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Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis

BACKGROUND: Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization–recommended or higher doses of first-line drugs achieve successful outcomes...

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Autores principales: Solans, Belén P, Béranger, Agathe, Radtke, Kendra, Mohamed, Ali, Mirzayev, Fuad, Gegia, Medea, Linh, Nguyen Nhat, Schumacher, Samuel G, Nahid, Payam, Savic, Radojka M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10156125/
https://www.ncbi.nlm.nih.gov/pubmed/36609692
http://dx.doi.org/10.1093/cid/ciac973
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author Solans, Belén P
Béranger, Agathe
Radtke, Kendra
Mohamed, Ali
Mirzayev, Fuad
Gegia, Medea
Linh, Nguyen Nhat
Schumacher, Samuel G
Nahid, Payam
Savic, Radojka M
author_facet Solans, Belén P
Béranger, Agathe
Radtke, Kendra
Mohamed, Ali
Mirzayev, Fuad
Gegia, Medea
Linh, Nguyen Nhat
Schumacher, Samuel G
Nahid, Payam
Savic, Radojka M
author_sort Solans, Belén P
collection PubMed
description BACKGROUND: Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization–recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures. METHODS: Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222). RESULTS: Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%–95%). At World Health Organization–recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9–18.8] vs 22.0 [13.8–30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4–23.2] vs 26.5 [21.3–31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations. CONCLUSIONS: There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.
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spelling pubmed-101561252023-05-04 Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis Solans, Belén P Béranger, Agathe Radtke, Kendra Mohamed, Ali Mirzayev, Fuad Gegia, Medea Linh, Nguyen Nhat Schumacher, Samuel G Nahid, Payam Savic, Radojka M Clin Infect Dis Major Article BACKGROUND: Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization–recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures. METHODS: Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic review was preregistered in PROSPERO (no. CRD42021274222). RESULTS: Of 304 studies identified, 46 were eligible for full-text review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%–95%). At World Health Organization–recommended doses, exposures to RIF, pyrazinamide, and ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9–18.8] vs 22.0 [13.8–30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4–23.2] vs 26.5 [21.3–31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations. CONCLUSIONS: There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing. Oxford University Press 2023-01-04 /pmc/articles/PMC10156125/ /pubmed/36609692 http://dx.doi.org/10.1093/cid/ciac973 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Major Article
Solans, Belén P
Béranger, Agathe
Radtke, Kendra
Mohamed, Ali
Mirzayev, Fuad
Gegia, Medea
Linh, Nguyen Nhat
Schumacher, Samuel G
Nahid, Payam
Savic, Radojka M
Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis
title Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis
title_full Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis
title_fullStr Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis
title_full_unstemmed Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis
title_short Effectiveness and Pharmacokinetic Exposures of First-Line Drugs Used to Treat Drug-Susceptible Tuberculosis in Children: A Systematic Review and Meta-Analysis
title_sort effectiveness and pharmacokinetic exposures of first-line drugs used to treat drug-susceptible tuberculosis in children: a systematic review and meta-analysis
topic Major Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10156125/
https://www.ncbi.nlm.nih.gov/pubmed/36609692
http://dx.doi.org/10.1093/cid/ciac973
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