect. Immun. 63, Market Landscape 4th edn (WHO, 2015). 4877 (2011).
1710–1717 (1995). This is a comprehensive landscape assessment of 140. [No authors listed.] Fifteen year follow up of trial of
98. Andersen, P., Munk, M. E., Pollock, J. M. & TB diagnostic technologies. BCG vaccines in south India for tuberculosis
Doherty, T. M. Specific immune-based diagnosis of 118. Theron, G. et al. Feasibility, accuracy, and clinical prevention. Tuberculosis Research Centre (ICMR),
tuberculosis. Lancet 356, 1099–1104 (2000). effect of point‑of‑care Xpert MTB/RIF testing for Chennai. Indian J. Med. Res. 110, 56–69 (1999).
99. Sester, M. et al. Interferon-γ release assays for the tuberculosis in primary-care settings in Africa: 141. Abubakar, I. et al. Systematic review and meta-
diagnosis of active tuberculosis: a systematic review a multicentre, randomised, controlled trial. Lancet analysis of the current evidence on the duration of
and meta-analysis. Eur. Respir. J. 37, 100–111 383, 424–435 (2013). protection by Bacillus Calmette–Guerin vaccination
(2011). 119. Churchyard, G. J. et al. Xpert MTB/RIF versus sputum against tuberculosis. Health Technol. Assess. 17,
100. Pande, T., Pai, M., Khan, F. A. & Denkinger, C. M. Use microscopy as the initial diagnostic test for 1–372 (2013).
of chest radiography in the 22 highest tuberculosis tuberculosis: a cluster-randomised trial embedded in This is a comprehensive overview of studies on the
burden countries. Eur. Respir. J. 46, 1816–1819 South African roll-out of Xpert MTB/RIF. Lancet Glob. protection offered by BCG vaccination.
(2015). Health 3, e450–e457 (2015). 142. Ellis, R. D. et al. Innovative clinical trial designs to
101. Esmail, H. et al. Characterization of progressive HIV- 120. World Health Organization. The use of loop-mediated rationalize TB vaccine development. Tuberculosis
associated tuberculosis using 2‑deoxy‑2-[18F]fluoro- isothermal amplification (TB‑LAMP) for the diagnosis (Edinb.) 95, 352–357 (2015).
d‑glucose positron emission and computed of pulmonary tuberculosis: policy guidance. WHO 143. AERAS. TB vaccine research and development:
tomography. Nat. Med. http://dx.doi.org/10.1038/ http://apps.who.int/iris/bitstre a business case for investment. AERAS http://www.
nm.4161 (2016). am/10665/249154/1/9789241511186-eng.pdf aeras.org/pdf/TB_RD_Business_Case_Draft_3.pdf
102. Kik, S. V., Denkinger, C. M., Chedore, P. & Pai, M. (2016). (2014).
Replacing smear microscopy for the diagnosis of 121. World Health Organization. The use of molecular line 144. Knight, G. M. et al. Impact and cost-effectiveness of
tuberculosis: what is the market potential? Eur. probe assays for the detection of resistance to new tuberculosis vaccines in low- and middle-income
Respir. J. 43, 1793–1796 (2014). second-line anti-tuberculosis drugs: policy guidance. countries. Proc. Natl Acad. Sci. USA 111, 15520–
103. World Health Organization. WHO monitoring of Xpert WHO http://www.who.int/tb/areas-of-work/laboratory/ 15525 (2014).
MTB/RIF roll-out. WHO http://www.who.int/tb/areas- WHOPolicyStatementSLLPA. 145. World Health Organization. Guidelines on the
of-work/laboratory/mtb-rif-rollout/en/ (2015). pdf?ua%2520=%25201 (2016). Management of Latent Tuberculosis Infection (WHO,
104. Albert, H. et al. Development, roll-out, and impact of 122. World Health Organization. Molecular line probe 2014).
Xpert MTB/RIF for tuberculosis: what lessons have assays for rapid screening of patients at risk of 146. Landry, J. & Menzies, D. Preventive chemotherapy.
we learnt, and how can we do better? Eur. Respir. J. multidrug-resistant tuberculosis (MDR‑TB): policy Where has it got us? Where to go next? Int. J. Tuberc.
