1. Drug metabolism and transport gene polymorphisms and efavirenz adverse effects in Brazilian HIV-positive individuals.
- Author
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de Almeida TB, de Azevedo MCVM, Pinto JFDC, Ferry FRA, da Silva GAR, de Castro IJ, Baker P, Tanuri A, Haas DW, and Cardoso CC
- Subjects
- Adult, Aged, Alkynes, Benzoxazines administration & dosage, Brazil, Constitutive Androstane Receptor, Cyclopropanes, Drug-Related Side Effects and Adverse Reactions pathology, Female, Genetic Association Studies, Humans, Male, Middle Aged, Polymorphism, Genetic, Reverse Transcriptase Inhibitors administration & dosage, Benzoxazines adverse effects, Benzoxazines metabolism, Drug-Related Side Effects and Adverse Reactions genetics, HIV Infections drug therapy, Inactivation, Metabolic genetics, Reverse Transcriptase Inhibitors adverse effects, Reverse Transcriptase Inhibitors metabolism
- Abstract
Objectives: There are limited data regarding efavirenz pharmacogenetics in admixed populations. The Brazilian population is highly admixed. In a Brazilian cohort, we sought to characterize associations between efavirenz adverse effects (all-cause and CNS) and polymorphisms in seven genes known or suspected to affect efavirenz metabolism and transport., Methods: We studied 225 HIV-positive individuals who had been prescribed efavirenz-containing regimens at a hospital in Rio de Janeiro, Brazil. Eighty-nine cases had efavirenz adverse effects, including 43 with CNS adverse effects, while 136 controls had no adverse effect of any antiretroviral after treatment for at least 6 months. A total of 67 candidate polymorphisms in ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3 genes were selected for association analysis. Admixture was assessed using 28 ancestry-informative polymorphisms previously validated for the Brazilian population. Associations were evaluated with logistic regression models adjusted for sex and genetic ancestry., Results: There was extensive African, European and Native American admixture in the cohort. Increased all-cause adverse effects were associated with the CYP2B6 genotype combination 15582CC-516TT-983TT (OR = 7.26, P = 0.003) and with the CYP2B6 slow metabolizer group 516TT or 516GT-983CT (OR = 3.10, P = 0.04). CNS adverse effects were nominally associated with CYP3A4 rs4646437 (OR = 4.63, P = 0.014), but not after adjusting for multiple comparisons., Conclusions: In a highly admixed Brazilian cohort, the CYP2B6 slow metabolizer genotype was associated with an increased risk of efavirenz adverse effects.
- Published
- 2018
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