Pharmacogenetics of dolutegravir plasma exposure among Southern Africans living with HIV

Abstract

Background Dolutegravir is a component of preferred antiretroviral therapy (ART) regimens. We characterised the pharmacogenetics of dolutegravir exposure following 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 non-linear mixed-effects modelling. Linear regression models examined associations with unexplained variability in dolutegravir area under the concentration-time curve (AUCVAR). Results Genetic associations were evaluable in 284 individuals. Of nine polymorphisms previously associated with dolutegravir pharmacokinetics, the lowest P-value with AUCVAR was UGT1A1 rs887829 (P = 1.8 x 10-4), which was also associated with log10 bilirubin (P = 8.6 x 10-13). After adjusting for rs887829, AUCvar was independently associated with rs28899168 in the UGT1A locus (P = 0.02), 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 to C/C. The lowest P-value for AUCVAR 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 AUCVAR. The novel rs28899168 association warrants replication. This study enhances understanding of dolutegravir pharmacogenetics in Africa.