48, 516–525 (2016). statement. WHO http://www.who.int/tb/features_ Lung Dis. 12, 1352–1364 (2008).
This is a comprehensive review on the archive/policy_statement.pdf (2008). 147. World Health Organization. Guidelines for Treatment
development, roll-out and impact of the Xpert 123. Pai, M. & Schito, M. Tuberculosis diagnostics in of Tuberculosis 4th edn (WHO, 2010).
MTB/RIF assay and the lessons learnt from the 2015: landscape, priorities, needs, and prospects. 148. Nahid, P. et al. Official American Thoracic Society/
experience. J. Infect. Dis. 211, S21–S28 (2015). Centers for Disease Control and Prevention/Infectious
105. Steingart, K. et al. Xpert® MTB/RIF assay for 124. Denkinger, C. M., Kik, S. V. & Pai, M. Robust, Diseases Society of America clinical practice
pulmonary tuberculosis and rifampicin resistance in reliable and resilient: designing molecular guidelines: treatment of drug-susceptible
adults. Cochrane Database Syst. Rev. 1, CD009593 tuberculosis tests for microscopy centers in tuberculosis. Clin. Infect. Dis. 63, e147–e195
(2014). developing countries. Expert Rev. Mol. Diagn. 13, (2016).
106. Boehme, C. C. et al. Rapid molecular detection of 763–767 (2013). These are the most recent TB treatment
tuberculosis and rifampin resistance. N. Engl. J. Med. 125. Denkinger, C. M., Nicolau, I., Ramsay, A., Chedore, P. guidelines, which are focused on drug-sensitive
363, 1005–1015 (2010). & Pai, M. Are peripheral microscopy centres ready TB.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 21

PRIMER

149. Saukkonen, J. J. et al. An official ATS statement: a systematic review and meta-analysis. PLoS Med. 9, 198. Bauer, M., Leavens, A. & Schwartzman, K.
hepatotoxicity of antituberculosis therapy. Am. e1001270 (2012). A systematic review and meta-analysis of the impact
J. Respir. Crit. Care Med. 174, 935–952 (2006). 176. Temprano Anrs Study Group. A trial of early of tuberculosis on health-related quality of life. Qual.
150. Volmink, J. & Garner, P. Directly observed therapy for antiretrovirals and isoniazid preventive therapy in Life Res. 22, 2213–2235 (2013).
treating tuberculosis. Cochrane Database Syst. Rev. Africa. N. Engl. J. Med. 373, 808–822 (2015). 199. Singla, N., Singla, R., Fernandes, S. & Behera, D.
4, CD003343 (2007). 177. Samandari, T. et al. 6‑Month versus 36‑month Post treatment sequelae of multi-drug resistant
151. O’Donnell, M. R. et al. Re‑inventing adherence: isoniazid preventive treatment for tuberculosis in tuberculosis patients. Indian J. Tuberc. 56, 206–212
toward a patient-centered model of care for drug- adults with HIV infection in Botswana: a randomised, (2009).
resistant tuberculosis and HIV. Int. J. Tuberc. Lung double-blind, placebo-controlled trial. Lancet 377, 200. Dheda, K. et al. Early treatment outcomes and HIV
Dis. 20, 430–434 (2016). 1588–1598 (2011). status of patients with extensively drug-resistant
152. Dheda, K., Barry, C. E. 3rd & Maartens, G. 178. Lawn, S. D., Myer, L., Edwards, D., Bekker, L. G. & tuberculosis in South Africa: a retrospective cohort
Tuberculosis. Lancet 387, 1211–1126 (2016). Wood, R. Short-term and long-term risk of study. Lancet 375, 1798–1807 (2010).
153. Dheda, K. et al. Global control of tuberculosis: from tuberculosis associated with CD4 cell recovery during 201. TB CARE I. International Standards for Tuberculosis
extensively drug-resistant to untreatable antiretroviral therapy in South Africa. AIDS 23, Care. WHO http://www.who.int/tb/publications/
tuberculosis. Lancet Respir. Med. 2, 321–338 1717–1725 (2009). ISTC_3rdEd.pdf (2014).
