BACKGROUND: To compare the effects of first-line antiretroviral therapy (ART) with dolutegravir plus lamivudine (DTG + 3TC) versus dolutegravir plus emtricitabine/tenofovir alafenamide (DTG + FTC/TAF) on the human immunodeficiency virus type 1 (HIV-1) reservoir and immune activation biomarkers in people with HIV (PWH). METHODS: DUALITY was a 48-week, single-center, randomized, open-label clinical trial in ART-naive PWH, randomized (1:1) to receive ART with DTG + 3TC (2DR group) or DTG + FTC/TAF (3DR group). We measured total and intact proviral HIV-1 DNA, cell-associated RNA in CD4+ T cells, frequency of HIV-infected CD4+ T cells able to produce p24, plasma soluble inflammatory markers, and activation and exhaustion markers in CD4+ and CD8+ T cells. RESULTS: Forty-four participants (22 per study arm) were enrolled, with baseline mean (standard deviation) log10 plasma viral load (pVL) 4.4 (0.7) copies/mL and CD4+ T-cell counts of 493 (221) cells/μL. At week 48, all participants had pVL <
50 copies/mL at week 48, except for 1 participant in the 2DR group who was resuppressed after treating syphilis. Changes from baseline in reservoir parameters and immune biomarkers were comparable between groups. CONCLUSIONS: First-line ART with DTG + 3TC showed similar reductions of HIV-1 persistence parameters and immune markers as DTG + FTC/TAF, supporting DTG/3TC among preferred first-line ART options for PWH.