For decades RAS mutations represented a chimera for drug developers, as all efforts put into attempting to pharmacologically inhibit them failed. Finally, in recent years, the advent of the KRAS G12C inhibitors sotorasib and adagrasib pushed the development of several new drugs; therefore, the landscape of RAS inhibitors evolved and now includes several compounds with different mechanisms of action. In this review we provide an updated summary of RAS inhibitor drugs, detailing their mechanism of action, pharmacokinetics and toxicity profile as well as efficacy studies.

Background/Objectives: People Living with HIV (PLWH) often have comorbidities require polypharmacy, increasing the risk of adverse events (AEs) associated with drug–drug/drug–supplement interactions (DDIs/DSIs). However, DDIs and DSIs, including those involving antiretrovirals (ARVs), and their related effects have not been exhaustively assessed. This study aimed to determine, in HIV patients on HAART who are taking multiple medications, the prevalence of DDIs and DSIs involving both ARVs and non-ARV co-medications, and their clinical relevance and consequences. Methods: In this longitudinal observational study, PLWH receiving HAART were consecutively enrolled at the University Hospital of Salerno and followed up during scheduled visits. Demographic, clinical, and pharmacological data were collected. DDIs/DSIs were identified using Drugs.com, Lexicomp, and the Liverpool HIV Interaction Checker. Interactions classified as major (Drugs.com), consider therapy modification or avoid combination (Lexicomp), and do not coadminister (Liverpool) were deemed highly clinically relevant. This assessment was supplemented with review of SmPCs and the available literature. Results: Among 84 PLWH, 229 interactions were identified, and 37/229 (16.2%) were highly clinically relevant. Eight patients (9.5%) experienced AEs predicted by the tools. Four were DDIs: cobicistat/alprazolam associated with sedation and dyspnoea, rilpivirine/hydroxychloroquine with QT prolongation, bictegravir/ursodeoxycholic acid with rising viremia, and atorvastatin/fenofibrate with myalgia. Four DSIs between bictegravir and supplements containing divalent ions have been associated with increasing viremia. After medication review, alprazolam was replaced with zolpidem, rilpivirine-based HAART with bictegravir/emtricitabine/tenofovir alafenamide, and atorvastatin/fenofibrate with simvastatin/ezetimibe, and ursodeoxycholic acid and supplements were discontinued. These interventions were temporally associated with clinical improvement of interaction-related AEs and good virological control. Conclusions: This study highlights the importance of predicting DDIs/DSIs in PLWH undergoing polypharmacy. Medication review supports clinical decision-making, preventing avoidable adverse outcomes.