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Background Integrase strand transfer inhibitors (INSTIs) are now the standard backbone of first-line antiretroviral therapy (ART), but virological failure with development of resistance to second-generation INSTIs has been increasingly reported worldwide. Using real-world data from the Italian Antiviral Response Cohort Analysis (ARCA) database, we described virologic failure (VF) and resistance patterns among treatment-naïve people with HIV (PWH) starting an INSTI-containing regimen.Methods We included treatment-naïve PWH in ARCA who started first-line INSTI-based ART (BIC/TAF/FTC, DTG/TAF/FTC, DTG/TDF/FTC, DTG/3TC and DTG/ABC/3TC), with a zenith HIV-1 RNA ≥200 copies/mL. Participants contributed follow-up time while they remained on an INSTI-containing regimen; observation ended when VF, defined as HIV-RNA >1000 cp/mL or two consecutive HIV- RNA > 50 cp/mL, occurred on INSTI. We described baseline characteristics and compared individuals who maintained virologic suppression with those who experienced VF. In those with a genotype available at VF, we assessed INSTI resistance.Results We analysed 1296 PWH (21.0% female; median age 44 years [IQR 34–53]; median zenith HIV-1 RNA 90,500 copies/mL [21,038–316,396]; median CD4 nadir 272 cells/µL [91–459]; 10.3% AIDS presenters) ( table 1). First regimens were BIC/FTC/TAF (31.5%), DTG/FTC/TDF (23.3%), DTG/ABC/3TC (27.5%), DTG/FTC/TAF (10.6%), and DTG/3TC (7.1%). VF occurred in 120/1296 (9.3%) after a median of 67 weeks (39–124), with a median HIV-1 RNA at VF of 4163 copies/mL (399–60,687). Compared with those who did not developed VF during the time of observation, those with VF were more frequently of Black ethnicity, more often reported injecting drug use, had higher zenith HIV-1 RNA, lower CD4 nadir (table 2). Genotypes at failure were available for 53/120 participants; among them, INSTI resistance mutations were detected in 3 (5.7%): one participant had G163R only, one had T66I only, and one had E97A plus E153F (table 3). Interestingly, these integrase mutations detected were consistent with Stanford HIVdb-like susceptible or low-level resistance categories to second-generation INSTIs.Discussion In this real-world ARCA cohort of ART-naïve PWH starting contemporary INSTI-based ART, VF was seen in about 10% of cases and INSTI resistance at failure was rare, in line with the high genetic barrier of second-generation INSTIs. As genotyping was not available for all VFs, we may have missed very uncommon resistance events; however, the few resistant cases suggest that most episodes were driven by other factors, mainly treatment interruptions or poor adherence. This is supported by the higher VF frequency in people who inject drugs and in Black participants, and by the longer time to suppression in those with more advanced disease and higher baseline viral load.Abstract SC11 Table 1–3