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INVITED REVIEW SERIES:
TUBERCULOSIS: CURRENT STATE OF KNOWLEDGE
SERIES EDITORS: CHI CHIU LEUNG, CHRISTOPH LANGE AND YING ZHANG
Diagnosis and treatment of latent infection with
Mycobacterium tuberculosis
CYNTHIA BIN-ENG CHEE,1* MARTINA SESTER,2* WENHONG ZHANG4 AND CHRISTOPH LANGE3
1
TB Control Unit, Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore, 2Department of
Transplant and Infection Immunology, Saarland University, Homburg, 3Clinical Infectious Diseases, Tuberculosis Center,
Research Center Borstel, Germany, and 4Department of Infectious Diseases, Fudan University, China
ABSTRACT
In clinical practice, latent infection with Mycoba-
cterium tuberculosis is defined by the presence of
an M. tuberculosis-specific immune response in the
absence of active tuberculosis. Targeted testing of
individuals from risk groups with the tuberculin skin
test or an interferon-g release assay is currently the
best method to identify those with the highest risk
for progression to tuberculosis. Positive predictive
values of the immunodiagnostic tests are substantially
influenced by the type of test, the age of the person who
The Authors: Cynthia B.-E. Chee, MBBS, FRCP, is senior con-
sultant respiratory physician at the Tuberculosis Control Unit and
Department of Respiratory and Critical Care Medicine, Tan Tock
Seng Hospital, Singapore. Her research interests are clinical and
public health aspects of TB. Martina Sester, PhD, is a Professor of
Transplant and Infection Immunology at Saarland University,
Germany, and her research interests focus on the characteriza-
tion of cellular immune responses for the control of clinically
relevant pathogens. Wenhong Zhang, MD, PhD, is a Professor of
Medicine at Fudan University, China. He is the director of the
Department of Infectious Diseases. His research interests include
diagnosis and treatment of infectious diseases, especially TB.
Christoph Lange, Dr. med. Dipl.-Biol, FIDSA, is a Professor of
Medicine at the University of Lübeck, Germany. At the Research
Center Borstel, Germany, he is the principal attending physician
of the Medical Clinic and the Head of the Division of Clinical
Infectious Diseases. His research interests include topics of the
prevention, diagnosis and treatment of TB.
Correspondence: Christoph Lange, Clinical Infectious Dis-
eases, Research Center Borstel, 23845 Borstel, Germany. Email:
clange@fz-borstel.de
Conflict of Interest Statement: MS and CL have received kits
free of charge from Cellestis and Oxford Immunotec to study the
performance of interferon-g release assay responses in immune-
compromised patients. CL has conducted investigator-initiated
clinical trials, where QuantiFERON-TB Gold In-Tube and
T-SPOT.TB test kits were provided by the manufacturers free of
charge. MS has a patent application entitled ‘In vitro process for
the quick determination of a patient’s status relating to infection
with Mycobacterium tuberculosis’ (international patent number
WO2011113953/A1).
*Contributed equally.
Received 29 September 2012; accepted 12 October 2012
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
is tested, the prevalence of tuberculosis in the society
and the risk group to which the person belongs. As a
general rule, testing should only be offered when pre-
ventive chemotherapy will be accepted in the case of a
positive test result. Preventive chemotherapy can effec-
tively protect individuals at risk from the development
of tuberculosis, although at least 3 months of combina-
tion therapy or up to 9 months of monotherapy are
required, and overall acceptance rate is low. Improve-
ments of the current generation of immunodiagnostic
tests could substantially lower the number of indivi-
duals that need to be treated to prevent a case of tuber-
culosis. If shorter treatment regimens were equally
effective than those currently recommended, accept-
ance of preventive chemotherapy could be much
improved.
Key words: interferon-g release assay, latent infection with
Mycobacterium tuberculosis, prevention, tuberculin skin test,
tuberculosis.
Abbreviations: CDC, US Centre for Disease Control and Pre-
vention; CI, confidence interval; HIV, human immunodeficiency
virus; IFN, interferon; IGRA, interferon-g release assay; INH, iso-
niazid; LTBI, latent infection with Mycobacterium tuberculosis;
PT, preventive therapy; PZA, pyrazinamide; RIF, rifampicin;
RPT, rifapentine; TB, tuberculosis; TST, tuberculin skin test.
INTRODUCTION
Based on information available on the frequency of
positive tuberculin skin test (TST) responses, the
World Health Organization estimates that one-third
of the world’s population is infected with Mycobacte-
rium tuberculosis, the causative microorganism of
tuberculosis (TB).1 However, only a small minority of
individuals with latent infection with M. tuberculosis
(LTBI), by definition diagnosed on the basis of a
positive TST or an interferon-g release assay (IGRA)
result, develops TB in the future.2,3 It is unclear how
well immunological tests, such as the TST or IGRA,
Respirology (2013) 18, 205–216
doi: 10.1111/resp.12002
206
identify individuals that are truly infected with
M. tuberculosis.4 Nevertheless, these tests are cur-
rently the best available diagnostic methods for the
routine risk evaluation of future TB development in
clinical practice.
Identification of individuals with a positive TST or
IGRA result from risk groups for the future develop-
ment of TB and preventive chemotherapy are efficient
measures for TB prevention.
This review describes the concept and immunopa-
thology of LTBI, current methods for the diagnosis
and treatment for the prevention of TB, and discusses
current areas of controversy and possibilities to
improve prevention of TB.
