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- Title
Pharmacogenetics of Dolutegravir Plasma Exposure Among Southern Africans With Human Immunodeficiency Virus.
- Authors
Cindi, Zinhle; Kawuma, Aida N; Maartens, Gary; Bradford, Yuki; Venter, Francois; Sokhela, Simiso; Chandiwana, Nomathemba; Wasmann, Roeland E; Denti, Paolo; Wiesner, Lubbe; Ritchie, Marylyn D; Haas, David W; Sinxadi, Phumla
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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 (AUCVAR).<bold>Results: </bold>Genetic associations were evaluable in 284 individuals. Of 9 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 = .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 with C/C. The lowest P value for AUCVAR genome-wide was CAMKMT rs343942 (P = 2.4 × 10-7).<bold>Conclusions: </bold>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.
- Subjects
SOUTH Africa; PHARMACOGENOMICS; HIV infections; PYRIDINE; HETEROCYCLIC compounds; RESEARCH funding; SUB-Saharan Africans; BILIRUBIN; HIV
- Publication
Journal of Infectious Diseases, 2022, Vol 226, Issue 9, p1616
- ISSN
0022-1899
- Publication type
journal article
- DOI
10.1093/infdis/jiac174