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The Tuberculosis Treatment Pipeline for Children

July 2018
by Lindsay McKenna

Pharmacokinetic (PK) and safety studies in children continue to progress, producing a steady flow of data (Table 2). Yet the translation of research and development gains into policy and access for children with tuberculosis (TB) remains painfully slow. Additionally, target drug exposures are evolving. Studies underway or recently completed in adults are evaluating how to optimize dosing for existing TB medicines, including rifampin, isoniazid, linezolid, and the fluoroquinolones. Continued investments in pediatric PK and safety studies, and rapid translation of findings into policy and practice, will be necessary for children to benefit from ongoing TB treatment optimization work.

TB disease severity and presentation are highly variable in children. Very young children (0 to <2 years old) more commonly develop disseminated TB, young children (2 to ≤12 years old) tend to have paucibacillary and non-cavitary TB, and older children (>12 years old) often present with adult-like pulmonary disease. Additionally, despite achieving lower drug exposures than adults, children generally have good TB treatment outcomes. As such, there is a need to determine if similarly good outcomes can be achieved in children with less-severe forms of TB using further simplified regimens and to optimize regimen composition, duration, and dosing for the more severe manifestations of TB disease also observed in children.

Several efficacy studies underway or planned will evaluate whether it is possible to shorten and optimize treatment for drug-sensitive TB (DS-TB) and drug-resistant TB (DR-TB) and TB meningitis (TBM) in children (Table 1). The advancement of such studies should serve as a further signal to the TB community regarding the importance of pediatric-specific interventions on TB.

 

Table 1. Ongoing and Planned TB Treatment Studies in Children


Study/Regimen


Status


Regimen


Population(s)


Funder(s)


DRUG-SUSCEPTIBLE TB


OptiRif Kids

 

 


Enrolling; results expected 2019


PK, safety, and dose optimization of rifampin for treatment of TB


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


Unitaid (STEP-TB Project)


SHINE

 

CTRI/2017/07/009119

 


Enrolling; results expected 2020


Efficacy and safety of 4 vs. 6 months of treatment (using updated WHO dosing guideline-adjusted FLD FDCs) for nonsevere TB


HIV-positive or HIV-negative infants, children, and adolescents 0–16 years old with nonsevere TB


BMRC, DFID, Wellcome Trust


TBM-KIDS

 

NCT02958709

 


Enrolling; results expected 2019


Efficacy and safety of high-dose rifampin ± levofloxacin for treatment of TBM


HIV-positive or HIV-negative infants and children 6 months to 12 years old with TBM


NICHD


SURE-TBM

 

 


Protocol in development


Efficacy and safety of high-dose rifampin, levofloxacin, and isoniazid with pyrazinamide for shortening treatment of TBM to 6 months


HIV-positive or HIV-negative infants, children, and adolescents 28 days to 15 years old with TBM

 


BMRC, DFID, Wellcome Trust


CO-TREATMENT WITH ARVs


IMPAACT P1106

 

NCT02383849


Enrolling; results expected 2020


PK and safety of rifampin and isoniazid with nevirapine or lopinavir/ritonavir


HIV-positive or HIV-negative low-birth-weight/premature infants


NIAID, NICHD


IMPAACT P1101

 

NCT01751568


Enrolling; interim results presented (see below); final results expected 2019


PK and safety of raltegravir with rifampin-containing TB treatment


ARV-naive, HIV-positive children and adolescents 2–12 years old with TB


NIAID, NICHD


Data in children 6 to <12 years old were presented at the 10th International Workshop on HIV Pediatrics in Amsterdam in July 2018.

 

Krogstad P, Samson P, Meters T, et al. Phase I/II study of raltegravir-containing regimen in HIV and TB co-treated children aged 6<12 years. Poster presented at: 10th International Workshop on HIV Pediatrics; 2018 July; Amsterdam, the Netherlands. Available from: http://regist2.virology-education.com/presentations/2018/10PED/30_krogstad.pdf.


