Invited Review

Treatment of Latent Tuberculosis Infection

in Children
Andrea T. Cruz,1,2,3 Amina Ahmed,5 Anna M. Mandalakas,1,4 and Jeffrey R. Starke1,2
1
The Tuberculosis Initiative of Texas Children’s Hospital, and Sections of 2Infectious Diseases, 3Emergency Medicine and
4
Retrovirology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas; and 5Division of Infectious Diseases,
Department of Pediatrics, Carolinas Medical Center, Charlotte, North Carolina

Corresponding Author: Andrea T. Cruz, MD, MPH, 6621 Fannin St, Ste A2210, Houston, TX 77030. E-mail: acruz@bcm.edu.
Received January 23, 2013; accepted March 14, 2013; electronically published May 19, 2013.

Treatment of latent tuberculosis infection (LTBI) is an effective way of preventing future cases of tuberculosis
disease. We review pediatric and adult studies of LTBI treatment (isoniazid and rifampin monotherapy,
isoniazid plus rifampin, isoniazid plus rifapentine, and rifampin plus pyrazinamide). Based upon this review
and our pediatric experience, we can offer recommendations for routine (isoniazid) and alternative courses of
therapy.
Key words. Latent Tuberculosis Infection; Directly Observed Preventive Therapy; Adherence

Treatment of latent tuberculosis infection (LTBI) is the
most effective strategy to prevent future cases of disease [1].
Most cases of childhood tuberculosis (TB) disease in low-
prevalence countries are preventable by screening for risk
factors, testing for LTBI, and offering therapy [2, 3].
Although LTBI therapy has been available and empha-
sized in industrialized nations, its use has been limited in
most resource-limited settings.
Regimens for LTBI have been evaluated and used for
over 6 decades. Over the last decade, however, concerns
about low completion rates [4], costs [5], and increasing
rates of drug resistance [6] have prompted research on
shorter-course LTBI regimens and the use of multidrug
regimens. In this review, we discuss available treatment
regimens for children with LTBI, as documented by either
the tuberculin skin test (TST) or an interferon gamma
release assay (IGRA). For each regimen, data for safety
and tolerability, efficacy, adherence, and scenarios in
which a clinician might consider using the regimen will be
discussed. English-language articles on the treatment of
LTBI in children were included: because many of the
studies regarding non-isoniazid (INH)–based regimens
were performed in adults and minimal or no pediatric data
are available in some instances, studies conducted in
adults were included as well. The method of LTBI diagno-
sis, preventive therapy in the human immunodeficiency
virus (HIV)–infected child, and treatment of children with
LTBI due to drug-resistant Mycobacterium tuberculosis
are outside the scope of this review.
REGIMENS
Several LTBI regimens are available (Table 1) [7–9].
Selection of a particular regimen should be based on
drug-susceptibility data from the source of infection (if
available), interaction with other medications the child is
receiving, drug availability, the time frame the family has
for completing therapy, costs, and adherence consider-
ations. Advantages to combination therapy include
shorter treatment duration and broadened coverage in the
event of single-drug resistance.
Isoniazid, 6 and 9 Months
There have been 29 randomized (17 in HIV-uninfected
persons and 12 in HIV-infected persons; 2 of the latter in-
cluded children) [10, 11] trials of INH for LTBI.
Efficacy or Effectiveness. Since the 1950s, researchers
conducted numerous studies to assess the efficacy of INH
treatment regimens for LTBI. In 1958, the US Public
Health Service (USPHS) conducted a seminal randomized
trial in Alaskan boarding school children aged 5–20 years
to compare the efficacy of 1.25 versus 5 mg/kg INH given
daily or 5 times weekly for 6 months [12]. During the
10-year follow-up period, 1.9% (10 of 513) of partici-
pants who received the higher dose progressed to TB

Journal of the Pediatric Infectious Diseases Society, Vol. 2, No. 3, pp. 248–58, 2013. DOI:10.1093/jpids/pit030
© The Author 2013. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society.
All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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 Pediatric Latent TB Infection Therapy 249

disease compared to 5.8% (31 of 536) of participants

References (adult and pediatric)

Most adverse events in children (Table 2) involve nonspecific gastrointestinal complaints without associated transaminitis or other evidence of hepatotoxicity (defined as AST/ALT 2–3 times the upper limit of normal (ULN)
who received the lower dose. The study also demonstrated

[32, 43, 44, 47, 51–54, 57]

the efficacy of INH 5 days per week. Although duration

[12–19, 20–24, 43, 57]

of INH therapy was increased to 24 months, there were

[1, 63, 64, 66, 72]

no additional benefits among the Alaskan Inuit over
[32–38, 57] the 6-month regimens [13, 14]. Through the 1960s, re-
searchers at the USPHS completed additional randomized
[8, 9] controlled trials (RCTs) that collectively studied >100 000
participants including children, TB contacts, and persons
increased rates of AEs and/or with positive TSTs; most studies compared 12 months of
increased efficacy over 6INH

Equivalent to 6–12 INH, but

daily INH with placebo [15]. When analysis was restricted

9INH confers 20%–30%
Estimated Efficacy

to participants who were adherent, the protective efficacy

Equivalent to 6–12 INH
Equivalent to 6–12 INH

was approximately 90%; however, substantial protection

Equivalent to 9 INH

was also conferred with irregular treatment, supporting

hepatotoxicity

intermittent therapy. Likewise, Hsu’s [16] observational

studies of 2494 children who were treated with INH daily
for 1 year and followed on average for 6 years, contri-
buting to 15 943 patient years, showed greater than 99%
protective efficacy given good adherence.
% Hepatotoxicity

The International Union Against Tuberculosis and Lung

1.2%–1.6%

Disease completed a direct comparison of 3-, 6-, and

2%–17%

This regimen is only recommended for persons who being treatment for TB disease and are later deemed to have latent TB infection.
0%–2%

6%–8%

12-month regimens of INH in 27 730 adults with TST in-

0.4%

duration >6 mm and fibrotic pulmonary lesions seen on

All intermittent therapy regimens should be administered via directly observed preventive therapy to ensure adherence [7].
Abbreviations: AEs, adverse events; INH, isoniazid; max, maximum; PZA, pyrazinamide; RIF, rifampin; RFP, rifapentine.

chest radiograph [17]. During 5 years of follow-up, 1.4%

11%–32%

20%–29%
1%–24%

2%–64%

of participants in the placebo group developed TB disease

% AEs‡

compared with 1.1%, 0.5%, and 0.4% in the 3-, 6-, and
4.9%
Table 1. Available Treatment Regimens for Latent Tuberculosis Infection in Children

12-month regimen groups, respectively. Among persons

taking 80% of their INH doses, efficacy for the 12-month
Completion Rates

regimen was higher (0.1% disease progression); participants

receiving the 6-month regimen had a 4-fold higher risk of
20%–93%

72%–96%
63%–97%

61%–70%

TB disease than those receiving the 12-month regimen.

82%

Similar studies have not been performed in children.

Secondary analysis of INH trials including adults and
Twice weekly†

children has significantly informed pediatric TB policy.

