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Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: e00725-17. doi: 10.1128/AAC.00725-17. Print 2017 Sep.

Persistent Loss of Hepatitis B Virus Markers in Serum without Cellular Immunity by Combination of Peginterferon and Entecavir Therapy in Humanized Mice.

Uchida T1,2, Imamura M1,2, Hayes CN1,2, Hiraga N1,2, Kan H1,2, Tsuge M1,2,3, Abe-Chayama H1,2,4, Zhang Y1,2, Makokha GN1,2, Aikata H1,2, Miki D2,5, Ochi H2,5, Ishida Y2,6, Tateno C2,6, Chayama K7,2,5.

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Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.
Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan.
PhoenixBio Co., Ltd., Higashihiroshima, Japan.
Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan


Nucleot(s)ide analogues and peginterferon (PEG-IFN) treatment are the only approved therapies for chronic hepatitis B virus (HBV) infection. However, complete eradication of the virus, as indicated by persistent loss of hepatitis B surface antigen (HBsAg), is rare among treated patients. This is due to long-term persistence of the HBV genome in infected hepatocytes in the form of covalently closed circular DNA (cccDNA). In this study, we investigated whether administration of a large dose of a nucleoside analogue in combination with PEG-IFN can achieve long-term loss of HBsAg in human hepatocyte chimeric mice. Mice were treated with a high dose of entecavir and/or PEG-IFN for 6 weeks. High-dose combination therapy with both drugs resulted in persistently negative HBV DNA in serum. Although small amounts of HBV DNA and cccDNA (0.1 and 0.01 copy/cell, respectively) remained in the mouse livers, some of the mice remained persistently negative for serum HBV DNA at 13 weeks after cessation of the therapy. Serum HBsAg and hepatitis B core-related antigen (HBcrAg) continued to decrease and eventually became negative at 12 weeks after cessation of the therapy. Analysis of the HBV genome in treated mice showed accumulation of G-to-A hypermutation and CpG III island methylation. Persistent loss of serum HBV DNA and loss of HBV markers by high-dose entecavir and PEG-IFN combination treatment in chimeric mice suggests that control of HBV can be achieved even in the absence of a cellular immune response.


DNA methylation; cccDNA; hepatitis B virus; human hepatocyte chimeric mouse; hypermutation; methylation

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