<i>CYP2B6</i> Haplotype Predicts Efavirenz Plasma Concentration in Black South African HIV-1-Infected Children: A Longitudinal Pediatric Pharmacogenomic Study

Abstract South Africa has the highest burden of the human immunodeficiency virus (HIV) infection globally. Efavirenz (EFV), a frequently used drug against HIV infection, displays a relationship between drug concentration and pharmacodynamics effects clinically. However, haplotype-based genetic variation in drug metabolism in a pediatric sample has been little considered in a longitudinal long-term context. CYP2B6 plays a key role in variation of EFV plasma concentration through altered drug metabolism. We report here on a prospective clinical pharmacogenomics/pharmacokinetic study of Bantu-speaking children, importantly, over a period of 24 months post-initiation of EFV-based treatment in South Africa. We characterized the HIV-1-infected children ( n  = 60) for the CYP2B6 c.516G>T , c.785A>G , c.983T>C , and c.1459C>T single nucleotide polymorphisms (SNPs). These SNPs were determined using polymerase chain reaction/restricted fragment length polymorphism and SNaPshot genotyping. Longitudinal mid-dose EFV plasma concentrations were determined by LC-MS/MS and association analyses with genotypes and haplotypes at 1, 3, and 24 months were performed. The CYP2B6 c.516T/T genotype showed significantly higher EFV plasma concentrations ( p  < 0.001) compared to non 516T-allele carriers at all three time points. The minor allele frequencies (MAF) for CYP2B6 c.516T , c.785G , c.983C , and c.1459T were 0.410, 0.408, 0.110, and 0.000 respectively. Haplotypes were constructed using CYP2B6 c.516G>T,–c.785A>G and c.983T>C . The haplotype T-G-T presented with significantly increased EFV plasma concentrations compared to the reference G-A-T haplotype at 1, 3, and 24 months ( p  = 0.009; p  = 0.003; p  = 0.001), suggesting that the T-G-T haplotype predisposes a risk of EFV plasma concentrations >4 μg/mL. The clinical implications of these pharmacogenomics observations for EFV toxicity and treatment resistance warrant further future research.