Direct-Acting Antivirals in Patients with Comorbidities for the Simplified Management of HCV Infection: An Expert Review with a Focus on Sofosbuvir–Velpatasvir

Introduction: Hepatitis C virus (HCV) infection often coexists with comorbidities, increasing vulnerability, complications, and adverse events. Direct-acting antivirals (DAAs) have dramatically improved HCV management, but they differ in drug–drug interaction (DDI) profiles. Sofosbuvir/velpatasvir (SOF/VEL) is associated with minimal clinically relevant interactions. Areas covered: A narrative review of the literature was conducted by searching PubMed and major international guidelines, focusing on studies published in the DAA era addressing HCV patients with major comorbidities, focusing on diabetes, metabolic syndrome, and cardiovascular disease; neuropsychiatric disorders; cancer; transplants; and use of substances or treatment with opioid agonists; and patients requiring hormone therapy including transgender patients. Expert opinion: Based on the literature and real-world data, managing polypharmacy in HCV patients with comorbidities is effective and well-tolerated, provided thorough drug review, potential DDI analysis, proactive monitoring, and coordinated multidisciplinary care are ensured. DAAs have dramatically improved the management of HCV patients; however, they have different DDI profiles that should be carefully checked. SOF/VEL has been shown to be associated with minimal clinically relevant interactions and offers a simple dosing regimen. DAA treatment is strongly advised in HCV comorbid patients not only to cure HCV but also to improve the course of comorbidities, provided that DDIs are no longer considered mere minor details.