Abstract
BACKGROUND: Considering the increased metastatic risk in hepatitis B surface antigen (HBsAg)-positive patients with nasopharyngeal carcinoma (NPC), we aimed to investigate the interactions among HBsAg, tumor burden indicators, and immune function in the accurate stratification of prognosis and treatment for this specific cohort. PATIENTS AND METHODS: We retrospectively analysed 1650 pathologically-confirmed patients with NPC from two centers and performed interaction and mediation analyses among HBsAg, plasma Epstein-Barr virus (EBV) DNA load, and absolute lymphocyte count (ALC), concerning distant metastasis. A 1:1 random matched-paired analysis was performed to evaluate survival according to risk and treatment stratification. Treatment-related adverse events were also compared. RESULTS: Overall, 17.3% (285/1650) of patients tested positive for HBsAg. Significant interactions occurred between HBsAg and low ALC (≤ 1.9×10(9)/L) (HL), as well as between HBsAg and high plasma EBV DNA load (> 4000 copies/mL) (HE), both independently predicting poor distant metastasis-free survival (DMFS). The influence of T and N staging on tumor metastasis was mediated by HL (+) and HE (+), respectively. Among patients with stage III-IVa NPC, interaction associations presented with a worse 5-year DMFS and higher rates of severe neutropenia and leukopenia among those treated with additional induction chemotherapy (IC) than among those treated with radiochemotherapy alone. CONCLUSIONS: Interactions exist between HBsAg positivity and high EBV/low ALC, mediating the effects of tumor staging and distant metastasis. The collective influence of viral infection, tumor burden, and reduced immune cells leads to worse DMFS in patients with HBsAg-positive NPC, requiring a tailored treatment beyond IC.