Curr Treat Options Infect Dis (2017) 9:371–379

DOI 10.1007/s40506-017-0135-7

Mycobacterial Infections (H Bach, Section Editor)

Treatment of Latent
Tuberculosis Infection
Patrick Tang, MD, PhD1,*
James Johnston, MD2
Address
*,1
Department of Pathology, Sidra Medical and Research Center, P.O. Box 26999,
Doha, Qatar
Email: [email protected]
2
British Columbia Centre for Disease Control, Vancouver, Canada

Published online: 22 September 2017

* The Author(s) 2017. This article is an open access publication

This article is part of the Topical Collection on Mycobacterial Infections

Keywords Latent tuberculosis infection I Chemoprophylaxis I Isoniazid I Rifampin I Interferon-gamma release assay I
Tuberculin skin test

Opinion statement
The treatment of latent tuberculosis infection (LTBI) is an essential component of
tuberculosis (TB) elimination in regions that have a low incidence of TB. However, the
decision to treat individuals with LTBI must consider the limitations of current diagnostic
tests for LTBI, the risk of developing active TB disease, the potential adverse effects from
chemoprophylactic therapy, and the importance of treatment adherence. When an indi-
vidual has been diagnosed with LTBI and active TB has been ruled out, this is followed by
an evaluation of the risks and benefits of LTBI treatment within the context of the regional
epidemiology of TB and public health priorities. Once the decision to treat LTBI has been
reached, and the infection is not suspected to be due to drug-resistant TB, the recom-
mended regimens include isoniazid and/or rifamycin-derivatives, and the choice of
regimen will depend upon the clinical considerations for that individual, such as patient
preference, concomitant medications, hepatic disease, pregnancy, or immunodeficiency.
As the duration of treatment of LTBI therapy is many months, therapy must be offered
within a plan that monitors for adverse drug reactions and emphasizes adherence. For
latent multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB) infec-
tion, the management is more complicated as there are few options for chemoprophylactic
therapy and little evidence regarding the efficacy or risks of these regimens.

Introduction
Tuberculosis is a leading cause of death worldwide [1]. remain viable within the host but the individual is
The causative organism is Mycobacterium tuberculosis, and asymptomatic and non-infectious. For the majority of
for most infected individuals, the organism establishes a LTBI cases, the M. tuberculosis remains latent for the
latent TB infection (LTBI), where the mycobacteria lifetime of the host. However, if the host immune
372 Mycobacterial Infections (H Bach, Section Editor)

system is unable to contain the mycobacteria, the organ- and T-SPOT.TB. A positive TST or IGRA can be an indica-
ism will have an opportunity to progress to an active, tion of infection with M. tuberculosis, especially when the
symptomatic infection in the host. The risk of develop- history indicates a risk of exposure to M. tuberculosis. The
ing active TB following LTBI is dependent on many value of these tests is greatest when they are performed
factors, especially the immunological status of the in- with the intent to treat all cases of LTBI that are identified,
fected host [2••]. If effective chemoprophylaxis is given and thus, they must be part of a program that includes
to individuals with LTBI, the risk of developing active TB patient counseling, treatment, and follow-up [8, 9].
is significantly reduced [3]. For the treatment of LTBI where the source is unlikely
The feasibility and public health impact of LTBI to be drug-resistant M. tuberculosis, there are four recom-
treatment depend in part on the epidemiology and mended regimens for therapy and there is considerable
health care resources of a region [4••]. In high resource, evidence for the risks and benefits of treatment: (1)
low TB incidence settings, identification, and treatment isoniazid daily or semi-weekly for 9 months, (2) isoni-
of LTBI cases are an important part of the public health azid daily or semi-weekly for 6 months, (3) isoniazid
strategy for TB prevention and elimination. In regions and rifapentine weekly for 3 months, or (4) rifampin
where the TB incidence is high, the feasibility and public daily for 4 months [2••, 10]. There are special consider-
health impact of LTBI therapy are less clear. ations when choosing a regimen such as HIV infection,
Diagnostic testing and clinical evaluation for LTBI are pregnancy, age, hepatic disease, and the potential to
typically targeted to individuals who are at high risk of interact with other medications. Because of the long
acquiring M. tuberculosis infection or at high risk of devel- duration of therapy and potential for adverse effects
oping active TB disease following infection with from these medications, patients must be monitored
M. tuberculosis [2••]. Testing includes a clinical and radio- for adherence and adverse events (e.g., liver toxicity from
logical evaluation which can rule out active TB disease and isoniazid [11], rash from rifampin [12], etc.).
determine risk of progression to active TB disease [5••]. In When the source of the LTBI is suspected to be drug-
the absence of active TB disease, immunologic testing for resistant M. tuberculosis, there is less evidence to guide the
LTBI is also required. Generally, there are two types of optimal regimen for LTBI treatment [13, 14]. Because of
immunologic tests available for the diagnosis of LTBI: the the lack of evidence and significant potential for adverse
Mantoux tuberculin skin test (TST) which measures a effects, the first decision is whether to closely follow the
delayed-type hypersensitivity reaction following intrader- patient with LTBI to ensure early detection and treat-
mal inoculation with M. tuberculosis antigens [6], and ment if active disease were to develop or to treat the
interferon-gamma release assays (IGRAs), which measure LTBI. The considerations for treatment of LTBI from
the release of interferon-gamma from T cells in blood drug-resistant TB include the individual risk for progres-
samples exposed to M. tuberculosis-specific peptides [7]. sion to active disease, the antibiotic susceptibility profile
The two commercially available IGRAs are US Food and of the source organism and the individual’s risk for
Drug Administration-approved: QuantiFERON-TB Gold adverse drug reactions from the proposed therapy.

