Einleitung Bei Patient*innen mit Autoimmuner Hepatitis (AIH) werden normwertige Transaminasen und Immunglobulin (IgG) als biochemische Remission angesehen und gelten als bester Surrogatmarker für eine histologische Remission.

The presence of selectively elevated IgG levels is a hallmark of AIH and has found its way into diagnostic scores. Nevertheless, about 15% of patients show normal IgG levels. The clinical significance of normal IgG values at diagnosis has so far not been explored in detail.

Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.

Background Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management. Aims The present study looks for differences between the two genotypes and analyzes predictive factors for SVR. Methods Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012. Results When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, p = 0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis. Conclusions The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis. Trial Registration Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany ML21645 ClinicalTrials.gov NCT02106156

BOC triple therapy through November 2012.They were further classified as black or Caucasian, and IFN-R (defined as treatment-naïve/prior relapsers achieving a 1 log drop in viral load (VL) after the 4 week PEG-IFN/ribavirin lead-in) or IFN-NR (defined as prior null responders or patients with , 1 log drop at the 4 week lead-in).Baseline characteristics of these groups were compared.The primary outcomes were achievement of VL below the lower limit of quantification (LLOQ) and discontinuation rates at 24 weeks.Statistical analysis (intention-to-treat) was performed to identify significant differences in these endpoints in black IFN-R vs. Caucasian IFN-R and black IFN-NR vs. Caucasian IFN-NR.The number of patients evaluated at each time point included those who had viral load data or discontinued therapy prior to that time point.In secondary analysis, rates of VL suppression at 8 and 12 weeks and incidence of adverse events (AE) on treatment were determined.Results: Black patients were 66% (67/101) of our total cohort, 49/67 (71%) with genotype 1a, 20/67 (30%) with compensated cirrhosis), and 45/67 (67%) with VL .800,000 IU/mL.Of these, 36/ 67 (54%) patients were IFN-R and 31/67 (46%) IFN-NR.The black cohort had lower median Metavir fibrosis scores (2.5 vs. 3.5) and statistically significant lower rates of cirrhosis (30% vs. 59%, p=0.005) than the Caucasian cohort.Primary and secondary outcomes are shown in the table.Commonly encountered AEs in the black cohort included fatigue (82%), dermatologic (52%), psychiatric (49%), gastrointestinal (42%), which did not differ significantly from the Caucasian cohort.Significant anemia (grade 2/3/4: 3%), thrombocytopenia (grade 3/4: 10%), and neutropenia (grade 3/ 4: 18%) occurred among blacks with 60% requiring ribavirin dose reduction, 21% epoetin alfa, and 8% filgrastim.Conclusions: Black IFN-R, compared to Caucasian IFN-R, had statistically significant lower rates of viral suppression at 8 and 12 weeks.Rates were also lower at 24 weeks, though not statistically significant.Given the large number of cirrhotics and low number of patients in the Caucasian IFN-NR group, definitive differences in outcomes in the Black IFN-NR could not be drawn.Overall, blacks had to discontinue treatment due to futility more often, though they had similar rates of AEs.

Burns from domestic irons are potentially preventable injuries which can result in significant morbidity. Several studies have reported these injuries in children but there are no reports to date in adults. Epidemiology, management and outcome of these injuries is described, and possible preventative strategies are discussed. We present a retrospective case note review of 50 adult and paediatric patients with electric iron burns. Cases were identified from data collected for a national burns database. Information regarding demographics, burn characteristics, treatment and long term outcome was gathered from the medical records. 42 children and 8 adults sustained a burn from an iron during the 4-year study period. The majority of paediatric patients were under 4 years of age. Most burns were small (< 1% TBSA) but despite this 30 (60%) patients were admitted to hospital and 13 (26%) required at least one surgical procedure. In children, most burns occurred at home and were commonly due to pulling the flex or knocking the iron from its surface. In adults, 50% of injuries were associated with epilepsy. Burns from domestic irons are relatively common and cause significant morbidity despite their small size. A bimodal presentation is seen with injuries occurring either before the age of 4 years or during adulthood, when they are typically associated with an underlying medical condition. Education campaigns and design features such as a retractable cord may further reduce the incidence of this type of burn.

