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Hepatitis B Virus Pregenomic RNA Is Present in Virions in Plasma and Is Associated With a Response to Pegylated Interferon Alfa-2a and Nucleos(t)ide Analogues
L. Jansen1,2, Neeltje A. Kootstra2, Karel A. van Dort2, R. Bart Takkenberg1, Hendrik W. Reesink1,2 and Hans L. Zaaijer3
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Author Affiliations
1Department of Gastroenterology and Hepatology
2Department of Experimental Immunology
3Department of Clinical Virology, Academic Medical Center, University of Amsterdam, The Netherlands
Correspondence: L. Jansen, MD, Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands ([email protected]).
Presented in part: Liver Meeting, Washington, D. C., 4 November 2013. Abstract 1079; International Liver Congress, London, United Kingdom, 10 April 2014. Abstracts 182 and 684.
Abstract
Background. Treatment of patients with chronic hepatitis B (CHB) with nucleos(t)ide analogues (NAs) suppresses hepatitis B virus (HBV) DNA production but does not affect the synthesis of the RNA pregenome or HBV messenger RNA. Whether HBV RNA–containing particles continue to be secreted into the bloodstream remains controversial.
Methods. We developed a sensitive polymerase chain reaction (PCR) assay to quantify the HBV RNA load in a supernatant of NA-treated HepG2-2.2.15 cells and in plasma specimens from 20 patients with CHB who were receiving NA therapy and 86 patients treated with pegylated interferon alfa (Peg-IFN) and adefovir.
Results. Treatment of HepG2-2.2.15 cells with NAs for 9 days reduced HBV DNA levels (by 1.98 log10 copies/mL), whereas HBV RNA levels increased (by 0.47 log10 copies/mL; P < .05). During long-term NA treatment of patients with CHB, HBV RNA levels remained higher than HBV DNA levels. Peg-IFN–based treatment induced a stronger decrease in the HBV RNA load than NA monotherapy, and this decline was more pronounced in responders than in nonresponders. In HBV e antigen–negative patients, a lower baseline plasma HBV RNA level was independently associated with response to Peg-IFN and adefovir (odds ratio, 0.44; P = .019). Immunoprecipitation with HBV core antigen–specific antibodies after removal of the HBV surface antigen envelope demonstrated the association of plasma HBV RNA with virions.
Conclusions. HBV RNA is present in virions in plasma specimens from patients with CHB. HBV RNA levels vary significantly from those of established viral markers during antiviral treatment, which highlights its potential as an independent marker in the evaluation of patients with CHB.
Key words
chronic hepatitis B HBV life cycle nucleocapsids immunoprecipitation response marker
Received March 4, 2015.
Accepted July 20, 2015.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected].
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