Non-nucleoside phenotypic hypersusceptibility cut-point determination from ACTG 359.
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.
Haubrich
Richard H
RH
University of California San Diego, San Diego, California 92103, USA. rhaubrich@ucsd.edu
Jiang
Hongyu
H
Swanstrom
Ronald
R
Bates
Michael
M
Katzenstein
David
D
Petch
Leslie
L
Fletcher
Courtney V
CV
Fiscus
Susan A
SA
Gulick
Roy M
RM
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
D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D020008:Delavirdine