Analysis of protective cellular immune responses against hepatitis C virus.

Hepatitis C virus (HCV) infection is a major cause of liver damage, with virus-induced end-stage disease such as liver cirrhosis and hepatocellular carcinoma resulting in a high rate of morbidity and mortality worldwide. There is now considerable evidence that CD4+ T cell responses to HCV play an important role in the outcome of infection. However, the functional status of HCV-specific CD4+ve T cells in persistent infection is poorly understood and it may be necessary to use a variety of techniques in their detection and analysis. The aim of my thesis is to determine aspects of cellular immunity that are associated with viral control, here mainly focusing on CD4+ T cell responses. The first data chapter (chapter 3) gives an analysis of RlBA-indeterminate blood donors negative for HCV-PCR in whom HCV-specific T cell responses were identified, typically focused on core-derived peptides, suggesting previous exposure to HCV. I next analyse the cytokine secretion patterns in chronically HCV-infected patients and compare them with those with resolved infection (chapter 4). Using overlapping peptides, I have been able to identify HCV-specific CD4+ T cells in persistent infection that recognise the mainly conserved core region. These cells characteristically produce IFN-y but not IL-2 (IFN-y+/IL-2'). In the next chapter (chapter 5) I show that these cells have lost their ability to proliferate (IFN-y+/IL-2" /proliferation10). . In the final data chapter (chapter 6), I studied the T cell responses in a cohort of seven individuals with antibody-deficiency (CVID), who received early interferon therapy after HCV infection through contaminated y-globulin. Even in the absence of antibody responses, substantial HCV-specific T cell responses could be recovered. The implications of my findings are discussed at the end of each data chapter. A general discussion of the overall findings and future work that may evolve from this work is outlined in chapter 7. Here, I also give some preliminary data on a cohort of acutely HCV-infected individuals with and without HIV infection, showing that HCV-specific CD4+ T cell responses in acute HCV are significantly reduced in co-infection when compared with HCV mono-infection. Overall the data in this thesis provide novel insights into the immune status in specific patient groups, and the functional status of HCV-specific CD4+ T cells in persistent infection

Rational development and application of biomarkers in the field of autoimmunity: A conceptual framework guiding clinicians and researchers.

Clear guidance is needed in the development and implementation of laboratory biomarkers in medicine. So far, no standardized phased approach is established that would pilot researchers and clinicians in this process. This leads to often incompletely validated biomarkers, which can bear the consequence of wrong applications, misinterpretation and inadequate management in the clinical context. In this conceptual article, we describe a stepwise approach to develop and comprehensively validate laboratory biomarkers. We will delineate basic steps including technical performance, pre-analytical issues, and biological variation, as well as advanced aspects of biomarker utility comprising interpretability, diagnostic and prognostic accuracy, and health-care outcomes. These aspects will be illustrated by using well-known examples from the field of immunology. The application of this conceptual framework will guide researchers in conducting meaningful projects to develop and evaluate biomarkers for the use in clinical practice. Furthermore, clinicians will be able to adequately interpret pre-clinical and clinical diagnostic literature and rationally apply biomarkers in clinical practice. Improvement in the implementation and application of biomarkers might relevantly change the management and outcomes of our patients for the better

Elbasvir/Grazoprevir, an Alternative in Antiviral Hepatitis C Therapy in Patients under Amiodarone Treatment

A sofosbuvir/ledipasvir combination is part of a first-line treatment of hepatitis C. However, in patients concurrently treated with amiodarone, cardiac side effects have been described, resulting in an official warning in 2015 by the American Food and Drug Administration and the European Medicines Agency when combining those substances. This deprived numerous hepatitis C patients with concurrent cardiovascular problems of receiving this highly effective treatment. Here we present a treatment alternative with an elbasvir/grazoprevir regimen, based on our successful treatment of a patient under concurrent amiodarone therapy. Our observations indicate that patients treated with amiodarone can finally benefit from effective antiviral therapy

Autoimmune hepatitis triggered by SARS-CoV-2 vaccination.

The development of autoimmune diseases has been reported after SARS-CoV-2 infection. Vaccination against SARS-CoV-2 could also trigger auto-immunity, as it has been described with other vaccines. An aberrant immune response induced by molecular mimicry and bystander activation, especially in predisposed individuals, is a potential mechanism. We report the case of a 76-year-old woman with Hashimoto thyroiditis and prior COVID-19 infection who developed severe autoimmune hepatitis (with typical features including strongly positive anti-smooth muscle antibody and markedly elevated immunoglobulins G, as well as typical histological findings) following SARS-CoV-2 vaccination (mRNA-1273 SARS-CoV-2 vaccine, Moderna®). The link between SARS-CoV-2 vaccination and the development of autoimmune diseases needs to be further investigated. Although a causality relationship cannot be proven, caution may be warranted when vaccinating individuals with known autoimmune diseases

Belimumab treatment in autoimmune hepatitis and primary biliary cholangitis - a case series.

