Mechanisms and Therapeutic Strategies for HCV/HBV-Associated B-Cell Non-Hodgkin’s Lymphomas: A Viewpoint

Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are increasingly recognized as significant etiological factors in the pathogenesis of B-cell non-Hodgkin's lymphomas (B-NHLs). Epidemiological and molecular studies have demonstrated a consistent association between chronic viral infection and B-NHLs. Multiple pathogenic mechanisms have been implicated in lymphomagenesis, both direct and indirect, including chronic antigenic stimulation, direct infection of B cells, and viral protein-mediated oncogenic signaling, It is likely that a combination of several pathogenic conditions is required to eventually lead to the development of lymphoma. The prevalence of B-cell lymphomas among individuals with chronic HCV or HBV infection presents a complex pathogenetic scenario, given the tumor heterogeneity and variable clinical behavior, and poses therapeutic challenges, due to the partial efficacy of current treatment options. The advent of direct-acting antivirals (DAAs) for HCV and high-genetic barrier nucleos(t)ide analogues (NAs) for HBV has improved patient outcomes. In indolent HCV-associated B-NHLs, antiviral therapy with DAAs alone often achieves sustained virologic response and may lead to lymphoma regression. Conversely, aggressive subtypes like diffuse large B-cell lymphomas require combination treatment with immunochemotherapy. In the setting of HBV-associated lymphomas, antiviral prophylaxis with potent NAs (e.g., entecavir or tenofovir) is essential to prevent HBV reactivation during rituximab-containing chemotherapy regimen. The integration of antiviral and anticancer therapies has been shown to enhance survival outcomes while mitigating hepatic toxicity. A comprehensive understanding of the biological interplay between chronic viral infection and B-cell transformation is critical for optimizing diagnostic and therapeutic strategies. Aim of this viewpoint is to provide evidence that early viral detection and prompt management remain the most effective strategies to improve survival rates and to reduce treatment-related morbidity in these patients.