Diagnosis of LTBI
The decision to treat LTBI must balance the individual and public health risks of
TB disease against the potential risks of preventative therapy. Certain risk factors
can elevate one’s risk for developing active TB including HIV infection, recent
exposure (G 2 years) to an active, infectious TB case, fibrotic changes on chest X-
ray consistent with past TB infection, silicosis, organ transplantation, immune
suppressing medications (such as tumor necrosis factor inhibitors and high-
dose glucocorticoid therapy), end stage kidney disease requiring dialysis, and
carcinomas of the head and neck. When an individual has a positive TST or
IGRA and one of these risk factors, treatment for LTBI is strongly recommended
[3]. Other risk groups include injection drug users, homeless, and incarcerated
individuals. It is also recommended that individuals in these risk groups be
Treatment of Latent Tuberculosis Infection Tang and Johnston Tang and Johnston 373

screened for LTBI and offered treatment if they have a positive TST or IGRA [15].
The evidence is not as clear for screening other high risk groups, such as recent
immigrants from high-incidence countries, people with diabetes, health care
workers, and people with an alcohol abuse history, and this will be dependent
on local resources and epidemiology.
The TST using the Mantoux technique has been in use for over 100 years [6]. A
standardized dose of 5 tuberculin units (TU) of M. tuberculosis purified protein
derivative (PPD) is injected intradermally, and the delayed hypersensitivity re-
sponse is assessed 48 to 72 h later. A positive TST reaction is based on both the
diameter of the TST induration and the clinical risk factors of the patient [8]. The
TST (and IGRAs) does not distinguish between latent and active TB infection, so
active TB infection must be ruled out in those who have a positive test result [4••].
An induration of 5 mm or more is considered positive in high-risk
individuals with the following risk factors: HIV infection, recent contact with
an active TB case within the past 2 years; fibronodular changes on chest X-ray
consistent with healed TB (but not previously treated); immune suppression
(e.g., from organ transplantation, TNF-α inhibitors, corticosteroids, etc.); or
end-stage kidney disease requiring dialysis.
An induration of 10 mm or more is considered positive in individuals who
are as follows: recent migrants from countries with high TB prevalence; injection
drug users; residents, and staff in high-risk congregate settings (e.g., prisons, long-
term care facilities, hospitals, homeless shelters, etc.); mycobacteriology labora-
tory staff; persons with clinical conditions which elevate TB risk such as diabetes,
malnutrition (low body weight), cigarette smoking, daily alcohol consumption
(9 3 drinks/day), silicosis, hematologic malignancies, and certain carcinomas
(e.g., the head and neck); or children exposed to adults in high-risk categories.
False negative TST reactions can occur in young children (G 5 years), early
infections (G 8 weeks post-infection), individuals who have recently received
vaccinations, immunocompromised individuals (such as HIV infection or
treatment with immunosuppressive drugs), and those who have disseminated
TB infection. False-positive TST reactions can occur in individuals who have had
BCG vaccinations or infection with non-tuberculous mycobacteria [2••].
Interferon-gamma release assays can be used in place of or in conjunction
with the TST to support the diagnosis of LTBI. In contrast to the TST, where a
mixture of many TB antigens is inoculated into the patient, IGRAs employ only
two or three M. tuberculosis-specific antigens in an in vitro blood test; these
antigens are not shared with the M. bovis BCG vaccine strain and most non-
tuberculous mycobacteria (except for M. marinum, M. kansasii, M. szulgai, and M.
flavescens) [16•]. As a result, IGRAs appear to be more specific than the TST.
Blood from the patient is incubated with the TB-specific antigens, and the
release of interferon-γ from the T cells is measured. An increased level of
interferon-γ release is indicative of infection with M. tuberculosis.
The most commonly used commercial IGRAs are the QuantiFERON-TB
Gold and the T-SPOT.TB assays [17]. The QuantiFERON-TB Gold test employs
three TB-specific antigens (ESAT-6, CFP-10, and TB7.7) which are incubated
with a whole blood sample from the patient. The production of interferon-γ by
the T cells in response to the TB antigens is measured using ELISA [16•]. The
QuantiFERON-TB Gold test is positive when the difference in interferon-γ
concentration between the TB antigens and the nil control is greater than or
equal to 0.35 IU/mL. In contrast to the QuantiFERON-TB Gold test, the T-
374 Mycobacterial Infections (H Bach, Section Editor)