Interval

Comstock [18] analyzed 2 large USPHS household contact

with abdominal complaints or > 5 times ULN even if asymptomatic) [1].
Weekly†

studies to compare TB case rates among immunocom-

Daily

Daily
Daily

Daily

*Nine months of INH is the preferred duration in the United States.

petent, adult contacts with varying durations of INH pre-

ventive therapy. His demonstration that INH efficacy
RIF: 10–15 (max: 600 mg)

PZA: 30–40 (max: 2–4 g)

INH: 10–15 (max: 300 mg)

plateaued at 9–10 months of treatment suggested that

RIF: 10–15 (max: 600 mg)

Only recommended for children 12 years old [8, 9].

Dose (mg/kg per day)

longer duration conferred no additional benefit. Re-

10–15 (max: 300 mg)
20–30 (max: 900 mg)
10–20 (max: 600 mg)

searchers performed a systematic review of 4 USPHS and

RFP: 900 mg

7 non-US randomized, placebo-controlled international

INH: 900 mg

studies and evaluated the protective efficacy of 6–12

months of INH to prevent TB in HIV-uninfected persons
(N = 73 375) [19]. They found that there was no difference
in efficacy for patients treated for 12 versus 6 months. This
Regimen (months)

review demonstrated a relative risk reduction of 0.40

9INH* or 6INH

(95% confidence interval, 0.31–0.52) and an absolute risk

3INH/RFP§

2RIF/PZA¶
3INH/RIF

reduction of 0.01. Approximately 20% of the subjects

were children. With these findings, it can be expected that
4RIF

the protective efficacy of INH should be substantially

†
‡

§
¶

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 250 Cruz et al

Table 2. Most Common Adverse Events Seen in Children Receiving Antituberculosis Medications
Medication Adverse Event Details References
Isoniazid Hepatotoxicity AST/ALT 2–3x ULN and symptoms or >5x ULN even if asymptomatic; can see [7, 29, 34, 44]
hyperbilirubinemia, and rarely coagulopathy and hepatic failure.
Rate of INH-associated hepatotoxicity is 0%–6.5% if given as monotherapy and
0.7%–17% if given in combination with RIF
Peripheral More common in adolescents; preventable with pyridoxine (B6). Administration of [7, 29]
neuropathy B6 should be considered for exclusively breast-fed infants, HIV-infected patients,
pregnant women, adolescents, and any patient with malabsorption.
Gastrointestinal Very common, especially if INH is given while the child is NPO. Many formulations [7, 29]
upseta of the suspension are sorbitol-based and can cause osmotic diarrhea. Consideration
should be given to using crushed tablets in lieu of the suspension for even young
infants if they are taking cereals or pureed foods.
Rash Both urticarial and non-urticarial rashes seen in approximately 2% of HCWs and in [7, 29, 78, 79]
patients receiving INH as part of multidrug therapy for disease.
Rifampin, Gastrointestinal Very common (up to 26% in 1 adolescent study), especially if rifampin is given while [36]
Rifapentine upseta the child is NPO.
Hepatotoxicity AST/ALT 2–3x ULN and symptoms or >5x ULN even if asymptomatic; can see [32, 33, 36–
hyperbilirubinemia, and rarely coagulopathy and hepatic failure. 38, 44]
Rate of rifampin-associated hepatotoxicity is 0%–2% if given as monotherapy and
0.7%–1.2% if given in combination with isoniazid.
Rash Estimated to occur in 2% of patients receiving RIF as part of multidrug therapy for [80]
disease.
Thrombocytopenia Seen in 3.4% of patients receiving RIF for LTBI monotherapy; no other cell lineages [82]
were suppressed, was asymptomatic in almost all cases, and resolved after RIF was
stopped.
Pyrazinamide Rash Estimated to occur in 2% of patients receiving RIF as part of multidrug therapy for [78, 80]
disease.
Hepatotoxicity Abdominal pain is seen in 4%–5% of children receiving PZA as part of multidrug [81]
therapy for disease, but hepatotoxicity is rare.
Joint pain Serum uric acid increases in more than 90% of children receiving PZA, but remains [81]
within the normal range for the majority, and rarely is associated with joint pain or
gout.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; HCW, healthcare workers; HIV, human immunodeficiency virus; INH, isoniazid;
LTBI, latent tuberculosis infection; NPO, nothing by mouth; RIF, rifampin; ULN, upper limit of normal.
a
Gastrointestinal upset includes nausea, vomiting, abdominal pain.

higher in young children because they have higher rates of
disease progression without therapy.
Adherence and Adverse Effects. Despite long-standing
recommendations for use of INH preventive therapy in
child contacts, children’s adherence to treatment is con-
sistently poor in high- and low-burden settings [7, 20–24].
At the Tuberculosis Clinic at Texas Children’s Hospital,
despite counseling the family and child on the importance
of LTBI therapy, recommending pharmacies dispensing
inexpensively priced medications, and scheduling close
follow-up, the completion rate for self-supervised therapy
with 9 months of INH was only 49% [24]. Adherence
rates in children are not solely associated with adverse
events. Extensive evidence suggests that INH is well
tolerated by children and adolescents [16, 20, 25–27]. One
large meta-analysis showed that the rates of jaundice and
mostly mild elevation in hepatic transaminases were
0.06% and 8%, respectively [28]. Given the low frequency
of hepatotoxicity, children should be monitored for symp-
toms of hepatotoxicity, rather than by routine laboratory
evaluation. Parents and other care givers must be educated
regarding potential side-effects (Table 2) [7, 29]. Any child
in whom hepatotoxicity is suspected should immediately
stop taking INH until physician evaluation and laboratory
analyses can occur. Children can be monitored via history
and clinical examination at monthly follow-up visits.
Recommendations. Current US and international INH
guidelines recommend similar daily or twice-weekly doses
but variable duration of therapy (Table 1), with US
guidelines recommending a 9-month duration and World
Health Organization recommending 6-month regimens [30].
The level of protection offered by a 9-month INH regimen
is 20%–30% higher than that afforded by a 6-month
course [13]. Given the low rates of completion of LTBI
therapy and the modest incremental benefit of 9 months
versus 6 months of INH, it would not be unreasonable to
accept 6 months of therapy rather than 9 months if
adherence becomes an issue late in therapy. An alternative
to daily therapy is twice-weekly therapy administered by
direct observation, which has been shown to increase
adherence when compared with self-administered therapy
(96% vs 49% completion) [24], and is safe (0.4% had
elevated hepatic transaminases; none had evidence of
synthetic hepatic dysfunction) and effective (only 1 child
who completed treatment in the cohort of 448 children
with LTBI progressed to disease) [31].

