Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years

Mutsa Bwakura Dangarembizi*, Pearl Samson, Edmund V. Capparelli, Carolyn Bolton Moore, Patrick Jean-Philippe, Stephen A. Spector, Nahida Chakhtoura, Alex Benns, Bonnie Zimmer, Lynette Purdue, Chivon Jackson, Carole Wallis, Jennifer L. Libous, Ellen G. Chadwick

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infected children younger than 36 months, but such data are lacking in those with tuberculosis (TB) coinfection.Methods:Phase I, 24-week safety and pharmacokinetic (PK) study of EFV in HIV-infected children aged 3 to <36 months, with or without TB. CYP2B6 516 genotype classified children into extensive metabolizers (516 TT/GT) and poor metabolizers [(PMs), 516 TT]. EFV doses were 25%-33% higher in children with HIV/TB coinfection targeting EFV area under the curve (AUC) 35-180 g × h/mL, with individual dose adjustment as necessary. Safety and virologic evaluations were performed every 4-8 weeks.Results:Fourteen children from 2 African countries and India with HIV/TB enrolled, with 11 aged 3 to <24 months and 3 aged 24-36 months, 12 extensive metabolizers and 2 PMs. Median (Q1, Q3) EFV AUC was 92.87 (40.95, 160.81) g × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) g × h/mL in children aged 24-36 months. AUC targets were met in 6/8 and 2/5 of the younger and older age groups, respectively. EFV clearance was reduced in PM's and older children. Pharmacokinetic modeling predicted adequate EFV concentrations if children younger than 24 months received TB-uninfected dosing. All 9 completing 24 weeks achieved viral suppression. Five/14 discontinued treatment early: 1 neutropenia, 3 nonadherence, and 1 with excessive EFV AUC.Conclusions:Genotype-directed dosing safely achieved therapeutic EFV concentrations and virologic suppression in HIV/TB-coinfected children younger than 24 months, but further study is needed to confirm appropriate dosing in those aged 24-36 months. This approach is most important for young children and currently a critical unmet need in TB-endemic countries.

Original languageEnglish (US)
Pages (from-to)473-480
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes
Volume81
Issue number4
DOIs
StatePublished - Aug 1 2019

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Keywords

  • HIV
  • children
  • efavirenz
  • pharmacokinetics
  • tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Bwakura Dangarembizi, M., Samson, P., Capparelli, E. V., Moore, C. B., Jean-Philippe, P., Spector, S. A., Chakhtoura, N., Benns, A., Zimmer, B., Purdue, L., Jackson, C., Wallis, C., Libous, J. L., & Chadwick, E. G. (2019). Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years. Journal of Acquired Immune Deficiency Syndromes, 81(4), 473-480. https://doi.org/10.1097/QAI.0000000000002061