Background:  Efavirenz (EFV) -based antiretroviral drug regimens are the preferred choice for the initial treatment of HIV-infected children older than 3 years. There is a concern about the subtherapeutic EFV plasma level in children with the current dosing guideline. The hepatic cytochrome P450 2B6 (CYP2B6) enzyme is the main catalyst of EFV metabolism. Single nucleotide polymorphisms (SNP) of CYP2B6 have been associated with high inter-individual variations in EFV plasma drug concentrations. Our primary objective was to determine the adequacy of EFV dosing and explore the influence of CYP2B6-516G>T polymorphisms on EFV plasma concentrations in Thai HIV-infected children.

Methods:  We assessed 66 HIV-infected children receiving an EFV-based ART for at least 4 weeks. Between 12 and 16 hours after EFV intake, a blood sample was drawn to measure the EFV plasma concentration and gene CYP2B6-516G>T polymorphisms. Patient’s clinical information included CD4 cell count, plasma HIV-1 RNA viral load, and drug adverse events were reviewed from medical records. EFV plasma concentrations were determined using high-performance liquid chromatography and CYP2B6-516G>T polymorphisms were analyzed using direct gene sequencing.

Results: The median age (range) was 12.3 (3.1 to 18.7) years. At a mean (SD) time of 14.8 (0.8) hours after drug intake, mean EFV plasma concentration (SD) was 3138 (3313) ng/mL. Of all the children, 8 (13%), 45 (71%), and 10 (16%) had an EFV concentration <1000 ng/mL, between 1000 and 4000 ng/mL, and >4000 ng/mL, respectively. CYP2B-516 G/G, G/T, and T/T genotypes were found in 48%, 41% and 11% children, respectively. The CYP2B6-516G>T allele frequency was 31.75%. The mean EFV concentration (SD) for children with G/G, G/T, and T/T genotypes were 1604 (729) ng/mL, 2635 (1199) ng/mL, and 11,582 (2972) ng/mL, respectively (p <0.001). A correlation between EFV concentrations above 4000 ng/mL and psychiatric side effects (p = 0.02) was observed, but there was no association with rash, hepatotoxicity or central nervous system disturbances. 

Conclusions:  Current EFV dosing guidelines provides adequate plasma drug concentrations in Thai children. CYP2B6-516G>T polymorphisms significantly affects the drug metabolism of EFV in children and psychiatric side effects of EFV are associated with EFV plasma concentrations above 4000 ng/mL.