Prevalence of HDV infection in Central Italy has remained stable across the last two decades with dominance of sub-genotypes 1 and characterized by elevated viral replication

HDV-prevalence in Italy and its fluctuations over-time are controversial. Furthermore, an extensive characterization of HDV-infected patients is still missing.The rate of HDV-seroprevalence and HDV-chronicity was assessed in 1,579 HBsAg+patients collected from 2005 to 2022 in Central-Italy.45.3% of HBsAg+patients received HDV-screening with an increasing temporal-trend: 15.6% (2005-2010), 45.0% (2011-2014), 49.4% (2015-2018), 71.8% (2019-2022). By multivariable-model, factors correlated with the lack of HDV-screening were ALT<2ULN and previous time-windows (P<0.002). Furthermore, 13.4% of HDV-screened patients resulted anti-HDV+ with a stable temporal trend. Among them, 80.8% had detectable HDV-RNA (median[IQR]:4.6[3.6-5.6]logcopies/ml) with altered ALT in 89.3% (median[IQR]:92[62-177]U/L). Anti-HDV+ patients from Eastern/South-eastern Europe were younger than Italians (44[37-54] vs 53[47-62]years, P<0.0001), less frequently NUC-treated (58.5% vs 80%, P=0.026) with higher HDV-RNA (4.8[3.6-5.8] vs 3.9[1.4-4.9]logcopies/ml, P=0.016) and HBsAg (9,461[4,159-24,532] vs 4,447[737-13,336]IU/ml, P=0.032). Phylogenetic-analysis revealed the circulation of HDV subgenotype-1e (47.4%) and -1c (52.6%). Notably, subgenotype-1e correlated with higher ALT than 1c (168[89-190] vs 58[54-88]U/l, P=0.015) despite comparable HDV-RNA.HDV-screening awareness is increasing over-time even if some gaps persist to achieve HDV-screening in all HBsAg+patients. HDV prevalence in tertiary-care centers tends to scarcely decline in native/non-native patients. Detection of subgenotypes, triggering variable inflammatory stimuli, supports the need to expand HDV molecular characterization.