Absence of a relation between efavirenz plasma concentrations and toxicity-driven evafirenz discontinuations in the EuroSIDA study

Department of Clinical Pharmacy, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Antiviral therapy (Impact Factor: 3.02). 02/2009; 14(1):75-83.
Source: PubMed


Co1nflicting data exist regarding the effect of efavirenz (EFV) plasma concentrations on central nervous system (CNS) toxicity. We aimed to determine whether patients with high EFV plasma concentrations have an increased likelihood of toxicity-driven EFV discontinuations.
EFV plasma concentrations were measured from patients in the EuroSIDA study starting EFV after 1 January 1999. Patients with a plasma concentration available were divided into those that discontinued EFV because of any toxicity or by the choice of the patient or physician within 2 years (TOXPC group) and those that continued EFV for > or = 2 years (no toxicity group). Multivariable logistic regression modelling was used to investigate the effects of the EFV plasma concentration and those of other potentially relevant factors on the risk of toxicity-induced EFV discontinuations.
A total of 843 patients were included. Of these patients, 138 patients (16.4%) discontinued EFV because of TOXPC and 705 (83.6%) patients continued EFV for 22 years. A total of 20 (14.5%) patients in the TOXPC group had high EFV plasma concentrations (>4.0 mg/l) compared with 99 (14.0%) patients in the no toxicity group (P = 0.890). A positive hepatitis C status (P = 0.026), but not the EFV plasma concentration, was an independent predictor of toxicity-driven EFV discontinuations.
No association was found between EFV plasma concentrations and the risk of EFV discontinuations because of (CNS) toxicity. This result questions the designation of EFV plasma concentrations >4.0 mg/l as being 'toxic', at least when defined by treatment discontinuation.

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    • "EFV tolerability is a major concern and, in fact, represents the main reason for premature antiretroviral treatment discontinuation (Lubomirov et al., 2011). Several studies have investigated the relationships between elevated EFV concentrations, genetic background, and neuropsychological effects, which have yielded controversial results as some associations have been found in some but not all studies (Marzolini et al., 2001; Gutierrez et al., 2005; Read et al., 2009; van Luin et al., 2009). In view of the conflicting results regarding the mechanism of EFV toxicity, Tovar-y-Romo et al. (2012) investigated, in vitro, the impact of EFV and two primary oxidized EFV metabolites on the function of primary neurone cultures, and found that the metabolite 8-hydroxy-efavirenz (8OH-EFV) (Fig. 1B) is a potent neurotoxin in vitro at concentrations 1 order of magnitude lower than those for EFV and 7-hydroxy-efavirenz (7OH-EFV). "
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    ABSTRACT: Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). Most metabolites profile analyses have been so far restricted to 8OH-EFV, 7OH-EFV and EFV-N-gln even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolites profiles analyses by tandem mass spectrometry of plasma, CSF and urine samples in 71 HIV patients under efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-Glucuronide, and 8OH-EFV-sulfate (identified for the first time) in humans were found 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6 and CYP3A metabolic pathways, the 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (p < 0.0001) which was also reflected by phase II metabolites 8OH-EFV-gln/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of CNS toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV - gln, 8OH-EFV-sulfate and 7OH-EFV - gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of these previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz need to be further examined in larger cohort studies.
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    • "Depending on the considered studies, efavirenz plasma concentrations above 4,000 ng/mL were [14], [43], [46], [47] or were not [24], [41], [48], [49] associated with efavirenz adverse events. In the 2NN study [50], no relationship was observed between CNS/psychiatric events and efavirenz exposure, except in Thailand (p<0.001, "
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