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Rifampin, 4 Months
There have been 3 randomized [32–34] and 8 observation-
al studies of rifampin (RIF) for LTBI [35–42].
Efficacy and Effectiveness. There have been 3 RCTs of RIF
monotherapy for LTBI; all included only adults. An early
study in Chinese adults with silicosis showed 3 months of
RIF to be as efficacious as 6 months of INH [32]. The
other 2 RCTs compared 4 months of RIF with 9 months
of self-administered INH, and researchers found higher
adherence rates (78%–91%) for the RIF arm compared
with the INH arms (60%–76%). Subsequent studies have
been largely observational [35–42]. One adolescent study
of RIF prospectively followed 157 high school students
who were prescribed 6 months of RIF after exposure to
INH-resistant M tuberculosis. No cases of active TB were
identified during a 2-year study period [36]. A large scale
international trial comparing 4 months of RIF with 9
months INH for the treatment of LTBI is now underway
with a separate pediatric arm.
Adherence and Adverse Effects. In two randomized trials,
4 months of treatment with RIF was compared with 9
months of treatment with INH, and the results indicated
significantly better treatment completion with the shorter
regimen [33, 34]. A retrospective review of 2149 patients
under programmatic conditions found that 72% of those
who received 4 months of RIF versus 53% of those who
received 9 months of INH completed treatment (P < .001),
and the treatment regimen was independently associated
with treatment completion [37].
Serious adverse events (Table 2) leading to discontinua-
tion of therapy occur significantly less often with 4
months of RIF treatment compared with 9 months of INH
treatment [33, 34, 37, 38]. In a large retrospective study,
adverse events resulting in permanent discontinuation of
medication occurred in 4.6% and 1.9% of adults in the 9
months of INH and 4 months of RIF groups, respectively
[37]. The incidence of adverse reactions is not as well de-
lineated in children. In the trial evaluating 6 months of
daily RIF for the treatment of LTBI in 157 adolescents,
26% reported anorexia, nausea, fatigue, or rash, but only
1.3% required permanent discontinuation of RIF due to
abdominal pain or elevation in serum transaminases [36].
Recommendations. Four months of RIF is recommended
as an acceptable alternative to a 9-month regimen of INH
for the treatment of adults with LTBI [1]. For children
with LTBI acquired from a source with INH-resistant,
RIF-susceptible M tuberculosis, the American Academy of
Pediatrics recommends a 6-month regimen of RIF [30].
The difference in duration recommended for pediatric
patients is due to the lack of data on the optimal treatment
duration in children, but there are minimal data to support
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Pediatric Latent TB Infection Therapy 251
the need for a 6-month regimen. In 2 case series, including
the only efficacy study that included children (one with
adolescents), no patients developed TB after completing 6
months of RIF [35, 36], compared with 1 case of disease
among 1379 adults treated for 4 months with RIF in a
second case series [37].
Although the optimal duration has not been established,
the results of an ongoing international trial evaluating 4
months of RIF treatment in children should provide addi-
tional information. No comparative trial of 6-month
versus 4-month regimens of RIF has been conducted, but
the benefits of improved adherence and safety are largely
demonstrated in trials using 4 months of RIF in adults [33,
34]. Based on this, we recommend 4 months of RIF for
LTBI treatment in children truly intolerant of INH or chil-
dren exposed to INH-resistant, RIF-susceptible M tubercu-
losis. In addition, 4 months of RIF is an acceptable
regimen in children infected from persons with fully drug-
susceptible M tuberculosis isolates, or for children with
LTBI acquired from an unknown source, given that the im-
proved adherence demonstrated with this shorter regimen
will increase the effectiveness of LTBI therapy. Of note,
RIF is substantially more expensive than INH for unin-
sured patients who are not receiving medication via
directly observed preventive therapy (DOPT).
Isoniazid + Rifampin, 3 Months
There are 9 randomized trials [32, 43–50] and 6 observa-
tional studies [51–56] of combination therapy with INH
and RIF for LTBI.
Efficacy and Effectiveness. A recent meta-analysis identi-
fied 5 high-quality RCTs comparing daily short-course
treatment with INH and RIF (INH/RIF) to 6–12 months
of INH [57]. The studies were conducted in Hong Kong,
Spain, and Uganda, and 3 studies included patients
infected with HIV. Among 1926 adults (972 treated with
INH/RIF, and 954 treated with INH) who were followed
for a mean of 13–37 months, the development of TB
disease was equivalent for both regimens. In HIV–infected
African adults with LTBI, there was no difference in death
or progression to disease when 3 months of daily INH/RIF
(administered via DOPT) was compared to either 6 months
of INH or 3 months of INH/Rifapentine (RPT) [43].
A study conducted exclusively among Greek children
compared 4 months of INH/RIF to 9 months of INH and
subsequently 4 months of INH/RIF to 3 months of INH/
RIF [44]. Some children had TB risk factors and were iden-
tified via contact investigations, whereas others were re-
cruited based on a positive TST alone. Although the study
was not adequately powered for efficacy, none of the 850
treatment-adherent patients progressed to clinical TB. The
 252 Cruz et al
authors concluded that 3 months of INH/RIF and 4
months of INH/RIF were equivalent to each other and su-
perior to 9 months of INH for the treatment of LTBI in
children given the improved adherence.
The largest programmatic experience using 3 months of
INH/RIF is from British observational studies, where 3–6
months of INH/RIF has been used to treat pediatric LTBI
since 1984 [51–53]. By comparing district notifications of
TB to patients treated for LTBI, Ormerod [51] demonstrat-
ed a significantly reduced incidence of childhood TB with
the introduction of INH/RIF compared with historical
control groups who received 9 months of INH. No addi-
tional protection was offered by a 6-month versus a
3-month regimen of INH/RIF [52].
Adherence and Adverse Effects. Adherence with 3 months
of INH/RIF is generally equivalent to or better than that of
longer regimens [47, 54, 55]. The rate of completion in
Greek children treated for LTBI was significantly lower for
9 months of INH (66%) compared with the shorter INH/
RIF regimens (78%–90%) [44]. The adherence with 3
months of INH/RIF in high-burden settings was higher
than for 6 months of INH (70% vs 28%) [55].
Serious adverse effects, including hepatotoxicity, have
occurred with similar or lower frequency with 3 months of
INH/RIF compared with 6–12 months of INH [32, 43,
47–49, 57]. In the Greek pediatric study, there were no
serious adverse events noted among 926 participants,
and modification of treatment was not required in any
patient [44].
Recommendations. Programmatic experience in England
and 1 Greek study suggest that 3 months of INH/RIF therapy
is as effective as 4 months [44, 51–53]. We recommend
3 months of INH/RIF based on this experience in the
United Kingdom and multiple studies establishing the safety
and tolerability of this regimen in children and adults
[43, 44, 48, 50].
Isoniazid and Rifapentine, 3 Months (Once-Weekly Dosing)
There have been 3 randomized trials [8, 43, 58] of combi-
nation therapy with INH and RPT.
Efficacy and Effectiveness. Rifapentine is a rifamycin with
a long half-life (
13 h) and with greater potency against
M tuberculosis than RIF. It has a US Food and Drug
Administration-approved indication for treating TB dis-
ease, but RPT’s use for treating LTBI is off-label. Three
studies were conducted to compare the use of once-weekly
RPT in combination with INH given via directly observed
therapy to treat LTBI [8, 43, 58]. In a small trial (206 close
contacts on this regimen), 1.46% of adult subjects treated
with this regimen developed TB disease compared with
0.52% of 193 subjects treated with 2 months of daily RIF
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and pyrazinamide (PZA) [58]. In the second study, of 328
HIV-infected adults who did not receive antiretroviral
therapy and who also tested positive for TST, 24 developed
TB disease, a rate of 2.0 per 100 patient years, compared
with a rate of 1.9 per 100 patient years among similar
patients treated for 6 months with self-administered, daily,
INH [43]. The most rigorous and best designed compara-
tive trial for treatment of LTBI was performed in a third
study in Brazil, Canada, Spain, and the United States [8].
This trial compared 11 or 12 doses of INH (15–25 mg/kg,
maximum 900 mg) and RPT (15 mg/kg, maximum 900 mg)
given as weekly DOPT with 9 months of daily self-
administered INH (5–15 mg/kg, maximum 300 mg). The
modified intention-to-treat analysis included 7731 partici-
pants with LTBI: 5466 close contacts, 1925 subjects with
TST conversion, 179 subjects with radiographic findings
of healed pulmonary TB, and 161 subjects who were in-
fected with HIV and were not taking antiretroviral drugs.
The completion rates of therapy were 82% and 69% for
the INH and RPT and INH regimens, respectively. Of
the 22 cases of TB disease observed during the average
30-month follow-up period, 7 occurred in the INH and
RPT group and 15 occurred in the INH group (hazard
ratio of 0.38 for the INH and RPT regimen). Initially, only
persons 12 years of age were enrolled. Although younger
children were enrolled later in the study after some
pediatric RPT pharmacokinetic data became available
[59], there was insufficient power to determine the efficacy
of treatment among children 2 to 11 years of age.
Adherence and Adverse Effects. In the large comparative
trial, permanent drug discontinuation was more common
with the INH regimen than with INH and RPT regimen
(31% vs 18%) [8]. It was obvious that adherence with the
INH and RPT regimen was enhanced by the use of DOPT
for all doses. Permanent discontinuation ascribed to adverse
effects was more common with INH and RPT (4.9% vs
3.7%) as was discontinuation attributed to hypersensitivity
reactions (2.9% vs 0.4%), but hepatotoxicity requiring
discontinuation of the regimen was significantly more
common with the INH regimen (2.0% vs 0.3%). In a
separate analysis, 1032 children (539 received INH and
RPT and 493 received INH) aged 2–17 years were
enrolled in the study. For this subset, completion of the
regimen was significantly higher in the INH-RPT group
(88% vs 80%), and the rates of discontinuation of either
regimen due to an adverse effect were very low and not
different (1.3% and 0.8% for INH plus RPT and INH,
respectively) [60]. There were 7 cases of possible drug
hypersensitivity in the INH and RPT group compared
with none in the INH group; there were no cases of
significant hepatotoxicity in either group.

