AIMS: Genetic factors, notably CYP2B6 516G → T [rs3745274] and 983 T → 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, 983 T → 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, 2.08 (1.68-2.94) µg/mL and 7.26 (4.82-8.34) µg/mL for extensive, intermediate, and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations [β = 0.28, 95% CI (0.21-0.35), P = 2.4 x10(-11) ]. Among individual CYP2B6 polymorphisms, 516G → T best predicted efavirenz concentrations [β =0.22, 95%CI (0.13-0.30), P = 1.27x10(-6) )]. There was also associations with 983 T → C [β =0.27, 95%CI (0.10 -0.44), P = 0.002)] and 15582C → T [β =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, 983 T → C, and 15582C → T best described efavirenz exposure in HIV-infected Black South African adults and children.
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