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Abstract
The persistence of covalently closed circular DNA (cccDNA) poses a major obstacle to curing chronic hepatitis B (CHB). Here, we used droplet digital PCR (ddPCR) for cccDNA quantitation. The cccDNA-specific ddPCR showed high accuracy with the dynamic range of cccDNA detection from 101 to 105 copies/assay. The ddPCR had higher sensitivity, specificity and precisely than qPCR. The results of ddPCR correlated closely with serum HB core-related antigen and HB surface antigen (HBsAg) in 24 HBV-infected human-liver-chimeric mice (PXB-mice). We demonstrated that in 2 PXB-mice after entecavir treatment, the total cccDNA content did not change during liver repopulation, although the cccDNA content per hepatocyte was reduced after the treatment. In the 6 patients with HBV-related hepatocellular carcinoma, ddPCR detected cccDNA in both tumor and non-tumor tissues. In 13 HBeAg-negative CHB patients with pegylated interferon alpha-2a, cccDNA contents from paired biopsies were more significantly reduced in virological response (VR) than in non-VR at week 48 (p = 0.0051). Interestingly, cccDNA levels were the lowest in VR with HBsAg clearance but remained detectable after the treatment. Collectively, ddPCR revealed that cccDNA content is stable during hepatocyte proliferation and persists at quantifiable levels, even after serum HBsAg clearance.
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1 Nagoya City University Graduate School of Medical Sciences, Department of Virology and Liver Unit, Nagoya, Japan (GRID:grid.260433.0) (ISNI:0000 0001 0728 1069); Kumamoto University, Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749)
2 Nagoya City University Graduate School of Medical Sciences, Department of Virology and Liver Unit, Nagoya, Japan (GRID:grid.260433.0) (ISNI:0000 0001 0728 1069)
3 Chulalongkorn University, Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Bangkok, Thailand (GRID:grid.7922.e) (ISNI:0000 0001 0244 7875)
4 Tokushima University, Department of Surgery, Tokushima, Japan (GRID:grid.267335.6) (ISNI:0000 0001 1092 3579)
5 National Center for Global Health and Medicine Research Institute, Department of Refractory Viral Infections, Tokyo, Japan (GRID:grid.45203.30) (ISNI:0000 0004 0489 0290)
6 Kumamoto University, Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto, Japan (GRID:grid.274841.c) (ISNI:0000 0001 0660 6749)
7 National Center for Global Health and Medicine Research Institute, Department of Refractory Viral Infections, Tokyo, Japan (GRID:grid.45203.30) (ISNI:0000 0004 0489 0290); National Institutes of Health, Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, USA (GRID:grid.94365.3d) (ISNI:0000 0001 2297 5165); Kumamoto University Hospital, Department of Clinical Sciences, Kumamoto, Japan (GRID:grid.411152.2) (ISNI:0000 0004 0407 1295)