HBV reactivation and prognosis after systemic therapy in HCC with undetectable HBV DNA: a multicenter retrospective study

There is a lack of research on hepatitis B virus (HBV) reactivation and prognosis in hepatocellular carcinoma (HCC) patients with undetectable HBV DNA after systemic therapy. This study aims to compare HBV reactivation (HBVr) and prognosis between patients treated with tyrosine kinase inhibitor (TKI) monotherapy and those receiving TKI combined with programmed cell death protein‑1 (PD-1) inhibitors. The retrospective study comprised 877 advanced HCC patients from two medical centers with undetectable HBV DNA, receiving TKI monotherapy (n = 419) or TKI plus PD-1 inhibitors (n = 458). HBVr rates, tumor progression, and overall survival (OS) were analyzed. The HBVr rate markedly higher in the combination cohort compared to the TKI monotherapy cohort (16.6% vs. 12.5%, P = 0.018). Multivariable regression analysis identified the combination therapy (HR 1.295, 95%CI 1.010-1.662, P = 0.042), ALT > 40 U/ml (HR 1.460, 95%CI 1.079-1.978, P = 0.014), Hepatitis B e antigen (HBeAg) positivity (HR 1.570, 95%CI 1.133-2.174, P = 0.007), and tumor size > 5 cm (HR 1.394, 95%CI 1.051-1.848, P = 0.021) as independent predictors of HBVr. Patients receiving antiviral prophylaxis had a lower HBVr rate than those not receiving it (27.4% vs. 33.7%, P = 0.013). Patients with HBVr had shorter progression-free survival (PFS) (P < 0.001) and OS (P < 0.001) compared to those without HBVr. TKI plus PD-1 inhibitors increases the risk of HBVr compared to TKI monotherapy, leading to higher tumor progression and shorter OS. Continuous antiviral therapy can help prevent HBVr after systemic treatment in HCC patients.