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Multicenter Study
. 2025 Dec 21;31(47):111637.
doi: 10.3748/wjg.v31.i47.111637.

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

Barbara Coco  1 , Maria Giovanna Quaranta  2 , Maria Elena Tosti  2 , Luigina Ferrigno  2 , Giuseppina Brancaccio  3 , Alessia Ciancio  4 , Carmine Coppola  5 , Vincenzo Messina  6 , Ivan Gentile  7 , Ernesto Claar  8 , Filomena Morisco  9 , Teresa Santantonio  10 , Mauro Viganò  11 , Irene Cacciola  12 , Maurizio Pompili  13   14 , Francesco Paolo Russo  15 , Antonio Izzi  16 , Grazia A Niro  17 , Nicola Coppola  18 , Alessandro Soria  19 , Alessandro Federico  20 , Giulia Morsica  21 , Massimo Puoti  22 , Erica Villa  23 , Pietro Lampertico  24 , Giovanni Battista Gaeta  25 , Loreta A Kondili  2   26 , Maurizia R Brunetto  1   27 ; PITER Collaborating Investigators
Collaborators, Affiliations
Multicenter Study

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

Barbara Coco et al. World J Gastroenterol. .

Abstract

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.

Keywords: Chronic hepatitis delta virus infection; Cirrhosis; Hepatitis delta virus; Migrant; Sex differences.

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Conflict of interest statement

Conflict-of-interest statement: These authors disclose the following: Kondili LA has received research grant from Gilead Sciences; Brunetto MR has served as advisory board member for AbbVie, Gilead Sciences, Janssen, Roche and speaker for AbbVie, Gilead Sciences, EISAI-MSD; Quaranta MG has received research grant from Gilead Sciences; Gentile I has received consultant honoraria from MSD, AbbVie, Gilead Sciences, Pfizer, GSK, Astrazeneca, Basilea, SOBI, Nordic/Infecto Pharm, Angelini, Moderna, Shionogi, Advanz Pharma, Abbottand Mundipharma Pharmaceuticals as well as has received departmental grants from Gilead Sciences and Advanz Pharma; Santantonio TA has received speaker honorarium and travel support from Gilead Sciences and Abbvie; Viganò M has served as Advisory Board/Speaker Bureau for Gilead Sciences, AbbVie, Kedrion, IPSEN; Soria A has received speaker honorarium, travel support and research funding from AbbVie and Gilead Sciences; Puoti M has received Abbvie, GSK, Gilead Sciences, Pfizer travel grants, speaker in own events; Lampertico P has served as Advisory Board/Speaker Bureau for Roche Pharma/Diagnostics, Gilead Sciences, GSK, AbbVie, Janssen, Myr, Eiger, Antios, Aligos, Vir, Grifols, Altona, Roboscreen; Coco B, Tosti ME, Ferrigno L, Brancaccio G, Ciancio A, Coppola C, Messina V, Claar E, Morisco F, Cacciola I, Pompili M, Russo FP, Izzi A, Niro GA, Coppola N, Alessandro F, Giulia M, Villa E, Gaeta GB and PITER Collaborating Investigators declare that they have no conflict of interest regarding this manuscript.

Figures

Figure 1
Figure 1
Flow chart of the patients enrolled in the study. HBsAg: Hepatitis B surface antigen; HDV: Hepatitis delta virus.
Figure 2
Figure 2
Age distribution in hepatitis B surface antigen +/anti-hepatitis delta virus positive and hepatitis B surface antigen +/anti-hepatitis delta virus negative patients with cirrhosis by sex. HDV: Hepatitis delta virus; HBV: Hepatitis B virus.
Figure 3
Figure 3
Cofactors for liver disease progression in hepatitis delta virus-RNA positive patients by sex. BMI: Body mass index; HTN: Hypertension; SLD: Steatotic liver disease; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus.
Figure 4
Figure 4
Number of comorbidities by sex in hepatitis delta virus-RNA positive patients and their eligibility for peg-interferon. 1Estimated by the presence of liver-related contraindications and extra-hepatic comorbidities. 2Absolute contraindications: Child-Pugh class B/C cirrhosis; Child-Pugh class A cirrhosis with portal hypertension (ascites, esophageal varices, platelets < 100000/μL); Portal thrombosis; Autoimmune diseases (hepatitis, systemic lupus erythematosus, rheumatoid arthritis, thyroiditis); Psychiatric disturbances; Ischemic heart disease; Ischemic brain disease; Inflammatory bowel disease; Celiac disease; Psoriasis; Solid tumors under chemotherapy. 3Relative contraindications: Age ≥ 70 years; Renal failure grade 4-5; Thalassemia trait; Nasal lymphoma. 4Among these male patients, 39.8% had received interferon therapy. 5Among these female patients, 31.5% had received interferon therapy. HDV: Hepatitis delta virus; IFN: Interferon.
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