Showing papers by "Beat Müllhaupt published in 2016"

Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial

Abstract: Summary Background Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. Methods We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600–1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). Findings Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70–96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81–100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66–96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60–91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84–98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93–100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91–100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84–100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78–100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86–100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3–98) of two CTP-C patients (12 weeks treatment); and four (80%, 34–99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55–100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56–92) of 18 patients (12 weeks treatment) and 16 (94%, 75–100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir–sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. Interpretation Ledipasvir–sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. Funding Gilead Sciences.

Correlation between Dual-Energy and Perfusion CT in Patients with Hepatocellular Carcinoma

Abstract: Purpose To develop a dual-energy contrast media-enhanced computed tomographic (CT) protocol by using time-attenuation curves from previously acquired perfusion CT data and to evaluate prospectively the relationship between iodine enhancement metrics at dual-energy CT and perfusion CT parameters in patients with hepatocellular carcinoma (HCC). Materials and Methods Institutional review board and local ethics committee approval and written informed consent were obtained. The retrospective part of this study included the development of a dual-energy CT contrast-enhanced protocol to evaluate peak arterial enhancement of HCC in the liver on the basis of time-attenuation curves from previously acquired perfusion CT data in 20 patients. The prospective part of the study consisted of an intraindividual comparison of dual-energy CT and perfusion CT data in another 20 consecutive patients with HCC. Iodine density and iodine ratio (iodine attenuation of the lesion divided by iodine attenuation in the aorta) from dual-energy CT and arterial perfusion (AP), portal venous perfusion, and total perfusion (TP) from perfusion CT were compared. Pearson R and linear correlation coefficients were calculated for AP and iodine density, AP and iodine ratio, TP and iodine density, and TP and iodine ratio. Results The dual-energy CT protocol consisted of bolus tracking in the abdominal aorta (threshold, 150 HU; scan delay, 9 seconds). The strongest intraindividual correlations in HCCs were found between iodine density and AP (r = 0.75, P = .0001). Moderate correlations were found between iodine ratio and AP (r = 0.50, P = .023) and between iodine density and TP (r = 0.56, P = .011). No further significant correlations were found. The volume CT dose index (11.4 mGy) and dose-length product (228.0 mGy · cm) of dual-energy CT was lower than those of the arterial phase of perfusion CT (36.1 mGy and 682.3 mGy · cm, respectively). Conclusion A contrast-enhanced dual-energy CT protocol developed by using time-attenuation curves from previously acquired perfusion CT data sets in patients with HCC could show good correlation between iodine density from dual-energy CT with AP from perfusion CT. (©) RSNA, 2016.

correlation between Dual- energy and Perfusion cT in Patients with

Abstract: Purpose: To develop a dual-energy contrast media–enhanced computed tomographic (CT) protocol by using time-attenuation curves from previously acquired perfusion CT data and to evaluate prospectively the relationship between iodine enhancement metrics at dual-energy CT and perfusion CT parameters in patients with hepatocellular carcinoma (HCC). Materials and Methods:

Alterations in Enterohepatic Fgf15 Signaling and Changes in Bile Acid Composition Depend on Localization of Murine Intestinal Inflammation.

Abstract: BACKGROUND: Fibroblast growth factor (FGF) 15/19 is part of the gut-liver crosstalk accounting for bile acid (BA) metabolism regulation. Dysregulation of fibroblast growth factor 15/19 signaling is observed in different pathological conditions, for example, in gastrointestinal diseases such as inflammatory bowel disease (IBD). To understand the molecular bases, we analyzed the enterohepatic regulation of Fgf15-mediated pathway in 2 different inflammatory bowel disease mouse models. METHODS: Target genes of the BA-farnesoid-X-receptor (Fxr)-Ffg15 axis were quantified by RT-PCR or western blotting in gut and liver of dextran sulfate sodium (DSS)-treated and IL10 mice. Serum Fgf15 levels were analyzed by ELISA. Biliary and fecal BA composition was differentiated by HPLC-MS/MS. RESULTS: Dextran sulfate sodium-treated mice with ileum-sparing colitis showed higher Fgf15 serum levels. In contrast, IL10 mice with ileitis had a trend toward decreased Fgf15 serum levels compared with controls and increased expression of Asbt as a negative Fxr-target gene. In hepatic tissue of both models, no histological changes, but higher interleukin 6 (IL-6) mRNA expression and down-regulation of Fxr and Cytochrom P450 7a1 mRNA expression were observed. Fibroblast growth factor receptor 4 up-regulation was in line with higher Fgf15 serum levels in dextran sulfate sodium-treated mice. A distinct fecal BA profile was observed in both models with significantly higher levels of taurine-conjugated BA in particular tauro-β-muricholic acid in IL10 mice. CONCLUSIONS: Ileum-sparing colitis is characterized by activation of Fxr-Fgf15 signaling with higher expression of Fxr-target gene Fgf15, whereas ileal inflammation showed no signs of Fxr-Fgf15 activation. Abundance of BA such as T-β-MCA may be important for intestinal Fxr activation in mice.

