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Interferon/Ribavirin-Free Antiviral Treatment in Septuagenarians and Octogenarians With Chronic Hepatitis C

DAA-based regimens for chronic hepatitis C infection encourage treatment of "difficult-to-treat" cohorts. This study investigated efficacy and safety of DAA-based regimens in HCV patients on dialysis or postkidney or liver/kidney transplantation. Twenty-five patients treated with DAA combinations were evaluated: 10 were on dialysis (eight: hemodialysis, two: peritoneal dialysis), eight were kidney transplant recipients, and seven were liver/kidney transplant recipients. Except for one patient treated with daclatasvir ([DCV]/60 mg/QD)/simeprevir ([SMV]/150 mg/QD), the others received sofosbuvir-based regimens ([SOF];400 mg/QD) combined with SMV:eight, DCV:13 or either ledipasvir ([LDV]90 mg/QD), ribavirin ([RBV];weight based) or pegylated interferon/RBV. HCV-RNA was determined by Abbott RealTime (LLOQ]:12 IU/ml) or Roche AmpliPrep/COBAS TaqMan assay (LLOQ:15 IU/ml); treatment response evaluated every 4 weeks, at the end of treatment, and 4 and 12 weeks thereafter. Twenty-four (96%) patients achieved SVR 12/24 (ITT-analysis). Mean treatment duration was 15.1 ± 5.1 weeks (±SD), and two patients terminated prematurely - both reached SVR12. Six patients were hospitalized due to complications of underlying disease. One patient achieved SVR24 but was re-infected (week 27). Kidney function remained stable; serum creatinine increased in only one patient - SOF was reduced to 400 mg/48 h. Treatment with DAA combinations in renally impaired HCV patients is highly effective and well tolerated. These findings call for further controlled trials and data from real-life cohorts.

First-generation HCV protease inhibitors represent a milestone in antiviral therapy for chronic hepatitis C infection (CHC), but substantially increased rates of viral clearance are offset by increased rates of infection and infection-associated deaths, especially of patients with advanced liver disease. We aimed to assess whether first generation protease inhibitors interfere with neutrophil function. We included 108 consecutive, retrospective CHC patients and 44 consecutive, prospective CHC patients who were treated with peginterferon and ribavirin with or without protease inhibitors according to the guidelines in the period of November 2012 to June 2015. 33 healthy volunteers served as controls. Infection data were evaluated in all patients. Neutrophil phagocytosis, oxidative burst, elastase and diamine oxidase levels during 12 weeks of triple (n = 23) or dual therapy (n = 21) were studied in the prospective part. In the retro- and prospective cohorts patients experiencing clinically relevant infections were significantly more frequent during protease inhibitor therapy (31% and 26%) than during therapy with peginterferon and ribavirin (13% and 0%). Neutrophil phagocytosis decreased to 40% of baseline with addition of protease inhibitors to P/R but recovered 6 months after end of treatment. Protease inhibitors also seemed to reduce serum elastase levels but did not impact on gut permeability. Impaired neutrophil function during triple therapy with first generation HCV protease inhibitors may explain the high infection rate associated to these treatments and be of relevance for treatment success and patient survival. Trial Registration ClinicalTrials.gov NCT02545400 ClinicalTrials.gov NCT02545335

Daclatasvir (DCV) is a potent, pangenotypic nonstructural protein 5A inhibitor with demonstrated antiviral efficacy when combined with sofosbuvir (SOF) or simeprevir (SMV) with or without ribavirin (RBV) in patients with chronic hepatitis C virus (HCV) infection. Herein, we report efficacy and safety data for DCV-based all-oral antiviral therapy in liver transplantation (LT) recipients with severe recurrent HCV. DCV at 60mg/day was administered for up to 24 weeks as part of a compassionate use protocol. The study included 97 LT recipients with a mean age of 59.3 +/- 8.2 years; 93% had genotype 1 HCV and 31% had biopsy-proven cirrhosis between the time of LT and the initiation of DCV. The mean Model for End-Stage Liver Disease (MELD) score was 13.0 +/- 6.0, and the proportion with Child-Turcotte-Pugh (CTP) A/B/C was 51%/31%/12%, respectively. Mean HCV RNA at DCV initiation was 14.3x6 log(10) IU/mL, and 37% had severe cholestatic HCV infection. Antiviral regimens were selected by the local investigator and included DCV+SOF (n=77), DCV+SMV (n=18), and DCV+SMV+SOF (n=2); 35% overall received RBV. At the end of treatment (EOT) and 12 weeks after EOT, 88 (91%) and 84 (87%) patients, respectively, were HCV RNA negative or had levels

