[DRESS as a rare differential diagnosis in eosinophilia, skin rash and acute hepatitis]. / DRESS als seltene Differentialdiagnose bei Eosinophilie, Hautexanthem und akuter Hepatitis.

A 21-year-old female patient presented with fever, pharyngitis, lymphadenopathy and generalized exanthema that had started 2 weeks prior. Allergies were not known, the family and travel history were negative. Due to depression, Duloxetine had been taken for 1.5 years, and due to bipolar disorder, a treatment with Lamotrigine was started four weeks prior but was stopped because of increased transaminase levels. Laboratory findings on admission showed eosinophilia (1.327 /nl), lymphocytosis and acute hepatitis (GOT 428 U/l, GPT 438 U/l) with deranged coagulation. Inflammatory parameters were increased. Ultrasound revealed hepatosplenomegaly with ascites. Acute viral or parasitic infection was excluded serologically. A skin biopsy showed a perivascular inflammatory infiltrate, compatible with a drug reaction. An inflammatory infiltrate was found in the liver biopsy, consistent with drug-induced hepatitis. Cough, dyspnea and pleural effusion occurred. In summary of the findings and with the help of the RegiSCAR-Score, the diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS) could be made. Under high-dose prednisolone therapy, a gradual decrease of transaminases and reconstitution of liver synthesis could be observed.In patients with eosinophilia, lymphadenopathy, acute hepatitis and generalized exanthema, DRESS is a rare but-due to its potentially life-threatening consequences-important differential diagnosis. The most important measure is to stop the suspected inducing medication immediately. Severe cases should be treated with high-dose systemic corticosteroids.

[Patient safety 4.0: "Failure of the Week" It's all about role modelling!] / Patient*innen-Sicherheit 4.0: "Fehler der Woche" ­ Um die Vorbildfunktion geht's!

BACKGROUND: The rate of mistakes and near misses in clinical medicine remains staggering. The tendency to cover up mistakes is rampant in "name-blame-shame" cultures. The need for safe forums where mistakes can be openly discussed in the interest of patient safety is evident. Following a comprehensive review of the literature, a semi-structured weekly conference, named "mistake of the week" (MOTW), was introduced, enabling physicians to voluntarily discuss their mistakes and near-misses. The MOTW is intended to encourage cultural change in how physicians approach, process, accept and learn from their own and their peers' mistakes. This study seeks to assess if physicians appreciate, benefit from and are motivated to participate in MOTW. METHODS: Physicians and medical students of the I. and II. Medizinische Klinik at the Academic Teaching Hospital Klinikum Konstanz (Germany) were eligible to participate voluntarily. Four groups of physicians (n=3-6) and one group of medical students (n=5) volunteered to participate in focus group interviews, which were videotaped, transcribed and analyzed. RESULTS: The following success factors are crucial for dealing with and voluntarily disclosing mistakes and near-misses: 1. Exemplification ("follow the boss's lead"), 2. Fixed time slots and a clear forum, 3. Reporting mistakes without fear of penalty or punishment, 4. A trusting working atmosphere. The key effects of the MOTW approach are: 1. People report their mistakes more, 2. Relief, 3. Psychological safety, 4. Lessons learned/errors (potentially) reduced. DISCUSSION: The MOTW conference models an ideal forum to mitigate hierarchy and promote a sustainable organizational dynamic in which mistakes and near misses can be discussed in an environment free from "name-blame-shame", with the ultimate goal of potentially improving patient care and safety.

Quality of life as a therapeutic objective in the management of hepatic encephalopathy and the potential role of rifaximin-α.

