The Indian Journal of Pediatrics

https://doi.org/10.1007/s12098-019-02861-3

REVIEW ARTICLE

Management of Latent Tuberculosis Infection in Children

from Developing Countries
Agam Jain 1 & Rakesh Lodha 1

Received: 28 September 2018 / Accepted: 10 January 2019

# Dr. K C Chaudhuri Foundation 2019

Abstract
Tuberculosis (TB), once widely prevalent throughout the world, experienced falling incidence rates in early twentieth century in
developed nations, even before the introduction of anti-TB drugs, attributed to improved hygiene and living conditions. Active
TB may develop following fresh infection or activation of latent tuberculosis infection (LTBI). LTBI is a state of persistent
bacterial viability, however, the host stays asymptomatic and there is no evidence of clinically active tuberculosis. Therefore,
treatment of all LTBI is considered as one of the ways to control tuberculosis. Diagnosis of LTBI relies on presence of immune-
reactivity to TB antigen and commonly used tests include tuberculin skin test and interferon gamma release assay (IGRA). At
present there is no diagnostic test that can identify an individual with LTBI who will progress to develop active disease or remain
asymptomatic. Therefore, it is unclear whom to treat. In the current scenario, treatment for LTBI is restricted to high risk groups
which include under-5 y contacts of adults with pulmonary TB. Various regimens for treatment of LTBI are evolving and consist
of isoniazid (INH) alone for 6–9 mo or combination of INH and rifampicin for 3–4 mo or once a week combination of rifapentin
and INH for 3 mo. There is a need for research to identify LTBI, risk factors for progression of LTBI to active disease and a shorter
regimen for treatment.

Keywords Interferon gamma assay . INH prophylaxis . IPT . Rifapentin . Tuberculin skin test

Introduction
Tuberculosis (TB) in humans is caused by Mycobacterium
tuberculosis complex, which consists of Mycobacterium
tuberculosis, Mycobacterium bovis, Mycobacterium africanum,
Mycobacterium microti, and Mycobacterium canetti. Of these,
M. tuberculosis is the main pathogenic organism. Upon expo-
sure to TB bacilli, 3 outcomes are possible: 1) Host eliminates
the infection either via innate or acquired immunological pro-
cesses; 2) Host contains the infection- but with persistent bac-
terial viability; 3) progressive disease.
Latent tuberculosis infection (LTBI) is a state of persistent
bacterial viability, however, the host stays asymptomatic and
there is no evidence of clinically active tuberculosis. The in-
fection is said to be controlled by the host immune system.
LTBI is said to represent a dynamic equilibrium between the
* Rakesh Lodha
rakesh_lodha@hotmail.com
1
Department of Pediatrics, AIIMS, New Delhi 110029, India
TB bacilli and the host immune system. When the immune
system is dominant the infection stays dormant, but as soon as
the host immune system falters, due to a variety of reasons, the
bacilli overpower and result in clinically active TB [1]. How
the bacilli evade eradication and stay viable is unclear and a
matter of active research with important therapeutic implica-
tions. Proposed mechanisms include: a) prevention of fusion
of macrophage phagosome with lysosome [2].b) Pathogenic
loci called Region of difference (RD-1) which encodes for a
bacterial secretion system called ESX-1 secretion system,
through which phagosome membrane is disrupted and bacte-
rial products as well as bacteria are released into cytoplasm
[3]. There is also a growing body of evidence that granuloma,
once thought to be protective against TB, might serve as a
double-edged sword [3].
TB, once widely prevalent throughout the world, experi-
enced falling incidence rates in early twentieth century in de-
veloped nations, even before the introduction of anti-TB
drugs, attributed to improved hygiene and living conditions.
After the Human immunodeficiency virus (HIV) epidemic,
there has been a resurgence of TB worldwide. India comes
under WHO High TB Incidence category (>100/100,000

