Baseline HDV-RNA Levels Could Stratify Clinical Risk Before, But Not After, Cirrhosis in Chronic Hepatitis D: A Multicentre European Study

Background and Aims: Chronic hepatitis D (CHD) is associated with rapid progression to liver cirrhosis. However, the prognostic relevance of quantitative serum HDV-RNA remains incompletely defined. We aimed to evaluate whether baseline HDV-RNA levels are associated with the risk of liver-related events in untreated patients with CHD and to validate these findings in two independent European cohorts. Methods: We conducted a multicentre retrospective-prospective cohort study including 260 untreated adults with CHD and detectable HDV-RNA. Patients were derived from a Spanish derivation cohort (n = 98) and two Italian validation cohorts (n = 100 and n = 62). Baseline serum qHDV-RNA was categorized in 1-log increments starting from 6 IU/mL. Results: During a median follow-up of 4.1 years, 74 patients (28%) experienced at least one liver-related event, with a significantly higher incidence in patients with cirrhosis than in those without cirrhosis (p < 0.001). Among noncirrhotic patients, increasing baseline HDV-RNA levels were consistently associated with a higher proportion of liver-related events across derivation and validation cohorts, whereas no events occurred at the lowest HDV-RNA category. In contrast, among patients with established cirrhosis, baseline HDV-RNA levels were not associated with the occurrence of liver-related events, and cumulative incidence was comparable across viral load categories. Conclusions: Baseline quantitative HDV-RNA allows early risk stratification in untreated patients with chronic hepatitis D before the development of liver cirrhosis. Once cirrhosis is established, clinical outcomes are largely independent of viral replication, emphasising the need to prioritise timely antiviral intervention and close surveillance at earlier disease stages.