ODYSSEY

 

NCT02259127


Enrolling; results expected 2019


Efficacy and safety of dolutegravir-based ART vs. standard of care


HIV-positive children and adolescents 6–18 years old starting first-line or switching to second-line ART, including children co-infected with TB


PENTA Foundation


IMPAACT P2006

 


Planned


Efficacy and safety of dolutegravir vs. lopinavir/ritonavir and interactions with rifampin-containing TB treatment


HIV-positive infants and children 1 month to 3 years old with TB


NIAID, NICHD


DRUG-RESISTANT TB


MDR-PK 1/ MDR-PK 2

 


Results presented/published (see below);

MDR-PK 2 still enrolling; additional results expected 2018–2020


PK, safety, and dose optimization of SLDs for treatment of MDR-TB


HIV-positive or HIV-negative infants, children, and adolescents with MDR-TB or exposure to MDR-TB


NICHD, SA MRC


Population PK models, combining PK data from multiple individuals, can predict and simulate how drugs behave in the body. Population PK models built using pediatric data from MDR-PK 1 and MDR-PK 2 determined that:

·       dosing levofloxacin at 15–20 mg/kg is safe and well tolerated but produces lower exposures in children compared to those in adults with the formulation studied (adult 250 mg tablets);

·       dosing moxifloxacin at 7.5–10 mg/kg produces considerably lower exposures in children compared to those in adults, and the effect is worse in smaller children;

·       dosing ofloxacin at 15–20 mg/kg is safe and well tolerated but produces lower exposures in children compared to those in adults;

·       dosing amikacin at 15–20 mg/kg produces maximum plasma concentrations at target levels for the majority of children.

 

These findings support exploring the safety and necessity of higher doses of fluoroquinolones in children.

 

MDR-TB treatment did not have any significant interaction with or effect on the PK of lopinavir/ritonavir in children with HIV and TB.

 

Analysis of ethionamide, PAS, high-dose INH, and terizidone data is ongoing. Analysis of linezolid and clofazimine data and of additional moxifloxacin data is also expected.

 

Garcia-Prats AJ, Draper HR, Finlayson H, et al. Clinical and cardiac safety of long-term levofloxacin in children treated for multidrug-resistant tuberculosis. Clin Infect Dis. 2018 May 16. doi: 10.1093/cid/ciy416.

 

van der Laan LE, Garcia-Pratts AJ, Schaaf HS, et al. Pharmacokinetics and drug-drug interaction of lopinavir-ritonavir administered with first- and second-line antituberculosis drugs in HIV-infected children treated for multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2018 Jan 25;62(2). pii: e00420-17. doi: 10.1128/AAC.00420-17. 

 

Denti P, Garcia-Prats AJ, Draper HR, et al. Levofloxacin population pharmacokinetics in South African children treated for multidrug-resistant tuberculosis. Antimicrob Agents Chemother. 2018 Feb;62(2):e01521-17. doi: 10.1128/AAC.01521-17.

 

Garcia-Prats T, Denti P, Draper H, et al. Population pharmacokinetics of levofloxacin in HIV-infected and -uninfected children with multidrug-resistant tuberculosis [OA-464-29]. Oral abstract presented at: 47th Union World Conference on Lung Health; 2016 October; Liverpool, UK.

 

Garcia-Prats T, Schaaf HS, Draper H, et al. Population pharmacokinetics of moxifloxacin and linezolid in children with multidrug-resistant tuberculosis. Presented at: 47th Union World Conference on Lung Health; 2016 October; Liverpool, UK.

 

Garcia-Prats T, Draper H, Finlayson H, et al. Safety and tolerability of levofloxacin in HIV-infected and –uninfected children treated for multidrug-resistant tuberculosis [O12]. Oral abstract presented at: TB2016; 2016 July; Durban, South Africa.

 

Garcia-Prats AJ, Draper HR, Thee S, et al. The pharmacokinetics and safety of ofloxacin in children with drug-resistant tuberculosis. Antimicrob Agents Chemother. 2015 Oct; 59(10):6073-9. doi: 10.1128/AAC.01404-15.

 

Garcia-Prats AJ, Schaaf HS. Emerging data on PK and safety of levofloxacin and amikacin informs care and design of new regimens. Presented at: Building on emerging knowledge to develop novel regimens for pediatric drug-resistant TB [symposium 27] at 46th Union World Conference on Lung Health; 2015 December 5; Cape Town, South Africa.

 

Thee S, Garcia-Prats AJ, McIlleron HM, et al. Pharmacokinetics of ofloxacin and levofloxacin for prevention and treatment of multidrug-resistant tuberculosis in children. Antimicrob Agents Chemother. 2014 May; 58(5):2948-51. doi: 10.1128/AAC.02755-13.


232

 

NCT01856634


Enrollment complete; interim results presented (see below); final results expected 2018


PK and safety of delamanid; OBR for treatment of MDR-TB

 


HIV-negative infants, children, and adolescents 0–17 years old with MDR-TB; children ≤5 years old will get pediatric formulation


Otsuka


Data on the PK and safety of delamanid available in children down to 6 years old (given the adult formulation) informed a recommendation from the WHO extending the use of delamanid for the treatment of MDR-TB in adults to children 6 years and older.