population). According to an estimate India has the highest
burden of pediatric TB among the 22 high burden countries,
accounting for about 27% of the pediatric TB cases in these
countries [4]. It has been estimated that about a quarter of the
world’s population is infected with tuberculosis [5] and the
lifetime risk of progression from TB infection to disease is
about 10% and a person with active pulmonary TB infects
3–6 individuals per year [6]. So, there is a huge population
which has a significant chance of developing active TB, which
during the initial phase of active disease may be asymptomatic
and hence not on treatment and thereby contribute significant-
ly to spread of TB within the community. Preventing this
progression from latent to active TB will be essential, if we
are to achieve the WHO END TB goal of reduction in inci-
dence of TB by 90% as compared to 2015, by 2035 [7].
How to Diagnose LTBI?
None of the currently available methods accurately diagnose
LTBI. However, due to paucity of available tools, they serve
as our only available options. The diagnosis of LTBI relies on
presence of immune-reactivity to TB antigen, which could be
due to disease, or a remote or a recent infection. Other diag-
nostic tools such as sputum examination, culture, nucleic acid
amplification tests are all negative in LTBI and positivity of
any of them excludes the diagnosis of LTBI and indicates an
active disease.
Immune-reactivity tests include tuberculin skin test (TST)
and interferon gamma release assays (IGRA). To label an
individual as having LTBI: there should be no evidence of
TB disease in that individual and there should be evidence
of infection in form of positive TST or IGRA. Whether to treat
such individuals or not is an entirely different discussion, cov-
ered in later sections.
No Evidence of Active TB Disease
Before making a diagnosis of LTBI it is essential to rule out
active TB as management for the two conditions is very dif-
ferent. Active TB may present with following symptomatolo-
gy: Fever, persistent cough, weight loss/ failure to gain
weight, decreased appetite, night sweats, hemoptysis and fa-
tigue. WHO conducted a meta-analysis [8] to determine the
frequency of symptoms in HIV-infected adolescent and adult
patients. A negative 4-symptoms screening rule (cough,
weight loss, fever, night sweats) had a negative predictive
value of upto 97% and thus, can be used in the field to exclude
active TB. No such screening rule has shown to have such
good value in pediatric age group. Other tools to exclude
active TB include a meticulous physical examination and
Indian J Pediatr
chest X-ray. If there is any evidence of active tuberculosis,
individual should be investigated for TB.
Immune-Reactive Tests
Diagnosis of LTBI rests mainly on positive TST or IGRA.
However, these tests are not without limitations.
Tuberculin Skin Test
TST is performed by Mantoux technique, which consists of
intradermal injection of tubercular antigen, usually on the
forearm, and assess for response 48–72 h later. Response is
measured as the horizontal diameter of induration and not the
erythema. The response is mediated by cell-mediated immu-
nity and is a type of delayed hypersensitivity reaction. The
antigen in TST is a purified protein derivative of various
strains. Antigens present in TST are also present in M.bovis
used in BCG vaccine and in some non-tubercular bacteria
such as M. avium [9]. The choice of antigen also varies. Two
prevalent types are Purified protein derivative-S (PPD-S) and
Purified protein derivative RT-23 (PPD RT 23). Five tubercu-
lin units (TU) of PPD-S is equivalent to 2 TU of PPD RT 23.
In India, PPD bioequivalent to PPD RT 23 is commonly avail-
able commercially. Cut-off for a positive test varies from re-
gion to region; in countries with high TB burden, cut-off is
taken as ≥10 mm, while in malnourished or immunosupressed
individuals, the cut-off of 5 mm is taken.
There are several issues with relying on TST in pediatric
age group especially under 5 age group. TST may be falsely
positive because of receipt of BCG vaccine, and exposure to
non-tubercular mycobacteria. Another concern is serial testing
and whether the previous TST will have a boosting effect,
which would be misinterpreted as false positive. Other issues
include requirement of 2-hospital visits and subjective end-
points. However, it is a low-cost and widely available test.
In a review, analyzing effect of BCG on TST, authors cal-
culated proportion of TST+ in BCG vaccinated and unvacci-
nated and assumed the difference between proportion of TST+
to reflect the false positive effect of BCG and multiplied the
difference in proportion with number of vaccinated to calcu-
late false positive rate. In the category of individuals vaccinat-
ed in infancy and considering TST+ as ≥10 mm, BCG was
associated with 8.5 false positive TST per 100 vaccinees. It
was also found that effect of BCG on TST wanes over time
and becomes irrelevant after 10 y. False positivity rate is
higher if vaccination is done after 1 y of age and if revaccina-
tion is done [10].
In another study conducted in Botswana in 1990s, in 783
children vaccinated with BCG during infancy and followed up
with a TST, 7% had a TST ≥10 mm, and a positive TST was
Indian J Pediatr

