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JAMA Pediatr. Author manuscript; available in PMC 2019 July 12.
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Published in final edited form as:

JAMA Pediatr. 2015 March ; 169(3): 247–255. doi:10.1001/jamapediatrics.2014.3158.

Treatment for Preventing Tuberculosis in Children and

Adolescents:
A Randomized Clinical Trial of a 3-Month, 12-Dose Regimen of a Combination of
Rifapentine and Isoniazid

M. Elsa Villarino, MD, MPH,

Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta,
Author Manuscript

Georgia

Nigel A. Scott, MS,

Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta,
Georgia

CDC Foundation, Atlanta, Georgia

Stephen E. Weis, DO,

Department of Medicine, University of North Texas Health Science Center at Ft Worth

Marc Weiner, MD,

Department of Medicine, Audie L. Murphy San Antonio Veterans Administration Medical Center,
San Antonio, Texas
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Marcus B. Conde, MD,

Department of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

Brenda Jones, MD,

Department of Medicine, University of Southern California, Los Angeles

Corresponding Author: Ruth N. Moro, MD, MPH, Division of Tuberculosis Elimination, Centers for Disease Control and
Prevention, Building 12, Mail Stop E-10, Atlanta, GA 30329 ([email protected]).
Author Contributions: Mr Scott and Dr Shang had full access to all the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis.
Study concept and design: Villarino, Weis, Weiner, Nachman, Oliveira, Shang, Sterling.
Acquisition, analysis, or interpretation of data: Villarino, Scott, Weiner, Conde, Jones, Moro, Shang, Goldberg, Sterling.
Drafting of the manuscript: Villarino, Scott, Weis, Weiner, Nachman, Goldberg, Sterling.
Critical revision of the manuscript for important intellectual content: Villarino, Weiner, Conde, Jones, Nachman, Oliveira, Moro,
Shang, Goldberg, Sterling.
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Statistical analysis: Villarino, Scott, Shang. Administrative, technical, or material support: Villarino, Weiner, Nachman, Goldberg.
Study supervision: Villarino, Goldberg, Sterling.
Conflict of Interest Disclosures: Mr Scott and Dr Moro report being employed by the CDC Foundation, which receives funds for
rifapentine research from Sanofi. Dr Weiner reports receiving a grant to perform rifapentine pharmacokinetics studies in children and
adults for the University of Texas Health Science Center at San Antonio from Sanofi. Dr Sterling reports giving a 1-day consultation
for Sanofi for presentation of PREVENT TB study data to the US Food and Drug Administration and being on the data safety
monitoring board for a clinical trial sponsored by Otsuka Pharmaceutical. No other disclosures were reported.
Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position
of the CDC.
Group Information: A list of the International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and the
Tuberculosis Trials Consortium (TBTC) members is included in eAppendix 1 in the Supplement.
Previous Presentation: Preliminary results of this study were presented at ID Week 2012, a Joint Meeting of the Infectious Diseases
Society of America, Society for Healthcare Epidemiology of America, HIV Medicine Association, and Pediatric Infectious Diseases
Society; October 20, 2012; San Diego, California.
 Villarino et al. Page 2

Sharon Nachman, MD,

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Department of Pediatrics, State University of New York at Stony Brook

Ricardo Oliveira, MD,

Department of Pediatrics, Pediatric Institute, Federal University of Rio de Janeiro, Rio de Janeiro,
Brazil

Ruth N. Moro, MD, MPH,

Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta,
Georgia

CDC Foundation, Atlanta, Georgia

Nong Shang, PhD,

Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta,
Georgia
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Stefan V. Goldberg, MD, and

Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta,
Georgia

Timothy R. Sterling, MD
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

International Maternal Pediatric and Adolescents AIDS Clinical Trials Group (IMPAACT) and
the Tuberculosis Trials Consortium (TBTC)

Abstract
IMPORTANCE—Three months of a once-weekly combination of rifapentine and isoniazid for
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treatment of latent tuberculosis infection is safe and effective for persons 12 years or older.
Published data for children are limited.

OBJECTIVES—To compare treatment safety and assess noninferiority treatment effectiveness of

combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent
tuberculosis infection in children.

DESIGN, SETTING, AND PARTICIPANTS—A pediatric cohort nested within a randomized,

open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-
up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong
(China), and Spain. Participants were children (aged 2–17 years) who were eligible for treatment
of latent tuberculosis infection.

INTERVENTIONS—Twelve once-weekly doses of the combination drugs, given with

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supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without
supervision by a health care professional, for 9 months.

MAIN OUTCOMES AND MEASURES—We compared rates of treatment discontinuation

because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The
equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis
disease diagnosed within 33 months of enrollment was the main end point for testing
effectiveness. The noninferiority margin was 0.75%.

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RESULTS—Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471
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in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the
isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation
attributed to an AE was −2.6 to 0.1, which was within the equivalence range. In the safety
population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of
493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or
treatment-attributed death. None of the 471 in the combination-therapy group developed
tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of
−0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the
noninferiority criterion.

CONCLUSIONS AND RELEVANCE—Treatment with the combination of rifapentine and

isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children
aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than
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did the isoniazid-only group and was safe.

