No Observable Correlation between Central Nervous System Side Effects and EFV Plasma Concentrations in Japanese HIV Type 1-Infected Patients Treated with EFV Containing HAART

Abstract

The present study assessed the relationship between central nervous system (CNS) side effects and plasma concentrations of efavirenz (EFV) in Japanese HIV-1-infected patients. Subjects consisted of 69 HIV-1-infected patients (57 therapy-naive and 12 therapy-experienced patients) being treated using EFV in combination with other antiretroviral agents at the outpatient HIV clinic. Successful virological treatment was achieved in 61 patients. Eight patients discontinued EFV containing therapy because CNS symptoms did not resolve (four patients), EFV-specific mutations were detected (two patients), or skin rash was observed (two patients). Mean EFV plasma concentration for 61 effectively treated patients, measured at 15 h postdosing, was 2.42 microg/ml (range: 0.78-6.82 microg/ml). This EFV concentration range contributed to suppressed viral load in these Japanese patients. Adverse CNS effects were observed in 19 patients soon after therapy onset. These effects disappeared within 1 month except for four patients who suffered severe CNS side effects. Mean EFV plasma concentrations were not significantly different between subjects with (2.45 +/- 1.08 microg/ml) and without (2.42 +/- 1.40 microg/ml) CNS side effects. We concluded no correlation existed between the plasma EFV concentration and the emergence of CNS side effects in Japanese HIV-1-infected patients. Further investigations, enforced with the drug concentration measurement at earlier time points and more appropriate assessment of CNS symptoms, are required.

The relation between treatment outcome and efavirenz, atazanavir or lopinavir exposure in the NORTHIV trial of treatment-naïve HIV-1 infected patients

“…Some investigators have found positive relations [15,17,18], whereas others have not [19,20]. This difference may be method-dependent.…”

Efavirenz as a cause of ataxia in children

“…One factor attributing to this individual variation in levels is polymorphism of the CYP2B6 enzyme on cytochrome P450, as EFV is a substrate of this enzyme. [9] The prevalence of the slow-metabolising genotype was 30% in a Botswana study, and other studies have also shown a relatively higher incidence of this genotype in African populations. [14] …”

“…[7] CNS symptoms are the most frequently reported side-effects in HIVpositive patients on EFV, and include dizziness, headache, confusion, stupor, impaired concentration, agitation, amnesia, depersonalisation, hallucinations, insomnia and strange dreams. [6,[8][9][10][11][12][13][14] The frequency of CNS side-effects is estimated to be 20 -40%. [10] The majority of patients who develop CNS and psychiatric adverse effects do so in the first 6 weeks of treatment, [11] with most symptoms resolving by 6 -10 weeks after treatment initiation.…”

“…However, other researchers have found no correlation between adverse effects and plasma concentrations. [8,9] Gutierrez et al [13] nevertheless found that CNS side-effects associated with long-term EFV administration were related to plasma levels.…”

Effect of Host Genetic Variation on the Pharmacokinetics and Clinical Response of Nnrtis

“…These CNS adverse effects are associated with the higher levels of EFV in plasma [38][39][40], while others failed to demonsrate the association [41,42]. Two studies have demonstrated the association between the CYP2B6 genotype and the incidence of CNS adverse effects [14,15].…”