Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin
Identifieur interne : 002968 ( Pmc/Curation ); précédent : 002967; suivant : 002969Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin
Auteurs : Sandra Soeria-Atmadja [Suède] ; Emma Österberg [Suède] ; Lars L. Gustafsson [Suède] ; Marja-Liisa Dahl [Suède] ; Jaran Eriksen [Suède] ; Johanna Rubin [Suède] ; Lars Navér [Suède]Source :
- PLoS ONE [ 1932-6203 ] ; 2017.
Abstract
Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults.
To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight.
EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records.
Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85–19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55–13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level).
Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.
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DOI: 10.1371/journal.pone.0181316
PubMed: 28886044
PubMed Central: 5590735
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Gustafsson</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Dahl, Marja Liisa" sort="Dahl, Marja Liisa" uniqKey="Dahl M" first="Marja-Liisa" last="Dahl">Marja-Liisa Dahl</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Eriksen, Jaran" sort="Eriksen, Jaran" uniqKey="Eriksen J" first="Jaran" last="Eriksen">Jaran Eriksen</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Rubin, Johanna" sort="Rubin, Johanna" uniqKey="Rubin J" first="Johanna" last="Rubin">Johanna Rubin</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country 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wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28886044</idno><idno type="pmc">5590735</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590735</idno><idno type="RBID">PMC:5590735</idno><idno type="doi">10.1371/journal.pone.0181316</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">002969</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002969</idno><idno type="wicri:Area/Pmc/Curation">002968</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002968</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin</title><author><name sortKey="Soeria Atmadja, Sandra" sort="Soeria Atmadja, Sandra" uniqKey="Soeria Atmadja S" first="Sandra" last="Soeria-Atmadja">Sandra Soeria-Atmadja</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Pediatrics, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Osterberg, Emma" sort="Osterberg, Emma" uniqKey="Osterberg E" first="Emma" last="Österberg">Emma Österberg</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Pediatrics, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Gustafsson, Lars L" sort="Gustafsson, Lars L" uniqKey="Gustafsson L" first="Lars L." last="Gustafsson">Lars L. Gustafsson</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Dahl, Marja Liisa" sort="Dahl, Marja Liisa" uniqKey="Dahl M" first="Marja-Liisa" last="Dahl">Marja-Liisa Dahl</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Eriksen, Jaran" sort="Eriksen, Jaran" uniqKey="Eriksen J" first="Jaran" last="Eriksen">Jaran Eriksen</name><affiliation wicri:level="1"><nlm:aff id="aff003"><addr-line>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Rubin, Johanna" sort="Rubin, Johanna" uniqKey="Rubin J" first="Johanna" last="Rubin">Johanna Rubin</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Pediatrics, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author><author><name sortKey="Naver, Lars" sort="Naver, Lars" uniqKey="Naver L" first="Lars" last="Navér">Lars Navér</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Pediatrics, Karolinska University Hospital, Stockholm</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden</addr-line></nlm:aff><country xml:lang="fr">Suède</country><wicri:regionArea>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="sec001"><title>Background</title><p>Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults.</p></sec><sec id="sec002"><title>Aim</title><p>To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight.</p></sec><sec id="sec003"><title>Method</title><p>EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records.</p></sec><sec id="sec004"><title>Results</title><p>Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85–19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55–13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to log<sub>e</sub> concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level).</p></sec><sec id="sec005"><title>Conclusion</title><p>Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Fillekes, Q" uniqKey="Fillekes Q">Q Fillekes</name></author><author><name sortKey="Natukunda, E" uniqKey="Natukunda E">E Natukunda</name></author><author><name sortKey="Balungi, J" uniqKey="Balungi J">J Balungi</name></author><author><name sortKey="Kendall, L" uniqKey="Kendall L">L Kendall</name></author><author><name sortKey="Bwakura Dangarembizi, M" uniqKey="Bwakura Dangarembizi M">M Bwakura-Dangarembizi</name></author><author><name sortKey="Keishanyu, R" uniqKey="Keishanyu R">R Keishanyu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ter Heine, R" uniqKey="Ter Heine R">R ter 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28886044</article-id><article-id pub-id-type="pmc">5590735</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0181316</article-id><article-id pub-id-type="publisher-id">PONE-D-16-28249</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pharmacology</subject><subj-group><subject>Pharmacokinetics</subject><subj-group><subject>Drug Metabolism</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Enzymology</subject><subj-group><subject>Enzyme Chemistry</subject><subj-group><subject>Enzyme Metabolism</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pediatrics</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Genetics</subject><subj-group><subject>Heredity</subject><subj-group><subject>Genetic Mapping</subject><subj-group><subject>Variant Genotypes</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Research and Analysis Methods</subject><subj-group><subject>Research Design</subject><subj-group><subject>Clinical Research Design</subject><subj-group><subject>Adverse Events</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pharmacology</subject><subj-group><subject>Adverse Reactions</subject></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical Microbiology</subject><subj-group><subject>Microbial Pathogens</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Immunodeficiency Viruses</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pathology and Laboratory Medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial Pathogens</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Immunodeficiency Viruses</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Immunodeficiency Viruses</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Immunodeficiency Viruses</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>RNA viruses</subject><subj-group><subject>Retroviruses</subject><subj-group><subject>Lentivirus</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical Microbiology</subject><subj-group><subject>Microbial Pathogens</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Retroviruses</subject><subj-group><subject>Lentivirus</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pathology and Laboratory Medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial Pathogens</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Retroviruses</subject><subj-group><subject>Lentivirus</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Retroviruses</subject><subj-group><subject>Lentivirus</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Anatomy</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Physiology</subject><subj-group><subject>Body Fluids</subject><subj-group><subject>Blood</subject><subj-group><subject>Blood Plasma</subject></subj-group></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Genetic variants in CYP2B6 and CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-infected children with diverse ethnic origin</article-title><alt-title alt-title-type="running-head">Genetic variants and variation in efavirenz plasma concentrations of HIV-infected children</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Soeria-Atmadja</surname><given-names>Sandra</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Österberg</surname><given-names>Emma</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gustafsson</surname><given-names>Lars L.