title: Mid-dosing interval concentration of atazanavir and virological outcome in patients treated for HIV-1 infection.
abstract: OBJECTIVE
  We investigated the clinical significance of monitoring the mid-dosing interval atazanavir (ATV) concentration (measured 12 +/- 2 h after intake; C(12 h)) in patients taking this drug once daily in the evening.
  
  
  METHODS
  We retrospectively selected HIV-infected patients harbouring ATV-susceptible virus who underwent therapeutic drug monitoring (TDM) of ATV C(12 h) during routine out-patient visits, and we correlated C(12 h) to the 24-week virological response and toxicity.
  
  
  RESULTS
  A total of 115 plasma samples from 86 patients (76.7% with baseline HIV RNA<50 HIV-1 RNA copies/mL) were analysed. ATV plasma concentrations showed high inter-individual variability. ATV plasma levels were higher in samples obtained from patients taking boosted regimens (P<0.001) and not concomitantly receiving acid-reducing agents (P=0.007). In a multivariate model, ritonavir boosting, use of acid-reducing agents and liver cirrhosis showed an independent association with ATV level. Virological response at 24 weeks was observed for 94 of the 115 samples (81.7%). We identified a concentration cut-off of 0.23 mg/L which predicted virological response at 24 weeks: samples with a C(12 h)< or =0.23 mg/L showed virological failure in 41.2% of cases, whereas samples with a C(12 h)>0.23 mg/L showed virological failure in 14.3% of cases (P=0.021). In multivariate analysis, C(12 h)>0.23 mg/L was an independent predictor of virological response [odds ratio (OR) 4.23, P=0.031]. ATV levels correlated with concomitant unconjugated bilirubin levels (r=0.223, P=0.037), but a concentration cut-off predictive of moderate/severe hyperbilirubinaemia could not be identified.
  
  
  CONCLUSIONS
  We identified a C(12 h) efficacy threshold that predicted virological response; this could be useful for morning TDM in selected subjects receiving ATV in the evening. Results must be interpreted with caution given the retrospective design of the study.
authors.affiliation: Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy. massifab@alice.it
authors.forename: M
authors.initials: M
authors.lastname: Fabbiani
authors.forename: S
authors.initials: S
authors.lastname: Di Giambenedetto
authors.forename: E
authors.initials: E
authors.lastname: Ragazzoni
authors.forename: M
authors.initials: M
authors.lastname: Colafigli
authors.forename: M
authors.initials: M
authors.lastname: Prosperi
authors.forename: R
authors.initials: R
authors.lastname: Cauda
authors.forename: P
authors.initials: P
authors.lastname: Navarra
authors.forename: A
authors.initials: A
authors.lastname: De Luca
mesh_terms: D000328:Adult; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000097:blood; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods*; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012189:Retrospective Studies; D019438:Ritonavir / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir; D001663:Bilirubin