IMMUNOPATHOLOGY OF LTBI
LTBI is defined by the presence of an M. tuberculosis-
specific immune response in the absence of clinical
and radiological disease. It is, however, unclear
whether such individuals harbour viable M. tubercu-
losis or just maintained the immune response after
eradication of M. tuberculosis. More recently, it has
been proposed that there is a spectrum of latent infec-
tion ranging from those with obvious TB lesions con-
taining live bacilli but without symptoms (‘near-
active’ TB) to those who have eradicated the infection
with virtually no chance of reactivation.6–8
During latent infection, the host immune system is
able to contain the bacilli in a state of non-replicating
persistence. The outcome of M. tuberculosis infection
depends on the interaction between the host immune
system and the bacteria. The bacilli enter the host
lung and survive in alveolar macrophages by arresting
phagosome maturation at an early stage and prevent-
ing its destruction and degradation within macro-
phages.9 Interactions between T cells and infected
macrophages thereafter initiate formation of a pro-
ductive granuloma. Antigens derived from M. tuber-
culosis are processed by antigen-presenting cells.
Subsequently, CD4 T cells are involved, which mature
into predominantly two functionally different phe-
notypes, T helper 1 (Th1) and Th2 cells. The former
principally secrete interleukin 2 and interferon
(IFN)-g, while the latter largely secrete interleukins 4,
5, 6 and 10. Containment of M. tuberculosis in granu-
lomatous lesions is under the control of cell-mediated
protective immunity that is largely mediated by T
lymphocytes and their cytokines.10
Recent advances in global gene expression profiling
provided valuable insights into host defence against
M. tuberculosis infection. Apart from producing
cytokines that activate macrophages and initiate
granuloma formation, T cells also express direct
microbicidal activities via a concerted action of per-
forins and granulysins, and antimicrobial peptides
such as cathelicidin.11,12 The important role of tumour
necrosis factor in controlling LTBI is demonstrated by
the observation that tumour necrosis factor antago-
nists used in the treatment of rheumatoid arthritis
can cause reactivation of active TB.13 This study was
the first showing in humans, rather than animal
models, that a cytokine played a key role in the immu-
Respirology (2013) 18, 205–216
CB-E Chee et al.
nopathogenesis from LTBI to active disease. Recently,
more clinical trials confirmed this new mechanism
for the progression from latency to active TB.14,15
Conventional CD4 and CD8 T cells recognize myco-
bacterial peptides in the context of gene products
of the major histocompatibility class I or class II
molecules.16 In addition, unconventional T cells com-
prising gd T cells and CD1-restricted T cells with spe-
cificity for non-proteinaceous antigens exist.17 A study
in HIV patients suggested that robust immune
responses of Vgamma2Vdelta2+ and CD8+ T effector
cells provide protective immunity to prevent the
development from latent infection to active TB.18
Moreover, increasing evidence is emerging that
memory T cells participate in protective immunity
against TB.19 It has been suggested that memory T
cells can persist in the absence of nominal antigen,
which could play a role in a number of purified
protein derivative-positive individuals that developed
an immune response strong enough to eradicate the
pathogen. The roles of regulatory T cells20 and Th17
in LTBI and active TB are worth commenting. It is
generally assumed that regulatory T cells reduce the
risk of immunopathology by suppressing ongo-
ing immune response after pathogen eradication.
Reduced Th17 responses were associated with the
clinical outcome of M. tuberculosis infection, and
suppression of Th17 responses through downregula-
tion of interleukin 6R expression may be an important
mechanism in the development of active TB.21,22
METHODS FOR THE DIAGNOSIS
OF LTBI
As opposed to active TB, where the diagnosis relies on
the detection of M. tuberculosis bacilli and/or clinical
symptoms, an LTBI is indirectly diagnosed by the
presence of a specific cellular immune response
directed towards mycobacterial antigens in the
absence of clinical disease.4 As such, the presence of a
specific immune response is a good proxy of a prior
or actual encounter with mycobacterial antigens.
However, when used in a clinical setting, a specific
immune response does not provide any direct evi-
dence for viable bacilli4,7 and hence does not repre-
sent a very specific indicator of an increased risk for
progression towards active TB.
Assays for the diagnosis of LTBI comprise the
in vivo TST or more recent developments of ex vivo
methods to detect a specific cellular immune
response based on the induction of cytokines after
stimulation of lymphocytes with mycobacterial anti-
gens.4 Obviously, the specificity of detecting an
immune response resulting from an encounter with
M. tuberculosis critically depends on the use of anti-
gens derived from bacilli of the M. tuberculosis
complex. The sensitivity of an immune-based assay is
determined by the overall percentage of responding
cells and by the general immune status of the tested
individual.
The TST and in vitro assays share common princi-
ples. The current TST has been in use for more than a
century. It is an in vivo assay that elicits a delayed
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
LTBI diagnosis and treatment
type hypersensitivity reaction towards tuberculin,
which represents a crude mixture of proteins
obtained from the sterile supernatant of liquid cul-
tures of M. tuberculosis. The extent of cellular infil-
trates correlates with a skin induration, which is
quantified 48–72 h after intradermal tuberculin
inoculation.4 Although well suited for use in resource
poor settings, a major drawback of the TST is its low
specificity, as a tuberculin-specific skin reaction may
not only originate from a previous encounter with
M. tuberculosis but also from M. bovis bacillus
Calmette–Guérin vaccination or infection with non-
tuberculous mycobacteria. In addition, the TST is
frequently falsely negative, especially in immuno-
compromised patients due to cutaneous anergy.23
Finally, the test requires two visits, and the intrader-
mal application of defined amounts of tuberculin and
correct measurement of induration requires well-
trained personnel to obtain standardized results.
