Correlation Between Risk of Hepatitis B Virus Recurrence and Tissue Expression of Covalently Closed Circular DNA in Living Donor Liver Transplant Recipients Treated With High-dose Hepatitis B Immunoglobulin

Song, Gi‐Won; Ahn, Chul‐Soo; Lee, S.-G.; Hwang, Shin; Kim, K.-H.; Moon, Deok‐Bog; Ha, Tae‐Yong; Jung, Dong‐Hwan; Park, G.-C.; Kang, Sang-Hyun; Jung, Bo‐Hyun; Kim, N.

doi:10.1016/j.transproceed.2014.06.074

Cited by 8 publications

(6 citation statements)

References 21 publications

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“…When recipients receive transplantation with liver from donors with previous history of HBV infection, but with negative serum HBsAg and HBV DNA, intrahepatic cccDNA could still be detected after LT[ 4 , 26 ]. Notably, detection of anti-HBc alone in the absence of HBsAg and HBV DNA in a donor should be treated as an indicator of occult infection and a low-level virus replication in the liver, which could be reactivated post-LT[ 18 , 27 , 28 ].…”

Section: Molecular Mechanisms Of Hepatitis B Reactivation In Liver Trmentioning

confidence: 99%

See 1 more Smart Citation

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Chauhan¹,

Lingala²,

Gadiparthi³

et al. 2018

WJH

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Chronic hepatitis B (CHB) is a major global health problem affecting an estimated 350 million people with more than 786000 individuals dying annually due to complications, such as cirrhosis, liver failure and hepatocellular carcinoma (HCC). Liver transplantation (LT) is considered gold standard for treatment of hepatitis B virus (HBV)-related liver failure and HCC. However, post-transplant viral reactivation can be detrimental to allograft function, leading to poor survival. Prophylaxis with high-dose hepatitis B immunoglobulin (HBIG) and anti-viral drugs have achieved remarkable progress in LT by suppressing viral replication and improving long-term survival. The combination of lamivudine (LAM) plus HBIG has been for many years the most widely used. However, life-long HBIG use is both cumbersome and costly, whereas long-term use of LAM results in resistant virus. Recently, in an effort to develop HBIG-free protocols, high potency nucleos(t)ide analogues, such as Entecavir or Tenofovir, have been tried either as monotherapy or in combination with low-dose HBIG with excellent results. Current focus is on novel antiviral targets, especially for covalently closed circular DNA (cccDNA), in an effort to eradicate HBV infection instead of viral suppression. However, there are several other molecular mechanisms through which HBV may reactivate and need equal attention. The purpose of this review is to address post-LT HBV reactivation, its risk factors, underlying molecular mechanisms, and recent advancements and future of anti-viral therapy.

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Section: Molecular Mechanisms Of Hepatitis B Reactivation In Liver Trmentioning

confidence: 99%

“…Liver transplantation (LT) is the most effective treatment in patients with CHB-related liver failure, cirrhosis and HCC. However, HBV reactivation following LT emerges as a major clinical challenge[ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Chauhan¹,

Lingala²,

Gadiparthi³

et al. 2018

WJH

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“…In addition, studies on liver transplantation for HBV-associated HCC have reported that high levels of cccDNA in tissues can lead to post-operative HBV recurrence despite the use of high-dose hepatitis B immunoglobulin prophylaxis during liver transplantation (24). Furthermore, univariate analyses have previously revealed significant associations between HCC recurrence and HBV reinfection (25). Therefore, the present study hypothesized that cccDNA may be involved in the development of HBV-associated HCC.…”

Section: Discussionmentioning

confidence: 78%

Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis

et al. 2019

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Chronic hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) is an intermediate in the life cycle of HBV. HBV-encoded X protein (HBx), a key viral oncoprotein, can be specifically ubiquitylated by male specific lethal 2 (MSL2), which causes upregulation of HBx activity and promotes transcription, cell proliferation and tumor growth. The present study compared the levels of cccDNA, MSL2 mRNA and HBx mRNA in tumor and peri-tumor tissues, and clarified the effect of antiviral therapy on these indicators. Levels of intrahepatic cccDNA, MSL2 mRNA and HBx mRNA were determined using quantitative PCR in patients with HBV-associated HCC who had undergone liver surgery. A total of 50 patients were included in the present study. Prior to surgery, 31 patients had undergone antiviral treatment. Intrahepatic cccDNA levels were significantly higher in the tumor tissues compared with the peri-tumor tissues (P= 0.001), particularly in the hepatitis B e antigen-positive (P= 0.008), tumor recurrence (P= 0.002) and <3 cm tumor size (P= 0.003) groups. Furthermore, in patients with preoperative cirrhosis, levels of cccDNA and MSL2 mRNA were significantly higher in tumor tissues compared with that in peri-tumor tissues (P<0.001 and P= 0.023, respectively). The expression levels of HBx mRNA in antiviral-treated tumors and peri-tumor tissues were significantly lower compared with those in untreated tissues (P= 0.026 and P= 0.035). The levels of cccDNA and MSL2 mRNA in the HBx-positive group were significantly higher in tumor tissues compared with those in peri-tumor tissues (P= 0.026 and P= 0.013). In conclusion, cccDNA participated in the tumorigenesis of HBV-associated HCC, and antiviral therapy was found to modulate hepatocarcinogenesis by decreasing the levels of HBx to inhibit the tumorigenic effect of MSL2 and cccDNA.

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“…When no DNA was detected after 55 PCR cycles, the sample was regarded as DNA not detected. Details of these PCR methods are described elsewhere (15,16). DNA was quantified using the values obtained after 55 PCR cycles.…”

Section: Liver Tumor Cell Lines (Part Iii)mentioning

confidence: 99%

“…The following primer sets were used: GAPDH control (Hs_GAPDH_1_SG) purchased from Abcam (Cambridge, UK); HBx forward, 5'-TGCCAACTGGATCCTTCG CGGGACGTCCTT-3'; and HBx reverse, 5'-GTTCACGGTGGTC TCCATG-3'. Relative transcription levels were measured as previously described (16). The data are expressed as the fold change in the HBx level from the treatment groups to the control group.…”

Section: Rna Isolation and Cdna Synthesis For Analysis Of Cccdna Andmentioning

confidence: 99%

Apoptosis of Hepatitis B Virus-expressing Liver Tumor Cells Induced by a High Concentration of Nucleos(t)ide Analogue

Tak

Hwang

Lee

et al. 2016

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Correlation Between Risk of Hepatitis B Virus Recurrence and Tissue Expression of Covalently Closed Circular DNA in Living Donor Liver Transplant Recipients Treated With High-dose Hepatitis B Immunoglobulin

Cited by 8 publications

References 21 publications

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Reactivation of hepatitis B after liver transplantation: Current knowledge, molecular mechanisms and implications in management

Antiviral therapy may decrease HBx, affecting cccDNA and MSL2 in hepatocarcinogenesis

Apoptosis of Hepatitis B Virus-expressing Liver Tumor Cells Induced by a High Concentration of Nucleos(t)ide Analogue

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