TRIAL REGISTRATION—clinicaltrials.gov Identifier: NCT00023452

A substantial portion of the global burden of active and latent tuberculosis (TB) is found in
children.1–3 Treatment of latent Mycobacterium tuberculosis infection (LTBI) in children is
beneficial, both for the child and for public health, because it prevents development of TB
and limits future M tuberculosis transmission.4–7 The benefits of treatment of LTBI are
greater for children than for adults for several reasons: LTBI in children younger than 5
years is always recently acquired (ie, within 5 years), and recent infection has a higher
likelihood of progression to disease than infection acquired less recently; children have an
increased risk of developing severe TB with sequela (eg, meningitis and disseminated
disease); children have more years at risk for the development of TB than adults; and
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children tolerate treatment for LTBI better than adults.

Soon after effective treatment was established for active TB, studies began to determine
whether treatment of LTBI could prevent active TB, as well as in what settings and with
what duration. In the 1950s and 1960s, Lincoln and Vera Cruz8,9 and Ferebee et al10,11
established that isoniazid given daily for 12 months was effective in preventing TB in adults
and children with LTBI. Shorter LTBI treatment regimens are associated with improved
adherence and treatment completion in adults and children.12–14 Supervised (ie, directly
observed) LTBI therapy in children increased adherence by 57% in South Africa.15 In the
United States, some TB control departments use directly observed therapy for the
administration of LTBI treatment to persons at highest risk of developing TB, including
children, if sufficient resources are available.16,17 Recently, the PREVENT TB (Three
Months of Rifapentine and Isoniazid for Latent Tuberculosis Infection)18 clinical trial
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demonstratedthat a short-course combination regimen of rifapentine and isoniazid for 3

months given with direct observation was as effective as the reference-standard 9-month
regimen of self-administered isoniazid in persons 12 years or older; combination therapy
with rifapentine and isoniazid was safe and had a higher treatment completion rate.
However, too few children were enrolled for safety and effectiveness to be evaluated
separately. Along with additional evidence from 2 smaller clinical trials,19,20 the findings of
the PREVENT TB trial led the Centers for Disease Control and Prevention to recommend

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use of the new 3-month regimen for treatment of LTBI in adults and children at least 12
years of age.21
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The pharmacokinetics of rifapentine in children younger than 12 years were not known at
the start of the PREVENT TB study. When these data became available in 2005,22
enrollment criteria were modified to include children aged 2 to 11 years. We report here the
results among all children aged 2 to 17 years from this multicenter randomized clinical trial.

Methods
Population, Treatment, and Monitoring
Children and adolescents were enrolled from 29 study sites in the United States, Canada,
Brazil, Hong Kong (China), and Spain in 23 Tuberculosis Trials Consortium (TBTC) sites
and 6 International Maternal Pediatric and Adolescents AIDS Clinical Trials Group
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(IMPAACT) sites. The study protocol was approved by institutional review boards at the
Centers for Disease Control and Prevention, the National Institutes of Health, and all study
sites. Children had informed consent signed by at least 1 parent and provided informed
assent in accordance with local human subjects protection regulations. Children were
eligible to participate in the trial if they met specific criteria indicating high risk for TB
according to age, tuberculin skin test (TST) results, and TB exposure history and did not
meet any study exclusion criteria (eAppendix 2 in the Supplement). Enrollment did not
require knowledge of human immunodeficiency virus (HIV) serostatus or HIV testing. The
age criterion for inclusion of children in the PREVENT TB trial changed with protocol
amendments over time: from June 5, 2001, to November 22, 2005, enrollment included
children aged 12 years to younger than 18 years; from November 23, 2005, to February 15,
2008 (starting as soon as was feasible after pharmacokinetic data became available), children
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aged 2 years to younger than 18 years; and from February 16, 2008 (end of parent trial
enrollment), to December 17, 2010, children aged 2 years to younger than 12 years
regardless of HIV serostatus and 12 years to younger than 18 years only if they were known
to be HIV seropositive (eFigure in the Supplement).

Children in the isoniazid-only group were prescribed 270 daily doses of isoniazid dispensed
in 30-day allotments. For this arm of the trial, isoniazid was either self-administered (ie, by
the patient or the parent, without supervision by a health care professional) or directly
observed, following the study site administration guidelines for children. If directly observed
therapy was used during isoniazid-only treatment, frequency remained daily. Children
enrolled in the combination-therapy group were prescribed a regimen of 12 weekly doses of
a combination of rifapentine and isoniazid (eTable in the Supplement23). All doses for
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rifapentine plus isoniazid were given by directly observed therapy. Directly observed therapy
was defined as treatment for which a study health care professional prepared and observed
ingestion of each dose. Completion of rifapentine plus isoniazid therapy was defined as
administration of 11 of no more than 12 weekly, directly observed therapy doses in 10 to 16
weeks. Completion of isoniazid only was defined as receipt of 240 of no more than 270
daily doses in 35 to 52 weeks. Receipt of isoniazid doses was assessed by interview with the
parent and child and verified by pill count at monthly clinic visits, which included
standardized symptom evaluations.

