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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.

Author information

1
Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan.
2
Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
3
Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
4
Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
5
Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan.
6
PhoenixBio Co., Ltd., Higashihiroshima, Japan.
7
Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan chayama@hiroshima-u.ac.jp.

Abstract

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.

KEYWORDS:

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

PMID:
28696237
PMCID:
PMC5571312
DOI:
10.1128/AAC.00725-17
[Indexed for MEDLINE]
Free PMC Article

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