SPOT.TB assay employs two TB-specific antigens (ESAT-6 and CFP-10) and
requires the isolation of peripheral blood mononuclear cells (PBMCs) from
the blood sample [16•]. Interferon-γ produced by each cell is detected in a
sandwich ELISA technique known as the enzyme-linked immunospot
(ELISPOT) assay. Each cell that produced interferon-γ would create a spot on
the microtiter well. If the negative well has less than or equal to five spots and
either of the antigen wells has more than six spots greater than the nil control, it
is considered positive. One of the concerns regarding the use of IGRAs is
reproducibility, especially when employed in serial screening of health care
workers [18]. Until more experience with these tests is accumulated and more
nuanced interpretation guidelines available, IGRA results that are near the
manufacturer-recommended cutoff points must be interpreted with caution [19].

Treatment regimens for LTBI

There are four potential drug regimens recommended for the treatment of LTBI
(Table 1). These regimens are recommended only for the treatment of LTBI when
the source organism is not suspected to be drug resistant. The 9-month isoniazid
regimen is supported by the most evidence [2••]. Although individuals who
complete 9 months of isoniazid have lower rates of reactivation compared to
6 months [20], when compliance, cost, and hepatotoxicity are considered, the 6-
month course of isoniazid is an acceptable alternative [21]. The efficacy and safety
of the 6-month isoniazid and various other regimens, including ones with
rifamycins, have been systematically reviewed [22–24]. In terms of efficacy at
preventing the reactivation of TB, no regimen showed superiority over the others.
In terms of safety, the 4-month rifampin and 3-month rifapentine plus isoniazid
regimens appear to have fewer hepatotoxicity events compared to the longer
isoniazid-only regimens. The shorter duration regimens are often preferred by
patients and result in greater compliance rates [20].
For clinicians and public health teams overseeing LTBI treatment programs,
regimens that incur additional resource requirements also be considered such as
the need for directly observed therapy (DOT) for the weekly dosing regimens and
the higher cost of rifapentine. As such, when there are no clinical factors restricting
the choice of treatment regimens, the choice must also take into account resource
capacities of each LTBI program. For individuals living with HIV who are taking
anti-retroviral drugs, the isoniazid-only regimens are often chosen to avoid drug
interactions between rifamycins and anti-retroviral therapy, and the 9-month
course is considered more efficacious than 6 months [25•]. For children, all the
four recommended regimens have been shown to have similar efficacies and rates
of adverse effects [26] with the caveat that the isoniazid plus rifapentine regimen
should not be used in children under 2 years old. The isoniazid-rifapentine
regimen is also currently not recommended in pregnant women and women
expecting to be pregnant during the treatment period but there are ongoing clinical
trials to evaluate the pharmacokinetics and safety of this regimen in pregnancy
(IMPAACT P2001). Finally, regimens containing pyrazinamide are no longer
recommended due to the increased risk of hepatotoxicity and death [27].
It is essential to monitor for adverse drug reactions during treatment. For
individuals taking self-administered therapy, monthly or more frequent assessments
by a health care provider is required [28••]. The potential reactions from isoniazid
 Treatment of Latent Tuberculosis Infection Tang and Johnston Tang and Johnston 375