In hemodialysis (HD) patients, a decrease of serum HCV RNA concentration during HD has been reported.To evaluate the effect of two different extracorporeal blood treatments, HD and hemodiafiltration (HDF), on HCV RNA concentration under standardized conditions.Eleven chronic HD patients with chronic hepatitis C (CHC) and thirty-three non-uremic patients with CHC as controls were studied. Blood samples were collected at baseline (t=0 min), 30 min (t=30), and 180 min (t=180) after start of HD or HDF. HCV RNA concentrations were determined by a real-time PCR assay. Values obtained 30 min and 180 min after start of HD or HDF were adjusted according to the ultrafiltration-induced hemoconcentration.Baseline HCV RNA concentrations were found to be similar in dialysis patients and controls (2.9E+06 vs. 5.8E+06 IU/ml). After adjustment for hemoconcentration, no significant differences of HCV RNA concentrations were observed when HD versus HDF treatments and blood samples collected pre versus those collected post membrane were compared. Adjusted HCV RNA concentrations increased by 13% (not significant) at 30 min and by 56% (p0.001) at 180 min after start of HD or HDF. Inhibitory effects on PCR through heparin and uremic toxins could be excluded.In contrast to recent publications, a significant increase of serum HCV RNA within 180 min after start of HD or HDF was observed. Changes in serum HCV RNA concentration are independent from HD and HDF procedures, dialysis membrane, heparin concentration, and uremic toxins.

Hintergrund Interferon α ist ein wichtiges Medikament zur Behandlung der chronischen Hepatitis C. Es induziert jedoch haufig depressive Zustandsbilder, die die Adharenz und die Lebensqualitat der Betroffenen beeintrachtigen. Mittels einer prospektiven Studie werden die Auswirkungen einer Interferontherapie auf die Entwicklung depressiver Episoden, auf die neuropsychologische Leistungsfunktionen und die gesundheitsbezogene Lebensqualitat untersucht.

The IL28B genotype is the most important pretreatment predictor of treatment outcome in patients with chronic hepatitis C. The impact of the rs12979860 genotype on relapse was retrospectively evaluated in genotype 1/4 patients who received response-guided therapy with peginterferon alpha-2a 180 μg/week plus ribavirin 1,000/1,200 mg/day in a large, randomized, multicenter study. Patients with a rapid virologic response (RVR: hepatitis C virus [HCV] RNA

BACKGROUND Sorafenib is the new reference standard for patients with advanced hepatocellular carcinoma (HCC). AIM To identify prognostic factors in sorafenib-treated HCC patients and to evaluate outcomes with respect to liver function. METHODS In this retrospective study, 148 HCC patients received sorafenib 400 mg b.d. across 11 Austrian institutions. Seventy-eight HCC patients who received best supportive care (BSC) in the pre-sorafenib era served as a control. RESULTS In sorafenib-treated patients, low baseline α-fetoprotein, low Child-Pugh (CP) score, compensated cirrhosis, and low baseline aspartate aminotransferase (AST) were associated with significantly longer overall survival (OS) on univariate analysis. CP score and baseline AST remained independent prognostic factors on multivariate analysis. In patients with Barcelona Clinic liver Cancer (BCLC) stage B or C HCC (sorafenib: n = 139; BSC: n = 39), CP-A patients had a median OS of 11.3 (sorafenib [n = 76]) vs. 6.4 (BSC [n = 17]) months (P = 0.010), and CP-B patients had a median OS of 5.5 (sorafenib [n = 55]) vs. 1.9 (BSC [n = 22]) months (P = 0.021). In the sorafenib group, median OS according to baseline AST was 11.8 (

Toxins accumulating in liver failure split into water solved (e.g. ammonia) and albumin bound substances (e.g. bilirubin). Because the latter cannot be removed by conventional haemodialysis, special liver support systems have been developed. The majority of data concerning elimination efficiency exist for the cell-free devices Molecular Adsorbent Recirculating System (MARS) and Prometheus, as they have been commercially available in Europe since many years. Overall, Prometheus provides higher clearances for most liver toxins, especially if they are tightly albumin bound. However, for bile acids and cytokines no such differences could be found. Single pass albumin dialysis (SPAD) can be assumed to be equally effective as MARS. None of the bioartificial liver support systems being developed is on the market today and published clearance data are scarce. In general, clearance efficiency for albumin bound substances is relatively low in all systems currently available. Besides optimizing biocompatibility and selectivity, future technologies should also focus on improved detoxification efficiency of liver support devices.

Background This study compared the results of exercise Doppler echocardiography (EDE) with right-sided heart catheterization (RHC) and evaluated the combination of EDE and cardiopulmonary exercise testing (CPET) as a screening method for early pulmonary vasculopathy in patients with connective tissue disease. Methods Patients (N = 52) with connective tissue disease (predominantly systemic sclerosis) and without known pulmonary arterial hypertension underwent both EDE and CPET. If systolic pulmonary arterial pressure (SPAP) was >40 mm Hg during exercise or peak oxygen uptake (o 2 ) was Results EDE showed an SPAP > 40 mm Hg during exercise in 26/52 patients. Additionally, CPET showed a peak o 2 40 mm Hg in 25 patients (n = 1 at rest, n=24 during exercise). SPAP values assessed by EDE showed no significant difference vs RHC at rest, 25 W, 50 W, and maximal exercise (difference [95% CI]: 0.3 [−2.7; 3.2], −1.3 [−7.1; 4.4], 0.9 [−7.7; 5.9], and −5.6 [−13.5; 2.2] mm Hg). Eight patients with exercise SPAP > 40 mm Hg had an exercise pulmonary arterial wedge pressure > 20 mm Hg, suggesting exercise-induced left ventricular diastolic dysfunction not detectable by EDE. Conclusions EDE appears to be a reasonable noninvasive method to detect SPAP increase during exercise in connective tissue disease. In combination with CPET, it may be a useful screening tool for early pulmonary vasculopathy, although RHC remains the gold standard for hemodynamic assessment. Trial registration clinicaltrials.gov; Identifier: NCT00609349 (Early Recognition of Pulmonary Arterial Hypertension)

