BACKGROUND: Dolutegravir (DTG, S/GSK1349572) is an integrase inhibitor with low nanomolar potency. Susceptibility to dolutegravir and raltegravir was determined for raltegravir-resistant clinical isolates. METHODS: Genotypic and phenotypic susceptibility to integrase inhibitors was examined using 39 clinical isolate samples obtained from 18 adults who had exhibited incomplete viral suppression on a raltegravir-based regimen. RESULTS: Of 39 samples evaluated, 30 had genotypic and phenotypic resistance to raltegravir. All samples lacking raltegravir resistance retained complete susceptibility to dolutegravir. Of the 30 samples with genotypic evidence of raltegravir resistance, the median level of phenotypic resistance to raltegravir was high (median fold change in inhibitory concentration at 50%, >81; range, 3.7 to >87), while the level of resistance to dolutegravir was close to that of wild-type variants (median fold change, 1.5; range, 0.9-19.0). Longitudinal samples from 5 subjects collected during long-term failure of raltegravir revealed time-dependent general decreases in phenotypic susceptibility to raltegravir, with minimal changes in phenotypic susceptibility to dolutegravir. The median fold change to dolutegravir for isolates containing changes at G140S + Q148H, G140S + Q148R, T97A + Y143R, and N155H (thus including raltegravir signature resistance codons) were 3.75, 13.3, 1.05, and 1.37, respectively. CONCLUSIONS: Dolutegravir retained in vitro activity against clinical isolates obtained from subjects who failed raltegravir-based therapy at near wild-type levels for variants containing the Y143 and N155 resistance mutations. Isolates with Q148 plus additional integrase mutations possessed a broader range of and more reduced susceptibility to dolutegravir.
BACKGROUND:Dolutegravir (DTG, S/GSK1349572) is an integrase inhibitor with low nanomolar potency. Susceptibility to dolutegravir and raltegravir was determined for raltegravir-resistant clinical isolates. METHODS: Genotypic and phenotypic susceptibility to integrase inhibitors was examined using 39 clinical isolate samples obtained from 18 adults who had exhibited incomplete viral suppression on a raltegravir-based regimen. RESULTS: Of 39 samples evaluated, 30 had genotypic and phenotypic resistance to raltegravir. All samples lacking raltegravir resistance retained complete susceptibility to dolutegravir. Of the 30 samples with genotypic evidence of raltegravir resistance, the median level of phenotypic resistance to raltegravir was high (median fold change in inhibitory concentration at 50%, >81; range, 3.7 to >87), while the level of resistance to dolutegravir was close to that of wild-type variants (median fold change, 1.5; range, 0.9-19.0). Longitudinal samples from 5 subjects collected during long-term failure of raltegravir revealed time-dependent general decreases in phenotypic susceptibility to raltegravir, with minimal changes in phenotypic susceptibility to dolutegravir. The median fold change to dolutegravir for isolates containing changes at G140S + Q148H, G140S + Q148R, T97A + Y143R, and N155H (thus including raltegravir signature resistance codons) were 3.75, 13.3, 1.05, and 1.37, respectively. CONCLUSIONS:Dolutegravir retained in vitro activity against clinical isolates obtained from subjects who failed raltegravir-based therapy at near wild-type levels for variants containing the Y143 and N155 resistance mutations. Isolates with Q148 plus additional integrase mutations possessed a broader range of and more reduced susceptibility to dolutegravir.
Authors: Jan van Lunzen; Franco Maggiolo; José R Arribas; Aza Rakhmanova; Patrick Yeni; Benjamin Young; Jürgen K Rockstroh; Steve Almond; Ivy Song; Cindy Brothers; Sherene Min Journal: Lancet Infect Dis Date: 2011-10-20 Impact factor: 25.071
Authors: Tamara Bar-Magen; Richard D Sloan; Daniel A Donahue; Björn D Kuhl; Alexandra Zabeida; Hongtao Xu; Maureen Oliveira; Daria J Hazuda; Mark A Wainberg Journal: J Virol Date: 2010-07-07 Impact factor: 5.103
Authors: Sherene Min; Louis Sloan; Edwin DeJesus; Trevor Hawkins; Lewis McCurdy; Ivy Song; Richard Stroder; Shuguang Chen; Mark Underwood; Tamio Fujiwara; Stephen Piscitelli; Jay Lalezari Journal: AIDS Date: 2011-09-10 Impact factor: 4.177
Authors: L Van Wesenbeeck; E Rondelez; M Feyaerts; A Verheyen; K Van der Borght; V Smits; C Cleybergh; H De Wolf; K Van Baelen; L J Stuyver Journal: Antimicrob Agents Chemother Date: 2010-10-18 Impact factor: 5.191
Authors: Said A Hassounah; Thibault Mesplède; Peter K Quashie; Maureen Oliveira; Paul A Sandstrom; Mark A Wainberg Journal: J Virol Date: 2014-06-11 Impact factor: 5.103
Authors: Chantelle Bennetto-Hood; Glenn Tabolt; Paul Savina; Edward P Acosta Journal: J Chromatogr B Analyt Technol Biomed Life Sci Date: 2013-12-03 Impact factor: 3.205
Authors: Mathieu Métifiot; Barry C Johnson; Evgeny Kiselev; Laura Marler; Xue Zhi Zhao; Terrence R Burke; Christophe Marchand; Stephen H Hughes; Yves Pommier Journal: Nucleic Acids Res Date: 2016-07-01 Impact factor: 16.971