Article

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

ABSTRACT

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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    • "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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