(2014). 179. Gupta, R. K. et al. Impact of human This publication describes the International
154. Fox, G. J. et al. Surgery as an adjunctive treatment immunodeficiency virus and CD4 count on Standards for TB Care.
for multidrug-resistant tuberculosis: an individual tuberculosis diagnosis: analysis of city-wide data 202. Das, J. et al. Use of standardised patients to assess
patient data metaanalysis. Clin. Infect. Dis. 62, 887– from Cape Town, South Africa. Int. J. Tuberc. Lung quality of tuberculosis care: a pilot, cross-sectional
895 (2016). Dis. 17, 1014–1022 (2013). study. Lancet Infect. Dis. 15, 1305–1313 (2015).
155. Calligaro, G. L., Moodley, L., Symons, G. & Dheda, K. 180. Lawn, S. D. et al. Reducing deaths from tuberculosis 203. Satyanarayana, S. et al. Quality of tuberculosis care
The medical and surgical treatment of drug-resistant in antiretroviral treatment programmes in sub- in India: a systematic review. Int. J. Tuberc. Lung Dis.
tuberculosis. J. Thorac Dis. 6, 186–195 (2014). Saharan Africa. AIDS 26, 2121–2133 (2012). 19, 751–763 (2015).
156. World Health Organization. The shorter MDR‑TB 181. Getahun, H. et al. Development of a standardized 204. McDowell, A. & Pai, M. Treatment as diagnosis and
regimen. WHO http://www.who.int/tb/Short_MDR_ screening rule for tuberculosis in people living with diagnosis as treatment: empirical management of
regimen_factsheet.pdf (2016). HIV in resource-constrained settings: individual presumptive tuberculosis in India. Int. J. Tuberc. Lung
These are the new guidelines from the WHO on participant data meta-analysis of observational Dis. 20, 536–543 (2016).
the shorter MDR‑TB regimen. studies. PLoS Med. 8, e1000391 (2011). 205. Satyanarayana, S. et al. Use of standardised patients
157. Pietersen, E. et al. Long-term outcomes of patients 182. World Health Organization. Guidelines for intensified to assess antibiotic dispensing for tuberculosis by
with extensively drug-resistant tuberculosis in South tuberculosis case-finding and isoniazid preventive pharmacies in urban India: a cross-sectional study.
Africa: a cohort study. Lancet 383, 1230–1239 therapy for people living with HIV in resource- Lancet Infect. Dis. http://dx.doi.org/10.1016/S1473-
(2014). constrained settings. WHO http://whqlibdoc.who.int/ 3099(16)30215-8 (2016).
158. Udwadia, Z. F. MDR, XDR, TDR tuberculosis: ominous publications/2011/9789241500708_eng.pdf (2010). 206. Wells, W. A., Uplekar, M. & Pai, M. Achieving
progression. Thorax 67, 286–288 (2012). 183. Getahun, H., Chaisson, R. E. & Raviglione, M. Latent systemic and scalable private sector engagement in
159. Alsultan, A. & Peloquin, C. A. Therapeutic drug Mycobacterium tuberculosis infection. N. Engl. tuberculosis care and prevention in Asia. PLoS Med.
monitoring in the treatment of tuberculosis: J. Med. 373, 1179–1180 (2015). 12, e1001842 (2015).
an update. Drugs 74, 839–854 (2014). 184. World Health Organization. Consolidated Guidelines This paper reviews recent experiences in
160. Jindani, A. et al. High-dose rifapentine with on the Use of Antiretroviral Drugs for Treating and engaging the private sector for TB care and
moxifloxacin for pulmonary tuberculosis. N. Engl. Preventive HIV Infection: Recommendations of a control.
