Background & Aim: Hepatitis D virus (HDV) superinfection of patients with chronic HBV infection results in rapid progression to liver cirrhosis. Little is known about HDV-specific T cells and how they contribute to the anti-virus immune response and liver disease pathogenesis. Methods: We isolated peripheral blood mononuclear cells from 28 patients with chronic HDV and HBV infection, identified HDV-specific CD8 + T-cell epitopes and characterized HDV-specific CD8 + T cells. We associated these with HDV sequence variations and clinical features of patients. Results: We identified 6 CD8 + T-cell epitopes; several were restricted by multiple HLA class I alleles. HDV-specific CD8 + T cells were as frequent as HBV-specific CD8 + T cells, but less frequent than T cells with specificity for cytomegalovirus, Epstein-Barr virus, or influenza virus.

Background Nonsteroidal anti-inflammatory drugs (NSAIDs), conventional and selective cyclooxygenase-2 (COX-2) inhibitors, are among the most widely used medications for the treatment of various inflammatory conditions. There is strong evidence of a possible association between the use of these drugs and the relapse of inflammatory bowel diseases (IBD). Objective Our objective was to examine the literature regarding the exacerbation of IBD associated with the use of conventional NSAIDs and selective COX-2 inhibitors and the underlying pathogenetic mechanisms. Study design We reviewed articles, including original papers, controlled trials, case reports, reviews, and editorials published in English at the PubMed, Scopus Database, and Science Direct database, searching with the following keywords: nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, Coxibs, inflammatory bowel diseases (IBD), ulcerative colitis (UC), Crohn's disease (CD). Results There is substantial evidence that exacerbation of IBD happens after treatment with NSAIDs, but the available data remain conflicting, and it is not clear whether selective COX-2 inhibitors are safer than traditional NSAIDs. However, there is some evidence that selective COX-2 inhibition and COX-1 inhibition (with low-dose aspirin) appear to be well-tolerated in the short term. Regarding the mechanisms of relapse, the reduction of prostaglandins appears to be the hallmark of the NSAIDs adverse effects. Conclusions Further randomized, double-blind, controlled trials should be performed to address this issue, and more in vitro studies to identify the pathways involved are required.

Activation of hepatitis B virus (HBV)-specific CD8 T cells by therapeutic vaccination may promote sustained control of viral replication by clearance of covalently closed circular DNA from infected hepatocytes. However, little is known about the exact targets of the CD8 T-cell response and whether HBV reproducibly evades CD8 T-cell immune pressure by mutation. The aim of this study was to address if HBV reproducibly selects substitutions in CD8 T-cell epitopes that functionally act as immune escape mutations. The HBV core gene was amplified and sequenced from 148 patients with chronic HBV infection, and the human leukocyte antigen (HLA) class I genotype (A and B loci) was determined. Residues under selection pressure in the presence of particular HLA class I alleles were identified by a statistical approach utilizing the novel analysis package SeqFeatR. With this approach we identified nine residues in HBV core under selection pressure in the presence of 10 different HLA class I alleles. Additional immunological experiments confirmed that seven of the residues were located inside epitopes targeted by patients with chronic HBV infection carrying the relevant HLA class I allele. Consistent with viral escape, the selected substitutions reproducibly impaired recognition by HBV-specific CD8 T cells. Conclusion: Viral sequence analysis allows identification of HLA class I-restricted epitopes under reproducible selection pressure in HBV core; the possibility of viral escape from CD8 T-cell immune pressure needs attention in the context of therapeutic vaccination against HBV. (HEPATOLOGY 2015;62:47-56) D espite an effective vaccine against hepatitis B virus (HBV) being available, chronic infections associated with the risk of progressive liver disease are an enormous public health problem affecting more than 240 million people worldwide. Effective suppression of viral replication by inhibition of the viral polymerase with nucleos(t)ide analogues is possible, but in most cases long-term or even lifelong treatment is necessary to avoid recurrence of viral replication. In this setting the concept of therapeutic vaccination potentially is an attractive strategy to achieve viral clearance.

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Simultaneous detection of anti-HBs and HBV DNA is a rare serological combination and has been described in acute and chronic HBV infection. To scrutinize viral and clinical patterns associated with concurrent detection of anti-HBs and HBV DNA. Simultaneous detection of anti-HBs and HBV DNA was observed in 64/1444 (4.4%) patients treated for HBV infection at the University Hospital of Essen from 2006 to 2016 (8 with acute, 20 with reactivated, and 36 chronic HBV infection). Clinical data and laboratory parameters were analyzed. Regions of the small hepatitis B surface antigen (SHB) and the reverse transcriptase (RT) were sequenced using next generation sequencing (NGS). Among the 64 patients with detectable HBV DNA and anti-HBs, 17 were HBsAg negative (HBsAg[-]), and two had acute liver failure. Patients with acute HBV infection had fewer genotype specific amino acid substitutions in the SHB region than patients with reactivated HBV infection (4 [4.5] vs 9 [16.25], P = 0.043). However, we could observe a significantly higher number of mutations in the a-determinant region when comparing chronically infected patients to patients with acute infection (0 [1] vs 1 [1], P = 0.044). The ratio of nonsynonymous to synonymous mutations (Ka/Ks) was on average >1 for the SHB region and <1 for the RT region. The Ka/Ks ratio (>1) in the SHB region indicates that anti-HBs might have exerted selection pressure on the HBsAg. In three cases the diagnosis of acute HBV infection would have been at least delayed by only focusing on HBsAg testing.

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Infection with the hepatitis D virus induces the most severe form of chronic viral hepatitis, affecting over 12 million people worldwide. Chronic HDV infection leads to rapid development of liver cirrhosis and hepatocellular carcinoma in ~70% of patients within 15 years of infection. Recent evidence suggests that an interplay of different components of the immune system are contributing to viral control and may even be implicated in liver disease pathogenesis. This review will describe general concepts of antiviral immune response and elicit the present evidence concerning the interplay of the hepatitis D virus with the immune system.