title: Discordant associations between SLCO1B1 521T→C and plasma levels of ritonavir-boosted protease inhibitors in AIDS clinical trials group study A5146.
abstract: OBJECTIVE
  Among HIV-positive patients prescribed ritonavir-boosted lopinavir, SLCO1B1 521T→C (rs4149056) is associated with increased plasma lopinavir exposure. Protease inhibitors (PIs) are also substrates for cytochrome P450 (CYP) 3A and ABCB1, which are induced by NR1I2. We characterized relationships between ABCB1, CYP3A4, CYP3A5, NR1I2, and SLCO1B1 polymorphisms and trough PI concentrations among AIDS Clinical Trials Group study A5146 participants.
  
  
  METHODS
  At study entry, subjects with virologic failure on PI-containing regimens initiated new ritonavir-boosted PI regimens. We studied associations between week 2 PI plasma trough concentrations and 143 polymorphisms in these genes, including 4 targeted polymorphisms.
  
  
  RESULTS
  Among 275 subjects with both drug concentrations and genetic data, allelic frequencies of SLCO1B1 521T→C were 15%, 1%, and 8% in whites, blacks, and Hispanics, respectively. Further analyses were limited to 268 white, black, or Hispanic subjects who initiated ritonavir-boosted lopinavir (n = 98), fosamprenavir (n = 69), or saquinavir (n = 99). Of targeted polymorphisms, SLCO1B1 521T→C tended to be associated with higher lopinavir concentrations, with a 1.38-fold increase in the mean per C allele (95% confidence interval, 0.97-1.96; n = 98; P = 0.07). With fosamprenavir, SLCO1B1 521T→C was associated with lower amprenavir concentrations, with a 35% decrease in the mean per C allele (geometric mean ratio 0.65; 95% confidence interval, 0.44-0.94; n = 69; adjusted P = 0.02). There was no significant association with saquinavir concentrations, and none of the remaining 139 exploratory polymorphisms were statistically significant after correcting for multiple comparisons.
  
  
  CONCLUSIONS
  With ritonavir-boosted PIs, a SLCO1B1 polymorphism that predicts higher lopinavir trough concentrations seems to predict lower amprenavir trough concentrations. The mechanism underlying this discordant association is uncertain.
authors.affiliation: Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Xinyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Camlin
authors.initials: C
authors.lastname: Tierney
authors.forename: Mary
authors.initials: M
authors.lastname: Albrecht
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Demeter
authors.forename: Gene
authors.initials: G
authors.lastname: Morse
authors.forename: Robin
authors.initials: R
authors.lastname: DiFrancesco
authors.forename: Carrie
authors.initials: C
authors.lastname: Dykes
authors.forename: Hongyu
authors.initials: H
authors.lastname: Jiang
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000235:genetics*; D000328:Adult; D005260:Female; D056726:Genetic Association Studies / Q000379:methods*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D019438:Ritonavir / Q000627:therapeutic use*
chemical_list: D017320:HIV Protease Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D019438:Ritonavir