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Background and Importance HIV treatment optimisation requires balancing clinical efficacy, tolerability, and economic sustainability. With multiple antiretroviral therapy (ART) options available, cost-effectiveness analysis using real-world data is essential to inform healthcare decision making and resource allocation in HIV care.Aim and Objectives To evaluate the cost-effectiveness of different ART regimens using treatment durability as primary effectiveness measure, employing real-world data from MOSAICO: an Italian multicentre study on people with HIV (PWH) virus suppressed.Material and Methods Cost-effectiveness analysis of 421 PLWH from the MOSAICO study with 24-month follow-up. Treatment durability was measured using restricted mean survival time (RMST). Monthly drug costs were standardised across regimens. Incremental cost-effectiveness ratios (ICER) were calculated using DTG/3TC as cost-minimising comparator. Bootstrap methodology (10,000 iterations) provided 95% confidence intervals accounting for people-level variability. In addition, the percentage of switches that saw the patient move to a lower-cost therapy than the previous one was calculated. Only therapies with at least 20 PLWH were selected.Results PWH were receiving the following therapies at baseline: B/F/TAF (n=21), DTG/3TC (n=65),TAF/FTC/EVG/COBI (n=47), TAF/FTC/RPV (n=102), DRV/COBI/FTC/TAF (n=51),ABC/3TC/DTG (n=77), FTC/TAF+RAL (n=20), FTC/TAF+DTG (n=38). Eight ART regimens were analysed. Compared to DTG/3TC, TAF/FTC/RPV showed favourable cost-effectiveness with ICER of €876 (95% CI: 714-1,259) per additional month of treatment durability gained (+2.81 months durability, +€2,352 monthly cost). B/F/TAF resulted in ICER of €2,607 (95% CI: -14,677 to 17,557) per additional month (+1.12 months, +€2,694). Triple therapy regimens (ABC/3TC/DTG, DRV/COBI/FTC/TAF) demonstrated negative durability differences (-1.15 and -1.80 months respectively) with higher costs, indicating dominance by DTG/3TC. FTC/TAF-based combinations showed reduced durability with mixed cost implications. Among 188 switches observed, 112 patients (59.6%) switched to less expensive therapies, suggesting a trend towards economic optimisation.Conclusion and Relevance DTG/3TC represents the most cost-effective option among analysed regimens, providing superior treatment durability at lowest cost. TAF/FTC/RPV offers reasonable cost-effectiveness for patients requiring alternative dual therapy. Notably, 59.6% of treatment switches were toward more economical regimens, indicating natural optimisation toward cost-effective options in clinical practice. Results support dual therapy strategies with significant potential for healthcare cost savings while maintaining clinical effectiveness. Narrow confidence intervals for TAF/FTC/RPV indicate robust cost-effectiveness estimates, while wide intervals for other regimens reflect greater outcome uncertainty. These real-world findings inform evidence-based HIV treatment guidelines and budget planning decisions.Conflict of Interest No conflict of interest