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

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.Methods and Results-Rates of virologic failure were similar in the 2 arms at week 16 (p=0.509). Treatment discontinuations were more common in the ABC arm (p=0.001). 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-resistant mutant L74V was selected for in combination with the uncommonly occurring EFV-resistant mutant 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 EFVhypersusceptible HIV variants in this patient population likely made it difficult to detect a benefit of

Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms

“…b | Compensation by increased dosage of a low-fitness mutant protein is shown 13,56 . c | Compensation by an intergenic mutation (dark green circle) is shown, which is relevant when protein complexes or protein interactions are involved in physiological activity 48,51 . Different proteins are shown as light blue and light green colours.…”

Effect of Natural Polymorphisms in the HIV-1 CRF02_AG Protease on Protease Inhibitor Hypersusceptibility

“…Patients with HIV-1 subtype B infection, exposed to NRTIs and presenting HS to efavirenz, had a better virologic response during therapeutic salvage that included NNRTIs (33). Such a benefit was corroborated by other clinical trials of salvage therapy (7,12,13,40). The PR drug resistance mutation N88S, which causes resistance to ATV and NFV, also confers HS to APV.…”

Clinical Management of HIV Drug Resistance

“…Hypersusceptibility may affect nucleotide selectivity or virus replication capacity [ 105 , 106 ]. Clinical advantage of NNRTI hypersusceptibility has not been extensively investigated, but patients with hypersusceptibility did experience higher reductions in viral RNA, suggesting a clinical advantage [ 103 , 107 ].…”