Global distribution and temporal analysis of R70Q/H oncogenic mutations in hepatitis C virus subtype 1b core protein

The hepatitis C virus (HCV) core protein is crucial in viral pathogenesis and hepatocarcinogenesis. Amino acid substitutions at position 70, particularly R70Q and R70H, are associated with an increased risk of hepatocellular carcinoma (HCC) and partial resistance to interferon-based therapy in genotype 1b infections. However, the global and temporal dynamics of these oncogenic mutations remain poorly understood. In this study, we analyzed 3,218 publicly available HCV subtype 1b core sequences to investigate the global distribution of R70Q/H mutations and their evolution across therapeutic eras. Our findings reveal notable regional disparities, with R70Q prevalence highest in Western Europe (77.4%) and Northern America (70.4%), while R70H was most frequent in Central America (45%). Temporal analysis of 1,351 dated sequences showed a significant decline in R70Q/H frequency during the pegylated interferon plus ribavirin era (2001-2010: 24%) compared to the conventional interferon period (1989-2000: 39%; p = 0.0081), followed by a resurgence in the direct-acting antivirals (DAAs) era (2014-present: 43%; p = 0.0183). These temporal shifts, including both the decline and resurgence, suggest a complex interplay between treatment-related selective forces, viral diversity, host factors, and possibly sampling bias. Our results underscore the need for regional molecular surveillance to guide HCC monitoring in HCV subtype 1b patients with R70Q/H mutations, even after viral clearance, and to inform targeted prevention strategies in high-prevalence areas.