A. Wranke

Anti-HDV IgM as a Marker of Disease Activity in Hepatitis Delta

Background Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker. Methods Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6–12). Results Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05). Conclusions Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.

Interferon-free therapy of chronic hepatitis C with direct-acting antivirals does not change the short-term risk for de novo hepatocellular carcinoma in patients with liver cirrhosis

Hepatitis C virus (HCV) clearance with IFN‐based therapies reduces the incidence of hepatocellular carcinoma (HCC). There has been some debate if IFN‐free therapy with direct‐acting antivirals alters the risk for HCC.

Antiviral treatment and liver-related complications in hepatitis delta

Hepatitis delta virus (HDV) is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG‐IFNα) is effective in only 25%‐30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long‐term outcome of hepatitis delta in relation to different antiviral treatment strategies. We studied 136 anti‐HDV‐positive patients who were followed for at least 6 months in a retrospective single‐center cohort (mean time of follow‐up, 5.2 years; range, 0.6‐18.8). Liver cirrhosis was already present in 62 patients at first presentation. Twenty‐nine percent of patients did not receive any antiviral treatment, 38% were treated with interferon alfa (IFNα)‐based therapies, and 33% received nucleos(t)ide analogues (NAs) only. Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, and variceal bleeding), hepatocellular carcinoma, liver transplantation, and liver‐related death developed in 55 patients (40%). Patients who received IFNα‐based therapies developed clinical endpoints less frequently than those treated with NA (P = 0.02; HR, 4.0) or untreated patients (P = 0.05; HR, 2.2; 17%, 64%, and 44%), respectively, which was significant in both chi‐square and Kaplan‐Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long‐term outcome in multivariate logistic regression analysis (P = 0.04; odds ratio, 0.25; 95% confidence interval, 0.07‐0.9). Loss of HDV RNA during follow‐up was more frequent in IFNα‐treated patients and strongly linked with a lower likelihood to experience liver‐related complications. Conclusion: IFNα‐based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. (Hepatology 2017;65:414‐425).

Antiviral therapy of hepatitis delta virus infection — progress and challenges towards cure

Hepatitis B-/D-virus co-infection causes the most severe form of viral hepatitis, frequently leading to liver cirrhosis, hepatic decompensation and consecutive liver-related mortality. Treatment options for hepatitis delta are limited. The only recommended therapy is pegylated interferon alpha which leads to virological responses in about 25-30% of patients. However, interferon therapy is associated with frequent side-effects and late HDV RNA relapses have been described during long-term follow even in patients who were HDV RNA negative 24 weeks after the end of therapy. Thus, alternative treatment options are urgently needed. Clinical studies have been performed exploring prenylation inhibitors, viral entry inhibitors and nucleic acid polymers to block particle release. We here summarize the progress and challenges towards cure of HDV infection.

Non-invasive fibrosis score for hepatitis delta.

Identifying advanced fibrosis in chronic hepatitis delta patients and thus in need of urgent treatment is crucial. To avoid liver biopsy, non‐invasive fibrosis scores may be helpful but have not been evaluated for chronic hepatitis delta yet.

Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN)

Chronic hepatitis D (delta) is a major global health burden. Clinical and virological characteristics of patients with hepatitis D virus (HDV) infection and treatment approaches in different regions world‐wide are poorly defined.

The third signal cytokine IL-12 rather than immune checkpoint inhibitors contribute to the functional restoration of hepatitis D virus-specific T-cells.

Background. Hepatitis D virus (HDV) infection affects 15–20 million individuals worldwide and causes severely progressive hepatitis. It is unknown to what extent cellular immune responses contribute to liver disease and control of viral replication in HDV infection. Methods. Immune cell frequencies and phenotypes were determined in 49 HDV-infected patients, 25 individuals with hepatitis B virus monoinfection and 18 healthy controls. T-cell proliferative and cytokine-producing capacities were analyzed by stimulation with overlapping peptides spanning the large HDV antigen. To restore T-cell responses, blocking antibodies (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed death ligand 1) or proinflammatory cytokines (interleukin [IL] 12) were used. Results. Immune cell frequencies and phenotypes did not vary between the groups. Exclusively, the senescence marker CD57 was significantly up-regulated in CD8+ T cells from patients with hepatitis delta. HDV-specific T-cell proliferation and cytokine production were weak and could only partly be rescued by blockade of the programmed death 1 pathway. However, a more robust and consistent increase in HDV-specific CD4+ and CD8+ T-cell responses was evident when the third signal cytokine IL-12 was added, which also affected cytomegalovirus- and Epstein-Barr virus–specific T cells. Conclusions. This investigation of virus-specific T-cell immunity in patients with HDV infection, the largest to date, revealed premature aging of immune cells and impaired T-cell functionality. This could be restored by blocking inhibitory pathways and, in particular, by supplementing with IL-12.

Dose-dependent impact of proton pump inhibitors on the clinical course of spontaneous bacterial peritonitis

Spontaneous bacterial peritonitis is a severe complication in patients with cirrhosis leading to acute kidney injury, hepatic encephalopathy and a high mortality. In this study, we aimed to investigate the impact of proton pump inhibitors and the potential relevance of the taken dosage on the incidence and clinical course of spontaneous bacterial peritonitis.

Viral dominance patterns in chronic hepatitis delta determine early response to interferon alpha therapy

Chronic hepatitis D is caused by coinfection of hepatitis B and hepatitis D virus. While HDV is the dominant virus over HBV in the majority of cases, mechanisms and consequences of viral dominance are largely unknown. We aimed to investigate associations between viral dominance patterns and patients’ characteristics and inflammatory features; 109 HDV‐infected patients treated with PEG‐IFNa‐2α within the international multicentre, prospective HIDIT‐2 trial were studied. Patients were classified as D‐ or B‐dominant if the viral load of one virus exceeded that of the other virus by more than 1log10. Otherwise, no viral dominance (ND) was described. We used Luminex‐based multiplex technology to study 50 soluble immune mediators (SIM) in pretreatment samples of 105 HDV RNA‐positive patients. Dominance of HDV was evident in the majority (75%) of cases. While only 7% displayed B‐dominance, 17% showed nondominance. D‐dominance was associated with downregulation of 4 interleukins (IL‐2ra, IL‐13, IL‐16 and IL‐18) and 5 chemokines/cytokines (CTACK (CCL27), MCP‐1 (CCL2), M‐CSF, TRAIL and ICAM‐1) while no analyte was increased. In addition, D‐dominance could be linked to a delayed HDV RNA response to pegylated interferon as patients with B‐dominance or nondominance showed higher early HDV RNA responses (61% at week 12) than D‐dominant patients (11%; P < .001). In conclusion, this study revealed unexpected effects of viral dominance on clinical and immunological features in chronic hepatitis delta patients. Individualizing PEG‐IFNa‐2α treatment duration should consider viral dominance. Overall, our findings suggest an activated but exhausted IFN system in D‐dominant patients.