Development of OXY111A, a novel hypoxia-modifier as a potential antitumor agent in patients with hepato-pancreato-biliary neoplasms - Protocol of a first Ib/IIa clinical trial

Abstract: Solid tumors, such as hepato-pancreato-biliary cancer, develop tumor hypoxia with tumor growth. Despite advances in surgery, a majority of these patients are in an unresectable condition. At this stage standard cytotoxic chemotherapy regimens are applied with limited success. Novel biological treatment options based on an antiangiogenic mechanism of action neglect other hypoxia mediated mechanisms (e.g. epithelial-mesenchymal transition, Warburg effect, and immunological response) leading to an increased invasiveness with a poor outcome. The novel antihypoxic molecule myo-inositoltrispyrophosphate (ITPP, OXY111A) acts as an allosteric effector of hemoglobin and promotes normoxia in hypoxic tumors. In preclinical studies, tumor growth was reduced and survival prolonged. Additionally, a beneficial side effect profile was observed. In this first Ib/IIa clinical trial we will assess safety and tolerability of OXY111A as well as a proof of concept regarding efficacy in patients with non-resectable primary and secondary tumors of the liver, pancreas, and biliary tract. The study design is exploratory, prospective, open-labelled and mono-centric. The study is divided in a dose escalation part with a maximum of 48 subjects and an extension part, in which 21 subjects will be included. The novel antihypoxic compound OXY111A has been tested in several cancer animal models showing beneficial effects for both survival and low side effect profiles. This first in patient application of OXY111A will reveal potential beneficial outcomes if anti-hypoxic therapy is added to standard cytotoxic treatment in patients with primary and secondary hepatopancreatobiliary tumors. Institution Ethical Board Approval ID: KEK-ZH-Nr. 2014-0374; Swiss regulatory authority Swissmedic (2015DR1009); ClinicalTrials.gov Identifier: NCT02528526 , prospectively registered on November 11th, 2014.

Influence of Ribavirin Serum Levels on Outcome of Antiviral Treatment and Anemia in Hepatitis C Virus Infection.

Abstract: Background Ribavirin blood levels vary considerably between patients with standard weight-based dosing. Their impact on sustained virological response (SVR) with pegylated interferon and ribavirin is controversial, but has mostly been studied before the IL28b gene polymorphism as a possible confounder was discovered. Methods The impact of serum ribavirin trough levels at week 4, at the end of treatment and of mean levels across the entire antiviral treatment with pegylated interferon and ribavirin on relapse, SVR rates and anemia was retrospectively studied by univariate and multivariable logistic regression analyses in 214 patients with HCV genotype 1–4 infection, including 88 patients with available IL28b genotyping. Results Mean ribavirin levels varied between 0.68–5.65 mg/l and significantly differed between patients with or without SVR. By multivariable regression including age, sex, HCV viral load, HCV genotype, liver fibrosis stage, prior treatments, immunosuppression and IL28b genotype, ribavirin levels consistently displayed significant influence on SVR and relapse without indication for a specific importance of higher concentrations early or late in the treatment course. Although hemoglobin decline was on average more pronounced in patients with higher ribavirin levels, hemoglobin remained relatively stable in a significant proportion of these, indicating that ribavirin levels alone are insufficient to predict anemia. Conclusion While data are scarce to draw conclusions applicable for modern DAA therapies, these results support ribavirin treatment based on serum levels instead of purely weight-based dosing in combination with pegylated interferon.

