title: Cerebrospinal fluid inhibitory quotients of antiretroviral drugs in HIV-infected patients are associated with compartmental viral control.
abstract: BACKGROUND
  Despite the efficacy of highly active antiretroviral treatment (HAART), a large proportion of human immunodeficiency virus (HIV)-infected patients may develop moderate neurocognitive impairment. Antiretroviral drug passage into the central nervous system may be relevant for preventing and treating HIV-associated neurocognitive disorder; nevertheless, clear cerebrospinal fluid (CSF) pharmacodynamic targets are not known.
  
  
  METHODS
  HAART-treated adults with wild-type HIV were prospectively enrolled. CSF concentrations (measured by mass spectrophotometric methods) and inhibitory quotients (CSF concentrations divided by in vitro 50% and 95% inhibitory concentrations) were compared among different drugs and related to CSF HIV RNA levels. CSF escape was defined as CSF HIV RNA >50 copies/mL despite contemporary plasma HIV RNA below that threshold.
  
  
  RESULTS
  One hundred twenty-seven patients (91 male [71.7%], 93 white [73.2%], with a median age of 46 years [interquartile range, 40.5-54.5 years]) provided 174 paired CSF and plasma samples. Twice-daily darunavir, once-daily darunavir, and efavirenz had the highest CSF 95% inhibitory quotients (18.5, 8.2, and 6.4, respectively). Higher nadir CD4 cell count (P = .01) and plasma HIV RNA <50 copies/mL (P < .001) were independent predictors of controlled CSF HIV RNA. Optimal drug exposure (CSF detectable drugs and 95% inhibitory quotient >1) was protective for CSF escape (P = .01).
  
  
  CONCLUSIONS
  Cerebrospinal fluid 95% inhibitory quotients may be used to compare antiretroviral drug compartmental exposure; they deserve longitudinal studies to assess the adequacy of CSF drug concentrations in treated HIV-infected patients.
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Alberione
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Bracchi
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Marinaro
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ecclesia
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
mesh_terms: D015526:AIDS Dementia Complex / Q000188:drug therapy* / Q000517:prevention & control* / Q000821:virology; D000328:Adult; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002555:Cerebrospinal Fluid / Q000737:chemistry* / Q000821:virology; D005260:Female; D006678:HIV / Q000302:isolation & purification*; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome
chemical_list: D044966:Anti-Retroviral Agents
keywords: CPE score; CSF escape; cerebrospinal fluid; inhibitory quotient; pharmacokinetic