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The urgent need in HCV-infected patients with liver disease mandated the rapid implementation of IFN-free DAA combination therapies following their regulatory approval in 2014 and 2015 without full knowledge of the optimal combinations and regimens. Investigating the evolution of the DAA utilization patterns and treatment outcomes could provide learnings for future situations. This was an analysis of a prospective observational database from the German Hepatitis C Registry (DHC-R) covering a period from May 2014 to September 2015. Adult patients had evidence of chronic HCV GT1 or GT4 infection and were treated with an IFN-free combination regimen of simeprevir (SMV) + sofosbuvir (SOF) or other IFN-free regimens: daclatasvir + sofosbuvir (DCV + SOF), ledipasvir/sofosbuvir (SOF/LDV), paritaprevir/r + ombitasvir ± dasabuvir (PrOD), with or without ribavirine (R). A total of 5496 subjects were followed during the period. During this period, clinical recommendations and treatment patterns evolved rapidly in response to new evidence from clinical trials and clinical routine and regulatory approval of additional regimens. High SVR12 rates were seen in this cohort, even in hard-to-treat patient subgroups. In the multivariate analysis, gender, age, advanced cirrhosis, and intensified treatment for cirrhotics were associated with treatment outcome. Despite limited knowledge of the optimal utilization of the newly approved DAA combinations and treatment durations as well as their comparative efficacy and safety profiles, high SVR rates were achieved regardless of the DAA combination. These outcomes were facilitated by the rapid adaptation of clinical recommendations. Future situations with high unmet medical need may follow a similar approach. Die dringende Behandlungsbedürftigkeit HCV-infizierter Patienten mit Lebererkrankung verlangte die rasche Einführung IFN-freier DAA-Kombinationstherapien nach ihrer Zulassung in 2014 und 2015 trotz unvollständigem Wissen über deren optimalen Einsatz. Die Untersuchung der Evolution des Einsatzes und der Ergebnisse könnte wichtige Erkenntnisse für zukünftige Situationen bergen. Diese Analyse einer prospektiven Kohorte des Deutschen Hepatitis C-Registers (DHC-R) deckt den Zeitraum von Mai 2014 bis September 2015 ab. Erwachsene Patienten mit chronischer HCV-GT1 oder GT4-Infektion wurden mit einer IFN-freien Therapie aus Simeprevir (SMV) + Sofosbuvir (SOF), oder anderen IFN-freien Regimen: Daclatasvir + Sofosbuvir (DCV + SOF), Ledipasvir/Sofosbuvir (SOF/LDV), Paritaprevir/r + Ombitasvir ± Dasabuvir (PrOD), mit oder ohne Ribavirin (R) behandelt. 5496 Patienten wurden während des Zeitraums beobachtet. In dieser Periode wandelten sich die klinischen Leitlinien und Behandlungsmuster rasch in Folge neuer Evidenz aus klinischen Studien und klinischer Erfahrung und der Zulassung von neuen Regimen. Hohe SVR12-Raten wurden in dieser Kohorte, selbst in schwierig zu behandelnden Patienten-Subgruppen, beobachtet. Die multivariate Analyse zeigte, dass Geschlecht, Alter, fortgeschrittene Zirrhose und die intensivierte Therapie bei Patienten mit Zirrhose mit dem Behandlungserfolg assoziiert waren. Trotz begrenzten Wissens um den optimalen Einsatz von neu zugelassenen DAA-Kombinationen und deren Behandlungsdauer sowie dem Vergleich ihrer Wirksamkeits- und Sicherheits-Profile wurden hohe SVR12-Raten mit verschiedenen DAA-Kombinationen erzielt. Diese Ergebnisse wurden unterstützt von einer raschen Adaption klinischer Therapie-Empfehlungen. Zukünftige Szenarien mit einem erheblichen ungedeckten medizinischen Bedarf könnten einem ähnlichen Ansatz folgen.