Recommendations. In December 2011, the Centers for
Disease Control and Prevention (CDC) stated that the
combination of INH and RPT given as 12 weekly DOPT
doses is recommended as an equal alternative to 9 months
of daily self-administered INH for treating LTBI in
otherwise healthy patients aged 12 years who are at high
risk for progression to TB disease. These risk factors
included recent exposure to contagious TB, conversion
from a negative to a positive test for TB infection, and
radiographic findings of healed pulmonary TB, including
HIV-infected persons who are otherwise healthy and not
taking antiretroviral medications [9]. The safety and
tolerability data for children aged 2–11 years were not
available when these recommendations were published,
but the CDC stated that INH-RPT can be considered on a
case-by-case basis for children aged 2–11 years when the
circumstances make completion of 9 months of INH
unlikely and the likelihood or the hazard of TB is great. It
is unlikely that a well powered study of the efficacy of
INH-RPT will be conducted among young children aged
2–11 years. However, given the favorable results of the
safety and tolerability data now available for this age
group, INH-RPT should be considered an acceptable
alternative when adherence with a self-administered
regimen is difficult or unlikely. Because of the lack of data
pertaining to the pharmacokinetics, safety, and tolerability
of RPT in children <2 years of age, INH-RPT should be
considered a secondary alternative to 9 months of INH.
Rifampin + Pyrazinamide, 2 Months
There have been 7 randomized [46, 48, 58, 61–64] and 7
observational trials [65–71] for the use of RIF and PZA
for LTBI; all were in adults.
Efficacy and Effectiveness
Studies demonstrated efficacy equivalent to 6 months of
INH in HIV-infected adults [61, 63] and higher rates of
completion than standard LTBI regimens [61, 66]. This
regimen was never recommended for LTBI treatment in
children, and it is no longer recommended for adults due
to high rates of hepatotoxicity [72].
Adherence and Adverse Events. The limitations to this
regimen were elevated rates of hepatotoxicity among
adults: 6%–8% of 2-month RIF/PZA recipients had grade
3–4 hepatotoxicity compared with 1%–2% of 6-month
INH recipients [64, 68]. Rates of hepatotoxicity may vary
by population; a retrospective study of Portuguese LTBI
patients who received 2 months of treatment with INH/
RIF/PZA showed comparable rates of hepatotoxicity
(1.5% vs 1.6%) to those who received 6 months of
treatment with INH [73]. Based on these data, the CDC
recommended that 2 months of RIF/PZA may be used
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Pediatric Latent TB Infection Therapy 253
with caution in selected cases for the following patients:
those without existing hepatic disease; those not taking
other potentially hepatotoxic medications; those able to
be cared for by an experienced clinician with close clinical
and laboratory monitoring; and those in whom longer
regimens are judged not likely to be completed [74].
Recommendations. Although it is not a recommended
regimen, 2 months of RIF/PZA may be useful for children
who are started on multidrug therapy for suspected TB
disease (based in part upon on TST or IGRA positivity)
and who are later found to have an alternative diagnosis.
In these patients, receipt of at least 2 months of RIF/PZA
constitutes an adequate course of LTBI therapy. Use of
RIF/PZA outside this circumstance is not recommended
given the risk of hepatotoxicity and availability of
alternative regimens.
ADHERENCE AND MONITORING
Approximately 50% of adult Americans who start LTBI
therapy do not complete it [4, 75], and a substantial
number refuse to initiate therapy; the rates are similar for
children [24, 75]. Completion rates are much higher for
children who receive medications via DOPT [24]. Almost
half of patients who do not complete therapy discontinue
it in the first 1–2 months after initiation [76]. Risk factors
for initiating but not completing therapy include initiation
of a 9-month course of therapy (vs shorter courses) [4],
residence in congregate settings [4], lack of insurance [77],
and perceived side effects [77, 78].
Poor adherence should not be surprising: many cultures
do not emphasize preventive care, and because the chil-
dren, by definition, are asymptomatic at initiation of LTBI
therapy, parents will only notice side effects, not improve-
ment. A child’s adherence relates to numerous factors in-
cluding the parents’ attitude regarding preventive therapy,
perceived ability to provide their child with treatment, and
social norms [79]. Predicting adherence in individual pa-
tients and families is challenging. Given the frequency of
nonadherence, it would be unwise for healthcare providers
to assume all children receive the intended regimen.
Strategies to address the most common reasons for nonad-
herence are listed in Table 3. One effective strategy to in-
crease completion rates is to offer DOPT via local health
departments or in schools regularly staffed by school
nurses. Although DOPT may not be available for all chil-
dren in all settings, it has been shown to increase adherence
in children with LTBI irrespective of socioeconomic status,
immigration status, and language of preference [24].
Children who receive LTBI therapy require frequent
monitoring to assess adherence, address family concerns,
 254 Cruz et al