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Clinician investigators reported adverse events (AEs) from enrollment through 60 days after
the last dose of study medications. Information regarding type, management, seriousness,24
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toxicity grade,25 and relatedness to the study medications (definite, probable, possible,
unlikely, or not related) was reported for each event. We categorized AEs as not attributed to
treatment when they had been determined to be unlikely or not related to the study drugs.
Serious AEs included death during therapy or within 60 days of the last dose, life-
threatening events, hospitalization, disability or permanent damage, and congenital anomaly.
Posttreatment follow-up began after the participant completed or discontinued treatment
with study medications. In each treatment arm, follow-up evaluations were conducted every
3 months until 21 months after enrollment, then every 6 months (months 27 and 33) until the
end of study follow-up (33 months after enrollment). Case finding was active, following
protocol guidelines, with follow-up evaluations conducted by telephone until the final visit,
which was in person and conducted at a clinic with specialized experience in the diagnosis
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and treatment of TB in children. The trial protocol defined TB in children as either

confirmed by M tuberculosis in culture or diagnosed clinically based on the TB diagnostic
criteria of the American Thoracic Society and Centers for Disease Control and Prevention,26
with diagnosis and treatment guidance from the American Academy of Pediatrics.27

Randomization, Study Objectives, and Populations for Analysis

The trial used a parallel-design unrestricted randomization method. Children were
randomized either individually or by household. If 2 or more inhabitants agreed to
participate in the trial, they were assigned to the same study treatment as the first enrolled
member of their household (eAppendix 3 in the Supplement). The primary objective of the
PREVENT TB pediatric study was the equivalence comparison of treatment safety between
the 2 study arms. The secondary objective was to assess the treatment effectiveness of
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combination therapy for noninferiority compared with the isoniazid-only regimen for the
prevention of TB. We used 3 study populations for analysis: (1) intention to treat–which
included all children in the study–for the analysis of demographic characteristics and
evaluation of differences between arms; (2) safety population–which included all children
who took 1 or more doses of the study medication; and (3) modified intention to treat–which
included all children who were protocol eligible–for the analysis of treatment completion
and treatment effectiveness (Figure 1). Follow-up continued through September 5, 2013.
Tuberculosis end points were evaluated and confirmed by consensus of an independent 3-
person panel of experts who were masked to the study arm and the study site that reported
the TB end point.

Sample Size, Study Power, and Statistical Methods

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We tested the hypothesis that there would be no difference in the rates of treatment
discontinuation attributed to AEs between the 2 treatment arms. We considered results with
5% or less difference between the rates of treatment discontinuation attributed to AEs to be
clinically equivalent. Assuming 15% loss to follow-up, 80% power, a type 1 error rate of
0.05, and 1% rate of discontinuation attributed to AEs in the standard treatment arm, the
sample size estimate for testing the main safety hypothesis was 322 children per arm. The
95% CI of the difference of the rates of discontinuation attributed to AEs was calculated and

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 Villarino et al. Page 6

then compared with the equivalence region (−5% to 5%). P values were calculated using the
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Fisher exact test to determine whether the rates were significantly different.

For the PREVENT TB core trial population composed mostly of adults and some
adolescents, the primary objective was an evaluation for noninferiority of the treatment
effectiveness of the combination therapy with rifapentine and isoniazid.18 In this nested
study, treatment effectiveness testing was a secondary objective, and there was neither a
separate sample size calculation nor a different proposed noninferiority margin for testing
the effectiveness in children. Because of the small number of TB endpoints available for the
estimation of noninferior effectiveness in children, the Wilson Score Interval for rare
binomial events28,29 was used. This procedure allowed the construction of a highly
conservative (ie, wider) 95% CI for comparison against the noninferiority margin. If the
upper bound of the 95% CI was less than the noninferiority margin of 0.75%, then the
noninferiority of the experimental arm would be established. To evaluate the potential effects
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of age and sex imbalances between study arms on the noninferiority test statistic, we ran a
Monte Carlo sampling distribution simulation, weighted for age and sex, to eliminate
potential bias from imbalances in enrollment (eAppendix 4 in the Supplement).

Results
We enrolled 1058 participants aged 2 to 17 years from June 11, 2001, through December 17,
2010. There were 552 in the combination-therapy group and 506 in the isoniazid-only group
(intention-to-treat population) (Table 1, Figure 1, and eFigure in the Supplement). Fifteen
children (3%) enrolled in the isoniazid-only group received at least some daily doses by
directly observed therapy. Of the 1058 children enrolled, 905 were eligible for the efficacy
analysis (modified intention-to-treat population) and 1032 received 1 or more dose of study
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medication (safety population). The most common reason for exclusion after enrollment was
the finding of a negative TST result 8 to 12 weeks after a baseline negative TST result
among children 5 years or younger who had a history of contact with an infectious patient
with TB (91 of 153 [59%] children) (Figure 1). Of 1058 children enrolled, 989 (93%) were
enrolled as contacts and 69 (7%) were enrolled with TST conversion (eAppendix 2 in the
Supplement). Five (<1%) were infected with HIV. The differences by treatment arm in age
and sex were larger than expected: the median age for the combination-therapy group was 10
years (interquartile range, 4–15) vs 12 years for the isoniazid-only group (interquartile
range, 4–15); in the combination-therapy group, 54% were male vs 48% male in the
isoniazid-only group (Table 1). The median TST size of the 929 participants with a TST
reaction size of 5 mm or greater at enrollment was 15 mm (interquartile range, 12–20) and
there was no significant difference in TST reaction size by age category (Table 1).
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The overall treatment completion rates were 88.1% in the combination-therapy group and
80.9% in the isoniazid-only group (P = .003) (Table 2). The rates of treatment
discontinuation attributed to AEs were 1.7% in the combination-therapy group and 0.5% in
the isoniazid-only group (P = .11) (Table 2). The 95% CI for the difference in rates of
discontinuation attributed to an AE was −2.6 to 0.1, which is within the equivalence range of
−5% to 5% (Table 2). The AEs that led to treatment discontinuation in the combination-
therapy group included 3 influenza-like events, 3 cutaneous events (all with pruritic rash and

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1 with oral blisters and fever), and 2 gastrointestinal tract events. The AEs that led to
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treatment discontinuation in the isoniazid-only group were 1 cutaneous reaction and 1

gastrointestinal tract event. In the combination-therapy group, treatment discontinuation
attributed to unavailability for follow-up for 3 months or more during the treatment phase
was significantly less than in the isoniazid-only group (P < .001) (Table 2), and no serious
AEs were reported (Table 3).