 

Dosing recommendations for administering delamanid to children are as follows (1.5–3.8 mg/kg): 12–17 years old, 100 mg twice daily; and 6–11 years old, 50 mg twice daily.

 

The use of delamanid in the treatment of multidrug-resistant tuberculosis in children and adolescents: Interim policy guidance. Geneva: World Health Organization; 2016. Available from: http://www.who.int/tb/publications/Delamanid_interim_policy/en/.


233

 

NCT01859923


Enrolling; final results expected 2020


Efficacy, safety, and PK of 6 months of delamanid; OBR for treatment of MDR-TB

 


HIV-negative infants, children, and adolescents 0–17 years old with MDR-TB; children ≤5 years old will get pediatric formulation


Otsuka


IMPAACT P2005

 

NCT03141060

 


Enrolling; final results expected 2021


PK and safety of delamanid; all-oral OBR for treatment of MDR-TB


HIV-positive or HIV-negative infants, children, and adolescents 0–18 years old with MDR-TB


NIAID, NICHD


JANSSEN C211

 

NCT02354014


Enrolling; final results expected 2025


PK and safety of bedaquiline; OBR for treatment of MDR-TB

 


HIV-negative infants, children, and adolescents 0–18 years old with MDR-TB; children ≤12 years old will get pediatric formulation


Janssen


IMPAACT P1108

 

NCT02906007


Enrolling; final results expected 2022


PK and safety of bedaquiline; OBR for treatment of MDR-TB


HIV-positive or HIV-negative infants, children, and adolescents 0–18 years old with MDR-TB


NIAID, NICHD


IMPAACT P2020

 


Protocol in development


Efficacy and safety of 6 months of bedaquiline, delamanid, and levofloxacin or clofazimine, plus linezolid for the first 8 weeks for treatment of RR-, MDR-, pre-XDR, and XDR-TB


HIV-positive or HIV-negative infants, children, and adolescents <15 years old with RR-, MDR-, pre-XDR, or XDR-TB


NIAID, NICHD

 

Table 2. Recently Completed TB Treatment Studies in Children


Study/Regimen


Status


Regimen


Population(s)


Funder(s)


DRUG-SENSITIVE TB


Treat Infant TB

 


Results published 2016

(see below)


PK of FLDs using updated WHO dosing guidelines for treatment of TB


HIV-positive or HIV-negative infants <12 months old with TB


Unitaid (STEP-TB Project)


When administered according to WHO-recommended pediatric weight-based doses, pyrazinamide and isoniazid achieved drug exposures in infants that are comparable to those in adults. Exposures of rifampin and ethambutol were lower than those achieved in adults. HIV-positive infants taking ARVs (abacavir, lamivudine, and lopinavir/ritonavir) achieved lower pyrazinamide and ethambutol exposures than did HIV-negative infants. Whether dosing adjustments are necessary requires further evaluation.

 

Bekker A, Schaaf HS, Draper HR, et al. Pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in infants dosed according to revised WHO-recommended treatment guidelines. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2171-9. doi: 10.1128/AAC.02600-15.


PHATISA

 

 


Results published 2015

(see below)


PK of FLDs using updated WHO dosing guidelines for treatment of TB


HIV-positive or HIV-negative infants ≤10 years old with TB


NIH, HHMI


When administered according to WHO-recommended pediatric weight-based doses, drug concentrations for isoniazid, rifampin, pyrazinamide, and ethambutol were below target therapeutic concentrations in most children. Whether drug exposure targets linked with good outcomes in adults are necessary to achieve good outcomes in children, especially considering differences in bacterial burden and severity and location of disease, requires investigation.

 

Hiruy H, Rogers Z, Mbowane C, et al. Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study. J Antimicrob Chemother. 2015 Apr;70(4):1115-23. doi: 10.1093/jac/dku478.


PK-PTBHIV01

 

NCT01687504


Results published 2017/2018

(see below)


PK of FLDs using updated WHO dosing guidelines for treatment of TB


HIV-positive or HIV-negative children 3 months to 14 years old with TB


NICHD


Children treated according to WHO dosing guidelines had low pyrazinamide and ethambutol exposures. Children with HIV and TB had significantly lower plasma exposure and a higher apparent oral clearance of rifampin, pyrazinamide, and ethambutol. Children with both HIV and TB were not yet started on antiretroviral drugs at the time of pharmacokinetic sampling, so observed lower exposures could be due to impaired absorption and/or enhanced metabolism or excretion. Whether children, especially children in the lower weight bands and/ or who have HIV and TB, need higher doses requires further investigation.

