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Abstract Details
Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B
Hepatology. 2022 Jan 24. doi: 10.1002/hep.32352. Online ahead of print.
Robin Erken12, Vladimir Loukachov1, Karel van Dort1, Anne van den Hurk1, R Bart Takkenberg2, Anniki de Niet2, Louis Jansen2, Sophie Willemse2, Henk Reesink3, Neeltje Kootstra1
Author information
Department of Experimental Immunology, Amsterdam UMC, location AMC, Amsterdam Infection & Immunity Institute, University of Amsterdam, Amsterdam, the Netherlands.
Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, location AMC, Amsterdam, the Netherlands.
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
Abstract
Background and aims: HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here, we quantified the levels of integrated HBV in patients with chronic hepatitis B (CHB) and analyzed the relation between HBV integration, virological activity (plasma HBV DNA and HBsAg levels), and clinical outcomes.
Approach and results: We developed and validated a multistep Arthrobacter luteus (Alu)-PCR that specifically amplifies integrated HBV and RT-Alu-PCR detecting mRNA transcripts derived from integrated HBV. Pretreatment liver biopsy samples and baseline characteristics of 124 patients with CHB either treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or receiving no treatment were available for analysis. Integrated HBV sequences containing open reading frame S and X (but not C) and S and X mRNA transcripts derived from integrated HBV could be detected and quantified in liver biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine aminotransferase plasma levels, and the liver histology activity index but not to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic regression analysis showed that lower baseline HBV integration levels were independently associated with HBsAg loss (functional cure) within 5 years follow-up.
Conclusions: Integrated HBV levels are strongly correlated with surrogate markers for virological activity but not to cccDNA levels and are predictive for HBsAg loss. Our data suggest that integrated HBV is closely related to HBV replication and may therefore be an important tool in the evaluation and development of treatment modalities aiming to cure CHB.