Four AEs attributed to treatment were scored as toxicity grade 3, including 3 of 539 (0.6%)
in the combination-therapy group (1 influenza-like event and 2 cutaneous events) and 1 of
493 (0.2%) in the isoniazid-only group (hepatomegaly and rash) (Table 3). No hepatic events
were attributed to treatment in either arm. One hepatic event was not attributed to treatment
in a 3-year-old with a new diagnosis of Kawasaki disease and elevated liver enzyme values.
No AEs were attributed to treatment among the 5 pediatric participants (aged 12–17 years)
who were known to be HIV infected. There were 2 deaths in adolescents, both in the
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isoniazid-only group. One was caused by cardiac arrhythmia on day 201 of study treatment,
and 1 was caused by a gunshot injury 657 days after completing treatment (Table 3).

The modified intention-to-treat population (n = 905) accumulated 2320 person-years of

follow-up. The cumulative proportion of children in whom TB was diagnosed was zero of
471 (0%) in the combination-therapy group vs 3 of 434 (cumulative rate, 0.74%) in the
isoniazid-only group (1 with sputum culture positive for M tuberculosis and 2 by clinical
criteria alone), for rates of 0 vs 0.27 per 100 person-years of follow-up. The observed
difference in the rates of TB was −0.74%, of which the upper limit of the 1-sided 97.5% CI
was 0.32%. This limit was below the noninferiority margin of 0.75% (Figure 2). The
strength of rejecting the null hypothesis and the claim of noninferiority of the combination
therapy with rifapentine and isoniazid compared with that of isoniazid only was not affected
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by the age and sex imbalance between the 2 study arms (eAppendix 4 in the Supplement).

Our trial was an open-label study in which children in the combination-therapy group were
seen for treatment every week by a study health care professional, whereas participants in
the isoniazid-only group were seen monthly. The knowledge of treatment assignment and
increased frequency of contact with the study health care professional in the combination-
therapy group could have introduced ascertainment bias when determining events to be
attributed to study drugs. However, visits for clinical evaluation occurred at the same
frequency (ie, monthly) in both study arms. The sample size obtained for this study
population was larger than necessary for the 80% power needed to assess the main
hypothesis of the safety of the 2 regimens. Unfortunately, we were unable to enroll children
younger than 2 years, and only 5 children with HIV infection were enrolled, limiting
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generalizability to those high-risk groups.

Evaluation of the effectiveness of any regimen for LTBI is challenging because of the large
sample size required for analysis.3,30,31 Our article describes a large pediatric population
(approximately 1000 participants), including 539 children younger than 12 years and 296
children aged 2 to 4 years. Trial enrollment was expanded to the lower age ranges as soon as
was feasible after completion of targeted pharmacokinetic studies. Even with active case

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finding, it is possible that some cases were missed. However, there is no evidence that
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ascertainment of cases varied by treatment arm.

Discussion
We found that combination therapy with rifapentine and isoniazid was well tolerated and
safe in children aged 2 to 17 years who were treated for LTBI. The overall treatment
completion rate was higher for combination therapy than isoniazid only (88.1% vs 80.9%).
This outcome was consistent with findings in the main study18 as well as those of previous
articles,12,13 which indicated that a shorter treatment regimen and direct observation of
therapy correlate with higher completion rates. The rates of treatment discontinuation
attributed to abandonment or refusal of further treatment for reasons other than medical
indication were high, and were significantly higher among children who were treated with
isoniazid only; the rates of treatment discontinuation attributed to an AE were low and
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similar in both treatment groups. Hepatotoxicity attributed to treatment–one of the AEs of

most concern in adults treated with isoniazid–was not observed in children in this study.
Deaths and serious AEs were rare and not related to either treatment regimen.

In general, children tolerate larger doses per kilogram of body weight and have fewer AEs
when treated with anti-TB medications.32 Drug exposure was 1.3-fold higher in children
compared with the exposures obtained with successful treatment for LTBI in adults in a
pharmacokinetic substudy.33 By nesting a case-control pharmacokinetic evaluation
comparing 81 children aged 2 to 11 years with 80 matched adults enrolled in the PREVENT
TB trial, we were able to verify that the weight-based dosage recommendations for LTBI
therapy with rifapentine (for 10–14 kg, 300 mg; 14.1–25 kg, 450 mg; 25.1–32 kg, 600 mg;
and 32.1–50 kg, 750 mg) achieved the minimum target area under the concentration curve
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from time zero to infinity in almost all children. After evaluating several approaches the
study protocol allowed for crushing the rifapentine tablets and producing a slurry by mixing
the crushed medication with some types of food.23 This method of medication
administration is not well standardized and adds complexity to treating children for LTBI.
There is, at present, no pediatric formulation for rifapentine; a water-dispersible tablet for
use in children is in development (Marilyn Maroni, MD, Sanofi, oral presentation, October
15, 2014).