In the recent years, in vitro tests have been devel-
oped, which overcome many of the operational and
conceptual disadvantages of the TST. These tests may
be applied ex vivo directly from whole-blood or iso-
lated lymphocyte fractions. An increase in specificity
is conferred by the use of antigens encoded in the
region of difference 1 (RD-1) genomic region of
M. tuberculosis that is deleted in the M. bovis bacillus
Calmette–Guérin strain and most non-tuberculous
mycobacteria species. These antigens termed early
secretory antigenic target-6 and culture filtrate
protein-10 may be used in vitro to stimulate T cell
activation and cytokine induction in an antigen-
specific manner.24 Typical read-out systems for
cytokine analysis require stimulation times as short
as 6–20 h and include the quantitation of cytokine
concentrations from supernatants using an enzyme-
linked immunosorbent assay, the enumeration of
cytokine-producing cells using an enzyme-linked
immunosorbent spot assay or the quantitation of
cytokine-producing cells using flow cytometric intra-
cellular cytokine staining.4 Although T cells secrete a
variety of mainly Th1 cytokines such as interleukin 2,
IFN-g or tumour necrosis factor-a, the cytokine IFN-g
is most commonly used as read-out. Whole blood
tests relying on IFN-g analysis by enzyme-linked
immunosorbent assay or enzyme-linked immuno-
sorbent spot assay are commercially available as
QuantiFERON-TB Gold In-Tube test (Cellestis, a
Qiagen company, Hilden, Germany) and as
T-SPOT.TB assay (Oxford Immunotec, Abingdon,
UK), respectively, and are commonly referred to as
IGRA. In addition to an increase in specificity, in vitro
assays are faster as compared with skin test and may
be performed together with additional stimulatory
reactions such as negative or positive controls to
internally control for antigen-non-specific reactivity
or general immune function, respectively. Although
an excess of T cell reactivity in the negative control or
a limited reactivity in the positive control is formally
scored as an indeterminate result, these outcomes
are still valuable to estimate the overall response
profile of a given individual in vivo, especially in the
situation of low T cell counts or any other type of
immunodeficiency.23,25
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
207
When formally evaluating the performance of TST
or IGRA, it is important to distinguish between their
potential to detect a specific immune response and
the clinical use of a given test result for assessing the
risk of progression towards active TB. Meta-analyses
on the performance of TST and IGRA to detect an
immune response towards M. tuberculosis in low-risk
controls have shown that the specificity of IGRA is
very high, especially in bacillus Calmette–Guérin-
vaccinated individuals.26 Evaluations of sensitivities
have used various clinical situations where the pres-
ence of a specific immune response is likely, such as
patients with TB, a history of active disease or close
contacts of index cases with active TB.26–28 Those
groups are suboptimal as a gold standard, as T cell
responses may frequently be absent. Nevertheless,
these studies have revealed that IGRA shows better
correlation with surrogate measures for M. tuberculo-
sis exposure and is of similar or even superior sensi-
tivity as compared with TST. Studies on superiority of
IGRA in very young children are more controversial in
outcome, as the percentage of indeterminate results
may be high.4 Nevertheless, a large European multi-
centre study on the comparative analysis of IGRA
and TST indicated a large percentage of IGRA-positive
results among TST-negative children, which indicates
that LTBI is underestimated based on the use of TST
only.29 Thus, IGRA seems superior to detect evidence
for the presence of a specifically immune response
towards M. tuberculosis, although this immune
response does not necessarily correspond to a status
of latent infection with viable bacilli. Instead, a spe-
cific immune response may be present in a wide spec-
trum of clinical states that include individuals with
active TB, non-symptomatic subclinical infections
and, finally, individuals where bacilli may have been
completely eliminated.7,23
The fact that TST- or IGRA-positive individuals may
originate from a diverse spectrum of clinical states
clearly indicates that TST or IGRA cannot by itself be
used to diagnose TB or to assess the potential risk for
the development of TB. According to a recent meta-
analysis, neither TST nor IGRA should be used in the
diagnosis of active TB, as the sensitivity of both assays
is not sufficiently high.30 In addition, analyses of TB
suspects with final diagnoses other than TB showed
that specificity for active TB was also low due to a
considerable extent of non-symptomatic indivi-
duals with detectable immunity (i.e. individuals with
LTBI).30 Recently, studies have accumulated, which
have analysed the negative and positive predictive
values of TST or IGRA to assess potential risk for
development of TB in close contacts of contagious
patients with active TB or in patients at risk for
progression due to immunosuppressive conditions
(Table 1).3,26 Of note, both TST and IGRA have a very
high negative predictive value in immunocompetent
individuals indicating that individuals without evi-
dence of specific immunity are unlikely to progress.26
When assessing positive predictive values for progres-
sion, IGRA seems to be superior over TST in the
setting of contact tracing in low-incidence countries.
