Publications by authors named "Heiner Wedemeyer"

467 Publications

The Detrimental Role of Regulatory T Cells in Nonalcoholic Steatohepatitis.

Hepatol Commun 2021 Aug 25. Epub 2021 Aug 25.

Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.

Nonalcoholic steatohepatitis (NASH) is induced by steatosis and metabolic inflammation. While involvement of the innate immune response has been shown, the role of the adaptive immune response in NASH remains controversial. Likewise, the role of regulatory T cells (Treg) in NASH remains unclear although initial clinical trials aim to target these regulatory responses. High-fat high-carbohydrate (HF-HC) diet feeding of NASH-resistant BALB/c mice as well as the corresponding recombination activating 1 (Rag)-deficient strain was used to induce NASH and to study the role of the adaptive immune response. HF-HC diet feeding induced strong activation of intrahepatic T cells in BALB/c mice, suggesting an antigen-driven effect. In contrast, the effects of the absence of the adaptive immune response was notable. NASH in BALB/c Rag1 mice was substantially worsened and accompanied by a sharp increase of M1-like macrophage numbers. Furthermore, we found an increase in intrahepatic Treg numbers in NASH, but either adoptive Treg transfer or anti-cluster of differentiation (CD)3 therapy unexpectedly increased steatosis and the alanine aminotransferase level without otherwise affecting NASH. Conclusion: Although intrahepatic T cells were activated and marginally clonally expanded in NASH, these effects were counterbalanced by increased Treg numbers. The ablation of adaptive immunity in murine NASH led to marked aggravation of NASH, suggesting that Tregs are not regulators of metabolic inflammation but rather enhance it.
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http://dx.doi.org/10.1002/hep4.1807DOI Listing
August 2021

Impact of the COVID-19 pandemic on patients with liver cirrhosis-the experience of a tertiary center in Germany.

Z Gastroenterol 2021 Sep 10;59(9):954-960. Epub 2021 Sep 10.

Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: The COVID-19 pandemic has caused a significant impact on the medical care of many diseases and has led to reduced presentations to the emergency department. Reduced presentations may be due to overwhelmed capacities of hospitals or collateral damage from fear of infection, lockdown regulations, or other reasons. The effect on patients with liver cirrhosis is not established.

Objective: We aim to assess the impact on the care of patients with liver cirrhosis in a tertiary center in Northern Germany.

Methods: All patients presenting to the emergency department with a diagnosis of cirrhosis between March 1 and May 31 from 2015-2020 were included. Reasons for presentation, duration of symptoms, the severity of liver disease, and 30-day mortality were assessed and compared between patients presenting during the COVID-19 pandemic and pre-COVID-19.

Results: Overall, 235 patients were included. Despite an overall decline in presentations to the emergency department by 11.7%, the frequency of patients presenting with liver cirrhosis has remained stable (non-significant increase by 19.5%). No significant difference could be detected for the MELD score, the CLIF-organ failure subscores, and the 30-day mortality before and during the COVID-19 pandemic. Up to 75% of patients with liver cirrhosis had symptoms >24 h before presenting to the emergency department.

Conclusion: Despite the overall trend of reduced emergency presentations during the COVID-19 pandemic, the frequency of presentations of patients with liver cirrhosis did not decline. Morbidity and mortality were not affected in a setting of disposable healthcare resources. The late presentation to the emergency department in many cirrhotic patients may open opportunities for interventions (i.e., with early telemedicine intervention).
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http://dx.doi.org/10.1055/a-1540-7726DOI Listing
September 2021

Quantification of polyreactive immunoglobulin G facilitates the diagnosis of autoimmune hepatitis.

Hepatology 2021 Sep 2. Epub 2021 Sep 2.

Liver Unit, Hospital Clínic Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain.

Background & Aims: Detection of autoantibodies is a mainstay of diagnosing autoimmune hepatitis (AIH). However, conventional autoantibodies for workup of AIH lack either sensitivity or specificity leading to substantial diagnostic uncertainty. We aimed to identify more accurate serological markers of AIH with a protein macro-array.

