Quantitative intrahepatic HBV cccDNA correlates with histological liver inflammation in chronic hepatitis B virus infection

Liang, Ling-Bo; Zhu, Xia; Yan, Libo; Du, Lingyao; Liu, Cong; Liao, Juan; Tang, Hong

doi:10.1016/j.ijid.2016.09.022

Cited by 18 publications

(15 citation statements)

References 25 publications

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“…Intrahepatic HBV cccDNA levels in paraffin-embedded liver tissue were measured with the real-time PCR method, as described previously. 6,18 For specifically amplification and quantification of cccDNA, we designed cccDNA-selective primers and a probe targeting the gap region between the viral genome direct repeat regions (DR1 and DR2). In the present study, the cellular DNA was quantified by determining the copy number of cellular house-keeping gene β-actin.…”

Section: Intrahepatic Hbv Cccdna Measurementmentioning

confidence: 99%

Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA

Chen

Wang

Tao

et al. 2019

Journal of Viral Hepatitis

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Summary The correlation between serum HBcrAg and HBV RNA is unclear, and correlations of intrahepatic cccDNA with HBcrAg, HBV RNA and HBsAg are rarely reported in the same cohort. This study aimed to assess the correlation of HBcrAg with HBV RNA and HBsAg, and investigate whether serum HBcrAg is superior to serum HBV RNA and HBsAg in reflecting intrahepatic HBV cccDNA in HBeAg‐positive and HBeAg‐negative CHB patients. In this study, 85 HBeAg‐positive and 25 HBeAg‐negative patients who have never received antiviral therapy were included. Among HBeAg‐positive patients, HBcrAg was correlated positively with HBsAg (r = 0.564, P < 0.001) and HBV RNA (r = 0.445, P < 0.001), and HBV RNA was also correlated positively with HBsAg (r = 0.323, P = 0.003). Among HBeAg‐negative patients, no significant correlation was observed between HBcrAg, HBsAg and HBV RNA. By multivariable linear regression, HBcrAg (β = −0.563, P < 0.001), HBsAg (β = −0.328, P < 0.001) and HBV RNA (β = 0.180, P = 0.003) were all associated with cccDNA levels among HBeAg‐positive patients, but only serum HBcrAg was associated with cccDNA level (β = 0.774, P = 0.000) among HBeAg‐negative patients. HBcrAg was better correlated with cccDNA as compared to HBsAg and HBV RNA, irrespective of HBeAg status. Among HBeAg‐positive patients, though HBcrAg level was influenced by hepatic inflammatory activity and HBV DNA levels, the good correlations of HBcrAg with cccDNA persisted after stratification by inflammatory activity and HBV DNA levels. In conclusion, correlations of serum HBcrAg, HBV RNA and HBsAg levels differ significantly between HBeAg‐positive and HBeAg‐negative patients, but serum HbcrAg correlates with cccDNA levels better than HBV RNA and HBsAg, irrespective of HBeAg status.

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Section: Intrahepatic Hbv Cccdna Measurementmentioning

confidence: 99%

Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA

Chen

Wang

Tao

et al. 2019

Journal of Viral Hepatitis

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“…However, little is known about the biology of cccDNA due to a lack of sensitive and accurate detection methods. Monitoring of cccDNA before, during and after antiviral therapy is also essential for routine management of chronic hepatitis B patients because it is an important predictor of outcomes [11,69,111]. A variety of methods for cccDNA detection and quantification have been developed for basic research and clinical application.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Detection of HBV Covalently Closed Circular DNA

Zhao

Yuan

et al. 2017

Viruses

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Chronic hepatitis B virus (HBV) infection affects approximately 240 million people worldwide and remains a serious public health concern because its complete cure is impossible with current treatments. Covalently closed circular DNA (cccDNA) in the nucleus of infected cells cannot be eliminated by present therapeutics and may result in persistence and relapse. Drug development targeting cccDNA formation and maintenance is hindered by the lack of efficient cccDNA models and reliable cccDNA detection methods. Southern blotting is regarded as the gold standard for quantitative cccDNA detection, but it is complicated and not suitable for high-throughput drug screening, so more sensitive and simple methods, including polymerase chain reaction (PCR)-based methods, Invader assays, in situ hybridization and surrogates, have been developed for cccDNA detection. However, most methods are not reliable enough, and there are no unified standards for these approaches. This review will summarize available methods for cccDNA detection. It is hoped that more robust methods for cccDNA monitoring will be developed and that standard operation procedures for routine cccDNA detection in scientific research and clinical monitoring will be established.