 

Antwi S, Yang H, Enimil A, et al. Pharmacokinetics of the first-line antituberculosis drugs in Ghanaian children with tuberculosis with or without HIV infection. Antimicrob Agents Chemother. 2017 Jan 25;61(2). pii: e01701-16. doi: 10.1128/AAC.01701-16.

 

Yang H, Enimil A, Gillani FS, et al. Evaluation of the adequacy of the 2010 Revised World Health Organization recommended dosages of the first-line antituberculosis drugs for children. Pediatr Infect Dis J. 2018 Jan;37(1):43-51. doi: 10.1097/INF.0000000000001687.

 

Horita Y, Alsultan A, Kwara A, et al. Evaluation of the adequacy of WHO revised dosages of the first-line anti-tuberculosis drugs in children with tuberculosis using population pharmacokinetic modeling and simulations. Antimicrob Agents Chemother. 2018 Jun 18. pii: AAC.00008-18. doi: 10.1128/AAC.00008-18.


CO-TREATMENT WITH ARVs


DATiC

 

NCT01637558


Results published 2016/17

(see below)


PK of FLDs using updated WHO dosing guidelines for treatment of TB and interactions with lopinavir/ritonavir and nevirapine


HIV-positive or HIV-negative infants, children, and adolescents 1 month to 12 years old with TB


NICHD


Children achieved isoniazid and pyrazinamide drug exposures comparable to those in adults. Ethambutol exposures were lower in children. Exposures of rifampin were variable, with only 17 percent of children achieving adult exposures and reduced exposures in the lowest and highest weight categories; the quality and formulation effect of available rifampin suspensions may have affected the PK of rifampin, contributing to the lower exposures observed.

 

Denti P, Gonzalez-Martinez C, Winckler J, et al. Pharmacokinetics of rifampin in African children: evaluation of the new WHO dosing guidelines. IJTLD. 2017;2(11):S203: Abstract OA-155-13.

 

McIlleron H, Hundt H, Smythe W, et al. Bioavailability of two licensed pediatric rifampicin suspensions: implications for quality control programs. IJTLD. 2016 Jul;20(7):915-9. doi: 10.5588/ijtld.15.0833.

 

Bekker A, Schaaf HS, Draper HR, et al. Pharmacokinetics of rifampin, isoniazid, pyrazinamide, and ethambutol in infants dosed according to revised WHO-recommended treatment guidelines. Antimicrob Agents Chemother. 2016 Mar 25;60(4):2171-9. doi: 10.1128/AAC.02600-15.

 

Hesseling AC. Tuberculosis in children. Presented at: Tuberculosis magic bullets and moving targets symposium at the 22nd Conference on Retroviruses and Opportunistic Infections; 2015 February 25; Seattle, WA.

 

Zvada S, Prins M, Mulligan C, et al. Pharmacokinetics of rifampicin, isoniazid and pyrazinamide in children on 2010 WHO/IUATLD guideline doses. Presented at: 7th International Workshop on Clinical Pharmacology of TB Drugs; 2014 September 5; Washington, D.C.


PK-TBHIV02

 

NCT01699633


Results expected 2018


PK and safety of nevirapine with rifampin-containing TB treatment


HIV-positive children 3 months to 3 years old with TB


NICHD


 

Analysis and presentation/publication pending.

 


IMPAACT P1070

 

NCT00802802


Results presented 2016

(see below)


PK and safety of efavirenz with rifampin-containing TB treatment


HIV-positive children 3 months to <3 years old with or without TB


NIAID, NICHD


Increasing the dose of efavirenz for children with HIV and TB with fast metabolism of drugs processed by the cytochrome P450 2B6 enzyme (encoded by the CYP2B6 gene) was safe and produced therapeutic concentrations and good virologic outcomes. A lower dose may be necessary for children with HIV and TB with slow CYP2B6 metabolism.

 

Bolton C, Samson P, Capparelli E, et al. Optimal use of efavirenz in HIV+/TB+ co-infected children aged 3 to ≤24 months (Abstract 458). Poster abstract presented at: Conference on Retroviruses and Opportunistic Infections; 2016 February; Boston, MA. Available from: http://www.croiconference.org/sessions/optimal-use-efavirenz-hiv-tb-coinfected-children-aged-3-24-months.


