Sex-based differences in hepatitis delta virus infection: Insights from the Italian PITER hepatitis delta virus cohort

BACKGROUND Hepatitis delta virus (HDV) infection is the most severe form of chronic viral hepatitis, yet sex-based clinical differences remain poorly defined. Understanding these differences may inform disease management and guide research. AIM To investigate sex-related differences in demographic and clinical characteristics of patients with chronic HDV infection in a nationwide, real-world Italian setting. METHODS We analyzed demographic, clinical, and virological data from 513 hepatitis B surface antigen/anti-HDV-positive patients, consecutively enrolled between 2019 and 2024, across 58 liver clinics in the Italian PITER HDV cohort. A propensity score-weighted logistic regression model evaluated the association between sex and cirrhosis and/or hepatocellular carcinoma. RESULTS Among 513 patients (61.6% male), median age (56.0 years) and age distribution were similar by sex (P = 0.41). Cirrhosis was frequent: 73.4% vs 66.0% (anti-HDV-positive) and 77.8% vs 74.2% (HDV RNA-positive) in males and females, respectively. HDV RNA levels were comparable (P = 0.93). The highest proportion of females with cirrhosis (33.8%) was in the 56-60-year group, similar to males (34.9%). Among patients with cirrhosis aged ≤ 40 years, females, (80.9% of whom of non-Italian origin), were more represented than males (16.1% vs 6.5% respectively, P < 0.05). Male sex was associated with cirrhosis (odds ratio = 1.85; 95% confidence interval: 1.004-3.40). Among HDV RNA-positive patients, males more often had hepatocellular carcinoma, elevated gamma-glutamyl transpeptidase, alcohol use, diabetes, hypertension, steatotic liver disease, and hepatitis C virus/human immunodeficiency virus coinfection. Interferon eligibility was similar. CONCLUSION HDV-infected females develop cirrhosis earlier, without liver disease cofactors, while males show advanced liver disease with multiple cofactors. Tailored care for young migrant women and cofactor-guided management for men may improve HDV outcomes, promoting equity.