Approach & Results: During the search for more precise autoantibodies to distinguish AIH from non-AIH liver diseases, IgG antibodies with binding capacities to many human and foreign proteins were identified with a protein macro-array and confirmed with solid phase ELISAs in AIH patients. Subsequently, polyreactive IgG (pIgG) were exemplarily quantified by reactivity against human huntingtin-interacting protein 1-related protein in bovine serum albumin blocked ELISA (HIP1R/BSA). Diagnostic fidelity of HIP1R/BSA binding pIgG to diagnose AIH was assessed in a retrospective training, a retrospective multicenter validation and a prospective validation cohort, in cryo-conserved samples from 1568 adults from ten centers from eight countries. Reactivity against HIP1R/BSA had a 25% and 14% higher specificity to diagnose AIH than conventional anti-nuclear and anti-smooth muscle antibodies, a significantly higher sensitivity than liver kidney microsomal antibodies and anti-soluble liver antigen/liver pancreas antigen and a 12-20% higher accuracy than conventional autoantibodies. Importantly, HIP1R/BSA reactivity was present in up to 88 % of patients with seronegative AIH and in up to 71% of AIH patients with normal IgG levels. Under therapy pIgG returns to background levels of non-AIH liver diseases.

Conclusions: pIgG could be used as a new promising marker to improve the diagnostic workup of liver diseases with a higher specificity for AIH compared to conventional autoantibodies and a utility in autoantibody negative AIH. Likewise, pIgG could be a major source of assay interference in untreated AIH.
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http://dx.doi.org/10.1002/hep.32134DOI Listing
September 2021

Risk of transfusion-transmitted hepatitis E virus infection from pool-tested platelets and plasma.

J Hepatol 2021 Aug 27. Epub 2021 Aug 27.

Institute of Virology, Hannover Medical School, Hannover, Germany. Electronic address:

Background And Aims: Immunocompromised patients are at risk of chronic hepatitis E which can be acquired by blood transfusions. Currently, screening of blood donors (BDs) for HEV RNA with a limit of detection (LOD) of 2000 IU/ml is required in Germany. However, this may result in up to 440,000 IU HEV RNA in blood products depending on their plasma volume. We studied the residual risk for transfusion-transmitted (tt) HEV infection when an LOD of 2000 IU/ml is applied.

Methods: Highly sensitive individual donor testing for HEV RNA on the Grifols Procleix Panther system (LOD 7.89 IU/ml) was performed. HEV loads were quantified by real time PCR.

Results: 31 of 16,236 donors (0.19 %) were HEV RNA positive. Three BDs had virus loads between 710 and 2000 IU/ml, a significant risk for tt hepatitis E in case of any type of blood product. Eight BDs had virus loads of >32 to 710 IU/ml, a risk for tt hepatitis E by platelet or plasma transfusions due to their higher plasma volume compared to red blood cell concentrates. Eight of these eleven potentially infectious BDs were seronegative for HEV indicating a recent infection. Only 8 of 31 donors had virus loads >2000 IU/ml and would also have been detected by the required screening procedure and 12 had very low HEV loads (<32 IU/ml).

Conclusions: Screening of BDs with an LOD of 2000 IU/ml reduced the risk for tt HEV infection by about 73% for red blood cell concentrates whereas merely a 42% risk reduction was achieved for platelet and fresh frozen plasma transfusions. Single donor screening (LOD < 32 IU/ml) should reach an almost 100% risk reduction.

Lay Summary: The risk of transfusion-transmitted hepatitis E in solid organ and hematopoietic stem cell recipients may not be sufficiently controlled by (mini-)pool HEV RNA screening of blood donors.
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http://dx.doi.org/10.1016/j.jhep.2021.08.018DOI Listing
August 2021

Outcome and safety of a surveillance biopsy guided personalized immunosuppression program after liver transplantation.

