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Dolutegravir Regimen Statistically Superior to Tenofovir/Emtricitabine/Efavirenz: 96-Wk Data
Sharon Walmsley, Juan Berenguer, Marie-Aude Khuong-Josses, Michael Kilby, Thomas Lutz, Daniel Podzamczer, Norman Roth, Catherine Granier, Brian Wynne, Keith Pappa *University Health Network, Toronto, ON, Canada, Hospital General Universitario Gregorio Maranon, Madrid, Spain, CHG – Hopital Delafontaine, Paris, France, Medical University of South Carolina, Charleston, SC, United States, Infektiologikum, Frankfurt, Germany, Bellvitge University Hospital, Barcelona, Spain, Prahan Market Clinic, Melbourne, Australia, GSK, London, United Kingdom, GSK, Philadelphia, PA, United States, 0GSK, Research Triangle Park, NC, United States
Background: At the primary 48-Week analysis, Dolutegravir (DTG) 50 mg + abacavir (ABC)/lamivudine (3TC) once daily was superior to Tenofovir (TDF)/Emtricitabine (FTC) /Efavirenz (EFV) in treatment-naive HIV-1 patients, with 88% vs. 81% suppressed virologically (plasma HIV <50c/mL by snapshot algorithm [P=0.003]); safety/tolerability was favorable for DTG + ABC/3TC. In order to access durability we now present 96 week final results. Methodology: SINGLE (ING114467) is an ongoing Phase III, randomized, multi-center, double-blind, double-dummy study comparing the efficacy and safety of DTG plus ABC/3TC fixed dose combination (FDC) to TDF/FTC/EFV (ATR) in treatment-naive HIV patients. Randomization was stratified by baseline plasma HIV-1 RNA (≤ vs >100,000 c/mL) and CD4 cell count (≤ vs > 200 cells/mm3). Results: 833 subjects were enrolled and treated (84% males; 32% non-white); treatment groups were similar at baseline. Through Week 96, 80% of DTG+ABC/3TC subjects and 72% of ATR subjects achieved <50 c/mL plasma HIV-1 RNA based on the FDA snapshot algorithm (difference 8.0%, 95% CI: +2.3%, +13.8% based on Cochran-Mantel-Haenszel analysis adjusted for strata), achieving pre-specified statistical superiority (P= 0.006). Differences in efficacy were primarily driven by a higher rate of discontinuation due to adverse events (AEs) in ATR recipients (11%), vs. 3% with DTG + ABC/3TC; most occurred prior to Week 48 (10% vs. 2%). Differences in time to viral suppression (28 vs 84 days; p< 0.0001, generalized Wilcoxon test) and the change from baseline in CD4+ cells over 96 weeks (325 vs. 281 cells/mm3, p = 0.004, adjusted repeated measure model) both favored the DTG + ABC/3TC arm. DTG+ABC/3TC was better tolerated than ATR, with nervous system (23 vs. 50%, p< 0.001) and psychiatric disorders AEs (32 vs. 40%, p=0.021) being more frequent with ATR, while insomnia was more frequent with DTG+ABC/3TC (17 vs. 11%, p=0.021, Fisher’s exact test). Few subjects experienced protocol defined virologic failure between Week 48 and 96 (occurrence increased from 4 to 6% of subjects in both arms). No treatment emergent primary integrase inhibitor (INI) or nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations were observed through 96 weeks for subjects receiving DTG+ABC/3TC, while EFV and NRTI primary resistance mutations were observed in six and one patient respectively in the ATR group. Conclusions: The DTG+ ABC/3TC regimen resulted in potent and durable suppression of viral replication over 96 weeks, which was statistically superior to an ATR regimen. DTG+ ABC/3TC maintained a favorable AE profile, with no treatment emergent primary INI or NRTI resistance mutations and a low rate of discontinuation due to virologic failure through 96 weeks.