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 language | English (US) |
|---|---|
| Pages (from-to) | 473-480 |
| Number of pages | 8 |
| Journal | Journal of Acquired Immune Deficiency Syndromes |
| Volume | 81 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 1 2019 |
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Keywords
- HIV
- children
- efavirenz
- pharmacokinetics
- tuberculosis
ASJC Scopus subject areas
- Infectious Diseases
- Pharmacology (medical)
Cite this
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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 journal › Article
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
UR - http://www.scopus.com/inward/record.url?scp=85068831205&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068831205&partnerID=8YFLogxK
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
ER -