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Background We aim to assess the virological and immunological effectiveness of DOR/3TC/TDF as a switch regimen after 144 weeks in clinical practice.Material and Methods This was an observational study enrolling virologically-suppressed people with HIV (PWH) switching to DOR/3TC/TDF in the multicenter cohort DOROTEA. Clinical history and virological parameters were collected. Kaplan-Meier survival analysis was performed to evaluate time to virological failure (VF), defined as one HIV-RNA >1000 copies/mL or two consecutive HIV-RNA >50 copies/mL, and Cox regression to explore predictors of VF.Results Overall, 439 PWH were included: 314 (71.5%) were males, with a median age of 51 years (IQR 43-58). Full population characteristics are shown in table 1.During 1098.3 PYFU, we observed 30 VF (2.73 per 100 PYFU). Of the 30 VF events, 11 (36.7%) maintained DOR/3TC/TDF and all regained virological suppression during follow-up, suggesting transient viremia rather than confirmed treatment failure.Estimated probabilities of maintaining virological suppression at 48 and 144 weeks were 97.2% (SD±0.9) and 91.4% (SD±1.6), respectively.At multivariate analysis, having experienced a prior VF (vs. not having a history of VF, aHR 6.04, 95%CI 2.13-17.18, p=0.001) was significantly associated with a higher risk of VF while a longer exposure to ARV (per 1-year increase, B -0.12, aHR 0.88, 95%CI 0.79-0.99, p=0.035) was inversely associated with VF, after adjusting for years of HIV infection, CDC stage, peak HIV-RNA, CD4+ cell count at baseline and CD4+ nadir count. VF occurred predominantly among individuals with a prior history of VF: at 144 weeks, the probability of maintaining virological suppression was 93.3% in those without prior VF compared to 72.5% in those with prior VF (log-rank p<0.001).Regarding emergent resistance mutations, among individuals with available genotypic testing at failure (9/30), no emergent resistance mutations to doravirine, lamivudine or tenofovir disoproxil fumarate were detected.Finally, CD4+ cell count and CD4/CD8 ratio progressively improved over time, with statistically significant increases at weeks 48, 96, and 144, indicating sustained immunological recovery. In particular, CD4+ cell increase was more pronounced in PWH with lower CD4+ count at baseline (per 10 cell/uL more, B -1.6, p=0.001) and less pronounced in those with a higher peak HIV-RNA (B 36.0, p=0.021) and a higher nadir CD4+ cell count (per 10 cell/uL more B 2.5, p=0.006) after adjusting for age, sex at birth, CDC stage, years since HIV diagnosis and years of ARV exposure.Conclusions In this real-world cohort, switching to DOR/3TC/TDF was associated with high rates of sustained virological suppression over 144 weeks, low incidence of virological failure, and no evidence of emergent resistance. Immunological parameters continued to improve over time. These findings support the long-term robustness of this regimen in virologically suppressed PWH.Abstract P46 Table 1Population characteristics at baseline