title: Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
abstract: BACKGROUND
  Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202.
  
  
  METHODS
  Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available.
  
  
  RESULTS
  Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance.
  
  
  CONCLUSIONS
  Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.
authors.affiliation: aDepartment of Medicine bDepartments of Pharmacology, Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee cThe Center for Human Experimental Therapeutics, University of Rochester Medical Center, Rochester dTranslational Pharmacology Research Core, University at Buffalo, SUNY, Buffalo, New York eDepartment of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania fDepartment of Medicine, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, California, USA gDepartment of Life Sciences, The Swiss Institute of Technology hDepartment of Microbiology, University Hospital, University of Lausanne, Lausanne, Switzerland.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Johnson
authors.forename: Charles
authors.initials: C
authors.lastname: Venuto
authors.forename: Marylyn D
authors.initials: MD
authors.lastname: Ritchie
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McLaren
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000097:blood; D005260:Female; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000627:therapeutic use*; D000099148:UGT1A1 Enzyme
chemical_list: D000069446:Atazanavir Sulfate; D001663:Bilirubin; D014453:Glucuronosyltransferase; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D019438:Ritonavir; D000099148:UGT1A1 Enzyme