Two remarkable studies from single centres in
Germany and the UK demonstrated a progression
Respirology (2013) 18, 205–216
 208

Respirology (2013) 18, 205–216

Table 1 Progression rates towards active tuberculosis in non-treated individuals with positive and negative results in TST or IGRA depending on risk group for
progression and origin of study

Citation Progression rate if Progression rate if Observation period

Risk factor Origin of study Test test is positive† test is negative† (median, months) Comments

Close contacts Diel et al.32 QFT-G-IT 12.9% (19/147) 0% (0/756) 43 —

Germany TST (5 mm) 3.1% (17/555) 0.6% (2/348)
Haldar et al.33 QFT-G-IT 12.5% (14/112) 1.0% (6/601) 24 No TST performed
UK
Immigrant close contacts Kik et al.34 QFT-G-IT 2.8% (5/178) 2.0% (3/149) 22 —
The Netherlands T-SPOT.TB 3.3% (6/181) 1.7% (2/118)
TST (15 mm) 2.7% (5/184) 0.7% (1/138)
HIV infection Aichelburg et al.43 QFT-G-IT 8.1% (3/37) 0% (0/738) 19 No TST performed
Austria
Renal transplantation Kim et al.31 T-SPOT.TB 5.6% (4/71) 0% (0/171) 21 Bias for TST-negative patients,
as those did not receive
South Korea
chemotherapy
Silicosis Leung et al.35 T-SPOT.TB 8.0% (12/151) 1.1% (1/90) 29 —
China TST (5 mm) 5.6% (9/161) 5.0% (4/80)
TNF antagonist therapy Jung et al.36 T-SPOT.TB 2.6% (3/114)‡ 0% (0/71)‡ 38 Bias for TST-negative patients,
‡ ‡ as those did not receive
South Korea TST (10 mm) 8.0% (2/25) 1.8% (3/163)
chemotherapy

†
Information is given for patients who did not receive or ‡ did not receive or complete chemotherapy.
HIV, human immunodeficiency virus; IGRA, interferon-g release assay; QFT-G-IT, QuantiFERON Gold In-Tube; TNF, tumour necrosis factor; TST, tuberculin skin test.

© 2012 The Authors

CB-E Chee et al.

Respirology © 2012 Asian Pacific Society of Respirology

LTBI diagnosis and treatment
rate of 12.9%32 and 12.5%,33 respectively, in adult IGRA
test-positive close contacts of acid-fast bacilli smear-
positive index cases who did not receive preventive
chemotherapy. The corresponding progression rate
for TST-positive individuals was only 3.1%.32 The
progression rates of IGRA in both studies are sub-
stantially higher than in other settings that were
potentially more heterogeneous in underlying risk
conditions or burden of remote infection.34–36 Never-
theless, it is plausible that IGRA is superior to the TST
in predicting progression to TB due to the independ-
ence of the IGRA test result from previous vaccination
with M. bovis bacillus Calmette–Guérin.26 Positive
predictive values of TST and IGRA do not appear to
differ widely in high-prevalence countries presum-
ably due to a higher specificity of TST for M. tubercu-
losis infection in this setting.3
When comparatively analysing results of immune-
based assays in patients with various types of immu-
nodeficiencies, the percentage of IGRA-positive
individuals is in general higher as compared with
TST-positive patients, which is indicative of a higher
sensitivity.23 Among immunocompromised patients,
the percentage of positive IGRA test results in
patients with rheumatoid arthritis,37,38 psoriasis39 or
chronic renal failure40 is higher than in patients with
HIV infection,41,42 yet the progression rate to TB in
patients from these groups is likely lower when
compared with HIV-infected individuals.43 Thus,
despite considerable improvement in detection of
M. tuberculosis-specific immune responses, the pre-
dominant proportion of individuals with positive
tests does not develop active TB. This emphasizes the
need for screening strategies where testing is tar-
geted to individuals with risk factors for TB to finally
increase specificity of risk assessment and to reduce
the extent of overtreatment.
LTBI TREATMENT REGIMENS
Persons deemed to have LTBI and who are at
increased risk for progression to active TB should be
considered candidates for preventive therapy (PT).
The groups with the highest risk are those recently
infected (e.g. close contacts of infectious TB cases,
recent TST converters), HIV-infected individuals and
persons with fibrotic lesions on chest radiograph con-
sistent with old, healed but previously untreated TB.44
Other risk groups include organ transplant recipients
on immunosuppressive treatment45,46 and persons
with silicosis, end-stage renal failure or those on
immunomodulatory therapy.15,47 Targeted testing and
treatment of LTBI in close contacts and other risk
groups are a key TB control and elimination strategy
in many high-income, low-TB prevalence countries.
In contrast, the top priority of TB programmes in
high-TB prevalence countries, of which many are
resource-constrained, should be the prompt detec-
tion and successful treatment of infectious TB cases
(i.e. ‘turning off the tap’ of TB transmission). In such
settings, international authorities recommend that
children under 5 years of age and persons of any age
with HIV infection who are close contacts of an infec-
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
209
tious index patient and who, after careful evaluation,
do not have active TB should be treated for presumed
LTBI with isoniazid (INH).48 The threshold for imple-
mentation of LTBI testing and treatment as a TB
control strategy and the priority groups to be targeted
should be determined by the health authorities of
each country or region according to the local situation
and resources available.
At the individual level, the decision for or against PT
must consider the potential risk and consequences
of developing active TB weighed against the risk of
adverse drug reaction (particularly hepatotoxicity)
and the likelihood of treatment adherence and com-
pletion. It is of utmost importance to exclude active
TB by history, physical examination, chest radiograph
and, if necessary, sputum examination before com-
mencing PT. The patient should be educated regard-
ing symptoms that may suggest hepatotoxicity (such
as nausea, vomiting, abdominal discomfort, unex-
plained fatigue), and to stop the medication and
return for evaluation should such symptoms occur.
Patients should be reviewed monthly for close clinical
monitoring of adverse drug effects and treatment
adherence. Table 2 shows the various recommended
PT regimens, the evidence for which is summarized
later. The interested reader is also referred to two
comprehensive reviews on this topic by Leung et al.,44
and Lobue and Menzies.50 Because these reviews
were published in 2010, new evidence has emerged,
which has influenced recommendations, and these
are included in the present review.
