Hepatitis C virus dynamics among intravenous drug users suggest that an annual treatment uptake above 10% would eliminate the disease by 2030.

In Switzerland, the prevalence of hepatitis C virus (HCV) among people who inject drugs (PWID) has been decreasing owing to active harm reduction efforts and an aging population. Recent advances in HCV therapeutics may provide an opportunity to direct treatment to high-risk populations, with a goal of reducing HCV prevalence and preventing new infections. In order to guide these efforts, the current project was undertaken with the following aims: (1) to develop a simple model to estimate the number of new HCV infections using available data on PWID; (2) to examine the impact of intervention strategies (prevention and treatment) on new and total HCV infections among PWID. A dynamic HCV transmission model was used to track HCV incidence and prevalence among active PWID according to their harm reduction status. The relative impact of treating 1, 5, 10 or 15% of HCV+ PWID with new oral direct acting antivirals was considered. In 2015, there were an estimated 10 160 active PWID in Switzerland, more than 85% of whom were engaged in harm reduction programmes. Approximately 42% of active PWID were HCV-RNA+, with 55 new viraemic infections occurring annually. By 2030, a 60% reduction in the HCV+ PWID population would be expected. In the absence of behavioural changes, the number of secondary infections would increase under all treatment scenarios. With high level treatment, the number of secondary infections would peak and then drop, corresponding to depletion of the viral pool. In Switzerland, 5% treatment of the 2015 HCV+ PWID population per year would result in a 95% reduction in total cases by 2030, whereas ≥10% treatment would result in a >99% reduction. Timely treatment of hepatitis C virus among people who inject drugs is necessary to reduce the prevalence and prevent new infections in Switzerland

The current and future burden of hepatitis B in Switzerland: a modelling study.

Chronic hepatitis B infection (defined as sustained detection of hepatitis B virus [HBV] surface antigen [HBsAg] protein in serum) is a leading cause of cirrhosis, hepatocellular carcinoma and liver-related deaths. A situation analysis carried out by the Swiss Federal Office of Public Health estimated the HBsAg prevalence in Switzerland to be 0.53% (95% CI: 0.32-0.89%) in 2015 (~44,000 cases). A lower prevalence of chronic HBV in the younger generation and the adoption of universal coverage in the first year of life are expected to decrease the burden of HBV; however, a number of people in key populations (including migrants) remain undiagnosed and untreated, and infected individuals remain at risk of progressing to cirrhosis, hepatocellular carcinoma and death. Our primary objective was to examine the current and estimate the future disease burden of HBV in Switzerland and the impact of migration. The secondary objective was to estimate the impact of changing future treatment numbers. A modelling study was performed using an existing, validated model (PRoGReSs Model) applied to the Swiss context. Model inputs were selected through a literature search and expert consensus. Population data from the Federal Statistical Office were used alongside prevalence data from the Polaris Observatory to estimate the number of HBV infections among people born abroad. The PRoGReSs Model was populated with and calibrated to the available data and what-if scenarios were developed to explore the impact of intervention on the future burden of disease. A Monte Carlo simulation was used to estimate 95% uncertainty intervals (95% UIs). In 2020, there were an estimated 50,100 (95% UI: 47,500-55,000) HBsAg+ cases among people born abroad. Among people born in Switzerland, there were approximately 62,700 (UI: 58,900-68,400) total HBV infections (0.72% [UI: 0.68-0.79%] prevalence). Prevalence among infants and children under the age of 5 were both <0.1%. By 2030, prevalence of HBV is expected to decrease, although morbidity and mortality will increase. Increasing diagnosis (90%) and treatment (80% of those eligible) to meet the global health sector strategy on viral hepatitis programme targets could prevent 120 cases of hepatocellular carcinoma and 120 liver-related deaths. Thanks to the historical vaccination programmes and the continued rollout of universal 3-dose coverage in the first year of life, Switzerland is expected to exceed the global health sector strategy targets for the reduction of incidence. While overall prevalence is decreasing, the current diagnosis and treatment levels remain below global health sector strategy targets

