P03. Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children

Sandra Soeria-Atmadja1,2, Emma Österberg1, Lars L Gustafsson3, Marja-Liisa Dahl3, Jaran Eriksen3, Johanna Rubin1,2 and Lars Navér1,2 Sandra Soeria-Atmadja1,2
Affiliates: 1Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden, 2Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden, 3Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

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Background
Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agent for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults. The aim of the study was to investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight

Methods
EFV plasma concentrations measured for clinical purposes from all children (< than 18 years old) at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected.

Results
Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements were included. Efavirenz plasma concentration varied 21-fold between measurements (n = 182) (2.7 – 61 μmol/L) (Figure 1) and 9-fold measured as mean EFV plasma concentration across the subjects (4.9 – 42.4 μmol/L) (Figure 2). A multivariate mixed-effects REML regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the studied gene polymorphisms to the intra- and interindividual variation were 6 and 75 %, respectively (Bryk/Raudenbush R-squared level). Asian origin was significantly related to lower loge mean concentration/(dose/weight) compared to African (p = 0.0085) and Hispanic origin (p = 0.038) (Figure 3).

Conclusions
Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration and Asian origin gave substantially lower plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzymes could improve clinical safety and be a way to achieve more predictable EFV plasma concentrations in HIV-infected children.