title: HIV-1 genotypic resistance patterns predict response to saquinavir-ritonavir therapy in patients in whom previous protease inhibitor therapy had failed.
abstract: BACKGROUND
  Tests for resistance to HIV drugs are available for clinical use; however, their predictive value has not been fully assessed.
  
  
  OBJECTIVE
  To determine HIV-1 genotypic predictors of a virologic response to saquinavir-ritonavir therapy in patients in whom at least one previous protease inhibitor-containing regimen had failed and to compare the predictive value of baseline genotype with that of standard clinical evaluation.
  
  
  METHODS
  Retrospective clinical cohort study.
  
  
  METHODS
  University-based HIV clinic.
  
  
  METHODS
  54 HIV-1-infected adults treated with saquinavir-ritonavir who had experienced virologic failure while receiving a protease inhibitor-containing regimen for at least 3 months.
  
  
  METHODS
  HIV-1 reverse transcriptase and protease gene sequences, CD4 cell counts, clinical characteristics, detailed antiretroviral treatment history, and plasma HIV-1 RNA levels at baseline and at three follow-up time points (median, 4, 12, and 26 weeks). Virologic failure was defined as a plasma HIV RNA level greater than 1000 copies/mL.
  
  
  RESULTS
  In 22 patients (41%), a plasma HIV-1 RNA level less than 500 copies/mL was achieved by week 12; in 15 patients (28%), this response was maintained through week 26. Clinical characteristics predicting a poorer response included a diagnosis of AIDS, lower CD4 cell count, and higher plasma HIV RNA level (P<0.03). Number of previous nucleoside reverse transcriptase inhibitors, previous protease inhibitor therapy, and duration of previous protease inhibitor therapy were predictors of poorer response (P<0.01). Multivariate regression models revealed that protease mutations present at the initiation of saquinavir-ritonavir therapy were the strongest predictors of virologic response. A model of clinical features explained up to 45% of the variation in virologic outcomes by week 12, whereas the explained variance was 71% when genotypic predictors were included.
  
  
  CONCLUSIONS
  In patients in whom protease inhibitor-containing antiretroviral therapy fails, HIV-1 genotype is predictive of virologic response to subsequent therapy. This predictive capacity adds to that of standard clinical evaluation.
authors.affiliation: Division of Infectious Diseases and Geographical Medicine, Stanford University School of Medicine, CA 94305, USA. azolopa@stanford.edu
authors.forename: A R
authors.initials: AR
authors.lastname: Zolopa
authors.forename: R W
authors.initials: RW
authors.lastname: Shafer
authors.forename: A
authors.initials: A
authors.lastname: Warford
authors.forename: J G
authors.initials: JG
authors.lastname: Montoya
authors.forename: P
authors.initials: P
authors.lastname: Hsu
authors.forename: D
authors.initials: D
authors.lastname: Katzenstein
authors.forename: T C
authors.initials: TC
authors.lastname: Merigan
authors.forename: B
authors.initials: B
authors.lastname: Efron
mesh_terms: D000328:Adult; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D004352:Drug Resistance, Microbial / Q000235:genetics; D004359:Drug Therapy, Combination; D010450:Endopeptidases / Q000235:genetics; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D016014:Linear Models; D008297:Male; D011237:Predictive Value of Tests; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000627:therapeutic use*; D019258:Saquinavir / Q000627:therapeutic use*
chemical_list: D017320:HIV Protease Inhibitors; D012194:RNA-Directed DNA Polymerase; D010450:Endopeptidases; D019258:Saquinavir; D019438:Ritonavir