OBJECTIVE: Quality of life (QoL) is impaired in patients with hepatic encephalopathy and rifaximin-α can improve QoL within 6 months. This study assessed the importance of QoL as a therapeutic objective in hepatic encephalopathy management; whether QoL is routinely assessed in hepatic encephalopathy patients in clinical practice and the role of rifaximin-α in this context. METHODS: A survey was conducted of healthcare professionals (HCPs) from Europe and Australia involved in hepatic encephalopathy management. HCPs rated the importance of a range of therapeutic objectives on a 1-7 Likert scale (1 = not at all important; 7 = extremely important). HCPs were also required to provide three patient record forms (PRFs) based on their last three hepatic encephalopathy patients. RESULTS: There were 218 HCP respondents, who provided 654 PRFs (patients treated with rifaximin-α, n = 347; patients not treated with rifaximin-α, n = 307). The mean Likert score was highest for the therapeutic objective 'improving a patient's QoL' (6.4), which was rated significantly more highly than all other therapeutic objectives, including 'reducing the patient's likelihood of hospital readmission' (6.1; P < 0.001) and 'preventing death of the patient' (6.1; P < 0.001). Despite this, only 28.3% of PRFs documented specific QoL data assessment. Patients receiving rifaximin-α were treated later in their disease course than those not receiving rifaximin-α. CONCLUSIONS: HCPs consider QoL improvement the main therapeutic objective in hepatic encephalopathy management, but most do not explicitly assess QoL. Earlier introduction of rifaximin-α may safeguard QoL improvement even when QoL monitoring is not possible.

Detection of SARS-CoV-2 from raw patient samples by coupled high temperature reverse transcription and amplification.

SARS-CoV-2 is spreading globally with unprecedented consequences for modern societies. The early detection of infected individuals is a pre-requisite to contain the virus. Currently, purification of RNA from patient samples followed by RT-PCR is the gold standard to assess the presence of this single-strand RNA virus. However, these procedures are time consuming, require continuous supply of specialized reagents, and are prohibitively expensive in resource-poor settings. Here, we report an improved nucleic-acid-based approach to detect SARS-CoV-2 with the ability to detect as little as five viral genome equivalents. The approach delivers results without the need to purify RNA, reduces handling steps, minimizes costs, and allows evaluation by non-specialized equipment. The use of unprocessed swap samples is enabled by employing a heat-stable RNA- and DNA-dependent DNA polymerase, which performs the double task of stringent reverse transcription of RNA at elevated temperatures as well as PCR amplification of a SARS-CoV-2 specific target gene. As results are obtained within 2 hours and can be read-out by a hand-held LED-screen, this novel protocol will be of particular importance for large-scale virus surveillance in economically constrained settings.

Long-term management of hepatic encephalopathy with lactulose and/or rifaximin: a review of the evidence.

A consolidated overview of evidence for the effectiveness and safety/tolerability of hepatic encephalopathy (HE) treatment over the long term is currently lacking. We identified and assessed published evidence for the long-term (≥6 months) pharmacological management of HE with lactulose and/or rifaximin. A literature search was conducted in PubMed (cutoff date 05 March 2018) using the search terms 'hepatic encephalopathy+rifaximin' and 'hepatic encephalopathy+lactulose'. All articles containing primary clinical data were manually assessed to identify studies in which long-term (≥6 months) effectiveness and/or safety/tolerability end points were reported for lactulose and/or rifaximin. Long-term effectiveness outcomes were reported in eight articles for treatment with lactulose alone and 19 articles for treatment with rifaximin, alone or in combination with lactulose. Long-term safety/tolerability outcomes were reported in six articles for treatment with lactulose alone and nine articles for treatment with rifaximin, alone or in combination with lactulose. These studies showed that lactulose is effective for the prevention of overt HE recurrence over the long term and that the addition of rifaximin to lactulose significantly reduces the risk of overt HE recurrence and HE-related hospitalization, compared with lactulose therapy alone, without compromising tolerability. Current evidence therefore supports recommendations for the use of lactulose therapy for the prevention of overt HE recurrence over the long term, and for the additional benefit of adding rifaximin to lactulose therapy. Addition of rifaximin to standard lactulose therapy may result in substantial reductions in healthcare resource utilization over the long term, by reducing overt HE recurrence and associated rehospitalization.

Design of the Prospective Real-world Outcomes Study of hepatic encephalopathy Patients' Experience on Rifaximin-α (PROSPER): an observational study among 550 patients.

