Despite the achievement of sustained virologic response (SVR) with direct-acting antivirals (DAAs) in chronic hepatitis C (HCV), viral clearance does not eliminate the risk of hepatocellular carcinoma (HCC), as persistent metabolic dysfunction, including obesity, insulin resistance, and metabolic dysfunction-associated steatotic liver disease (MASLD), continues to drive fibrosis progression and hepatic carcinogenesis.¹ Prior studies have shown that patients with MASLD have a much higher cumulative five-year incidence of HCC (10.4%) compared to those without MASLD (3.5%).¹ At the AASLD Annual Meeting 2025, Dr. Eiichi Ogawa from Kyushu University Hospital, Japan, presented data highlighting MASLD as a major determinant of HCC risk following HCV cure, emphasizing the need for post-SVR risk stratification and long-term monitoring.¹

The retrospective multicenter cohort study aimed to provide a deeper understanding of how MASLD affects the risk of HCC development after achieving SVR.¹ It included adults aged 18 and older with chronic HCV who achieved SVR following oral DAA treatment.¹ Patients were excluded if they had treatment failure, decompensated cirrhosis, excessive alcohol intake, active or suspected HCC at baseline, prior history of HCC or liver transplantation, non-liver malignancies, coinfection with hepatitis B virus or human immunodeficiency virus (HIV), or inadequate medical records.¹ Ultimately, the study focused on 2,689 patients, with a median follow-up of 6.2 years.¹ MASLD was defined as steatotic liver disease with at least one associated cardiometabolic risk factor, assessed through imaging and clinical parameters.¹ Patients were categorized by fibrosis stage using Fibrosis-4 Index (FIB-4) scores.¹ The study evaluated outcomes including the development of HCC, factors linked to HCC incidence, and survival following SVR.¹

Among the cohort, 975 patients had MASLD, characterized by a higher body mass index, greater prevalence of diabetes, and a higher proportion of cirrhosis compared to those without MASLD (all p<0.001).¹ Across all fibrosis strata, patients with MASLD displayed a significantly higher cumulative incidence of HCC compared to those without MASLD.¹ Notably, no HCC cases were observed among patients with FIB-4 <1.45 during follow-up.¹

In patients with intermediate fibrosis (FIB-4 1.45-3.25), 5.1% of those with MASLD developed HCC, compared to 1.6% without MASLD.¹ The cumulative HCC incidence rate was significantly higher in patients with MASLD compared to their non-MASLD counterparts (log-rank p<0.001), with an annual incidence of 0.84% (95% CI: 0.53-1.30).¹ Among patients with advanced fibrosis (FIB-4 >3.25), the incidence of HCC was 16.0% in those with MASLD compared to 9.8% in patients without MASLD, with a significantly higher cumulative incidence rate in the MASLD group (log-rank p<0.001).¹ The annual HCC incidence was markedly higher in patients with MASLD, reaching 2.80% (95% CI: 2.19-3.56) compared to 1.62% (95% CI: 1.27-2.07) in those without MASLD.¹

Six years after achieving SVR, HCC occurred exclusively in patients with MASLD.¹ Multivariable analyses confirmed MASLD as an independent predictor of HCC development across fibrosis stages.¹ In patients with intermediate fibrosis, MASLD was associated with a more than threefold increased risk of HCC (adjusted HR=3.39; 95% CI: 1.59-7.23, p=0.002). In those with advanced fibrosis, the risk remained nearly doubled (adjusted HR=1.70; 95% CI: 1.19-2.43; p=0.004).¹ Importantly, these associations persisted even after propensity score matching, reinforcing the validity of the findings.¹ Other risk factors included older age, male sex, lower serum albumin levels, and higher alpha-fetoprotein levels.¹ Despite the increased incidence of HCC, there was no significant difference in overall survival between patients with and without MASLD, likely due to recent advancements in HCC treatment that have improved short-term survival outcomes.¹

In conclusion, this large multicenter study demonstrates that MASLD is a key driver of HCC risk, even after HCV cure through DAA treatment, and this risk is independent of fibrosis stage.¹ These findings highlight the need to incorporate MASLD into post-cure risk stratification and stress the importance of long-term surveillance for patients with MASLD.¹ Addressing metabolic dysfunction may be crucial for reducing the residual burden of HCC in the post-HCV eradication era.¹