</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dahl</surname><given-names>Marja-Liisa</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Eriksen</surname><given-names>Jaran</given-names></name><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rubin</surname><given-names>Johanna</given-names></name><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-6027-0211</contrib-id><name><surname>Navér</surname><given-names>Lars</given-names></name><role content-type="http://credit.casrai.org/">Conceptualization</role><role content-type="http://credit.casrai.org/">Data curation</role><role content-type="http://credit.casrai.org/">Formal analysis</role><role content-type="http://credit.casrai.org/">Funding acquisition</role><role content-type="http://credit.casrai.org/">Investigation</role><role content-type="http://credit.casrai.org/">Methodology</role><role content-type="http://credit.casrai.org/">Project administration</role><role content-type="http://credit.casrai.org/">Resources</role><role content-type="http://credit.casrai.org/">Supervision</role><role content-type="http://credit.casrai.org/">Validation</role><role content-type="http://credit.casrai.org/">Visualization</role><role content-type="http://credit.casrai.org/">Writing – original draft</role><role content-type="http://credit.casrai.org/">Writing – review & editing</role><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Seedat</surname><given-names>Soraya</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Stellenbosch University, SOUTH AFRICA</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><corresp id="cor001">* E-mail: <email>lars.naver@ki.se</email></corresp></author-notes><pub-date pub-type="epub"><day>8</day><month>9</month><year>2017</year></pub-date><pub-date pub-type="collection"><year>2017</year></pub-date><volume>12</volume><issue>9</issue><elocation-id>e0181316</elocation-id><history><date date-type="received"><day>14</day><month>7</month><year>2016</year></date><date date-type="accepted"><day>29</day><month>6</month><year>2017</year></date></history><permissions><copyright-statement>© 2017 Soeria-Atmadja et al</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Soeria-Atmadja et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="pone.0181316.pdf"></self-uri><abstract><sec id="sec001"><title>Background</title><p>Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults.</p></sec><sec id="sec002"><title>Aim</title><p>To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight.</p></sec><sec id="sec003"><title>Method</title><p>EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records.</p></sec><sec id="sec004"><title>Results</title><p>Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85–19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55–13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to log<sub>e</sub> concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level).</p></sec><sec id="sec005"><title>Conclusion</title><p>Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.</p></sec></abstract><funding-group><award-group id="award001"><funding-source><institution>The Swedish Order of Freemason Foundation for Children</institution></funding-source><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-6027-0211</contrib-id><name><surname>Navér</surname><given-names>Lars</given-names></name></principal-award-recipient></award-group><award-group id="award002"><funding-source><institution>The Samariten Foundation</institution></funding-source><principal-award-recipient><name><surname>Soeria-Atmadja</surname><given-names>Sandra</given-names></name></principal-award-recipient></award-group><award-group id="award003"><funding-source><institution>The Jerring Foundation</institution></funding-source><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-6027-0211</contrib-id><name><surname>Navér</surname><given-names>Lars</given-names></name></principal-award-recipient></award-group><award-group id="award004"><funding-source><institution>Karolinska Institutet Funds</institution></funding-source><award-id>2013tobi37895</award-id><principal-award-recipient><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0001-6027-0211</contrib-id><name><surname>Navér</surname><given-names>Lars</given-names></name></principal-award-recipient></award-group><award-group id="award005"><funding-source><institution>the Swedish Research Council</institution></funding-source><award-id>2011-3440 and VR-Link 2012-3466</award-id><principal-award-recipient><name><surname>Gustafsson</surname><given-names>Lars L.</given-names></name></principal-award-recipient></award-group><funding-statement>The study was supported by grants from the Swedish Order of Freemason Foundation for Children (LN), the Samariten Foundation (SSA), the Jerring Foundation (LN), Karolinska Institutet Funds (2013tobi37895) (LN) and the Swedish Research Council (2011-3440 and VR-Link 2012-3466) (LLG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="3"></fig-count><table-count count="3"></table-count><page-count count="16"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>The authors confirm that the paper and the supplemental table contain all information supporting the main results of the study. All individual data cannot be shared publicly due to ethical restrictions from the Regional Ethical Review Board in Stockholm. Data files will be made available after completion of a supplementary application to the Regional Ethical Review Board in Stockholm. Requests for data should be made to author Lars Navér, <email>lars.naver@ki.se</email> and the Regional Ethical Review Board in Stockholm, phone number +46-8-524 800 00, <ext-link ext-link-type="uri" xlink:href="http://www.epn.se">www.epn.se</ext-link>.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>The authors confirm that the paper and the supplemental table contain all information supporting the main results of the study. All individual data cannot be shared publicly due to ethical restrictions from the Regional Ethical Review Board in Stockholm. Data files will be made available after completion of a supplementary application to the Regional Ethical Review Board in Stockholm. Requests for data should be made to author Lars Navér, <email>lars.naver@ki.se</email> and the Regional Ethical Review Board in Stockholm, phone number +46-8-524 800 00, <ext-link ext-link-type="uri" xlink:href="http://www.epn.se">www.epn.se</ext-link>.</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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