Rapid, robust and sustained antiviral response with once-daily (QD) dolutegravir (DTG, S/GSK1349572), a next generation integrase inhibitor (INI) in combination therapy in antiretroviral-naïve adults: 48 week results from SPRING-1 (ING112276)
Background: DTG, has demonstrated potent antiviral activity with QD, unboosted dosing. SPRING-1 is an ongoing dose-ranging study from which the 50mg QD dose was selected for Phase III evaluation in INI-naïve subjects.
Methods: Multicentre, partially-blinded Phase IIb study in therapy-naïve adults receiving 10mg, 25mg or 50mg DTG or efavirenz (EFV) 600mg QD with TDF/FTC or ABC/3TC.
Results: 205 subjects received study drug. Plasma HIV-1 RNA declined faster across DTG doses vs. EFV; subjects maintained their responses to Week 48. A trend for higher CD4+ cell increases was observed across DTG arms vs EFV (+231 vs +174 cells/mm3; p=0.076). Response rates using superlow assay (< 2c/mL) are also shown. Four subjects across the DTG and EFV arms met protocol-defined virologic failure criteria; two continue on study after virologic re-suppression. No integrase-associated mutations have been observed to date. No new safety issues occurred to Week 48. Fewer grade 2-4 drug-related AEs were reported on DTG (8%) than EFV (20%); 6 subjects (2 on DTG; 4 on EFV) withdrew due to AEs. The most frequent events were gastrointestinal (2% vs 4%, DTG vs, EFV respectively), metabolic (3% vs 0%), psychiatric (0% vs 6%) and rash (0% vs 4%). No SAE was considered related to DTG. Mean change in LDL cholesterol was +0.55mg/dL and +15.88mg/dL among DTG and EFV subjects, respectively.
Conclusion: Once-daily, unboosted DTG was well-tolerated with little impact on lipids. DTG's rapid and robust potency was further substantiated using a highly sensitive assay for HIV RNA. Based on these results, Phase III studies are underway.
|Planned Week 48 Interim Analysis Results||DTG 10 mg (n=53)||DTG 25 mg (n=51)||DTG 50 mg (n=51)||EFV control (n=50)|
|Mean baseline HIV-1 RNA (log10 copies/mL)||4.42||4.38||4.58||4.46|
|%<50c/mL at 16, 24 and 48 wks (by TLOVR)||96%, 96%, 91%||90%, 90%, 88%||92%, 92%, 90%||58%, 82%, 82%|
|%<2c/mL at 16, 24 and 48 wks||n/d||n/d||49%, 67%, 53%||36%, 48%, 60%|
J. Van Lunzen1, F. Maggiolo2, B. Phung3, O. Tsybakova4, B. Young5,6, J. Gatell7, S. Almond8, M. St. Clair9, C. Brothers9, S. Min9
1University Medical Center, Hamburg-Eppendorf, Germany, 2Ospedali Riuniti de Bergamo, Bergamo, Italy, 3Hôpital Bichat-Claude Bernard, Paris, France, 4AIDS Center, Smolensk, Russian Federation, 5Rocky Mountain CARES/DIDC, Denver, United States, 6Health Connections International, Amsterdam, Netherlands, 7University of Barcelona, Barcelona, Spain, 8GlaxoSmithKline, Mississauga, Canada, 9GlaxoSmithKline, Research Triangle Park, United States