Persons with risk factors other than HIV
infection for progression to TB disease
INH monotherapy
INH, synthesized in 1912, was found to have bacteri-
cidal activity against M. tuberculosis in the 1950s. The
United States Public Health Service conducted a
series of randomized, controlled trials in the 1950s
and 1960s that demonstrated the efficacy of 12
months of daily INH (12INH) in reducing the rate of
active TB among immunocompetent, TST-positive
household contacts,51,52 residents of mental institu-
tions53 and native Alaskans in high-TB prevalence
communities.54 The protective effect of INH persisted
for up to 19 years in the Alaskan study. In the 1970s,
the International Union Against TB conducted a trial
in Eastern Europe evaluating 12, 24 and 52 weeks of
INH PT in 28 000 tuberculin-positive persons with
previously untreated fibrotic lesions on chest radio-
graph. This showed a reduction in development of
culture-positive TB of 21%, 65% and 75% among
those randomized to 12, 24 and 52 weeks of INH,
respectively. Among those who completed and com-
plied with treatment, the reduction in TB rates was
30%, 69% and 93%, respectively.55 Cost-effectiveness
analysis of this trial data indicated that the 24-week
regimen was more cost-effective than the 12- or
52-week regimen. This led most public health pro-
grammes to adopt 6 months of INH (6INH) as the
standard duration for PT.56 Subsequent review of data
from the International Union Against TB and United
Respirology (2013) 18, 205–216
210
Table 2 Recommended LTBI treatment regimens
INH monotherapy
Regimen Drug dosage, dosing schedule
INH for 6 months Daily, self-administered
5 mg/kg up to maximum of
300 mg/day
Twice weekly, DOT (ATS/CDC)
15 mg/kg, up to maximum of
900 mg/dose
INH for 9 months Daily, self-administered
5 mg/kg up to maximum of
300 mg/day
Twice weekly, DOT
15 mg/kg, up to 900 mg/dose
maximum
INH for at least — WHO86
36 months
Alternative regimens to INH monotherapy
Regimen Drug dosage, dosing schedule
RIF for 4 months Daily, self-administered
10 mg/kg, 600 mg/day maximum
RIF for 6 months Daily, self-administered
10 mg/kg, 600 mg/day maximum
RIF + INH for 3 months Daily, self-administered
RIF: 10 mg/kg, maximum 600 mg/day
INH: 5 mg/kg up to maximum of
300 mg/day
RPT + INH for 3 months Once weekly, DOT
(to be administered INH: 15 mg/kg, 900 mg maximum
only under DOT)
RPT: 10.0–14.0 kg: 300 mg
14.1–25.0 kg: 450 mg
25.1–32.0 kg: 600 mg
32.1–49.9 kg: 750 mg
ⱖ50 kg: 900 mg maximum
ART, antiretroviral therapy; ATS, American Thoracic Society; CDC, US Centres for Disease Control and Prevention; DOT, directly
observed treatment; HIV, human immunodeficiency virus; INH, isoniazid; ISTC, International Standards for Tuberculosis Care;
LTBI, latent infection with Mycobacterium tuberculosis; PT, preventive therapy; RIF, rifampicin; RPT, rifapentine; TB, tuberculosis;
WHO, World Health Organization.
Respirology (2013) 18, 205–216
CB-E Chee et al.
Recommending authority and remarks
WHO, ISTC48,96
Children <5 years old and HIV-infected persons of
any age who are household contacts of infectious
TB cases
WHO49
Children, adults and adolescents living with HIV should
receive at least 6 months of INH PT as part of a
comprehensive package of HIV care (strong
recommendation)
NICE, UK66
Equal alternative to 3RIF + INH
Recommended regimen for HIV-infected persons of
any age
ATS/CDC58
Alternative regimen to 9INH
Except for HIV-infected, children or those with fibrotic
lesions on chest radiograph
ATS/CDC
Preferred PT regimen for all risk groups
Adult and adolescents living with HIV in high-TB
prevalence and transmission settings (conditional
recommendation)
Recommending authority and remarks
ATS/CDC
Alternative to 9INH
Contacts of INH-resistant, RIF-susceptible
index cases
UK
Contacts, aged 35 or younger, of INH-resistant,
RIF-susceptible TB cases
UK
Equal alternative to 6INH
Not recommended for HIV-infected persons
CDC80
Equal alternative to self-administered 9INH in persons
ⱖ12 years old
Not recommended for children <2 years, HIV-infected
persons on ART, pregnant women or women
expecting to become pregnant during treatment,
those with LTBI with presumed INH or RIF resistance
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
LTBI diagnosis and treatment
States Public Health Service studies (including the
Alaskan study) by Comstock in 1999 concluded that
the optimal protection from INH appeared to be
obtained by 9–10 months.57 Based on this reanalysis,
the American Thoracic Society and US Centres for
Disease Control and Prevention (CDC) in 2000 recom-
mended 9 months of INH (9INH) as the standard
for LTBI treatment.58 A meta-analysis of 11 trials
involving 73 375 non-HIV-infected persons, however,
showed no significant difference between 6- and
12-month courses of INH in reducing the risk of
developing active TB compared with placebo.59 Ran-
domized, controlled trials on the efficacy of INH PT in
persons with HIV infection and silicosis are discussed
later. The use of INH PT for transplant recipients,
those on immunomodulatory therapy, and those with
medical conditions other than HIV infection and sili-
cosis is extrapolated from evidence from the earlier
studies.
