Editorial: Chronic Hepatitis Delta—We Need More Screening to Improve Knowledge on the Natural History

Hepatitis delta virus (HDV) is a defective single-stranded RNA virus 1. The estimated anti-HDV seroprevalence among HBsAg-positive individuals is 4.5%, corresponding to more than 12 million people with serological evidence of HDV infection 2. Chronic HDV infection is the most aggressive form of chronic viral hepatitis. Three meta-analyses or systematic reviews 3-5 including the study of Telep et al. recently published 5 have demonstrated that patients with chronic HDV are at significantly higher risk than patients with chronic hepatitis B of developing serious liver-related complications, including hepatic decompensation, hepatocellular carcinoma (HCC), liver transplantation, and liver-related death. The caveats of the study of Telep et al. that we have to emphasise are the following: (1) the studies were done mainly in Europe; (2) several cohorts have short follow-up; (3) low numbers of patients were followed in some studies (less than 100 patients); (4) most of the studies were done in tertiary centres; (5) patients positive for anti-HDV were not always tested by PCR; (6) the quality of HDV PCR was very heterogeneous, until 2015 when a WHO standard was available and remains poorly standardised 6; 7 many patients were treated with interferon and/or Peg-Interferon and/or nucleoside/nucleotide analogs. Telep et al. confirm the high burden of disease in HDV-infected patients 5. The incidence of cirrhosis ranged from 0% to 63%, hepatic decompensation and HCC occurred in up to 52% and 19% of cases, respectively. Liver-related mortality ranged from 0% to 19%. Incidence rates varied substantially across studies—for example, hepatic decompensation ranged from 0 to 115.4 per 1000 person-years, and HCC from 0 to 54.4 per 1000 person-years 5. Cirrhosis, detectable HDV RNA and treatment by Peg-Interferon consistently emerged as key predictors of disease progression. Notably, patients with detectable HDV RNA are up to seven times more likely to require liver transplantation compared to those who are RNA-negative. However, the strength of the association varied, likely due to considerable heterogeneity in study design, population characteristics, and endpoint definitions 7. Most of the included studies were retrospective, with limited adjustment for potential confounders. The Table we present below, adapted from Kamal et al. 8 is an attempt to list most of the factors that can modify the natural history of chronic hepatitis delta, which are important to take into account (Table 1). In the future, we should be able to answer the questions asked by our patients: for example, if I have chronic hepatitis delta infection and a FIB-4 < 1.45, is there a benefit to be treated? Public health strategies must also address persistent gaps in HDV screening and diagnosis. Universal testing among HBsAg-positive individuals is strongly recommended, yet remains poorly implemented. The true burden of HDV is likely underestimated, particularly among underserved and high-risk populations 9. Until recently, pegylated interferon alfa was the only treatment for chronic hepatitis D. Bulevirtide is the first approved therapy for HDV in Europe. When combined with pegylated interferon, it significantly increases rates of undetectable HDV RNA at Week 24. New antiviral therapies may lead to increased rates of virological cure and consequently reduced hepatic events 10. J. Ventre: writing – review and editing. A. Abergel: writing – review and editing, supervision. This article is linked to Telep et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70251. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.