Association of efavirenz hypersusceptibility with virologic response in ACTG 368, a randomized trial of abacavir (ABC) in combination with efavirenz (EFV) and indinavir (IDV) in HIV-infected subjects with prior nucleoside analog experience.
OBJECTIVE
To evaluate the association of efavirenz hypersusceptibility (EFV-HS) with clinical outcome in a double-blind, placebo-controlled, randomized trial of EFV plus indinavir (EFV+IDV) vs. EFV+IDV plus abacavir (ABC) in 283 nucleoside-experienced HIV-infected patients.


RESULTS
Rates of virologic failure were similar in the 2 arms at week 16 (p = .509). Treatment discontinuations were more common in the ABC arm (p = .001). Using logistic regression, there was no association between virologic failure and either baseline ABC resistance or regimen sensitivity score. Using 3 different genotypic scoring systems, EFV-HS was significantly associated with reduced virologic failure at week 16, independent of treatment assignment. In some patients on the nucleoside-sparing arm, the nucleoside-resistance mutation L74V was selected for in combination with the uncommonly occurring EFV-resistance mutations K103N+L100I; L74V was not detected as a minority variant, using clonal sequence analysis, when the nucleoside-sparing regimen was initiated.


CONCLUSIONS
Premature treatment discontinuations in the ABC arm and the presence of EFV-HS HIV variants in this patient population likely made it difficult to detect a benefit of adding ABC to EFV+IDV. In addition, L74V, when combined with K103N+L100I, may confer a selective advantage to the virus that is independent of its effects on nucleoside resistance.
Demeter
Lisa M
LM
University of Rochester, Rochester, New York 14642, USA. lisa_demeter@urmc.rochester.edu
DeGruttola
Victor
V
Lustgarten
Stephanie
S
Bettendorf
Daniel
D
Fischl
Margaret
M
Eshleman
Susan
S
Spreen
William
W
Nguyen
Bach-Yen
BY
Koval
Christine E
CE
Eron
Joseph J
JJ
Hammer
Scott
S
Squires
Kathleen
K
D000328:Adult; D000368:Aged; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000627:therapeutic use*; D004311:Double-Blind Method; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D000099227:Abacavir
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D017320:HIV Protease Inhibitors; D019469:Indinavir; D000099227:Abacavir; C098320:efavirenz