Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa.

ABSTRACT: AIMS:Genetic factors, notably CYP2B6 516G?T [rs3745274] and 983T?C [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children. METHODS:Steady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3. RESULTS:Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516G?T, 983T?C, and 15582C?T [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) µg ml(-1), 2.08 (1.68-2.94) µg ml(-1) and 7.26 (4.82-8.34) µg ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (? = 0.28, 95% CI 0.21, 0.35, P?=?2.4 × 10(-11)). Among individual CYP2B6 polymorphisms, 516G?T best predicted efavirenz concentrations (??=?0.22, 95% CI 0.13, 0.30, P?=?1.27 × 10(-6)). There was also associations with 983T?C (? = 0.27, 95% CI 0.10, 0.44, P?=?0.002) and 15582C?T (??=?0.11, 95% CI 0.01, 0.22, P?=?0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations. CONCLUSIONS:Composite CYP2B6 genotype based on CYP2B6 516G?T, 983T?C, and 15582C?T best described efavirenz exposure in HIV-infected Black South African adults and children.

SUBMITTER: Sinxadi PZ 

PROVIDER: S-EPMC4500334 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature