Editorial: Immune Checkpoint Inhibitors and HBV Reactivation in Liver Cancer—Reassurance With Vigilance. Authors' Reply

Stephen Chan reports receiving advisory board fees from AstraZeneca, Eisai, and MSD; reports being an invited speaker for AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, MSD, and Roche; and reports research funding (personal) from Bayer, Eisai, Ipsen, MSD, and Sirtex. The authors' declarations of personal and financial interests are unchanged from those in the original article [1]. We thank Wu and Lee for their insightful comments [2] on our study evaluating the risk of hepatitis B virus (HBV) reactivation (HBVr) in 1596 patients with liver cancer and current or past HBV infection treated with immune checkpoint inhibitors (ICIs) or tyrosine kinase inhibitors (TKIs) [1]. Our analysis showed a 12-month cumulative incidence of HBVr of 1.6% in ICI users, comparable to 1.7% in TKI users, all under high nucleos(t)ide analogue (NA) coverage of 93.2%. These findings support that ICIs do not inherently increase HBVr risk compared to TKIs when NA prophylaxis is provided. Previous meta-analyses, which are also represented in the AGA guideline, classify ICIs as posing a moderate-to-high risk of HBVr in HBsAg-positive patients, and a low risk in those with past infection [3-5]. Similarly, in our cohort, HBVr occurred in 1% (4/387) of ICI users with prophylaxis versus 20% (2/10) without NA prophylaxis. Although the small number of patients without prophylaxis limits definitive conclusions, this finding is consistent with previous studies and highlights the importance of NA prophylaxis in HBsAg-positive patients [4]. Although previous studies suggested a low risk of HBVr in patients with past infection, a subset of these individuals may remain susceptible. In our cohort, the 12-month cumulative incidence of HBVr was 9.2% in this group, compared with 0.6% among those with current infection [1]. This observation aligns with evidence that covalently closed circular DNA persists after HBsAg seroclearance and can serve as a reservoir for HBVr under immunosuppression. Although data on monitoring intervals were unavailable in our cohort, these results indicate the importance of close monitoring and the need for NA prophylaxis in selected hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (anti-HBc)-positive patients. Approximately one-third of our cohort had hepatocellular carcinoma (HCC) and concurrent cancers. While concurrent malignancy was not associated with HBVr, it correlated with higher mortality. Immune-related adverse events (irAEs) are common in ICI-treated HCC, and corticosteroids are often required for managing moderate to severe irAEs, raising concerns about HBVr and hepatitis flares [6, 7]. In our multivariable models, prior or concomitant corticosteroid, immunosuppressant, or chemotherapy use was not associated with increased HBVr or mortality among ICI users [1]. However, the high rate of NA prophylaxis may have mitigated the risk of HBVr. Emerging evidence suggests ICIs may enhance HBV-specific immunity and promote HBsAg seroclearance [8]. In contrast, our previous work reported a low (< 1%) HBsAg seroclearance rate in patients with chronic hepatitis B receiving immunotherapy [9]. Similarly, in this cohort, HBsAg seroclearance remained uncommon, occurring in 3.8% (3/80), 0% (0/61), and 0.9% (2/214) of users of atezolizumab/bevacizumab, nivolumab/ipilimumab, and pembrolizumab, respectively. These rates are lower than those reported elsewhere [8], yet this should be interpreted with caution due to the small numbers and relatively short follow-up [1]. This intriguing observation warrants further mechanistic and clinical investigation. Our findings suggested that ICIs can be safely integrated into HBV-endemic settings with NA prophylaxis. Unresolved questions remain regarding optimal management of HBsAg-negative/anti-HBc-positive patients and the long-term immunologic effects of ICIs. Future studies are needed to refine monitoring, risk stratification, and prophylaxis strategies. Terry Cheuk-Fung Yip: writing – original draft, conceptualization. Dorothy Cheuk-Yan Yiu: conceptualization, writing – original draft. Stephen Lam Chan: writing – review and editing, conceptualization. Terry Cheuk-Fung Yip has served as an advisory committee member and a speaker for Gilead Sciences. He received a research grant from Gilead Sciences. The other authors declare 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.70388. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.