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Background We aim to analyze the tolerability and cardiovascular safety of DOR/3TC/TDF after 144 weeks of observation in a multicenter cohort.Methods This was an observational study enrolling virologically suppressed people with HIV (PWH) switching to DOR/3TC/TDF in our multicenter cohort; we collected their clinical history as well as laboratory parameters. For a subgroup, SCORE-2 and METS-IR metabolic scores were available. We performed Kaplan–Meier survival analysis to evaluate time to treatment discontinuation (TD), Cox regression to identify predictors of TD, and linear mixed-effects models to assess changes in metabolic parameters over time.Results We analyzed data from 439 PWH: 314 (71.5%) were males, with a median age of 51 years (IQR 43-58). Full population characteristics are shown in table 1.During 1256.5 PYFU, we observed 150 TD (11.9 per 100 PYFU), mainly driven by switches to long-acting regimens rather than toxicity or clinical failure. In particular, reasons for TD were: switch to a LA regimen (37, 8.4% of total population), toxicity (34, 7.7%), treatment intensification (16, 3.6%), pregnancy (7, 1.4%), death (no AIDS-related, 7, 1.4%), other/unknown (49, 11.2%). Estimated probabilities of maintaining DOR/3TC/TDF were 89.7% (SD±1.5) at 48 weeks and 70.8% (SD±1.3) at 144 weeks. In our regression analysis, we found no predictors of TD.Analyzing cardiovascular (CV) risk scores, we observed a significant overall reduction in METS-IR over time, reaching statistical significance at week 144 (p=0.009). The reduction was more pronounced in PWH with a higher baseline score (B 0.17, p=0.035) and those with a longer time from HIV diagnosis (B -0.28, p=0.047) while it was less pronounced in PWH with a longer exposure to ARV treatment (B 0.40, p=0.020), after adjusting for age and sex at birth.SCORE-2 trends were overall stable over time. A statistically significant increase was observed among women at week 144 (p=0.009); however, the absolute change was small and of uncertain clinical relevance, particularly in light of the limited female sample size.In subgroup analyses, previous exposure to TAF was associated with significant reduction in SCORE-2 at week 144 (p=0.024) and in METS-IR at both week 48 (p=0.034) and 144 (p=0.012), whereas no significant changes were observed among those without prior TAF exposure. These metabolic improvements occurred without significant changes in Body Mass Index. Consistently, we observed significant improvements in total cholesterol, triglycerides, and LDL cholesterol at week 48 and 144 (p<0.001 for all).Conclusions In this large real-world cohort, DOR/3TC/TDF showed high durability and was associated with significant improvements in lipid profile and insulin resistance without weight gain. Cardiovascular risk remained overall stable, with evidence of metabolic benefit among individuals switching from TAF. These findings support the long-term metabolic safety of this regimen in clinical practice.Abstract OC69 Table 1Population charateristics at baseline