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Association of Pharmacogenetic Markers with Premature Discontinuation of First-line Anti-HIV Therapy: An Observational Cohort Study

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

In: Journal of Infectious Diseases, 2011, vol. 203, no. 2, p. 246-257

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    Titre
    • Association of Pharmacogenetic Markers with Premature Discontinuation of First-line Anti-HIV Therapy: An Observational Cohort Study
    Auteur
    • Lubomirov, Rubin. Institute of Microbiology
    • Colombo, Sara. Institute of Microbiology
    • di Iulio, Julia. Institute of Microbiology
    • Ledergerber, Bruno. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich
    • Martinez, Raquel. Institute of Microbiology
    • Cavassini, Matthias. Infectious Diseases Service, University Hospital Center, University of Lausanne, Lausanne
    • Hirschel, Bernard. Infectious Disease/HIV Unit, Division of Infectious Diseases, University Hospital, Geneva
    • Bernasconi, Enos. Ospedale Regionale, Lugano
    • Elzi, Luigia. University Hospital, Basel
    • Vernazza, Pietro. Kantonsspital, St. Gallen
    • Furrer, Hansjakob. University Clinic for Infectious Diseases, Bern University Hospital and University of Bern, Bern, Switzerland
    • Günthard, Huldrych F.. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich
    • Telenti, Amalio. Institute of Microbiology
    Type de document
    • Postprint
    Langue
    • Anglais
    Publié dans
    • Journal of Infectious Diseases, 2011, vol. 203, no. 2, p. 246-257. Oxford University Press
    Autre version électronique
    Identifiant OAI-PMH
    • oai:doc.rero.ch:291345
    Summary
    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