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

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 × 10−4), which was also associated with log10 bilirubin (P = 8.6 × 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 × 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 × 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.

Impact of Genetic Variants in ABCG2, NR1I2, and UGT1A1 on the Pharmacokinetics of Dolutegravir in Children

“…Additionally, a recent study in adults from South Africa found that the rs2231137 SNP in ABCG2 had no effect on dolutegravir concentrations. 22 Thus, even in adults, the impact of rs2231137 on dolutegravir PK is unclear.…”

“…Children from the United States comprised 21 (36%) of participants, with the remainder of the children being from countries in Africa, Thailand, and Brazil. The median (Q1-Q3) log 10 plasma HIV RNA was 4.79 (4.15-5.31) and the median (Q1-Q3) CD4 + lymphocyte percentage was 23 (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Children had been on another antiretroviral regimen a median (Q1-Q3) of 2.8 (1.2-6.4) years before study entry.…”

Determinants of early change in serum creatinine after initiation of dolutegravir‐based antiretroviral therapy in South Africa

“…Plasma dolutegravir concentrations were measured by liquid chromatography with mass tandem spectrometry detection using an AB SCIEX API 4000 instrument, in the Division of Clinical Pharmacology at the University of Cape Town as described elsewhere. 10 A population pharmacokinetic model was developed from the intensively sampled cohort using non-linear mixed-effects modelling. Individual 24-h dolutegravir area under the concentration-time curve (AUC 0-24h ) values were estimated from sparse samples using a post hoc Bayesian estimation method that accounted for participant characteristics.…”

“…While this was not significant after correcting for multiple testing, it lends support to the concept that UGT1A1 homozygous minor allele carriers of the UGT1A1 polymorphism rs887829 exhibited a 26% reduction in dolutegravir clearance compared to those homozygous for the major allele. 10 The rs929596 and rs887829 polymorphisms have been mapped to a UGT1A cluster located on Chromosome 2 that houses multiple protein-coding, and non-encoding, genes. 40 These polymorphisms were in moderate LD in this population (R 2 = .75), which suggests that their effects may not be entirely independent.…”

“…In a southern African population, UGT1A1 polymorphisms rs887829 and rs28899168 were associated with increased plasma dolutegravir exposure. 10 A moderate exposure-response relationship has been reported between dolutegravir and change in creatinine clearance over time. 3 It is possible that UGT1A1 variants that affect dolutegravir exposure could explain some of the variability in changes in creatinine with dolutegravir.…”