Pharmacogenetics of the Late-Onset Efavirenz Neurotoxicity Syndrome (LENS)

Abstract

Background The late-onset efavirenz neurotoxicity syndrome (LENS) presents as ataxia and/or encephalopathy with supratherapeutic efavirenz plasma concentrations (>4 µg/mL). Efavirenz is primarily metabolized by cytochrome P450 2B6 (CYP2B6), with CYP2A6 as an accessory pathway. We hypothesized that participants with LENS would predominantly be CYP2B6 slow metabolizers. The aim of our study was to determine the frequency of CYP2B6 slow metabolizers in participants with LENS. Methods Adult HIV-positive participants on efavirenz-based antiretroviral therapy presenting with LENS were prospectively enrolled. Genetic polymorphisms known to be associated with increased efavirenz plasma concentrations in CYP2B6 (rs3745274, rs28399499, rs4803419) and CYP2A6 (rs28399433) were selected and used to determine proportions of slow metabolizers. Pharmacokinetic analyses were performed using liquid chromatography–tandem mass spectrometry. Median (IQR) plasma efavirenz and 8-hydroxyefavirenz were described. Results Fifteen participants were enrolled. Thirteen (13/15) were Black-African and 13 were female. Median weight was 49.9kg with a median duration on efavirenz of 2.2 years. All 15 participants were successfully genotyped as slow CYP2B6 metabolizers, with 6 participants additionally having CYP2A6 heterozygous genotype. Thirteen were receiving the CYP2A6 enzyme inhibitor isoniazid, and all 15 were genotypic NAT2 slow or intermediate acetylators. Efavirenz plasma concentration was markedly increased at 50.5 (47.0–65.4) µg/mL; 8-hydroxyefavirenz concentration was markedly decreased at 0.10 (0.07–0.15) µg/mL. Conclusions Our cohort provides definitive evidence that LENS is associated with the CYP2B6 slow metabolizer genotype, with a median efavirenz plasma concentration >12-fold higher than the defined upper limit of the therapeutic range. Isoniazid and low body weight are important contributors to LENS development.

Biotransformation of Efavirenz and Proteomic Analysis of Cytochrome P450s and UDP-Glucuronosyltransferases in Mouse, Macaque, and Human Brain-Derived In Vitro Systems

“…T/T genotype is associated with higher plasma and CSF concentrations of EFV (Haas et al, 2004;Nightingale et al, 2016), as well as late onset efavirenz neurotoxicity syndrome (van Rensburg et al, 2021). Further, in silico modeling indicates that measurements of EFV in the CSF likely underrepresent the EFV penetration into the brain (Curley et al, 2017).…”

“…Up until 2018, EFV was one component of the first line treatment (WHO, 2018), and is still utilized in resource limited settings. EFV is associated with neurological adverse events, such as dizziness, depression, impaired concentration, disordered sleep, and anxiety (Fumaz et al, 2002;Gutierrez et al, 2005;Romao et al, 2011;Ma et al, 2016;Checa et al, 2020;Hakkers et al, 2020;van Rensburg et al, 2021). Higher plasma concentrations of EFV and its primary metabolite, 8-hydroxyefavirenz (8-OHEFV), have been linked to poorer neurocognitive performance and mood changes (Grilo et al, 2016;Hakkers et al, 2020).…”

Late-onset efavirenz toxicity: A descriptive study from Pretoria, South Africa

“…In a study using pharmacokinetic simulations, the efavirenz concentrations in brain tissue were found to be higher compared to plasma or CSF concentrations and in a recent study of patients with late-onset efavirenz toxicity, the 8-hydroxy-efavirenz levels were even decreased. 12 , 25…”

“… 11 A recent study of 15 patients with late-onset efavirenz toxicity found that all had polymorphisms of CYP2B6 which result in slower metabolism of efavirenz. 12 Isoniazid inhibits the CYP2A6 enzyme, which is an accessory pathway to metabolise efavirenz. Although usually only a small proportion of efavirenz is metabolised via this enzyme, it becomes more important in slow metabolisers.…”

“…Polymorphisms in the CYP2B6 , have also been associated with slower efavirenz metabolism and toxicity. 12 If not recognised early, these side effects can lead to significant morbidity and to the death of patients. 8 …”