Carboxylesterase 2 (CES2) is instrumental for conversion of ester-containing prodrugs in cancer treatment. Novel treatment strategies are exceedingly needed for cholangiocarcinoma (CCA) patients. Here, we assessed CES2 expression by immunohistochemistry in a CCA cohort comprising 171 non-liver fluke associated, intrahepatic (n = 72) and extrahepatic (perihilar: n = 56; distal: n = 43) CCAs. Additionally, 80 samples of high-grade biliary intraepithelial neoplastic tissues and 158 corresponding samples of histological normal, non-neoplastic biliary tract tissues were included. CES2 expression was highest in non-neoplastic biliary tissue and significantly decreased in CCA. Patients showing any CES2 expression in tumor cells had a significantly better overall survival compared to negative cases (p = 0.008). This survival benefit was also maintained after stratification of CES2-positive cases, by comparing low, medium and high CES2 expression levels (p-trend = 0.0006). Evaluation of CCA subtypes showed the survival difference to be restricted to extrahepatic tumors. Correlation of CES2 expression with data of tumor-infiltrating immune cells showed that particularly CD8+ T cells were more frequently detected in CES2-positive CCAs. Furthermore, treatment of CCA cell lines with the prodrug Irinotecan reduced cell viability, increased cytotoxicity and modulated inflammatory gene expression. In conclusion, reduced CES2 expression is associated with poor outcome and low CD8+ T cell infiltration in CCA patients. Further clinical studies could show, whether CES2 expression may serve as a predictive marker in patients treated with prodrugs converted by CES2.

Background & Aims Clinical manifestation of hepatic involvement in sarcoidosis can vary from asymptomatic disease to severe complications such as cirrhosis and portal hypertension. However, data on hepatic sarcoidosis are limited, and evidence-based recommendations are lacking. Our study aimed to assess the features and clinical course of hepatic sarcoidosis in a predominantly Caucasian cohort. Methods We performed a retrospective study including all patients with hepatic sarcoidosis between 2004 and 2020 in 5 German centres. The median follow-up time was 36 months (range 0.0–195). Data on demographic parameters, clinical manifestations, diagnostic test results, treatment, and outcome were collected. Results A total of 1,476 patients with sarcoidosis and 62 patients with hepatic involvement (4.2%) were identified. Of the patients, 51.6% were female, and 80.6% were Caucasian. Most patients were asymptomatic and were observed to have a cholestatic pattern of liver enzyme elevations. Cirrhosis was detected in 9 patients (14.5%), of whom 6 developed clinical manifestations of portal hypertension. Fifty-four patients were medically treated, most commonly with glucocorticoids (69.4%) or ursodeoxycholic acid (UDCA) (40.3%). Levels of alkaline phosphatase (ALP) decreased by 60.8% on average from baseline in patients treated with glucocorticoids and by 59.9% in patients treated with UDCA. Seventeen patients received treatment augmentation with a second line agent, of whom 8 patients normalised ALP levels during follow-up. None of the patients underwent liver transplantation or developed hepatocellular carcinoma (HCC). Three of the patients died during follow-up owing to liver-related complications. Conclusions Hepatic involvement in sarcoidosis was found in 4.2% of patients with sarcoidosis and was clinically significant in 14.5% of those. These findings highlight the importance of early identifying, monitoring, and treating hepatic sarcoidosis, given its increased mortality when associated with end-stage liver disease. Lay summary Clinical diagnostic and surveillance of hepatic involvement in sarcoidosis has not been standardised, and management of hepatic involvement is a clinical challenge, since it remains poorly characterised in many ways. Our results show that one-third of patients with hepatic sarcoidosis presented with clinically significant portal hypertension, 14.5% suffered from cirrhosis, and 3 patients died owing to liver-related complications. Regarding pharmacological treatment options, corticosteroids and UDCA were the medical agents most frequently used, and both of them have been shown to induce biochemical response in the majority of patients. These findings highlight the importance of correctly and early identifying hepatic involvement in sarcoidosis, because of the potentially progressive course of disease., Graphical abstract, Highlights • There has been little research on clinical characteristics and the clinical outcome of patients with hepatic sarcoidosis. • One-third of patients with hepatic sarcoidosis presented with clinically significant portal hypertension, and 14.5% suffered from cirrhosis. • Biochemically, a cholestatic pattern of liver enzyme elevations was the most common abnormality. • The correct and early identification of hepatic involvement in sarcoidosis is crucial because of the potentially progressive course of disease.