Die Hepatitis B ist die haufigste chronische Virusinfektion der Leber. Sie betrifft zumindest geschatzte 350 Millionen Menschen weltweit und ist die haufigste leberbedingte Todesursache. In der letzten Zeit gab es dramatische Entwicklungen sowohl in der Diagnostik als auch in der Medikamentenentwicklung der chronischen Hepatitis B. Heute ist die chronische Hepatitis B in der uberwiegenden Mehrzahl der Patienten eine gut behandelbare Erkrankung und die wichtigste Herausforderung bleibt die rechtzeitige Identifikation der betroffenen Patienten, bevor diese eine fortgeschrittene Lebererkrankungen mit den assoziierten Komplikationen erleiden. Die rasche Entwicklung der medikamentosen Therapie verlangte nach einer Neufassung der Osterreichischen Konsensusempfehlungen zur Behandlung der Hepatitis B, welche bisher nach den Versionen von 1994 und 1998 in ihrer dritten Version von 2005 vorlagen. Alle Kapitel des 3. Konsensus-Statements von 2005 wurden uberarbeitet, mit Ausnahme des Kapitels uber die Leberbiopsie, welches weiterhin in der Version von 2005 Gultigkeit hat. Im Speziellen spielen nun virologische Parameter fur Behandlungsentscheidungen eine zentrale Rolle, die HBV-Genotypisierung wird nun fur die Wahl des Therapeutikums vermehrt in Betracht gezogen und die orale Erstlinientherapie fur die chronische Hepatitis B hat sich verandert. Dieser Konsensus-Bericht beinhaltet die entscheidenden Fortschritte der Behandlung der Hepatitis B und verandert das klinische Management von Patienten mit Hepatitis B in Osterreich entscheidend.

Objective Primary biliary cirrhosis (PBC) is frequently associated with hypercholesterolemia and with an increased cardiovascular morbidity and mortality. Statins lower serum cholesterol levels and may thus improve the cardiovascular risk in PBC patients. The aim of our study was to prospectively examine the efficacy of low-dose atorvastatin on cholestasis as well as cardiovascular risk markers such as dyslipidemia and vascular function in patients with PBC. Methods Nineteen patients with early-stage (biopsy proven and AMA positive) PBC and low-density lipoprotein cholesterol (LDL-C) above 130 mg/dL were included in this single-center study and treated with atorvastatin 10 mg per day for one year. Results Concentrations of total cholesterol, LDL-C, LDL triglycerides, oxLDL, IgG and sVCAM-1 decreased significantly after 48 weeks of atorvastatin treatment. Flow-mediated dilation (FMD) of the brachial artery as an indicator of vascular function significantly increased, while carotid artery intima-media thickness and vascular wall stiffness did not progress under treatment. No statistical differences in liver enzymes were observed except a transient increase of alkaline phosphatase. Conclusion Treatment with low-dose atorvastatin is safe in early-stage PBC, effectively reduces total cholesterol, LDL-C, LDL triglycerides, oxLDL and sVCAM-1 and improves vascular function as reflected by FMD, without affecting cholestasis progression. Therefore, statin therapy should be considered in PBC patients with additional risk factors for cardiovascular disease.

Anticoagulation for extracorporeal liver support is delicate due to underlying coagulation disorders in patients with liver failure and to the associated elevated bleeding risk. To date, there has been no detailed report on anticoagulation issues in patients treated with Prometheus, a device based on the principle of fractionated plasma separation and adsorption. We studied 17 patients from two centers treated with Prometheus, comparing standard anticoagulation with heparin (15 treatments) and a combination of heparin and the synthetic prostacyclin epoprostenol (22 treatments). Standard coagulation tests, proteins C and S, and thrombin-antithrombin (TAT) complex were determined, and adverse events were recorded. All but two treatments could be completed as scheduled, although filter exchange due to filter clotting was required in 24% of the treatments. Three out of 17 patients developed severe bleeding complications within 24 h of treatment. There were no overt thrombotic events. Addition of epoprostenol neither reduced coagulation-related adverse events nor improved standard coagulation parameters. Protein C, but not protein S, showed a significant reduction (23 +/- 18%) after Prometheus treatments, but levels rebounded to baseline within 18 h. TAT levels--a measure for activation of coagulation--were only altered by Prometheus in patients where TAT was already elevated before treatment. In conclusion, anticoagulation of Prometheus with heparin is feasible but still associated with a relatively high frequency of filter clotting and a considerable risk of severe bleeding in this high-risk patient population. As addition of epoprostenol did not prove beneficial, other strategies, such as regional anticoagulation with citrate, should be further evaluated.

