Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B

Lai, Ching–Lung; Wong, Danny Ka‐Ho; Ip, Philip; Kopaniszen, M; Seto, Wai‐Kay; Fung, James; Huang, Fung‐Yu; Lee, Brian; Cullaro, Giuseppe; Chong, Chun Kong; Wu, Ringo; Cheng, Clio Yuen Man; Yuen, Jason; Ngai, Vincent; Yuen, Man‐Fung

doi:10.1016/j.jhep.2016.08.022

Cited by 141 publications

(148 citation statements)

References 35 publications

(50 reference statements)

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“…Integrated HBV DNA as a source of HBsAg may also help explain why levels of HBsAg and serum HBV DNA correlate in untreated HBeAg positive chronically HBV infected individuals, particularly those with high HBV serum DNA, but correlate less well or not at all in HBeAg negative patients and in those on NUC therapy (27–30). …”

Section: Discussionmentioning

confidence: 99%

RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg

et al. 2017

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Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure and hepatocellular carcinoma. Evidence exists that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with ARC-520, a RNA interference (RNAi)-based therapeutic targeting HBV transcripts, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients that were HBeAg negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors (NUCs). The molecular basis for this unexpected differential response was investigated in chimpanzees chronically infected with HBV. Several independent lines of evidence demonstrated that HBsAg was expressed not only from the episomal cccDNA minichromosome, but also from transcripts arising from HBV DNA integrated into the host genome. The latter was the dominant source in HBeAg negative chimpanzees. Many of the integrants detected in chimpanzees lacked target sites for the siRNAs in ARC-520, explaining the reduced response in HBeAg negative chimpanzees and by extension in HBeAg negative patients. Our results uncover a heretofore under-recognized source of HBsAg that may represent a strategy adopted by HBV to maintain chronicity in the presence of host immune surveillance and could alter trial design and endpoint expectations of new therapies for chronic HBV.

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Section: Discussionmentioning

confidence: 99%

RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg

et al. 2017

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“…221,222 The regulation of the intrahepatic pool of cccDNA involves several factors including the dynamics of infection in the liver and the intrahepatic antiviral immune response. 223 Furthermore, cccDNA transcriptional activity is controlled by fine epigenetic regulation which can involve viral and host factors.…”

Section: New Biomarkers Of Hbv Infectionmentioning

confidence: 99%

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

Lampertico¹,

Agarwal²,

Berg³

et al. 2017

Journal of Hepatology

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“…NAs can potently block reverse transcription of pgRNA and suppress production of new RC-DNA containing virions (see Figure 1B) but not viral transcription and antigen production. As depletion of cccDNA by the interrupted supply of new RC-DNA appears to occur with very slow kinetics, many patients will likely require life-long NA-treatment to keep the virus under control [20,21]. Conversely, very few copies of cccDNA per liver suffice to reactivate full-blown infection once therapeutic and/or immune-mediated control are weakened or lost.…”

Section: The Central Role Of Cccdna In Hbv Replicationmentioning

confidence: 99%

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Schreiner

Nassal

2017

Viruses

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Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system.

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Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B

Cited by 141 publications

References 35 publications

RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg

RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg

EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

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