Drug metabolism and transport gene polymorphisms and efavirenz adverse effects in Brazilian HIV-positive individuals

• Published in: Journal of antimicrobial chemotherapy Vol. 73; no. 9; pp. 2460 - 2467
• Main Authors: de Almeida, Tailah Bernardo, de Azevedo, Marcelo Costa Velho Mendes, Pinto, Jorge Francisco da Cunha, Ferry, Fernando Rafael de Almeida, da Silva, Guilherme Almeida Rosa, de Castro, Izana Junqueira, Baker, Paxton, Tanuri, Amilcar, Haas, David W, Cardoso, Cynthia C
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-09-2018
• Subjects: Adult; Aged; Alkynes; Benzoxazines - administration & dosage; Benzoxazines - adverse effects; Benzoxazines - metabolism; Brazil; Constitutive Androstane Receptor; Cyclopropanes; Drug-Related Side Effects and Adverse Reactions - genetics; Drug-Related Side Effects and Adverse Reactions - pathology; Female; Genetic Association Studies; HIV Infections - drug therapy; Humans; Inactivation, Metabolic - genetics; Male; Middle Aged; Original Research; Polymorphism, Genetic; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - adverse effects; Reverse Transcriptase Inhibitors - metabolism; Brazil
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dky190

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.
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.
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.
In a highly admixed Brazilian cohort, the CYP2B6 slow metabolizer genotype was associated with an increased risk of efavirenz adverse effects.