Virologic failure to approved combinations of direct antiviral agents (DAA) in patients with chronic hepatitis C virus (HCV) infection is rare. Mostly it involves difficult to treat patients with advanced liver disease and prior interferon-experience. Before approval of VOX/VEL/SOF, a restricted number of patients received rescue treatment, and the choice of DAA combinations for re-treatment were selected on an individual basis. In the present analysis, patient characteristics and rescue-regimens after virologic failure mainly based on first generation DAAs are described. Data were obtained from the German Hepatitis C-Registry (DHC-R), which is a national multicenter real-world cohort currently including about 16 500 patients recruited by more than 250 centers. The present analysis is based on 6683 patients who initiated a DAA therapy and for whom follow-up data (per-protocol analysis) were available. Among the patients, 188 (2.8 %) experienced a virologic relapse. Compared to SVR-patients, relapse patients were significantly more often male (77.7 % versus 56.9 %, respectively, p 0.001), showed cirrhosis significantly more (48.4 % versus 28.1 %, respectively, p 0.001) and a prior interferon-containing therapy (46.3 % versus 39.0 %, respectively, p = 0.049). The majority of patients who relapsed were infected with genotype 1 (47.4 %) followed by genotype 3 (29.8 %), and 95 relapse patients started DAA re-treatment. Characteristics of patients with rescue-treatment are similar to these of patients with relapse after initial DAA treatment. Thirty-one of 39 patients with complete follow-up data achieved SVR (79.5 %), and 8 patients had a relapse again (20.5 %). Patients who received rescue treatment including a new DAA class according to guidelines, except patients who received VOX/VEL/SOF, showed higher SVR rates than the entire group (21/25, 84 %). All patients who received VOX/VEL/SOF achieved SVR (n = 4, 100 %). Patients with failure with DAA combination therapies are a difficult but urgent to treat population with the frequent presence of cirrhosis and prior treatment failure with interferon-based therapies. Rescue therapy with inclusion of a new DAA class leads to high SVR rates, but multiple targeted therapy with VOX/VEL/SOF seems to be most effective. Virologisches Versagen nach einer zugelassenen Kombinationstherapie aus direkt antiviral wirkenden Medikamenten (DAA) bei Patienten mit chronischer Hepatitis-C-Virus(HCV)-Infektion ist sehr selten. Zumeist handelt es sich, aufgrund von fortgeschrittener Lebererkrankung und vorangegangenen interferonbasierten Therapien, um schwierig zu behandelnde Patienten. Vor Zulassung von VOX/VEL/SOF erhielt eine geringe Zahl von Patienten eine Rescue-Therapie, und die Wahl der DAA-Kombination zur Re-Therapie unterlag individuellen Entscheidungskriterien. Die vorliegende Arbeit beschreibt Charakteristika und Rescue-Therapien, überwiegend basierend auf DAAs der ersten Generation, bei Patienten nach virologischem Versagen. Die Daten entstammen dem Deutschen Hepatitis C-Register (DHC-R). Dieses ist eine nationale, multizentrische, Real-World-Kohorte, die derzeit über 16 500 Patienten aus über 250 Zentren einschließt. Die aktuelle Analyse basiert auf 6683 Patienten mit initialer DAA-Therapie und kompletten Follow-up-Daten (Per-Protocol(PP)-Analyse). 188 Patienten (2,8 %) aus der PP-Population hatten einen virologischen Relapse. Die Relapse-Patienten waren verglichen zur SVR-Population signifikant häufiger männlich (77,7 % versus 56,9 %, p 0,001), hatten signifikant häufiger eine Zirrhose (48,4 % versus 28,1 %, p 0,001) und eine interferonbasierte Vortherapie (46,3 % versus 39,0 %, p = 0,049). Die meisten Patienten mit virologischem Versagen waren mit Genotyp 1 (57,4 %) gefolgt von Genotyp 3 (29,8 %) infiziert. 95 der Relapse-Patienten erhielten eine DAA-Re-Therapie. Die Charakteristika von Patienten mit Rescue-Therapie sind vergleichbar mit denen von Patienten mit Relapse nach initialer DAA-Therapie. 31 von 39 Patienten mit kompletten Follow-up-Daten erreichten SVR (79,5 %) und 8 Patienten erlitten einen erneuten Relapse (20,5 %). Patienten, die eine den Leitlinien entsprechende Rescue-Therapie mit einer neuen DAA-Klasse erhalten haben, ausgenommen VOX/VEL/SOF, zeigten höhere SVR-Raten als die Gesamtgruppe (21/25, 84 %). Alle Patienten, die VOX/VEL/SOF erhielten, erreichten einen SVR (n = 4, 100 %). Versager nach DAA-Kombinationstherapie entsprechen einer schwierig und zugleich dringlich zu behandelnden Patientengruppe mit häufigem Vorliegen einer Zirrhose und Versagen einer interferonbasierten Vortherapie. Rescue-Therapie mit einer neuen DAA-Klasse führt zu hohen SVR-Raten, eine Multi-Target-Therapie mit VOX/VEL/SOF scheint am effektivsten zu sein.

