The hepatitis D virus (HDV), the smallest virus known to infect man, causes the most severe form of chronic viral hepatitis, hepatitis delta. It is estimated that about 15 to 20 million people are ...suffering from chronic HDV infection. HDV is a defective satellite virus depending on the hepatitis B surface antigen (HBsAg) for transmission. Chronic hepatitis delta is associated with a rapid progression of liver fibrosis and a high prevalence of liver cirrhosis, even in younger patients. Immunization against hepatitis B virus (HBV) protects from HDV infection, but there is no specific vaccine against HDV available for HBsAg-positive individuals. Treatment options for hepatitis delta patients are limited. So far, only interferon-alpha has shown an antiviral efficacy against HDV. Recent trials showed sustained virological response rates concerning HDV in 25 %–30 % of patients treated with pegylated interferons. HDV is dominant over HBV in the majority of cases, but HBV DNA-positive subjects should be treated with HBV polymerase inhibitors. Combination therapy of pegylated interferon-alpha and adefovir showed a more pronounced HBsAg decline, but the exact role of combination therapies in hepatitis delta requires further investigation. Alternative future treatment strategies may include prenylation inhibitors and HBV entry inhibitors, which are in early clinical development.
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a poor prognosis and one for which immunotherapy remains a viable option. Experimental tumor models have shown that ...regulatory T cells, a functionally unique subset of T cells, can suppress effective antitumor immune responses. This suppression might explain the poor outcome of some of the immunotherapy protocols currently being used. A better understanding of the role of regulatory T cells in HCC is important for design of future immunotherapy-based clinical protocols. We have studied regulatory T cells from 84 patients with HCC and 74 controls, including healthy donors, patients with chronic hepatitis B virus and hepatitis C virus infection and nonviral liver cirrhosis. Regulatory T cells were identified by fluorescence-activated cell sorting using a panel of antibodies and by real-time PCR analysis for Foxp3 expression. Functional studies were done to analyze their inhibitory role. Finally, regulatory T cells were analyzed in tumors and ascites from patients with HCC. Patients with HCC have increased numbers of CD4+CD25+ regulatory T cells in their peripheral blood, which express high levels of HLA-DR, GITR, and low or no CD45RA. These cells were anergic toward T-cell receptor stimulation and, when cocultured with activated CD4+CD25- cells, potently suppressed their proliferation and cytokine secretion. There were also high numbers of regulatory T cells in tumor-infiltrating lymphocytes of HCC patients comparable with the increase in their peripheral blood. Our data suggest that the increase in frequency of regulatory T cells might play a role in modulation of the immune response against HCC and could be important in design of immunotherapeutic approaches.
Background and Aims
Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically investigate the ...involvement of Hippo signalling in HBV surface antigen (HBsAg)‐dependent neoplastic transformation.
Methods
Liver tissue and hepatocytes from HBsAg‐transgenic mice were examined for the Hippo cascade and proliferative events. Functional experiments in mouse hepatoma cells included knockdown, overexpression, luciferase reporter assays and chromatin immunoprecipitation. Results were validated in HBV‐related HCC biopsies.
Results
Hepatic expression signatures in HBsAg‐transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg‐transgenic hepatocytes. Suppression and inactivation of MST1/2 led to the loss of YAP phosphorylation and the induction of BMI1 expression in vivo and in vitro. Increased BMI1 directly mediated cell proliferation associated with decreased level of p16INK4a, p19ARF, p53 and Caspase 3 as well as increased Cyclin D1 and γ‐H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual‐luciferase reporter assays confirmed that the YAP/TEAD4 transcription factor complex bound and activated the Bmi1 promoter. In chronic hepatitis B patients, paired liver biopsies of non‐tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof‐of‐concept, treatment of HBsAg‐transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1‐related cell cycle.
Conclusion
HBV‐associated proliferative HCC might be related to the HBsAg‐YAP‐BMI1 axis and offer a potential target for the development of new therapeutic approaches.
Gastroenterology has made crucial advances in diagnostic and interventional endoscopic procedures, opening up improvements in the treatment of many patients. Thus, organ-preserving treatments are ...increasingly being made possible, replacing more invasive organ resecting surgical procedures. At the same time, the degree of complexity and risks varies widely between different endoscopic procedures. In many cases, simpler endoscopic procedures are now offered on an outpatient basis. Further potential for cross-sectoral performance of endoscopic procedures exists in the case of complex endoscopic procedures, which, however, require special structural, procedural and personnel requirements in order to provide quality-assured treatment, enable post-interventional monitoring and, if necessary, take measures to ensure the success of the treatment. We summarize the essential prerequisites and limitations for cross-sector performance of endoscopic procedures in gastroenterology.
Considerate patient selection is vital to ensure the best possible outcomes after transjugular intrahepatic portosystemic shunt (TIPS) insertion. However, data regarding the impact of intrapulmonary ...vascular dilatations (IPVDs) or hepatopulmonary syndrome (HPS) on the clinical course after TIPS implantation is lacking. Hence, this study aimed to investigate the relevance of IPVD and HPS in patients undergoing TIPS implantation.
Contrast enhanced echocardiography and blood gas analysis were utilized to determine presence of IPVD and HPS. Multivariable competing risk analyses were performed to evaluate cardiac decompensation (CD), hepatic decompensation (HD), and liver transplant (LTx)-free survival within 1 year of follow-up.