Am J Transplant 2021 Aug 28. Epub 2021 Aug 28.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Graft survival beyond year 1 has not changed after orthotopic liver transplantation (OLT) over the last decades. Likewise, OLT causes comorbidities such as infection, renal impairment and cancer. We evaluated our single-center real-world individualized immunosuppression program after OLT, based on 211 baseline surveillance biopsies (svLbx) without any procedural complications. Patients were classified as low, intermediate and high rejection risk based on graft injury in svLbx and anti-HLA donor-specific antibodies. While 32% of patients had minimal histological inflammation, 57% showed histological inflammation and 23% advanced fibrosis (>F2), which was not predicted by lab parameters. IS was modified in 79% of patients after svLbx. After immunosuppression reduction in 69 patients, only 5 patients showed ALT elevations and three of these patients had a biopsy-proven acute rejection, two of them related to lethal comorbidities. The rate of liver enzyme elevation including rejection was not significantly increased compared to a svLbx control cohort prior to the initiation of our structured program. Immunosuppression reduction led to significantly better kidney function compared to this control cohort. In conclusion, a biopsy guided personalized immunosuppression protocol after OLT can identify patients requiring lower immunosuppression or patients with graft injury in which IS should not be further reduced.
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http://dx.doi.org/10.1111/ajt.16817DOI Listing
August 2021

GALAD Score Detects Early-Stage Hepatocellular Carcinoma in a European Cohort of Chronic Hepatitis B and C Patients.

Pharmaceuticals (Basel) 2021 Jul 27;14(8). Epub 2021 Jul 27.

Department of Gastroenterology and Hepatology, University Hospital Essen, 45147 Essen, Germany.

Despite vaccination programs and direct antiviral treatments, the incidence of virus-related hepatocellular carcinoma (HCC) remains high, while ultrasound-based detection rates for early-stage HCC is continuously low. To address this insufficiency, we set out to characterize whether the GALAD score, which incorporates gender, age, and serum levels of AFP, AFP isoform L3 (AFP-L3), and des-gamma-carboxy-prothrombin (DCP), can improve early-stage HCC detection in a Caucasian HBV/HCV cohort. In a retrospective German single-center study, 182 patients with HBV, 223 with HCV and 168 with other etiology (OE) of chronic liver disease (CLD) were enrolled. HCC was confirmed in 52 HBV, 84 HCV and 60 OE CLD patients. The diagnostic performance of the single biomarkers in HCC detection was compared to the GALAD model. At initial diagnosis, most patients were at (very) early BCLC 0 ( = 14/7%) or A ( = 56/29%) or intermediate stage BCLC B ( = 93/47%) HCC in all three subgroups. In the BCLC 0/A cohort, GALAD exhibited an AUC of 0.94 discriminating HCC from non-HCC, surpassing AFP (AUC 0.86), AFP-L3 (AUC 0.83) and DCP (AUC 0.83). In the HBV population, GALAD achieved an AUC of 0.96, in HCV an AUC of 0.98 and in OE an AUC of 0.99, clearly superior to the biomarkers alone. Furthermore, in HCV patients GALAD showed a significantly higher specificity (89%) versus AFP (64%) alone. In chronic viral hepatitis, the GALAD model showed superior performance in detection of early-stage HCC, while exhibiting higher specificity in HCV patients compared to AFP alone. We conclude that the GALAD score shows potential for HCC surveillance in Caucasian HBV/HCV patients.
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http://dx.doi.org/10.3390/ph14080735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8401792PMC
July 2021

Endoscopic vacuum assisted closure (E-VAC) of upper gastrointestinal leakages.

Scand J Gastroenterol 2021 Aug 21:1-4. Epub 2021 Aug 21.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Objectives: Endoscopic vacuum-assisted closure (E-VAC) of leaks of the upper gastrointestinal tract is an increasingly applied endoscopic technique. Data on indication, clinical success, complications and prognostic factors are still sparse.

Methods: Patients treated with E-VAC between 2012 and 2019 at a tertiary referral center have been retrospectively analyzed.

Results: Overall, 116 patients treated with E-VAC were identified. Indication for E-VAC placement was postoperative leakage in 94/116 (81%), iatrogenic perforations 7/116 (6%) and others 15/116 (13%). In 92/116 (79%) of the patients E-VAC therapy showed successful wound closure. The first E-VAC after detection of insufficiency was significantly more often placed intracavitary in patients with E-VAC failure ( = .031). There was a trend for longer intensive care unit treatment for patients with E-VAC failure ( = .069). Complications occurred significantly more often in patients with E-VAC failure ( = .009). Platelet count was significantly higher in patients with E-VAC success at day of insufficiency detection (257/Thsd/µL (interquartile range [IQR], 185-362) vs. 195 (IQR, 117-309);  = .039). Platelet count (375 Thsd/µL (IQR, 256-484) vs. 190 (IQR, 129-292)), hemoglobin (9.5 g/dL (IQR, 8.8-10.1) vs. 8.7 g/dL (IQR, 8.15-9.35)) and C-reactive protein level (79 mg/L (IQR, 39.7-121.9) vs. 152 mg/L (IQR, 73.7-231)) at day 14 differed significantly. The 30 days mortality rate was 33.3% (8/24) in E-VAC failure compared with 2.2% in patients with E-VAC success ( = .001).

