The plasma and intracellular exposure of intramuscularly administered long-acting cabotegravir and rilpivirine in people with HIV

Objectives: Long-acting (LA) intramuscular cabotegravir (CAB) and rilpivirine (RPV) represent a novel antiretroviral therapy (ART) option for people with HIV (PWH), offering improved adherence and patient convenience. The aim was to evaluate plasma and intracellular (IC) exposure of CAB and RPV in PWH switching from oral ART to LA injectable regimens and to assess correlations with virological outcomes and clinical parameters. Methods: This is a monocentric prospective observational cohort study. We enrolled 177 PWH who switched to CAB/RPV intramuscular injections every 8 weeks without oral lead-in. Plasma and IC drug concentrations in peripheral blood mononuclear cells were measured at baseline and at every follow-up visit over 12 months. Virological suppression, immunological parameters and correlations with PK data were analysed. Results: At baseline, 93.6% of participants had undetectable viral load (<20 copies/mL). CAB and RPV plasma trough concentrations showed moderate intra-individual and high inter-individual variability, with RPV IC accumulation ∼ 5-fold higher than plasma, and CAB IC exposure about 15% of plasma levels. A transient decrease in plasma and IC concentrations was observed at month 3, without impact on virological suppression. Virological blips occurred in 15.3% of participants, with no significant association to drug concentrations. Two virological failures are reported with onset of NNRTI and INSTI major and accessory resistance mutation. Conclusions: LA CAB and RPV achieve plasma exposures consistent with clinical trials, maintaining virological suppression despite pharmacokinetic variability. Intracellular accumulation, especially of RPV, may contribute to sustained virological control. These findings support the use of LA CAB/RPV as a robust ART option in real-world clinical practice.