BACKGROUND: Hepatic encephalopathy (HE) is one of the most important severe complications of liver cirrhosis. Thought to be caused by elevated blood levels of gut-derived neurotoxins (particularly ammonia) entering the brain, HE manifests as a wide range of neurological or psychiatric abnormalities, which increase the risk of mortality, result in substantial morbidity and negatively affect the quality of life (QoL) of both patients and their caregivers. HE is also associated with a substantial economic burden. Rifaximin-α 550 mg is a locally acting oral antibiotic that reduces the effects of ammonia-producing intestinal flora, and which is used to help reduce the recurrence of overt HE. The efficacy of rifaximin-α 550 mg was established in a randomised controlled trial and long-term extension study. However, 'real-world' evidence is also required to assess how this efficacy may translate into effectiveness in clinical practice, including the potential impact of treatment on healthcare resource utilisation. METHODS: The Prospective Real-world Outcomes Study of HE Patients' Experience on Rifaximin-α 550 mg (PROSPER) is a multinational, multicentre, observational study that will be conducted under real-world clinical practice conditions. Comprising a retrospective phase (up to 12 months) and a prospective phase (up to 24 months), and employing a robust statistical methodology, PROSPER has been specifically designed to minimise the bias associated with observational studies. The primary endpoint will be the effect of rifaximin-α 550 mg treatment on HE- and liver-related hospitalisation rate and duration of hospitalisation. Secondary endpoints will include comprehensive assessments of the impact of treatment on the QoL and workplace productivity of patients and caregivers, a global assessment of treatment effectiveness and safety/tolerability. Approximately 550 patients will be enrolled. CONCLUSIONS: PROSPER will provide valuable real-world information on the effectiveness of rifaximin-α 550 mg in reducing the recurrence of HE, and its impact on the QoL and work productivity of patients and their caregivers. By providing data on both the direct costs (e.g., hospitalisation rate, duration of hospitalisation) and indirect costs (such as work productivity) of HE, PROSPER should help confirm whether rifaximin-α 550 mg treatment represents a good use of economic resources. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02488993.

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation.

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP-/-) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1ß, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP-/- mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP-/- mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

Voluntary distance running prevents TNF-mediated liver injury in mice through alterations of the intrahepatic immune milieu.

Physical activity confers a broad spectrum of health benefits. Beyond the obvious role in metabolically driven diseases, the role of physical activity in acute liver injury is poorly explored. To study the role of physical activity in acute liver injury, a novel model of voluntary distance running in mice was developed and mice were subjected to acute liver injury induced by N-galactosamine (GalN) and lipopolysaccharide (LPS). Analyses included histological stains, immunoblotting, qRT-PCR and FACS analysis. Voluntary distance running increased to an average of 10.3 km/day after a learning curve. Running lead to a decrease in the absolute numbers of intrahepatic CD4+ T and B lymphocytes and macrophages after 7 weeks. In parallel, hepatic mRNA expression of inflammatory cytokines including IL-6 and IL-1beta, TGF-beta and monocyte chemoattractant protein-1 (MCP-1/CCL2) were suppressed, while TNF-α was not affected by exercise. Likewise, expression of the macrophage-specific antigen F4/80 was downregulated 1.6-fold from exercise. Notably, acute liver injury from GaIN/LPS was significantly blunted following 7 weeks of voluntary exercise as determined by liver histology, a 84.6% reduction of alanine aminotransferase (P<0.01) and a 54.6% reduction of aspartate aminotransferase (P<0.05) compared with sedentary mice. Additionally, proinflammatory cytokines, activation of caspase 3 and JNK were significantly lower, while antiapoptotic protein A20 increased. Voluntary distance running alters the intrahepatic immune phenotype producing an environment that is less susceptible to acute liver injury.

Medication and Treatment Adherence Following Hospital Discharge.

BACKGROUND: Patients' drug regimens often need to be changed when they pass from one care sector to another, but these changes sometimes pose a safety risk. To avoid such risks, a new inter-sector transition concept was developed incorporating discharge medication plans and counseling modules for the patients themselves and the doctors receiving them into their care. METHODS: A prospective interventional trial was carried out in two internal medicine wards of a general hospital. After data acquisition from the control group, the transition concept was developed and evaluated in an independent intervention group. The discharge medication plan and the first post-discharge prescription were compared to identify patients who had at least one medication change that increased the post-discharge risk of either failure to achieve the therapeutic goal (category A, first endpoint) or of patient's lack of treatment adherence (category B). Gaps in care after discharge were also analyzed. RESULTS: 200 consecutive patients were enrolled in the trial. In the intention-to-treat analysis, the percentage of patients with potentially jeopardizing medication changes in category A declined from 54% (54/100) in the control group to 15% (15/100) in the intervention group. (p<0.001). For medication changes in category B, there was a corresponding decline from 53% (53/100) to 7% (7/100) (p < 0.001). Gaps in care were seen in 28% (28/100) of control patients and 18% (18/100) of patients in the intervention group (p = 0.031). CONCLUSION: The likelihood of a potentially jeopardizing medication change upon hospital discharge can be markedly reduced with the aid of a modular transition concept. Gaps in care can be closed in this way as well.

