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Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study.

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Lubomirov Rubin, Colombo Sara, di Iulio Julia, Ledergerber Bruno, Martinez Raquel, Cavassini Matthias, Hirschel Bernard, Bernasconi Enos, Elzi Luigia, Vernazza Pietro, Furrer Hansjakob, Günthard Huldrych F, Telenti Amalio, Swiss HIV Cohort Study,
Project Pharmacocinétique de population, pharmacogénétique, et profils métaboliques de la thérapie anti-HIV
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Original article (peer-reviewed)

Journal The Journal of infectious diseases
Volume (Issue) 203(2)
Page(s) 246 - 57
Title of proceedings The Journal of infectious diseases
DOI 10.1093/infdis/jiq043

Abstract

BACKGROUND Poor tolerance and adverse drug reactions are main reasons for discontinuation of antiretroviral therapy (ART). Identifying predictors of ART discontinuation is a priority in HIV care. METHODS A genetic association study in an observational cohort to evaluate the association of pharmacogenetic markers with time to treatment discontinuation during the first year of ART. Analysis included 577 treatment-naive individuals initiating tenofovir (n = 500) or abacavir (n = 77), with efavirenz (n = 272), lopinavir/ritonavir (n = 184), or atazanavir/ritonavir (n = 121). Genotyping included 23 genetic markers in 15 genes associated with toxicity or pharmacokinetics of the study medication. Rates of ART discontinuation between groups with and without genetic risk markers were assessed by survival analysis using Cox regression models. RESULTS During the first year of ART, 190 individuals (33%) stopped 1 or more drugs. For efavirenz and atazanavir, individuals with genetic risk markers experienced higher discontinuation rates than individuals without (71.15% vs 28.10%, and 62.5% vs 14.6%, respectively). The efavirenz discontinuation hazard ratio (HR) was 3.14 (95% confidence interval (CI): 1.35-7.33, P = .008). The atazanavir discontinuation HR was 9.13 (95% CI: 3.38-24.69, P < .0001). CONCLUSIONS Several pharmacogenetic markers identify individuals at risk for early treatment discontinuation. These markers should be considered for validation in the clinical setting.
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