CYP2B6 genotype-directed dosing is required for optimal efavirenz exposure in children 3–36 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 PK’s were performed at week 2. EFV dose was adjusted if outside the target area under the curve (AUC) 35–180 mcg*hr/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.

The Pharmacogenetics of Efavirenz Metabolism in Children: The Potential Genetic and Medical Contributions to Child Development in the Context of Long‐Term ARV Treatment

“…This conclusion stands in contrast to findings in a third study, carried out in four non-Western tuberculosis endemic countries (India, South Africa, Uganda, Zimbabwe; Moore et al, 2017), that used the dosage formula used by the PACTG 382 and 1021 studies. It focused on the PK/PG of EFV of young HIV+ children, 3-36 months old, an age group that had not been included in high numbers in any previous study (n = 47; median age 1.6, IQR 1.1-2.3).…”

Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin

“…The use of EFV has been extended to ages 3 months to 3 years in the United States. Recently CYP2B6 genotype-directed dosing was considered to be required for optimal efavirenz exposure in this age group [ 41 ]. Studies in adults have reported differences related to ethnicity with higher EFV plasma concentrations in Hispanics and Africans than in Caucasians [ 42 – 44 ], probably related to interethnic differences in occurrence of different polymorphisms in drug metabolizing enzymes.…”

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz‐Containing Antiretroviral Therapy

“…With respect to CYP2B6 ontogeny, CYP2B6 mRNA expression levels and CYP2B6 activity are very low during fetal development and approach adult levels by 1 year of age . Modeling based on data from a 24‐week prospective cohort trial of efavirenz plus two nucleoside reverse transcriptase inhibitors in HIV‐positive children 3 months to <36 months of age predicted that FDA‐approved doses would produce subtherapeutic plasma concentrations in almost one third of children who are CYP2B6 NMs (c.516G/G) or IMs (c.516G/T) and supratherapeutic plasma concentrations in >50% of children who are CYP2B6 PMs (c.516T/T) . Subtherapeutic concentrations in this population may also be confounded by poor absorption.…”

“…38 Modeling based on data from a 24-week prospective cohort trial of efavirenz plus two nucleoside reverse transcriptase inhibitors in HIV-positive children 3 months to <36 months of age predicted that FDA-approved doses would produce subtherapeutic plasma concentrations in almost one third of children who are CYP2B6 NMs (c.516G/G) or IMs (c.516G/T) and supratherapeutic plasma concentrations in >50% of children who are CYP2B6 PMs (c.516T/T). 39 Subtherapeutic concentrations in this population may also be confounded by poor absorption. Given these data, similar to DHHS guidelines, we do not recommend use of efavirenz in infants and children aged 3 months to <3 years, except under special circumstances, such as tuberculosis coinfection.…”