Conclusions: E-VAC is an emerging highly effective interventional endoscopic technique for gastrointestinal wound closure even in highly selected patients.
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http://dx.doi.org/10.1080/00365521.2021.1963836DOI Listing
August 2021

Reaching the Unreachable: Strategies for HCV Eradication in Patients With Refractory Opioid Addiction-A Real-world Experience.

Open Forum Infect Dis 2021 Aug 17;8(8):ofab325. Epub 2021 Jun 17.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

To achieve global hepatitis C virus (HCV) eradication, barriers prohibiting treatment access need to be overcome. We established a strategy to initiate antiviral therapy in patients with severe, refractory heroin addiction. All patients achieved sustained virological response. Outreach programs of hepatologists might be a reasonable way to overcome barriers to HCV treatment.
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http://dx.doi.org/10.1093/ofid/ofab325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339280PMC
August 2021

The changing characteristics of patients infected with chronic hepatitis C virus from 2014 to 2019: Real-world data from the German Hepatitis C-Registry (DHC-R).

J Viral Hepat 2021 Aug 2. Epub 2021 Aug 2.

Leberstiftungs-GmbH Deutschland, Hannover, Germany.

The number of patients diagnosed with hepatitis C virus (HCV) is markedly higher than the number initiating treatment indicating gaps in the care cascade, likely centred around reaching at-risk populations. Understanding changing characteristics of patients with HCV allows for targeted programs that increase linkage to care. We investigated changes in demographic and clinical characteristics of patients registered in the German Hepatitis C-Registry (DHC-R) from 1 January 2014 to 31 December 2019. The DHC-R is an ongoing, noninterventional, multicentre, prospective, observational cohort registry including 327 German centres. Patient characteristics were analysed over time in 7 phases for all patients completing a screening visit. Overall, 14,357 patients were enrolled. The percentage of treatment-naïve/non-cirrhotic patients increased from 34.4% in phase 1 (1 January-31 December 2014) to 68.2% in phase 7 (1 August-31 December 2019). The proportion of migrants, alcohol users, people who inject drugs, and those receiving opiate substitution therapy increased in later registry phases. Most patients (60.1%) were receiving comedication at baseline. The most prescribed comedications were drugs used to treat opioid dependence which increased from 9.2% in phase 1 to 24.0% in phase 7. The patients' mean age decreased from 52.3 years in phase 1 to 48.7 years in phase 7. From 2014 to 2019, the proportion of at-risk patients enrolling in the registry increased. To eliminate viral hepatitis as a major public health threat, a continued commitment to engaging underserved populations into the HCV care cascade is needed.
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http://dx.doi.org/10.1111/jvh.13586DOI Listing
August 2021

Primary sclerosing cholangitis with moderately elevated serum-IgG4 - characterization and outcome of a distinct variant phenotype.

Liver Int 2021 Jul 30. Epub 2021 Jul 30.

Department of Internal Medicine I, University of Bonn, Bonn, Germany.

Background And Aims: Immunoglobulin G4-associated cholangitis (IAC) is characterized by distinctly elevated immunoglobulin G4 in serum (sIgG4) and responds well to corticosteroid therapy. Primary Sclerosing Cholangitis (PSC) is a progressive liver disease without causal treatment options usually not responding to immunosuppression. Increased serum levels of sIgG4 in patients with PSC, that do not meet criteria of IAC, have been reported in 10%-25%. Therefore, we aimed to characterize this subgroup of patients in a retrospective, multicenter study.

Methods: sIgG4 values of 289 patients with PSC from three German university hospitals were analysed. Patients with elevated sIgG4 levels were identified and further characterized by clinical and biochemical parameters and by cholangiographic presentation. Clinical endpoints, death and liver transplantation were compared between groups. Parameters associated with outcome were identified with Cox regression analysis.