associated with household contact with an active TB patient There is significant conversion and reversion with all the
[11]. The study also found a decrease in size of TST with age. three tests. Conversion was much higher with IGRA but this
The study concluded that BCG does not have a significant may vary from country to country, depending on BCG
effect on TST and TST positivity reflects TB exposure. coverage.
Upon follow-up, after a year of TST administration, some of
the participants with positive TST had developed active TB
and were on anti-tubercular therapy and some were symptom- Treatment
atic, suggestive of TB [11].
After a diagnosis of LTBI has been reached, the next question
Interferon Gamma Release Assay (IGRA) that arises is whom to treat? It was found that some groups had
a high rate of progression from LTBI to active TB and cur-
In IGRA, peripheral blood T cells or mononuclear cells are rently WHO recommends treatment of LTBI in these groups
stimulated with tubercular antigen and their response, in form of children only (Table 1) [13]:
of amount of IFN gamma secreted, is measured. There are main-
ly two commercially available versions: QuantiFERON-TB
HIV Infected
Gold (QFT) and T-SPOT. Antigens used for stimulation in
IGRA are from region of difference, found exclusively in
A Cochrane review in 2010 found that treatment of LTBI in
M.tuberculosis. Antigens used are: early secreted antigen target
TST+ HIV+ individuals of all age groups reduced the risk of
6 (ESAT-6), culture filtrate protein 10 (CFP-10) and TB7.7. T-
active TB by 62% (RR 0.38[0.25–0.57]) [14]. Another
spot, uses only 2 antigens, in which, stimulation with ESAT-6
Cochrane review on treatment of LTBI in HIV infected chil-
and CFP-10 is done separately whereas in QFT stimulation with
dren found that, in children not on ART, treatment of LTBI
all three antigens is done simultaneously. IGRA also uses mito-
reduced the risk of active TB by 69% (Hazards Ratio
gen and un-stimulated controls. Mitogen stimulation serves as
0.31[0.11–0.87]). However, treatment of LTBI in children on
positive control and ensures immune-competency of subject.
Antiretroviral therapy (ART) did not yield a significant benefit
Un-stimulated controls serve as negative control and reduce
(RR-0.76 [0.5–1.14]) [15]. It was found that the protective
non-specific false positives [9]. Thus, IGRA offers several ad-
effect of 6 mo INH therapy lasted for about 5 y in HIV infected
vantages: more specific, no boosting effect in serial testing, and
adult patients [16]. Although there is no evidence for treat-
requirement of a single hospital visit. That being said, it has been
ment of LTBI in HIV+ children on ART, given the synergistic
found that IGRA has significant transient conversion and rever-
effect in adult patients [13], treatment of LTBI is recommend-
sions, and cost and availability is also a factor in developing
ed even in patients on ART. There is no evidence of repeated
countries.
course of preventive therapy.
A study [12] conducted in 2418 US healthcare workers in
2011, which compared TST, QuantiFERON-TB Gold (QFT)
and T-SPOT results at baseline and follow-up serial testing at Household Contacts of Adult Patients with TB
6, 12 and 18 mo found these results: A baseline TST positive
(≥10 mm) and negative IGRA was strongly associated with Household contact, according to WHO, is defined as a per-
BCG vaccination with a odds ratio of 33.4 (20.3–57). Out of son who shared the same enclosed living space as the index
125 participants with baseline positive TST, 54 (43%) had a case for one or more nights or for frequent or extended
repeat TST and 29 of these 54 (53.7%) participants reverted to daytime periods during the 3 mo before the start of current
a negative TST. Reversion rate was 56.8% with QFT and treatment [13].
63.9% with T-spot. The reversion rate was lower in partici- In a study conducted in 1950s in Puerto Rican children, age
pants who had a baseline triple positive compared to a single 1–19 y, pre BCG vaccination TST with PPD-RT-19-20-21
positive [12]. Conversion to positive occurred in 21 of 2293
(0.9%) participants by TST, 138 of 2263 (6.1%) by QFT, and Table 1 Groups for whom treatment of LTBI is recommended
177 of 2137 (8.3%) by T- spot. TST conversion was associated
Serial No. Group Quality of evidence
with BCG vaccination. Interestingly, of the 21 TST con-
verters, 12 underwent a repeat TST later and 11 (91.7%) 1 HIV infected children High quality
reverted to negative. Rate of reversion was 76.4% and 2 Children <5 y with contact High quality
77.1% with QFT and T-spot respectively. Rate of conversion 3 Children ≥ 5 y with contact Low quality
or reversion in IGRA was higher in those patients with base- 4 Immunosuppressed Low to very low quality
line value close to cut-off.