J. Med. 371, 1599–1608 (2014). Public Health Approach (WHO, 2016). 207. Dowdy, D. W., Azman, A. S., Kendall, E. A. &
161. Dorman, S. E. et al. Substitution of moxifloxacin for 185. Denkinger, C. M. et al. Xpert MTB/RIF assay for the Mathema, B. Transforming the fight against
isoniazid during intensive phase treatment of diagnosis of extrapulmonary tuberculosis: tuberculosis: targeting catalysts of transmission. Clin.
pulmonary tuberculosis. Am. J. Respir. Crit. Care a systematic review and meta-analysis. Eur. Respir. J. Infect. Dis. 59, 1123–1129 (2014).
Med. 180, 273–280 (2009). 44, 435–446 (2014). 208. Frieden, T. R., Fujiwara, P. I., Washko, R. M. &
162. World Health Organization. Guidelines for the 186. Havlir, D. V. et al. Timing of antiretroviral therapy for Hamburg, M. A. Tuberculosis in New York City —
Programmatic Management of Drug-Resistant HIV‑1 infection and tuberculosis. N. Engl. J. Med. turning the tide. N. Engl. J. Med. 333, 229–233
Tuberculosis — 2011 Update (WHO, 2011). 365, 1482–1491 (2011). (1995).
163. Gillespie, S. H. et al. Four-month moxifloxacin-based 187. Blanc, F. X. et al. Earlier versus later start of 209. Suarez, P. G. et al. The dynamics of tuberculosis in
regimens for drug-sensitive tuberculosis. N. Engl. antiretroviral therapy in HIV-infected adults with response to 10 years of intensive control effort in
J. Med. 371, 1577–1587 (2014). tuberculosis. N. Engl. J. Med. 365, 1471–1481 Peru. J. Infect. Dis. 184, 473–478 (2001).
164. Merle, C. S. et al. A four-month gatifloxacin- (2011). 210. Comstock, G. W. & Philip, R. N. Decline of the
containing regimen for treating tuberculosis. N. Engl. 188. Abdool Karim, S. S. et al. Integration of antiretroviral tuberculosis epidemic in Alaska. Public Health Rep.
J. Med. 371, 1588–1598 (2014). therapy with tuberculosis treatment. N. Engl. J. Med. 76, 19–24 (1961).
165. Lee, M. et al. Linezolid for treatment of chronic 365, 1492–1501 (2011). 211. World Health Organization. The End TB strategy.
extensively drug-resistant tuberculosis. N. Engl. 189. Manosuthi, W. et al. Time to initiate antiretroviral Global strategy and targets for tuberculosis
J. Med. 367, 1508–1518 (2012). therapy between 4 weeks and 12 weeks of prevention, care and control after 2015. WHO http://
166. Tiberi, S. et al. Ertapenem in the treatment of tuberculosis treatment in HIV-infected patients: www.who.int/tb/post2015_TBstrategy.pdf?ua%20
multidrug-resistant tuberculosis: first clinical results from the TIME study. J. Acquir. Immune Defic. =%201 (2015).
experience. Eur. Respir. J. 47, 333–336 (2016). Syndr. 60, 377–383 (2012). 212. Uplekar, M. et al. WHO’s new End TB strategy.
167. Cox, E. & Laessig, K. FDA approval of bedaquiline 190. Mfinanga, S. G. et al. Early versus delayed initiation Lancet 385, 1799–1801 (2015).
— the benefit–risk balance for drug-resistant of highly active antiretroviral therapy for HIV-positive This paper describes the new End TB Strategy by
tuberculosis. N. Engl. J. Med. 371, 689–691 adults with newly diagnosed pulmonary tuberculosis the WHO.
(2014). (TB‑HAART): a prospective, international, 213. Lienhardt, C. et al. Translational research for
168. Zumla, A. et al. Tuberculosis treatment and randomised, placebo-controlled trial. Lancet Infect. tuberculosis elimination: priorities, challenges, and
management — an update on treatment regimens, Dis. 14, 563–571 (2014). actions. PLoS Med. 13, e1001965 (2016).
trials, new drugs, and adjunct therapies. Lancet 191. Uthman, O. A. et al. Optimal timing of antiretroviral This paper reviews the biggest research priorities
Respir. Med. 3, 220–234 (2015). therapy initiation for HIV-infected adults with newly for TB.
