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Background and aims Immune checkpoint inhibitors (ICI) are increasingly used in cancer therapy. Elevated liver enzymes frequently occur in patients treated with ICI but evaluation is poorly described. We sought to better understand causes of liver enzyme elevation, investigation and management. Methods Patients treated with anti-PD-1, PDL-1 or CTLA-4 therapy in Phase I/II clinical trials between August 2012 and December 2018 were included. Clinical records of patients with significant liver enzyme elevations were retrospectively reviewed. Results Of 470 ICI-treated patients, liver enzyme elevation occurred in 102 (21.6%), attributed to disease progression (56; 54.9%), other drugs/toxins (7; 6.9%), other causes (22; 21.6%) and ICI immunotoxicity (17; 16.7%; 3.6% of total cohort). Immunotoxicity was associated with higher peak ALT than other causes of enzyme elevation (N = 17; M = 217, 95% CI 145–324 for immunotoxicity, N = 103; M = 74, 95% CI 59–92 for other causes; ratio of means 0.34, 95% CI 0.19–0.60, p = Conclusions Liver enzyme elevation is common in patients receiving ICI, but often has a cause other than immunotoxicity. A biochemical signature with higher ALT and ALT/AST ratio, a history of prior ICI exposure and other organ immunotoxicities may help to identify patients at a higher likelihood of immunotoxicity. Liver biopsy can be safely deferred in most patients. We propose an approach to diagnostic evaluation in patients with liver enzyme elevations following ICI exposure.

Contains fulltext : 220003.pdf (Publisher’s version ) (Closed access) BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is associated with an increased risk of gallbladder cancer (GBC). Gallbladder polyps potentially harbour malignancy and thus international guidelines recommend prophylactic cholecystectomy for gallbladder polyps of any size in patients with PSC. To best inform patient care we sought to quantify the malignant risk of gallbladder polyps in patients with PSC. METHODS: A retrospective cohort study of patients followed in secondary and tertiary care settings in two large PSC clinics in North America was performed. RESULTS: In total, 453 patients were included with a median (IQR) follow-up time of 7.7 (4.1-12) years. A gallbladder polyp was radiographically detected in 16% (n = 71) with median size (range) of 4 (2-18) mm. In this group, post-cholecystectomy histology (n = 17) reported benign or no polyp in 77% (n = 13), dysplasia in 5.9% (n = 1) and malignancy in 18% (n = 3). The GBC rate was 8.8 (95% CI 1.8-25.7) per 1000 person-years in patients with a radiographically detected gallbladder polyp. GBC was associated with polyps >10 mm, interval growth or mass-like lesions on pre-operative imaging. In patients who did not have cholecystectomy (n = 50), the polyp was only transiently seen in 80% (n = 40), remained stable or decreased in size in 10% (n = 5) and increased in size in 6% (n = 3). The majority of gallbladder polyps did not show significant growth over time (0.041 mm/year [95% CI -0.017 to 0.249]). CONCLUSIONS: Most gallbladder polyps in patients with PSC are benign. Short-term surveillance imaging may be considered prior to recommending immediate cholecystectomy in patients with PSC without high-risk imaging features.

BACKGROUND & AIMS: Sofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England's National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure. METHODS: We collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response (SVR) in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon. RESULTS: We identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an SVR, compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid [E] at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system. CONCLUSIONS: A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV G3 containing this variant reduces odds of SVR. In addition, we identified rare combinations of variants in HCV G3 that reduce response to sofosbuvir.

Non-cirrhotic portal hypertension (NCPH) comprises a heterogeneous group of liver disorders causing portal hypertension without cirrhosis and carries a high risk of variceal bleeding. Recent guidelines, based largely on patients with viral cirrhosis, suggest low likelihood of high risk varices (HRV) in patients with a liver stiffness measurement (LSM) 150 × 109/L. In NCPH, LSM is often higher than healthy controls but lower than matched cirrhotic patients. The aim of this study was to assess whether LSM or other noninvasive assessments of portal hypertension could predict HRV in NCPH patients. Methods. Records of patients with NCPH seen at a single centre between 2007 and 2018 were reviewed retrospectively. Primary outcome measure was presence or absence of HRV at gastroscopy within 12 months of clinical assessment. Association of LSM or other clinical features of portal hypertension (spleen size, platelet count, platelet count/spleen length ratio (PSL), LSM-spleen length/platelet count ratio score (LSP)) with HRV and ability of these variables to predict HRV was analysed. Results. Of 44 patients with NCPH who met inclusion criteria, 34% (15/44) had HRV. In a multivariate model, spleen size and PSL correlated with HRV but platelet count, LSM, and LSP did not (spleen size: β = 0.35, p = 0.02; OR 1.42, 95% CI 1.06-1.92; PSL: β = -1.47, p = 0.02; OR 0.23, 95% CI 0.07-0.80). There was no significant difference between spleen size and PSL in predicting HRV (AUROC 0.81 (95% CI 0.66 – 0.91) versus 0.71 (95% CI 0.54 – 0.84), respectively, p = 0.400). Spleen size >17.2cm had sensitivity 78.6% and specificity 64.3% for prediction of HRV. Conclusions. In NCPH patients, spleen size may predict risk of HRV at gastroscopy within 12 months. LSM and platelet count are not useful to assess risk of HRV in NCPH.

