Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy.

By B. Werle-Lapostolle, S. Bowden, S. Locarnini, K. Wursthorn, J. Petersen, G. Lau, C. Trépo, P. Marcellin, Z. Goodman, W. Delaney and 5 more. Gastroenterology, 2004

903 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Epidemiology, Virology

View Paper: https://www.semanticscholar.org/paper/5ca307399b79ac7d19d70f9ae4266d34d261dfd1

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Citations in the corpus

Acyclic nucleoside phosphonates: a key class of antiviral drugs (2005, background): “It is re-assuring that long-term adefovir dipivoxil therapy was recently found to significantly decrease cccDNA levels, as this could open new perspectives for the progressive clearance of these reservoirs and 'curing' of the infected cell”
Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus (2012, positive): “HBV cccDNA (double-stranded DNA without nick and gap) was quantified by real-time PCR using a protocol as previously described Werle-Lapostolle et al., 2004) with modifications.”
Occult hepatitis B virus infection. (2007, result): “In fact, the quantification of intra-hepatic viral DNA in different sets of chronic HBV infected individuals demonstrated that the amount of HBV DNA in the liver of occult HBV infected patients is often comparable to that detected in HBsAg positive individuals [51].”
HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B (2015, background): “…around thousand fold 77 can be increased by reducing the levels of RC-DNA in the template preparation, for example, pretreatment with Plasmid-Safe DNase, 79 which degrades DNA with free ends; notably though, RC-DNA with a nearly complete (+)-strand is not a substrate (reference 64 and ﬁ gure 5A).”
Statements from the Taormina expert meeting on occult hepatitis B virus infection. (2008, background): “The molecular basis of persistent OBI is related to the long-lasting persistence of HBV cccDNA in the nuclei of hepatocytes [4,26,41–45].”