Table 1. Treatment regimens for LTBI

Isoniazid—9 months
Isoniazid:
Standard dosage Adults 5 mg/kg/day (up to 300 mg/day) p.o. for
9 months or 900 mg twice weekly p.o. for 9 months
Children 10–15 mg/kg/day (up to 300 mg/day) p.o.
for 9 months or DOT 20–30 mg/kg (up to 900 mg)
twice weekly p.o. for 9 months
Contraindications Caution in people with hepatic impairment; contraindicated
in people with acute hepatic disease, or prior isoniazid
hepatic injury
Main drug interactions Increases serum phenytoin, carbamazepine. Increases
hepatotoxicity when combined with rifampin, pyrazinamide,
ethanol, and acetaminophen
Main side effects Asymptomatic hepatic aminotransferase elevation, clinical
symptomatic hepatitis, and peripheral neuropathy
Isoniazid—6 months
Isoniazid:
Standard dosage Adults 5 mg/kg/day (up to 300 mg/day) p.o. for 6 months
or 900 mg twice weekly × 6 months
Children 10–15 mg/kg/day (up to 300 mg/day) p.o. for
6 months or DOT 20–30 mg/kg (up to 900 mg) twice
weekly for × 6 months
Contraindications Caution in people with hepatic impairment; contraindicated
in people with acute hepatic disease, or prior isoniazid
hepatic injury
Main drug interactions Increases serum phenytoin, carbamazepine. Increases
hepatotoxicity with rifampin, pyrazinamide, alcohol,
and acetaminophen
Main side effects Asymptomatic hepatic aminotransferase elevation, clinical
symptomatic hepatitis, and peripheral neuropathy
Isoniazid and Rifapentine—12 weeks
Isoniazid:
Standard dosage Age 2–11: 25 mg/kg rounded to nearest 50 or 100 mg with a
maximum 900 mg p.o. weekly (DOT); over age 12: 15 mg/kg
rounded to nearest 50 or 100 mg maximum 900 mg p.o. weekly (DOT)
Contraindications Caution in people with hepatic impairment; contraindicated
in people with acute hepatic disease or prior isoniazid hepatic injury
Main drug interactions Increases serum phenytoin, carbamazepine. Increases hepatotoxicity
with rifampin, pyrazinamide, alcohol, and acetaminophen
Main side effects Asymptomatic hepatic aminotransferase elevation, clinical symptomatic
hepatitis, and peripheral neuropathy
Rifapentine:
Standard dosage Weight 9 50 kg 900 mg; 32.1–50 kg 750 mg; 25.1–32 kg 600 mg;
14.1–25 kg 450 mg; 10–14 kg 300 mg. All given p.o. weekly under DOT
376 Mycobacterial Infections (H Bach, Section Editor)

Contraindications Prior hypersensitivity reaction; caution in HIV infected

individuals with careful attention paid to drug-drug
interactions with antiretrovirals
Main drug interactions Warfarin, methadone, anticonvulsants, and multiple antiretrovirals.
Main side effects Rash, orange discoloration of body fluids, hepatotoxicity,
and hypersensitivity reaction, ranging from flu-like syndrome
to anaphylaxis (3.5%). Nausea, vomiting, and hepatotoxicity
Rifampin—4 months
Rifampin:
Standard dosage 10 mg/kg/day (up to 600 mg) p.o. daily for 4 months
Contraindications Prior hypersensitivity reactions; caution in HIV infected individuals
with careful attention paid to drug-drug interactions with
antiretrovirals
Main drug interactions Warfarin, methadone, anticonvulsants, and multiple antiretrovirals
Main side effects Rash, orange discoloration of body fluids, hematologic syndromes,
flu-like illness, and hepatotoxicity

