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. 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. 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. 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.>
