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Background and Importance Long-acting antiretroviral therapy represents a major advance in HIV management by improving adherence and reducing treatment burden. Long-acting intramuscular cabotegravir and rilpivirine provide an effective and safe alternative to daily oral regimens, promoting treatment continuity and enhancing the quality of life of people living with HIV (PLHIV).Aim and Objectives To analyse the persistence, adherence, and safety of long-acting intramuscular cabotegravir/rilpivirine (CAB/RPV) in PLHIV.Material and Methods This was a retrospective, multicentre, observational study conducted in three hospitals. All patients who initiated long-acting CAB/RPV between July 2023 and March 2025 and received at least three doses were included. Collected data included demographic characteristics, previous antiretroviral therapy (ART), viral load (VL) and CD4+ cell count (both at baseline and last visit), and concomitant non-ART medications. Persistence was defined as the time (months) from treatment initiation to discontinuation; reasons for discontinuation were also recorded. Safety was assessed by the occurrence of adverse events (AEs), and adherence was measured as the proportion of injections administered within the recommended dosing window. Data were extracted from outpatient management software and electronic medical records.Results Fifty-seven patients (17.5% women) were included, with a mean age of 53.1 ± 10 years. Prior to switching, 22 patients were on DTG/3TC, 13 on DTG/RPV, nine on RPV/FTC/TAF, eight on BIC/FTC/TAF, three on DRV/c, and two on RPV+ABC/3TC. All patients had VL < 50 copies/mL. Median CD4+ cell count at baseline and last visit was 756.5 (560–973) and 646.5 (532–853) cells/μL, respectively. Mean persistence was 9.6 ± 4 months. Reasons for discontinuation included virological failure (n=2; one developed resistance to RPV and one intermediate resistance to RPV and CAB), adverse reactions (n=5), loss to follow-up (n=2), and drug interaction with acenocoumarol (n=1). The most common AEs were local pain (61.4%), general malaise (12.3%), fever (2.5%), radiating pain (2.5%), vasovagal symptoms (1.7%), fatigue (1.7%), and headache (1.7%). A total of 322/325 (99%) injections were administered within the dosing window. No significant drug interactions were detected.Conclusion and Relevance Long-acting intramuscular CAB/RPV appears to be an effective and safe strategy for PLHIV. Despite high adherence, close monitoring for adverse events and early detection of virological failure are essential to optimise long-term persistence.Conflict of Interest No conflict of interest