Estimates assume that 400,000 to 500,000 people are chronically infected with Hepatitis C in Germany. About 27% of end-stage liver cirrhosis and 25% of hepatocellular carcinoma are associated with HCV. The economic relevance of hepatitis C results from high costs for antiviral treatment as well as accompanying and secondary diseases. The aim of the study was to gain information on epidemiological characteristics, treatment outcomes and costs. Underlying data were collected in a non-interventional trial between 2008 and 2011. Inclusion criteria were a confirmed HCV diagnosis and need for antiviral treatment. Besides sociodemographic and clinical parameters, HCV related resource utilization was gathered for a subgroup of patients. Data presented are mean values. Data on 7,637 patients receiving antiviral treatment with peginterferon-α-2a and ribavirin were collected. This analysis relates on 3,708 patients without HIV coinfection and/or drug substitution treatment. Mean age was 43.7 years, 60.3% were male. Most patients had a genotype-1 (61.3%) or genotype-3 infection (28.5%). The majority of patients was treatment-naïve (86.5%), 7.3% were relapser and 5.6% non-responder. Main sources of infection were injection drug use (34.8%) and blood products (14.2%). Mean duration of infection was 13.6 years. In average 48.9% of treatment-naïve GT-1(4-6) and 63.0% of GT-2/3 patients achieved SVR. For prior relapse patients and non-responder SVR-rates were: GT-1(4-6): 35.4%; GT-2/3: 58.5 and GT-1(4-6): 23.3% GT-2/3: 37.9%, respectively. Costs for antiviral treatment amount for €20,889 in GT-1(4-6) patients and €13,610 in GT-2/3 patients. Costs for the management of adverse events or HCV-related diseases sum up for €11.70. Ambulatory care, diagnostics procedures and hospital care amount for a small proportion of total costs. This study provides an overview on epidemiologic characteristics, treatment outcomes and treating costs in routine care. Treatment of HCV is costly and mainly affected by length of antiviral therapy.

BOC triple therapy through November 2012.They were further classified as black or Caucasian, and IFN-R (defined as treatment-naïve/prior relapsers achieving a 1 log drop in viral load (VL) after the 4 week PEG-IFN/ribavirin lead-in) or IFN-NR (defined as prior null responders or patients with , 1 log drop at the 4 week lead-in).Baseline characteristics of these groups were compared.The primary outcomes were achievement of VL below the lower limit of quantification (LLOQ) and discontinuation rates at 24 weeks.Statistical analysis (intention-to-treat) was performed to identify significant differences in these endpoints in black IFN-R vs. Caucasian IFN-R and black IFN-NR vs. Caucasian IFN-NR.The number of patients evaluated at each time point included those who had viral load data or discontinued therapy prior to that time point.In secondary analysis, rates of VL suppression at 8 and 12 weeks and incidence of adverse events (AE) on treatment were determined.Results: Black patients were 66% (67/101) of our total cohort, 49/67 (71%) with genotype 1a, 20/67 (30%) with compensated cirrhosis), and 45/67 (67%) with VL .800,000 IU/mL.Of these, 36/ 67 (54%) patients were IFN-R and 31/67 (46%) IFN-NR.The black cohort had lower median Metavir fibrosis scores (2.5 vs. 3.5) and statistically significant lower rates of cirrhosis (30% vs. 59%, p=0.005) than the Caucasian cohort.Primary and secondary outcomes are shown in the table.Commonly encountered AEs in the black cohort included fatigue (82%), dermatologic (52%), psychiatric (49%), gastrointestinal (42%), which did not differ significantly from the Caucasian cohort.Significant anemia (grade 2/3/4: 3%), thrombocytopenia (grade 3/4: 10%), and neutropenia (grade 3/ 4: 18%) occurred among blacks with 60% requiring ribavirin dose reduction, 21% epoetin alfa, and 8% filgrastim.Conclusions: Black IFN-R, compared to Caucasian IFN-R, had statistically significant lower rates of viral suppression at 8 and 12 weeks.Rates were also lower at 24 weeks, though not statistically significant.Given the large number of cirrhotics and low number of patients in the Caucasian IFN-NR group, definitive differences in outcomes in the Black IFN-NR could not be drawn.Overall, blacks had to discontinue treatment due to futility more often, though they had similar rates of AEs.