Saccharomyces boulardii to Prevent Antibiotic-Associated Diarrhea: A Randomized, Double-Masked, Placebo-Controlled Trial.

Background. Antibiotic-associated diarrhea (AAD) and Clostridium difficile-associated diarrhea (CDAD) are common complications of antibiotic use. Data on the efficacy of probiotics to prevent AAD and CDAD are unclear. We aimed to evaluate the efficacy of Saccharomyces boulardii to prevent AAD and CDAD in hospitalized adult patients. Methods. We conducted a multicenter, phase III, double-masked, randomized, placebo-controlled trial in hospitalized patients who received systemic antibiotic treatment in 15 hospitals in Germany between July 2010 and October 2012. Participants received Perenterol forte 250 mg capsules or matching placebo twice per day within 24 hours of initiating antibiotic treatment, continued treatment for 7 days after antibiotic discontinuation, and were then observed for 6 weeks. Results. Two thousand four hundred forty-four patients were screened. The trial was stopped early for futility after inclusion of 477 participants. Two hundred forty-six patients aged 60.1 ± 16.5 years and 231 patients aged 56.5 ± 17.8 were randomized to the S boulardii group and the placebo group, respectively, with 21 and 19 AADs in the respective groups (P = .87). The hazard ratio of AAD in the S boulardii group compared with the placebo group was 1.02 (95% confidence interval, .55-1.90; P = .94). Clostridium difficile-associated diarrhea occurred in 0.8% of participants (4 of 477). Nine serious adverse events were recorded in the S boulardii group, and 3 serious adverse events were recorded in the placebo group. None were related to study participation. Conclusions. We found no evidence for an effect of S boulardii in preventing AAD or CDAD in a population of hospitalized patients without particular risk factors apart from systemic antibiotic treatment. ClinicalTrials.gov Identifier. NCT01143272.

ITPA Genotypes Predict Anemia but Do Not Affect Virological Response with Interferon-Free Faldaprevir, Deleobuvir, and Ribavirin for HCV Infection.

BACKGROUND & AIM: Whether inosine triphosphatase (ITPA) gene polymorphisms predict anemia during interferon-free therapy in chronic hepatitis C virus (HCV)-infected patients is unknown. We examined the relationship between two ITPA polymorphisms, anemia, and sustained virological response 12 weeks post-treatment (SVR12) in patients receiving the NS3/4A protease inhibitor faldaprevir, the non-nucleoside polymerase inhibitor deleobuvir, and ribavirin. METHODS: HCV genotype 1-infected, treatment-naïve patients (N = 362) were randomized and treated in one of five treatment arms with faldaprevir and deleobuvir with or without ribavirin. Two ITPA polymorphisms (rs1127354 and rs6051702) were genotyped and defined as ITPA-deficient (rs1127354 AA or AC; rs6051702 CC or CA) or ITPA-non-deficient (rs1127354 CC; rs6051702 AA) according to their association with ITPA deficiency. Baseline and on-treatment variables associated with anemia and SVR12 were identified using logistic regression. RESULTS: In the pooled ribavirin-containing arms, 10.1% (32/316) of patients experienced on-treatment hemoglobin <10 g/dL, and 32.6% (103/316) experienced on-treatment hemoglobin <10 g/dL or a change from baseline ≥3.5 g/dL. Of the latter group, 99% (102/103) had the ITPA-non-deficient rs1127354 genotype. Other variables associated with on-treatment hemoglobin <10 g/dL or a decrease ≥3.5 g/dL were age, baseline hemoglobin, rs6051702 genotype, and plasma ribavirin concentration. In a multivariate analysis, high plasma ribavirin concentration, low baseline hemoglobin, HCV genotype 1b, and IL28B genotype CC were associated with higher SVR12. CONCLUSIONS: The ITPA rs1127354 CC and rs6051702 AA genotypes may predict ribavirin-induced anemia during treatment with interferon-free, ribavirin-containing regimens. With this interferon-free regimen, SVR was associated with ribavirin levels, but not with anemia or ITPA genotypes. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01132313.

Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial.

UNLABELLED: Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 µg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00803309.

STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection.

BACKGROUND & AIMS: The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS: Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg.

Efficacy and safety of faldaprevir, deleobuvir, and ribavirin in treatment-naive patients with chronic hepatitis C virus infection and advanced liver fibrosis or cirrhosis.

Patients with advanced hepatic fibrosis or cirrhosis with chronic hepatitis C virus (HCV) infection represent an unmet need. The HCV NS3/4A inhibitor, faldaprevir, was evaluated in combination with the nonnucleoside NS5B inhibitor, deleobuvir, with or without ribavirin in treatment-naive patients with HCV genotype 1 infection in the SOUND-C2 study. Here, the efficacy and safety of this interferon-free regimen in a subset of patients with advanced liver fibrosis, including those with compensated cirrhosis, were assessed. Patients (n=362) were randomized to once-daily faldaprevir with either twice-daily (BID) or three-times-daily (TID) deleobuvir for 16 (TID16W), 28 (TID28W and BID28W), or 40 (TID40W) weeks with or without ribavirin (TID28W-NR). Patients were classified according to fibrosis stage (F0 to F2 versus F3 to F4) and the presence of cirrhosis (yes/no). In total, 85 (24%) patients had advanced fibrosis/cirrhosis (F3 to F4) and 33 (9%) had cirrhosis. Within each treatment arm, differences in rates of sustained virologic response 12 weeks after completion of treatment (SVR12) between patients with mild to moderate fibrosis (F0 to F2) versus F3 to F4 did not show a consistent pattern and were not statistically significant (63% versus 47% for TID16W, 53% versus 76% for TID28W, 48% versus 67% for TID40W, 70% versus 67% for BID28W, and 40% versus 36% for TID28W-NR, respectively; P > 0.05 for each arm). The most frequent adverse events in patients with/without cirrhosis were gastrointestinal and skin events, which were mostly mild or moderate in intensity. The degree of liver fibrosis did not appear to affect the probability of achieving SVR12 following treatment with the interferon-free regimen of faldaprevir, deleobuvir, and ribavirin. (This study has been registered at ClinicalTrials.gov under registration no. NCT01132313.).

Predictive scores in primary biliary cirrhosis: a retrospective single center analysis of 204 patients.

GOALS: The aim of this study was to assess the long-term outcome of primary biliary cirrhosis (PBC) patients and to test the clinical value of various outcome models, such as the Mayo Risk Score (MRS), in a large single-center cohort in Germany. BACKGROUND: PBC is a chronic autoimmune liver disease with a female gender predominance and a peak incidence in the fifth decade of life. PBC is characterized by portal inflammation and immune-mediated destruction of intrahepatic bile ducts in liver histology and the presence of antimitochondrial antibodies in the serum of nearly 95% of patients. In 5% to 20% of patients an overlap syndrome with autoimmune hepatitis (AIH) is diagnosed. Ursodeoxycholic acid is widely accepted as the standard medical treatment. STUDY: A total of 204 patients with PBC or PBC/AIH were retrospectively analyzed with regard to their clinical, biochemical, serological, and histologic features. PBC was diagnosed on the basis of the American Association for the Study of Liver Diseases criteria. Specific PBC scores, such as the MRS, the European and the Yale model, as well as nonspecific scores such as the Child-Pugh, the Model for End-stage Liver Disease, and Aspartate Aminotransferase to Platelet Ratio Index score were analyzed for their utility to predict the clinical outcome of patients. RESULTS: One hundred eighty-four patients with PBC alone and 20 with primary biliary cirrhosis/autoimmune hepatitis overlap were followed up for an average of 7.0 (range, 0.5 to 33.2) years. Importantly, baseline values of serum bilirubin, alkaline phosphatase, immunoglobulin M (IgM) and IgG, as well as antimitochondrial antibodies titers did not allow in properly predicting patient's outcome. The MRS proved clinical applicability. Patients with an R-value <6 did not develop liver-related complications. The Aspartate Aminotransferase to Platelet Ratio Index score had a significant correlation with the histologic degree of liver fibrosis, with limited value of scores between 1.0 and 1.5. Patients with a Model for End-stage Liver Disease score ≥8 (n=17) had a significantly higher risk to undergo liver transplantation or liver-related death. Outcome was less favorable than predicted by the European model. All scores showed low positive predictive values, limiting their applicability in clinical practice. CONCLUSIONS: Herein, we demonstrate that clinical risk scores in PBC should be interpreted with care. The MRS proved to be helpful to predict a favorable outcome. Novel approaches to predict outcome are needed to identify patients who may benefit from alternative, intensified treatment regimens.

