Editorial: Predicting Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients With Metabolic Dysfunction—Do Existing Scores Clear the Bar? Authors' Reply

We thank Dr. Con for his editorial on our recent publication, in which we investigated risk factors for hepatocellular carcinoma (HCC) and adverse liver-related outcomes in patients with chronic hepatitis B (CHB) and concomitant metabolic dysfunction or metabolic dysfunction associated steatotic liver disease (MASLD) [1]. We also evaluated the applicability of the PAGE-B score in this population. Patients affected by both conditions carry an excess risk of adverse outcomes; therefore, effective risk stratification is of major clinical importance [2]. In our multicenter cohort, we identified older age, lower platelet count, lower albumin and cirrhosis as key risk factors for HCC development. Importantly, PAGE-B effectively stratified HCC risk in CHB patients with concomitant metabolic dysfunction and/or MASLD. Patients with low PAGE-B scores without cirrhosis had a negligible risk of HCC and may not require HCC surveillance. Conversely, in patients with cirrhosis, a residual risk persisted even at low PAGE-B scores, indicating a need for continued surveillance in this subgroup. In our population of patients with metabolic dysfunction, the presence of steatotic liver disease (SLD) was not associated with an increased risk of adverse outcomes. This is consistent with data showing that metabolic dysfunction was associated with more severe histological lesions in antiviral-treated CHB, whereas steatosis was not. Our findings also align with results from another study, which showed a higher risk of developing advanced fibrosis in patients with metabolic comorbidities but showed no additional risk in subjects with concomitant SLD [3]. These findings suggest that the elevated risk of HCC in CHB patients with MASLD is primarily attributable to underlying metabolic dysfunction and its effects on hepatocarcinogenesis and does not require steatosis or steatohepatitis. Given the high risk of adverse liver-related outcomes in patients with CHB and metabolic dysfunction, risk stratification is of major clinical importance [4, 5]. Recent studies have shown that simple risk scores such as PAGE-B stratify the risk of adverse outcomes in patients with HBV monoinfection and in CHB patients with hepatitis delta or HIV co-infection, and we therefore applied this score in our cohort [6-9]. As noted in the editorial, receiver operating characteristic (ROC) analysis was not performed in our study, since our primary aim was not to study the overall discriminative performance of PAGE-B, but rather to assess whether low PAGE-B scores could be used to identify patients in whom HCC surveillance could be safely deferred due to a low predicted risk of HCC. In this cohort, we observed a very low 5-year cumulative incidence of HCC (0.6%) in non-cirrhotic patients with a low PAGE-B score, suggesting that these patients do not require HCC surveillance. Conversely, a small but non-negligible risk of HCC was observed in those with cirrhosis, suggesting a need for further risk stratification in this population. In conclusion, we hope that our study helps individualise management of the increasingly large group of CHB patients co-affected by metabolic dysfunction and/or MASLD. However, additional studies are needed to improve prediction of outcomes, particularly for patients with cirrhosis and for patients without cirrhosis yet with intermediate or high PAGE-B scores. The authors' declarations of personal and financial interests are unchanged from those in the original article [2]. Lesley A. Patmore: conceptualization, writing – original draft. Milan J. Sonneveld: writing – review and editing, supervision. L.A.P.: Received research support and consultancy fee from Gilead Sciences. M.J.S.: Research support and consultancy from Roche, Gilead, Albireo/Ipsen, Fujirebio. This article is linked to Patmore et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70360 and https://doi.org/10.1111/apt.70371. The authors have nothing to report.