Table 3. Common Reasons for Failing to Initiate or Defaulting on LTBI Therapy, and Potential Strategies to Address Familial
Concernsa
Category Variable Explanation Strategy to Address Barriers
Failure to Knowledge LTBI has never been explained to them Explain risk of progression to disease if untreated
initiate Explain abundance of data showing treatment is
therapy effective
Refer families to reputable websites to read about
LTBI (eg, CDC)
Cultural LTBI treatment not emphasized in many Emphasize that the US has resources to be able to invest
developing nations; stigma around TB in strategies, unlike many developing nations
Explain that US recommendations are (for the most
part) in line with WHO recommendations used in the
families’ country of origin
Linguistic Lack of explanatory materials in the family’s Explain rationale and recommended treatment plan via
language of comfort a translator (not the child translating for family)
Provide family information sheets in their language of
comfort
Concern about They may have heard about risk of Education lower risk of adverse events in children
adverse events hepatotoxicity for TB medications compared with adults
List out potential adverse effects and formulate a plan
about what the family will do if the child were to
develop any symptoms
Provide family ways to contact you if symptoms were
to develop
Duration of therapy Family uncomfortable given long duration of Offer shorter-course therapy
therapy
Financial constraints Child lacks insurance and family reluctant to Offer health department-supervised therapy if available;
start medication without knowing cost if not, guide the family on where the medication can
be purchased inexpensively
Failure to Forgetting the Families need frequent reinforcement; by Frequent clinic visits
complete importance of definition, they will not see an improvement Reinforce child’s desire to take the medication by
therapy taking the in their child and may only notice side giving the child small gifts (eg, stickers, a book) at
medication effects each clinic visit
Concern for perceived Parents may attribute esoteric side effects to Clearly state what medication effects may be (verbally
adverse effects the medication and in written form in a language comprehensible to
the family) and the spectrum of coverage for TB
medications (eg, that they do not prevent child from
developing other infectious diseases)
Forgetting to take Chaotic home situation; children often do not Instruct family to connect medication administration to
medication take daily medication for long periods something else they do each day
School-aged children may find it easier to take
medication in the morning before school, because
after school, schedules may vary each day
Offer health department-supervised therapy, if
available
Administer the medicine outside the home (eg,
school-based clinic)
Be sure that forgetting the medicine is not a reflection
of not prioritizing LTBI treatment
Financial constraints Child lacks insurance and family reluctant to Offer health department-supervised therapy, if available;
continue medication without knowing cost if not, guide the family on where the medication can
be purchased inexpensively
Abbreviations: CDC, Centers for Disease Control and Prevention; LTBI, latent tuberculosis infection; TB, tuberculosis; US, United States: WHO, World Health
Organization.
a
Adapted from references 24, 75–77.

and assess for potential side effects (Tables 2 and 4) [80–82].
For the otherwise healthy child who only receives TB
medication(s), baseline and serial laboratory evaluation is
unnecessary. Results of studies have shown that 3% of
children who receive TB medications have asymptomatic
elevation in transaminases 2–3 times the upper limit of
normal (ULN) [83]; in these cases, modification of therapy
is not needed. Elevations >3 times ULN with accompany-
ing symptoms or >5 times ULN without symptoms define
hepatotoxicity. Hepatotoxicity may range from isolated
transaminitis to hyperbilirubinemia to hepatic failure.
If children are receiving other potentially hepatotoxic
medications or have known or suspected hepatic dysfunc-
tion, measurement of baseline hepatic transaminases may
be warranted. Obtaining transaminase concentrations is
also warranted for the child who develops abdominal
complaints, anorexia, or malaise while taking TB medica-
tion. Most children who receive TB medications with

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 Pediatric Latent TB Infection Therapy 255

Table 4. Common Symptoms When Children Are Receiving LTBI Therapy and Strategies to Address These Complaintsa
Symptom
Abdominal pain immediately after taking
medication
Abdominal pain hours after taking
medication or abdominal pain associated
with vomiting, icterus, or other symptoms
Diarrhea in association with INH
Numbness/tingling in hands/feet
Joint pain
Rash
Other infectious diseases
Headache
Abbreviations: HIV, human immunodeficiency virus; INH, isoniazid; NPO, nothing by mouth; PZA, pyrazinamide; TB, tuberculosis.
a
Please warn families about orange urinary (and occasionally, tears and sweat) discoloration with rifampin, and warn adolescent females that rifampin, among its
many drug interactions, inactivates oral contraceptives. Other drug interactions include HIV protease inhibitors, non-nucleoside reverse-transcriptase inhibitors,
corticosteroids, and phenytoin.
Possible Cause
Taking INH without food while NPO
can cause self-limited gastric irritation
May be due to hepatotoxicity
Many INH suspension formulations are
sorbitol-based, causing an osmotic
diarrhea
INH can cause pyridoxine (vitamin B6)
deficiency-associated peripheral
neuropathy
PZA can increase serum uric acid,
although this rarely results in
symptoms
PZA is the most common TB medication Strategy contingent upon extent and character of rash.
causing rash
Common childhood infections
Nonspecific, not traditionally associated After assuring a normal examination and being sure the
with any of the first-line TB
medications
Strategy
Instruct family to give child medication with food and
see if symptoms resolve
Stop the medication and see in clinic immediately for a
more thorough history, physical examination, and
laboratory evaluation. Although most children do not
need baseline hepatic transaminases, if a child were to
develop symptoms while on LTBI therapy, clinician
threshold for obtaining transaminases should be low
Evaluation for other common causes of abdominal
pain (eg, constipation) also should occur
Change infants and children to tablets (which can be
crushed and mixed with food) once they are eating
cereal or some pureed foods
Supplement the following groups with B6:
• Exclusively breastfed infants
• Adolescents
• HIV-infected persons
• Persons with risk of malnutrition or malabsorption
Check uric acid; if elevated, stop PZA and consider an
alternative regimen
Urticarial rashes or rashes associated with wheezing
or angioedema should result in immediate cessation
of the medication
Remind family that TB medications only kill TB; most
have no spectrum of activity for other common
infections
Instruct them that children can still receive common
antibiotics (and antiviral drugs) while taking TB
medications
history does not have “red flags,” explain to families
that headaches are one of the most common locations
for pediatric pain

abdominal complaints have normal laboratory evaluation.
Even in children with transaminitis, many cases will be
due to viral infections rather than medication toxicity.
CONCLUSIONS
The decision to initiate therapy for LTBI in children is
made easier by the very favorable risk/benefit ratio com-
pared with adults: risks are minimized because children
tolerate TB medications better than adults, and children
benefit more because they have increased risk of progres-
sion to disease.
Six treatment regimens for LTBI have been demonstrat-
ed to have efficacy based mainly on studies in adults, but
only the effectiveness of INH alone has been studied exten-
sively in children. For TB disease, drug regimens that have
been shown to be effective in adults have been at least
equally effective in children, and it is likely that the same
would be true of regimens to treat LTBI. It is unlikely that
large clinical trials of the newer regimens adequately
powered to determine efficacy will be conducted in chil-
dren because of cost. However, the safety and tolerability
of additional or alternative drugs and regimens can be es-
tablished with smaller numbers of children. There are
ample data to confirm that RIF for all ages of children and
RPT for children 2 years of age are safe and well tolerat-
ed by the large majority of children.
The American Academy of Pediatrics and the CDC cur-
rently recommend 9 months of INH as preferred therapy
for children. However, there is increasing concern that the
effectiveness of this regimen in clinical practice is far less
than the efficacy demonstrated in clinical trials because
the estimated completion rate for 9 months of self-
administered INH often is less than 50%. Shorter

