Progression to cirrhosis in chronic hepatitis D with mild-to-moderate fibrosis: Insights from a multicenter European cohort

Background & Aims: Hepatitis delta virus (HDV) is the most aggressive form of chronic viral hepatitis. As new therapies emerge, a clearer understanding of its natural history – particularly in early disease stages – is needed. We assessed real-world outcomes of HDV-infected patients with mild-to-moderate fibrosis and identified predictors of progression to cirrhosis. Methods: We performed a multicenter, international, retrospective study including adult patients with active HDV infection (HDV-RNA positive) and no advanced fibrosis at baseline, confirmed by histology or liver stiffness measurement (TE-LSM) within the first year of diagnosis. Demographic, clinical, biochemical, and virological variables were collected at baseline and annually thereafter. The primary outcome was development of cirrhosis; secondary outcomes included liver-related events and longitudinal changes in fibrosis markers. Results: The cohort included 168 patients (median age 37.5 [31–45] years; 53% male; 56% Caucasian). Fewer than 15% had HIV/HCV coinfection or metabolic/alcohol-related risk factors. At baseline, 36% had ALT ≥2 × the upper limit of normal and median TE-LSM was 7.6 (6–9) kPa. Over a median follow-up of 62 (40–94) months, 37 patients (22%) developed cirrhosis. Two developed ascites (one required liver transplantation), and one developed hepatocellular carcinoma and died. HDV clearance occurred in 32 patients (19%), either spontaneously (n = 14) or after antiviral therapy (n = 18). In the multivariate analysis, only TE-LSM ≥7 kPa independently predicted progression (HR 6.02 [1.76–20.6]; p = 0.004). FIB-4 ≥1.45 also identified higher-risk patients when TE-LSM was unavailable (HR 3.51 [1.68–7.34]; p <0.01). Neither antiviral therapy nor changes on HDV RNA or ALT overtime remained as independent predictors. Conclusions: Despite mild-to-moderate baseline fibrosis, over 20% of patients progressed to cirrhosis within 5 years. Baseline non-invasive markers effectively stratify risk and may inform prioritization of emerging HDV therapies. Impact and implications: Patients with HDV and mild-to-moderate fibrosis remain at substantial risk of progression, with more than 20% developing cirrhosis during a median follow-up of 5 years. Liver stiffness measured by transient elastography (TE-LSM) was the strongest predictor of progression. FIB-4 may have a prognostic value when TE-LSM is not available, whereas ALT levels and HDV-RNA, both at baseline and during follow-up, did not influence fibrosis outcomes. These findings support improved early risk stratification and may help clinicians identify which patients with apparently early-stage disease warrant closer monitoring or timely treatment intervention.