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Sci Transl Med. 2017 Sep 27;9(409). pii: eaan0241. doi: 10.1126/scitranslmed.aan0241.

RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg.

Author information

1
Arrowhead Pharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA. cwooddell@arrowheadpharma.com.
2
Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
3
Department of Medicine and Therapeutics and Institute of Digestive Disease, Chinese University of Hong Kong, Hong Kong, China.
4
Liver Transplant Program, Stanford University Medical Center, San Diego, CA 92037, USA.
5
Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria 3000, Australia.
6
WHO Regional Reference Laboratory for Hepatitis B, Doherty Institute, Melbourne, Victoria, Australia.
7
Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
8
Unit of Infectious Diseases and Hepatology, University of Parma, Parma 43126, Italy.
9
Azienda Ospedaliero-Universitaria of Parma, Parma 43126, Italy.
10
Arrowhead Pharmaceuticals, 502 South Rosa Road, Madison, WI 53719, USA.
11
Arrowhead Pharmaceuticals, 225 South Lake Avenue, Suite 1050, Pasadena, CA 91101, USA.
12
Hong Kong Polytechnic University, Hong Kong, China.

Abstract

Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. Evidence suggests that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with an RNA interference (RNAi)-based therapeutic targeting HBV transcripts, ARC-520, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors (NUCs). HBeAg positivity is associated with greater disease risk that may be moderately reduced upon HBeAg loss. The molecular basis for this unexpected differential response was investigated in chimpanzees chronically infected with HBV. Several lines of evidence demonstrated that HBsAg was expressed not only from the episomal cccDNA minichromosome but also from transcripts arising from HBV DNA integrated into the host genome, which was the dominant source in HBeAg-negative chimpanzees. Many of the integrants detected in chimpanzees lacked target sites for the small interfering RNAs in ARC-520, explaining the reduced response in HBeAg-negative chimpanzees and, by extension, in HBeAg-negative patients. Our results uncover a heretofore underrecognized source of HBsAg that may represent a strategy adopted by HBV to maintain chronicity in the presence of host immunosurveillance. These results could alter trial design and endpoint expectations of new therapies for chronic HBV.

PMID:
28954926
PMCID:
PMC5830187
DOI:
10.1126/scitranslmed.aan0241
[Indexed for MEDLINE]
Free PMC Article

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