Current standard anti-HCV therapy with peginterferon/ribavirin is effective in only half of the patients and limited by side-effects that often necessitate discontinuation. Therefore, new treatments are being developed including specifically targeted antiviral therapy for HCV (STAT-C). Clinical development is most advanced for telaprevir, a HCV NS3/4A protease inhibitor. Phase 1 trials demonstrated potent antiviral effect but rapid emergence of resistance mutations which could be controlled by simultaneous administration of peginterferon. Phase 2 clinical trials (the PROVE trials) demonstrated superior efficacy of a telaprevir-based triple combination regimen for 24 weeks as compared to standard of care at an acceptable safety profile in chronic HCV genotype 1 infection both in the treatment-naive (SVR 65% vs. 44%) and treatment-experienced (SVR 51% vs. 14%) setting. Phase 3 trials are currently ongoing in treatment-naive as well as treatment-experienced HCV genotype 1 patients and SVR data are expected for the second half of 2010.

Background: Indocyanine green (ICG) clearance has been proposed as a quantitative liver function test several decades ago. Interest in this method has been renewed following the development of finger pulse densitometry for noninvasive estimation of the ICG plasma disappearance rate (PDR). On the other hand, the model for end-stage liver disease (MELD), which is based on routine laboratory parameters, is widely used for estimation of short-term survival in cirrhosis, but its prognostic value in critically ill cirrhotic patients is unclear. Aims: The aim of the present study was to compare the diagnostic accuracy of ICG PDR vs. MELD for estimation of short-term prognosis in cirrhotic patients. Methods: Ninety consecutive cirrhotic patients who were admitted for decompensated disease or were being evaluated for liver transplantation were screened. Patients who underwent liver transplantation within the following 90 days and those with hepatocellular carcinoma were excluded. In the remaining 70 patients, routine laboratory parameters and ICG clearance were analysed. Following an injection of ICG 0.25 mg/kg, PDR was measured by finger pulse densitometry. The diagnostic accuracy of ICG PDR and MELD for prediction of 90-day survival was assessed by receiver–operating characteristic (ROC) curve analysis. Results: ROC curve analysis revealed superior diagnostic accuracy for MELD as compared with ICG PDR in predicting 90-day survival (area under the ROC curve 0.89 vs. 0.71). A MELD cut-off of 22 provided the best discrimination for prediction of 90-day survival. Conclusions: MELD is superior to ICG PDR for estimation of short-term survival in patients with decompensated cirrhosis.

Oxidative stress is believed to play an important role in acute-on-chronic liver failure (AoCLF). Albumin, an important transport vehicle, was found to be severely oxidized in AoCLF patients. Extracorporeal liver support systems may exert beneficial effects in AoCLF via removal of albumin-bound toxins. At present, two systems are commercially available, the molecular adsorbents recirculating system (MARS) and fractionated plasma separation, adsorption and dialysis (FPAD, also known as Prometheus). The aim of this study was to compare the effect of MARS and Prometheus treatments on the redox state of human serum albumin. Eight patients with AoCLF underwent alternating treatments with either MARS or Prometheus in a randomized cross-over design. Sixteen treatments (eight MARS and eight Prometheus) were available for analysis. The fraction of human mercaptalbumin (HMA), human nonmercaptalbumin-1 (HNA1), and human nonmercaptalbumin-2 (HNA2) were measured before and after single MARS and Prometheus treatments and during follow-up. In AoCLF patients the oxidized fractions of albumin, HNA1, and HNA2 were markedly increased. Both MARS and Prometheus treatments resulted in a shift of HNA1 to HMA, while HNA2 was not significantly affected. This shift in albumin fractions was transient and disappeared within 24 h after treatment. There were no significant differences between MARS and Prometheus treatments with respect to the redox state of albumin. Both MARS and Prometheus treatments lead to transient improvements of the redox state of albumin, which could be beneficial in the treatment of AoCLF.

Hepatitis C virus (HCV) infection represents a substantial risk to both, health care workers and patients. It is of major importance to detect health care workers with HCV infection and to establish regulations how to deal with infected individuals working in specific health care settings. Currently, there are no consistent recommendations, regulations or guidelines concerning prevention of health care worker-to-patient transmission of HCV. Questions arising include: Should health care workers be screened or tested individually on HCV infection and what kind of assay(s) should be used? When and how often should health care workers be tested? How should health care workers with HCV infection be managed? Based on these questions, this article reviews the most relevant published literature. Furthermore, suggestions for establishing a future common regulatory framework are provided.

Recent epidemiologic studies suggest that more than 175 million individuals are infected with hepatitis C virus (HCV) worldwide. In the past few years, outcome studies in chronic HCV patients are no longer focusing solely on traditional end points such as mortality rates but on psychosocial well-being such as health-related quality of life (HRQoL), emotional states, and neuropsychological functioning. The purpose of our exploratory study was to assess cross sectionally the frequency of depression, posttraumatic stress symptoms, cognitive deficits, and impairments in HRQoL in chronic HCV patients prior to antiviral treatment, and to investigate how cognitive impairments and emotional distress were related to quality of life. We recruited 34 chronic HCV patients who had presented for initial assessment of the need for antiviral therapy. Psychometric observer-rating and self-rating scales were administered to evaluate posttraumatic stress symptoms (PTSS-10), depressive symptoms (BDI), HRQoL (SF-36 Health Status Questionnaire), and cognitive functioning (SKT). 32.4 % (n = 11) of the sample suffered from clinical depression, and 8.8 % (n = 3) had a posttraumatic stress syndrome. 8.8 % (n = 3) of the sample showed cognitive impairments. Significant impairments in HRQoL were found in the health-related domains vitality, role-emotional, and role-physical. The severity of emotional distress as measured on the BDI and PTSS-10 was associated with decrements in HRQoL. However, lower cognitive function scores on the SKT were not associated with lower HRQoL SF-36 values. Chronic HCV patients seem to face a major risk of depression, posttraumatic stress symptoms, and cognitive dysfunction, and the presence of emotional distress is associated with impairments in quality of life. We therefore underscore the need for early and comprehensive bio-psycho-social diagnosis and therapy of chronic HCV patients in order to treat emotional distress and enhance patients; quality of life at an early stage before initiating antiviral therapy, as well as to expand the pool of patients eligible to receive antiviral therapy.

For the design of peptide-based vaccines against the hepatitis C virus it is essential to acquire more information on frequently recognized epitopes in patients with successful immune control of HCV in the context of different HLA types. A matrix approach using 393 15mer peptides from conserved HCV regions overlapping by 13 amino acids was applied in 52 HCV-recovered individuals. Candidate peptides were further tested in two independent laboratories. 38 peptides induced IFN-gamma responses in ELISPOT assays including 15 previously unknown epitopes. There was no particular immune dominance as only five peptides were recognized by more than three individuals. Seven out of 14 peptides tested in more detail could be confirmed to be immunogenic using ELISPOT and cytotoxicity assays. While only 33% of HCV-recovered individuals recognized recombinant HCV proteins, 81% of individuals tested positive in the matrix approach (p0.001). The strength, frequency and breadth of HCV-specific T cell responses were similar in spontaneously recovered patients than in interferon-recovered patients. In conclusion (i) we identified novel HCV epitopes in conserved regions, (ii) confirmed the inter-individual diversity of HCV-specific T cell responses and (iii) found no significant differences in HCV-specific T cell responses between spontaneously recovered and IFN-recovered patients.

Currently available anti-hepatitis C virus (HCV) therapy is effective in only half of infected patients and is limited by adverse effects that often necessitate discontinuation. Therefore, new treatments are being developed, including optimization of current standard treatment with peginterferon plus ribavirin, specifically targeted antiviral therapy for HCV, novel immunomodulatory agents and treatments aimed at reducing fibrosis. This review focuses on novel anti-HCV drugs that are currently in an advanced stage of clinical development. Albinterferon-alpha-2b, a fusion molecule of albumin and interferon-alpha-2b, has a longer half-life than peginterferon, which enables a bi-weekly administration interval. Preliminary data indicate similar response rates for albinterferon-alpha-2b plus ribavirin compared with peginterferon-alpha-2b plus ribavirin, but possible benefits with respect to quality of life. Telaprevir, a NS3/4 protease inhibitor, demonstrated a rapid and profound antiviral effect in phase I trials that was synergistic with that of peginterferon-alpha-2a. Recently completed phase II trials on triple combination treatment with telaprevir, peginterferon-alpha-2a and ribavirin given for 12-24 weeks reported sustained virological response in up to 68% of patients with treatment-naive HCV genotype 1 infection.

Gasoline, ingested intentionally or accidentally, is toxic. The majority of reported cases of gasoline intoxication involve oral ingestion or inhalation. Data are scarce on complications and outcomes following hydrocarbon poisoning by intravenous injection.Following a suicide attempt by intravenous self-injection of 10 ml of gasoline, a 26-year-old medical student was admitted to the intensive care unit (ICU) with hemoptysis, symptoms of acute respiratory failure, chest pain, and severe abdominal cramps. Gas exchange was severely impaired and a chest x-ray indicated chemical pneumonitis. Initial treatment consisted of mechanical ventilation, supportive hyperventilation, administration of nitrogen oxide (NO), and prednisone. Unfortunately, the patient developed multi-organ dysfunction syndrome (MODS) complicated by life-threatening severe vasoplegia within 24 hours after gasoline injection. High doses of vasopressors along with massive amounts of parenteral fluids were necessary. Despite fluid replacement, renal function worsened and required hemofiltration on 5 sequential days. After 12 days of intensive care management, the patient recovered completely and was discharged to a psychiatric care facility.Intravenous gasoline injection causes major injury to the lungs, the organ bearing the first capillary bed encountered. Treatment of gasoline poisoning is symptomatic because no specific antidote is available. Early and aggressive supportive care may be conducive to a favorable outcome with minimal residual pulmonary sequelae.

