title: Non-nucleoside phenotypic hypersusceptibility cut-point determination from ACTG 359.
abstract: OBJECTIVE
  Non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility (HS) improves virologic response to those agents, but phenotypic susceptibility cut-points, and methods to determine the cut-points, have not been completely defined.
  
  
  METHODS
  Phenotypic drug susceptibility (fold change in IC50 [FC]) was determined for 96 randomly selected antiretroviral-experienced, NNRTI-naive patients who received a delavirdine (DLV)-containing regimen in ACTG 359. A weighted FC score was used to account for other regimen agents. Regression models were used to define baseline DLV HS cut-points using week 4 or week 16 responses.
  
  
  RESULTS
  At study entry, DLV HS was present in 36% (35/96) of patients. Models explored HS cut-points from 0.2-1.0 using the week 4 virologic response. Using either a binary or continuous endpoint, DLV HS cut-points between 0.3 and 0.4 were identified. The classification and regression tree (CART) analysis identified baseline DLV FC <0.44 as a predictor of week 4 response.
  
  
  CONCLUSIONS
  In relating drug HS to virologic response, several different analytic methods identified a DLV HS FC cut-point of 0.3-0.4. In refining phenotypic cut-points, early virologic responses (not confounded by rebound) may be better metrics than later responses, especially for drugs with low genetic barriers, such as DLV.
authors.affiliation: University of California San Diego, San Diego, California 92103, USA. rhaubrich@ucsd.edu
authors.forename: Richard H
authors.initials: RH
authors.lastname: Haubrich
authors.forename: Hongyu
authors.initials: H
authors.lastname: Jiang
authors.forename: Ronald
authors.initials: R
authors.lastname: Swanstrom
authors.forename: Michael
authors.initials: M
authors.lastname: Bates
authors.forename: David
authors.initials: D
authors.lastname: Katzenstein
authors.forename: Leslie
authors.initials: L
authors.lastname: Petch
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.forename: Susan A
authors.initials: SA
authors.lastname: Fiscus
authors.forename: Roy M
authors.initials: RM
authors.lastname: Gulick
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D020008:Delavirdine / Q000627:therapeutic use*; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D012367:RNA, Viral / Q000097:blood; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine