The British Society of Gastroenterology guidelines on the management of cholangiocarcinoma were originally published in 2002. This is the first update since then and is based on a comprehensive ...review of the recent literature, including data from randomised controlled trials, systematic reviews, meta-analyses, cohort, prospective and retrospective studies.
Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of ...controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV.
Background and Aims
GS‐9688 (selgantolimod) is a toll‐like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Antiviral activity of GS‐9688 has previously been ...evaluated in vitro in HBV‐infected hepatocytes and in vivo in the woodchuck model of CHB. Here we evaluated the potential of GS‐9688 to boost responses contributing to viral control and to modulate regulatory mediators.
Approach and Results
We characterized the effect of GS‐9688 on immune cell subsets in vitro in peripheral blood mononuclear cells of healthy controls and patients with CHB. GS‐9688 activated dendritic cells and mononuclear phagocytes to produce IL‐12 and other immunomodulatory mediators, inducing a comparable cytokine profile in healthy controls and patients with CHB. GS‐9688 increased the frequency of activated natural killer (NK) cells, mucosal‐associated invariant T cells, CD4+ follicular helper T cells, and, in about 50% of patients, HBV‐specific CD8+ T cells expressing interferon‐γ. Moreover, in vitro stimulation with GS‐9688 induced NK‐cell expression of interferon‐γ and TNF‐α, and promoted hepatocyte lysis. We also assessed whether GS‐9688 inhibited immunosuppressive cell subsets that might enhance antiviral efficacy. Stimulation with GS‐9688 reduced the frequency of CD4+ regulatory T cells and monocytic myeloid‐derived suppressor cells (MDSCs). Residual MDSCs expressed higher levels of negative immune regulators, galectin‐9 and programmed death‐ligand 1. Conversely, GS‐9688 induced an expansion of immunoregulatory TNF‐related apoptosis‐inducing ligand+ NK cells and degranulation of arginase‐I+ polymorphonuclear MDSCs.
Conclusions
GS‐9688 induces cytokines in human peripheral blood mononuclear cells that are able to activate antiviral effector function by multiple immune mediators (HBV‐specific CD8+ T cells, CD4+ follicular helper T cells, NK cells, and mucosal‐associated invariant T cells). Although reducing the frequency of some immunoregulatory subsets, it enhances the immunosuppressive potential of others, highlighting potential biomarkers and immunotherapeutic targets to optimize the antiviral efficacy of GS‐9688.
At present chronic liver disease (CLD), the third commonest cause of premature death in the United Kingdom is detected late, when interventions are ineffective, resulting in considerable morbidity ...and mortality. Injury to the liver, the largest solid organ in the body, leads to a cascade of inflammatory events. Chronic inflammation leads to the activation of hepatic stellate cells that undergo trans-differentiation to become myofibroblasts, the main extra-cellular matrix producing cells in the liver; over time increased extra-cellular matrix production results in the formation of liver fibrosis. Although fibrogenesis may be viewed as having evolved as a "wound healing" process that preserves tissue integrity, sustained chronic fibrosis can become pathogenic culminating in CLD, cirrhosis and its associated complications. As the reference standard for detecting liver fibrosis, liver biopsy, is invasive and has an associated morbidity, the diagnostic assessment of CLD by non-invasive testing is attractive. Accordingly, in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice. Due to differing disease prevalence and treatment efficacy, disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection. To facilitate this, a review of the pathogenesis of both conditions is also conducted. Finally, the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed, including the current use of antifibrotic therapy.
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•Study patients had recurrent hepatitis C infection following liver transplantation.•The study included patients with cirrhosis (18%) and genotype 3 HCV (44%).•Twelve weeks of ...sofosbuvir/velpatasvir resulted in an SVR12 of 96%.•No liver transplant rejection episodes or deaths occurred.•Treatment did not impact immunosuppressive therapy.
Sofosbuvir, an NS5B inhibitor, combined with velpatasvir, an NS5A inhibitor (SOF/VEL), produces high sustained virologic response rates 12 weeks after treatment (SVR12) in patients with genotype 1–6 HCV infection, and has no anticipated clinically relevant drug-drug interactions with immunosuppressants. This study evaluated the safety and efficacy of SOF/VEL in adults with recurrent chronic genotype 1–4 HCV infection after liver transplant.
Patients received SOF/VEL 400/100 mg daily for 12 weeks. Patients could be treatment experienced or treatment naïve with no cirrhosis or with compensated cirrhosis. The primary endpoints were SVR12 and discontinuations due to adverse events.
A total of 79 patients were enrolled and treated in this study (37 47% had genotype 1, 3 4% genotype 2, 35 44% genotype 3, and 4 5% genotype 4 HCV). Of these, 81% were male, 82% were white, 18% had compensated cirrhosis, and 59% were treatment experienced. The most commonly used immunosuppressants were tacrolimus (71%), mycophenolic acid (24%), cyclosporine (14%), and azathioprine (11%). Median (range) time from liver transplantation was 7.5 (0.3, 23.9) years. The SVR12 rate was 96%. By genotype, SVR12 rates were 95% (genotype 1), 100% (genotype 2), 97% (genotype 3), and 100% (genotype 4). Two patients experienced virologic relapse: one with genotype 1a infection was non-cirrhotic and treatment naïve, and one with genotype 3 infection was non-cirrhotic and treatment experienced. One patient discontinued SOF/VEL due to hyperglycemia. No serious or severe adverse events were deemed SOF/VEL-related by the investigator, and no liver transplant rejection episodes or deaths occurred during the study period.
Treatment with SOF/VEL for 12 weeks was highly effective and well tolerated in genotype 1–4 HCV-infected liver transplant recipients with and without cirrhosis.
Sofosbuvir/velpatasvir is a combination of two drugs in one tablet that is approved for the treatment of patients with chronic hepatitis C virus (HCV) infection. When patients with chronic HCV infection receive a liver transplant, the HCV infection usually recurs, and damages the transplanted liver. This study tested the effects of 12 weeks of sofosbuvir/velpatasvir treatment in patients who had HCV recurrence after a liver transplant. Three months following the end of treatment, 96% of patients were cured of HCV infection.
Clinical trial number: NCT02781571.
Liver disease is the fifth most common cause of premature death in the Western world, with the irreversible damage caused by fibrosis, and ultimately cirrhosis, a primary driver of mortality. Early ...detection of fibrosis would facilitate treatment of the underlying liver disease to limit progression. Unfortunately, most cases of liver disease are diagnosed late, with current strategies reliant on invasive biopsy or fragile lab‐based antibody technologies. A robust, fully synthetic fluorescent‐polymer sensor array is reported, which, rapidly (in 45 minutes), detects liver fibrosis from low‐volume serum samples with clinically relevant specificity and accuracy, using an easily readable diagnostic output. The simplicity, rapidity, and robustness of this method make it a promising platform for point‐of‐care diagnostics for detecting and monitoring liver disease.
A fluorescent‐polymer‐based sensor array, capable of distinguishing patients with and without liver fibrosis from a small volume of serum is demonstrated. The robust sensor operates in minutes rather than hours and does not require the cold‐chain transport and storage of the existing antibody‐based techniques, making it an excellent candidate for translation into a point‐of‐care diagnostic tool.
Natural killer cells are a key component in the immune control of viral infections. Their functions are controlled by inhibitory receptors for major histocompatability complex (MHC) class I, ...including the killer cell immunoglobulin‐like receptors (KIR). KIR2DL3 in combination with its cognate human leukocyte antigen (HLA)‐C ligand has been shown to be associated with spontaneous resolution of viremia following hepatitis C virus (HCV) infection. In order to determine if this gene combination is advantageous across all potential outcomes following HCV exposure, we studied individuals with apparent resistance to HCV infection who remain seronegative and aviremic despite long‐term injection drug use and also individuals chronically infected with HCV who successfully clear HCV with treatment. Homozygosity for KIR2DL3 in combination with group 1 HLA‐C allotypes was more frequent in exposed seronegative aviremic individuals as compared to those with chronic HCV (25.0% versus 9.7%, P = 0.003, odds ratio OR = 3.1, 95% confidence interval CI = 1.3‐7.1) in a model similar to that found for those spontaneously resolving HCV. In individuals undergoing treatment for HCV, those with KIR2DL3 and group 1 HLA‐C were more likely to make a sustained virological response (SVR) (P = 0.013, OR = 2.3, 95% CI = 1.1‐4.5). KIR and HLA‐C protection in both treatment response and spontaneously resolving HCV was validated at the allelic level, in which KIR2DL3‐HLA‐Cw*03 was associated with SVR (P = 0.004, OR = 3.4, 95% CI = 1.5‐8.7) and KIR2DL3/KIR2DL3‐HLA‐Cw*03 was associated with spontaneous resolution of HCV infection (P = 0.01, OR = 2.3, 95% CI = 1.2‐4.4). Conclusion: KIR and HLA‐C genes are consistently beneficial determinants in the outcome of HCV infection. This advantage extends to the allelic level for both gene families. (HEPATOLOGY 2010.)
Background and Aims
The rising incidence of chronic liver disease (CLD) has increased the need for early recognition. This systematic review assesses the diagnostic accuracy of the enhanced liver ...fibrosis (ELF) test in cases of advanced fibrosis and cirrhosis due to multiple etiologies in at‐risk populations.
Methods
Studies evaluating the ELF accuracy in identifying advanced fibrosis or cirrhosis, defined as METAVIR stage F ≥ 3 and F = 4 or equivalent, in patients with non‐alcoholic fatty liver disease (NAFLD), alcohol liver disease (ALD), or viral hepatitis were included. Liver biopsy was used as the reference standard. Medline and Embase databases were searched. The QUADAS‐2 tool was used as a framework to assess risk of bias and applicability. The area under the receiver operator curve (AUROC) was extracted as a summary measure of diagnostic accuracy.
Results
Thirty‐six studies were included: 11 hepatitis C, 4 hepatitis B, 9 NAFLD, 2 ALD, and 10 mixed. The ELF test showed good diagnostic performance in detecting advanced fibrosis in patients with viral hepatitis (AUROC 0.69 to 0.98) and excellent performance in NAFLD (AUROC 0.78 to 0.97) and ALD (AUROC from 0.92 to 0.94). There is also evidence of good diagnostic performance for detecting cirrhosis in patients with viral hepatitis (AUROC 0.63 to 0.99), good performance in NAFLD (AUROC 0.85 to 0.92), and excellent performance in patients with ALD (AUROC 0.93 to 0.94).
Conclusion
This systematic review supports the use of the ELF test across a range of CLD as a possible alternative to liver biopsy in selected cases.
The detection of fibrosis within nonalcoholic fatty liver disease (NAFLD) is important for ascertaining prognosis and the stratification of patients for emerging therapeutic intervention. We ...validated the Original European Liver Fibrosis panel (OELF) and a simplified algorithm not containing age, the Enhanced Liver fibrosis panel (ELF), in an independent cohort of patients with NAFLD. Furthermore, we explored whether the addition of simple markers to the existing panel test could improve diagnostic performance. One hundred ninety‐six consecutively recruited patients from 2 centers were included in the validation study. The diagnostic accuracy of the discriminant scores of the ELF panel, simple markers, and a combined panel were compared using receiver operator curves, predictive values, and a clinical utility model. The ELF panel had an area under the curve (AUC) of 0.90 for distinguishing severe fibrosis, 0.82 for moderate fibrosis, and 0.76 for no fibrosis. Simplification of the algorithm by removing age did not alter diagnostic performance. Addition of simple markers to the panel improved diagnostic performance with AUCs of 0.98, 0.93, and 0.84 for the detection of severe fibrosis, moderate fibrosis, and no fibrosis, respectively. The clinical utility model showed that 82% and 88% of liver biopsies could be potentially avoided for the diagnosis of severe fibrosis using ELF and the combined panel, respectively. The ELF panel has good diagnostic accuracy in an independent validation cohort of patients with NAFLD. The addition of established simple markers augments the diagnostic performance across different stages of fibrosis, which will potentially allow superior stratification of patients with NAFLD for emerging therapeutic strategies. (HEPATOLOGY 2007.)
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