Characteristics of Foreign-Born Persons in the Swiss Hepatitis C Cohort Study: Implications for Screening Recommendations

Abstract: BACKGROUND Switzerland recommends individuals who originate from high-prevalence countries to be screened for hepatitis C virus (HCV) infection However, not all these persons are equally at risk We thus aimed to describe the number and characteristics of persons with HCV infection born outside of Switzerland METHODS We compared characteristics of anti-HCV-positive individuals in the Swiss Hepatitis C Cohort Study (SCCS) and of HCV cases reported to the Federal Office of Public Health (FOPH), with those of the general population in Switzerland Persons who inject drugs (PWID) and persons who do not inject drugs (non-PWID) were compared by age groups for different countries of origin (represented by ≥1% of participants in the SCCS or FOPH) RESULTS We included 4,199 persons from the SCCS and 26,610 cases from the FOPH Both groups had similar characteristics In both data sources non-PWID were more frequent in foreign-born than in Swiss-born persons (63% versus 34% in the SCCS) The only subgroup with a clearly higher proportion both in the SCCS and FOPH than in the general population were persons over 60 years from Italy and Spain, with a 37- and 28-fold increase in the SCCS These persons were non-PWID (99%), less frequently HIV- and anti-HBc positive and more often female than PWID from Italy and Spain; cirrhosis at enrolment was frequent (31%) Their HCV genotypes were consistent with those observed in elderly non-PWID of their birth countries In the FOPH a higher proportion than in the general population was also seen for cases from Georgia and Russia CONCLUSION The identification of subgroups in which HCV infection is particularly frequent might allow for better targeting HCV screening among foreign-born persons in Switzerland and elsewhere

Liver cancer with concomitant TP53 and CTNNB1 mutations: a case report.

Abstract: In the spectrum of molecular alterations found in hepatocellular carcinoma (HCC), somatic mutations in the WNT/β-catenin pathway and the p53/cell cycle control pathway are among the most frequent ones. It has been suggested that both mutations occur in a mutually exclusive manner and they are used as molecular classifiers in HCC classification proposals. Here, we report the case of a treatment-naive mixed hepatocellular/cholangiocellular carcinoma (HCC/CCC) with morphological and genetic intratumor heterogeneity. Within the predominant part of the tumor with hepatocellular differentiation, a p.D32V mutation in exon 3 of the CTNNB1 gene occurred concomitantly with a TP53 intron 7/exon 8 splice site mutation. Intratumor heterogeneity challenges the concept of CTNNB1 and TP53 gene mutations being mutually exclusive molecular classifiers in HCC, which has implications for HCC classification approaches.

Fatal Liver and Lung Alveolar Echinococcosis with Newly Developed Neurologic Symptoms due to the Brain Involvement.

Abstract: The fox tapeworm Echinococcus multilocularis causes human alveolar echinococcosis, commonly affecting the liver. However, in ∼1% of cases, systematic spread of the disease involves the brain as well. A patient had a 6-year history of liver and lung alveolar echinococcosis that was considered not suitable for surgery, and treatment with albendazole was introduced. After the appearance of neurologic disturbances, an intracranial mass lesion was demonstrated by radiologic imaging. The lesion was surgically removed, and histologic analysis revealed metacestode tissue of E. multilocularis. Despite the surgical resection of the lesion, the patient died of progression of systemic alveolar echinococcosis. The authors highly recommend implementing neurologic monitoring to the follow-up algorithm for patients with systemically disseminated alveolar echinococcosis. When neurologic symptoms occur, radiologic imaging of the brain should be obtained immediately. Surgery should be considered for all intracranial echinococcal lesions, unless the lesion is located in the eloquent brain area.

Microbial Communities of Conducting and Respiratory Zones of Lung-Transplanted Patients.

Abstract: Background: Lung transplantation (LT) is a recognized treatment for end-stage pulmonary disease. Bacteria from the recipient nasopharynx seed the new lungs leading to infections and allograft damage. Understanding the characteristics and topological variations of the microbiota may be important to apprehend the pathophysiology of allograft dysfunction. Objectives: To examine the characteristics and relationship of bacterial compositions between conducting and respiratory zones of the allograft. Methods: We performed 16S rRNA gene sequencing on bronchial aspirates (BAs) and bronchoalveolar lavages (BALs) collected in pairs in 19 patients at several time-points post-LT. Results: The respiratory zone was characterized independently of the time post-LT by a higher bacterial richness than the conducting zone (p=0.041). The phyla Firmicutes and Proteobacteria dominated both sampling zones, with an inverse correlation between these two phyla (Spearman r=–0.830). Samples of the same pair, as well as pairs from the same individual clustered together (Pseudo-F=3.8652, p<0.01). Microbiota of BA and BAL were more closely related in samples from the same patient than any sample across different patients, with variation in community structure being mainly inter-individual (p<0.01). Both number of antibiotics administered (p<0.01) and time interval post-LT (p<0.01) contributed to the variation in global microbiota structure. Longitudinal analysis of BA-BAL pairs of 2 patients showed dynamic wave like fluctuations of the microbiota. Conclusions: Our results show that post-transplant respiratory zones harbour higher bacterial richness, but overall similar bacterial profiles as compared to conductive zones. They further support an individual microbial signature following lung transplantation.

