Efavirenz concentrations in CSF exceed IC50 for wild-type HIV
Year: 2010
Type: article
Study design: Observational Study
Abstract: 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.
DOI: 10.1093/jac/dkq434
Authors: B. M. Best, P. P. Koopmans, S. L. Letendre, E. V. Capparelli, S. S. Rossi, D. B. Clifford, A. C. Collier, B. B. Gelman, G. Mbeo, J. A. McCutchan, D. M. Simpson, R. Haubrich, R. Ellis, I. Grant, on behalf of the CHARTER Group, I. Grant, J. A. McCutchan, R. J. Ellis, T. D. Marcotte, D. Franklin, R. J. Ellis, J. A. McCutchan, T. Alexander, S. Letendre, E. Capparelli, R. K. Heaton, J. H. Atkinson, S. P. Woods, M. Dawson, J. K. Wong, C. Fennema-Notestine, M. J. Taylor, R. Theilmann, A. C. Gamst, C. Cushman, I. Abramson, F. Vaida, T. D. Marcotte, R. von Jaeger, J. McArthur, M. Smith, S. Morgello, D. Simpson, L. Mintz, J. A. McCutchan, W. Toperoff, A. Collier, C. Marra, T. Jones, B. Gelman, E. Head, D. Clifford, M. Al-Lozi, M. Teshome
Institutions: University of California San Diego, Rady Children's Hospital-San Diego, Radboud University Medical Center, Washington University in St. Louis, University of Washington, The University of Texas Medical Branch at Galveston, Johns Hopkins University, Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2124431940