Summary Aims: To study whether circulatory changes during large volume paracentesis (LVP) in patients with liver cirrhosis and tense ascites as assessed by novel non-invasive haemodynamic measuring technology are reversed by subsequent albumin infusion. Materials and methods: Eleven patients with portal hypertensive ascites secondary to liver cirrhosis of Child's class B or C were studied during LVP (10.7 ± 4.4 l) and subsequent infusion of albumin. Digital arterial pulse waves were continuously measured by vascular unloading technique providing data for beat-to-beat values of systolic (Ps), diastolic (Pd) and mean arterial pressures (Pm), respectively, as well as for heart rate (Fh), stroke volume (Vs), cardiac output (Qco) and peripheral resistance (R). Data extrapolated to the end of paracentesis, albumin infusion and follow-up phases were compared with the end of the equilibration phase. Results: At the end of paracentesis, Ps, Pm and Pd changed by −14 ± 15% (p

Binding and transport of a number of endogenous and exogenous compounds is an important function of the main plasma protein, albumin. In vivo and in vitro, albumin may be oxidatively modified in different ways with different agents at different sites. These modifications have various consequences on the physiological functions of albumin. Diabetes mellitus, liver diseases and nephropathy are just a few examples of disorders in which oxidative stress is involved and altered albumin functions have been described. This review is focussed on the consequences of oxidative modification on the binding properties of albumin. These range from no effect to decreased or increased binding affinities depending on the ligand under investigation and the type of modification. Indicators for modification include glycosylation, disulphide formation or the content of carbonyl groups. The redox state of albumin can affect the binding properties in several ways, including altered conformation and consequently altered affinities at binding sites and altered binding when the binding reaction itself is redox sensitive. The physiological or pathophysiological concentrations of different oxidatively modified albumin molecules vary over a wide range and are crucial in assessing the clinical relevance of altered ligand binding properties of a particularly modified albumin species in various disease conditions.

Artificial extracorporeal liver support or 'liver dialysis' has been used in patients with severe liver failure with increasing frequency since the Molecular Adsorbents Recirculating System (MARS), a variant of albumin dialysis, was introduced in 1999. Nevertheless, liver dialysis must still be thought of as experimental because its contribution to improved patient survival has not been proven in large randomized trials. Prometheus is a novel device for fractionated plasma separation via an albumin-permeable filter that was developed to improve removal of albumin-bound toxins. Initial studies have proven clinical use of Prometheus to be feasible and safe. Head-to-head comparisons of Prometheus and MARS have shown treatment with the former to be more efficient with respect to removal of most albumin-bound and water-solved markers. As controlled studies with clinical end points are lacking, it is not known whether the observed greater detoxification capacity of Prometheus will translate into clinical benefit; two small studies indicate that there might be a beneficial effect in hepatic encephalopathy and pruritus. In a recent randomized comparison of MARS and Prometheus, however, hemodynamic improvement was observed in response to MARS, but not Prometheus, treatment. A large randomized controlled trial investigating the effect of Prometheus on survival--the HELIOS study--has been initiated. First results are expected in 2008 and will be crucial to establishing a role for Prometheus in the field of extracorporeal liver support.

BackgroundThe aim of this exploratory study is to gain for the first time a more comprehensive picture of the impact of changes of quinolinic acid concentrations on depressive symptomatology during and after IFN-α therapy.MethodsThe quinolinic acid concentrations of 35 HCV patients are examined in a prospective survey over the entire period of IFN-α treatment as well as three months later at six different times (baseline, one, three, six and nine months after the beginning of IFN-α treatment, and after the end of treatment).ResultsDuring IFN-α treatment Hamilton Depression Rating Scale scores rise significantly. At the same time there is greater activity of indoleamine 2,3-dioxygenase, with a resulting increase in plasma kynurenine concentrations. Compared to baseline values quinolinic acid concentrations increase significantly during therapy, reflecting an increased neurotoxic challenge. In addition, patients with higher scores in the Hamilton Depression Rating Scale at six and nine months after starting therapy show significantly higher levels of quinolinic acid concentration.ConclusionsThe increase of quinolinic acid during IFN-α therapy might contribute to depressive symptomatology through the neurotoxic challenge caused by quinolinic acid. Subsequently, our exploratory study results support the inflammatory hypothesis of depression. The awareness of relevant risk factors of IFN-α treatment-induced depression is essential to develop preventative treatment strategies.

Hepatic encephalopathy (HE) is a common problem after insertion of a trans-jugular intrahepatic portosystemic shunt (TIPS), which may be difficult to manage. We present a case of severe post-TIPS HE unresponsive to high doses of L-ornithine-L-aspartate (LOLA) despite reduction of venous ammonia levels in a dose-dependent fashion. Ultimately, high-grade HE was successfully treated by a reduction stent and the patient subsequently underwent successful liver transplantation.

Currently available anti-HCV therapy is effective in only half of the patients and limited by side effects that often necessitate discontinuation. Therefore, new treatment strategies are being developed including (i) the optimization of current regimens, (ii) the use of additional agents working via novel mechanisms, and (iii) anti-fibrotic strategies. Many new antiviral compounds are now being studied in preclinical and clinical trials. This review will focus on drugs that have already entered the stage of phase 2 or phase 3 studies.

