The interplay between hepatitis B virus and antitumor drugs in the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains a lethal global health burden, with chronic hepatitis B virus (HBV) infection constituting a primary etiological driver. Most patients present with advanced disease, where systemic pharmacotherapies-chemotherapy, molecularly targeted agents, and immunotherapies-form the cornerstone of treatment. Despite therapeutic advances, outcomes for HBV-positive advanced HCC patients remain suboptimal. Critically, certain chemotherapeutic agents directly promote HBV replication, precipitating viral reactivation that may cause treatment interruption, fulminant hepatitis, or hepatic decompensation. While targeted and immunotherapeutic agents paradoxically demonstrate antiviral properties, HBV reactivation occurs during these treatments through poorly characterized mechanisms. Furthermore, HBV actively confers resistance to chemotherapeutic and targeted therapies through multiple molecular pathways. This review synthesizes current evidence on the bidirectional interplay between HBV and antitumor pharmacotherapies, highlighting how viral reactivation and drug resistance collectively undermine treatment efficacy. Elucidating these complex interactions is imperative for developing novel strategies to overcome therapeutic refractoriness in HBV-associated HCC.