INH hepatotoxicity
Following two fatalities in an outbreak of hepatitis
among TB contacts receiving INH PT in 1970,60 the
United States Public Health Service undertook a
survey of 21 health departments that found a 1% rate
of hepatitis and eight deaths among 13 838 individu-
als who received INH. Hepatotoxicity increased with
older age and daily alcohol consumption.61 A meta-
analysis of six studies involving 38 257 adult patients
treated with INH monotherapy showed a 0.6% inci-
dence of clinical hepatitis (range 0–2.9%).62 Subse-
quent observational studies among 11 141 patients in
US Public Health Clinics that utilized clinical moni-
toring reported INH hepatotoxicity rates of 0.1% with
no fatalities in either study, providing reassurance
as to the safety of INH PT when patients are care-
fully selected and clinically monitored for adverse
effects.63,64
Rifampicin monotherapy and
rifampicin-containing regimens
Concern regarding INH hepatotoxicity and the pro-
longed duration of INH PT resulting in low rates
of patient acceptance and adherence has prompted
the search for shorter and better tolerated regimens.
Rifampicin (RIF) is bactericidal, with good sterilizing
activity against M. tuberculosis. A randomized, con-
trolled trial in Chinese men with silicosis in Hong
Kong compared 3 months of RIF + INH (3RIF + INH)
with 3 months of RIF monotherapy (3RIF), 6INH and
placebo.65 The cumulative percentage of patients with
active pulmonary TB over 5 years among those who
received placebo was significantly higher than among
any of the treatment groups with no significant differ-
ence between the three treatment regimens (placebo
27%, 3RIF + INH: 16%, 6INH 14% and 3RIF 10%). This
study formed the basis for the recommendation of
3RIF + INH for non-HIV-infected persons by the UK
health authorities66 and that of 4 months of RIF (4RIF)
as an alternative to 9INH by the American Thoracic
Society and CDC.58 Meta-analysis of pooled data from
four studies involving 3586 patients showed that com-
pared with 9INH, 4RIF was associated with significant
reduction in risk of non-completion (relative risk 0.53;
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
211
95% confidence interval (CI) 0.44–0.63) and hepato-
toxicity (relative risk 0.12; 95% CI 0.05–0.30). The
authors also calculated that the 4RIF strategy was
cost-effective, resulting in US$213 savings per patient
treated.67 Apart from the Hong Kong study, there are
no other randomized, controlled trials comparing the
efficacy of RIF monotherapy with standard INH PT
regimens in reducing active TB. A multicentre trial
comparing the effectiveness of 4RIF with 9INH is cur-
rently underway and is expected to be completed
in 2016.68 In addition to the Hong Kong study, 3–4
months of RIF + INH was evaluated against standard
therapy (6–12INH) for efficacy in a Spanish non-HIV-
infected cohort and three HIV-infected cohorts. A
meta-analysis of these five studies showed that short-
course RIF + INH was equivalent to standard INH
therapy in terms of efficacy, proportion of severe
side-effects and mortality.69 An observational study
comparing 4RIF + INH with 12INH in two sequential
cohorts with radiographic evidence of previous TB
showed that both regimens had similar rates of treat-
ment completion and adverse effects, both increased
life expectancy compared with no treatment and
4RIF + INH was cost-saving compared with 12INH.70
A randomized, controlled study in Greece comparing
3–4 months of RIF + INH with 9INH in children found
that patients randomized to 9INH were less compli-
ant than those who received RIF + INH. Although
none developed clinical disease during follow up, new
radiographic findings suggestive of possible active
disease were more common in those who received
9INH. Serious adverse effects were not detected.71
Several randomized, controlled studies in the 1990s
showed that 2–3 months of RIF + pyrazinamide (PZA)
was as efficacious as 6–12INH in reducing active TB
in the HIV-infected population.72–75 This led to the
recommendation of 2RIF + PZA in the 2000 Ameri-
can Thoracic Society/CDC statement. The resultant
widespread use of this regimen in the US was unfor-
tunately followed by reports of severe and fatal hepa-
totoxicity among non-HIV-infected persons, leading
the American Thoracic Society and CDC in 2003 to
issue a recommendation against its use.76
Three months of once-weekly, directly
observed rifapentine and INH
Rifapentine (RPT) is a rifamycin with a long half-life
and greater potency against M. tuberculosis than RIF.
A regimen of once-weekly doses of directly observed
RPT + INH for 12 weeks was compared with self-
administered 2RIF + PZA in 399 TST-positive, adult,
largely HIV-negative household contacts in Brazil.
Follow up for more than 2 years showed a TB inci-
dence rate ratio of 2.8 for RPT + INH versus RIF + PZA
(95% CI 0.2–26.8), and hepatotoxicity was 10% in the
RIF + PZA group versus 1% in the RPT + INH group.77
This regimen was evaluated against three other regi-
mens (twice-weekly, directly observed RIF + INH for
12 weeks, self-administered 6INH and INH conti-
nuously for up to 6 years) in 1148 HIV-infected,
TST-positive South African adults who were not on
antiretroviral therapy. No significant difference was
found in the rate of active TB over 4 years (incidence
rates of 1.4–2.0 per 100 person-years). Serious adverse
Respirology (2013) 18, 205–216
212
reactions were more common in the continuous INH
group (18.4 per 100 person-years) than in the other
treatment groups (8.7–15.4 per 100 person-years).78 A
large-scale, multicentre study in the US, Canada,
Brazil and Spain involving 7731 subjects compared
once-weekly, directly observed RPT + INH for 12
weeks (‘combination therapy’) with self-administered
9INH. This predominantly HIV-negative study popu-
lation comprised TST-positive persons of whom 71%
were close contacts and 25% recent TST converters.
