title: Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa.
abstract: OBJECTIVE
  Genetic factors, notably CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children.
  
  
  METHODS
  Steady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3.
  
  
  RESULTS
  Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516G→T, 983T→C, and 15582C→T [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) µg ml(-1), 2.08 (1.68-2.94) µg ml(-1) and 7.26 (4.82-8.34) µg ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (β = 0.28, 95% CI 0.21, 0.35, P = 2.4 × 10(-11)). Among individual CYP2B6 polymorphisms, 516G→T best predicted efavirenz concentrations (β = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10(-6)). There was also associations with 983T→C (β = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582C→T (β = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations.
  
  
  CONCLUSIONS
  Composite CYP2B6 genotype based on CYP2B6 516G→T, 983T→C, and 15582C→T best described efavirenz exposure in HIV-infected Black South African adults and children.
authors.affiliation: Division of Clinical of Pharmacology, Division of Exercise and Endocrine Metabolism, University of Cape Town, Cape Town, South Africa.
authors.forename: Phumla Z
authors.initials: PZ
authors.lastname: Sinxadi
authors.affiliation: Vanderbilt University Medical Center, Department of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Leger
authors.affiliation: Division of Clinical of Pharmacology, Division of Exercise and Endocrine Metabolism, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen M
authors.initials: HM
authors.lastname: McIlleron
authors.affiliation: Division of Clinical of Pharmacology, Division of Exercise and Endocrine Metabolism, University of Cape Town, Cape Town, South Africa.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Smith
authors.affiliation: Division of Exercise and Endocrine Metabolism, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Dave
authors.affiliation: Division of Exercise and Endocrine Metabolism, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Naomi S
authors.initials: NS
authors.lastname: Levitt
authors.affiliation: Division of Clinical of Pharmacology, Division of Exercise and Endocrine Metabolism, University of Cape Town, Cape Town, South Africa.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
authors.affiliation: Vanderbilt University School of Medicine, Department of Medicine, Nashville, Tennessee, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D048588:Benzoxazines / Q000097:blood* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044383:Black People / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013019:South Africa; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; C000716327:NR1I3 protein, human; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz
keywords: CYP2B6; HIV therapy; South Africa; efavirenz; pharmacogenetics