CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection

for the IMPAACT P1070 team, Carolyn Bolton Moore, Edmund V. Capparelli, Pearl Samson, Mutsa Bwakura-dangarembizi, Patrick Jean-philippe, Carol Worrell, Barbara Heckman, Lynette Purdue, Stephen A. Spector, Alex Benns, William Borkowsky, Amy Loftis, Elizabeth Hawkins, Carole Wallis, Ellen G. Chadwick

Research output: Contribution to journalArticle

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Abstract

OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on FDA-approved doses. RESULTS:: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow up; 38?516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, PK modeling predicted that 83% of participants met the AUC target (31/38?516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?50% with 516TT genotypes. CONCLUSION:: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to out-perform other dosing approaches.

LanguageEnglish (US)
JournalAIDS
DOIs
StateAccepted/In press - Mar 18 2017

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efavirenz
Area Under Curve
HIV Infections
Genotype
Reverse Transcriptase Inhibitors
Coinfection
Nucleosides
Capsules
Cytochrome P-450 CYP2B6
Tuberculosis
Age Groups

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection. / for the IMPAACT P1070 team.

In: AIDS, 18.03.2017.

Research output: Contribution to journalArticle

@article{9022ade7748847d7bf453b3ac430539b,
title = "CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection",
abstract = "OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on FDA-approved doses. RESULTS:: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow up; 38?516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75{\%}, PK modeling predicted that 83{\%} of participants met the AUC target (31/38?516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?50{\%} with 516TT genotypes. CONCLUSION:: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to out-perform other dosing approaches.",
author = "{for the IMPAACT P1070 team} and Moore, {Carolyn Bolton} and Capparelli, {Edmund V.} and Pearl Samson and Mutsa Bwakura-dangarembizi and Patrick Jean-philippe and Carol Worrell and Barbara Heckman and Lynette Purdue and Spector, {Stephen A.} and Alex Benns and William Borkowsky and Amy Loftis and Elizabeth Hawkins and Carole Wallis and Chadwick, {Ellen G.}",
year = "2017",
month = "3",
day = "18",
doi = "10.1097/QAD.0000000000001463",
language = "English (US)",
journal = "AIDS",
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TY - JOUR

T1 - CYP2B6 Genotype-directed dosing is required for optimal efavirenz exposure in children 3 to 36 months with HIV infection

AU - for the IMPAACT P1070 team

AU - Moore,Carolyn Bolton

AU - Capparelli,Edmund V.

AU - Samson,Pearl

AU - Bwakura-dangarembizi,Mutsa

AU - Jean-philippe,Patrick

AU - Worrell,Carol

AU - Heckman,Barbara

AU - Purdue,Lynette

AU - Spector,Stephen A.

AU - Benns,Alex

AU - Borkowsky,William

AU - Loftis,Amy

AU - Hawkins,Elizabeth

AU - Wallis,Carole

AU - Chadwick,Ellen G.

PY - 2017/3/18

Y1 - 2017/3/18

N2 - OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on FDA-approved doses. RESULTS:: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow up; 38?516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, PK modeling predicted that 83% of participants met the AUC target (31/38?516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?50% with 516TT genotypes. CONCLUSION:: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to out-perform other dosing approaches.

AB - OBJECTIVES:: To determine safety, efficacy and genotypic-specific dose requirements of EFV in children aged 3 - <36 months of age with HIV infection with or without TB co-infection. DESIGN:: IMPAACT P1070 was a 24 week prospective cohort trial of EFV (as open capsules) plus two nucleoside reverse transcriptase inhibitors in children with HIV infection 3-?<?36 months without tuberculosis (Cohort 1). METHODS:: CYP2B6 G516T genotype was determined and intensive PKʼs were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35 -180?mcghr/mL. PK and CYP2B6 G516T genotype data were used to model EFV exposures based on FDA-approved doses. RESULTS:: Forty-seven participants, median age 19 months, initiated the study regimen with 24 weeks median follow up; 38?516GG/GT and 9 516TT genotypes. Initially, median EFV AUC was higher in 516TT versus 516GG/GT (median 490 vs 107 p?=?0.0001) with all 516TT above AUC target. Following an amendment that reduced the 516TT EFV dose by 75%, PK modeling predicted that 83% of participants met the AUC target (31/38?516GG/GT, 8/9 516TT). In contrast, modeling using P1070 data predicted that FDA-approved doses would produce sub-therapeutic AUCs in almost one third of participants with 516GG/GT and excessive AUCs in?>?50% with 516TT genotypes. CONCLUSION:: CYP2B6 G516T genotype strongly influences EFV exposures in this age group. Genotype-directed dosing yields therapeutic EFV concentrations and appears to out-perform other dosing approaches.

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DO - 10.1097/QAD.0000000000001463

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JO - AIDS

T2 - AIDS

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SN - 0269-9370

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