The pharmacokinetic substudy confirmed that food increases rifapentine bioavailability in

children by 40%.33 However, crushing the tablets to give them with food resulted in a 26%
decrease in bioavailability, and between-subject variability in clearance was 40%.33 An
evaluation of whether food influenced the safety or effectiveness of treatment was beyond
the scope of this study. Current recommendations do not address whether combination
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therapy with rifapentine and isoniazid should be given with food.21

Our study also demonstrated that, in children, directly observed, once-weekly therapy with
rifapentine plus isoniazid for 12 doses was as effective as isoniazid that was mostly self-
administered daily for 9 months. The clinical trial setting might have increased the effect of
isoniazid compared with its effect in an operational setting without the close monitoring and
motivation of a clinical trial. This difference between clinical trial and operational settings

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might have less influence on a much shorter regimen, giving the short regimen an
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effectiveness advantage. Furthermore, the shorter regimen might encourage more treatment
starts because of the promise of a briefer time commitment. More treatment starts and
greater completion rates might together result in a standard regimen whereby rifapentine
plus isoniazid prevent more cases of TB than are prevented by isoniazid alone.

Conclusions
Latent TB infection and TB in children are sentinel events for recent M tuberculosis
transmission. Treating children with LTBI with a well-tolerated and safe regimen that is
more likely to be completed than previous treatment regimens provides an improved
opportunity to diminish the reservoir from which future TB cases and subsequent
transmission will arise, although this effect will be smaller in high-incidence settings.
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A 3-month (12-dose) regimen given by direct observation is a new alternative regimen to

isoniazid for treatment of LTBI in children and adolescents.34

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
Funding/Support: Sanofi provided the rifapentine for this study and has donated more than $2.5 million to the
CDC Foundation to supplement available US federal funding for rifapentine research.

Role of the Funder/Sponsor: Sanofi had no role in the design and conduct of the study; collection, management,
analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit
the manuscript for publication.
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REFERENCES
1. Swaminathan S, Rekha B. Pediatric tuberculosis: global overview and challenges. Clin Infect Dis.
2010;50(suppl 3):S184–S194. [PubMed: 20397947]
2. World Health Organization. Global Tuberculosis Report 2012. Geneva, Switzerland: World Health
Organization; 2012.
3. Perez-Velez CM, Marais BJ. Tuberculosis in children. N Engl J Med. 2012;367(4):348–361.
[PubMed: 22830465]
4. Ferebee SH. An epidemiological model of tuberculosis in the United States. Bull Nat Tubercu
Assoc. 1967;53:4–7.
5. Heymann SJ, Brewer TF, Wilson ME, Colditz GA, Fineberg HV. Pediatric tuberculosis: what needs
to be done to decrease morbidity and mortality. Pediatrics. 2000;106(1):1. [PubMed: 10878140]
6. Morrison J, Pai M, Hopewell PC. Tuberculosis and latent tuberculosis infection in close contacts of
Author Manuscript

people with pulmonary tuberculosis in low-income and middle-income countries: a systematic

review and meta-analysis. Lancet Infect Dis. 2008;8(6):359–368. [PubMed: 18450516]
7. Rutherford ME, Hill PC, Triasih R, Sinfield R, van Crevel R, Graham SM. Preventive therapy in
children exposed to Mycobacterium tuberculosis: problems and solutions. Trop Med Int Health.
2012; 17(10):1264–1273. [PubMed: 22862994]
8. Lincoln EM. The effect of antimicrobial therapy on the prognosis of primary tuberculosis in
children. Am Rev Tuberc. 1954;69(5):682–689. [PubMed: 13148531]
9. Lincoln EM, Vera Cruz PG. Progress in treatment of tuberculosis: results of antimicrobial therapy in
a group of 420 children with tuberculosis. Pediatrics. 1960;25(6):1035–1042. [PubMed: 14417033]

JAMA Pediatr. Author manuscript; available in PMC 2019 July 12.

 Villarino et al. Page 10

10. Ferebee S, Mount FW, Anastasiades A. Prophylactic effects of isoniazid on primary tuberculosis in
children: a preliminary report. Am Rev Tuberc. 1957;76(6):942–963. [PubMed: 13488005]
Author Manuscript

11. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis: a general review. Bibl Tuberc.
1970; 26:28–106. [PubMed: 4903501]
12. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations
of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. Bull
World Health Organ. 1982;60(4):555–564. [PubMed: 6754120]
13. Horsburgh CR Jr, Goldberg S, Bethel J, et al.; Tuberculosis Epidemiologic Studies Consortium.
Latent TB infection treatment acceptance and completion in the United States and Canada. Chest.
2010;137(2):401–409. [PubMed: 19793865]
14. Spyridis NP, Spyridis PG, Gelesme A, et al. The effectiveness of a 9-month regimen of isoniazid
alone versus 3- and 4-month regimens of isoniazid plus rifampin for treatment of latent
tuberculosis infection in children: results of an 11-year randomized study. Clin Infect Dis.
2007;45(6):715–722. [PubMed: 17712755]
15. van Zyl S, Marais BJ, Hesseling AC, Gie RP, Beyers N, Schaaf HS. Adherence to anti-tuberculosis
chemoprophylaxis and treatment in children. Int J Tuberc Lung Dis. 2006;10(1):13–18. [PubMed:
Author Manuscript