Background Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. Methods In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. Results We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. Conclusions This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

Liver function tests (alanine aminotransferase, ALT; gamma-glutamyltransferase, GGT) not always normalize after elimination of hepatitis C virus (HCV) by direct acting antivirals (DAAs), possibly indicating concomitant non-viral liver diseases. We analysed factors determining the biochemical response (normalized ALT/GGT) of DAA therapy in a large real-world cohort.The German Hepatitis C-Registry is a national multicenter registry study. Normal ALT was defined ≤35 U/L (female) and ≤50 U/L (male) or, according to AASLD, ≤19 U/L (female) and ≤30 U/L (male), normal GGT ≤40 U/L (female) and ≤60 U/L (male).At baseline, ALT was elevated in 3705/4946 (74.9%), ALT (AASLD) in 4669/4946 (94.4%) and GGT in 3018/4906 (61.5%). In this study, 97% of patients achieved SVR12. At week 12 after end of therapy, ALT was elevated in 451/4946 (9.1%), ALT according to AASLD in 1906/4946 (38.5%) and GGT in 863/4879 (17.7%). Persistently elevated ALT after DAA therapy was independently associated with high body mass index (BMI), age70 years, liver cirrhosis, diabetes, alcohol consumption and not achieving SVR12. Using the stricter AASLD criteria, opioid substitution and male sex were additional predictors. Higher GGT at week 12 was associated with high BMI, age70 years, liver cirrhosis, diabetes, alcohol consumption, opioid substitution and non-SVR. Importantly, persistently elevated liver tests after treatment, particularly GGT, were associated with hepatic decompensation and mortality during 4-years follow-up.Risk factors at baseline (obesity, diabetes, liver cirrhosis, alcohol consumption) are independently associated with persistently elevated liver function tests after SVR, indicating that these patients warrant further hepatological follow-up.German Clinical Trials Register (DRKS; ID DRKS00009717).