Results: 14.5% of patients with PSC showed increased sIgG4 levels (PSC-IgG4), presented with significantly higher (P < .02) albumin, aspartate-aminotransferase, bilirubin and alkaline phosphatase and had a significant lower prevalence of a concomitant autoimmune hepatitis (P = .025). Cholangiogram obtained via ERC showed extrahepatic dominant strictures more often in the PSC-IgG4 subgroup (P = .047). The disease severity models Amsterdam-Oxford-Score (P = .018) and Mayo-Risk-Score (P = .025) predicted lower survival rates for the PSC-IgG4 subgroup. Transplant-free survival after first diagnosis of PSC was shorter in patients with elevated sIgG4 (11.6 vs 15.1 years, P = .001).

Conclusion: Patients with PSC and elevated sIgG4 should be considered as a distinct subgroup, characterized by different clinical and cholangiographical features and are associated with an inferior outcome.
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http://dx.doi.org/10.1111/liv.15028DOI Listing
July 2021

Prothrombotic immune thrombocytopenia after COVID-19 vaccination.

Blood 2021 07;138(4):350-353

Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

We report 5 cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and thrombotic microangiopathy. All patients had thrombocytopenia and markedly elevated D-dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients, although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependent manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in 3 patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.
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http://dx.doi.org/10.1182/blood.2021011958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084604PMC
July 2021

BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment.

Cell Death Dis 2021 Jul 26;12(8):736. Epub 2021 Jul 26.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.
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http://dx.doi.org/10.1038/s41419-021-04020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313681PMC
July 2021

Antimicrobial resistance in patients with decompensated liver cirrhosis and bacterial infections in a tertiary center in Northern Germany.

BMC Gastroenterol 2021 Jul 20;21(1):296. Epub 2021 Jul 20.

Department for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Background And Aims: Bacterial infections are common in patients with decompensated liver cirrhosis and a leading cause of death. Reliable data on antibiotic resistance are required to initiate effective empiric therapy. We here aim to assess the antimicrobial resistance profile of bacteria among patients with liver cirrhosis and infection.

Methods: Overall, 666 cirrhotic patients admitted to Hannover Medical School between January 2012 and April 2018 with ascites were assessed for bacterial infection. In case of infection, bacteria cultured from microbiological specimens of ascites, blood or urine were identified and analyzed for resistances against common antibiotic agents. Furthermore, analyses compared two periods of time and community-acquired vs. nosocomial infections.

Results: In 281 patients with infection, microbiological sampling was performed and culture-positive results were obtained in 56.9%. Multidrug-resistant (MDR)-bacteria were found in 54 patients (19.2%). Gram-positive organisms were more common (n = 141/261, 54.0%) and detected in 116/192 culture-positive infections (60.4%). Comparing infections before and after 2015, a numerical decline for MDR-bacteria (23.8% vs. 15.6%, p = 0.08) was observed with a significant decline in meropenem resistance (34.9% vs. 19.5%, p = 0.03). MDR-bacteria were more frequent in the case of nosocomial infections. Of note, in ascites the majority of the tested bacteria were resistant against ceftriaxone (73.8%) whereas significantly less were resistant against meropenem (27.0%) and vancomycin (25.9%).

Conclusions: In our tertiary center, distinct ratios of gram-positive infection with overall low ratios of MDR-bacteria were found. Adequate gram-positive coverage in the empiric therapy should be considered. Carbapenem treatment may be omitted even in nosocomial infection. In contrast, 3rd generation cephalosporins cannot be recommended even in community-acquired infection in our cirrhotic population.
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http://dx.doi.org/10.1186/s12876-021-01871-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290615PMC
July 2021

An unusual cause of erythema on both lower legs in a patient with Crohn´s disease.

Gastroenterology 2021 Jul 16. Epub 2021 Jul 16.

Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

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http://dx.doi.org/10.1053/j.gastro.2021.07.015DOI Listing
July 2021

Poor clinical and virological outcome of nucleos(t)ide analogue monotherapy in HBV/HDV co-infected patients.

Medicine (Baltimore) 2021 Jul;100(28):e26571

Department of Gastroenterology and Hepatology, University Hospital Essen, Germany.

