Dolutegravir is non-inferior to raltegravir and shows durable response through 96 weeks: results from the SPRING-2 trial
Background: The integrase inhibitor dolutegravir (DTG) given 50 mg once daily was non-inferior to raltegravir (RAL) 400 mg twice daily through Week (W) 48, with proportion achieving plasma HIV-1 RNA < 50 c/mL (snapshot algorithm) 88% on DTG and 85% on RAL; (difference was 2.5%; (95% CI: -2.2% to 7.1%), which met 10% non-inferiority criteria (Lancet, 2013). DTG demonstrated a favorable tolerability profile. W96 results are presented here.
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 or RAL, 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 NRTI selection.
Results: 827 subjects were randomized; baseline characteristics for DTG (n=413) and RAL (n=414) subjects were comparable. The proportion with HIV RNA < 50 c/mL at W96 was 81% versus 76% for DTG and RAL, respectively (difference 4.5%; 95% CI: -1.1%, 10.0%). Secondary analyses supported non-inferiority: per-protocol (DTG 83% vs. RAL 80%), and treatment-related discontinuation=failure (93% vs. 91%). Virologic non-response occurred less frequently on DTG (DTG 5%; RAL 10%). Median CD4 cells/mm3 increases from baseline were similar (DTG +276; RAL +264). Most commonly reported (13-15% in either group) adverse events (AEs) were nausea, headache, diarrhea, and nasopharyngitis. Discontinuation due to AEs was 2% in each group, with few such events between W48 and W96. There was no further increase in serum creatinine in either arm after W48. At virologic failure, there was no genotypic integrase and no NRTI resistance in the DTG group vs. 1 subject and 4 subjects, respectively, in the RAL group (all occurred during the first 48 weeks).
Conclusion: At W96, 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 and similar safety profiles for DTG and RAL. If approved, DTG combined with a potent NRTI backbone could be an important first-line option for HIV treatment.
F. Raffi1, H. Jaeger2, D. Motta3, H. Albrecht4, E. Belonosova5, J.M. Gatell6, J.-G. Baril7, P. Domingo8, C. Brennan9, S. Almond10, S. Min9, SPRING-2 Study Group
1Nantes University Hospital, Infectious and Tropical Diseases Department, Nantes, France, 2MUC Research GmbH, Muenchen, Germany, 3Spedali Civili di Brescia, Brescia, Italy, 4University of South Carolina School of Medicine/Palmetto Health, Columbia, United States, 5Orel Regional Center for AIDS, Orel, Russian Federation, 6Hospital Clinic i Provincial, Barcelona, Spain, 7Clinique Medicale du Quartier Latin, Montreal, Canada, 8Hospital Santa Cruz y San Pablo, Barcelona, Spain, 9GlaxoSmithKline, Medicine Discovery and Development, Research Triangle Park, United States, 10GlaxoSmithKline, Clinical Statistics, Mississauga, Canada