Efficacy of SpyGlass(TM)-directed biopsy compared to brush cytology in obtaining adequate tissue for diagnosis in patients with biliary strictures.

AIM: To evaluate the diagnostic yield (inflammatory activity) and efficiency (size of the biopsy specimen) of SpyGlass(TM)-guided biopsy vs standard brush cytology in patients with and without primary sclerosing cholangitis (PSC). METHODS: At the University Medical Center Mainz, Germany, 35 consecutive patients with unclear biliary lesions (16 patients) or long-standing PSC (19 patients) were screened for the study. All patients underwent a physical examination, lab analyses, and abdominal ultrasound. Thirty-one patients with non-PSC strictures or with PSC were scheduled to undergo endoscopic retrograde cholangiography (ERC) and subsequent peroral cholangioscopy (POC). Standard ERC was initially performed, and any lesions or strictures were localized. POC was performed later during the same session. The Boston Scientific SpyGlass System(TM) (Natick, MA, United States) was used for choledochoscopy. The biliary tree was visualized, and suspected lesions or strictures were biopsied, followed by brush cytology of the same area. The study endpoints (for both techniques) were the degree of inflammation, tissue specimen size, and the patient populations (PSC vs non-PSC). Inflammatory changes were divided into three categories: none, low activity, and high activity. The specimen quantity was rated as low, moderate, or sufficient. RESULTS: SpyGlass(TM) imaging and brush cytology with material retrieval were performed in 29 of 31 (93.5%) patients (23 of the 29 patients were male). The median patient age was 45 years (min, 20 years; max, 76 years). Nineteen patients had known PSC, and 10 showed non-PSC strictures. No procedure-related complications were encountered. However, for both methods, tissues could only be retrieved from 29 patients. In cases of inflammation of the biliary tract, the diagnostic yield of the SpyGlass(TM)-directed biopsies was greater than that using brush cytology. More tissue material was obtained for the biopsy method than for the brush cytology method (P = 0.021). The biopsies showed significantly more inflammatory characteristics and greater inflammatory activity compared to the cytological investigation (P = 0.014). The greater quantity of tissue samples proved useful for both PSC and non-PSC patients. CONCLUSION: SpyGlass(TM) imaging can be recommended for proper inflammatory diagnosis in PSC patients. However, its value in diagnosing dysplasia was not addressed in this study and requires further investigation.

SILEN-C3, a phase 2 randomized trial with faldaprevir plus pegylated interferon α-2a and ribavirin in treatment-naive hepatitis C virus genotype 1-infected patients.

