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 HF,
Telenti A;
Swiss HIV Cohort Study.
Battegay M, Bernasconi E, Böni J, Bucher HC, Bürgisser P, Calmy A, Cattacin S, Cavassini M, Dubs R, Egger M, Elzi L, Fischer M, Flepp M, Fontana A, Francioli P, Furrer H, Fux CA, Gorgievski M, Günthard HF, Hirsch HH, Hirschel B, Hösli I, Kahlert C, Kaiser L, Karrer U, Kind C, Klimkait T, Ledergerber B, Martinetti G, Müller N, Nadal D, Paccaud F, Pantaleo G, Rauch A, Regenass S, Rickenbach M, Rudin C, Schmid P, Schultze D, Schüpbach J, Speck R, de Tejada BM, Taffé P, Telenti A, Trkola A, Vernazza P, Weber R, Yerly S.
Source
Institute of Microbiology, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
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.
- PMID:
- 21288825
- [PubMed - indexed for MEDLINE]
- PMCID:
- PMC3071070
Free PMC ArticleFigure 1.
Genetic risk of tenofovir discontinuation at 1 year. Cumulative rates of discontinuation for 500 participants stratified by ABCC4 and ABCC2 genetic variants: (A) by ABCC4 rs899494 genotypes CC (0), CT (1), and TT (2); (B) by ABCC2 rs2273697 genotypes GG (0), GA (1), and AA (2); and (C) by ABCC2 rs717620 genotypes CC (0), CT (1), and TT (2). Pa, covariate adjusted P value, estimated from Cox regression models. NOTE. CC: individuals without the genetic risk allele ABCC4 rs899494; CT: individuals carrying 1 risk allele ABCC4 rs899494; TT: individuals carrying 2 risk alleles ABCC4 rs899494; GG: individuals without genetic risk allele ABCC2 rs2273697; GA: individuals carrying 1 genetic risk allele ABCC2 rs2273697; AA: individuals carrying 2 genetic risk alleles ABCC2 rs2273697.
J Infect Dis. J Infect Dis;203(2):246-257.
Figure 3.
Genetic risk of lopinavir discontinuation at 1 year. Cumulative rates of discontinuation for 184 participants stratified by hypertriglyceridemia (A) and pharmacokinetic (B) genetic scores. Pa, covariate adjusted P value.
J Infect Dis. J Infect Dis;203(2):246-257.
Figure 2.
Genetic risk of efavirenz discontinuation at 1 year. Cumulative rates of discontinuation for 272 participants stratified by CYP2B6, CYP2A6, and CYP3A4 genetic variants by six-group genetic score (A) and by dichotomized genetic score. Pa, covariate adjusted P value (B).
J Infect Dis. J Infect Dis;203(2):246-257.
Figure 4.
Genetic risk of atazanavir discontinuation at 1 year. Cumulative rates of discontinuation for 121 participants stratified by UGT1A1, NR1I2, and ABCB1 genetic variants: (A) by UGT1A1 rs8175347 genotypes *1/*1, *1/*28 or *37, and *28/*28 or *37; (B) by NR1I2 rs2472677 genotypes TT (0), CT (1), and CC (2); (C) by ABCB1 rs1045642 genotypes CC (0), CT (1), and TT (2); (D) by UGT1A1/ABCB1 additive genetic score. Pa, covariate adjusted P value. NOTE. TT: individuals carrying 2 risk alleles ABCC4 rs899494; CT: individuals carrying 1 risk allele ABCC4 rs899494; CC: individuals without the genetic risk allele ABCC4 rs899494.
J Infect Dis. J Infect Dis;203(2):246-257.
Publication Types
MeSH Terms
Substances