OBJECTIVES: Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity. PATIENTS AND METHODS: Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm. RESULTS: Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load. CONCLUSIONS: Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue.
OBJECTIVES:Dolutegravir is a second-generation integrase strand transfer inhibitor (InSTI) that has been recently approved by the FDA to treat antiretroviral therapy-naive as well as treatment-experienced HIV-infected individuals, including those already exposed to the first-generation InSTI. Despite having a different mutational profile, some cross-resistance mutations may influence its susceptibility. The aim of this study was to evaluate the impact of a raltegravir-containing salvage regimen on dolutegravir activity. PATIENTS AND METHODS: Blood samples of 92 HIV-infected individuals with virological failure (two or more viral loads >50 copies/mL after 6 months of treatment) using raltegravir with optimized background therapy were sequenced and evaluated according to the Stanford University HIV Drug Resistance Database algorithm. RESULTS: Among the 92 patients analysed, 32 (35%) showed resistance to dolutegravir, in most cases associated with the combination of Q148H/R/K with G140S/A mutations. At genotyping, patients with resistance to dolutegravir had viral load values closer to the highest previously documented viral load. CONCLUSIONS: Changes in viraemia during virological failure may indicate the evolution of raltegravir resistance and may predict the emergence of secondary mutations that are associated with a decrease in dolutegravir susceptibility. Early discontinuation of raltegravir from failing regimens might favour subsequent salvage with dolutegravir, but further studies are necessary to evaluate this issue.
Authors: Philip L Tzou; Soo-Yon Rhee; Diane Descamps; Dana S Clutter; Bradley Hare; Orna Mor; Maxime Grude; Neil Parkin; Michael R Jordan; Silvia Bertagnolio; Jonathan M Schapiro; P Richard Harrigan; Anna Maria Geretti; Anne-Geneviève Marcelin; Robert W Shafer Journal: J Antimicrob Chemother Date: 2020-01-01 Impact factor: 5.790
Authors: Xue Zhi Zhao; Steven J Smith; Daniel P Maskell; Mathieu Metifiot; Valerie E Pye; Katherine Fesen; Christophe Marchand; Yves Pommier; Peter Cherepanov; Stephen H Hughes; Terrence R Burke Journal: ACS Chem Biol Date: 2016-02-05 Impact factor: 5.100
Authors: Aurelio Orta-Resendiz; Roberto A Rodriguez-Diaz; Luis A Angulo-Medina; Mario Hernandez-Flores; Luis E Soto-Ramirez Journal: AIDS Res Ther Date: 2020-02-10 Impact factor: 2.250