Hepatic Notch1 deletion predisposes to diabetes and steatosis via glucose-6-phosphatase and perilipin-5 upregulation

Notch signaling pathways have recently been implicated in the pathogenesis of metabolic diseases. However, the role of hepatic Notch signaling in glucose and lipid metabolism remains unclear and needs further investigation as it might be a candidate therapeutic target in metabolic diseases such as nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD). We used hepatocyte-specific Notch1 knockout (KO) mice and liver biopsies from NASH and NAFLD patients to analyze the role of Notch1 in glucose and lipid metabolism. Hepatocyte-specific Notch1 KO mice were fed with a high fat diet (HFD) or a regular diet (RD). We assessed the metabolic phenotype, glucose and insulin tolerance tests, and liver histology. Hepatic mRNA expression was profiled by Affymetrix Mouse Gene arrays and validated by quantitative reverse transcription PCR (qPCR). Akt phosphorylation was visualized by immunoblotting. Gene expression was analyzed in liver biopsies from NASH, NAFLD, and control patients by qPCR. We found that Notch1 KO mice had elevated fasting glucose. Gene expression analysis showed an upregulation of glucose-6-phosphatase, involved in the final step of gluconeogenesis and glucose release from glycogenolysis, and perilipin-5, a regulator of hepatic lipid accumulation. When fed with an HFD KO mice developed overt diabetes and hepatic steatosis. Akt was highly phosphorylated in KO animals and the Foxo1 target gene expression was altered. Accordingly, a reduction in Notch1 and increase in glucose-6-phosphatase and perilipin-5 expression was observed in liver biopsies from NAFLD/NASH compared with controls. Notch1 is a regulator of hepatic glucose and lipid homeostasis. Hepatic impairment of Notch1 expression may be involved in the pathogenesis of human NAFLD/NASH

Autochthonous hepatitis E as a cause of acute-on-chronic liver failure and death: histopathology can be misleading but transaminases may provide a clue.

Acute decompensation and death have been observed in patients with acute hepatitis E virus (HEV) infection and preexisting liver cirrhosis. However, the clinical, laboratory and histological features need to be fully characterised. Some of us recently described the histological presentation of hepatitis E in a large panel of liver tissue specimens. Here, we conducted a case-control study to investigate the clinical and laboratory features of the subset of patients with HEV-related acute-on-chronic liver failure (ACLF) and death. Each patient was matched to three control patients with histologically confirmed severe alcoholic hepatitis based on sex, age, total bilirubin, INR, serum creatinine and MELD score on admission. Of 5 patients who died in a context of HEV-related ACLF, 3 (60%) were male and the median age was 66 years (range 51–76). Median alanine aminotransferase (ALT) at presentation was 2610 U/l (range 705–3134) and aspartate aminotransferase (AST) 2818 U/l (range 1176–8611). Liver function was heavily altered in all patients. Histological analyses revealed steatohepatitis on a background of cirrhosis, suggestive of an alcoholic or nonalcoholic origin. Based on histopathology, alcoholic hepatitis was initially suspected in two patients and corticosteroid treatment was initiated. Ribavirin was started in four patients. Median time from hospitalisation to death was 17 days (range 6–25 days). AST levels in patients with HEV-related ACLF were significantly higher as compared to the matched patients with severe alcoholic hepatitis. Typical histopathological features of viral hepatitis may be absent in ACLF caused by HEV infection. HEV infection should be sought in acute decompensation of cirrhosis and ACLF even in the absence of histological changes suggesting viral infection

Real-life experience of chronic hepatitis C treatment in Switzerland: a retrospective analysis.

Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C. We analysed the use of different generations of DAAs over time in Switzerland and investigated factors predictive of treatment failure. This retrospective study was conducted within the framework of the Swiss Association for the Study of the Liver and the Swiss Hepatitis C Cohort Study; it included all patients with chronic hepatitis C treated with DAAs between January 2015 and December 2019 at eight Swiss referral centres. A total of 3088 patients were included; 57.3% were male, and the median age was 54 years. Liver cirrhosis was present in 23.9% of the cohort, 87.8% of whom were compensated. The overall sustained virological response (SVR) rate (defined as undetectable HCV RNA at week 12 after the first course of DAA-based treatment) was 96.2%, with an increase over time. The rate of treatment failure dropped from 8.3% in 2015 to 2.5% in 2019. Multivariable analysis revealed that female sex, the use of the latest generation of pangenotypic DAA regimens, Caucasian origin, and genotype (gt) 1 were associated with SVR, whereas the presence of active hepatocellular carcinoma (HCC), gt 3, and increasing liver stiffness were associated with treatment failure. Notably, the presence of active HCC during treatment increased the risk of DAA failure by a factor of almost thirteen. SVR rates increased over time, and the highest success rates were identified after the introduction of the latest generation of pangenotypic DAA regimens. Active HCC, gt 3 and increasing liver stiffness were associated with DAA failure

Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitro study

<p>Abstract</p> <p>Background</p> <p>Sorafenib is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma (HCC), setting a new standard for first-line treatment. However, no one has yet been able to predict sensitivity to sorafenib. Pre-treatment pERK level has been shown to be associated with favorable response to such therapy in a phase II clinical study, indicating that pERK may be a potential biomarker for treatment of HCC with sorafenib.</p> <p>Methods</p> <p>The effects of sorafenib and 5-fluorouracil (5-FU) on cell proliferation were evaluated by cell viability assays in four HCC cell lines (SMMC-7721, MHCC97-L, MHCC97-H and HCCLM6) with different metastatic potential and basal pERK expression levels. Expression levels of pERK were determined by immunocytochemical quantification together with western blot analysis, and pERK density values were also calculated. Correlation analyses were then carried out between the IC₅₀values of drugs and pERK density values. After basal ERK phosphorylation was down-regulated with U0126 in MHCC97-H cells, cellular responsiveness to sorafenib was assessed by cell viability assay.</p> <p>Results</p> <p>Basal pERK levels increased stepwise in cell lines in accordance with their metastatic potential. Sorafenib inhibited ERK phosphorylation in a dose-dependent manner in all four cell lines at a concentration between 5 and 20 μM, but the degree of inhibition was significantly different according to their basal pERK expression level (<it>P </it>< 0.0001). In contrast, no significant change was observed after 5-FU treatment. Correlation analyses between the IC₅₀values and pERK densities revealed that the effects of sorafenib on cell proliferation were significantly correlated with basal pERK levels (Spearman r = -0.8671, <it>P </it>= 0.0003). Resistance to 5-FU was also significantly associated with basal pERK expression in these HCC cell lines (Spearman r = 0.7832, <it>P </it>= 0.0026). After the basal ERK phosphorylation level in MHCC97-H cells was reduced with U0126, they were significantly less sensitive to sorafenib-mediated growth inhibition, with an IC₅₀of 17.31 ± 1.62 μM versus 10.81 ± 1.24 μM (<it>P </it>= 0.0281).</p> <p>Conclusion</p> <p>In this <it>in vitro </it>study, pERK was confirmed to be a potential biomarker predictive of sensitivity to sorafenib in treating HCC. The RAF/MEK/ERK pathway may be involved in drug resistance to traditional chemotherapy in HCC.</p

