JOURNAL OF BACTERIOLOGY AND VIROLOGY ISSN:1598-2467(Print) 2093-0429(Online)

Globally, an estimated 50 million individuals are chronically infected with the Hepatitis C virus (HCV), with approximately one million new infections occurring annually. According to the 2024 WHO report, 242,000 deaths from HCV-related liver diseases, including cirrhosis and hepatocellular carcinoma (HCC), were recorded in 2022. The virus demonstrates striking geographic heterogeneity in prevalence and possesses a complex and intriguing phylogenetic history. In line with the global hepatitis eradication strategy, the WHO has set ambitious targets of reducing new HCV infections by 90% and HCV-related mortality by 65% by 2030. Direct-acting antiviral (DAA) therapies, which target critical viral proteins and host-pathogen interactions, have revolutionized treatment by achieving sustained virologic response (SVR) rates exceeding 95%. Nevertheless, resistance-associated substitutions (RASs) and high cost of therapy remain significant barriers to universal access, particularly in low– and middle-income countries. These limitations underscore the urgent need for effective prophylactic vaccines that provide broad immunoprotection across the diverse HCV genotypes. This multidimensional review synthesizes current knowledge on the molecular and phylogenetic evolution of HCV, highlighting genotype-specific features that contribute to viral persistence and pathogenesis. Furthermore, it examines therapeutic advances, challenges in antiviral defense, and emerging candidate molecules for vaccine development. By integrating molecular insights with an evolutionary perspective, this review aims to provide a comprehensive framework for understanding HCV biology and suggesting future strategies towards global eradication.