Over a follow-up period of 33 months, the cumulative
TB incidence rates were 0.19% and 0.43% among
subjects in the combination therapy group and
INH monotherapy group, respectively. There was less
hepatotoxicity in the combination therapy group
(0.4% vs 2.7%) but more adverse (mostly hypersensi-
tivity) reactions leading to discontinuation of therapy
(4.9% vs 3.7%).79 Based on these three studies, the US
CDC in December 2011 recommended once-weekly,
directly observed RPT + INH for 12 weeks as an
equivalent alternative to self-administered 9INH in
otherwise healthy persons more than 12 years of age
with risk factors for developing active TB.80
PT regimens for HIV-infected persons
HIV infection is the strongest known risk factor for the
development of TB disease. A meta-analysis of seven
randomized, controlled trials that compared INH
with placebo in 4539 subjects showed a risk ratio of
0.40 (95% CI 0.24–0.65) and 0.84 (95% CI 0.54–1.30)
for TST-positive and -negative persons, respectively.81
Shorter, RIF-containing regimens (2RIF + PZA, 3RIF +
INH) were compared with 6–12INH in several rand-
omized, controlled studies. A systematic review of 12
studies that included 8578 participants showed that
LTBI treatment (regardless of regimen, frequency or
duration of treatment) reduced the risk of active TB,
especially in those with positive TST (relative risk 0.38;
95% CI 0.35–0.57) versus TST-negative (relative risk
0.89; 95% CI 0.54–1.24). Compared with INH mono-
therapy, multidrug regimens were much more likely
to require discontinuation due to side-effects.82 A
major concern is the durability of protective effect of
PT in HIV-infected persons in high-TB prevalence set-
tings. It was observed among HIV-positive individuals
in sub-Saharan Africa that the protective effect of
6INH was lost within 6–18 months of its comple-
tion.83,84 A recent study in Botswana, a TB-endemic
setting, that randomized 1995 HIV-positive subjects
to 6INH or 36 months of INH (36INH) showed that
36INH was more effective than 6INH for preventing
TB in those who were TST-positive. antiretroviral
therapy was provided to those with CD4 cell count
<200/mL. TB incidence was reduced by 50% in those
who received 360 days of antiretroviral therapy versus
those who did not receive antiretroviral therapy.
Severe INH-associated hepatotoxicity rates in those
who received 36INH were similar or below that with
shorter courses of INH, with almost all cases occur-
ring during the first 9 months of treatment.85 In
another TB-endemic setting, 12-week courses of
intermittent RPT + INH or RIF + INH, and continuous
INH (for up to 6 years) were not found to be superior
Respirology (2013) 18, 205–216
CB-E Chee et al.
to 6INH in TST-positive, HIV-infected South African
adults (median CD4 cell count 484/mL) who were
not on antiretroviral therapy.78 Based on the Botswana
study, the World Health Organization 2011 guidelines
included a conditional recommendation that adults
and adolescents living with HIV in high-TB preva-
lence and transmission settings should receive at
least 36 months of INH PT.86
Regimens for contacts of drug-resistant TB
To date, there are no published randomized, control-
led trials on PT for persons presumed to be latently
infected with INH-resistant or INH- and RIF-resistant
(i.e. multidrug-resistant (MDR)) strains. Two case
series reported that contacts of INH-resistant cases
who completed 6 months of RIF did not develop
active TB; in one of these studies, contacts who
received INH had the same rate of active TB as those
who did not receive any PT.87,88
A recent systematic review concluded that based
on the available evidence, it is not possible to support
or reject the use of PT for contacts of MDR-TB.89
Currently recommended PT regimens for MDR-TB
contacts are based on expert opinion. The US CDC
recommends at least two drugs (combinations of
PZA, ethambutol and/or fluoroquinolone), to which
the source case’s M. tuberculosis isolate is suscepti-
ble, for 6–12 months.90 However, poor tolerance with
high rates of hepatotoxicity and premature discon-
tinuation has been reported in persons prescribed
with these regimens (all of whom received PZA).91–93
Fluoroquinolone monotherapy has been suggested
as a safer alternative;94 this, however, raises concern
regarding the generation of resistance to this key
second-line anti-TB drug. Some paediatric experts
support the use of high-dose INH and a fluoroqui-
nolone (ideally levofloxacin) for a minimum of 6
months in children younger than 5 years or who are
HIV-infected.95 In view of the lack of evidence for
efficacy and poor tolerability of MDR PT regimens, a
reasonable option would be close observation for at
least 2 years for MDR-TB contacts who are otherwise
healthy and do not have risk factors for rapid disease
progression and dissemination. This approach is rec-
ommended by UK health authorities, World Health
Organization and European CDC.66,96,97
AREAS OF CONTROVERSY AND
FUTURE DIRECTIONS
Immunodiagnosis of LTBI has the primary purpose to
identify individuals with the highest risk among risk
groups for the future development of TB. The key
factors that allow an understanding of the impact of
immunodiagnosis for TB prevention are predictive
values of the diagnostic tests and the efficacy of pre-
ventive chemotherapy. Predictive values of the diag-
nostic tests are dependent upon the prevalence of the
disease and on the pretest probability of the indi-
vidual for the development of TB.
