Hepatocarcinogenesis associated with hepatitis B, delta and C viruses

Shirvani-Dastgerdi, Elham; Schwartz, Robert E.; Ploß, Alexander

doi:10.1016/j.coviro.2016.07.009

Cited by 44 publications

(51 citation statements)

References 132 publications

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“…Selection of HBV isolates with truncated S proteins has been reported during nucleos(t)ide analogue treatment and may contribute to HCC development [22–24]. In this regard, the emergence of rtS78T/sC69* mutation has been occasionally reported in the literature [21,22,25].…”

Section: Discussionmentioning

confidence: 99%

Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy

Shirvani-Dastgerdi

Winer

Celià-Terrassa

et al. 2017

Journal of Hepatology

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Background & Aims Patients chronically infected with the hepatitis B virus (HBV) that are on long-term treatment with nucleoside or nucleotide analogues are at risk of selecting HBV strains with complex mutational patterns. We herein report two cases of HBV-infected patients with insufficient viral suppression despite dual antiviral therapy with entecavir (ETV) and tenofovir (TDF), of which one patient died from aggressive hepatocellular carcinoma (HCC). Methods Serum samples of the patients from different time-points were analyzed by ultra-deep pyrosequencing analysis. Identified HBV mutations were functionally analyzed after transient transfection of replication-competent HBV vectors into hepatoma cells in vitro. We assessed replication efficacy, resistance to antivirals and potential impact on HBV secretion (viral particles, exosomes). Results Sequencing analyses revealed the selection of the rtS78T HBV polymerase mutation in both cases that simultaneously creates a premature stop codon at sC69 and thereby deletes almost the entire small HBV surface protein. One of the patients had an additional 261-bp deletion in the preS1/S2 region. Functional analyses of the mutations in vitro revealed that the rtS78T/sC69* mutation, but not the preS1/S2 deletion, significantly enhanced viral replication and conferred reduced susceptibility to ETV and TDF. The sC69* mutation caused truncation of HBs protein, leading to impaired detection by commercial HBsAg assay, without causing intracellular HBsAg retention or affecting HBV secretion. Conclusions The rtS78T/c69* HBV mutation associated with enhanced replication and insufficient response to antiviral treatment may favor long-term persistence of these isolates. Along with increased production of HBV transcripts and the sustained secretion of viral particles in the absence of antigenic domains of S protein, this HBV mutation may predispose to carcinogenic effects.

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Section: Discussionmentioning

confidence: 99%

Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy

Shirvani-Dastgerdi

Winer

Celià-Terrassa

et al. 2017

Journal of Hepatology

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“…HBV/HDV coinfection has been linked with a higher risk for the development of hepatocellular carcinoma [21]. …”

Section: Discussionmentioning

confidence: 99%

Hepatitis D, B and C virus (HDV/HBV/HCV) coinfection as a diagnostic problem and therapeutic challenge

Lorenc¹,

Sikorska

Stalke

et al. 2017

ceh

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Coinfection with hepatitis D virus (HDV) in chronic hepatitis B is associated with more rapid progression to liver cirrhosis. We present two cases of infection with hepatitis D, B and C viruses. Both male patients were primarily diagnosed as infected with hepatitis B virus (HBV) and hepatitis C virus (HCV), HBsAg-positive and anti-HCV-positive. The first patient was treated with interferon, lamivudine and pegylated interferon. A full virological and biochemical response was achieved. The second patient was treated with interferon and ribavirin, lamivudine and twice with pegylated interferon. In the ultrasound elastography progression of liver fibrosis to F4 was described.HDV infection should be considered in patients with HBV minireplication, high activity of aminotransferases and progression of liver disease despite a good virological response to anti-HBV treatment. Efficacy of interferon in HDV infection is severely limited.

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Section: Letter To the Editormentioning

confidence: 99%

“…Infection with HBV and HCV is one of the prominent source of chronic liver infections worldwide. It is estimated that approximately 350 million individuals are HBV and 200 million individuals are HCV carriers globally [3,4].Although the knowledge about the molecular virology of these viruses is well established, the molecular mechanism from acute infection to HCC development are still not well known. The research data showed that HCC is a typical inflammation-related cancer but the exact mechanism is still not clear.…”

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Hepatocellular Carcinoma in Pakistan: An Insight into Future

Afzal¹

2017

J Cancer Sci Ther

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Carcinoma (HCC) is one of the most prevalent type of cancer across the world and constitutes around 7% of all cancers. Approximately 750,000 new cases of liver cancer are reported per year globally [1,2]. The incidence of HCC increases with age and is highest in people aged around 70 years [2]. The distribution and onset of HCC varies significantly in different geographical regions of the world, might be due to causative factors and genetic makeup of the inhabitants. Among the risk factors for HCC, Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are well-known and their role is well established. Majority of HCC are viral borne and HBV/HCV are the main culprits behind 80% HCC globally [1]. Infection with HBV and HCV is one of the prominent source of chronic liver infections worldwide. It is estimated that approximately 350 million individuals are HBV and 200 million individuals are HCV carriers globally [3,4].Although the knowledge about the molecular virology of these viruses is well established, the molecular mechanism from acute infection to HCC development are still not well known. The research data showed that HCC is a typical inflammation-related cancer but the exact mechanism is still not clear. Viral induced liver injury is mainly due to human immune response against viruses and there is no evidence that viral replication plays any role in liver injury directly [5]. T cells are recruited to liver during the acute stage of HBV and HCV infection. These cells are the key players in anti-viral immune response and help for resolution of infection as well as prevents development of chronic infection. However, there are studies supporting the role of these T cells in liver injury during HBV and HCV infection [6,7]. In liver injury the pathological process resulted into hostile environment which leads to survival of intrahepatic stem cells, also known as hepatic progenitor cells (in humans) rather than the regenerated hepatocytes. Abnormal dedifferentiation of hepatic progenitor cells during HBV/HCV infection under the influence of immune cells and certain cytokines, may lead to the tumorigenesis of human hepatocellular carcinoma [8,9].Pakistan is a country with very high burden of viral hepatitis. Available data showed that there are around nine million HBV [10] and 11 million HCV carriers in Pakistan [11,12]. It is difficult to study the natural history of these diseases. The asymptomatic infection, difficulty to ascertain exact time of infection onset, data collection from general population, different risk groups and persons with multiple risk factors make it more difficult to generalize the natural history of the disease to whole country or whole population. However, it can be estimated that around 5% to 10% of chronic virally infected individuals develop HCC [13]. In recent years HBV infection goes down probably due to massive vaccination campaign by Government but the burden of HCV is on raise. Although the country is endemic for these infections but data regarding the prevalence of HBV and ...

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Hepatocarcinogenesis associated with hepatitis B, delta and C viruses

Cited by 44 publications

References 132 publications

Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy

Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy

Hepatitis D, B and C virus (HDV/HBV/HCV) coinfection as a diagnostic problem and therapeutic challenge

Hepatocellular Carcinoma in Pakistan: An Insight into Future

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