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Background: With advances in antiretroviral therapy for HIV treatment, newer drug combinations provide improved efficacy, safety, and compliance. This study evaluates switching to a regimen of doravirine (DOR), tenofovir disoproxil fumarate (TDF), and lamivudine (3TC) in a cohort of people living with HIV (PLWH). Methods: this Italian retrospective study included 426 PLWH who switched from rilpivirine (RPV)/TDF/emtricitabine (FTC) to DOR/3TC/TDF. The analysis focused on treatment effectiveness, safety, and metabolic and renal markers. Results: this study reports a treatment failure (defined as virological failure or discontinuation of the regimen) rate of 2.34% (95% confidence interval, 1.28-4.50%), with significant improvement in CD4 counts (+49.93 cells/µL, p < 0.001). Notably, the switch to DOR/3TC/TDF did not result in adverse metabolic effects or significant changes in renal function. Analysis of lipid profiles showed stabilization in the majority of PLWH. Conclusions: this study indicates that switching to a DOR/3TC/TDF from RPV/TDF/FTC is an effective and well-tolerated option for PLWH, with benefits in terms of maintaining viral suppression, CD4 count recovery, and metabolic health, without evidence of renal impairment. These results support the continued use of DOR/3TC/TDF as part of HIV treatment strategies and highlight the need for ongoing research to refine ART regimens for different populations.