Submandibular responses to stimulation of the parasympathetic chorda tympani nerve have been investigated in anaesthetized sheep before, during and after an intracarotid infusion of endothelin, which reduced the blood flow through the gland by 56+/-5%. Stimulation of the peripheral end of the chorda tympani nerve produced a frequency-dependent increase in the flow of submandibular saliva, and in sodium, potassium and protein output. The reduction in submandibular blood flow, which occurred in response to endothelin, was associated with a decrease in the flow of saliva at all frequencies tested amounting on average to 44+/-6% (P0.01). The flow of saliva was linearly related to the blood flow before and after endothelin. Both parameters were also linearly related during the infusion of endothelin and the regression lines were parallel. Salivary sodium concentration was significantly increased at the lower frequencies (1 and 2 Hz). Protein output was generally reduced but the difference only achieved statistical significance during stimulation at 1 Hz (P0.01). Thus, submandibular secretory responses to parasympathetic stimulation are significantly attenuated by reducing the blood flow through the gland in this way.

Endothelin-1 is a potent vasoconstrictor and a therapeutic target in pulmonary arterial hypertension. Endothelial cells are the physiological source of endothelin-1 but in vitro data from our group shows that interferons (IFNα, IFNβ or IFNγ) induce endothelin-1 in pulmonary vascular smooth muscle cells. IFNs are integral to innate immunity and their antiviral and immunomodulatory capability has been harnessed therapeutically; for example, IFNα plays a critical role in the treatment of chronic hepatitis C infection. However, in some patients, IFN causes pneumonitis and possibly irreversible pulmonary arterial hypertension. In this study, we found that of 16 patients undergoing a six-month course of IFNα therapy, two demonstrated considerably increased serum levels of endothelin-1. We propose that IFN therapy results in elevated levels of endothelin-1 in some patients and when clinically significant levels are reached, pulmonary side effects could ensue. This hypothesis can be easily tested in IFN-treated patients by measuring serum endothelin-1 levels and cardiopulmonary physiological parameters.

Treatment for those infected with chronic hepatitis C virus [HCV] has until recently been hampered by the lack of therapies other than pegylated interferon and ribavirin, which have limited efficacy and a difficult side effect profile. To address this, multiple new direct acting antiviral drugs which specifically target the non-structural proteins involved in HCV replication are in phase II/III development. This review will discuss the HCV replication cycle, mechanisms of action of the new direct acting antiviral drugs, results from published trials into their efficacy and the potential for interferon free treatment regimens in the future.

Chronic hepatitis C infection represents a significant and growing health problem worldwide. Patients with genotype 1 hepatitis C respond poorly to the current standard of care, pegylated interferon and ribavirin, which is frequently associated with unpleasant side effects. Consequently new agents with improved efficacy and tolerability are needed. The efficacy and safety of the direct-acting antiviral agent telaprevir in the treatment of genotype 1 hepatitis C infection have been demonstrated in a number of clinical trials. The addition of telaprevir to standard therapy considerably improves response rates and allows response-guided shortening of treatment duration in a substantial number of treatment-naïve patients. Side effects associated with telaprevir therapy include rash, anaemia, gastrointestinal disturbance and anorectal discomfort. Telaprevir-resistant variants have been identified in patients who have failed telaprevir-containing therapy, and whether selection of these variants will compromise future therapeutic options is currently unknown. The efficacy and safety of telaprevir in the treatment of the most challenging patients, including those with recurrent hepatitis C following liver transplantation and those co-infected with HIV, remains to be established.

Incorporation of screen based simulators into medical training has recently gained momentum, as advances in technology have coincided with a government led drive to increase the use of medical simulation training to improve patient safety with progressive reductions in working hours available for junior doctors to train. High fidelity screen based simulators hold great appeal for endoscopy training. Potentially, their incorporation into endoscopy training curricula could enhance speed of acquisition of skills and improve patient comfort and safety during the initial phase of learning. They could also be used to demonstrate competence as part of the future relicensing and revalidation of trained endoscopists. Two screen based simulators are widely available for lower gastrointestinal endoscopy training, with a third recently produced in prototype. The utility of these simulators in lower gastrointestinal endoscopy training has been investigated, and construct and expert validity has been shown. Novices demonstrate a learning curve with simulator training that appears to represent real learning of colonoscopy skills. This learning transfers well to the real patient environment, with improvements in performance and patient discomfort scores in subsequent initial live colonoscopy. The significant limitations of currently available screen based simulators include cost implications, and restrictions on a role in certification and revalidation. Many questions remain to be answered by future research, including how best to incorporate screen based simulators into a colonoscopy training programme, their role in training in therapeutic endoscopy and the impact of simulator training on patient safety.