Overall, 265 patients were included, of whom 136 had IPVD and 71 fulfilled the HPS criteria. Patients with IPVD had lower Freiburg index of post-TIPS survival (FIPS) scores, lower creatinine, and more often received TIPS because of variceal bleeding. Presence of IPVD was associated with a significantly higher incidence of CD (hazard ratio HR, 1.756; 95% confidence interval CI, 1.011–3.048; P = .046) and HD (HR, 1.841; 95% CI, 1.255–2.701; P = .002). However, LTx-free survival was comparable between patients with and without IPVD (HR, 1.081; 95% CI, 0.630–1.855; P = .780). Patients with HPS displayed a trend towards more CD (HR, 1.708; 95% CI, 0.935–3.122; P = .082) and HD (HR, 1.458; 95% CI, 0.934–2.275; P = .097) that failed to reach statistical significance. LTx-free survival did not differ in those with HPS compared with patients without HPS, respectively (HR, 1.052; 95% CI, 0.577–1.921; P = .870).
Screening for IPVD before TIPS implantation could help to further identify patients at higher risk of CD and HD.
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Background
Transplanting kidneys from deceased donors with hepatitis C virus (HCV) viremia has been controversial for some time. Direct‐acting antiviral agents have been shown to be highly effective ...in treating HCV infection. We report our experience with transplanting kidneys from HCV‐positive donors with detectable viremia into HCV‐negative recipients, followed by early treatment with a sofosbuvir‐based antiviral regimen.
Methods
Data were collected from seven HCV‐negative recipients receiving kidneys from five deceased HCV‐viremic donors. Before transplantation, all intentional transplanted recipients had given informed consent regarding the acceptance of an HCV‐viremic kidney. Recipients were closely monitored after transplant with measurements of HCV viremia, liver and renal function, and trough levels of immunosuppressive drugs.
Results
Four donors were infected with HCV genotype 1; the other with HCV genotype 3a. HCV viremia was detectable in all seven renal transplant recipients within 3 days after transplant. After determination of HCV genotype, antiviral treatment with a sofosbuvir‐based regimen (sofosbuvir/ledipasvir, n = 4; sofosbuvir/velpatasvir, n = 3) was initiated within a median of 7 days after transplantation and was continued for 8 to 12 weeks. For all recipients, viral load was below the level of detection at the end of treatment, and all exhibited a sustained virologic response 12 weeks later. All recipients exhibited normal liver enzyme activity at the end of treatment. Renal allograft function and trough levels of tacrolimus remained stable.
Conclusions
Early administration of a sofosbuvir‐based regimen to HCV‐negative recipients of kidneys from HCV‐viremic donors is feasible and safe. The definition of an optimal therapeutic approach warrants further investigation.
At least 17% of the population in Germany has been infected with the hepatitis E virus (HEV); thus, HEV infections are more frequent than was previously assumed. However, fewer than 500 HEV ...infections were reported to the Robert Koch Institute in 2013.
Review of pertinent literature retrieved by a selective search in PubMed.
Persons living in Germany generally acquire hepatitis E infection within the country by consuming infected and undercooked pork; in rare cases, hepatitis E infections are imported from the tropics. HEV can be transmitted via blood products, blood transfusions, and organ transplantation. More than 99% of HEV infections are asymptomatic and self-limiting, but there are also severe cases with acute liver failure. Immunosuppressed persons can develop chronic HEV infection, potentially leading, within a few years, to liver cirrhosis with life-threatening sequelae. Moreover, HEV infection may be associated with extrahepatic manifestations such as Guillain-Barré syndrome. In two retrospectively evaluated case series, ribavirin was found to be active against HEV and can be used to treat either acute or chronic HEV infection.
Hepatitis E must be considered in the differential diagnosis of elevated hepatic enzyme levels and of systemic and neurological conditions of uncertain origin. The infection is usually self-limiting but can take a severe course in immunosuppressed persons. In such cases, ribavirin can be used as an antiviral treatment.
Hepatitis D virus (HDV) superinfection in patients with hepatitis B virus (HBV) is associated with rapid progression to liver cirrhosis and hepatocellular carcinoma. Treatment options are limited, ...and no vaccine is available. Although HDV-specific CD8+ T cells are thought to control the virus, little is known about which HDV epitopes are targeted by virus-specific CD8+ T cells or why these cells ultimately fail to control the infection. We aimed to define how HDV escapes the CD8+ T-cell–mediated response.
We collected plasma and DNA samples from 104 patients with chronic HDV and HBV infection at medical centers in Europe and the Middle East, sequenced HDV, typed human leukocyte antigen (HLA) class I alleles from patients, and searched for polymorphisms in HDV RNA associated with specific HLA class I alleles. We predicted epitopes in HDV that would be recognized by CD8+ T cells and corresponded with the identified virus polymorphisms in patients with resolved (n = 12) or chronic (n = 13) HDV infection.
We identified 21 polymorphisms in HDV that were significantly associated with specific HLA class I alleles (P < .005). Five of these polymorphisms were found to correspond to epitopes in HDV that are recognized by CD8+ T cells; we confirmed that CD8+ T cells in culture targeted these HDV epitopes. HDV variant peptides were only partially cross-recognized by CD8+ T cells isolated from patients, indicating that the virus had escaped detection by these cells. These newly identified HDV epitopes were restricted by relatively infrequent HLA class I alleles, and they bound most frequently to HLA-B. In contrast, frequent HLA class I alleles were not associated with HDV sequence polymorphisms.
We analyzed sequences of HDV RNA and HLA class I alleles that present epitope peptides to CD8+ T cells in patients with persistent HDV infection. We identified polymorphisms in the HDV proteome that associate with HLA class I alleles. Some variant peptides in epitopes from HDV were only partially recognized by CD8+ T cells isolated from patients; these could be mutations that allow HDV to escape the immune response, resulting in persistent infection. HDV escape from the immune response was associated with uncommon HLA class I alleles, indicating that HDV evolves, at the population level, to evade recognition by common HLA class I alleles.
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