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Background Clinical trials and observational studies have demonstrated the efficacy of CAB/RPV long-acting (LA) regimen, and some risk factors have been proposed as predictors of virological failure (VF); however, additional data are required to better characterize this outcome.Material and Methods We enrolled a cohort of virologically suppressed (VS), HBsAg - PWH starting CAB/RPV LA. We excluded PWH with HIV subtypes A1/A6, BMI >30 kg/m 2, presence of major RPV resistance mutations, or a history of prior VF on NNRTIs. We evaluated incidence of VF (defined as 2 consecutive HIV-RNA >50 cp/mL or a single HIV-RNA >1000 cp/mL), treatment discontinuations (TD), and time to VF and TD estimated by Kaplan–Meier curves. Predictors of VF and TD were evaluated using Cox regression. Genotypic resistance testing (GRT) results at VF were collected when available.Results Of 478 PWH who started CAB/RPV LA across 8 Clinical centers, 419 met inclusion criteria; exclusions were due to BMI >30 kg/m 2 (n=29), prior VF on NNRTIs (n=18), presence of major RPV mutation (n=6), and A1/A6 HIV subtype (n=7). Baseline characteristics are shown in table 1.During 692 PYFU (median FU 1.9 years), 5 VFs occurred (incidence 0.72 per 100 PYFU). The probability of maintaining VS was 99.1% (±0.5%) at 48 wks and 98.1% (±0.9%) at 144 wks. Cox regression identified no significant predictors of VF. GRT at VF was available for 3 PWH and revealed resistance mutations: 1 participant experienced VF at 19 months after switching from RPV/DTG, developing E138A, M230L, and Q148R; a second, switching from TAF/FTC/RPV, had VF after 12 months with a newly detected Q148K (not present on prior GRT). A third experienced VF after 4 months with K103N, E138K, and Q148R; this latter case received the second injectable dose after 8 wks and had no prior GRT available. Two PWH with a determination of HIV-RNA >1000 cps/mL during FU continued CAB/RPV LA, with subsequent undetectability; one of them, had a HIV-RNA 1021 cps/mL after 24 months, 2 wks after HPV vaccination.With respect to durability, 56 PWH discontinued CAB/RPV: the main causes of TD were injection-site reactions (ISR) (n=21, 4.9%), regimen intensification (n=10, 2.3%), neurological toxicity (n=7, 1.6%), and patient request (n=5, 1.2%). One participant occurred in HBV acute infection (previous HBsAg and HbcAb negative). 50% of TDs occurred within the first 6 months of FU.In a sensitivity analysis, which included 138 PWH with known baseline BMI and HIV subtype, we found no VF.Conclusions These real-world data confirm the high efficacy and tolerability of CAB/RPV LA, supporting their role in individualized antiretroviral care. Although rarely, VF associated with emergence of resistance mutations did occur, including in patients switching from RPV-containing regimens. Larger studies with longer follow-up are needed to identify factors associated with VF and resistance emergence beyond the ones which are already known.Abstract SC21 Table 1Population characteristics at baseline