Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy1 ☆
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Background & aims Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is a unique episomal replicative intermediate responsible for persistent infection of hepatocytes. Technical constraints have hampered the direct study of cccDNA maintenance and clearance mechanisms in patients. The aim of this study was to develop a sensitive and specific assay for quantifying cccDNA in biopsy samples from chronic hepatitis B patients during different natural history phases and in patients undergoing antiviral therapy.Methods Intrahepatic cccDNA levels were quantified by a specific real-time PCR assay. Ninety-eight liver biopsy samples from patients in the major phases of the natural history of chronic hepatitis B and 32 pairs of samples from patients receiving adefovir dipivoxil (ADV) therapy were assessed.Results cccDNA was detected, at levels ranging over 3 orders of magnitude, in patients in different phases of the natural history of chronic hepatitis B. cccDNA levels were strongly correlated with levels of total intracellular HBV DNA and serum HBV DNA. Forty-eight weeks of ADV therapy resulted in a significant 0.8 log decrease in cccDNA copies/cell. Changes in cccDNA were correlated with a similar reduction in serum HBsAg titer but not with a decrease in the number of HBV antigen-positive cells during ADV treatment.Conclusions cccDNA persists throughout the natural history of chronic hepatitis B, even in patients with serologic evidence of viral clearance. Long-term ADV therapy significantly decreased cccDNA levels by a primarily noncytolytic mechanism.
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HBV cccDNA exhibits staggering stability and declines slowly under antiviral therapy, representing a major barrier to viral eradication.
“Moreover, HBV cccDNA exhibits staggering stability and declines slowly under antiviral therapy, thus representing a major barrier to viral eradication.3,4,5,6”
From The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo (2014) · cites this paper as [4]
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- Huiling Yang, Manuel Tsiang, Anant Jain, Craig James, Rick Fallis, John Fry, and Michael Wulfsohn of Gilead Sciences for their support and advice during this study; Hans Will and Maura Dandri for critical review of this manuscript; and Brian Sutton and Jennifer Elder of Inveresk (Cary, North Carolina) for advice and independent validation of statistical analyses. P.M. represents the Adefovir Dipivoxil cccDNA Study Group, which also includes the following clinical investigators: Peter Buggisch (Uni- versita ¨tskrankenhaus Hamburg-Eppendorf, Germany);
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- Authors
- Werle–Lapostolle, B., Bowden, S., Locarnini, S., Wursthorn, K., Petersen, J., Lau, G., Trepo, C., Marcellin, P., Goodman, Z., & Delaney IV, W. E.
- Affiliations
- Victorian Infectious Diseases Reference Laboratory (AU)
- Leibniz Institute of Virology (LIV) (DE)
- Queen Mary Hospital (CN)
- Inserm (FR)
- Armed Forces Institute of Pathology (US)
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 126
- Issue
- 7
- Pages
- 1750-1758
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2050571266
- Cited by
- 905
- References
- 45
- Citations by year
- 2026: 12 · 2025: 25 · 2024: 24 · 2023: 32 · 2022: 34 · 2021: 39 · 2020: 40 · 2019: 49 · 2018: 41 · 2017: 57 · 2016: 50 · 2015: 53 · 2014: 56 · 2013: 43 · 2012: 48
- FWCI
- 24.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- covalently closed circular DNA, hepatitis B virus, chronic hepatitis B, adefovir dipivoxil, antiviral therapy, viral persistence, natural history of hepatitis B, hepatitis B surface antigen, liver biopsy
- MeSH terms
- Adenine, Antiviral Agents, Biopsy, DNA, Circular, DNA, Viral, Hepatitis B Core Antigens, Hepatitis B Surface Antigens, Hepatitis B virus, Humans, Immunohistochemistry, Polymerase Chain Reaction, Hepatitis B, Chronic, Organophosphonates
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