title: Determination of clinically relevant cutoffs for HIV-1 phenotypic resistance estimates through a combined analysis of clinical trial and cohort data.
abstract: BACKGROUND
  Clinically relevant cutoffs are needed for the interpretation of HIV-1 phenotypic resistance estimates as predicted by "virtual" phenotype HIV resistance analysis.
  
  
  METHODS
  Using a clinical data set containing 2596 treatment change episodes in 2217 patients in 8 clinical trials and 2 population-based cohorts, drug-specific linear regression models were developed to describe the relation between baseline characteristics (resistance, viral load, and treatment history), new treatment regimen selected, and 8-week virologic outcome.
  
  
  RESULTS
  These models were used to derive clinical cutoffs (CCOs) for 6 nucleoside/nucleotide reverse transcriptase inhibitors (zidovudine, lamivudine, stavudine, didanosine, abacavir, and tenofovir), 3 unboosted protease inhibitors (PIs; indinavir, amprenavir, and nelfinavir), and 4 ritonavir-boosted PIs (indinavir/ritonavir, amprenavir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir). The CCOs were defined as the phenotypic resistance levels (fold change [FC]) associated with a 20% and 80% loss of predicted wild-type drug effect and depended on the drug-specific dynamic range of the assay.
  
  
  CONCLUSIONS
  The proposed CCOs were better correlated with virologic response than were biological cutoffs and provide a relevant tool for estimating the resistance to antiretroviral drug combinations used in clinical practice. They can be applied to diverse patient populations and are based on a consistent methodologic approach to interpreting phenotypic drug resistance.
authors: Virco BVBA, Mechelen, Belgium. bwinters@vrcbe.jnj.com
authors: Bart
authors: B
authors: Winters
authors: Julio
authors: J
authors: Montaner
authors: P Richard
authors: PR
authors: Harrigan
authors: Brian
authors: B
authors: Gazzard
authors: Anton
authors: A
authors: Pozniak
authors: Michael D
authors: MD
authors: Miller
authors: Sean
authors: S
authors: Emery
authors: Frank
authors: F
authors: van Leth
authors: Patrick
authors: P
authors: Robinson
authors: John D
authors: JD
authors: Baxter
authors: Marie
authors: M
authors: Perez-Elias
authors: Delivette
authors: D
authors: Castor
authors: Scott
authors: S
authors: Hammer
authors: Alex
authors: A
authors: Rinehart
authors: Hans
authors: H
authors: Vermeiren
authors: Elke
authors: E
authors: Van Craenenbroeck
authors: Lee
authors: L
authors: Bacheler
mesh_terms: D002986:Clinical Trials as Topic; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors