title: Plasma Efavirenz Concentrations Are Associated With Lipid and Glucose Concentrations.
abstract: Efavirenz-based antiretroviral therapy (ART) has been associated with dyslipidemia and dysglycemia, risk factors for cardiovascular disease. However, the pathogenesis is not well understood. We characterized relationships between plasma efavirenz concentrations and lipid and glucose concentrations in HIV-infected South Africans.Participants on efavirenz-based ART were enrolled into a cross-sectional study. The oral glucose tolerance test was performed after an overnight fast, and plasma drawn for mid-dosing interval efavirenz, fasting total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglycerides concentrations.Among 106 participants (77 women), median age was 38 years, median CD4 + T-cell count was 322 cells/μL, median duration on ART was 18 months, and median (interquartile range) efavirenz concentration was 2.23 (1.66 to 4.10) μg/mL. On multivariable analyses (adjusting for age, sex, body mass index, and ART duration) doubling of efavirenz concentrations resulted in mean changes in mmol/L (95%CI) of: total cholesterol (0.40 [0.22 to 0.59]), LDL cholesterol (0.19 [0.04 to 0.30]), HDL cholesterol (0.14 [0.07 to 0.20]), triglycerides (0.17 [0.03 to 0.33]), fasting glucose (0.18 [0.03 to 0.33]), and 2-h glucose concentrations (0.33 [0.08 to 0.60]). Among 57 participants with CYP2B6 genotype data, associations between slow metabolizer genotypes and metabolic profiles were generally consistent with those for measured efavirenz concentrations.Higher plasma efavirenz concentrations are associated with higher plasma lipid and glucose concentrations. This may have implications for long-term cardiovascular complications of efavirenz-based ART, particularly among populations with high prevalence of CYP2B6 slow metabolizer genotypes.
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine, University of Cape Town (PZS, HMM, PJS, GM); Division of Endocrinology and Diabetic Medicine, Department of Medicine, University of Cape Town. Cape Town, South Africa (JAD, NSL); Vanderbilt University School of Medicine, Departments of Medicine, Pharmacology, Pathology, Microbiology & Immunology (DWH); Meharry Medical College, Department of Internal Medicine, Nashville, TN, United States of America (DWH).
authors.forename: Phumla Zuleika
authors.initials: PZ
authors.lastname: Sinxadi
authors.forename: Helen Margaret
authors.initials: HM
authors.lastname: McIlleron
authors.forename: Joel Alex
authors.initials: JA
authors.lastname: Dave
authors.forename: Peter John
authors.initials: PJ
authors.lastname: Smith
authors.forename: Naomi Sharlene
authors.initials: NS
authors.lastname: Levitt
authors.forename: David William
authors.initials: DW
authors.lastname: Haas
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
mesh_terms: D000328:Adult; D000480:Alkynes; D048588:Benzoxazines / Q000097:blood* / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects*; D003430:Cross-Sectional Studies; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000494:pharmacology
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D001786:Blood Glucose; D003521:Cyclopropanes; D008055:Lipids; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz