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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.
Solans, Belén P; Béranger, Agathe; Radtke, Kendra; Mohamed, Ali; Mirzayev, Fuad; Gegia, Medea; Linh, Nguyen Nhat; Schumacher, Samuel G; Nahid, Payam; Savic, Radojka M.
Affiliation
  • Solans BP; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
  • Béranger A; UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA.
  • Radtke K; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
  • Mohamed A; UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA.
  • Mirzayev F; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
  • Gegia M; UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA.
  • Linh NN; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco Schools of Pharmacy and Medicine, San Francisco, California, USA.
  • Schumacher SG; UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, California, USA.
  • Nahid P; Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
  • Savic RM; Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland.
Clin Infect Dis ; 76(9): 1658-1670fc, 2023 05 03.
Article in En | MEDLINE | ID: mdl-36609692
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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Full text: 1 Collection: 01-internacional Health context: 10_ODS3_salud_sexual_reprodutiva / 2_ODS3 / 3_ND Database: MEDLINE Main subject: Tuberculosis / HIV Infections Type of study: Guideline / Systematic_reviews Limits: Adolescent / Adult / Child / Humans Language: En Journal: Clin Infect Dis Year: 2023 Document type: Article

Full text: 1 Collection: 01-internacional Health context: 10_ODS3_salud_sexual_reprodutiva / 2_ODS3 / 3_ND Database: MEDLINE Main subject: Tuberculosis / HIV Infections Type of study: Guideline / Systematic_reviews Limits: Adolescent / Adult / Child / Humans Language: En Journal: Clin Infect Dis Year: 2023 Document type: Article