Background Cholangiocarcinoma (CCA) may arise in the intra- or extrahepatic biliary tract and is associated with a poor prognosis. Despite recent advances, to date there is still no established targeted therapeutic approach available. Non-surgical therapeutic agents are urgently needed, as most patients are non-eligible to surgical resection. Anti-PD-L1 therapy prevents cancer cells from evading the immune system and has emerged as a new treatment option in several cancer entities. Recently, PD-L1 expression has been analyzed in comparably small CCA patient cohorts. However, a systematic validation of different PD-L1 antibodies has not been performed in CCA so far. Methods We stained a tissue microarray consisting of 170 patients, including 72 intrahepatic cholangiocarcinomas (iCCAs), 57 perihilar cholangiocarcinomas (pCCAs) and 41 distal cholangiocarcinomas (dCCAs) by immunohistochemistry and evaluated PD-L1 positivity in tumor and stromal cells. We analyzed three different PD-L1 antibodies (clones 28–8, SP142, and SP263) that are frequently used and recommended for predictive diagnostic testing in other cancer types. Results For PD-L1 antibody clone SP263, 5% of iCCAs, 4% of pCCAs and 3% of dCCAs exhibited PD-L1 expression on tumor cells, thereby showing the highest frequencies of PD-L1 positivity. Accordingly, highest PD-L1 positivity rates of stromal cells with 31% in iCCA, 40% in pCCA and 61% in dCCA were detected for clone SP263. Agreement of PD-L1 positivity in tumor cells was moderate for clone 28–8 and SP263 (κ = 0.44) and poor between 28-8 and SP142 (κ = 0.13), as well as SP142 and SP263 (κ = 0.11), respectively. Statistical analyses of PD-L1 expression (clone SP263) on tumor cells with clinicopathological data revealed a positive correlation with shortened overall survival in CCA patients. Conclusions Selection of appropriate PD-L1 antibodies and careful evaluation of immunohistochemical staining patterns have a significant impact on PD-L1 testing in CCA. Clinical trials are necessary to investigate the putative beneficial effects of PD-L1 targeted immunotherapy in CCA patients. Electronic supplementary material The online version of this article (10.1186/s12885-018-5254-0) contains supplementary material, which is available to authorized users.

Polymorphisms of GVIA calcium-independent PLA2 (iPLA2β) implicate its role in plasma lipids, type-2 diabetes, and nonalcoholic fatty liver disease (NAFLD). iPLA2β is thought as a target for NAFLD therapy. We investigated the role of hepatic phospholipids in three NAFLD models: genetic Ob/Ob mice, long-term high-fat diet (HFD)-fed mice (representing obese NAFLD), and mice fed with methionine-choline-deficient (MCD) diet (representing nonobese NAFLD). A defect in hepatic fatty-acyl remodeling of phosphatidylcholine (PC) was observed in these three NAFLD models. By using iPLA2β-null mice, our profiling results revealed that the defect in PC remodeling was rescued in obese NAFLD associated with fatty liver and obesity protection. The rescue of PC remodeling and steatosis protection was not observed in MCD-fed mice. Our results indicate a critical role of hepatic PC for protection by iPLA2β inactivation, suggesting that iPLA2β inhibitors may be used as a therapy for obese but not nonobese NAFLD.

Norursodeoxycholic acid is an orally administered side chain-shortened homologue of ursodeoxycholic acid that undergoes hepatic enrichment with hepatoprotective, anti-inflammatory, and antifibrotic activity. We assessed the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease.We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial in tertiary referral hospitals and medical centres in Austria (n=6) and Germany (n=23) for patients with non-alcoholic fatty liver disease with or without diabetes. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and serum alanine aminotransferase (ALT) concentrations of more than 0·8 times the upper limit of normal were randomly assigned (1:1:1) using a computer-generated central randomisation. Patients were randomly assigned to receive either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks with a subsequent 4-week follow-up period. All individuals involved in the trial were masked to treatment allocation. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment assessed in the intention-to-treat population. This trial is registered with EudraCT, number 2013-004605-38.Between March 30, 2015, and Sept 20, 2016, of 198 individuals included in the analysis, 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change -27·8%, 95% repeated CI -34·7 to -14·4; p0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. 112 treatment-emergent adverse events occurred in the 1500 mg group, 99 in the 500 mg group, and 103 in the placebo group. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated encouraging further studies.Dr Falk Pharma GmbH.

