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

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 n...

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Published in	Hepatology (Baltimore, Md.) Vol. 73; no. 1; pp. 41 - 52
Main Authors	Huang, Qi, Zhou, Bin, Cai, Dawei, Zong, Yuhua, Wu, Yaobo, Liu, Shi, Mercier, Alexandre, Guo, Haitao, Hou, Jinlin, Colonno, Richard, Sun, Jian
Format	Journal Article
Language	English
Published	United States John Wiley and Sons Inc 01.01.2021
Subjects	Adolescent Adult Aged Antiviral Agents - therapeutic use Biomarkers - blood DNA, Circular - drug effects DNA, Viral - blood DNA, Viral - drug effects Female Hepatitis B Core Antigens - blood Hepatitis B e Antigens - blood Hepatitis B virus - drug effects Hepatitis B virus - genetics Hepatitis B, Chronic - drug therapy Hepatitis B, Chronic - genetics Hepatitis B, Chronic - virology Humans Lamivudine - therapeutic use Liver - drug effects Liver - virology Male Middle Aged Mutation Original Retrospective Studies Treatment Outcome Viral Load Young Adult
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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.
AbstractList	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. 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.BACKGROUND AND AIMSHepatitis 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.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.APPROACH AND RESULTSIn 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.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.CONCLUSIONSThe 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. 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. In this study, we retrospectively monitored the emergence and reversion of the rtM204I/V mutant, a signature lamivudine resistance (LAM ) 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 LAM 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. LAM 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% LAM mutations fully reversed back to wild type within 24-48 weeks. 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.
Author	Zhou, Bin Mercier, Alexandre Liu, Shi Huang, Qi Cai, Dawei Colonno, Richard Hou, Jinlin Guo, Haitao Wu, Yaobo Sun, Jian Zong, Yuhua
AuthorAffiliation	4 Cancer Virology Program UPMC Hillman Cancer Center Department of Microbiology and Molecular Genetics University of Pittsburgh Pittsburgh PA 1 Assembly Biosciences, Inc. South San Francisco CA 3 Department of Microbiology and Immunology Indiana University Indianapolis IN 2 State Key Laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis Research Department of Infectious Diseases Nanfang Hospital Southern Medical University Guangzhou China
AuthorAffiliation_xml	– name: 1 Assembly Biosciences, Inc. South San Francisco CA – name: 4 Cancer Virology Program UPMC Hillman Cancer Center Department of Microbiology and Molecular Genetics University of Pittsburgh Pittsburgh PA – name: 2 State Key Laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis Research Department of Infectious Diseases Nanfang Hospital Southern Medical University Guangzhou China – name: 3 Department of Microbiology and Immunology Indiana University Indianapolis IN
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Copyright	2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
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Notes	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Undefined-3 Clinical trial number: NCT00962533, ISRCTN79659320. These authors contributed equally to this work. 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. 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.).
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Hepatology. 2021 May;73(5):2076-2077 – reference: 32772386 - Hepatology. 2021 May;73(5):2075-2076 – reference: 32320077 - J Med Virol. 2020 Aug;92(8):935-937
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Snippet	Background and Aims Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a pivotal role in the establishment and persistence of HBV infection.... Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) plays a pivotal role in the establishment and persistence of HBV infection. Understanding the...
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SubjectTerms	Adolescent Adult Aged Antiviral Agents - therapeutic use Biomarkers - blood DNA, Circular - drug effects DNA, Viral - blood DNA, Viral - drug effects Female Hepatitis B Core Antigens - blood Hepatitis B e Antigens - blood Hepatitis B virus - drug effects Hepatitis B virus - genetics Hepatitis B, Chronic - drug therapy Hepatitis B, Chronic - genetics Hepatitis B, Chronic - virology Humans Lamivudine - therapeutic use Liver - drug effects Liver - virology Male Middle Aged Mutation Original Retrospective Studies Treatment Outcome Viral Load Young Adult
Title	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
URI	https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fhep.31240 https://www.ncbi.nlm.nih.gov/pubmed/32189364 https://www.proquest.com/docview/2379016658 https://pubmed.ncbi.nlm.nih.gov/PMC7898704
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