Efavirenz Pharmacokinetics in HIV-1-Infected Children Are Associated With CYP2B6-G516T Polymorphism

Abstract

CYP2B6-G516T polymorphisms significantly affect the CL/F rate of EFV in children. Changes in hepatic enzyme activity by age may need to be considered when evaluating the impact of genetic variants on antiretroviral pharmacokinetics in children.

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

“…Although there are a number of reasons for these differential responses, recent pharmacogenetic studies suggest that at least some of these variable responses to NNRTI containing regimens are predictable based on variants in genes responsible for metabolizing and transporting antiretrovirals including PIs, NNRTIs and NRTIs [12]. Compelling data, confirmed by several cohorts, demonstrate that the single nucleotide polymorphism (SNP) in CYP2B6 (CYP2B6-G516T or CYP2B6*6) significantly alters EFV pharmacokinetics in HIV-infected patients [13][14][15][16][17][18][19][20][21]. In addition, other studies have shown the importance of the CYP2B6 SNP on central nervous system (CNS) adverse effects related to EFV use [14,15] and NVP pharmacokinetics [15,22,23].…”

“…Numerous studies have investigated the relationship between the CYP2B6-C1459T genotype and plasma EFV pharmacokinetics in HIV-infected adults [14,17,20,37] and children [21]. However, to date, no significant effect has been observed.…”

“…The actual influence of the CYP2B6-G516T genotypes on clinical responses has been evaluated in only a few studies [14,17,21,54] (Table 1). Haas et al evaluated the impact of the CYP2B6 genotype on virologic and immunologic responses over 24 weeks in 157 HIVinfected adults receiving EFV as a component of HAART and have shown no differences in immunologic (P = 0.15) or virologic responses (P = 0.74) among the patients with the CYP2B6-G516T genotypes after 24 weeks of therapy [14].…”

“…Efavirenz-Several studies have identified a relationship between CYP2B6-G516T gene polymorphisms and plasma EFV pharmacokinetics in HIV-infected adults [13][14][15][16][17][18][19][20] and children [21] (Table 1). All available data have shown that the subjects with the CYP2B6-516-T/T genotype (homozygous variants) have consistently higher EFV concentrations compared to those with the CYP2B6-516-G/T (heterozygous variant) and G/ G genotype (wild type).…”

“…We evaluated the association between the CYP2B6-G516T genotype and EFV pharmacokinetics in 71 HIV-1 infected children receiving HAART [21]. Children with the T/T genotype had significantly lower EFV oral clearance rates (3.0 L/h/m 2 ) than those with the G/T genotype (5.7 L/h/m 2 , P = 0.02) and the G/G genotype (7.0 L/h/m 2 , P = 0.003) ( Figure 3A).…”