Cabotegravir: a novel HIV integrase inhibitor combined with rilpivirine as the first long-acting injectable program for the treatment of HIV infection

Cabotegravir, a novel HIV integrase inhibitor, shares structural similarity with dolutegravir and bictegravir. Its oral half-life is 32 hours, but cabotegravir nanosuspension for intramuscular injection yields half-lives ranging from 25to 54days, enabling extendedinterval dosing. Drug interactions are minimal, although oral doses require spacing from polyvalent cations, and potent uridine glucuronosyltransferase induction (e.g., rifampin, carbamazepine) requires avoidance due to anticipated subtherapeutic cabotegravir exposure through extended intervals. Randomized clinical trials combined cabotegravir treatment with rilpivirine to demonstrate treatment efficacy in patients living with HIV who had attained virologic suppression, lacked known/suspected mutations to either component, and had not experienced prior HIV treatment failure. Together, oral cabotegravir and rilpivirine maintained viral suppression in the LATTE study while the combination, given intramuscularly, performed comparably to conventional oral therapy in LATTE-2. FLAIR and ATLAS, respectively, demonstrated HIV suppression maintenance for monthly injections in treatment-naive participants and treatment-experienced patients, with ATLAS-2M supporting the efficacy of injections given every 2 months. Investigations to date show an excellent safety profile. Injectable cabotegravir causes short-lived, mild injection site reactions (primarily administration site pain/soreness) that decrease in frequency over time, produce attributable discontinuation rates ≤ 2%, and generate satisfaction scores that favor injectable therapy over oral therapy. Virologic failure with resistance development is rare, primarily occurs in the first year of therapy, and is associated with baseline proviral DNA mutations to coadministered rilpivirine. A key component of the first U.S. Food and Drug Administration (FDA)-approved injectable maintenance treatment program for HIV, injectable cabotegravir heralds a new era in HIV treatment innovation. Here we provide a detailed review of the clinical pharmacology, administration and available formulations of the novel HIV integrase inhibitor cabotegravir with in-depth analysis of the clinical trial data, safety, satisfaction and viral resistance development when combined with rilpivirine as the first long-acting injectable program for the treatment of HIV infection.