169. Andries, K. et al. A diarylquinoline drug active on the diagnosed pulmonary tuberculosis: a systematic 214. Zak, D. E. et al. A blood RNA signature for
ATP synthase of Mycobacterium tuberculosis. review and meta-analysis. Ann. Intern. Med. 163, tuberculosis disease risk: a prospective cohort study.
Science 307, 223–227 (2005). 32–39 (2015). Lancet 387, 2312–2322 (2016).
170. Matsumoto, M. et al. OPC‑67683, a nitro-dihydro- 192. Yan, S. et al. Early versus delayed antiretroviral 215. Hawn, T. R. et al. Tuberculosis vaccines and
imidazooxazole derivative with promising action therapy for HIV and tuberculosis co‑infected patients: prevention of infection. Microbiol. Mol. Biol. Rev. 78,
against tuberculosis in vitro and in mice. PLoS Med. a systematic review and meta-analysis of randomized 650–671 (2014).
3, e466 (2006). controlled trials. PLoS ONE 10, e0127645 (2015). 216. Fletcher, H. A. et al. T‑Cell activation is an immune
171. Brigden, G. et al. Principles for designing future 193. Torok, M. E. et al. Timing of initiation of antiretroviral correlate of risk in BCG vaccinated infants. Nat.
regimens for multidrug-resistant tuberculosis. Bull. therapy in human immunodeficiency virus (HIV) — Commun. 7, 11290 (2016).
World Health Organ. 92, 68–74 (2014). associated tuberculous meningitis. Clin. Infect. Dis. 217. World Health Organization. Systematic Screening for
172. Stop TB Partnership’s Working Group on New Drugs. 52, 1374–1383 (2011). Active Tuberculosis. Principles and Recommendations
Drug pipeline. New TB Drugs http://www.newtbdrugs. 194. Dodd, P. J., Gardiner, E., Coghlan, R. & Seddon, J. A. (WHO, 2013).
org/pipeline.php (2016). Burden of childhood tuberculosis in 22 high-burden 218. Steingart, K. R. et al. Fluorescence versus
This is a regularly updated website resource on countries: a mathematical modelling study. Lancet conventional sputum smear microscopy for
the new TB drug pipeline. Glob. Health 2, e453–e459 (2014). tuberculosis: a systematic review. Lancet Infect. Dis.
173. IFPMA. TB Drug Accelerator Program. IFPMA http:// 195. Dodd, P. J., Sismanidis, C. & Seddon, J. A. Global 6, 570–581 (2006).
partnerships.ifpma.org/partnership/tb-drug- burden of drug-resistant tuberculosis in children: 219. Cruciani, M. et al. Meta-analysis of BACTEC MGIT
accelerator-program (2012). a mathematical modelling study. Lancet Infect. Dis. 960 and BACTEC 460 TB, with or without solid
174. Getahun, H., Gunneberg, C., Granich, R. & Nunn, P. 16, 1193–1201 (2016). media, for detection of mycobacteria. J. Clin.
HIV infection-associated tuberculosis: 196. Perez‑Velez, C. M. & Marais, B. J. Tuberculosis in Microbiol. 42, 2321–2325 (2004).
the epidemiology and the response. Clin. Infect. Dis. children. N. Engl. J. Med. 367, 348–361 (2012). 220. Ling, D. I., Zwerling, A. & Pai, M. GenoType MTBDR
50, S201–S207 (2010). 197. World Health Organization. Guidance for National assays for the diagnosis of multidrug-resistant
175. Suthar, A. B. et al. Antiretroviral therapy for Tuberculosis Programmes on the Management of tuberculosis: a meta-analysis. Eur. Respir. J. 32,
prevention of tuberculosis in adults with HIV: Tuberculosis in Children 2nd edn (WHO, 2014). 1165–1174 (2008).

