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The aim of this study was to explore the role of genetic variation in achieving therapeutic efavirenz plasma concentrations in a cohort of Ugandan children and the linkage between genetic CYP2B6 variants, EFV plasma variability, viral resistance and viral outcome.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Ninety\u2010nine treatment\u2010na\u00efve children, aged 3\u201312\u2009years and living with HIV, were followed for 24\u2009weeks after ART initiation assessing mid\u2010dose efavirenz plasma concentrations, HIV RNA, HIV drug resistance and adherence. Polymorphisms in genes coding for drug\u2010metabolizing enzymes were genotyped. Efavirenz concentrations were determined by liquid chromatography coupled with high\u2010resolution tandem mass spectrometry. Metabolizer phenotype was predicted from composite genotypes of CYP2B6 (c.516G&gt;T and c.983\u2009T&gt;C). A mixed effects restricted maximum likelihood regression model was used to identify important factors for efavirenz exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Efavirenz plasma concentrations were below the therapeutic interval (1000\u20134000\u2009mg\/mL) in 12\u201317% and above in 21\u201324% of measurements. Eight children had persisting subtherapeutic concentrations, five of which failed virologically and three acquired at least one new resistant mutation. Multivariate modelling explained 70% of interindividual variation in plasma concentration, with treatment duration, adherence, CYP2B6c.136A&gt;G, and metabolizer phenotype as independent predictors of EFV concentration. In univariate analysis, metabolizer phenotype explained 50% of interindividual variation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Metabolizer phenotype explained 50% of interindividual variation in efavirenz plasma concentration. Autoinduction was not confirmed and &gt;33% of the concentrations were outside the therapeutic interval. Subtherapeutic concentrations worsened virological resistance and outcomes. Genotype\u2010based dosing may help avert both sub\u2010 and supratherapeutic efavirenz plasma concentrations in Ugandan children.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.16272","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T05:09:19Z","timestamp":1728450559000},"page":"464-478","source":"Crossref","is-referenced-by-count":3,"title":["Sub\u2010 and supratherapeutic efavirenz plasma concentrations with risk for HIV therapy failure are mainly genetically explained in Ugandan children: The prospective GENEFA cohort study"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0552-6872","authenticated-orcid":false,"given":"Sandra","family":"Soeria\u2010Atmadja","sequence":"first","affiliation":[{"name":"Department of Clinical Science Intervention and Technology, Division of Paediatrics, Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Paediatrics Karolinska University Hospital  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5264-1916","authenticated-orcid":false,"given":"Pauline","family":"Amuge","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine Children's Foundation\u2010Uganda  Kampala Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0312-6242","authenticated-orcid":false,"given":"Sarah","family":"Nanzigu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology &amp; 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