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

• Published in: HIV clinical trials Vol. 9; no. 1; p. 11
• Main Authors: Demeter, Lisa M, DeGruttola, Victor, Lustgarten, Stephanie, Bettendorf, Daniel, Fischl, Margaret, Eshleman, Susan, Spreen, William, Nguyen, Bach-Yen, Koval, Christine E, Eron, Joseph J, Hammer, Scott, Squires, Kathleen
• Format: Journal Article
• Language: English
• Published: England 01.01.2008
• Subjects: Adult; Aged; Alkynes; Anti-HIV Agents - therapeutic use; Benzoxazines - therapeutic use; CD4 Lymphocyte Count; Cyclopropanes; Dideoxynucleosides - therapeutic use; Double-Blind Method; Drug Resistance, Viral; Drug Therapy, Combination; Female; HIV Infections - drug therapy; HIV Infections - virology; HIV Protease Inhibitors - therapeutic use; HIV-1 - drug effects; HIV-1 - isolation & purification; Humans; Indinavir - therapeutic use; Male; Middle Aged; Treatment Outcome
• ISSN: 1528-4336
• DOI: 10.1310/hct0901-11

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. 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. 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.