title: Therapeutic monitoring and variability of atazanavir in HIV-infected patients, with and without HCV coinfection, receiving boosted or unboosted regimens.
abstract: BACKGROUND
  Adequate plasma trough concentrations (Ctrough) of protease inhibitors are required to maintain antiviral activity throughout the dosing interval. Therapeutic drug monitoring is used in clinical practice to optimize dosage and avoid toxic or subtherapeutic drug exposure. The pharmacokinetic variability of Atazanavir (ATV) can be relatively large, as a result of several factors. One of the affecting factors may be hepatic impairment due to hepatitis C virus (HCV) coinfection.
  
  
  METHODS
  We collected trough plasma samples from human immunodeficiency virus (HIV)-1-infected outpatients, with and without HCV coinfection and/or cirrhosis, receiving stable highly active antiretroviral therapy containing ATV. In the total population, we mainly compared the 2 regimens: 300ATV + 100RTV OD [ritonavir (RTV), once daily (OD)] versus 400ATV OD. We used a threshold value of 0.15 μg/mL, based on the proposed therapeutic range (0.15-0.85 μg/mL). Plasma concentrations of ATV were determined by a validated assay using high-performance liquid chromatography with ultraviolet detection. A total of 214 HIV-infected outpatients were included. For each regimen, we compared 3 groups of subjects: HIV+/HCV-, HIV+/HCV+, and HIV+/HCV+ with cirrhosis.
  
  
  RESULTS
  In the whole study population, we observed a large variability and found suboptimal Ctrough levels (<0.15 μg/mL) in 23 subjects (2 belonging to the 300/100 OD group and 21 to the 400 OD group). For the standard dosage regimen of 300ATV + 100RTV OD, we did not find a statistical difference between HIV-infected patients without HCV coinfection versus HIV-infected patients with HCV coinfection: median 0.85 (interquartile range 0.53-1.34) and 0.95 (0.70-1.36) μg/mL, respectively. In HIV+/HCV+-infected patients with cirrhosis, we found a median Ctrough of 0.70 (0.43-1.0) μg/mL, with no statistical difference when compared with HIV+/HCV- infected patients. For the 400ATV OD (n=90) dosage regimen, the total median ATV Ctrough was 0.40 (0.23-1.0) μg/mL. In this group, we found a statistically significant difference between HIV+/HCV- and HIV+/HCV+-infected patients: median Ctrough was 0.23 (0.11-0.42) and 0.52 (0.20-1.0) μg/mL, respectively. In HIV+/HCV+ subjects with cirrhosis, the Ctrough median value was 0.42 (0.13-0.75) μg/mL, and there was a significant difference when compared with HIV patients without coinfection.
  
  
  CONCLUSIONS
  Therapeutic drug monitoring of ATV in patients receiving unboosted regimen may be useful to identify those HIV-infected subjects, with or without HCV coinfection, who may benefit from adding low RTV doses, or the subset of patients in whom removal of RTV could be attempted without the risk of suboptimal plasma ATV exposure.
authors.affiliation: Clinical Pharmacokinetics Laboratory, Infectious Diseases Department, Clinical Epidemiology and Biometric Unit, Foundation IRCCS S. Matteo Hospital, Pavia, Italy. regazzim@smatteo.pv.it
authors.forename: Mario
authors.initials: M
authors.lastname: Regazzi
authors.forename: Paola
authors.initials: P
authors.lastname: Villani
authors.forename: Roberto
authors.initials: R
authors.lastname: Gulminetti
authors.forename: Maria
authors.initials: M
authors.lastname: Cusato
authors.forename: Michela
authors.initials: M
authors.lastname: Brandolini
authors.forename: Carmine
authors.initials: C
authors.lastname: Tinelli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Barassi
authors.forename: Renato
authors.initials: R
authors.lastname: Maserati
authors.forename: Laura
authors.initials: L
authors.lastname: Sighinolfi
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Arminio Monforte
authors.forename: Gian Vico
authors.initials: GV
authors.lastname: Melzi D'Eril
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D000069446:Atazanavir Sulfate; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D005355:Fibrosis / Q000097:blood / Q000821:virology; D006678:HIV / Q000302:isolation & purification; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D016174:Hepacivirus / Q000302:isolation & purification; D006526:Hepatitis C / Q000097:blood* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage* / Q000097:blood* / Q000493:pharmacokinetics; D012189:Retrospective Studies; D019438:Ritonavir / Q000627:therapeutic use
chemical_list: D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D019438:Ritonavir