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Rapid Turnover of Hepatitis B Virus Covalently Closed Circular DNA Indicated by Monitoring Emergence and Reversion of Signature‐Mutation in Treated Chronic Hepatitis B Patients
Qi Huang
Bin Zhou
Dawei Cai
Yuhua Zong
Yaobo Wu
Shi Liu
Alexandre Mercier
Haitao Guo
Jinlin Hou
Richard Colonno
Jian Sun
First published: 19 March 2020
https://doi.org/10.1002/hep.31240
Citations: 4
Supported by the funding from Assembly Biosciences, NIH (AI110762, AI123271, and AI134818 to H.G.), National Science and Technology Major Project (2017ZX10202202 to J.S. and 2018ZX10301202 to J.H.), Natural Science Foundation of China (81871668 to J.S.; 81600475 and U1401226 to B.Z.), Guangzhou Science and Technology Plan Project (201804020001 to J.S.), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S131), and Guangdong Natural Science and Technology (2016A030313550 to J.S.).
Potential conflict of interest: Dr. Mercier was employed by Assembly Biosciences. Dr. Cai is employed by Assembly Biosciences. Dr. Colonno is employed by and owns stock in Assembly Biosciences. Dr. Guo received grants from and owns stock in Arbutus. He consults for Assembly and Aligos. Dr. Hou consults for and received grants from Bristol‐Myers Squibb and Johnson & Johnson. He consults for AbbVie, Arbutus, Gilead, and Roche. Dr. Huang is employed by and owns stock in Assembly Biosciences. Dr. Zong was employed by Assembly Biosciences.
Clinical trial number: NCT00962533, ISRCTN79659320.
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Abstract
Background and Aims
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a pivotal role in the establishment and persistence of HBV infection. Understanding the turnover time of preexisting cccDNA pools would be helpful in designing strategies to clear HBV by fully blocking the de novo generation of cccDNA.
Approach and Results
In this study, we retrospectively monitored the emergence and reversion of the rtM204I/V mutant, a signature lamivudine resistance (LAMR) mutation serving as a biomarker of cccDNA turnover in liver biopsies and longitudinal serum samples from two clinical trials. Methodologies were optimized to differentially isolate and sequence HBV virion DNA, cccDNA, and HBV RNA from clinical samples. A strong correlation was observed between LAMR composition of cccDNA with that of serum and intrahepatic HBV RNA in paired liver and serum samples (r = 0.96 and 0.90, respectively), suggesting that serum HBV RNA can serve as a surrogate marker of cccDNA genetic composition when liver biopsies are unavailable. LAMR mutations emerged and increased from undetectable to 40%‐90% within 16‐28 weeks in serum HBV RNA from telbivudine‐treated patients experiencing virological breakthrough. Similarly, in lamivudine‐resistant patients who switched to interferon therapy, serum HBV‐RNA population bearing 100% LAMR mutations fully reversed back to wild type within 24‐48 weeks.
Conclusions
The genetic composition dynamics of serum HBV RNA and biopsy cccDNA in treated HBV patients indicates that cccDNA turnover occurs relatively rapidly (several months), offering a possibility of HBV cure with finite therapy through completely blocking cccDNA replenishment.
Abbreviations
ALT
alanine aminotransferase
cccDNA
covalently closed circular DNA
CHB
chronic hepatitis B
HBeAg
hepatitis B e antigen
HBV
hepatitis B virus
LAMR
lamivudine resistance
LdT
telbivudine
Nucs
nucleos(t)ide analogues
PegIFN
pegylated interferon alfa‐2a
rcDNA
relaxed circular DNA
SDS
sodium dodecyl sulfate
VB
virological breakthrough
WT
wild type
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发表于 2020-12-3 11:49
