Activity of a next generation integrase inhibitor (INI), S/GSK1349572, in subjects with HIV exhibiting raltegravir resistance: initial results of VIKING study (ING112961)
Presented by Joe Eron (United States).
J. Eron1, J. Durant2, I. Poizot-Martin3, J. Reynes4, V. Soriano5, P. Kumar6, G. Richmond7, D. Vittecoq8, T. Fujiwara9, M. Ait-Khaled10, S. Min11, D. Thomas11, R. Cuffe10, J. Yeo10
1UNC School of Medicine, AIDS Research Clinical Care, Chapel Hill, United States, 2Hôpital l'Archet, Nice, France, 3Hôpital Sainte Marguerite, Marseille, France, 4Hôpital Gui de Chauliac, Montpellier, France, 5Instituto de Salud Carlos III, Madrid, Spain, 6Georgetown University, Washington, United States, 7Fort Lauderdale, Florida, United States, 8Hôpital Paul Brousse, Villejuif, France, 9Shionogi & Co., Ltd., Osaka, Japan, 10GlaxoSmithKline, London, United Kingdom, 11GlaxoSmithKline, Research Triangle Park, United States
Background: S/GSK1349572, a novel INI, demonstrated potent activity in a Phase 2a study and has limited cross-resistance to raltegravir (RAL) and elvitegravir in vitro. The activity of S/GSK1349572 is being explored in an ongoing 24-week Phase 2b study involving subjects with RAL-resistant HIV.
Methods: 27 antiretroviral therapy-experienced, adult subjects, with screening plasma HIV-1 RNA ≥1000c/mL showing genotypic resistance to RAL and ≥ two other ART classes, were enrolled. The Screening integrase-coding region genotypes included Q148H/K/R alone or with ≥ one Q148-associated mutation, N155H and/or Y143H ± additional mutations. Subjects received S/GSK1349572 50mg QD while continuing their failing regimen (without RAL) to Day 11 when the background regimen was optimised, where feasible, and S/GSK1349572 continued. The antiviral activity through Day 11 (for primary endpoint), and available safety data are presented.
Results: The median (range) fold-changes (FC) in susceptibility vs wild-type at Baseline were 161 (0.57- >166, n=27) to RAL and 1.46 (0.55-35, n=27) to S/GSK1349572. By Day 11, 21 of 27 subjects achieved plasma HIV-1 RNA< 400 c/mL or ≥0.7 log10 c/mL decline (primary endpoint), although the number of responders differed according to Baseline INI genotype: 16/16 with N155H or Y143H or Q148 single mutant pathways; 3/4 with Q148 plus one mutation; 0/5 with Q148 plus ≥2 mutations; 2/2 other. A strong correlation between baseline FC to S/GSK1349572 and Day 11 change from baseline in plasma HIV-1 RNA was observed (correlation r=0.79, p-value < 0.001). S/GSK1349572 was well tolerated: the most frequent AEs were diarrhoea (n=3) and insomnia (n=3), two subjects experienced an SAE considered unrelated to study drug.
Conclusion: Despite the high level resistance to raltegravir, the majority of subjects showed good antiviral responses through Day 11 of this pilot study. The ongoing study continues to characterise S/GSK1349572 activity against a wide range of RAL resistant viruses including low frequency variants.
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