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The Tuberculosis Prevention Pipeline for Children

July 2018
by Lindsay McKenna

Tuberculosis (TB) prevention research is advancing (see The Tuberculosis Prevention Pipeline), yet the inclusion of children in these studies to ensure they benefit from such advances is inconsistent. Promisingly, studies to evaluate the use of levofloxacin or delamanid for the prevention of TB among close contacts of people with multidrug-resistant TB (MDR-TB) are progressing in children.

In contrast, a phase III trial validated a once-daily regimen of isoniaizid and rifapentine (1HP) for the prevention of TB, but only in adults and adolescents living with HIV. The pediatric research community again finds itself playing an all-too-familiar game of catch-up. A study to inform 1HP dosing for children living with HIV has become a new urgent need. Additionally, a study to evaluate the efficacy of 1HP relative to other preventive therapy options for children may be warranted—especially in children under five years old—given their less developed immune systems and increased risk of TB disease progression. In fact, an even longer established rifapentine-containing TB prevention regimen, three months of once-weekly rifapentine and isoniazid (3HP), still requires execution of a long-planned pharmacokinetic (PK) and safety study to inform dosing for children under two years old; this study (TBTC 35) has yet to open.

Table 1 presents an overview of TB prevention studies in children that are ongoing or planned, and Table 2 presents results from TB prevention studies in children that have been completed in recent years.

Table 1. Ongoing and Planned TB Prevention Studies in Children

 

Study Name

 

Status

 

Regimen

 

Population(s)

 

Funder(s)

 

TBTC 35

 

Planned; opening 2018

 

PK and safety of 3HP FDC for prevention of TB

 

HIV-positive and HIV-negative infants and children 0–12 years old with LTBI

 

TBTC, Sanofi

 

WHIP3TB

 

NCT02980016

 

Enrolling; results expected 2019

 

Part A: Efficacy and safety of 3HP vs. 6H for prevention of TB

Part B: Efficacy and safety of 3HP given once versus 3HP given once a year for 2 years for prevention of TB

 

HIV-positive adults, adolescents, and children ≥2 years old

 

The Aurum Institute, USAID, KNCV

 

TB-CHAMP

 

ISRCTN92634082

 

 

Enrollment complete; results expected 2020

 

Efficacy, safety, and PK of 6 months of daily levofloxacin vs. placebo for prevention of MDR-TB

(substudy planned using delamanid for child contacts of FQ-R TB patients)

 

HIV-positive and HIV-negative infant and child household contacts 0–5 years old; children will get new pediatric formulation

 

BMRC, Wellcome Trust, DFID, SA MRC

 

ACTG A5300/ IMPAACT P2003B (PHOENIx)

 

Planned; opening 2018

 

Efficacy and safety of 6 months of daily delamanid vs. 6 months of daily isoniazid for prevention of MDR-TB

 

High-risk infant, child, adolescent, and adult household contacts of individuals with MDR-TB

 

 

NIAID, NICHD

 

V-QUIN

 

ACTRN12616000215426

 

Enrolling; final results expected 2021

 

Efficacy and safety of 6 months of daily levofloxacin vs. placebo for prevention of MDR-TB

 

 

HIV-positive and HIV-negative adult household contacts; inclusion of adolescents and children <15 years old expected in 2018

 

NHMRC

 

Table 2. Recently completed TB Prevention Studies in Children

Study Name

Status

Regimen

Population(s)

Funder(s)

P4v9

 

NCT00170209

Results published 2018

Efficacy and safety of 4R vs. 9H for prevention of TB

HIV-positive and HIV-negative infants, children, and adolescents 0–18 years old

CIHR, McGill University

Treatment with four months of daily rifampin (4R) was as effective as nine months of daily isoniazid (9H) for the prevention of TB in children. Both regimens were well tolerated and safe. Treatment completion rates were better for 4R.

 

Diallo T, Abjobimey M, Ruslami R, et al. Safety and side effects of rifampin versus isoniazid in children. N Engl J Med. 2018 Aug 2;379:454-63. doi: 10.1056/NEJMoa1714284.

