{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T18:56:53Z","timestamp":1782413813274,"version":"3.54.5"},"reference-count":37,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2016,7,22]],"date-time":"2016-07-22T00:00:00Z","timestamp":1469145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,8,1]],"date-time":"2016-08-01T00:00:00Z","timestamp":1470009600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["G1000417\/94909"],"award-info":[{"award-number":["G1000417\/94909"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Efavirenz (EFZ) has been associated with neuropsychiatric side effects. Recently, the 8-hydroxy-EFZ (8OH-EFZ) metabolite has been shown to be a potent neurotoxin\n            <jats:italic>in vitro<\/jats:italic>\n            , inducing neuronal damage at concentrations of 3.3 ng\/ml. EFZ induced similar neuronal damage at concentrations of 31.6 ng\/ml. We investigated the effect of genotype and blood-brain barrier integrity on EFZ metabolite concentrations in cerebrospinal fluid (CSF). We measured CSF drug concentrations in subjects from two separate study populations: 47 subjects with tuberculous meningitis (TBM) coinfection in Vietnam receiving 800 mg EFZ with standard antituberculous treatment and 25 subjects from the PARTITION study in the United Kingdom without central nervous system infection receiving 600 mg EFZ. EFZ and metabolite concentrations in CSF and plasma were measured and compared with estimates of effectiveness and neurotoxicity from available published\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            data. The effect of the\n            <jats:italic>CYP2B6<\/jats:italic>\n            c.516G\u2192T genotype (GG genotype, fast EFV metabolizer status; GT genotype, intermediate EFV metabolizer status; TT genotype, slow EFV metabolizer status) was examined. The mean CSF concentrations of EFZ and 8OH-EFZ in the TBM group were 60.3 and 39.3 ng\/ml, respectively, and those in the no-TBM group were 15.0 and 5.9 ng\/ml, respectively. Plasma EFZ and 8OH-EFZ concentrations were similar between the two groups. CSF EFZ concentrations were above the\n            <jats:italic>in vitro<\/jats:italic>\n            toxic concentration in 76% of samples (GG genotype, 61%; GT genotype, 90%; TT genotype, 100%) in the TBM group and 13% of samples (GG genotype, 0%; GT genotype, 18%; TT genotype, 50%) in the no-TBM group. CSF 8OH-EFZ concentrations were above the\n            <jats:italic>in vitro<\/jats:italic>\n            toxic concentration in 98% of the TBM group and 87% of the no-TBM group; levels were independent of genotype but correlated with the CSF\/plasma albumin ratio. Potentially neurotoxic concentrations of 8OH-EFZ are frequently observed in CSF independently of the\n            <jats:italic>CYP2B6<\/jats:italic>\n            genotype, particularly in those with impaired blood-brain barrier integrity.\n          <\/jats:p>","DOI":"10.1128\/aac.00280-16","type":"journal-article","created":{"date-parts":[[2016,5,10]],"date-time":"2016-05-10T03:05:16Z","timestamp":1462849516000},"page":"4511-4518","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["Efavirenz and Metabolites in Cerebrospinal Fluid: Relationship with\n            <i>CYP2B6<\/i>\n            c.516G\u2192T Genotype and Perturbed Blood-Brain Barrier Due to Tuberculous Meningitis"],"prefix":"10.1128","volume":"60","author":[{"given":"Sam","family":"Nightingale","sequence":"first","affiliation":[{"name":"Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom"},{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"},{"name":"Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Thi Hong","family":"Chau","sequence":"additional","affiliation":[{"name":"Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Fisher","sequence":"additional","affiliation":[{"name":"Brighton and Sussex University Hospitals NHS Trust, Brighton, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Nelson","sequence":"additional","affiliation":[{"name":"St. Stephen's AIDS Research Trust and Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Winston","sequence":"additional","affiliation":[{"name":"St. Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Else","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel F.","family":"Carr","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Taylor","sequence":"additional","affiliation":[{"name":"Birmingham Heartlands Hospital, Heart of England NHS Foundation Trust, Birmingham, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Ustianowski","sequence":"additional","affiliation":[{"name":"North Manchester General Hospital, Pennine Acute Hospitals NHS Trust, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Back","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Munir","family":"Pirmohamed","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Solomon","sequence":"additional","affiliation":[{"name":"Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom"},{"name":"Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Farrar","sequence":"additional","affiliation":[{"name":"Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam"},{"name":"Centre for Tropical Medicine, University of Oxford, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Est\u00e9e","family":"T\u00f6rok","sequence":"additional","affiliation":[{"name":"University of Cambridge, Department of Medicine, Cambridge, United Kingdom"},{"name":"Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom"},{"name":"Public Health England, Clinical Microbiology and Public Health Laboratory, Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saye","family":"Khoo","sequence":"additional","affiliation":[{"name":"Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, United Kingdom"},{"name":"Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Antiretroviral therapy for HIV infection in adults and adolescents; recommendations for a public health approach, 2010 revision","author":"World Health Organization","year":"2010","unstructured":"World Health Organization. 2010. Antiretroviral therapy for HIV infection in adults and adolescents; recommendations for a public health approach, 2010 revision. World Health Organization, Geneva, Switzerland."},{"key":"e_1_3_2_3_2","volume-title":"British HIV Association (BHIVA) guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy 2012 (updated November 2013)","author":"British HIV Association","year":"2013","unstructured":"British HIV Association. 2013. British HIV Association (BHIVA) guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy 2012 (updated November 2013). 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AIDS 18:2391\u20132400.","journal-title":"AIDS"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e328328d577"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21287"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2011.09.008"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2013.12.022"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.195701"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir230"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001772"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.5414\/CPP40507"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa040573"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13365-016-0448-1"},{"key":"e_1_3_2_27_2","volume-title":"Abstr Br Mass Spectrom Soc Meet","author":"Amara AB","year":"2011","unstructured":"Amara AB, Tjia J, Dutton J, Else LJ, Back DJ, Khoo SK. 2011. Development and validation of a HPLC-MS\/MS assay to quantify the antiretroviral (ARV) drug, efavirenz and its major metabolites in plasma, abstr BMS S11-1240. Abstr Br Mass Spectrom Soc Meet, Cardiff, United Kingdom."},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10337-010-1882-5"},{"key":"e_1_3_2_29_2","first-page":"129","article-title":"Protein analysis in cerebrospinal fluid. II","volume":"33","author":"Blennow K","year":"1993","unstructured":"Blennow K, Fredman P, Wallin A, Gottfries CG, Karlsson I, Langstrom G, Skoog I, Svennerholm L, Wikkelso C. 1993. Protein analysis in cerebrospinal fluid. II. Reference values derived from healthy individuals 18-88 years of age. 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Bristol-Myers Squibb Company, Princeton, NJ."}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00280-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00280-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:51:47Z","timestamp":1645476707000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00280-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,8]]},"references-count":37,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2016,8]]}},"alternative-id":["10.1128\/AAC.00280-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.00280-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,8]]},"assertion":[{"value":"2016-02-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-05-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-07-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}