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Acknowledgements (AusAID), the Global Health Innovative Technology (GHIT) (FIND) and TB Alliance. [Au:OK?] M.A.B. receives royalties
M.P. is a recipient of a Canada Research Chair award from the Fund, the US FDA and the US National Institute of Allergy and for an antigen used in one of the interferon-γ release assays
Canadian Institutes of Health Research (CIHR), and acknowl- Infectious Diseases (NIAID) of the NIH. S.S. is a full-time (IGRA) tests (QuantiFERON) but did not contribute to this
edges grant support from the CIHR and the Bill and Melinda employee of the Indian Council of Medical Research (ICMR), a section of the document. He serves on the Vaccine Advisory
Gates Foundation. M.A.B. acknowledges grant support from Government of India agency. M.S. is a full-time employee of Committee for Aeras. K.D. has obtained speaker fees at
the CIHR, the Public Health Agency of Canada and the TB Alliance, which has received current or past grant support industry-sponsored symposia and grants from FIND, eNose
US National Institutes of Health (NIH). D.D. acknowledges from AusAID, the Bill and Melinda Gates Foundation, DFID, Company, Statens Serum Institut and bioMeriux, and grants
grant support from the NIH, CIHR, US Centers for Disease DGIS, the European Commission (EC), GHIT, the Indonesia and personal fees from ALERE, Oxford Immunotec, Cellestis
Control and Prevention, US Agency for International Health Fund, NIAID/NIH, UNITAID, the US Agency for (now Qiagen), Cepheid, Antrum Biotec and Hain Lifescience.
Development and the Bill and Melinda Gates Foundation. K.D. International Development (USAID) and the FDA. D.M. In addition, K.D. has a patent “Characterisation of novel
acknowledges grant support from the European Developing acknowledges grant support from CIHR. tuberculosis specific urinary biomarkers” pending, a patent
Clinical Trials Partnership, the South African Medical Research “A smart mask for monitoring cough-related infectious dis-
Council and the South African National Research Foundation. Author contributions eases” pending and a patent “Device for diagnosing EPTB”
M.D. is supported by the CIHR Foundation Grant Introduction (M.P.); Epidemiology (D.D.); Mechanisms/patho- issued. C.C.B. is employed by FIND, a not-for-profit organiza-
(FDN‑143273) as well as a CIHR New Investigator Award. physiology (M.A.B. and M.D.); Diagnosis, screening and pre- tion driving the development and delivery of new diagnostics
C.C.B. acknowledges grant support for Foundation for vention (M.P., C.C.B., M.A.B. and A.G.); Management (D.M., for tuberculosis (TB). FIND has contractual relationships with
Innovative New Diagnostics (FIND) from several governments M.S., K.D., H.G. and S.S.); Quality of life (M.P., K.D. and more than 20 in vitro diagnostic companies, several of which
(Australia, the Netherlands, the United Kingdom and M.R.), Outlook (M.R.); Overview of Primer (M.P.). M.P. and are mentioned in the article. M.R. declares no financial con-
Switzerland), the Bill and Melinda Gates Foundation and the M.A.B. contributed equally to this work. flicts. He serves as observer on the Board of Directors of the
NIH. A.G. is a full-time employee of Aeras, which has received TB Alliance, and as External Clinical Research Expert for the
current or past grant support from the Bill and Melinda Gates Competing interests [Au:OK?] US National Institute of Allergy and Infectious
Foundation, the UK Department for International M.P. declares no financial conflicts. He serves as a consultant Diseases (NIAID) HIV/AIDS Clinical Trials Network Strategic
Development (DFID), the Dutch Ministry of Foreign Affairs for the Bill and Melinda Gates Foundation, and on advisory Working Group (SWG), NIH. [Au:OK?] All other authors
(DGIS), the Australian Agency for International Development committees of Foundation for Innovative New Diagnostics declare no competing interests.

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ToC blurb

000 Tuberculosis
Madhukar Pai, Marcel A. Behr, David Dowdy,
Keertan Dheda, Maziar Divangahi, Catharina
C. Boehme, Ann Ginsberg, Soumya Swaminathan,
Melvin Spigelman, Haileyesus Getahun, Dick Menzies
and Mario Raviglione
Tuberculosis (TB) is an airborne infectious disease with
still high morbidity and mortality rates, especially in
low-income countries. Advances in diagnosis and
treatment have been made, but new vaccines and
drugs are needed to achieve the goal of the End TB
Strategy by 2035.

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