Background & Aims: A 5-fold increase of hepatic copper concentration is considered as the best available test for diagnosis of hepatic Wilson's disease (WD). However, the sensitivity and specificity of this test have never been fully investigated. Methods: Copper content was measured by flame atomic absorption spectroscopy in 114 liver biopsies obtained at diagnosis of WD, in 219 patients with noncholestatic liver diseases (including 144 with chronic hepatitis C and 44 with nonalcoholic fatty liver disease), and in 26 without evidence of liver disease. Results: Liver copper content was >250 μg/g in 95 WD patients (83.3%), between 50 and 250 μg/g in 15, and below 50 μg/g in 4. It did not correlate with age ( r 2 = .003), the grade of fibrosis, or the presence of stainable copper. Liver copper content was >250 or between 50 and 250 μg/g in 3 (1.4%) and 20 (9.1%) of 219 patients with noncholestatic liver diseases, respectively. By lowering the cutoff from 250 to 75 μg/g, the sensitivity of liver copper content to diagnose WD increased from 83.3% (95% confidence interval, 75.2%–89.6%) to 96.5% (91.3%–99.1%), but the specificity decreased from 98.6% (96.0%–99.7%) to 95.4% (91.8%–97.8%). Conclusions: There is no gold standard for the diagnosis of WD. Liver copper content is a useful parameter, but a value below 250 μg/g does not exclude WD. Diagnosis requires the combination of a variety of clinical and biochemical tests.

Summary Background : The effects of lactulose and polyethylene glycol on colonic transit are poorly established. Aim: To assess the effects of these laxatives on colonic transit in normal subjects. Methods : Colonic transit (mean residence time, cumulative counts in stool, counts remaining in the proximal or distal colon) was measured scintigraphically in normal subjects on the second and third day of a 3-day ingestion of 67–134 g/day lactulose, or 59 g/day polyethylene glycol. Results : At similar stool weight (lactulose: 653 ± 120 g/day; polyethylene glycol: 522 ± 66 g/day), transit was significantly slower during 99 g/day lactulose when compared with 59 g/day polyethylene glycol; this was most pronounced in the distal colon (mean residence time: lactulose – 403 ± 55 min; polyethylene glycol – 160 ± 41.9 min). Short chain fatty acid concentration in 24-h stool correlated significantly with counts remaining in the distal colon at 12 h(r = 0.79, P = 0.001). Increasing lactulose doses were significantly associated with increasing stool weight (r = 0.79) and shorter mean residence time in the total (r = −0.56) and distal colon (r = −0.64). The sum of faecal carbohydrates plus short chain fatty acids was associated with stool weight (r = 0.95, P

Liver biopsy is recommended before antiviral treatment, particularly for patients with hepatitis C virus (HCV) genotype 1 infection, but it may cause complications and is limited by sampling error. Several non-invasive tests comprising routine laboratory parameters (simple fibrosis tests) have been proposed to predict fibrosis in chronic HCV. The aim of the current study was to validate and compare the diagnostic accuracies of the simple fibrosis tests, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), cirrhosis discriminant score (CDS), age-platelet (AP) index, Pohl score, AST-to-platelet ratio index (APRI), and platelet count per se. Staging was performed in liver biopsy specimens of 194 treatment-naive patients with chronic HCV according to Ishak et al. by two independent pathologists. Receiver operating characteristic curve analysis showed comparable diagnostic accuracies of CDS, AP index, APRI, and platelet count for prediction of significant fibrosis (F3-F6) (area under the ROC curve [AUROC], 0.71, 0.74, 0.80, and 0.71, respectively; pathologist A) and for prediction of cirrhosis (F5-F6) (AUROC, 0.91, 0.91, 0.90, and 0.89, respectively; pathologist A). Diagnostic accuracy of APRI for prediction of significant fibrosis was superior to that of AAR (P.05). Significant fibrosis was reliably predicted by APRIor = 1.5 and platelet count150 x10(9)/L in 24% and 22% of the patients, respectively, whereas cirrhosis was reliably excluded by APRI2.0 and platelet countor = 150 x10(9)/L in 85% and 78% of the patients, respectively. In conclusion, simple fibrosis tests may render liver biopsy unnecessary only in a minority of patients with chronic HCV. Improved serum fibrosis markers with greater sensitivity for severe fibrosis or cirrhosis are needed.