was given and the children were followed up. Among TST+
children, active TB case rates were maximum (164/100,000
TST reactors) in age group 1–6 y, followed by a dip in case
rates in 7–12 y age group, and again a rise in adolescent, 13–
18 y age group [17]. Another study comparing incidence of
active TB in children of patients with sputum positive TB vs.
sputum negative TB, found the incidence to be highest in
children who were less than 5 y old [18]. A meta-analysis
looking at the prevalence of active TB among contacts, found
the prevalence to be 10% in children under 5 vs. 8.4% in 5–14
y age group vs. 3.2% in >15 y old [19]. Another review,
estimated the prevalence of active TB among contacts in un-
der 5 to be 8.5% vs. 6% in 6–14 y old [20].
An analysis [13] by WHO found that risk of progression
from LTBI to active TB was highest in under 5 children (RR
of 22.9 vs. 8.2 in 5–14 y vs. 13.4 in >15 y age group). As the
risk of progression was maximum in under 5 children, WHO
strongly recommends treatment of LTBI in this age group.
However, in high burden country, like ours, WHO also rec-
ommends treatment of LTBI in children >5y old and adults,
though the evidence for same is not very conclusive [13].
Immunosuppressed
WHO recommends treatment of LTBI in patients on anti-TNF
treatment, organ or hematological transplant recipients, dialy-
sis, and silicosis.
Treatment Strategies
The recommended therapies for LTBI in high TB burden
countries are shown in Table 2.
Table 2 Drug regimen for treatment of LTBI
Serial No Regimen Frequency Duration
1 Isoniazid Daily 6–9 mo
2 Rifampicin plus isoniazid Daily 3–4 mo
3 Rifampicin Daily 3–4 mo
4 Rifapentine plus isoniazid Weekly 3 mo
Indian J Pediatr
A randomized controlled trial (RCT) comparing 4 mo ri-
fampicin vs. 9 mo isoniazid found the two therapies to be
similar in efficacy and side-effect profile, however rifampicin
arm had better adherence rates [21]. A recent meta-analysis
[22] demonstrated the efficacy of these regimens vs. placebo.
Isoniazid for 6 mo had an odds ratio of 0.65(0.5–0.83), isoni-
azid plus rifampicin had an odds ratio of 0.53(0.36–0.78) and
weekly rifapentine plus isoniazid had an odds ratio of 0.36
(0.18–0.73).
Rifapentine based regimes can be administered weekly ow-
ing to its long half-life. However, there is no significant dif-
ference in drug interaction profile compared to rifampicin, and
caution must be undertaken, while prescribing any of these
with ARTs.
Isoniazid can lead to hepatotoxicity and peripheral neurop-
athy. Rifamycins lead to gastrointestinal intolerance and hep-
atotoxicity; though, there is no significant difference in ad-
verse effects between rifampicin and rifapentine. The overall
risk of serious adverse effects is low. Alternative regimens to
isoniazid monoprophylaxis have a better safety profile and
adherence rate [23, 24].
Systematic reviews conducted did not reveal an increased
risk of isoniazid resistance [25] or rifamycin resistance [26]
with preventive therapy.
Caveats
Upon exposure to TB bacilli, host may eradicate infection
either via innate immunity (in which case TST/IGRA would
be negative) or acquired immunity processes (TST/IGRA pos-
itive). The immune-reactivity based tests just indicate that the
immune system of that individual has been exposed to
Dose
10 mg/kg; max-300 mg
Rifampicin-15 mg/kg; max 600 mg
Isoniazid-10 mg/kg; max-300 mg
15 mg/kg; max-600 mg
Rifapentine:
10.0–14.0 kg = 300 mg
14.1–25.0 kg = 450 mg
25.1–32.0 kg = 600 mg
32.1–50.0 kg = 750 mg
> 50 kg = 900 mg
Isoniazid:
Individuals aged ≥12 y: 15 mg/kg Individuals aged 2–11 y: 25 mg/kg
Max: 900 mg
Indian J Pediatr
tubercular antigen and is not equivalent to TB disease. For