Chronic hepatitis C virus infection is associated with a significant health burden. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. The introduction of direct-acting antivirals (DAA) has led to an increase in sustained virologic response rates (SVR), but is accompanied by higher treatment costs. The aim of this study was to assess the outcomes and costs of treating hepatitis C virus infected patients with DAAs in clinical practice in Germany.Data were derived from a noninterventional study including a pharmacoeconomic subset of 2673 patients with genotypes 1 and 3 who initiated and completed treatment between February 2014 and February 2017. Sociodemographic and clinical parameters as well as resource utilization were collected using a web-based data recording system. Costs were calculated using official remuneration schemes.The mean age of the patients was 54.6 years; 48% were men. 93.5% of all patients achieved an SVR. The average total treatment costs wereOV0556;67 979 (OV0556;67 131 medication costs,OV0556;824 ambulatory care,OV0556;24 hospital costs). The average costs per SVR ofOV0556;72 705 were calculated. Differences in SVR and costs according to genotype, treatment regimen, treatment experience, and cirrhosis were observed. Quality-of-life data showed no or a minimal decrease during treatment.This analysis confirms high SVR rates for newly introduced DAAs in a real-world setting. Costs per SVR estimated are comparable to first-generation DAA. Given the fact that the costs for the currently used treatment regimens have declined, it can be assumed that the costs per SVR have also decreased. Our insight into real-world outcomes and costs can serve as a basis for a comparison with the mentioned newly introduced treatment regimens.

ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse.DesignWe analysed multicentric case–control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed.ResultsThe Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (pConclusionThe Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%–4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.

BackgroundIn pivotal studies with direct-acting antivirals (DAAs), rates of sustained virological response in hepatitis C genotype 1 infection are >90%.ObjectiveThe objective of this article is to assess real-world safety and effectiveness of DAA treatment in a prospective multicenter registry study.MethodsThe German Hepatitis C-Registry includes 6606 patients with genotype 1 from 246 centers, treated between February 2014 and June 2016 at the discretion of the physician.ResultsA total of 4846 patients completed treatment and follow-up; 51% of these patients were treatment experienced and 28% had liver cirrhosis. Comorbidities were reported in 76% of patients, including HIV co-infection in 8%. SVR12 was 92% with 91% in GT1a and 93% in GT1b. HIV co-infected patients (n = 247) had an SVR12 of 92%. Treatment was discontinued prematurely in 2.5%. In multivariate analysis, SVR12 was dependent on the choice of antiviral regimen (OR 1.33 (1.24–1.43); p

Background & Aims Ledipasvir/sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study, 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the Summary of Product Characteristics (SmPC), 8-week treatment may be considered in naive non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of an 8-week regimen of LDV/SOF under real-world conditions. The aim of the present study was to characterise patients receiving 8 weeks of LDV/SOF compared to those receiving 12 weeks of LDV/SOF, and to describe therapeutic outcomes in routine clinical practice. Methods The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. Results Overall, 84.6% (2,034/2,404) of the safety population (intention-to-treat-1 [ITT1]) and 98.2% (2,029/2,066) of the per protocol (PP) population achieved sustained virological response at week 12 (SVR12). In the 8-week group, 85.1% (824/968) of ITT1 and 98.3% (821/835) of PP patients achieved SVR12, while in the 12-week group, 85.5% (1,210/1,415) of ITT1, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). Conclusions Under real-world conditions a high proportion of eligible patients receiving 8-week LDV/SOF treatment achieved SVR12. Relapse occurred more frequently in patients who did not meet the selection criteria according to the SmPC. Lay summary In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8-week) resulted in equivalent cure rates to 12-week treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Clinical Trial number: DRKS00009717 (German Clinical Trials Register, DRKS)

