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Changes in weight and body composition were assessed in long-term suppressed HIV-infected patients switching to dolutegravir/rilpivirine (n = 37), and compared with similar patients switching to darunavir/lamivudine (n = 17). At month 12, weight significantly increased with dolutegravir/rilpivirine (1.8 kg, IQR −1.2 to 4.1; 2.5%; P = 0.03). A follow-up DXA (median, 16 months) showed similar increases in trunk (7.8%), arms (5.6%), and legs (6.2%) fat mass, without changes in lean mass. Despite lower weight gain (0.70 kg, IQR −0.8 to 4.0, P = 0.28), fat mass increase was similar in the darunavir/lamivudine group. Baseline fat mass and CD4 counts were the only factors explaining fat mass gain.