title: Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid.
abstract: OBJECTIVE
  To determine HIV-1 RNA in cerebrospinal fluid (CSF) of successfully treated patients and to evaluate if combination antiretroviral treatments with higher central nervous system penetration-effectiveness (CPE) achieve better CSF viral suppression.
  
  
  METHODS
  Viral loads (VLs) and drug concentrations of lopinavir, atazanavir, and efavirenz were measured in plasma and CSF. The CPE was calculated using 2 different methods.
  
  
  RESULTS
  The authors analyzed 87 CSF samples of 60 patients. In 4 CSF samples, HIV-1 RNA was detectable with 43-82 copies per milliliter. Median CPE in patients with detectable CSF VL was significantly lower compared with individuals with undetectable VL: CPE of 1.0 (range, 1.0-1.5) versus 2.3 (range, 1.0-3.5) using the method of 2008 (P = 0.011) and CPE of 6 (range, 6-8) versus 8 (range, 5-12) using the method of 2010 (P = 0.022). The extrapolated CSF trough levels for atazanavir (n = 12) were clearly above the 50% inhibitory concentration (IC50) in only 25% of samples; both patients on atazanavir/ritonavir with detectable CSF HIV-1 RNA had trough levels in the range of the presumed IC50. The extrapolated CSF trough level for lopinavir (n = 42) and efavirenz (n = 18) were above the IC50 in 98% and 78%, respectively, of samples, including the patients with detectable CSF HIV-1 RNA.
  
  
  CONCLUSIONS
  This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF.
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. alexia.cusini@insel.ch
authors.forename: Alexia
authors.initials: A
authors.lastname: Cusini
authors.forename: Pietro L
authors.initials: PL
authors.lastname: Vernazza
authors.forename: Sabine
authors.initials: S
authors.lastname: Yerly
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Fux
authors.forename: Janine
authors.initials: J
authors.lastname: Rohrbach
authors.forename: Nicolas
authors.initials: N
authors.lastname: Widmer
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hirschel
authors.forename: Roman
authors.initials: R
authors.lastname: Gaudenz
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
authors.forename: Franziska
authors.initials: F
authors.lastname: Zenger
authors.forename: Chistine
authors.initials: C
authors.lastname: Gutmann
authors.forename: Milos
authors.initials: M
authors.lastname: Opravil
authors.forename: Huldyrich F
authors.initials: HF
authors.lastname: Günthard
mesh_terms: D000328:Adult; D000480:Alkynes; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000821:virology*; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D061466:Lopinavir / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics; D010949:Plasma / Q000737:chemistry / Q000821:virology; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D012367:RNA, Viral / Q000134:cerebrospinal fluid; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000480:Alkynes; D044966:Anti-Retroviral Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009842:Oligopeptides; D011725:Pyridines; D012367:RNA, Viral; D061466:Lopinavir; D000069446:Atazanavir Sulfate; C098320:efavirenz