Background and Aims: New therapies for chronic HCV infection have substantially increased rates of sustained virological response (SVR). However relapse after therapy remains a problem, especially in patients with cirrhosis. We have developed a novel capture- fusion assay to study patient-derived HCV (1). Here we demonstrate that this assay can identify pre-treatment sofosbuvir (SOF), interferon (IFN) and ribavirin (RBV) sensitivity in patients with G3 HCV, and RBV sensitivity correlates with treatment outcome. Methods: Archived pre-treatment sera were obtained from 10 G3 patients treated with pegIFN/RBV, 4 with SVR and 6 who relapsed, and from 4 G3 patients treated with SOF/RBV, 3 with SVR and 1 who relapsed. THP-1 cells were exposed to donor serum, fused with Huh7.5 cells and treated with SOF, IFN or RBV before qPCR assessment of HCV replication. Results are given as mean ± sem and p values were calculated using Mann Whitney U test. Results: No difference in pre-treatment IFN sensitivity was seen between patients with SVR and those who relapsed after pegIFN/RBV (IFN IC50 0.61±0.11 IU/mL for patients with SVR versus 0.55±0.09 IU/mL for relapse, p = 0.61). However pre-treatment isolates from patients with SVR were significantly more sensitive to RBV than those from patients who relapsed (ribavirin IC50 0.62±0.05 mM for patients with SVR versus 1.25±0.13 m Mf or relapse, p = 0.01). Amongst patients treated with SOF/RBV, pre- treatment SOF sensitivity was similar between patients with SVR and relapse (SOF IC50 0.036±0.016 mM for SVR versus 0.023 m Mf or the patient who relapsed). However pre-treatment RBV sensitivity appeared greater in patients with SVR than relapse (RBV IC50 0.377±0.037 mM for SVR versus 1.049 mM for the patient who relapsed).

1145 PRE-TREATMENT PREDICTION OF TELAPREVIR RESPONSE USING A NOVEL CAPTURE-FUSION ASSAY FOR HCV REPLICATION M.E. Cunningham, A. Javaid, J.A. Waters, J. Davidson-Wright, J.L. Wong, T. Haque, M. Macartney, G. Dusheiko, W. Rosenberg, M. Jacobs, G.R. Foster. Digestive Diseases, Blizard Institute, Queen Mary, University of London, Department of Virology, Institute of Liver and Digestive Health, Division of Infection and Immunity, Royal Free and University College London, London, UK E-mail: m.e.cunningham@qmul.ac.uk

Introduction HCV replicates poorly in vitro, so testing of novel antiviral therapies currently relies on modified viral replicons, based on genotype (G)1, or the G2 JFH-1 virus. A model allowing patient virions to be cultured would facilitate drug discovery and allow direct sensitivity testing. Here we describe the development of a novel HCV replication assay, its validation using the antiviral agents alisporivir and telaprevir and its value in identifying responses to interferon and ribavirin. Methods CD14 (+) monocytes derived from patients with chronic HCV infection, or pre-stimulated THP-1 cells infected with serum from G1 and G3 HCV infected donors, were fused with HuH7 cells and treated with antiviral agents at various concentrations. The fused cells were maintained in tissue culture for up to 5 days, before extraction of HCV RNA and quantification by PCR. p Values were derived using the Mann–Whitney U test for comparison of non-parametric data. Results are expressed as mean±SEM. Results Replicating HCV from patients infected with diverse genotypes could be successfully transferred to HuH7 cells using the monocyte “capture-fusion” approach. RNA increased fivefold in fused cells and viral protein production as well as viral release could be demonstrated, confirming the presence of complete viral replication cycles in this new model. Treatment of G1 and G3 fused/infected Huh7 cells with escalating concentrations of alisporivir showed greater drug efficacy in cells infected with G3 than G1 (IC 50 0.026±0.008 μM vs 0.109±0.02 μM, p=0.0286). Conversely, telaprevir showed greater efficacy in fused/infected cells with G1 than fused/infected cells with G3 HCV. Treatment with 0.1 μM telaprevir, which approximates its IC 50 in replicon cells, resulted in a reduction of HCV RNA by 66.15±10.43% in G1 cells vs 21.56±3.16% in G3 infected cells (p=0.016). We examined sensitivity to interferon and ribavirin in samples from patients who did (N=3), or did not (N=4), respond to therapy. We found no significant difference in the viral sensitivity, suggesting that for interferon based therapies host factors play a more important role than virological response. Conclusion These data confirm the value of a capture-fusion model for HCV replication in studying the replication of patient-derived HCV and demonstrate that for interferon and ribavirin based treatments, host factors dominate the response. However viral response determines the clinical response to direct acting anti-viral agents. This technique may be useful in identifying the most appropriate treatment strategies for patients with HCV planning therapy with the new direct acting antiviral agents. Competing interests M Cunningham: None declared, A Javaid: None declared, J Waters: None declared, G Foster grant/research support from: Roche, Janssen, Tibotec, Novartis, Consultant for: Abbott, BI, BMS, Chughai, Janssen, Merck, Novartis, Roche, Tibotec.