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“…Chronic liver inflammation induced by HBV infection leads to fibrosis, cirrhosis, and HCC [ 94 ], one of the leading causes of death in CHB patients. Although correlation between HBV cccDNA in the liver and liver inflammation has been largely controversial in published literature [ 91 , 145 ], higher levels of intrahepatic HBV cccDNA positively correlated with serum ALT levels and were clearly shown to be associated with more severe liver inflammation in HBeAg-positive patients [ 33 ]. A study with treatment-naive patients demonstrated that more than one copy of cccDNA per cell and liver inflammation grade ≥ 1 are independent prognostic factors for the risk of liver inflammation, and the authors infer that higher baseline levels of HBV cccDNA might significantly increase the risk of liver inflammation.…”

Section: Covalently Closed Circular Dna and Adverse Chronic Hepatimentioning

confidence: 99%

“…A study with treatment-naive patients demonstrated that more than one copy of cccDNA per cell and liver inflammation grade ≥ 1 are independent prognostic factors for the risk of liver inflammation, and the authors infer that higher baseline levels of HBV cccDNA might significantly increase the risk of liver inflammation. Moreover, increased HBV DNA/cccDNA ratio is related to active viral replication and is associated with liver disease progression and poor disease outcomes [ 33 ].…”

Section: Covalently Closed Circular Dna and Adverse Chronic Hepatimentioning

confidence: 99%

“…Monitoring cccDNA, including cccDNA epigenetics and mutations, and novel surrogate markers of cccDNA activity, such as secreted HBV RNA, are important for (i) helping to define groups of patients susceptible to IFN therapy [ 29 , 30 , 31 ]; (ii) determining end-points of NA treatment [ 16 , 32 ]; (iii) predicting the risk of HCC and cirrhosis [ 33 ]; and, (iv) identifying potential drug resistance [ 34 ]. It should be underscored that in patients receiving these therapeutics, a decline of HBV biomarkers below certain threshold levels testifies to a sustained antiviral response, in which HBV replication is suppressed dramatically and immune cells can effectively control the disease [ 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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Clinical Implications of Hepatitis B Virus RNA and Covalently Closed Circular DNA in Monitoring Patients with Chronic Hepatitis B Today with a Gaze into the Future: The Field Is Unprepared for a Sterilizing Cure

Kostyusheva

Kostyushev

Brezgin

et al. 2018

Genes

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Chronic hepatitis B virus (HBV) infection has long remained a critical global health issue. Covalently closed circular DNA (cccDNA) is a persistent form of the HBV genome that maintains HBV chronicity. Decades of extensive research resulted in the two therapeutic options currently available: nucleot(s)ide analogs and interferon (IFN) therapy. A plethora of reliable markers to monitor HBV patients has been established, including the recently discovered encapsidated pregenomic RNA in serum, which can be used to determine treatment end-points and to predict the susceptibility of patients to IFN. Additionally, HBV RNA splice variants and cccDNA and its epigenetic modifications are associated with the clinical course and risks of hepatocellular carcinoma (HCC) and liver fibrosis. However, new antivirals, including CRISPR/Cas9, APOBEC-mediated degradation of cccDNA, and T-cell therapies aim at completely eliminating HBV, and it is clear that the diagnostic arsenal for defining the long-awaited sterilizing cure is missing. In this review, we discuss the currently available tools for detecting and measuring HBV RNAs and cccDNA, as well as the state-of-the-art in clinical implications of these markers, and debate needs and goals within the context of the sterilizing cure that is soon to come.

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Quantitative intrahepatic HBV cccDNA correlates with histological liver inflammation in chronic hepatitis B virus infection

Abstract: A higher baseline intrahepatic HBV cccDNA level may increase the risk of liver inflammation. Further investigations will be required to validate HBV cccDNA as an intrahepatic virological marker of patients who require extended outpatient management.

Cited by 18 publications

References 25 publications

Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA

Serum HBcrAg is better than HBV RNA and HBsAg in reflecting intrahepatic covalently closed circular DNA

Detection of HBV Covalently Closed Circular DNA

Clinical Implications of Hepatitis B Virus RNA and Covalently Closed Circular DNA in Monitoring Patients with Chronic Hepatitis B Today with a Gaze into the Future: The Field Is Unprepared for a Sterilizing Cure

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