Pharmacogenetics of Dolutegravir Plasma Exposure Among Southern Africans With Human Immunodeficiency Virus

Steady-state dolutegravir concentration-time data from Southern Africans were analyzed using nonlinear mixed effects. We characterized genetic associations with unexplained variability in dolutegravir area under the concentration-time curve (AUC(VAR)). UGT1A1 rs887829 and UGT1A rs28899168 were independently associated with dolutegravir AUC(VAR). Background Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterized the pharmacogenetics of dolutegravir exposure after ART initiation in the ADVANCE trial in South Africa. Methods Genome-wide genotyping followed by imputation was performed. We developed a population pharmacokinetic model for dolutegravir using nonlinear mixed-effects modeling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUC(VAR)). Results Genetic associations were evaluable in 284 individuals. Of 9 polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P value with AUC(VAR) was UGT1A1 rs887829 (P = 1.8 x 10(-4)), which was also associated with log(10) bilirubin (P = 8.6 x 10(-13)). After adjusting for rs887829, AUC(VAR) was independently associated with rs28899168 in the UGT1A locus (P = .02), as were bilirubin concentrations (P = 7.7 x 10(-8)). In the population pharmacokinetic model, rs887829 T/T and C/T were associated with 25.9% and 10.8% decreases in dolutegravir clearance, respectively, compared with C/C. The lowest P value for AUC(VAR) genome-wide was CAMKMT rs343942 (P = 2.4 x 10(-7)). Conclusions In South Africa, rs887829 and rs28899168 in the UGT1A locus were independently associated with dolutegravir AUC(VAR). The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.