The Medical Impact of Hepatitis D Virus Infection in Natives and Immigrants: The Italian Paradigm

Abstract

Background and aim: Ongoing migratory flows are reconstituting the hepatitis D virus (HDV) reservoir in Italy. We aimed to characterise the current clinical and virologic features of HDV infection in both native Italians and migrants.

Methods: We enrolled 515 hepatitis B surface antigen (HBsAg)-positive patients with detectable anti-HDV antibodies from 32 Italian centres between August 2022 and July 2024; all patients underwent centralised virologic assessment.

Results: Overall, 432 out of 515 (83.9%) patients were HDV-RNA-positive (4.39, 1.30-5.82 Log IU/mL; 99.0% HDV genotype-1). HDV-RNA levels correlated with ALT (r_s = 0575, 0.514-0.630) and hepatitis B core-related antigen (r_s = 0.521, 0.455-0.581). Native Italians (n = 317; 61.6%) were older than migrants (n = 198; 38.4%) (median age: 60, 55-65 vs. 46, 39-54 years; p < 0.001) and were more frequently male (68.1% vs. 49.5%; p < 0.001), with a higher prevalence of liver cirrhosis (70.3% vs. 50.5%; p < 0.001) and hepatocellular carcinoma (14.8% vs. 0.5%; p < 0.001). Among Italians, 223 (70.3%) had liver cirrhosis, 46 (14.5%) had chronic hepatitis D (CHD) without cirrhosis and 48 (15.1%) exhibited inactive/minimal disease with low viremia (≤ 3 Log IU/mL). Among migrants, 100 (50.5%) had liver cirrhosis, 58 (29.3%) had CHD and 40 (20.2%) showed inactive/minimal disease with low viremia (≤ 3 Log IU/mL).

Conclusions: The current clinical landscape of chronic HDV infections in Italy is heterogeneous, changing the perspective of CHD as uniformly severe; although cirrhosis remains common, a substantial proportion of both native Italians and migrants present with milder forms of disease.

Keywords: HDV; HDV‐RNA; chronic hepatitis D; cirrhosis; epidemiology.

FIGURE 1

Patients' distribution according to Italian province of residence.

FIGURE 2

HDV‐RNA and ALT levels among Italians (A) and migrants (B) by cirrhosis status. Solid black lines indicate median ALT values across HDV‐RNA level classes. A distinct proportion of patients in both groups were either non‐viremic or had borderline viremia (< 1.5 Log IU/mL) with normal ALT. A minority exhibited marginal viremia (between 1.5 and 2.5 Log IU/mL), accompanied by normal ALT in Italians or mildly elevated ALT in migrants. Among patients with HDV‐RNA > 3 Log IU/mL, viremia increased in parallel with ALT levels. ALT, alanine aminotransferase; n, number.

FIGURE 3

Clinical phenotypes of patients according to HDV‐RNA patterns and the presence of liver cirrhosis. Patients with inactive/minimal disease were defined by the absence of liver cirrhosis and HDV‐RNA ≤ 3.00 Log IU/mL. Abbreviations: CHD, chronic hepatitis D; HDV, hepatitis D virus; n, number.

FIGURE 4

Phylogenetic analysis of HDV sequences. Phylogenetic tree of 446 HDV nucleotide sequences, including 55 reference sequences (indicated by coloured dots). HDV‐1 subgenotypes are highlighted in shades of blue, whereas sequences shown in black (n = 24) represent borderline cases for which subgenotype assignment was not possible. Taxa highlighted in orange correspond to HDV‐2, red to HDV‐3, purple to HDV‐4, green to HDV‐5, brown to HDV‐6, yellow to HDV‐7 and sage to HDV‐8. The evolutionary history was inferred using the Neighbour‐Joining method, and all evolutionary analyses were performed in MEGA11.