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BackgroundHDV depends on HBsAg for its infectivity. HBsAg can derive from cccDNA and also from the integration of the so-called linear HBV-DNA in the genome of infected hepatocytes. Here, we elucidate the contribution of HBsAg production from linear HBV-DNA integration in sustaining HDV activity and its pathogenetic potential.Material and Methods70 liver biopsies from eAg-negative individuals (74% NUC-treated) were included: 35 with CHB and 35 with CHD. Droplet-digital PCR was used to quantify intrahepatic levels of cccDNA, pgRNA, HDV-RNA and HBs transcripts from cccDNA and from integrated HBV-DNA (Grudda, 2022). Next-generation sequencing by Illumina was applied to assess the integration of linear HBV-DNA in hepatocytes’ genome (in 22 CHB and 32 CHD).ResultsIndividuals with CHD and CHB had comparable age and NUC-treatment duration. CHD was characterized by lower cccDNA and pgRNA than CHB (median [IQR]: 1 [0.02–12] vs 24 [8–93] copies (cps)/1000 cells and 8 [1–147] vs 518 [57–3,894] cps/1000cells, P<0.0001 for both). In CHD, no correlation was observed between cccDNA and intrahepatic HDV-RNA, supporting that HDV replicative activity is not strictly related to the extent of HBV reservoir.At least 1 event of linear HBV-DNA integration was observed in 100% and 78.1% (25/32) of individuals with CHB and CHD (total number of unique HBV-integration events: 847 in CHB and 427 in CHD). Furthermore, in both CHB and CHD, a comparable production of HBs transcripts was observed, with >99% of them from integrated HBV-DNA (median [IQR] cps/1000cells: 12,776 [4,570–55,977] in CHB and 6,041 [323–29,446] in CHD).Among the 427 HBV-integration events observed in CHD, 180 involved coding regions of the hepatocytes’ genome, corresponding to a median (IQR) number of 5 (2–10) unique events per patient. Notably, the number of HBV-integration events in coding regions showed a positive correlation with the amount of integration-derived HBsAg transcripts and with serum HBsAg (Rho=0.54 and 0.64, P<0.01 for both). Even more, HBV-integration events were significantly more frequent in individuals with CHD characterized by higher serum HBsAg levels (median [IQR] number of unique HBV-integration events: 10 [7–16] in people with vs 2 [1–7] in people without serum HBsAg >4 logIU/ml; P=0.01).In 19/25 individuals with CHD characterized by >1 HBV-integration event, HBV-DNA integrants localised in human genes regulating cell proliferation. Among the 60 genes identified, 40 genes are already known to be specifically involved in hepatocarcinogenesis.ConclusionsHDV persistence is independent from the intrahepatic HBV reservoir and is sustained by HBsAg production from integrated HBV-DNA. Higher HBsAg levels (>4logIU/ml) can reflect an enrichment of HBV-DNA integration events in coding regions of hepatocytes’ genome.Localization of HBV integrants suggests that these events may potentially induce hepatocytes proliferation, paving the way for carcinogenesis.

\"The living world runs on genomic software-- what Dawn Field and Neil Davies call the 'biocode'--the sum of all DNA on Earth. In Biocode, they tell the story of a new age of scientific discovery: the growing global effort to read and map the biocode, and what that might mean for the future.\"--Publisher's web site.