Patients with sepsis frequently present with acute renal failure requiring intermittent renal replacement therapy and haemodynamic monitoring. To date, the effect of haemodialysis on PiCCO monitoring has not been determined.To determine the effect of haemodialysis on the measurement of haemodynamic variables using transpulmonary thermodilution.Prospective observational study.Medical ICU in a university hospital.Thirty patients with sepsis and acute renal failure undergoing intermittent haemodialysis.None.Cardiac index, global end-diastolic volume index and extravascular lung water index measured with or without haemodialysis.Significant correlations were found for all variables measured with and without haemodialysis (r = 0.55 to 0.91, P0.01). Measurements of cardiac index without and with haemodialysis were significantly different [4.71 vs. 4.18 lmin(-1)m(-2), difference -0.54 (SD 0.70), 95% confidence interval (CI) -0.80 to -0.28; P0.01], as were values of global end-diastolic volume index without and with haemodialysis [864.8 vs. 775.3 ml m(-2), difference -89.5 (SD 191.8), 95% CI -161.2 to -17.9; P = 0.02]. Measurements of extravascular lung water index without and with haemodialysis did not differ significantly [10.3 vs. 10.0 ml kg(-1), difference -0.3 (SD 2.0), 95% CI -1.1 to 0.5; P = 0.42].Although significant correlations were found for cardiac index, global end-diastolic volume index and extravascular lung water index with and without haemodialysis, cardiac index and global end-diastolic volume index were significantly reduced during haemodialysis, but not extravascular lung water index, when measured by the PiCCO system in patients with septic shock. Although differences were small, the variability of within-patient differences may be clinically important and care should be taken in relying solely on such measurements.

Summary Background Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection. Methods In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918. Findings Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4·04 log 10 IU/mL (1·71–7·20); 11 patients were infected with HCV genotype 1a and nine patients with genotype 1b. All patients achieved a sustained virological response 12 weeks after the end of treatment (20 [100%] of 20 patients). Treatment was well tolerated; there were no drug-related serious adverse events. Up to 12 weeks after treatment, 22 possible or probable drug-related adverse events were reported. There was one serious adverse event, which was judged unrelated to the study drug; one patient was admitted to hospital for surgery of a ruptured cruciate ligament. Interpretation Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations. Funding Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF).

Objectives The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. Methods When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7–21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). Results Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. Conclusion DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

Background: The combination of sofosbuvir (SOF), ribavirin (RBV) and peg-interferon-alfa-2a (peg-IFN-alfa-2a) as well as the combination of SOF and RBV for the treatment of patients infected with hepatitis c virus (HCV) has improved rates of sustained virological response (SVR) considerably in recent trials. However, there is only limited data concerning the efficacy and safety in a “real-life” cohort. Methods: We analyzed a cohort of 119 patients with chronic HCV infection treated at four investigational sites in Germany. All patients received either a combination treatment of SOF, RBV and peg-IFN-alfa-2a or SOF and RBV. Results: The rates of SVR at 12 weeks after end of treatment (SVR 12) were as follows: Among 76 patients with genotype 1 infection the SVR 12 rate was 74 % (n = 56), among 14 patients with genotype 2 infection the SVR 12 rate was 79 % (n = 11), among 24 patients with genotype 3 infection the SVR 12 rate was 92 % (n = 22) and among 5 patients with genotype 4 infection the SVR 12 rate was 80 % (n = 4). Of all 26 patients with a relapse in our cohort, 69 % (n = 18) of these patients presented with liver cirrhosis and 58 % (n = 15) were treatment experienced. Notably, the level of HCV-RNA after 4 weeks of treatment was a significant predictor of treatment response in genotype 1 patients. Patients with HCV-RNA levels ≥ 12 IU ml-1 after 4 weeks of treatment achieved SVR 12 only in 30 % (n = 17/56, p