Faldaprevir is an investigational hepatitis C virus (HCV) NS3/4A protease inhibitor which, when administered for 24 weeks in combination with pegylated interferon α-2a and ribavirin (PegIFN/RBV) in treatment-naive patients in a prior study (SILEN-C1; M. S. Sulkowski et al., Hepatology 57:2143-2154, 2013, doi:10.1002/hep.26276), achieved sustained virologic response (SVR) rates of 72 to 84%. The current randomized, open-label, parallel-group study compared the efficacy and safety of 12 versus 24 weeks of 120 mg faldaprevir administered once daily, combined with 24 or 48 weeks of PegIFN/RBV, in 160 treatment-naive HCV genotype 1 patients. Patients with maintained rapid virologic response (HCV RNA of <25 IU/ml at week 4 and undetectable at weeks 8 and 12) stopped all treatment at week 24, otherwise they continued PegIFN/RBV to week 48. SVR was achieved by 67% and 74% of patients in the 12-week and 24-week groups, respectively. Virologic response rates were lower in the 12-week group from weeks 2 to 12, during which both groups received identical treatment. SVR rates were similar in both groups for patients achieving undetectable HCV RNA. Most adverse events were mild or moderate, and 6% of patients in each treatment group discontinued treatment due to adverse events. Once-daily faldaprevir at 120 mg for 12 or 24 weeks with PegIFN/RBV resulted in high SVR rates, and the regimen was well tolerated. Differences in the overall SVR rates between the 12-week and 24-week groups were not statistically significant and possibly were due to IL28B genotype imbalances; IL28B genotype was not tested, as its significance was not known at the time of the study. These results supported phase 3 evaluation. (This study has been registered at ClinicalTrials.gov under registration no. NCT00984620).

Defer or treat? Reasons for treatment decisions in patients with chronic hepatitis C genotype 1 in the early era of directly acting antiviral agents.

BACKGROUND: In chronic genotype 1 hepatitis C, telaprevir or boceprevir plus peginterferon and ribavirin have become the new standard of care. Aim of this study was to identify factors contributing to the decision whether to defer or treat with the current triple regimens. METHODS: Prospective assessment of eight parameters on 0-4-point scales by the attending physician at a German tertiary referral centre between 1st September 2011 and 31st December 2012. RESULTS: 307 patients were evaluated at least once by one of the 11 hepatologists involved; 267 patients were considered, but only 163 were recommended to receive triple therapy. Multivariate regression analysis revealed that a higher degree of fibrosis was most strongly associated with a recommendation for treatment (OR 2.69), followed by the patients' demand (OR 2.27), presumed efficacy (OR 1.62), and tolerability (OR 1.58). A high risk of decompensation was associated with the decision to defer (OR 0.39). Speed of progression, compliance, extrahepatic manifestation, gender and age were not significantly related to the recommendation. Treatment was finally started in 101 patients (32.9%). CONCLUSION: In chronic genotype 1 hepatitis C, advanced fibrosis and patients' preference are the main rationales to choose treatment rather than deferral in a real-life setting.

Trends in epidemiology, treatment, and survival of hepatocellular carcinoma patients between 1998 and 2009: an analysis of 1066 cases of a German HCC Registry.

GOALS: The aim of this study was to analyze clinical presentation, course of disease, and management of patients with hepatocellular carcinoma (HCC) in a German referral center between 1998 and 2009. BACKGROUND: HCC is a rare tumor in Germany, but its incidence has increased over the last 30 years. New therapies such as chemoembolization with drug-eluting beads, selective internal radiotherapy, and sorafenib were introduced recently; however, the impact on clinical management and overall survival (OS) is unclear. STUDY: In this retrospective analysis, 1066 patients with HCC, separated into two 6-year periods (n=385; 1998 to 2003 and n=681; 2004 to 2009) were evaluated. RESULTS: The number of patients presenting each year (64 vs. 114 per year), with an age over 80 years or with nonalcoholic steatohepatitis increased significantly between periods. The main risk factors were alcoholic liver disease in 51.7%, chronic hepatitis C virus in 28.2%, and chronic hepatitis B virus in 13.4% of patients with liver cirrhosis and HCC. Patients presented with more advanced tumor stages and with worse liver function in period 2. The majority (61.6%) of patients received local treatment over a spectrum of Barcelona Clinic Liver-Cancer (BCLC) stages, whereas systemic therapy was offered to a minority (8.8%) and limited to BCLC stage C patients only. OS decreased in BCLC stage A and D and improved in BCLC stage B and C and decreased for all patients from 16.5 to 15.3 months between periods. CONCLUSIONS: No improvement of OS was observed when comparing time periods, partly because of the more advanced stage of HCC and because of the increasing age in the second time period. Improved and new therapeutic options and the intensification of surveillance programs are likely to increase survival of HCC patients in the future.