Efavirenz concentrations in CSF exceed IC50 for wild-type HIV.

TitleEfavirenz concentrations in CSF exceed IC50 for wild-type HIV.
Publication TypeJournal Article
Year of Publication2011
AuthorsBest, BM, Koopmans, PP, Letendre, SL, Capparelli, EV, Rossi, SS, Clifford, DB, Collier, AC, Gelman, BB, Mbeo, G, J McCutchan, A, Simpson, DM, Haubrich, R, Ellis, R, Grant, I
Corporate AuthorsCHARTER Group
JournalJ Antimicrob Chemother
Date Published2011 Feb
KeywordsAdult, Anti-HIV Agents, Benzoxazines, Brain, CHARTER, Chromatography, High Pressure Liquid, Female, HIV Infections, Humans, Inhibitory Concentration 50, Internal, Male, Middle Aged, Nervous System Diseases, Random Allocation, Viral Load

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 1 h 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 39 ng/mL (plasma) and <0.1 ng/mL (CSF).RESULTS: Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV.CONCLUSIONS: Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.

Alternate JournalJ. Antimicrob. Chemother.
PubMed ID21098541
PubMed Central IDPMC3019085
Grant List5U10 HD031318 / HD / NICHD NIH HHS / United States
K24 AI064086 / AI / NIAID NIH HHS / United States
U01 AI069432 / AI / NIAID NIH HHS / United States
N01 MH22005 / MH / NIMH NIH HHS / United States
P30 AI036214 / AI / NIAID NIH HHS / United States
K24 AI064086-06 / AI / NIAID NIH HHS / United States