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 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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efavirenz
Tuberculosis
HIV
Area Under Curve
Genotype
Coinfection
Pharmacokinetics
Safety

Keywords

  • HIV
  • children
  • efavirenz
  • pharmacokinetics
  • tuberculosis

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Bwakura Dangarembizi, Mutsa ; Samson, Pearl ; Capparelli, Edmund V. ; Moore, Carolyn Bolton ; Jean-Philippe, Patrick ; Spector, Stephen A. ; Chakhtoura, Nahida ; Benns, Alex ; Zimmer, Bonnie ; Purdue, Lynette ; Jackson, Chivon ; Wallis, Carole ; Libous, Jennifer L. ; Chadwick, Ellen. / Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years. In: Journal of Acquired Immune Deficiency Syndromes. 2019 ; Vol. 81, No. 4. pp. 473-480.
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title = "Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years",
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.",
keywords = "HIV, children, efavirenz, pharmacokinetics, tuberculosis",
author = "{Bwakura Dangarembizi}, Mutsa and Pearl Samson and Capparelli, {Edmund V.} and Moore, {Carolyn Bolton} and Patrick Jean-Philippe and Spector, {Stephen A.} and Nahida Chakhtoura and Alex Benns and Bonnie Zimmer and Lynette Purdue and Chivon Jackson and Carole Wallis and Libous, {Jennifer L.} and Ellen Chadwick",
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Bwakura Dangarembizi, M, Samson, P, Capparelli, EV, Moore, CB, Jean-Philippe, P, Spector, SA, Chakhtoura, N, Benns, A, Zimmer, B, Purdue, L, Jackson, C, Wallis, C, Libous, JL & Chadwick, E 2019, 'Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years', Journal of Acquired Immune Deficiency Syndromes, vol. 81, no. 4, pp. 473-480. https://doi.org/10.1097/QAI.0000000000002061

Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years. / Bwakura Dangarembizi, Mutsa; Samson, Pearl; Capparelli, Edmund V.; Moore, Carolyn Bolton; Jean-Philippe, Patrick; Spector, Stephen A.; Chakhtoura, Nahida; Benns, Alex; Zimmer, Bonnie; Purdue, Lynette; Jackson, Chivon; Wallis, Carole; Libous, Jennifer L.; Chadwick, Ellen.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 81, No. 4, 01.08.2019, p. 473-480.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Establishing Dosing Recommendations for Efavirenz in HIV/TB-Coinfected Children Younger Than 3 Years

AU - Bwakura Dangarembizi, Mutsa

AU - Samson, Pearl

AU - Capparelli, Edmund V.

AU - Moore, Carolyn Bolton

AU - Jean-Philippe, Patrick

AU - Spector, Stephen A.

AU - Chakhtoura, Nahida

AU - Benns, Alex

AU - Zimmer, Bonnie

AU - Purdue, Lynette

AU - Jackson, Chivon

AU - Wallis, Carole

AU - Libous, Jennifer L.

AU - Chadwick, Ellen

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

KW - HIV

KW - children

KW - efavirenz

KW - pharmacokinetics

KW - tuberculosis

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U2 - 10.1097/QAI.0000000000002061

DO - 10.1097/QAI.0000000000002061

M3 - Article

VL - 81

SP - 473

EP - 480

JO - Journal of Acquired Immune Deficiency Syndromes

JF - Journal of Acquired Immune Deficiency Syndromes

SN - 1525-4135

IS - 4

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