Abstract
BackgroundBlood-cerebrospinal fluid (CSF) barrier transporters affect the influx and efflux of drugs. The antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (BBB) and blood-CSF barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (CNS) penetration.ObjectivesWe investigated genetic polymorphisms associated with CSF disposition of tenofovir and emtricitabine.MethodWe collected paired plasma and CSF samples from 47 HIV-positive black South African adults who were virologically suppressed on efavirenz, tenofovir and emtricitabine. We considered 1846 single-nucleotide polymorphisms from seven relevant transporter genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, SLCO1B1 and ABCC4) and 782 met a linkage disequilibrium (LD)-pruning threshold.ResultsThe geometric mean (95% confidence interval [CI]) values for tenofovir and emtricitabine CSF-to-plasma concentration ratios were 0.023 (0.021–0.026) and 0.528 (0.460–0.605), respectively. In linear regression models, the lowest p-value for association with the tenofovir CSF-to-plasma ratio was ABCB1 rs1989830 (p = 1.2 × 10−3) and for emtricitabine, it was ABCC5 rs11921035 (p = 1.4 × 10−3). None withstood correction for multiple testing.ConclusionNo genetic polymorphisms were associated with plasma, CSF concentrations or CSF-to-plasma ratios for either tenofovir or emtricitabine.
Highlights
Tenofovir and emtricitabine are part of the current first-line antiretroviral therapy (ART) regimens for HIV-positive adults in resource-limited settings and both are widely used in high-income countries.[1]
Higher cerebrospinal fluid (CSF) tenofovir concentrations and lower emtricitabine concentrations have been reported, which may be explained by polymorphisms in drug transporters or altered blood–brain barrier (BBB) permeability.[4,5]
A polymorphism in ABCG2 rs2231142 has been associated with 1.5-fold increased plasma tenofovir exposure and Thai patients carrying ABCC4 3463 AG or GG had an 11% greater tenofovir clearance compared with AA.[12,13]
Summary
Tenofovir and emtricitabine are part of the current first-line antiretroviral therapy (ART) regimens for HIV-positive adults in resource-limited settings and both are widely used in high-income countries.[1] Infection of the central nervous system (CNS) by HIV-1 occurs early in infection and its clearance is reliant on adequate CNS antiretroviral concentrations.[2] there are limited data regarding determinants of cerebrospinal fluid (CSF) penetration by tenofovir and emtricitabine. Data from small cohorts indicate that CSF concentrations of tenofovir and emtricitabine are 5% and 50% of plasma concentrations, respectively.[3,4,5]. The antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (BBB) and blood-CSF barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (CNS) penetration
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