16466031]
16. Pediatric Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent
tuberculosis infection in children and adolescents. Pediatrics. 2004;114(4):1175–1201. doi:
10.1542/peds.2004-0809.
17. Centers for Disease Control and Prevention. Latent tuberculosis infection: a guide for primary
health care providers. Bethesda, MD: US Dept of Health and Human Services, Centers for Disease
Control and Prevention; 2013 http://www.cdc.gov/tb/publications/LTBI/default.htm. Accessed
November22, 2014.
18. Sterling TR, Villarino ME, Borisov AS, et al.; TB Trials Consortium PREVENT TB Study Team.
Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med.
2011;365(23): 2155–2166. [PubMed: 22150035]
19. 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(8):922–926. [PubMed: 16474028]
20. Martinson NA, Barnes GL, Moulton LH, et al. New regimens to prevent tuberculosis in adults with
Author Manuscript

HIV infection. N Engl J Med. 2011;365(1):11–20. [PubMed: 21732833]

21. Centers for Disease Control and Prevention. Recommendations for use of an isoniazid-rifapentine
regimen with direct observation to treat latent Mycobacterium tuberculosis infection. MMWR
Morb Mortal Wkly Rep. 2011;60(48):1650–1653. [PubMed: 22157884]
22. Blake MJ, Abdel-Rahman SM, Jacobs RF, Lowery NK, Sterling TR, Kearns GL. Pharmacokinetics
of rifapentine in children. Pediatr Infect Dis J. 2006;25(5):405–409. [PubMed: 16645503]
23. Peloquin CA, Durbin D, Childs J, Sterling TR, Weiner M. Stability of antituberculosis drugs mixed
in food. Clin Infect Dis. 2007;45(4):521.
24. Food and Drug Administration. Guidance for industry and investigators on safety reporting
requirements for investigational new drug applications and BA/BE studies. Washington, DC: US
Dept of Health and Human Services, Food and Drug Administration; 2012 http://www.fda.gov/
downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm227351.pdf. Accessed
November 22, 2014.
25. Cancer Therapy Evaluation Program. Common terminology criteria for adverse events. Bethesda,
Author Manuscript

MD: National Cancer Institute, US National Institutes of Health; 1999 http://ctep.cancer.gov/

protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf. Accessed November 22,
2014.
26. American Thoracic Society; US Department of Health and Human Services; US Public Health
Service; Centers for Disease Control and Prevention. Diagnostic standards and classification of
tuberculosis in adults and children. Washington, DC: US Dept of Health and Human Services,
Public Health Service; 2000.
27. Pickering LK, Baker CJ, Kimberlin DW, Long SS. Red Book: 2012 Report of the Committee on
Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2012.

JAMA Pediatr. Author manuscript; available in PMC 2019 July 12.

 Villarino et al. Page 11

28. Agresti AC, Brent A. Approximate is better than “exact” for interval estimation of binomial
proportions. Am Stat. 1998;52(2):119–126. doi: 10.2307/2685469.
Author Manuscript

29. Newcombe RG. Interval estimation for the difference between independent proportions:
comparison of eleven methods. Stat Med. 1998;17 (8):873–890. [PubMed: 9595617]
30. Brent AJ, Anderson ST, Kampmann B. Childhood tuberculosis: out of sight, out of mind? Trans R
Soc Trop Med Hyg. 2008;102(3):217–218. [PubMed: 17996915]
31. Burman WJ, Cotton MF, Gibb DM, Walker AS, Vernon AA, Donald PR. Ensuring the involvement
of children in the evaluation of new tuberculosis treatment regimens. PLoS Med. 2008;5(8):e176.
[PubMed: 18715115]
32. Starke JR. Childhood tuberculosis: treatment strategies and recent advances. Paediatr Respir Rev.
2001;2(2):103–112. [PubMed: 12531056]
33. Weiner MS, Mac Kenzie WR, Wing D, et al. Rifapentine pharmacokinetics and tolerability in
children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis
infection [published online January 16,2014]. J Ped Infect Dis Soc. doi:10.1093/jpids/pit077.
34. World Health Organization. Guidelines on the management of latent tuberculosis infection.
Geneva, Switzerland: World Health Organization; 2015 http://www.who.int/tb/publications/
Author Manuscript

ltbi_document_page/en/. Accessed November 22,2014.

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 Villarino et al. Page 12
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Figure 1. Flowchart of Study Participants (Children Aged 2–17 Years): CONSORT Criteria
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This flowchart shows the number of participants who were enrolled, received the assigned
treatment, and were analyzed for the safety and effectiveness outcomes. Combination drug
therapy indicates 3 months of directly observed once-weekly combination of rifapentine and
isoniazid; isoniazid therapy, 9 months of self-administered daily isoniazid; DST, drug
susceptibility testing; MITT, modified intention-to-treat; TB, tuberculosis; TST, tuberculin
skin test.
a Eligibility screening data for the randomized clinical trial were obtained from March 31,

2005, onward, with the implementation of an eligibility screening log. This log was
implemented in response to the publication of the CONSORT (Consolidated Standards of
Reporting Trials) reporting recommendations for randomized clinical trials, which were
vetted after the PREVENT TB trial started.
b Enrollment of participants was allowed before Mycobacterium tuberculosis culture and
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susceptibility data were available in the source case of tuberculosis.

c Results of TST not confirmed as positive on postenrollment TST repeated at 8 to 12 weeks;

enrollment of close contacts was allowed if children were younger than 5 years or human
immunodeficiency virus seropositive and enrolling clinicians had the option to discontinue
treatment.

