Editorial: Immune Checkpoint Inhibitors and HBV Reactivation in Liver Cancer—Reassurance With Vigilance

The introduction of immune checkpoint inhibitors (ICIs) has dramatically transformed the treatment landscape for advanced hepatocellular carcinoma (HCC). These agents have superseded tyrosine kinase inhibitors (TKIs) as the sole standard of treatment, leading to notable improvements in patient survival. However, their use raised concerns about treatment-related adverse events, particularly HBV reactivation (HBVr), a critical issue in endemic regions. While TKIs have been associated with a moderate risk of HBVr in HCC patients [1, 2], the risk profile of ICIs remains debated. Recent studies reported HBVr rates of up to 7% in HBsAg-positive patients and < 0.1% in HBsAg-negative/anti-HBc–positive patients not receiving nucleos(t)ide analogue (NUC) prophylaxis [3, 4]. In this context, Yiu et al. conducted a territory-wide retrospective cohort study in Hong Kong, comparing HBVr risk between ICI- and TKI-treated patients with current or past HBV infection [5]. The 12-month cumulative incidence of HBVr was low and comparable between ICI (1.6%) and TKI (1.7%) groups. A higher risk was noted in patients with past HBV infection and in those with prior TACE, while NUC prophylaxis significantly reduced reactivation events. These findings indicate that the incorporation of ICIs does not intrinsically increase the risk of viral reactivation beyond that seen with TKIs, particularly when NUC prophylaxis is in place. Despite these important insights, several uncertainties remain. More than 93% of patients received NUC prophylaxis, limiting the assessment of those without antiviral coverage, especially in the ICI subgroup. Additionally, about one-third of patients had concurrent cancers, suggesting metastatic liver cancer. In such patients, prior or concomitant chemotherapy (present in 35% of patients) may confound HBVr risk. Immune-related adverse events (irAEs), particularly immune-mediated hepatitis, are also common in ICI-treated HCC [6]. Corticosteroids, used in approximately 25% of patients possibly for the management of irAEs, may also influence the risk of HBVr and warrant closer study. Beyond reactivation risk, ICIs may also exert favourable effects on HBV immunity. Emerging evidence suggests they can enhance HBV-specific immune responses [7], and recent studies have reported higher rates of HBsAg seroclearance in cancer patients receiving ICIs compared with TKIs [8]. These findings raise the intriguing possibility that ICIs could contribute to functional cure strategies, highlighting a complex interplay between immune activation and viral dynamics. The role of NUC prophylaxis in ICI-treated HCC remains a key question in clinical practice. Current APASL and AGA guidelines classify ICIs as moderate to high risk for HBVr, while EASL guidelines categorise them as low risk in HBsAg-positive patients [4, 9, 10]. In practice, distinguishing HBVr from immune-mediated hepatitis is challenging, particularly in the absence of prophylaxis. Accordingly, NUC prophylaxis is generally recommended for HBsAg-positive individuals. In contrast, these guidelines classify ICIs as low risk in HBsAg-negative/anti-HBc–positive patients, suggesting that routine prophylaxis may not be necessary. However, the findings of Yiu et al. indicate that this subgroup is not risk-free, emphasising the need for vigilant monitoring and further prospective evaluation. In summary, ICIs appear safe in HBV-infected HCC patients under antiviral prophylaxis, but careful monitoring remains essential. The evolving evidence underscores both the reassurance and the caution needed when integrating immunotherapy into HBV-endemic settings. Romeo Kuo-Cheng Wu: writing – original draft. I-Cheng Lee: conceptualization, writing – review and editing. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. I.-C.L. has received honoraria from Gilead Sciences, Bristol-Meyers Squibb, GlaxoSmithKline, Abbvie, Merck Sharp & Dohme, Bayer, Eisai, Ipsen and Roche and has served in an advisory role for Gilead Sciences. R.K.-C.W. declares no conflicts of interest. This article is linked to Yiu et al papers. To view these articles, visit https://doi.org/10.1111/apt.70367 and https://doi.org/10.1111/apt.70408. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.