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 256 Cruz et al
regimens with single or multiple drugs should result in
higher rates of adherence. Therefore, it is reasonable to
consider shorter regimens for children when a 9-month
regimen of INH is unlikely to be completed.
Regimen selection must balance efficacy (degree of pro-
tection described in trials) with the rates and types of
adverse events (low in children for all the described regi-
mens), adherence, and (if available) drug susceptibilities
for the isolate obtained from the person with TB disease
who has been in contact with the child. The increasing in-
cidence of drug shortages also supports the wisdom of
having several regimens. A highly efficacious regimen may
have limited effectiveness in routine clinical use if a sub-
stantial number of patients do not complete the regimen.
For children 12 years and older, the best alternative to 9
months of INH therapy for LTBI may be 12 weekly doses
of INH + RPT administered by DOPT. This regimen is
short, effective, well tolerated, and has the advantage of
the fewest number of doses. Unfortunately, it is not current-
ly recommended to give this regimen as self-administered
treatment. Rifapentine has been in short supply, so many
health departments have not yet been able to scale-up
widespread use of this regimen. The next best alternative
to 9 months of INH alone is 4 months of RIF (to optimize
adherence). Acceptable but less well studied regimens are
3 months of daily INH + RIF or 6 months of INH. A
regimen of 2 months of RIF + PZA should be considered
acceptable only for children with TB LTBI in whom TB
disease was suspected initially and who were treated with
INH, RIF, PZA, and ethambutol therapy for 2 months.
Historically, there has been a single recommended
regimen for the treatment of LTBI for all children.
However, numerous studies and programs have demon-
strated that this monolithic approach is not sufficient to
meet the needs and abilities of all patients and families.
There are several safe, available regimens that can be used
to serve the needs of both patients and providers in the
various clinical and epidemiologic circumstances in which
LTBI is identified and managed.
Acknowledgments
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest. Conflicts that the editors consider rele-
vant to the content of the manuscript have been disclosed.
References
1. American Thoracic Society. Targeted tuberculin testing and treat-
ment of latent tuberculosis infection. Am J Respir Crit Care Med
2000; 161:S221–47.
2. Lobato MN, Sun SJ, Moonan PK, et al. Underuse of effective
measures to prevent and manage pediatric tuberculosis in the
United States. Arch Pediatr Adolesc Med 2008; 162:426–31.
Downloaded from https://academic.oup.com/jpids/article-abstract/2/3/248/1018973
by guest
on 11 June 2018
3. DuPreez K, Hesseling AC, Mandalakas AM, et al. Opportunities
for chemoprophylaxis in children with culture-confirmed tuber-
culosis. Ann Trop Paediatr 2011; 31:301–10.
4. Horsburgh CR Jr, Goldberg S, Bethel J, et al. Latent TB infection
treatment acceptance and completion in the United States. Chest
2010; 137:401–9.
5. Finnell SME, Christenson JC, Downs SM. Latent tuberculosis in-
fection in children: a call for revised treatment guidelines.
Pediatrics 2009; 123:816–22.
6. Smith SE, Kurbatova EV, Cavanaugh JS, Cegielski JP. Global iso-
niazid resistance patterns in rifampin-resistant and rifampin-
susceptible tuberculosis. Int J Tuberc Lung Dis 2012; 16:203–5.
7. Stop TB Partnership Childhood TB Subgroup World Health
Organization. Guidance for National Tuberculosis Programmes
on the Management of Tuberculosis in Children. Chapter 1:
Introduction and diagnosis of tuberculosis in children. Int J
Tuberc Lung Dis 2006; 10:1091–7.
8. Sterling TR, Villarino ME, Borisov AS, et al. Three months of
rifapentine and isoniazid for latent tuberculosis infection. N Engl
J Med 2011; 365:2155–66.
9. Centers for Disease Control and Prevention. Recommendations
for use of an isoniazid-rifapentine regimen with direct observa-
tion to treat latent Mycobacterium tuberculosis infection.
MMWR Morb Mortal Wkly Rep 2011; 60:1650–3.
10. Zar HJ, Cotton MF, Strauss S, et al. Effect of isoniazid prophy-
laxis on mortality and incidence of tuberculosis in children with
HIV: randomized controlled trial. BMJ 2007; 334:136.
11. Golub JE, Pronyk P, Mohapi L, et al. Isoniazid preventive
therapy, HAART, and tuberculosis risk in HIV-infected adults in
South Africa: a prospective cohort. AIDS 2009; 23:631–6.
12. Comstock GW, Hammes LM, Pio A. Isoniazid prophylaxis in
Alaskan boarding schools: a comparison of two doses. Am Rev
Respir Dis 1969; 100:773–9.
13. Comstock GW, Ferebee SH. How much isoniazid is needed for
prophylaxis? Am Rev Respir Dis 1970; 101:780–2.
14. Comstock GW, Baum C, Snider DE Jr. Isoniazid prophylaxis
among Alaskan Eskimos: a final report of the bethel isoniazid
studies. Am Rev Respir Dis 1979; 119:827–30.
15. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis.
A general review. Bibl Tuberc 1970; 26:28–106.
16. Hsu KH. Isoniazid in the prevention and treatment of tuberculo-
sis. A 20-year study of the effectiveness in children. JAMA 1974;
229:528–33.
17. International Union Against Tuberculosis Committee on
Prophylaxis. Efficacy of various durations of isoniazid preventive
thearpy for tuberculosis: five years of follow-up in the IUAT trial.
Bull World Health Organ 1982; 60:555–64.
18. Comstock GW. How much isoniazid is needed for prevention of
tuberculosis among immunocompetent adults? Int J Tuberc
Lung Dis 1999; 3:847–50.
19. Smieja M, Marchetti C, Cook D, Smaill F. Isoniazid for prevent-
ing tuberculosis in non-HIV infected persons. Cochrane
Database Syst Rev 2000; 2:CD001363.
20. Marais BJ, Van Zyl S, Schaaf HS, et al. Adherence to isoniazid
preventive chemotherapy: a prospective community based study.
Arch Dis Child 2006; 91:762–5.
21. Ferebee SH, Mount FW. Tuberculosis mortality in a controlled
trial of the prophylactic use of isoniazid among household con-
tacts. Am Rev Respir Dis 1962; 85:490–510.
22. Van Wyk SS, Reid AJ, Mandalakas AM, et al. Operational chal-
lenges in managing isoniazid preventive therapy in child contacts:
a high-burden setting perspective. BMC Public Health 2011; 11:
544.
23. Lobato MN, Mohle-Boetani JC, Royce SE. Missed opportunities
for preventing tuberculosis among children younger than five
years of age. Pediatrics 2000; 106:e75.