A person with a positive TST or IGRA result follow-
ing recent exposure to a patient with infectious TB has
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
LTBI diagnosis and treatment
a higher risk for the progression to active TB than a
person with a positive test result not belonging to any
risk group. As background frequencies of positive
results in immunodiagnostic tests can be higher than
10% in low-TB incidence countries, it is important to
target immunodiagnostic testing only to risk groups.
In countries of low TB prevalence, the negative pre-
dictive values of the IGRA and the TST are close to
100%, indicating that individuals with a negative
test result in either test have a very low likelihood of
progression to active disease in the years following
testing, even if belonging to a risk group.26 When the
risk is already very low, it cannot be substantially
reduced by preventive chemotherapy.
Recent studies provide convincing information that
IGRA is superior to the TST to identify individuals
at risk for the progression to TB. It is apparent that
without preventive chemotherapy, >85% of close
adult TB contacts with a positive IGRA result do not
develop TB within 2 years when the risk for TB is high-
est.26,32,33 In a recent UK study, 35 adult contacts were
required to be screened to identify one contact devel-
oping TB at 2 years.33 Despite this success, better
characterization of the predictive values of immuno-
diagnostic tests for the future development of TB in
close contacts of patients with contagious TB and in
other patients at risk is needed.
An ideal test for LTBI should have a substantially
improved positive predictive value to justify the indi-
cation for preventive chemotherapy. Based on pro-
mising findings on immunophenotypical changes
in specific immunity in patients with active TB,98,99
improvements in the diagnosis of patients at risk
could be possible when cytokines other than IFN-g
or combinations of different read-outs are being
considered.100 Interleukin 298,99,101–103 and interferon-
gamma induced protein 10 (IP-10)104–106 are among the
cytokines that are being evaluated to optimize immu-
nodiagnostic assays to diagnose TB and to predict TB
development in individuals from risk groups. As this
requires simultaneous analysis of multiple param-
eters, flow cytometry is particularly well suited
to define more complex immunophenotypical or
functional signatures characteristic for indivi-
duals with LTBI to progress to active TB. Other less
hypothesis-driven approaches such as transcriptom-
ics, proteomics or metabolomics could further aid in
the discovery of biomarkers to identify patients at
risk for progression towards active TB, but technical
requirements are not yet suitable for use in a clinical
setting.107–109 Using blood transcriptional profiling, an
IFN-inducible, neutrophil-driven whole-blood tran-
script signature was identified for active TB, which
was also found in a subset of 10–25% of individuals
with LTBI, suggesting that this transcript signature
could potentially identify patients with LTBI with
higher microbiological burden or subclinical dis-
ease.107 Likewise, an analysis of the transcription
profiles of purified protein derivative-stimulated
peripheral blood mononuclear cells identified a com-
bination of IP-10, the cation transport adenosine
triphosphatase 10A and Toll-like receptor 6 gene
expression that discriminated active TB from LTBI
with a sensitivity 71% and a specificity 89%.108
© 2012 The Authors
Respirology © 2012 Asian Pacific Society of Respirology
213
Together, these findings provide further insight as
to the immunological determinants promoting
progression of LTBI to active TB and should be
developed further towards establishing biomarkers
suitable for point-of-care diagnosis of patients at
risk.
Additional efforts should focus on more targeted
screening of patients at risk, an improvement of
acceptance rates for PT and finally patients on shorter
treatment regimens. Even though the duration of pre-
ventive treatment regimens is becoming shorter,79 the
duration of preventive chemotherapy is far too long to
be acceptable, for example, compared with the eradi-
cation for Helicobacter pylori to prevent gastritic
ulcerative disease or gastric carcinoma.110 Although
the efficacy of preventive chemotherapy has been
ascertained to be 90% for 9 months of daily INH
monotherapy,57,59,111,112 69% for 6 months of daily INH
therapy111 and 65% for 3 months of daily combination
therapy with INH and RIF,65,69 acceptance of preven-
tive chemotherapy is as low as 20% in some coun-
tries.113 These areas need to be targeted to increase
public health impact on TB prevention. Resources
could be saved if tests were only offered to individuals
from risk groups willing to accept preventive chemo-
therapy in case of a positive test result—intention to
test is intention to treat.114
CONCLUSIONS
Preventive chemotherapy can be an effective, effica-
cious and efficient intervention to reduce the risk
for the development of TB. Targeted testing for
M. tuberculosis-specific immune responses should
be performed in individuals from groups where posi-
tive test results are related to a substantial increase
in the risk for the progression to TB, such as specifi-
cally in recent contacts in countries of low TB
incidence and HIV-infected individuals, and more
generally in cases where preventive chemotherapy
has an impact on the risk reduction to progress to
TB. Resources could be saved, if candidates for
immunodiagnostic testing were only investigated if
they agree to be treated in the event of a positive test
result.
In patients with psoriasis, rheumatoid arthritis, dia-
betes mellitus and chronic renal failure, and trans-
plant recipients, health-care workers and contacts
of patients with MDR/extensively drug-resistant
TB, the evidence for targeted immunodiagnostic
testing and preventive chemotherapy is less clear. In
children younger than 5 years of age who are house-
hold contacts of infectious index cases, prophylactic
chemotherapy may be warranted without immuno-
diagnosis, as their overall risk for the progression to
TB is very high.
Awareness for and acceptance of preventive
chemotherapy could be raised if the positive predic-
tive value of diagnostic tests could be improved and
future drug regimens allowed for much shorter treat-
ment periods than those currently recommended.
Respirology (2013) 18, 205–216
214
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Respirology © 2012 Asian Pacific Society of Respirology