There is currently no accepted therapeutic regimen for patients with chronic hepatitis C who failed to respond to standard combination treatment with interferon-α plus ribavirin. We investigated triple combination treatment with induction dosing of interferon-α plus ribavirin plus amantadine in these difficult-to-treat patients. Nonresponders (n=67), breakthroughs (n=16) and relapsers (n=19) to previous interferon/ribavirin combination treatment of at least 6 months were included. For the first 16 weeks, patients received interferon-α2a 6MU daily, ribavirin 800–1200 mg/d, and amantadine 200 mg/d. In cases of undetectable HCV RNA at week 12, treatment was continued with interferon-α2a 6MU every other day and the same doses of ribavirin and amantadine until week 48. In cases of HCV RNA positivity at week 12, treatment was stopped. A total of 102 patients were enrolled (80%: genotype 1, 19%: cirrhosis). HCV RNA was negative in 35/102 patients (34%) at week 12 and in 27/102 patients (26%) at the end of treatment. Virological response was sustained in 15/102 patients (15%). Ontreatment virological response was higher in previous relapsers/breakthroughs than in previous nonresponders (week 12: 49% vs. 27%, p

Sudden hearing loss has been reported on standard interferon (IFN)-alpha2 therapy. This is the first report on the occurrence of sudden hearing loss in six cases of chronic hepatitis C in temporal relation to treatment with pegylated (PEG)-IFN alfa2a or b/ribavirin combination therapy. Three patients were treated in an ongoing randomized placebo-controlled trial comparing the addition of 200 mg amantadine or placebo to the combination of 180 microg PEG-IFN alpha2a (PEGASYS, Roche, Basel, CH)/wk and 1-1.2 g ribavirin/d (COPEGUS, Roche, Nutley, USA) in de novo patients infected with HCV genotype 1. Sudden hearing loss and tinnitus developed on day 1 and after 4, 23, 25, 36, and 40 wk of treatment, respectively.Sudden hearing loss may occur in about 1% of patients on PEG-IFN/ribavirin combination therapy. This rate was not different to that observed in an untreated population. Possible mechanisms involved include direct ototoxicity of IFN, autoimmunity, and hematological changes. In contrast to published cases on auditory disability due to standard IFN, hearing loss did not fully resolve after discontinuation of therapy with PEG-IFN. On the other hand, symptoms did not worsen on continued treatment. Therefore, the decision whether to continue or to stop the treatment when signs of ototoxicity appear is based on the clinical judgment of the treating physician.

An increase in the prevalence of obesity and the metabolic syndrome as a result of changes in eating habits, both quantitative (over-eating) and qualitative (e.g. high fructose consumption), and a lack of exercise contribute to fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is a clinical histological spectrum ranging from steatosis to non-alcoholic steatohepatitis (NASH) and affects more than 30% of the general population [1].

Background/aims: Initial high-dose interferon-α induction therapy in combination with ribavirin improves sustained response rates in treatment-naive patients. This prospective, randomized, controlled study tested whether non-responders or relapsers to interferon monotherapy also benefit from induction therapy. Methods: Patients with chronic hepatitis C who had not responded to (n=75) or relapsed (n=80) after previous interferon therapy were randomized to receive three different interferon doses during the first 14 weeks of therapy (A: 10 MU IntronA®/day for 2 weeks, followed by 10 MU/2 days for 12 weeks; B:5 MU/d for 14 weeks; C: 5 MU/2 days for 14 weeks) followed in all by 5 MU/2 days for 24 weeks. All patients received 1–1.2 g ribavirin/day throughout the whole study. Results: The rates of viral clearance at any time on treatment were similar in all groups. Sustained response rates were also not different among the groups in interferon nonresponders (A 32%, B 29%, C 31%) and relapsers (A 64%, B 68%, C 71%), respectively, as well as in patients with different genotypes. As expected, sustained response rates were higher in patients with genotype non-1 than in those with genotype 1. Conclusion: High-dose induction therapy does not improve the outcome of interferon/ribavirin therapy in interferon nonresponders or relapsers.

Even with pegylated (PEG) interferons (IFN), therapy of chronic hepatitis C (genotype 1) remains unsatisfactory. The initial viral response to IFN identifies patients infected with IFN resistant viruses not responding to standard IFN/ribavirin therapy. The impact of primary IFN unresponsiveness for PEG-IFN-alpha-2a/ribavirin therapy is unknown. Viral load was measured in 22 chronic hepatitis C (genotype 1) patients before and 24 h after 9 MU IFN-alpha-2a (days 0 and 1), and before and during weekly 180 microg PEG-IFN-alpha-2a (days 7, 8, 11, 14 and 21) administration. Thereafter, ribavirin (800 mg/d) was added for 6 months. Virological responders continued treatment for a further 6 months. Twenty-eight patients treated with standard IFN/ribavirin therapy in a previous study using an analogous protocol served as historic controls. After 6 months 15 (68.2%) patients were (HCV-RNA) negative, eight of whom (36.4%) had a sustained response. The decrease in viral load 24 h after 9 MU IFN-alpha-2a was greater in virological responders (1.05 log [0.25-1.67]) than in nonresponders (NR) (0.34 [0.14-0.65]; P=0.003). In contrast, viral decline was not different between responders and NRs during the first 2 weeks on PEG-IFN-alpha-2a. All patients with an initial decline > 1.4 log became sustained responders. Five of 12 patients with a log change < 0.8 became end of treatment responders, two had a sustained response. Antiviral response to PEG-IFN-alpha-2a is different to that on standard IFN. In spite of a lower initial response PEG-IFN-alpha-2a/ribavirin combination therapy may overcome predicted IFN unresponsiveness.