24. Cruz AT, Starke JR. Increasing adherence for latent tuberculosis
infection therapy with health department-administered therapy.
Pediatr Infect Dis J 2012; 31:193–5.
25. Wu SS, Chao CS, Vargas JH, et al. Isoniazid-related hepatic
failure in children: a survey of liver transplantation centers.
Transplantation 2007; 84:173–9.
26. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated
with isoniazid preventive therapy: a 7-year survey from a public
health tuberculosis clinic. JAMA 1999; 281:1014–8.
27. Palusci VJ, O’Hare D, Lawrence RM. Hepatotoxicity and trans-
aminase measurement during isoniazid chemoprophylaxis in
children. Pediatr Infect Dis J 1995; 14:144–8.
28. Donald PR. Antituberculous drug-induced hepatotoxicity in chil-
dren. Pediatr Rep 2011; 3:e16.
29. Pediatric Tuberculosis Collaborative Group. Targeted tuberculin
skin testing and treatment of latent tuberculosis infection in chil-
dren and adolescents. Pediatrics 2004; 114:1175–201.
30. American Academy of Pediatrics. Tuberculosis. In: Pickering LK,
Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report
of the Committee on Infectious Disease. 28th ed. Elk Grove
Village, IL: American Academy of Pediatrics; pp 2009: 680–701.
31. Cruz AT, Starke JR. Twice-weekly therapy for children with tu-
berculosis infection or exposure. Int J Tuberc Lung Dis 2013; 17:
1–6.
32. Hong Kong Chest Service/Tuberculosis Research Center,
Madras/British Medical Research Council. A double-blind
placebo-controlled clinical trial of three antituberculosis chemo-
prophylaxis regimens in patients with silicosis in Hong Kong.
Am Rev Respir Dis 1992; 145:36–41.
33. Menzies D, Dion MJ, Rabinovitch B, et al. Treatment completion
and costs of a randomized trial of rifampin for 4 months versus
isoniazid for 9 months. Am J Respir Crit Care Med 2004; 170:
445–9.
34. Menzies D, Long R, Trajman A, et al. Adverse events with 4
months rifampin or 9 months isoniazid as therapy for latent TB
infection: results of a randomized trial. Ann Intern Med 2008;
149:689–97.
35. Polesky A, Farber HW, Gottlieb DJ, et al. Rifampin preventive
therapy for tuberculosis in Boston’s homeless. Am J Respir Crit
Care Med 1996; 154:1473–7.
36. Villarino ME, Ridzon R, Weismuller PC, et al. Rifampin preven-
tive therapy for tuberculosis infection. Am J Respir Crit Care
Med 1997; 155:1735–8.
37. Page KR, Sifakis F, Montes de Oca R, et al. Improved adherence
and less toxicity with rifampin vs isoniazid for treatment of
latent tuberculosis: a retrospective study. Arch Intern Med 2006;
166:1863–70.
38. Lardizabal A, Passannante M, Kojakali F, et al. Enhancement of
treatment completion for latent tuberculosis infection with 4
months of rifampin. Chest 2006; 130:1712–7.
39. Haley CA, Stephan S, Vossel LF, et al. Successful use of rifampi-
cin for Hispanic foreign-born patients with latent tuberculosis in-
fection. Int J Tuberc Lung Dis 2008; 12:160–7.
40. Fountain FF, Tolley EA, Jacobs AR, Self TH. Rifampin hepato-
toxicity assocaited with treatment of latent tuberculosis infec-
tion. Am J Med Sci 2009; 337:317–20.
41. Fresard I, Bridevaux PO, Rochat T, Janssens JP. Adverse effects
and adherence to treatment of rifampin 4 months versus isonia-
zid 6 months for latent tuberculosis. Swiss Med Weekly 2011;
141:w13240.
42. Daskalaki I, Dogbey MC, Tolbert-Warren C, et al. Tolerability
of rifampin monotherapy for latent tuberculosis infection in chil-
dren. Pediatr Infect Dis J 2011; 30:1014–5.
43. Martinson NA, Barnes GL, Moulton LH, et al. New regimens to
prevent tuberculosis in adults with HIV infection. N Engl J Med
2011; 365:11–20.
Downloaded from https://academic.oup.com/jpids/article-abstract/2/3/248/1018973
by guest
on 11 June 2018
Pediatric Latent TB Infection Therapy 257
44. Spyridis NP, Sypridis PG, Gelesme A, et al. The effectiveness of a
9-month regimen of isoniazid alone versus 3- and 4-month regi-
mens of isoniazid plus rifampin for treatment of latent tuberculo-
sis infection in children: results of an 11-year randomized study.
Clin Infect Dis 2007; 45:715–22.
45. Martinez-Alfaro E, Cuadra F, Slera J, et al. Evaluation of 2 tuber-
culosis chemoprophylaxis regimens in patients infected with
human immunodeficiency virus. Med Clin (Barc) 2000; 15:
161–5.
46. Rivero A, Lopez-Cortez L, Castillo R, et al. Randomized trial of
three regimens to prevent tuberculosis in HIV-infected pa-
tients with anergy. Enferm Infecc Microbiol Clin 2003; 21:
287–92.
47. Geijo MP, Herranz CR, Vano D, et al. Short-course isoniazid
and rifampin compared with isoniazid for latent tuberculosis in-
fection: A randomized clinical trial [in Spanish]. Enferm Infecc
Microbiol Clin 2007; 25:300–4.
48. Rivero A, Lopez-Cortes L, Castillo R, et al. Randomized clinical
trial investigation three chomoprophylaxs regimens for latent tu-
berculosis infection in HIV-infected patients [in Spanish]. Enferm
Infecc Microbiol Clin 2007; 25:305–10.
49. Whalen CC, Johsnon JL, Okwera A, et al. A trial of three regi-
mens to prevent tuberculosis in Ugandan adults infected with the
human immunodeficiency virus. N Engl J Med 1997; 337:
801–8.
50. Martinez-Alfaro E, Solera I, Serna E, et al. Compliance, tolerance
and effectiveness of a short chemoprophylaxis regimen for the
treatment of tuberculosis [in Spanish]. Med Clin (Barc) 1998;
111:401–4.
51. Ormerod LP. Reduced incidence of tuberculosis by prophylactic
chemotherapy in subjects showing strong reactions to tuberculin
testing. Arch Dis Child 1987; 62:1005–8.
52. Ormerod LP. Rifampicin and isoniazid prophylactic chemothera-
py for tuberculosis. Arch Dis Child 1998; 78:169–71.
53. Bright-Thomas R, Nandwani S, Smith J, et al. Effectiveness of 3
months of rifampicin and isoniazid chemoprophylaxis for the
treatment of latent tuberculosis infection in children. Arch Dis
Child 2010; 95:600–2.
54. Jasmer RM, Snyder DC, Chin DP, et al. Twelve months of isonia-
zid compared with four months of isoniazid and rifampin for
