دورية أكاديمية
Pharmacogenetics of the Late-Onset Efavirenz Neurotoxicity Syndrome (LENS).
| العنوان: | Pharmacogenetics of the Late-Onset Efavirenz Neurotoxicity Syndrome (LENS). |
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| المؤلفون: | van Rensburg R; Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University, Cape Town, South Africa., Nightingale S; HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa., Brey N; Division of Neurology, Department of Medicine, Stellenbosch University, Cape Town, South Africa., Albertyn CH; Division of Neurology, Department of Medicine, Stellenbosch University, Cape Town, South Africa., Kellermann TA; Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University, Cape Town, South Africa., Taljaard JJ; Division of Infectious Diseases, Department of Medicine, Stellenbosch University, Cape Town, South Africa., Esterhuizen TM; Division of Epidemiology and Biostatistics, Department of Global Health, Stellenbosch University, Cape Town, South Africaand., Sinxadi PZ; Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa., Decloedt EH; Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University, Cape Town, South Africa. |
| المصدر: | Clinical infectious diseases : an official publication of the Infectious Diseases Society of America [Clin Infect Dis] 2022 Aug 31; Vol. 75 (3), pp. 399-405. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 9203213 Publication Model: Print Cited Medium: Internet ISSN: 1537-6591 (Electronic) Linking ISSN: 10584838 NLM ISO Abbreviation: Clin Infect Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Jan. 2011- : Oxford : Oxford University Press Original Publication: Chicago, IL : The University of Chicago Press, c1992- |
| مواضيع طبية MeSH: | Anti-HIV Agents*/adverse effects , Arylamine N-Acetyltransferase*/genetics , HIV Infections* , Neurotoxicity Syndromes*/drug therapy , Neurotoxicity Syndromes*/genetics, Adult ; Alkynes/therapeutic use ; Benzoxazines/adverse effects ; Cyclopropanes/therapeutic use ; Cytochrome P-450 CYP2B6/genetics ; Female ; Humans ; Isoniazid/therapeutic use ; Male ; Pharmacogenetics ; Polymorphism, Single Nucleotide |
| مستخلص: | Background: The late-onset efavirenz neurotoxicity syndrome (LENS) presents as ataxia and/or encephalopathy with supratherapeutic efavirenz plasma concentrations (>4 µg/mL). Efavirenz is primarily metabolized by cytochrome P450 2B6 (CYP2B6), with CYP2A6 as an accessory pathway. We hypothesized that participants with LENS would predominantly be CYP2B6 slow metabolizers. The aim of our study was to determine the frequency of CYP2B6 slow metabolizers in participants with LENS. Methods: Adult HIV-positive participants on efavirenz-based antiretroviral therapy presenting with LENS were prospectively enrolled. Genetic polymorphisms known to be associated with increased efavirenz plasma concentrations in CYP2B6 (rs3745274, rs28399499, rs4803419) and CYP2A6 (rs28399433) were selected and used to determine proportions of slow metabolizers. Pharmacokinetic analyses were performed using liquid chromatography-tandem mass spectrometry. Median (IQR) plasma efavirenz and 8-hydroxyefavirenz were described. Results: Fifteen participants were enrolled. Thirteen (13/15) were Black-African and 13 were female. Median weight was 49.9kg with a median duration on efavirenz of 2.2 years. All 15 participants were successfully genotyped as slow CYP2B6 metabolizers, with 6 participants additionally having CYP2A6 heterozygous genotype. Thirteen were receiving the CYP2A6 enzyme inhibitor isoniazid, and all 15 were genotypic NAT2 slow or intermediate acetylators. Efavirenz plasma concentration was markedly increased at 50.5 (47.0-65.4) µg/mL; 8-hydroxyefavirenz concentration was markedly decreased at 0.10 (0.07-0.15) µg/mL. Conclusions: Our cohort provides definitive evidence that LENS is associated with the CYP2B6 slow metabolizer genotype, with a median efavirenz plasma concentration >12-fold higher than the defined upper limit of the therapeutic range. Isoniazid and low body weight are important contributors to LENS development. Competing Interests: Potential conflicts of interest. All authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.) |
| فهرسة مساهمة: | Keywords: ataxia; efavirenz; encephalopathy; neurotoxicity; pharmacogenetics |
| المشرفين على المادة: | 0 (Alkynes) 0 (Anti-HIV Agents) 0 (Benzoxazines) 0 (Cyclopropanes) EC 1.14.14.1 (Cytochrome P-450 CYP2B6) EC 2.3.1.5 (Arylamine N-Acetyltransferase) EC 2.3.1.5 (NAT2 protein, human) JE6H2O27P8 (efavirenz) V83O1VOZ8L (Isoniazid) |
| تواريخ الأحداث: | Date Created: 20211209 Date Completed: 20220902 Latest Revision: 20221127 |
| رمز التحديث: | 20221213 |
| DOI: | 10.1093/cid/ciab961 |
| PMID: | 34882770 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1537-6591 |
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| DOI: | 10.1093/cid/ciab961 |