Efavirenz concentrations in CSF exceed IC50 for wild-type HIV

• Published in: Journal of antimicrobial chemotherapy Vol. 66; no. 2; pp. 354 - 357
• Main Authors: Best, B. M., Koopmans, P. P., Letendre, S. L., Capparelli, E. V., Rossi, S. S., Clifford, D. B., Collier, A. C., Gelman, B. B., Mbeo, G., McCutchan, J. A., Simpson, D. M., Haubrich, R., Ellis, R., Grant, I., Ellis, R. J., Marcotte, T. D., Franklin, D., Alexander, T., Letendre, S., Capparelli, E., Heaton, R. K., Atkinson, J. H., Woods, S. P., Dawson, M., Wong, J. K., Fennema-Notestine, C., Taylor, M. J., Theilmann, R., Gamst, A. C., Cushman, C., Abramson, I., Vaida, F., von Jaeger, R., McArthur, J., Smith, M., Morgello, S., Simpson, D., Mintz, L., Toperoff, W., Collier, A., Marra, C., Jones, T., Gelman, B., Head, E., Clifford, D., Al-Lozi, M., Teshome, M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.02.2011
• Subjects: Adult; Age; Alkynes; Anti-HIV Agents - blood; Anti-HIV Agents - cerebrospinal fluid; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; antiretroviral therapy; Antiviral agents; Benzoxazines - blood; Benzoxazines - cerebrospinal fluid; Benzoxazines - therapeutic use; Biological and medical sciences; Brain; Central nervous system; Cerebrospinal fluid; Chromatography, High Pressure Liquid; Cognition; Cyclopropanes; Drugs; Efavirenz; Female; High-performance liquid chromatography; HIV Infections - cerebrospinal fluid; HIV Infections - complications; HIV Infections - drug therapy; HIV Infections - virology; Human immunodeficiency virus; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Inhibitory Concentration 50; Male; Mass spectroscopy; Medical sciences; Middle Aged; Nervous System Diseases - cerebrospinal fluid; Nervous System Diseases - drug therapy; Nervous System Diseases - virology; Neurological diseases; Original Research; Pharmacology. Drug treatments; Random Allocation; Replication; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral Load; Antiretroviral agent; Benzoxazine derivatives; RNA-directed DNA polymerase; Acetylenic compound; Non nucleoside compound; CNS; Cerebrospinal fluid; Efavirenz; Reverse transcriptase inhibitor; non-nucleoside reverse transcriptase inhibitors; Antiviral; Immunopathology; Enzyme; Transferases; Enzyme inhibitor; Retroviridae; AIDS; Pharmacology; Concentration; Wild type; Immune deficiency; Lentivirus; Infection; Virus; Allosteric inhibitor; Nucleotidyltransferases; Viral disease; Human immunodeficiency virus
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkq434

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. 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). 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. 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.