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.

TitleAssociation 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.
Publication TypeJournal Article
Year of Publication2008
AuthorsDemeter LM, Degruttola V, Lustgarten S, Bettendorf D, Fischl M, Eshleman S, Spreen W, Nguyen B-Y, Koval CE, Eron JJ, Hammer S, Squires K
JournalHIV Clin Trials
Volume9
Issue1
Pagination11-25
Date Published2008 Jan-Feb
ISSN1528-4336
KeywordsAdult, Aged, Anti-HIV Agents, Benzoxazines, CD4 Lymphocyte Count, Dideoxynucleosides, Double-Blind Method, Drug Resistance, Viral, Drug Therapy, Combination, Female, HIV Infections, HIV Protease Inhibitors, HIV-1, Humans, Indinavir, Male, Middle Aged, Treatment Outcome
Abstract

PURPOSE: 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.

METHOD AND 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.

CONCLUSION: 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.

DOI10.1310/hct0901-11
Alternate JournalHIV Clin Trials
PubMed ID18215978
PubMed Central IDPMC2821073
Grant List2 R01 AI-041387 / AI / NIAID NIH HHS / United States
5R01 AI-51164 / AI / NIAID NIH HHS / United States
AI027659 / AI / NIAID NIH HHS / United States
AI25868 / AI / NIAID NIH HHS / United States
AI25879 / AI / NIAID NIH HHS / United States
AI25903 / AI / NIAID NIH HHS / United States
AI25924 / AI / NIAID NIH HHS / United States
AI27658 / AI / NIAID NIH HHS / United States
AI27660 / AI / NIAID NIH HHS / United States
AI27664 / AI / NIAID NIH HHS / United States
AI27670 / AI / NIAID NIH HHS / United States
AI27675 / AI / NIAID NIH HHS / United States
AI32782 / AI / NIAID NIH HHS / United States
AI3844 / AI / NIAID NIH HHS / United States
AI38858 / AI / NIAID NIH HHS / United States
AI50410 / AI / NIAID NIH HHS / United States
N01-AI-38858 / AI / NIAID NIH HHS / United States
R01 AI-041387 / AI / NIAID NIH HHS / United States
RR-00044 / RR / NCRR NIH HHS / United States
RR00044 / RR / NCRR NIH HHS / United States
RR00046 / RR / NCRR NIH HHS / United States
RR00865 / RR / NCRR NIH HHS / United States
RR05096 / RR / NCRR NIH HHS / United States
U01 AI069511 / AI / NIAID NIH HHS / United States
U01 AI069511-04 / AI / NIAID NIH HHS / United States
U01-AI-27658 / AI / NIAID NIH HHS / United States
UM1 AI069423 / AI / NIAID NIH HHS / United States
UM1 AI069511 / AI / NIAID NIH HHS / United States