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


Lubomirov, R; Colombo, S; di Iulio, J; Ledergerber, B; Martinez, R; Cavassini, M; Hirschel, B; Bernasconi, E; Elzi, L; Vernazza, P; Furrer, H; Günthard, H F; Telenti, A (2011). Association of pharmacogenetic markers with premature discontinuation of first-line anti-HIV therapy: an observational cohort study. Journal of Infectious Diseases, 203(2):246-257.

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.

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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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2011
Deposited On:12 Jan 2012 22:09
Last Modified:20 Sep 2018 07:30
Publisher:University of Chicago Press
ISSN:0022-1899
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/infdis/jiq043
PubMed ID:21288825

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