title: Pharmacokinetic and pharmacodynamic determinants of early virological response to enfuvirtide-based regimens in HIV-positive patients.
abstract: BACKGROUND
  Early virological response (VR) to enfuvirtide-based salvage regimens at week 12 has been described as a predictor of long-term therapeutic success. The relationship between enfuvirtide plasma exposure and VR has not yet been investigated in the clinical setting. Our aim was to investigate the role of enfuvirtide plasma exposure as a determinant of early VR in the clinical setting.
  
  
  METHODS
  Forty-two multidrug-experienced patients starting a salvage enfuvirtide-based regimen were prospectively evaluated over a 12 week period. HIV-RNA levels and enfuvirtide C(trough) were regularly measured. VR was considered as achievement of viral load (VL) undetectability and/or a decrease of more than 1 log at week 12.
  
  
  RESULTS
  Optimized background score (OBS) and enfuvirtide C(trough) concentrations were associated with VL decrease at week 12. An OBS > or =2 and enfuvirtide C(trough) >2100 ng/mL were associated with VR. The pharmacokinetic/pharmacodynamic (PK/PD) analysis confirmed this exposure-response relationship both in the total population and in different groups according to OBS <2 or > or =2. Higher estimates of IC(50) were calculated for the OBS <2 group when compared with the OBS > or =2 group (7551 versus 2330 ng/mL, respectively), without a marked difference in I(0) (0.31 versus 0.21 log) and I(max) (-2.64 versus -3.33 log).
  
  
  CONCLUSIONS
  Enfuvirtide plasma exposure and OBS were found to significantly influence the magnitude and rate of early VR. The PK/PD modelling of enfuvirtide concentrations was different in our clinical setting, compared with previous data obtained under trial conditions. Therefore, optimization of enfuvirtide plasma exposure could deserve further evaluation as a determinant of therapeutic response in HIV-positive patients.
authors.affiliation: Department of Infectious Diseases, University of Turin, Turin, Italy. danifarre@hotmail.com
authors.forename: Daniel Gonzalez
authors.initials: DG
authors.lastname: de Requena
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.forename: Antonella
authors.initials: A
authors.lastname: Castagna
authors.forename: Hamid
authors.initials: H
authors.lastname: Hasson
authors.forename: Diego Aguilar
authors.initials: DA
authors.lastname: Marucco
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.forename: Mauro
authors.initials: M
authors.lastname: Sciandra
authors.forename: Laura
authors.initials: L
authors.lastname: Trentini
authors.forename: Andrea
authors.initials: A
authors.lastname: Calcagno
authors.forename: Adriano
authors.initials: A
authors.lastname: Lazzarin
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
mesh_terms: D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D023581:HIV Fusion Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D010446:Peptide Fragments / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D010949:Plasma / Q000737:chemistry / Q000821:virology; D011446:Prospective Studies; D016879:Salvage Therapy; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide