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S/GSK1349572: a next generation integrase inhibitor with activity against integrase inhibitor resistant clinical isolates from patients experiencing virologic failure while on raltegravir therapy
M. Underwood1, B. Johns1, A. Sato2, T. Fujiwara2, W. Spreen1
1GlaxoSmithKline, RTP, United States, 2Shionogi & Co., Ltd., Osaka, Japan
Background: S/GSK1349572 is a next generation integrase inhibitor (INI) with low nM potency. Susceptibility to S/GSK1349572 and raltegravir (RAL) was determined for INI resistant clinical isolates from therapy experienced patients treated with RAL plus optimized background regimen.
Methods: Thirty-nine clinical isolate samples were examined; 30 had IN coding region mutations and 21 of those (21/30) were longitudinal samples from 9 patients. Mutations included: N155H; G140S,Q148H; G140S,Q148R; T97A,Y143R; T97A,Y143C; and more complex samples including: E92Q,N155N/H,G140G/S,Q148Q/R; and E138E/K,G140G/S,Q148Q/H,N155N/D. Susceptibility was evaluated using Monogram Biosciences Integrase PhenoSense assay.
Results: Table presents fold change (FC) IC50 versus wildtype for representative IN mutants.
| | S/GSK1349572 | RAL | | | Genotype | Median FC | Range FC | Median FC | Range FC | N | | N155H | 1.37 | 1.22-1.45 | 19.0 | 14.0-36.0 | 5 | | G140S,Q148H | 3.75 | 2.05-15.0 | >87 | 58->87 | 7 | | G140S,Q148R | 13.3 | 7.57-19.0 | >87 | >87->87 | 2 | | T97A,Y143R | 1.05 | 1.04-1.06 | >81 | >81->81 | 2 |
Median FC IC50 against the 30 IN-mutant isolates was 1.52 (range 0.87-19.0) for S/GSK1349572, and >81 (range 3.74->87) for RAL. Although high level resistance to RAL was common, only 4 IN-mutant isolates had a S/GSK1349572 FC >5. No consistent correlation existed between FCs for S/GSK1349572 and RAL. All longitudinal virologic failure samples were more susceptible (and 19/21 were >5-fold more susceptible) to S/GSK1349572 than RAL. These data in combination with robust virologic responses and inhibitory quotients observed during 10 day S/GSK1349572 monotherapy suggest potential to treat patients with RAL resistance.
Conclusions: S/GSK1349572 exhibited in vitro activity against clinical isolates obtained from patients failing raltegravir-based therapy. These data suggest a virologic profile distinct from RAL, and consistent with potential for S/GSK1349572 to treat patients with RAL resistance. These observations need to be confirmed in clinical studies, and support further development of S/GSK1349572.
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