BARRIERS AND LIMITATIONS IN ANTIVIRAL THERAPY FOR HEPATITIS C

Abstract

Over the past three decades, the management of hepatitis C virus (HCV) infection has undergone a remarkable transformation, progressing from interferon (IFN)-based regimens with limited efficacy to highly effective pan-genotypic direct-acting antivirals (DAAs). In the early 1990s, alpha-interferon monotherapy represented the standard of care; however, sustained virological response (SVR) rates were low, and treatment was frequently complicated by significant adverse effects, restricting its clinical utility. The subsequent introduction of pegylated interferon (peg-IFN) improved the pharmacokinetic profile of IFN, permitting less frequent dosing and modestly enhanced response rates. Combination therapy with ribavirin further increased SVR rates, particularly in non-genotype 1 infections, though it was associated with additional toxicities, including hemolytic anemia and neuropsychiatric disturbances.

The advent of first-generation DAAs, such as telaprevir and boceprevir, marked a pivotal advance. When administered in combination with peg-IFN and ribavirin, these protease inhibitors significantly improved outcomes in genotype 1 HCV infection. Nonetheless, their use was limited by high rates of adverse events and the emergence of drug resistance. The development of second-generation DAAs, exemplified by sofosbuvir and ledipasvir, enabled IFN-free regimens with superior efficacy and safety profiles. Most recently, pan-genotypic DAAs—including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir—have revolutionized therapy by achieving consistently high SVR rates across all genotypes, offering shorter treatment durations, and demonstrating excellent tolerability. These regimens now constitute the cornerstone of HCV management, providing a globally accessible and highly effective therapeutic solution.