[13] Integrase inhibitor resistance involves complex interactions among primary and secondary resistance mutations: a novel mutation L68V/I associates with E92Q and increases resistance

17th International HIV Drug Resistance Workshop

10-14 June 2008, Sitges, Spain

INTEGRASE INHIBITOR RESISTANCE INVOLVES COMPLEX INTERACTIONS AMONG PRIMARY AND SECONDARY RESISTANCE MUTATIONS: A NOVEL MUTATION L68V/I ASSOCIATES WITH E92Q AND INCREASES RESISTANCE

Antivir Ther. 2008; 13(Suppl. 3):A15 (abstract no. 13)

D Goodman¹, R Hluhanich², J Waters¹, NA Margot², S Fransen³, S Gupta³, W Huang³, N Parkin³, K Borroto-Esoda¹, ES Svarovskaia¹, MD Miller² and DJ McColl²
¹Gilead Sciences, Inc., Durham, NC, USA; ²Gilead Sciences, Inc., Foster City, CA, USA; ³Monogram Biosciences, South San Francisco, CA, USA

BACKGROUND: Elvitegravir (EVG, GS-9137) is a boosted once-daily (QD) integrase inhibitor (INI) being developed for antiretroviral therapy. Previously, we presented genotypic and phenotypic data on INI-resistant viruses from patients receiving EVG 125 mg QD in a Phase II study (GS-US-183-0105). Here, we studied the INI susceptibility and viral fitness of viruses containing different INI-resistance mutations.

METHODS: IN clones were isolated from patients treated with EVG in the Phase II study. The INI susceptibility (EVG and raltegravir [RAL]) and replication capacity (RC) of patient-derived IN clones and site-directed mutants (SDM) were measured using the PhenoSense HIV integrase assay. Relative fitness (1+s) of SDM viruses was also determined using a growth competition assay.

RESULTS: E92Q, Q148R/H/K and/or N155H mutations were each detected in 11/28 (39%) EVG virological failure patients. Two (7%) patients had both E92Q and Q148R as mixtures whereas four (14%) had both E92Q and N155H mutations as mixtures. By clonal analysis, E92Q+N155H but not E92Q+Q148R were found on the same viral genome. Compared with single mutants, E92Q+N155H further reduced INI susceptibility and conferred further reductions in RC and relative fitness. Six of 11 patients with E92Q also had an L68V/I IN mutation, which occurred only in the presence of E92Q (6/6). L68V caused low-level reduced susceptibility to EVG. Double mutant viruses with L68V/I+E92Q combined had further reduced EVG susceptibility versus E92Q alone (57- to 89-fold versus 33-fold). L68V+E92Q reduced susceptibility to RAL versus E92Q alone (12-fold versus 6-fold). L68V/I alone, or in combination with E92Q, had no effect on relative fitness.

CONCLUSIONS: Evolution of INI resistance involves complex interactions among both primary and secondary drug-selected mutations. Evidence for mutual exclusion of the E92Q and Q148R mutations was demonstrated by clonal analysis. Viruses containing E92Q or N155H mutations had reduced relative fitness; their combination further reduced viral fitness and enhanced resistance to INIs. Novel secondary EVG-selected mutations, L68V and L68I, were shown to be strongly linked to E92Q and enhanced resistance to INI, but did not affect relative viral fitness. Acquisition of higher phenotypic drug resistance is a significant factor in the evolution of INI resistance pathways.

2008-06-10
13

Copyright © 2008 - International Medical Press Ltd.. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.