PK-PTBHIV03

 

NCT01704144


Results presented 2018

(see below)


PK and safety of efavirenz with rifampin-containing TB treatment


HIV-positive children and adolescents 3–14 years old with TB


NICHD


Children with HIV and TB had significantly lower efavirenz plasma exposure and trough concentrations than children with HIV alone. The proportion of children with subtherapeutic efavirenz exposure was higher among children with HIV and TB (47.4 vs. 17.6 percent). Studies to examine virologic outcomes in children with HIV and TB on efavirenz are necessary.

 

Kwara A, Yang H, Antwi S, et al. Effect of antituberculosis therapy on the pharmacokinetics of efavirenz in children. Poster abstract presented at: Conference on Retroviruses and Opportunistic Infections; 2018 March; Boston, MA. Available from: http://www.croiconference.org/sessions/effect-antituberculosis-therapy-pharmacokinetics-efavirenz-children.


HIVPED001

 

NCT02348177


Results presented 2017

(see below)


PK and safety of superboosted lopinavir/ritonavir (1:1) with rifampin-containing TB treatment


HIV-positive infants and children with TB weighing 3–15 kg; DNDi developing standalone ritonavir booster formulation

 


DNDi, AFD, UBS Optimus Foundation, MSF


Exposures following superboosted doses of lopinavir/ritonavir (1:1) with rifampin were noninferior to exposures following standard doses of lopinavir/ritonavir (4:1) without rifampin. Virological efficacy and safety were also comparable. These results led to strengthened WHO recommendations to use superboosting in children with HIV and TB on lopinavir/ritonavir.

 

Rabie H, Denti P, Lee J, et al. Lopinavir/ritonavir 1:1 super-boosting overcomes rifampicin interactions in children. Presented at: Annual Conference on Retroviruses and Opportunistic Infections; 2017 February; Seattle, WA. Available from: http://www.croiconference.org/sessions/lopinavirritonavir-11-super-boosting-overcomes-rifampicin-interactions-children.

 

Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. Geneva: World Health Organization; 2016. Available from: http://www.who.int/hiv/pub/arv/arv-2016/en/.


DRUG-RESISTANT TB


TASK-002 (BDQ Crush Study)


Results published 2018

(see below)


Bioequivalence of bedaquiline 400 mg tablets administered whole or crushed and suspended in water


Healthy adult volunteers


NIAID, NICHD


There was no significant difference in the bioavailability of bedaquiline administered whole or crushed and suspended in water, and the suspension was well tolerated; predefined bioequivalence criteria were also fulfilled. This suggests that the currently available formulation of bedaquiline could be used to treat children to bridge the gap between when pediatric dosing and safety have been established and when the pediatric dispersible formulation will be routinely available.
 

Svensson EM, du Bois J, Kitshoff R, et al. Relative bioavailability of bedaquiline tablets suspended in water: implications for dosing in children. Br J Clin Pharmacol. 2018 Jun 27. doi: 10.1111/bcp.13696.

 

ABBREVIATIONS

AFD: French Development Agency
ART: antiretroviral therapy
ARV: antiretroviral
BMRC: British Medical Research Council
CIHR: Canadian Institutes of Health Research
DFID: Department for International Development (United Kingdom)
DNDi: Drugs for Neglected Diseases Initiative
FDC: fixed-dose combination
FLD: first-line drug
FQ-R: fluoroquinolone-resistant tuberculosis
HHMI: Howard Hughes Medical Institute
HIV: human immunodeficiency virus
IMPAACT: International Maternal, Pediatric, Adolescent AIDS Clinical Trials Group, U.S. National Institutes of Health
INH: isoniazid
LTBI: latent tuberculosis infection
MDR-TB: multidrug-resistant tuberculosis
MSF: Médecins Sans Frontières
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
NIH: U.S. National Institutes of Health
OBR: optimized background regimen
PAS: Para-aminosalicylic acid
PENTA: Pediatric European Network for Treatment of AIDS
PK: pharmacokinetics
Pre-XDR TB: pre-extensively drug-resistant tuberculosis
RR-TB: rifampin-resistant tuberculosis
SA MRC: South African Medical Research Council
SLD: second-line drug
TB: tuberculosis
TBM: tuberculous meningitis
TBTC: Tuberculosis Trials Consortium, U.S. Centers for Disease Control and Prevention
TST: tuberculin skin test
UBS: Union Bank of Switzerland
WHO: World Health Organization
XDR-TB: extensively drug-resistant tuberculosis