HIV breakthrough infection after 6 years of daily TDF/FTC oral PrEP with objectively documented optimal adherence.

Oral Pre-Exposure Prophylaxis (PrEP) is highly effective for HIV prevention when adherence is optimal, with rare HIV breakthrough infections usually happening within 1-2 years since PrEP start. After 6 years of daily PrEP, routine HIV testing identified seroconversion in a 46-year-old Italian cisgender man. He reported high adherence, confirmed by pharmacy refill history and plasma tenofovir concentration. Genotypic resistance test identified a recombinant HIV-1 strain with M184V and K70E reverse transcriptase mutations. Immediate antiretroviral therapy with FTC/TAF/DRV/c+DTG was initiated, achieving rapid viral suppression. A hair sample was sent for therapeutic drug monitoring and results were consistent with correct daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) before the acquisition of HIV infection. This case represents a rare 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, underlying the importance of periodic HIV surveillance.