Mutsa Bwakura Dangarembizi1, Pearl Samson2,3, Edmund V Capparelli4,5, Carolyn Bolton Moore6,7, Patrick Jean-Philippe8, Stephen A Spector4,5, Nahida Chakhtoura9, Alex Benns3, Bonnie Zimmer3, Lynette Purdue8, Chivon Jackson10, Carole Wallis11, Jennifer L Libous12, Ellen G Chadwick13. 1. Department of Paediatrics and Child Health, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe. 2. Harvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, MA. 3. Frontier Science and Technology Research Foundation, Amherst, NY. 4. Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, La Jolla, CA. 5. Rady Children's Hospital, San Diego, CA. 6. Centre for Infectious Disease Research in Zambia, Lusaka, Zambia. 7. University of Alabama at Birmingham, Birmingham, AL. 8. National Institutes of Allergy and Infectious Diseases, Bethesda, MD. 9. Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health, Bethesda, MD. 10. Department of Pediatrics, Texas Children's Hospital Baylor College of Medicine, Houston, TX. 11. BARC-SA and Lancet Laboratories, Johannesburg, South Africa. 12. IMPAACT Operations Center, FHI360, Durham, NC. 13. Northwestern University's Feinberg School of Medicine, Chicago, IL.
Abstract
BACKGROUND: 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 μg × 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) μg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) μg × 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.
BACKGROUND:CYP2B6 516 genotype-directed dosing improves efavirenz (EFV) exposures in HIV-infectedchildren 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-infectedchildren 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 μg × 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) μg × h/mL in 8/9 evaluable children aged 3 to <24 months and 319.05 (172.56, 360.48) μg × 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-coinfectedchildren 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.
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