CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children

Abstract

The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

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

“…Similarly, Penzak et al evaluated 23 HIVinfected adults who received NVP and showed that the median NVP concentration in individuals with the CYP2B6-516-T/T (7.6 μg/mL) was higher than those in individuals with the G/G genotype (4.2 μg/mL) or with the G/T genotype (5.6 μg/mL) [22]. Our recent data analyzing 126 HIV-1 infected children receiving NVP as a component of HAART demonstrated a significant association between the CYP2B6-G516T and NVP oral clearance [23]. NVP oral clearance in children with the CYP2B6-516-T/T genotype (1.6 L/hr/m 2 ) was significantly decreased compared to those with the -G/G (2.3 L/hr/m 2 , P = 0.001) and -G/T genotype (2.1 L/hr/m 2 , P = 0.003) ( Figure 3B).…”

“…Our previous data in 72 children who received EFV as a component of HAART [21] did not demonstrate differences in immunologic or virologic outcomes when analyzed in association with CYP2B6-G516T gene polymorphisms despite significant differences in EFV oral clearance. However, our recent study in 126 children with advanced HIV infection who received NVP as a component of HAART demonstrated different findings [23]. Children with the CYP2B6-516-T/T genotype had the greatest increase in CD4 + T-cell percentages (+9.0%) compared to those with the -G/G (+3.2%, P = 0.008) and -G/T genotype (+5.0%, P = 0.04) at week 12.…”

“…Nevirapine-Compared to EFV, few studies have evaluated the relationship between the CYP2B6 genotypes and NVP pharmacokinetics [15,22,23] (Table 1). Rotger et al assessed the CYP2B6-G516T in 59 HIV-infected subjects who received NVP as a component of HAART [15].…”

“…We evaluated 14 pairs of cerebrospinal fluid (CSF) and plasma NVP levels from 11 children with known or suspected HIV encephalopathy, or presence of symptoms consistent with neurological decline attributable to HIV-related neurologic diseases [23]. The median NVP CSF: plasma ratio was 0.62 in children with the ABCB1-3435-C/T or -T/T compared to 0.43 in children with the ABCB1-3435-C/C genotype (P = 0.01).…”

“…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].…”