Rilpivirine Activates STAT1 in Non-Parenchymal Cells to Regulate Liver Injury in People Living with HIV and MASLD.

Liver fibrosis is a key determinant of the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Its increasing prevalence and a lack of effective treatments make it a major health problem worldwide, particularly in people living with HIV, among whom the prevalence of advanced fibrosis is higher. We have published preclinical data showing that Rilpivirine (RPV), a widely used anti-HIV drug, selectively triggers hepatic stellate cell (HSC) inactivation and apoptosis through signal transducer and activator of transcription (STAT)1-mediated pathways, effects that clearly attenuate liver fibrosis and promote regeneration. We performed a retrospective, cross-sectional study of RPV-induced effects on steatosis, inflammation, and fibrosis in liver biopsies from well-controlled HIV-infected subjects diagnosed with MASLD. Patients on RPV exhibited similar levels of HIV-related parameters to those not receiving this drug, while showing a tendency toward improved liver function and lipid profile, as well as an enhanced activation of STAT1 in hepatic non-parenchymal cells in those with identified liver injury. This protective effect, promoting STAT1-dependent HSC inactivation, was observed at different stages of MASLD. Our results suggest that RPV-based therapy is especially indicated in HIV-infected patients with MASLD-derived liver injury and highlight the potential of RPV as a new therapeutic strategy for liver diseases.