Hepatitis delta in Spain: a nationwide prospective characterization of active infection and liver disease severity

OBJECTIVES: Hepatitis delta virus (HDV) infection is associated with rapid progression to cirrhosis and liver-related complications. We aimed to characterize the clinical and virological profile of anti-HDV-positive individuals in Spain and identify factors associated with active infection and advanced fibrosis. METHODS: This nationwide, multicentre, prospective observational study included adults with positive anti-HDV serology enrolled between April 2024 and March 2026 across 72 hospitals in 15 Spanish Autonomous Communities. Demographic, virological, laboratory, and clinical data were collected in a centralized database. Multivariable logistic regression was used to identify factors independently associated with active HDV infection and advanced liver fibrosis. RESULTS: Among 1112 anti-HDV-positive individuals, 670 (60%) were male, median age was 54 years (IQR, 43-61 years), and 457 of 926 (49%) were born in Spain. HIV coinfection and anti-hepatitis C virus (HCV) positivity were present in 189 of 944 (20%) and 217 of 1112 (21%) individuals, respectively. HDV-RNA was detectable in 436 of 1047 patients (42%), with a median viral load of 4.1 (IQR, 2.9-5.1) log IU/mL. Genotype 1 accounted for 108 of 121 (89%) genotyped infections. Advanced fibrosis was present in 222 of 536 (41%) evaluable patients and was more frequent in those with active infection than in nonviremic individuals (155 of 261, 59% vs. 59 of 256, 23%; p <0.001). Active HDV infection was independently associated with younger age, hepatitis B virus antiviral therapy, lower platelet count, and lower albumin levels, whereas African origin was associated with lower odds of detectable HDV-RNA. Advanced fibrosis was independently associated with active HDV infection, hepatitis B virus antiviral therapy, and higher gamma-glutamyltransferase levels, whereas higher platelet count and haemoglobin levels were associated with lower odds of advanced fibrosis. CONCLUSIONS: Active HDV infection and advanced liver disease remain common in Spain. These findings support systematic HDV-RNA testing, standardized fibrosis assessment, and close clinical follow-up of anti-HDV-positive individuals.