Background and Purpose Chronic hepatic inflammation results in liver fibrosis. As effective anti-fibrogenic agents are lacking, we investigated ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE), a synthetic bile acid–phospholipid conjugate with anti-inflammatory and anti-apoptotic properties for tis effects on hepatic fibrogenesis. Experimental Approach To stimulate fibrogenesis, LX2 hepatic stellate cells were cultured with conditioned medium from CL48 liver cells after exposure to stress-inducing conditions – methionine–choline-deficient (MCD) medium or TNFα/cycloheximide (CHX) – with or without UDCA-LPE preincubation. Anti-fibrogenic effects of UDCA-LPE were further studied in CL48 and LX2 cells and in primary human hepatic stellate cells (HHStec) directly exposed to TGF-β1. To test UDCA-LPE in vivo, C57BL/6 mice were fed a MCD diet for 11 weeks followed by 30 mg·kg−1 UDCA-LPE 3× per week for 2.5 weeks. Key Results Expression of α-smooth muscle actin (α-SMA), α1-collagen, vimentin and TGF-β1 was down-regulated by up to 93% by UDCA-LPE in LX-2 cells cultured with conditioned medium. Also, UDCA-LPE inhibited Smad3 phosphorylation in CL48 cells incubated with MCD medium or TNFα/CHX and in LX2 cells exposed to conditioned medium. UDCA-LPE also decreased phosphorylated Smad3 and Smad2 directly induced by TGF-β1. Inhibition of TGF-β1/Smad2/3 signalling with down-regulation of target genes was confirmed in HHStec. In vivo, UDCA-LPE decreased hepatic α-SMA, α1-collagen and TGF-β1 expression and markedly lowered α-SMA protein and collagen deposition in MCD mice. Conclusions and Implications By blocking TGF-β1/Smad2/3 signalling, UDCA-LPE suppressed key mediators of hepatic fibrogenesis. Thus, UDCA-LPE could be suitable for prevention of fibrotic progression of chronic liver disease.

Hepatic fat accumulation and changes in lipid composition are hallmarks of nonalcoholic fatty liver disease (NAFLD). As an experimental approach for treatment of NAFLD, we synthesized the bile acid–phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE). Previous work demonstrated profound hepatoprotective properties of the conjugate in vitro and in vivo. Here we investigated the effects of UDCA-LPE in two nutritional mouse models of NAFLD. C57BL/6 mice were fed a high-fat diet (HFD) for 28 weeks, resulting in steatosis with hyperlipidemia. In a second model, mice received a methionin–choline-deficient (MCD) diet for up to 11 weeks, which induced advanced nonalcoholic steatohepatitis (NASH). Establishment of liver injury was followed by intraperitoneal injections of 30 mg/kg UDCA-LPE three times a week for different time periods. UDCA-LPE ameliorated both HFD- and MCD-induced increases in alanine aminotransferase (ALT) values near to normalization. As for metabolic parameters, UDCA-LPE reduced elevated serum triglyceride and cholesterol values in HFD mice. Liver histology showed improvement of steatosis in HFD and MCD mice concomitant with reductions in hepatic triglyceride and cholesterol levels. Additionally, the conjugate lowered serum caspase-8 activity in both models and decreased lipid hydroperoxides in MCD mice. Abundance of proinflammatory lysophosphatidylcholine (LPC), which was detectable in both HFD and MCD mice, was reduced by UDCA-LPE. Quantitative reverse transcriptase-polymerase chain reaction qRT-PCR of liver specimens revealed that UDCA-LPE strongly down-regulated inflammatory genes and modified the expression of genes involved in lipid metabolism. Conclusion: The current study demonstrates that UDCA-LPE improves hepatic injury at different stages of NAFLD. By concurrently lowering hepatic lipid overloading as well as susceptibility of hepatocytes toward inflammatory stimuli, the conjugate may be able to ameliorate disease progression. Thus, UDCA-LPE represents a promising compound suitable for the treatment of NAFLD. (HEPATOLOGY 2012 )