Surgical Site Infections, Risk Factors, and Outcomes After Liver Transplant

IMPORTANCE Surgical site infections (SSIs) are one of the most common health care-associated infections. Surgical site infections can have harmful effects in liver transplant (LT) recipients. OBJECTIVE To assess the incidence of SSI after LT and identify risk factors associated with SSIs and whether SSIs are associated with death and graft loss. DESIGN, SETTING, AND PARTICIPANTS A multicenter cohort study encompassing data on LT performed at all Swiss transplant centers between May 1, 2008, and September 30, 2020, was conducted. Data analyses were performed in 2023. EXPOSURE Liver transplant. MAIN OUTCOMES AND MEASURES Frequency of SSIs within 90 days after transplant, risk factors associated with SSIs, and association of SSIs with 1-year death or graft loss. Surgical site infections were defined according to Centers for Disease Control and Prevention criteria with SSIs occurring within 90 days after LT. For association with posttransplant outcomes, 1-year follow-up data were analyzed. RESULTS Among 1333 LT recipients in the Swiss Transplant Cohort Study, 1158 adults were included in analyses. Median age was 57.2 (IQR, 49.3-62.8) years and 792 were men (68.4%). Seventy patients (6.0%) had an SSI. Most SSIs were deep incisional (9 [12.8%]) or organ-space infections (54 [77.1%]). In most SSIs (56 [80.0%]), bacteria were detected, most frequently Enterococcus spp (36 of 75 [48.0%]) and Escherichia coli (12 of 75 [16.0%]). In multivariable analysis, prior liver transplant (odds ratio [OR] 4.01; 95% CI, 1.44-11.18; P = .008) and living liver donation (OR, 4.08; 95% CI, 1.37-12.16; P = .01) were independent risk factors associated with SSIs. Surgical site infections were independently associated with graft loss and/or death (hazard ratio [HR], 3.24; 95% CI, 1.82-5.79; P < .001); this association was observed in separate analyses on graft loss (HR, 2.97; 95% CI, 1.32-6.68; P = .02) and death (HR, 3.25; 95% CI, 1.44-7.35; P = .01). CONCLUSIONS AND RELEVANCE The findings of this study suggest that prior liver transplant and living liver donation are independent risk factors associated with SSIs and that SSIs are independently associated with graft loss and/or death, highlighting the relevance of this health care-associated infection

Lipid Nanocapsules Loaded with Rhenium-188 Reduce Tumor Progression in a Rat Hepatocellular Carcinoma Model

International audienceBACKGROUND: Due to their nanometric scale (50 nm) along with their biomimetic properties, lipid nanocapsules loaded with Rhenium-188 (LNC(188)Re-SSS) constitute a promising radiopharmaceutical carrier for hepatocellular carcinoma treatment as its size may improve tumor penetration in comparison with microspheres devices. This study was conducted to confirm the feasibility and to assess the efficacy of internal radiation with LNC(188)Re-SSS in a chemically induced hepatocellular carcinoma rat model. METHODOLOGY/PRINCIPAL FINDINGS: Animals were treated with an injection of LNC(188)Re-SSS (80 MBq or 120 MBq). The treated animals (80 MBq, n = 12; 120 MBq, n = 11) were compared with sham (n = 12), blank LNC (n = 7) and (188)Re-perrhenate (n = 4) animals. The evaluation criteria included rat survival, tumor volume assessment, and vascular endothelial growth factor quantification. Following treatment with LNC(188)Re-SSS (80 MBq) therapeutic efficiency was demonstrated by an increase in the median survival from 54 to 107% compared with control groups with up to 7 long-term survivors in the LNC(188)Re-SSS group. Decreased vascular endothelial growth factor expression in the treated rats could indicate alterations in the angiogenesis process. CONCLUSIONS/SIGNIFICANCE: Overall, these results demonstrate that internal radiation with LNC(188)Re-SSS is a promising new strategy for hepatocellular carcinoma treatment

Effective Inhibition of Xenografts of Hepatocellular Carcinoma (HepG2) by Rapamycin and Bevacizumab in an Intrahepatic Model

10.1007/s11307-009-0213-4Molecular Imaging and Biology115334-342CPIM