{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T01:48:48Z","timestamp":1781920128415,"version":"3.54.5"},"reference-count":75,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2011-3440"],"award-info":[{"award-number":["2011-3440"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["VR-Link 2012-3466"],"award-info":[{"award-number":["VR-Link 2012-3466"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011727","name":"Stockholm l\u00e4ns Landsting","doi-asserted-by":"publisher","award":["ALF project 20170343"],"award-info":[{"award-number":["ALF project 20170343"]}],"id":[{"id":"10.13039\/501100011727","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006741","name":"Stiftelsen Frimurare Barnhuset i Stockholm","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006741","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008352","name":"Stiftelsen Samariten","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008352","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007373","name":"Stiftelsen Sven Jerrings Fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007373","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018713","name":"Center for Innovative Medicine","doi-asserted-by":"publisher","award":["20180823"],"award-info":[{"award-number":["20180823"]}],"id":[{"id":"10.13039\/501100018713","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is used in antiretroviral therapy (ART) against HIV. EFV is mainly metabolized by CYP2B6 to 8-hydroxyefavirenz (8-OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxyefavirenz (7-OH-EFV). Previous studies have only examined these metabolites in adults, indicating that EFV-hydroxy-metabolites might contribute to central nervous system (CNS) toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>This study aimed to quantify EFV and its metabolites including a recently identified EFV metabolite named EFAdeg in plasma and to explore their association with CYP2B6 metabolizer phenotypes and CNS adverse effects, in Ugandan children. Additionally, we examined signs of EFV autoinduction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We prospectively followed 99 Ugandan ART-na\u00efve children in 2015\u20132016, aged 3\u201312 years with plasma sampling at 2, 6, 12, and 24 weeks after initiating-EFV-based ART. Using liquid chromatography high-resolution tandem mass spectrometry, we quantified EFV, 8-OH-EFV, 7-OH-EFV and EFAdeg in both unconjugated and conjugated forms. Genotyping for single nucleotide polymorphisms (SNP) in CYP2B6 and CYP2A6 was performed. CYP2B6 metabolizer phenotypes were predicted by the composite genotype of the two SNPs CYP2B6 c.516G&amp;gt;T and CYP2B6 c.983T&amp;gt;C. CNS adverse effects were assessed\n                      <jats:italic>via<\/jats:italic>\n                      a questionnaire. Autoinduction was investigated in a multivariate restricted maximum likelihood regression model (REML) with log\n                      <jats:sub>(e)<\/jats:sub>\n                      ((8-OH-EFV + EFAdeg)\/EFV) as the outcome variable.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Metabolite\/EFV ratios in plasma varied significantly with CYP2B6 metabolizer phenotypes. Conjugated 8-OH-EFV (8-OH-EFV -glucuronide and 8-OH-EFV-sulfate) and conjugated EFAdeg constituted the major circulating forms of EFV in extensive and intermediate metabolizers, while the parent drug EFV dominated in slow metabolizers, who also displayed the highest levels of 7-OH-EFV. CNS symptoms were common, transient and mild and significantly associated with EFV plasma concentrations above 4,000\u00a0ng\/mL and slow CYP2B6 metabolizer phenotype. None of the metabolites in plasma were associated with an increased risk of CNS toxicity. Evidence of autoinduction of EFV metabolism was observed among extensive metabolizers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This first study of EFV metabolites in children revealed distinct distribution patterns influenced by CYP2B6 metabolizer phenotype. Mild CNS-related adverse effects were associated with high EFV levels and slow CYP2B6 metabolizer phenotype, but not with EFV hydroxy metabolites. Autoinduction of EFV metabolism was observed in CYP2B6 extensive metabolizers.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1778383","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T05:43:08Z","timestamp":1777009388000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Efavirenz metabolism and CNS toxicity in Ugandan children: impact of CYP2B6 genotype and plasma metabolite profiles"],"prefix":"10.3389","volume":"17","author":[{"given":"Sandra","family":"Soeria-Atmadja","sequence":"first","affiliation":[{"name":"Department of Clinical Science, Intervention and Technology, Division of Pediatrics, Karolinska Institutet","place":["Stockholm, Sweden"]},{"name":"Department of Pediatrics, Karolinska University Hospital","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Pettersson 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