Titi

 

Results presented 2018

Implementation study of 3HR FDC or 6H for prevention of TB

HIV-positive and HIV-negative infant and child contacts <5 years old

Expertise-France/the Union

Analysis and publication pending. First results will be presented at the Union World Conference on Lung Health in the Hague in October 2018.

Tshepiso [sub-study]

 

 

Results published 2017

(see below)

PK and safety of nevirapine with rifampin and isoniazid for prevention of TB

HIV-exposed infants receiving nevirapine for HIV prophylaxis born to mothers with TB

NIAID

Rifampin-based TB preventive treatment significantly reduces nevirapine concentrations in HIV-exposed infants and should be avoided.

 

McIlleron H, Denti P, Cohn S, et al. Prevention of TB using rifampicin plus isoniazid reduced nevirapine concentrations in HIV-exposed infants. J Antimicrob Chemother. 2017 Jul 1;72(7):2028-34. https://doi.org/10.1093/jac/dkx112.

TBTC 26 (PREVENT TB)

 

NCT00023452

NCT00164450

 

Results published 2015

(see below)

Efficacy, safety, and PK of 3HP vs. 9H for prevention of TB

Mostly HIV-negative child and adolescent contacts 2–17 years old

TBTC, IMPAACT

Treatment with three months of once-weekly isoniazid and rifapentine (3HP) was as effective as nine months of daily isoniazid (9H) for the prevention of TB in children. Both regimens were well tolerated and safe. Treatment completion rates were better for 3HP.

 

A 2-fold greater rifapentine dose in children (23 mg/kg) resulted in drug exposures that were 1.3-fold higher compared to exposures in adults administered a standard dose (11 mg/kg) associated with successful TB prevention. Food increased bioavailability in children. Crushing tablets decreased bioavailability in children.

 

Weight-based dosing recommendations for rifapentine administered as 3HP to children are as follows: 10-14 kg, 300 mg; 14.1-25 kg, 450 mg; 25.1-32 kg, 600 mg; and 32.1-50 kg, 750 mg. 

 

Villarino ME, Scott NA, Weis SE, et al. 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. JAMA Pediatr. 2015 Mar;169(3):247-55. doi: 10.1001/jamapediatrics.2014.3158.

 

Weiner M, Savic RM, MacKenzie WR, et al. Rifapentine pharmacokinetics and tolerability in children and adults treated once weekly with rifapentine and isoniazid for latent tuberculosis infection. JPIDS. 2014 Jun 1;3(2):132–145. doi: 10.1093/jpids/pit077.

 

Latent tuberculosis infection: Updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018. Available from: http://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/.

 

ABBREVIATIONS
1HP: 1 month of once-daily isoniaizid and rifapentine
3HP: 3 months of once-weekly isoniaizid and rifapentine
p3HP: 3HP given once a year for 2 years
3HR: 3 months of daily isoniazid and rifampin
4R: 4 months of daily rifampin
6H: 6 months of daily isoniazid
9H: 9 months of daily isoniazid
BMRC: British Medical Research Council
CIHR: Canadian Institutes of Health Research
DFID: Department for International Development (United Kingdom)
FDC: fixed-dose combination
FQ-R: fluoroquinolone-resistant tuberculosis
HIV: human immunodeficiency virus
IMPAACT: International Maternal, Pediatric, Adolescent AIDS Clinical Trials Group, U.S. National Institutes of Health (United States)
KNCV: KNCV Tuberculosis Foundation (the Netherlands)
LTBI: latent tuberculosis infection
MDR-TB: multidrug-resistant tuberculosis
NHMRC: National Health and Medical Research Council (Australia)
NIAID: National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health
NICHD: National Institute of Child Health and Human Development, U.S. National Institutes of Health
PK: pharmacokinetics
SA MRC: South African Medical Research Council
TB: tuberculosis
TBTC: Tuberculosis Trials Consortium, U.S. Centers for Disease Control and Prevention
USAID: United States Agency for International Development