Efavirenz concentrations in CSF exceed IC₅₀ for wild-type HIV

Objectives: HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This study's objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF. Methods: CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39ng/mL (plasma) and <0.1ng/mL (CSF). Results: Eighty participants (age 44+8 years; 79+15kg; 20 females) had samples drawn 12.5+5.4h postdose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145ng/mL in plasma (IQR 1384-4423) and 13.9ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1h of each other was 0.005 (IQR 0.0026-0.0076; n=69). The CSF/IC50 ratio was 26 (IQR 8-41) using the published IC₅₀ for wild-type HIV (0.51ng/mL). Two CSF samples had concentrations below the efavirenz IC₅₀ for wild-type HIV. Conclusions: Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wildtype IC₅₀ in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.