BACKGROUND The majority of patients with autoimmune hepatitis (AIH) achieve complete remission with established treatment regiments. In patients with intolerance or insufficient response to these drugs, the remaining options are limited and novel treatment approaches necessary. In primary biliary cholangitis (PBC), ursodeoxycholic acid (UDCA) and fibrates have improved prognosis dramatically, but there remains a proportion of patients with refractory disease.In patients with refractory AIH and/or PBC, we used a novel treatment strategy with the anti-B cell activating factor, belimumab. The first three patients had concomitant Sjögren's disease. The connecting element between all three diseases is B cell activation, including elevated levels of the B cell activating factor (BAFF). Furthermore, belimumab has been shown to be beneficial in Sjögren's disease. AIMS AND METHODS To retrospectively investigate treatment response in six patients with AIH or PBC with or without concomitant Sjögren's disease treated with the anti-BAFF therapy belimumab at the University Hospital in Bern, Switzerland. RESULTS In all three patients with AIH, belimumab improved disease control and helped by-pass or reduce problematic side effects from corticosteroids and calcineurin inhibitors. In PBC patients (n = 3), there was no clear improvement of liver function tests, despite reduction or normalization of IgM. All patients with concomitant Sjögren's disease (n = 3) had an improvement of sicca symptoms and two out of three patients experienced an initially marked reduction in fatigue, which lessened over time. CONCLUSIONS Belimumab may be a promising treatment option for patients with AIH and further investigations are needed. In PBC however, response was not convincing. The effects on sicca symptoms and fatigue were encouraging

Mycophenolate mofetil as second line treatment in autoimmune hepatitis – A retrospective single center analysis

Background: Most patients with autoimmune hepatitis respond to standard treatment with steroids and azathioprine. While the disease is usually fatal if untreated, patients who respond well to therapy have an excellent prognosis. Nevertheless, second-line treatment is necessary in approximately 20% of patients, due to either intolerance or insufficient response to first line treatment.While data for mycophenolate mofetil (MMF) in patients intolerant to azathioprine is encouraging, MMF seems of less benefit in patients with insufficient response to first line treatment, but analyzed data on this issue is limited. Aim: To evaluate the efficacy and safety of MMF as a second-line therapy in patients with AIH. Methods: Retrospective analysis of a monocentric database of AIH patients who received medical care from 2000 to 2022. Clinical, immunological and biochemical parameters were assessed at different time points including last follow-up. Results: Overall, 144 patients with AIH were identified. Fifty out of 144 (35%) AIH patients received MMF. Forty (80%) received MMF due to first line treatment intolerance, while ten (20%) due to insufficient response to first line treatment.Remission with MMF monotherapy was 81.5% in the intolerance group versus 30% in the insufficient response group. Patients switched to MMF because of an insufficient response, more often needed additional prednisolone doses higher than 5 mg/day, a switch to third-line treatment or combination regiments, to achieve disease control. Conclusions: Patients treated with MMF because of intolerance to first line treatment show a good disease control under MMF in the majority of cases. Efficacy is considerably lower in the patients switched to MMF because of an insufficient response to first line treatment

Hepatic manifestations of drug reaction with eosinophilia and systemic symptoms syndrome

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening drug reaction, which can affect multiple organs. Patients with DRESS syndrome and hepatic manifestations may present alterations ranging from mild hepatitis to acute liver failure. The diagnosis might be difficult, and the management of these patients is challenging. This report analyzes a series of five cases reporting the clinical presentation, which ranged from acute hepatitis to liver failure, and discussed their treatment

Short‐term fully closed‐loop insulin delivery using faster insulin aspart compared to standard insulin aspart in type 2 diabetes

We evaluated the efficacy and safety of short‐term fully closed‐loop insulin delivery using faster versus standard insulin aspart in type 2 diabetes. Fifteen adults with insulin‐treated type 2 diabetes underwent 22 hours of closed‐loop insulin delivery with either faster or standard insulin aspart in a double‐blind randomised crossover design. Basal‐bolus regimen was replaced by model predictive control algorithm‐directed insulin delivery based on sensor glucose levels. The primary outcome was time with plasma glucose in target range (5.6‐10.0mmol/l) and did not differ between treatments (mean difference [95%CI] ‐3.3% [8.2;1.7], p=0.17). Mean glucose and glucose variability were comparable, as was time spent below and above target range. Hypoglycaemia (<3.5mmol/l) occurred once with faster insulin aspart and twice with standard insulin aspart. Mean total insulin dose was higher with faster insulin aspart (mean difference [95%CI] 3.7U [0.7;6.8], p=0.021). No episodes of severe hypoglycaemia or other serious adverse events occurred. In conclusion, short‐term fully closed‐loop in type 2 diabetes may require higher dose of faster insulin aspart compared to standard insulin aspart to achieve comparable glucose control.Swiss National Science Foundation (P1BEP3_165297), UDEM Scientific Fund, Cambridge Biomedical Research Centre - NIHR