Effect of Dolutegravir coMpared to Darunavir/Cobicistat, both with Tenofovir Disoproxil Fumarate/Emtricitabine, On the severity of neuRopsychiatric efFects at 24 weeks of treatment in people living with HIV and baseline nEuropsychiatric disorders with no prior antiretrOviral therapy experience (MORFEO)

Abstract Background Neuropsychiatric adverse events (NPAEs) associated with dolutegravir (DTG) represent a challenge for clinical retention in people living with HIV (PWH), particularly among those with pre-existing mental health conditions. We aimed to compare the psychiatric safety, tolerability, and virological efficacy of DTG versus darunavir/cobicistat (DRV/c), both combined with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), in treatment-naive adults with baseline neuropsychiatric vulnerabilities. Methods MORFEO was a phase IV, randomized, open-label, active-controlled trial conducted in Mexico. Naive adult males presenting with baseline vulnerabilities across standardized scales (ISI, PHQ-9, HADS, PSQI) were assigned (1:1) to DTG vs DRV/c + TDF/FTC for 24 weeks. Longitudinal psychometric trajectories, virological suppression (RNA HIV-1 < 50 copies/mL), safety, and predictors of discontinuation were evaluated. Results Fifty-three male participants were randomized. Allocation to DTG (RR = 2.23, 95% CI: 1.62–3.07; P = 0.023) and severe baseline insomnia (ISI ≥ 15: RR = 9.6, 95% CI: 1.04–90.1; P = 0.031) independently predicted treatment discontinuation. Intragroup repeated-measures analyses showed that DRV/c conferred broad, sustained stabilization across all psychometric domains, including depressive symptoms (HADS-D: P < 0.001), sleep duration (P = 0.031), and daytime dysfunction (P = 0.044). Conversely, the DTG arm failed to achieve significant improvements in HADS-D, sleep duration, or daytime dysfunction. Conclusions In treatment-naive PWH with baseline neuropsychiatric vulnerabilities, both regimens achieved high, comparable 24-week virological suppression and reduced general distress. However, DRV/c showed a more uniform longitudinal stabilization across depressive symptoms, sleep duration, and daytime functioning, alongside fewer discontinuations than DTG. Baseline mental health screening is essential to tailor initial ART and safeguard treatment retention. Trial registration Clinical Trials identifier R20243502050