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 Villarino et al. Page 13
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Figure 2. Difference in Tuberculosis Disease Rates Between the 2 Treatment Regimens Over
Time (MITT Population)
The figure shows how the noninferiority criterion was met when none of the 471 patients in
the combination-therapy arm developed tuberculosis vs 3 of 434 in the isoniazid-only arm
(cumulative rate, 0.74%), for a difference of −0.74% and an upper bound of the 97.5% CI of
the difference of +0.32%. Per-protocol population effectiveness analysis showed similar
results. The difference in cumulative TB disease rate is the rate in the combination-therapy
arm minus the rate in the isozanid-only arm. The noninferiority margin was 0.75% for all
analyses. Combination drug therapy indicates 3 months of directly observed, once-weekly
combination of rifapentine and isoniazid; isoniazid only, 9 months of self-administered daily
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isoniazid; MITT, modified intention-to-treat; TB, tuberculosis.

a None had evidence of re-exposure to infectious TB: (1) one 14-year-old female was

diagnosed 72 days after the first dose, with 2 cultures positive for Mycobacterium
tuberculosis; (2) one 5-year-old male was clinically diagnosed 818 days after the first dose;
and (3) one 2-year-old male was clinically diagnosed 839 days after the first dose.
b One-sided 97.5% CI for the difference in cumulative TB disease rates (percentage) using a

conservative adjustment for a rare binomial event.28

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Table 1.

Clinical and Demographic Characteristics of the Study Population

a
Patients by Treatment Arm
Villarino et al.

b
Characteristic Isoniazid (n = 506) Rifapentine Plus Isoniazid (n = 552) Total (N = 1058) P Value
Indication for treatment of LTBI

Close contact 470 (92.9) 519 (94.0) 989 (93.5) .46

Recent TST result converter 36 (7.1) 33 (5.9) 69 (6.5) .46

Age, median (IQR) 12 (4–15) 10 (4–15) 11 (4–15) .02

c 241 (47.6) 297 (53.8) 538 (50.9) .005

Male sex

2–4 y 66 (13.0) 85 (15.4) 151 (14.3)

5–11 y 45 (8.9) 68 (12.3) 113 (10.7)

12–17y 130 (25.7) 144 (26.1) 274 (25.9)

Race/ethnicity

North America

c 301/431 (69.8) 337/453 (74.4) 638/884 (72.2) .13

White Hispanic

2–4 y 92/431 (21.3) 113/453 (24.9) 205/884 (23.2)

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5–11 y 82/431 (19.0) 93/453 (20.5) 175/884 (19.8)

12–17 y 127/431 (29.5) 131/453 (28.9) 258/884 (29.2)

c 18/431 (4.2) 22/453 (4.9) 40/884 (4.5) .75

White non-Hispanic

2–4 y 2/431 (0.5) 3/453 (0.7) 5/884 (0.6)

5–11 y 2/431 (0.5) 6/453 (0.1) 8/884 (0.9)

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a
Patients by Treatment Arm
b
Characteristic Isoniazid (n = 506) Rifapentine Plus Isoniazid (n = 552) Total (N = 1058) P Value
12–17 y 14/431 (3.2) 13/453 (2.9) 27/884 (3.1)
Villarino et al.

c 56/431 (13.0) 51/453 (11.3) 107/884 (12.1) .47

Black

2–4 y 11/431 (2.6) 17/453 (3.8) 28/884 (3.2)

5–11 y 8/431 (1.9) 8/453 (1.8) 16/884 (1.8)

12–17 y 37/431 (8.6) 26/453 (5.7) 63/884 (7.1)

c 56/431 (13.0) 43/453 (9.5) 99/884 (11.2) .11

Other

2–4 y 13/431 (3.0) 11/453 (2.4) 24/884 (2.7)

5–11 y 7/431 (1.6) 15/453 (3.3) 22/884 (2.5)

12–17 y 36/431 (8.4) 17/453 (3.8) 53/884 (6.0)

c,d 73/504 (14.5) 98/551 (17.8) 171/1055 (16.2) .16

Brazil

2–4 y 10/504 (2.0) 24/551 (4.4) 34/1055 (3.2)

5–11 y 9/504 (1.8) 11/551 (2.0) 20/1055 (1.9)

12–17y 54/504 (10.7) 63/551 (11.4) 117/1055 (11.1)

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Enrollment site

US/Canada 431 (85.2) 453 (82.1) 884 (83.6) .18

Brazil/Spain/Hong Kong 75 (14.8) 99 (17.9) 174 (16.4) .18

e 1/111 (0.9) 4/105 (3.8) 5/216 (2.3) .20

HIV seropositive

Persons enrolled in a cluster 155 (30.6) 197 (35.7) 352 (33.3) .09

c,f 15 (11–20) 15 (12–20) 15 (12–20)

TST reaction size, median (IQR), mm
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a
Patients by Treatment Arm
b
Characteristic Isoniazid (n = 506) Rifapentine Plus Isoniazid (n = 552) Total (N = 1058) P Value
2–4 y 14 (11–18) 15 (13–20) 15 (12–20)
Villarino et al.