Orbital Pseudotumor as a Rare Extrahepatic Manifestation of Hepatitis C Infection.

Abstract: Hepatitis C is frequently accompanied by immune-related extrahepatic manifestations affecting the skin, kidneys, central and peripheral nervous system and exocrine glands. We present the case of a 40-year-old man with left-sided ptosis, exophthalmos and headache. MRI demonstrated left-sided orbital pseudotumor with lacrimal and retro-orbital contrast enhancement extending to the cavernous sinus and the vestibulocochlear nerve. Immunological tests of serum and cerebrospinal fluid identified hepatitis C virus (HCV) as a potential causative agent but did not indicate any additional infectious, malignant or immunological disorder. Hepatological evaluation revealed no signs of advanced liver disease. After initial spontaneous improvement, the patient subsequently developed vestibulocochlear failure with gait disorder, tinnitus and transient left-parietal sensory loss. Lacrimal biopsy demonstrated lymphocytic infiltrate, prompting steroid treatment. After initial improvement, steroids could not be tapered below 40 mg daily for several months due to recurrent symptoms. Twelve months after the initial presentation, the patient's chronic HCV infection was successfully treated with sofosbuvir, simeprevir and ribavirin and he remains now free of symptoms without steroids. In patients with chronic hepatitis C, lymphocytic infiltrate of the salivary and lacrimal glands is a frequent phenomenon. However, the extent of the lymphocytic infiltrate beyond the lacrimal gland to the tip of the orbit, cavernous sinus and vestibulocochlear nerve as in our patient is highly unusual. For all symptomatic extrahepatic manifestations of hepatitis C infection, treatment of HCV as the underlying immune stimulus is recommended, and it helped to control the symptoms in our patient. In addition, long-term follow-up for recurrent lymphocyte infiltrate and development of lymphoma is warranted.

Access to therapy and therapy outcomes in the Swiss Hepatitis C Cohort Study: a person-centred approach.

Abstract: Socio-demographic and behavioural characteristics are associated with delayed diagnosis and disease progression in HCV-infected persons. However, many analyses focused on single variables rather than groups defined by several variables. We used latent class analysis to study all 4488 persons enrolled in the Swiss Hepatitis C Cohort Study. Groups were identified using predefined variables at enrolment. The number of groups was selected using the Bayesian information criterion. Mortality, loss to follow-up, cirrhosis, treatment status and response to antivirals were analysed using Laplace and logistic regressions. We identified five groups and named them according to their characteristics: persons who inject drugs, male drinkers, Swiss employees, foreign employees and retirees. Two groups did not conform to common assumptions about persons with chronic hepatitis C and were already in an advanced stage of the disease at enrolment: 'male drinkers' and 'retirees' had a high proportion of cirrhosis at enrolment (15% and 16% vs 9.0). 'Male drinkers' also had high substance use, but they were well educated and were likely to be employed. This analysis may help identifying high-risk groups which may benefit from targeted interventions.

A significant effect of the killer cell immunoglobulin-like receptor ligand human leucocyte antigen-C on fibrosis progression in chronic C hepatitis with or without liver transplantation.

Abstract: Background & Aims: The interaction of killer cell immunoglobulin–like receptors with their human leucocyte antigen ligands drives the activation and inhibition of natural killer cells. Natural killer cells could be implicated in the development of liver fibrosis in chronic hepatitis C. Methods: We analysed 206 non-transplanted and 53 liver transplanted patients, selected according to their Metavir fibrosis stage. Several variables such as the number of activator killer cell immunoglobulin–like receptors or the human leucocyte antigen ligands were considered in multinomial and logistic regression models. Possible confounding variables were also investigated. Results: The killer cell immunoglobulin–like receptors were not significant predictors of the fibrosis stage. Conversely, a significant reduction of the human leucocyte antigen-C1C2 genotype was observed in the most advanced fibrosis stage group (F4) in both cohorts. Furthermore, the progression rate of fibrosis was almost 10 times faster in the subgroup of patients after liver transplantation, and human leucocyte antigen-C1C2 was significantly reduced in this cohort compared with non-transplanted patients. Conclusion: This study suggests a possible role of killer cell immunoglobulin–like receptors and their ligands in the development of liver damage. The absence of C1 and C2 ligands heterozygosity could lead to less inhibition of natural killer cells and a quicker progression to a high level of fibrosis in patients infected with hepatitis C virus, especially following liver transplantation.