title: Sequencing of protease inhibitor therapy: insights from an analysis of HIV phenotypic resistance in patients failing protease inhibitors.
abstract: OBJECTIVE
  To characterize the pattern of HIV-1 susceptibility to protease inhibitors in patients failing an initial protease inhibitor-containing regimen.
  
  
  METHODS
  A cross-sectional analysis of antiretroviral susceptibility.
  
  
  METHODS
  HIV clinics in six metropolitan areas.
  
  
  METHODS
  Eighty-eight HIV-infected adults with HIV RNA > 400 copies/ml after > or = 6 months of antiretroviral therapy, including the use of one protease inhibitor for > or = 3 months.
  
  
  METHODS
  The frequency and magnitude of decreased susceptibility, measured with a phenotypic assay using recombinant constructs, to five protease inhibitors. Decreased susceptibility was defined as > 2.5-fold increase in the 50% inhibitory concentration (IC50) compared with drug sensitive control virus.
  
  
  RESULTS
  At study entry, patients were being treated with nelfinavir (63%), indinavir (25%), or another protease inhibitor (11%). HIV isolates from these patients were susceptible (fold change < 2.5) to all five protease inhibitors in 18% of patients and to none in 8%. Isolates from patients receiving nelfinavir were less likely to have reduced susceptibility to other protease inhibitors than isolates from patients treated with indinavir (P < 0.001) or one of the other three agents (P < 0.001), even after adjustment for the duration of prior protease inhibitor use. Reduced susceptibility to saquinavir and amprenavir was observed significantly less frequently than for the other protease inhibitors.
  
  
  CONCLUSIONS
  The frequency of protease inhibitor cross-resistance and the magnitude of changes in susceptibility varied according to the initial protease inhibitor used in the failing treatment regimen. Significantly less protease inhibitor cross-resistance was demonstrated for isolates from patients failing a nelfinavir-containing regimen compared with those from patients receiving other protease inhibitors.
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, San Jose, California 95128, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Kemper
authors.forename: M D
authors.initials: MD
authors.lastname: Witt
authors.forename: P H
authors.initials: PH
authors.lastname: Keiser
authors.forename: M P
authors.initials: MP
authors.lastname: Dubé
authors.forename: D N
authors.initials: DN
authors.lastname: Forthal
authors.forename: M
authors.initials: M
authors.lastname: Leibowitz
authors.forename: D S
authors.initials: DS
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Rigby
authors.forename: N S
authors.initials: NS
authors.lastname: Hellmann
authors.forename: Y S
authors.initials: YS
authors.lastname: Lie
authors.forename: J
authors.initials: J
authors.lastname: Leedom
authors.forename: D
authors.initials: D
authors.lastname: Richman
authors.forename: J A
authors.initials: JA
authors.lastname: McCutchan
authors.forename: R
authors.initials: R
authors.lastname: Haubrich
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D003430:Cross-Sectional Studies; D004352:Drug Resistance, Microbial; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019469:Indinavir / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D019888:Nelfinavir / Q000494:pharmacology / Q000627:therapeutic use; D010641:Phenotype; D012367:RNA, Viral / Q000097:blood; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D019469:Indinavir; D019888:Nelfinavir