Four drug regimens recommended for the treatment of LTBI

include peripheral neuropathy and effects on liver function from asymptomatic

elevations in liver enzymes to severe hepatotoxicity [21, 29, 30]. Rifamycin-
containing regimens may lead to cutaneous reactions,
hypersensitivity, gastrointestinal intolerance, hematological syndromes, and hepa-
totoxicity [31, 32]. In addition, patients must be advised that rifampin and
rifapentine will cause an orange discoloration of body fluids and that contact lenses
may become stained [33]. It is important to elicit the list of current medications from
the patient to determine potential drug interactions with isoniazid and rifamycins.
For example, isoniazid can increase levels of phenytoin and carbamazepine, and
rifamycins can decrease levels of many drugs including oral contraceptives, warfarin,
and sulfonylureas [34]. Patients must also be educated to contact their health care
provider if certain symptoms develop such as abdominal pain, anorexia, nausea,
vomiting, dark urine, pale stools, jaundice, or persistent weakness [2••].
The indications for performing routine baseline laboratory testing for serum
aspartate aminotransferase, alanine aminotransferase, and bilirubin can vary
between different institutions and regions. Generally, baseline liver function
tests are indicated for isoniazid-containing regimens in the presence of risk
factors for hepatic toxicity, such as age 9 35 years, pre-existing liver disease,
regular alcohol use, HIV infection, pregnancy, or within 3 months postpartum
[2••, 28••]. These tests are typically performed at the monthly assessments and
the frequency of testing dependent on age and risk factors.

Treatment for contacts of MDR-TB

There have been few studies to determine the effectiveness of LTBI treatment for
contacts of drug-resistant TB cases [13, 14]. Existing studies also use a wide
range of treatment regimens in different patient populations, making the com-
parison of the efficacy of different regimens difficult [35•]. Fluoroquinolone-
 Treatment of Latent Tuberculosis Infection Tang and Johnston Tang and Johnston 377

based treatment regimens appear most promising such as a fluoroquinolone

alone or in combination with ethambutol [36, 37•, 38], but no regimen has
been fully evaluated in a randomized control trial setting. At present, there are at
least three ongoing randomized trials (VQUIN, TB-CHAMP, PHOENIx) evalu-
ating LTBI treatment in MDR-TB contacts. Results, however, will not be avail-
able for several years [39].
The decision to treat LTBI in an individual exposed to an MDR-TB source
case must be based on individual-risk assessments for each patient and the drug
susceptibility profile of the suspected source organism. This treatment program
must also take into account the quality of the drug susceptibility results, prior
exposure of the patient to active TB; the resources required to follow the patient
during treatment and monitor for adverse drug reactions, as well as the poten-
tial for inducing acquired drug resistance [40]. The cost of treatment and
diversion of resources from the treatment of active MDR-TB cases must also
be taken into consideration [4••]. In some cases and settings, clinical and/or
periodic radiologic examinations for at least 2 years may be preferable to
prophylactic treatment for contacts of MDR-TB cases [13].
The quality of evidence to support the treatment of contacts of MDR-TB still
remains low. Current treatment guidelines for MDR-TB contacts with LTBI are
based on expert opinion and observational studies only [13]. In a recent
systematic review and meta-analysis evaluating observational studies on LTBI
therapy in MDR-TB contacts, the authors found that MDR-TB contacts treated
for LTBI had a reduced incidence of active TB, suggesting that treatment may be
effective in preventing progression to MDR-TB [35•]. In particular,
fluoroquinolone-based regimens (with or without ethambutol) ranging from
6 to 12 months in duration appear to be most promising. In contrast, however,
pyrazinamide-based regimens have high rates of discontinuation related to
adverse effects. LTBI therapy in MDR-TB contacts should be considered in
consultation with a physician with expertise in MDR-TB therapy. Alternatively,
given the paucity of evidence to support LTBI treatment in MDR-TB contacts,
close clinical and radiological follow-up could be considered a viable alterna-
tive especially in regions with low TB incidence [41].
Conclusions
Although the management of active TB cases is first and foremost for all TB
control programs, the goal of TB elimination also requires the identification
and treatment of LTBI. Diagnostic tests for LTBI are most effective when targeted
at individuals who are at high risk for acquiring TB infection or at high risk for
reactivation of LTBI. Chemoprophylactic treatment of individuals with LTBI
must balance the risks and benefits of treatment for these asymptomatic indi-
viduals as the various regimens use drugs which have the potential for serious
adverse effects. The regimen backed by the most evidence is 9 months of
isoniazid therapy. However, with considerations for adverse effects, patient
uptake and adherence, alternative regimens with shorter duration and/or with
rifamycins are also effective for reducing the likelihood of TB reactivation. For
individuals exposed to cases of MDR-TB, there is currently little evidence to
recommend specific drug regimens but ongoing randomized control trials
should yield new recommendations in the upcoming years.
378 Mycobacterial Infections (H Bach, Section Editor)

Compliance with ethical standards

Conflict of interest
Patrick Tang and James Johnston declare that they have no conflict of interest.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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