Year: 2018
Type: article
Study design: Observational Study
Abstract: BACKGROUND: There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz. OBJECTIVES: We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance. METHODS: We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. RESULTS: We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (β = 0.38, P = 2.7 × 10-03), plasma 7-hydroxy-efavirenz (β = 0.59, P = 3.7 × 10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (β = -0.31, P = 1.8 × 10-04) and CSF efavirenz (β = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (β = -0.55, P = 3.5 × 10-05), ABCB1 rs115780656 (β = -0.65, P = 4.1 × 10-05) and CYP2A6 -48A→C (β = -0.59, P = 0.01). CYP2A6 -48A→C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (β = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance. CONCLUSIONS: We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.
DOI: 10.1093/jac/dky481
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: bronze
Funders: Vanderbilt University, South African Medical Research Council, University of Cape Town, National Institutes of Health, Medical Research Council, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, European and Developing Countries Clinical Trials Partnership
Awards: G1276011396, G1571747198, G1597187361, G1819583291, Vanderbilt HIV Clinical Trials Unit, G285461174, G3463285819, G3810609436, G4273213264, G4417181633, G5452137875, G555987577, International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, G622809771, G7612270860, G7742187551, G7930728156, G8217102994, G8653183194, G9000014638, G9000039438, G9000123282, G9000126704, G9000177955, G9000263428, G9000271989, G9000292181, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, Vanderbilt Institute for Clinical and Translational Research (VICTR), AIDS Clinical Trial Group Laboratory Center, Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), Pharmacogenomics of HIV Therapy, Vanderbilt HIV Clinical Trials Unit (CTU), IMPAACT Leadership Group
OpenAlex ID: W2905017348