Introduction Although genotype (G)3 HCV is generally regarded as “easy to treat”, based on clinical trial data showing response rates of up to 80%, real world studies have shown substantially lower rates of treatment response (45%), particularly in patients with advanced fibrosis or cirrhosis. Most patients who fail treatment for G3 HCV initially respond to antiviral therapy, but relapse after the end of treatment. HCV RNA has been demonstrated in peripheral blood mononuclear cells from patients with chronic HCV, but whether viral replication occurs in these cells remains controversial. This study tests the hypothesis that viable HCV in monocytes at the end of treatment predicts relapse in patients with G3 HCV. Methods CD14 (+) monocytes from patients at the end of treatment for G3 HCV were isolated and fused with HuH7 cells. The fused cells were maintained in tissue culture for up to 5 days, before extraction of HCV RNA and quantification by PCR. p Values were derived using the Mann–Whitney U test for comparison of non-parametric data. Results are expressed as mean ± SEM. Results HCV RNA increased up to fivefold in fused compared to unfused monocytes. Viral protein production was demonstrated in fused cells by indirect immunofluorescence, confirming that viral replication occurs in the fused cells. Fused monocytes from patients who relapsed after treatment showed a significantly greater increase in HCV RNA than those from patients with a sustained virological response (246.8±103.9%, compared to 5±33.9%, p=0.02). Conclusion These data demonstrate that the presence of replication-competent HCV in monocytes at the end of treatment predicts relapse in patients with G3 HCV. Monocytes may act as a sanctuary site for HCV virions during interferon-based treatment, facilitating relapse after withdrawal of therapy. Competing interests M Cunningham: None declared, A Javaid: None declared, J Waters: None declared, G Foster Grant/Research Support from: Roche, Janssen, Tibotec, Novartis, Consultant for: Abbott, BI, BMS, Chughai, Janssen, Merck, Novartis, Roche, Tibotec.

Introduction A significant proportion of patients with chronic hepatitis C (HCV) progress to cirrhosis with its attendant complications. Most studies evaluating the natural history of HCV infection have taken development of cirrhosis as an endpoint. We therefore sought to establish, by means of a systematic review and analysis of the literature, the natural history of compensated HCV cirrhosis. Methods A systematic literature review was performed. Where studies compared treated vs untreated patients, or HCV vs hepatitis B infection, only data regarding untreated, HCV monoinfected patients were included. Weighted mean annual percentage rates for death or transplantation, complications of cirrhosis and development of hepatocellular carcinoma (HCC) were calculated from the raw data. Results Our search returned 12 papers which met the inclusion criteria. Despite some heterogeneity (inclusion of other causes of cirrhosis or HCV patients who had received antiviral therapy) we extracted data from these studies relating to 2138 patients. In compensated HCV cirrhosis the estimated rate of death or transplantation is 4.75% per annum, of decompensation is 5.61% per annum and of HCC is 3.76% per annum. Five studies reported combined outcomes for both treated and untreated patients. When considered together, these studies reported significantly lower annual percentage rates of HCC than those reporting untreated patients only (mean 2.51%±0.37 vs 5.20%±0.76, p=0.016), but not of decompensation (mean 5.34%±0.79 vs 9.58%±1.14, p=0.057) or death or transplantation (mean 3.84%±0.53 vs 4.76%±0.62, p=0.29). Conclusion The estimated annual percentage rates of death or transplantation, decompensation and HCC confirm the relatively slow progress of compensated HCV cirrhosis, but highlight the need for continued vigilance for the occurrence of HCC. Heterogeneity in reporting, particularly the lack of distinction of outcomes according to treatment status or sustained virological response, means that the summary data presented may underestimate rate of disease progression, particularly HCC development. It will be important to ensure a clear distinction is made between treatment responders, partial responders and non-responders in future studies on the outcome of HCV cirrhosis.