Background:  Dolutegravir (DTG; S/GSK1349572), a once-daily, unboosted integrase inhibitor (INI), has shown rapid and durable antiviral responses with a favorable tolerability profile. SPRING-1 is a four-arm dose-ranging study designed to select a phase 3 dose; all arms were continued through 96 weeks to assess durability of response and safety profiles across DTG doses.

Methods:  In this multicenter, partially blinded, phase 2b, dose-ranging study, therapy-naïve HIV-infected adults were randomized 1:1:1:1 to receive DTG 10, 25, or 50 mg every day or efavirenz (EFV) 600 mg every day with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) or abacavir (ABC)/lamivudine (3TC) and stratification based on screening HIV-1 RNA (viral load) and NRTI selection. The primary endpoint for this study is proportion of subjects with viral load <50 copies/mL at week 16, with a planned analysis at week 96.

Results:  Two hundred and five subjects received study drug: 86% male, 20% non-white, 26% >100,000 copies/mL viral load, 67% TDF/FTC. At week 96 the proportion of subjects with viral load <50 copies/mL (TLOVR) was 88% for the DTG 50 mg dose vs 72% for EFV, responses in the DTG 10 mg and 25 mg arms were 79% and 78%, respectively. There were no cases of protocol-defined virologic failure (PDVF, confirmed viral load >400 copies/mL) on the DTG 50 mg arm through 96 weeks; no new cases of PDVF occurred on any arm between weeks 48 and 96. No genotypic or phenotypic evidence of INI or NNRTI resistance was observed through week 96 in any of the treatment arms. The median change from baseline in CD4⁺ cells in the combined DTG arms trended higher for DTG (combined) (+338.5 cells/mm³) vs EFV (+301 cells/mm³) (p = 0.155). No new safety issues occurred between week 48 and week 96. Through 96 weeks, fewer grade 2 to 4 drug-related adverse events (AE) were reported on DTG (11%) than EFV (24%), the most frequent being gastrointestinal (3% vs 4%, DTG vs EFV, respectively), psychiatric (0% vs 6%), and rash (0% vs 4%). Fewer subjects withdrew due to AE on DTG (4/155, 3%) when compared to EFV (5/50, 10%).

Conclusions:  Once-daily, unboosted DTG demonstrated durable antiviral activity for all dosing arms, with 88% responders through 96 weeks at the selected 50 mg every day dose. DTG had a favorable safety profile through 96 weeks of treatment.