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Background Oral PrEP is highly effective for HIV prevention when adherence is optimal. True PrEP failures—HIV acquisition despite documented adequate drug exposure—are rare, and reported cases have typically occurred within the first 1–2 years of PrEP use. We report a late-breaking case of breakthrough HIV infection occurring after prolonged daily PrEP use, representing the longest duration before failure reported to date.Methods Clinical, behavioural, virologic, and pharmacologic data were collected from a 46-year-old MSM receiving daily TDF/FTC since 2019 through a community-based PrEP program in Milan, Italy. Adherence was assessed by self-report, pharmacy dispensing records, plasma and hair tenofovir therapeutic drug monitoring (TDM). HIV diagnosis, resistance testing, and treatment outcomes were reviewed.Results After approximately six years of daily PrEP, routine quarterly HIV testing identified seroconversion in October 2025. The patient reported high adherence (29/30 doses in the prior month), confirmed by pharmacy refill history and plasma tenofovir concentration (75 ng/mL within 24 hours of last dose), consistent with optimal recent adherence. Fourth-generation HIV Ag/Ab testing and Western blot were fully positive, with HIV-1 RNA 29,500 copies/mL and CD4 count 1,165 cells/mm 3, making acute infection unlikely. GRT identified a recombinant HIV-1 strain (CRF24_BG) with M184V and K70E reverse transcriptase mutations, conferring high-level resistance to emtricitabine and low-level resistance to tenofovir. It was not possible to determine whether these resistance-associated mutations were transmitted at acquisition or selected during infection under drug pressure. Immediate antiretroviral therapy with FTC/TAF/DRV/c+DTG was initiated, achieving viral suppression (36 copies/mL) within one month. After that, the patient requested switching to long-acting regimen and he was started on CAB/RPV LA, with very good tolerability and maintaining viral suppression.A hair sample was sent to the University of California in San Francisco (US) for TDM monitoring before cART start. Results came back in February 2026 and were consistent with correct daily TDF/FTC before the acquisition of HIV infection during PrEP (figure 1 and figure 2): in particular, tenofovir concentration remained >0.038 ng/mg in every hair segment, which is the median tenofovir hair concentration after 7 doses/week for 6 weeks.Conclusions This case represents a rare, well-documented true PrEP failure after the longest reported duration of daily TDF/FTC PrEP with confirmed optimal adherence. It highlights that breakthrough HIV infection can occur even after many years of successful PrEP use. Ongoing HIV surveillance and access to alternative strategies remain critical for long-term sustainability. Abstract CC6 Figure 1–2