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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.