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 G.
N1 - Funding Information:
From the aDepartment of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe; bHarvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, MA; cFrontier Science and Technology Research Foundation, Amherst, NY; dDivision of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA; eRady Children’s Hospital, San Diego, CA; fCentre for Infectious Disease Research in Zambia, Lusaka, Zambia; gUniversity of Alabama at Birmingham, Birmingham, AL; hNational Institutes of Allergy and Infectious Diseases, Bethesda, MD; iEunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD; jDepartment of Pediatrics, Texas Children’s Hospital Baylor College of Medicine, Houston, TX; kBARC-SA and Lancet Laboratories, Johannesburg, South Africa; lIMPAACT Operations Center, FHI360, Durham, NC; and mNorthwestern University’s Feinberg School of Medicine, Chicago, IL Supported by Aurobindo Pharma Limited, that generously donated the efavirenz capsules and did not participate in the study design or data analysis. Overall support for the IMPAACT Network was provided by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC), and UM1AI106716 (IM-PAACT LC), with cofunding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health (NIMH). Funders participated as study team members in study design and analysis. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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
C2 - 31241542
AN - SCOPUS:85068831205
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 -