Efficacy and safety of the HIV-1 maturation inhibitor GSK3640254 plus two NRTIs in adults naive to antiretroviral therapy (DOMINO): 24-week results from a randomised phase 2b study

Background: There is an unmet need for antiretrovirals with novel mechanisms of action that can provide additional options for people with HIV-1. DOMINO evaluated the efficacy and safety of the maturation inhibitor GSK3640254 (GSK'254) plus two nucleoside reverse transcriptase inhibitors (NRTIs) in adults naive to antiretroviral therapy. Methods: who were naive to antiretroviral therapy. Participants were centrally randomised to receive once-daily oral GSK'254 100, 150, or 200 mg (double-blinded dose) or open-label dolutegravir (DTG) 50 mg, each with open-label NRTIs. The primary endpoint was proportion with Snapshot HIV-1 RNA <50 copies/mL at Week 24 (intention-to-treat-exposed population). Safety was assessed through Week 24. This trial is registered at ClinicalTrials.gov, NCT04493216 (trial closed). Findings: Screenings occurred between November 18, 2020, and January 31, 2022; 161 participants were randomised (sex assigned at birth: 24% female; 76% male). At Week 24, proportions with HIV-1 RNA <50 copies/mL were 83% (33/40), 91% (39/43), and 76% (32/42) in the GSK'254 100-mg, 150-mg, and 200-mg groups, respectively, vs 92% (33/36) in the DTG group. One participant receiving DTG and eight participants receiving GSK'254 had protocol-defined virologic failure (no resistance detected). All GSK'254 doses were generally well tolerated, with few participants reporting drug-related serious adverse events (GSK'254: 150 mg, 2% [1/43]; 200 mg, 2% [1/42]). Interpretation: GSK'254 plus two NRTIs demonstrated efficacy and safety with no treatment-emergent resistance, consistent with DTG plus two NRTIs, supporting potential further evaluation of maturation inhibitors.