Once-daily dolutegravir (DTG; S/GSK1349572) is non-inferior to raltegravir (RAL) in antiretroviral‑naive adults: 48 week results from SPRING-2 (ING113086)
Background: The integrase inhibitor, Dolutegravir (DTG; S/GSK1349572), has shown rapid and durable antiviral response, with a favorable tolerability profile.
Methods: In this multicenter, double-dummy-blinded, Phase III, non-inferiority study, HIV-1 infected ART-naive adults with HIV-1 RNA ≥1000 c/mL and no evidence of viral resistance were randomized 1:1 to receive DTG 50 mg QD or RAL 400 mg BID, in addition to investigator-selected backbone NRTIs of either TDF/FTC or ABC/3TC. Subjects were stratified by screening HIV-1 RNA (≤ and >100,000 c/mL) and backbone NRTI selection. The primary endpoint was proportion of subjects with HIV-1 RNA < 50 c/mL through Week 48 (FDA “snapshot” algorithm).
Results: 827 subjects were randomized (DTG n=413, RAL n=414). At baseline: median age 36 years, 14% female, 15% non-white, 28% HIV-1 RNA >100,000 c/mL, 41% ABC/3TC. Proportion of subjects meeting the primary endpoint was 88% for DTG and 85% for RAL; difference (2.5%; 95% CI: -2.2% to 7.1%) met 10% non-inferiority criteria. For subjects with HIV-1 RNA >100,000 c/mL, response rate was 82% for DTG vs 75% for RAL. Secondary analyses supported non-inferiority: HIV-1 RNA < 50 c/mL per-protocol (DTG 90% vs RAL 88%), treatment-related discontinuation=failure (93% vs 92%) and virologic non-response (5% vs 8%). Median CD4 increases were similar (230 cells/mm3 each). Most commonly reported (≥10%) adverse events (AEs) were nausea (DTG 14%, RAL 13%), headache (12% each), nasopharyngitis (11%, 12%) and diarrhea (11% each). Discontinuation due to AEs was 2% in each group. At virologic failure, there was no genotypic integrase or NRTI resistance in the DTG group vs 1 subject and 4 subjects, respectively, in the RAL group.
Conclusions: At week 48, once-daily DTG was non-inferior to twice-daily RAL in treatment-naive HIV-1 infected subjects, with no evidence of emergent resistance to DTG in virologic failure. DTG plus NRTIs could be an option for first-line HIV treatment.
F. Raffi1, A. Rachlis2, H.-J. Stellbrink3, W.D. Hardy4, C. Torti5, C. Orkin6, M. Bloch7, D. Podzamczer8, V. Pokrovsky9, S. Almond10, D. Margolis11, S. Min11, The SPRING-2 Team
1University of Nantes, Nantes, France, 2Sunnybrook & Women's College Health Sciences Centre, Toronto, Canada, 3IPM Study Center, Hamburg, Germany, 4Cedars-Sinai Medical Center, Los Angeles, United States, 5Azienda Ospedaliera Spedali Civili, Brescia, Italy, 6Royal London Hospital, London, United Kingdom, 7Holdsworth House Medical Practice, Darlinghurst, Australia, 8Hospital Universitari de Bellvitge, Barcelona, Spain, 9Russian Federal Guidance Centre of AIDS, Moscow, Russian Federation, 10GlaxoSmithKline, Mississauga, Canada, 11GlaxoSmithKline, Research Triangle Park, United States