example, a person who was exposed to TB but eliminated
the infection, may have a positive IGRA or TST, but they will
not benefit from treatment. Whether to give significance to a
positive test will vary from situation to situation.
Then there are concerns with use of TST. In most develop-
ing countries, TST is the mainstay of diagnosis as IGRA is
costly and resource intensive and unavailable. These develop-
ing countries also have a high BCG coverage, whose effect on
TST wanes over time, but may result in significant false pos-
itives in initial years of life, the period also recommended for
treatment for LTBI.
In a study, conducted at a tertiary care center in India,
among treatment naïve pulmonary TB patients, isoniazid re-
sistance was found in 8.7% of the isolates at baseline [27].
This figure is expected to worsen in patients who have re-
ceived anti-tubercular therapy. This has bearing on choice of
prophylactic therapy. Choice of prophylactic therapy may
have to be individualized based on local resistance patterns.
Recently, the concept of reactivation of TB several years
after infection also has come under question [28]. It has been
shown in multiple studies that risk of TB two years after in-
fection becomes practically negligible. In studies comparing
isoniazid prophylaxis vs. placebo, risk of TB in placebo group
after 1 y of infection was similar to treated group. Other evi-
dence substantiating these claims come from autopsies, in
which calcified nodes were inoculated in guinea pigs and were
found to be sterile [28]. It is being suggested that most of the
TB disease is a result of new infection rather than a remote
one. This is in conflict with the prevalent concept of LTBI and
its treatment. Currently available tools are unable to differen-
tiate between a recent or remote infection and thus among the
patients being treated for LTBI, there may be a subset, that
may not warrant treatment at all.
There are several questions still left unanswered: How do
you assess response to LTBI therapy? What if a person has been
latently infected with a multi drug resistant (MDR) bacilli?
How to diagnose and manage such cases? How do you interpret
a positive TST/IGRA in an individual who has been previously
treated for tuberculosis or LTBI? They can develop reinfection.
How to diagnose LTBI in patients who are immune-
compromised enough to not mount a positive TST/IGRA?
Mass chemoprophlaxis for tuberculosis as a tool to halt
transmission is an interesting idea, but there are several hur-
dles. Treatment for LTBI is protracted and compliance cannot
be ensured in asymptomatic individuals. Drugs used for LTBI
treatment may have significant adverse effects and risk-benefit
ratio for the entire population might be unfavorable. Besides,
TB is rampant in large part of the world, even if such an
exercise is undertaken, there is always a risk of re-
introduction of infection.
Further Research Areas
There are still lots of lacunae in our knowledge of tubercular
infection. Future research should focus on identifying new
tools to reliably diagnose LTBI, and to differentiate infection
from disease and a remote infection from a recent one. Other
avenues include a more specific skin antigen test. Further
studies, evaluating role of IGRA in a high TB burden and
wide BCG coverage settings should be undertaken.
Authors’ Contributions AJ: Performed literature search and wrote man-
uscript; RL: Planned the literature search and was involved in manuscript
writing. RL will act as guarantor for this paper.
Compliance with Ethical Standards
Conflict of Interest None.
Source of Funding None.
Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
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