persons with radiographic evidence of previous tuberculosis. Am
J Resp Crit Care Med 2000; 162:1648–52.
55. Van Zyl S, Marais BJ, Hesseling AC, et al. Adherence to anti-
tuberculosis chemoprophylaxis and treatment in children. Int J
Tuberc Lung Dis 2006; 10:13–8.
56. McNab BD, Marciniuk DD, Alvi RA, et al. Twice weekly isonia-
zid and rifampin treatment of latent tuberculosis infection in
Canadian Plains Aborigines. Am J Resp Crit Care Med 2000;
162:989–93.
57. Ena J, Walls V. Short-course therapy with rifampin plus isonia-
zid, compared with standard therapy with isoniazid for latent tu-
berculosis infection: a meta-analysis. Clin Infect Dis 2005; 40:
670–6.
58. Schechter M, Zajdenverg R, Falco G, et al. Weekly rifapentine/
isoniazid or daily rifampin/pyrazinamide for latent tuberculosis
in household contacts. Am J Respir Crit Care Med 2006; 173:
922–6.
59. Blake MJ, Abdel-Rahman SM, Jacobs RF, et al.
Pharmacokinetics of rifapentine in children. Pediatr Infect Dis J
2006; 25:405–9.
60. Villarino E, Scott N, Weis S, et al. Tolerability among children of
three months of once-weekly rifapentine+isoniazid (3HP) vs 9
months of daily INH (9H) for treatment of latent tuberculosis in-
fection: The PREVENT TB study (TBTC Study 26/ACTG 5259).
Infectious Disease Society of America Annual Meeting Abstract
1323, San Diego, CA, October 20, 2012.
 258 Cruz et al
61. Gordin F, Chaisson RE, Matts JP, et al. Rifampin and pyrazina-
mide vs isoniazid for prevention of tuberculosis in HIV-infected
persons: an international randomized trial. Terry Biern
Community Programs for Clinical Research on AIDS, the Adult
AIDS Clinical Trials Group, the Pan American Health
Organization, and the Centers for Disease Control and Prevention
Study Group. JAMA 2000; 283:1445–50.
62. Leung CC, Law WS, Chang KC, et al. Initial experience on ri-
fampin and pyrazinamide versus isoniazid in the treatment of
latent tuberculosis infection among patients with silicosis in
Hong Kong. Chest 2003; 124:2112–8.
63. Halsey NA, Coberly JS, Desormeaux J, et al. Randomised
trial of isoniazid versus rifampicin and pyrazinamide for preven-
tion of tuberculosis in HIV-1 infection. Lancet 1998; 351:786–92.
64. Jasmer RM, Saukkonen JJ, Blumberg HM, et al. Short-course ri-
fampin and pyrazinamide compared with isoniazid for latent tu-
berculosis infection: a multicenter clinical trial. Ann Intern Med
2002; 137:640–7.
65. Gordin FM, Cohn DL, Matts JP, et al. Hepatotoxicity of rifam-
pin and pyrazinamide in the treatment of latent tuberculosis in-
fection in HIV-infected persons: is it different than in
HIV-uninfected persons. Clin Infect Dis 2004; 15:561–5.
66. Bock NN, Rogers T, Tapia JR, et al. Acceptability of short-
course rifampin and pyrazinamide treatment of latent tuberculo-
sis infection among jail inmates. Chest 2001; 119:833–7.
67. Diaz A, Diez M, Bleda MJ, et al. Eligibility for and outcome of
treatment of latent tuberculosis infection in a cohort of
HIV-infected people in Spain. BMC Infect Dis 2010; 10:267.
68. Cook PP, Maldonado RA, Yarnell CT, Holbert D. Safety and
completion of short-course therapy for treatment of latent tuber-
culosis infection. CIin Infect Dis 2006; 43:271–5.
69. Priest DH, Vossel LF Jr, Sherfy EA, et al. Use of intermittent ri-
fampin and pyrazinamide therapy for latent tuberculosis infec-
tion in a targeted tuberculin testing program. Clin Infect Dis
2004; 15:1764–71.
70. Van Hest R, Baars H, Sik S, et al. Hepatotoxicity of rifampin-
pyrazinamide and isoniazid preventive therapy and tuberculosis
treatment. Clin Infect Dis 2004; 15:488–96.
71. McNeill L, Allen M, Estrada C, Cook P. Pyrazinamide and ri-
fampin versus isoniazid for the treatment of latent tuberculosis:
Downloaded from https://academic.oup.com/jpids/article-abstract/2/3/248/1018973
by guest
on 11 June 2018
improved completion rates, but more hepatotoxicity. Chest
2003; 123:102–6.
72. Gao XF, Wang L, Liu GJ, et al. Rifampicin plus pyrazinamide
versus isoniazid for treating latent tuberculosis infection: a meta-
analysis. Int J Tuberc Lung Dis 2006; 10:1080–90.
73. Duarte R, Carvalho A, Correia A. Two-month regimen of isonia-
zid, rifampin, and pirazinamid for latent tuberculosis infection.
Public Health 2012; 126:760–2.
74. Centers for Disease Control and Prevention. Update: adverse
event data and revised American Thoracic Society/CDC recom-
mendations against the use of rifampin and pyrazinamide for
treatment of latent tuberculosis infection – United States, 2003.
MMWR Morb Mortal Wkly Rep 2003; 52:735–9.
75. Powell DA, Perkins L, Wang SH, et al. Completion of therapy for
latent tuberculosis in children of different nationalities. Pediatr
Infect Dis J 2008; 27:272–4.
76. Parsyan AE, Saukkonen J, Barry MA, et al. Predictors of failure
to complete therapy for latent tuberculosis infection. J Infect
2007; 54:262–6.
77. Kwara A, Herold JS, Machan JT, Carter EJ. Factors associated
with failure to complete isoniazid treatment for latent tuberculo-
sis infection in Rhode Island. Chest 2008; 133:862–8.
78. Stuart RL, Wilson J, Grayson ML. Isoniazid toxicity in health-
care workers. Clin Infect Dis 1999; 28:895–7.
79. Skinner D, Mandalakas AM. Pasting together the preventive
therapy puzzle. Int J Tuberc Lung Dis 2013; 17:175–7.
80. Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side
effects from first-line antituberculosis drugs among patients
treated for active tuberculosis. Am J Respir Crit Care Med 2003;
167:1472–7.
81. Sanchez-Albisua I, Vidal ML, Joya-Verde G, et al.
Tolerance of pyrazinamide in short-course chemotherapy for
pulmonary tuberculosis in children. Pediatr Infect Dis J 1997;
16:760–3.
82. Lee SH, Yim JJ, Kim HJ, et al. Adverse events and development
of tuberculosis after 4 months of rifampicin prophylaxis in a tu-
berculosis outbreak. Epidemiol Infect 2012; 140:1028–35.
83. O’Brien RJ, Long MW, Cross FS, et al. Hepatotoxicity from iso-
niazid and rifampin among children treated for tuberculosis.
Pediatrics 1983; 72:491–9.