developed, calibrated using emerging response data, and used to predict virologic responses.Results: PopPK modeling suggested modest time-dependent increases in ASV clearance.Steady-state AUC was 37% higher among Japanese patients.Age was a covariate explaining 16.6% variability in clearance.Higher ASV AUC correlated with greater incidence of ≥Grade 2 adverse liver events; however, at the 200 mg BID dose relative risk for these events was similar to placebo in Japanese patients and those aged >60 years (odds ratios: 1.09 versus 1.06 for non-Japanese; 1.08 versus 1.06 for age ≤60 years).Concomitant administration of DCV or alfa/RBV did not affect the timing or risk of liver events.VK modeling and simulation successfully predicted on-treatment response in AI447016, AI447017 and AI447011 populations.Sustained virologic response (SVR) was projected to be lower in GT1b interferonineligible and null-responders receiving ASV 200 mg QD (70%) versus BID (76%) in combination with DCV alone.ASV 200 mg QD and BID in combination with DCV+alfa/RBV were projected to achieve similar SVR rates among GT1a null-responders (83.3-84.5%);however, 200 mg BID could theoretically improve SVR rates.Conclusions: An integrated quantitative analysis supported an equivalent tablet dose of ASV 200 mg BID for phase-3 to maximize antiviral response and minimize adverse events.The ASV 100 mg BID softgel formulation used in phase-3 studies approximates the 200 mg BID tablet exposures.

note 24 of the 68 patients (35.3%) did not have an evaluable HCV RNA week 8 value.Over the first 12weeks 11.9% and 5.9% of the patients required dose modifications of ribavirin and peginterferon alfa-2a, respectively and 2 (3.0%) and 17 (25.4%)patients had haemoglobin ,8.5 g/dL and ≥8.5 but ,10 g/dL respectively.Adverse events reported in at least 15% of patients included fatigue (52.9%), nausea (26.5%), headache (25.0%), skin disorder (23.5%), dysgeusia (19.1%), pruritus (19.1%), myalgia (17.6%), anaemia (16.2%) andarthralgia (16.2%).Conclusion: Real world experience with BOC plus peginterferon alfa-2a/ribavirin in Germany show similar virological outcomes and side effects to the phase 3 trials.Week 8 HCV RNA values essential to determine suitability for reduced treatment duration were not collected in a significant proportion of patients.

Autoantibodies in hepatitis C virusinfected patients may indicate autoimmune hepatitis or other immune-mediated diseases. This may impact safety and efficacy of interferon-based therapy of chronic hepatitis C. We investigated the association between a positive test result for a variety of autoantibodies and the initiation and efficacy of therapy for chronic hepatitis C. We analysed an observational cohort of 24306 patients for an association between autoantibodies and treatment outcome. 8241 patients were tested simultaneously for antinuclear antibodies (ANA), liver kidney microsomal antibodies (LKM), smooth muscle antibodies (SMA) and antimitochondrial antibodies (AMA). Matched-pair analysis was performed matching one autoantibody-positive patient to three controls. Control patients had negative tests for all four antibodies. Analyses were performed for patients with a single positive autoantibody test and for patients with multiple positive autoantibody tests. A positive test result for ANA, LKM, SMA or AMA did not affect the physician's decision to initiate therapy with pegylated interferon and ribavirin. In addition, a positive test for one or multiple autoantibodies did not adversely affect sustained virologic response. There was no difference in fibrosis stage or alanine transaminase at baseline or during therapy irrespective of antibody status. Thyroid dysfunction was more frequent in patients with positive LKM antibodies (P=0.004). Initiation of therapy for chronic hepatitis C and outcome were not affected by the presence of ANA, LKM, SMA or AMA. Routine testing of these autoantibodies seems not warranted. Determination of autoantibodies should be guided by individualized clinical decisions.

s(± SD) of 8.4 (±8.9) weeks from the time of viral breakthrough.Resistance patterns were detected in 6 of 8 (75%) patients and all patients had cross-resistance to boceprevir.All 4 patients with higher-level resistance patterns were genotype 1a.Both patients who tested sensitive were genotype 1b.Conclusion: Similar to findings in clinical trials, viral breakthrough with DAA for treatment of chronic HCV infection is associated with genotype 1a, advanced liver fibrosis, and prior null treatment response.Comparable patterns of resistance were also seen in clinical practice.In our study, however, a significant proportion of patients experienced viral breakthrough after completion of the DAA portion of triple therapy.More frequent virologic assessments during the PR treatment phase may be useful in a subset of "higher-risk" patients to expedite compliance with stopping rules and decrease unnecessary treatment burden.Treatment Response of Patients with Viral Breakthrough *Time between confirmation of viral breakthrough and testing of resistance **Any reduction in dosing of either ribavirin or interferon during treatment course ND = not detectable, defined as a viral load of less than 5 IU per millimeter; vBT = viral breakthrough RBV = ribavirin; IFN = interferon-alfa Higher-level resistance: V36M + R155K, Lower-level resistance: A156S, T54S All viral load results are expressed as IU per millimeter.