5–11 y 15 (12–20) 15 (12–20) 15 (12–20) .46

12–17y 15 (11–20) 15 (11–19) 15 (11–20)

c 19 (17–23) 19 (16–23) 19 (17–23)

BMI, median, (IQR)

2–4 y 16 (15–18) 17 (15–18) 16 (15–18)

5–11 y 17 (16–20) 18 (16–21) 18 (16–21) .29

12–17y 22 (19–26) 22 (20–26) 22 (20–26)

Homeless 5 (0.9) 3 (0.5) 8 (0.8) .49

Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HIV, human immunodeficiency virus; IQR, interquartile range; LTBI, latent tuberculosis
infection; TST, tuberculin skin test.
a
Includes all children aged 2 to 17 years. Data are presented as number/total (percentage) unless otherwise specified.
b
P values are for Fisher exact test comparing proportions and the median scores for comparing continuous distributions. Although randomization was unrestricted, there was evidence in the parent study that
household-based clustering resulted in some imbalance between arms.
c
P value refers to the overall characteristic by regimen, not age group.
d
Race not reported in US categories. Three children were outside North America or Brazil: 2 in the 5 to 11 age group and 1 in the 12 to 17 age group.

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e
Of children with known HIV status.
f
Of children with TST result size greater than 0 mm (combined total, 929; 449 in the isoniazid-only group and 480 in the combination-therapy group). A total of 129 close contacts had enrollment TST
result size of zero; of these, 128 were younger than 5 years, and 1 was aged 12 years and HIV seropositive.
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Table 2.

Tolerability and Reasons for Discontinuation Among Children in the Modified Intention-to-Treat Population

Patients, No. (%)

a b
Villarino et al.

Characteristic Isoniazid (n = 434) Rifapentine Plus Isoniazid (n = 471) P Value Difference (95% CI)
Treatment completion 351 (80.9) 415 (88.1) .003 −7.2 (−2.0 to −2.5)

Reason for not completing treatment

All reasons 83 (19.2) 56 (11.9) .003 7.2 (2.5 to 12.0)

c 2 (0.5) 8 (1.7) .11 −1.2 (−2.6 to 0.1)

Discontinuation because of AE

Withdrawal of informed consent 5 (1.2) 4 (0.9) .74 0.3 (−1.0 to 1.6)

Lost for ≥3 mo during treatment 26 (6.0) 5 (1.1) <.001 4.9 (2.5 to 7.4)

Physician decision to cancel other than AE 7 (1.6) 3 (0.6) .21 1.0 (−0.4 to 2.4)

Participant refusal 15 (3.5) 16 (3.4) >.99 0.1 (−2.3 to 2.4)

d 28 (6.5) 20 (4.3) .18 2.2 (−0.7 to 5.2)

Total dose count and/or administration period outside of protocol guidelines

Abbreviation: AE, adverse event.

a
P value based on Fisher exact test.
b
95% CI for the difference in proportions using the Wilson Score Interval method.

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c
Combination-therapy group included 3 influenza-like AEs (grade 2), 3 cutaneous (all with pruritic rash [2 were grade 2], 1 with oral blisters and fever [grade 3]), and 2 gastrointestinal reactions (1 was
grade 1 and 1 was grade 2). Isoniazid-only group included 1 cutaneous AE (grade 2) and 1 gastrointestinal reaction (grade 3).
d
Measure of adherence.
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Table 3.

Safety End Points Among Children Who Received at Least 1 Dose of Study Medication

Patients, No. (%)

a b
Villarino et al.

Characteristic Isoniazid (n = 493) Rifapentine Plus Isoniazid (n = 539) P Value Difference (95% CI)
AEs attributed to treatment

Grades 1 and 2 5 (1.0) 11 (2.0) .21 −1.0 (−2.5 to 0.5)

Grade 3 1 (0.2) 3 (0.6) .63 −0.4 (−1.1 to 0.4)

Grade 4 0 0 NA NA

Grade 5, death 0 0 NA NA

Serious AEs 0 0 NA NA

AEs not attributed to treatment

Grades 1 and 2 35 (7.1) 25 (4.6) .11 2.0 (−0.4 to 5.3)

Grade 3 5 (0.2) 3 (0.6) .49 0.4 (−0.6 to 1.5)

Grade 4 2 (0.4) 1 (0.2) .61 0.2 (−0.5 to 0.9)

c 2 (0.4) 0 .23 0.4 (−0.2 to 1.0)

Grade 5, death

d 7 (1.4) 0 .01 1.0 (0.4 to 2.5)

Serious AEs

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Abbreviations: AE, adverse event; NA, not available.
a
P value based on Fisher exact test.
b
95% CI for the differences in proportions using the Wilson Score Interval method.
c
Death 1 was due to malignant arrhythmia in a 16-year-old girl on day 201 of study treatment; death 2, gunshot injury in a 16-year-old boy at study day 901 (approximately 657 days after the end of the
study treatment phase).
d
Serious AEs include deaths while receiving therapy or within 60 days of the last dose, life-threatening events, hospitalization, disability or permanent damage, and congenital anomaly. For children aged 2
through 16 years, 6 had 1 serious AE and 1 had more than 1 serious AE.
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