Abstract: Co-infection of Hepatitis B (HBV) and Delta viruses (HDV) represent the most severe form of viral hepatitis. While treatment with pegylated Interferon alpha (PEG-IFNα) is well established, therapy with nucleoside or nucleotide analogues (NA) has been a matter of debate. We aimed to investigate the role of NA treatment in a well-defined single centre cohort.In a retrospective approach, we observed 53 HDV RNA positive and/or anti-HDV-positive patients recruited at a German referral centre between 2000 and 2019. Patients were followed for at least 3 months (mean time of follow up: 4.6 years; range: 0.2-14.1 years). Patients who had liver transplantation or hepatocellular carcinoma at the time of presentation were excluded. 43% (n = 23) were treated with NA, 43% (n = 23) received IFNα-based therapies and 13% (n = 7) were untreated.Liver cirrhosis was already present in 53% (28/53) of patients at first presentation. During follow-up, liver-related endpoints developed in 44% of all patients (n = 23). NA-treatment was associated with a significantly worse clinical outcome (P = .01; odds ratio [OR] = 4.92; CI = 1.51-16.01) compared to both, untreated (P = .38; OR = 0.46; CI = 0.80-2.61) and IFNα-based-treated patients (P = .04; OR = 0.29; CI = 0.89-0.94) in univariate logistic regression analysis. HBsAg levels declined by more than 50% during NA-based therapy in only 7 cases (7/23; mean time: 3.6 years; range: 0.8-8.5 years) and during IFNα-based therapy in 14 cases (14/23; mean time: 2.8 years, range 0.7-8.5 years). HDV RNA became undetectable during follow up in 30% of patients receiving NA alone (7/23; mean time: 5.0 years; range: 0.6-13.5 years), in 35% of patients receiving IFNα-based therapy (8/23; mean time: 2.9 years, range: 0.3-7.6 years).The effect of NA in patients with HBV/HDV co-infection is limited. Treatment with NA was associated with a higher likelihood of clinical disease progression. Interferon alpha therapy was beneficial in reducing liver complications and improves long-term outcome.
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http://dx.doi.org/10.1097/MD.0000000000026571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284709PMC
July 2021

Prospects and Challenges for T Cell-Based Therapies of HCC.

Cells 2021 Jun 30;10(7). Epub 2021 Jun 30.

Clinic for Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.

The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.
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http://dx.doi.org/10.3390/cells10071651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304292PMC
June 2021

Anti-CD20 Therapy Alters the Protein Signature in Experimental Murine AIH, but Not Exclusively towards Regeneration.

Cells 2021 Jun 11;10(6). Epub 2021 Jun 11.

Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany.

Background: Autoimmune hepatitis (AIH) is a chronic autoimmune inflammatory disease that usually requires lifelong immunosuppression. Frequent recurrences after the discontinuation of therapy indicate that intrahepatic immune regulation is not restored by current treatments. Studies of other autoimmune diseases suggest that temporary depletion of B cells can improve disease progression in the long term.

Methods: We tested a single administration of anti-CD20 antibodies to reduce B cells and the amount of IgG to induce intrahepatic immune tolerance. We used our experimental murine AIH (emAIH) model and treated the mice with anti-CD20 during the late stage of the disease.

Results: After treatment, the mice showed the expected reductions in B cells and serum IgGs, but no improvements in pathology. However, all treated animals showed a highly altered serum protein expression pattern, which was a balance between inflammation and regeneration.

Conclusions: In conclusion, anti-CD20 therapy did not produce clinically measurable results because it triggered inflammation, as well as regeneration, at the proteomic level. This finding suggests that anti-CD20 is ineffective as a sole treatment for AIH or emAIH.
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http://dx.doi.org/10.3390/cells10061471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231180PMC
June 2021

[New therapeutic options for hepatitis D].

MMW Fortschr Med 2021 06;163(12):62-63

Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.

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http://dx.doi.org/10.1007/s15006-021-0023-4DOI Listing
June 2021

Telemonitoring-Supported Exercise Training in Employees With Metabolic Syndrome Improves Liver Inflammation and Fibrosis.

Clin Transl Gastroenterol 2021 Jun 18;12(6):e00371. Epub 2021 Jun 18.

Institute of Sports Medicine, Hannover Medical School, Hannover, Germany.

Introduction: Metabolic syndrome (MetS) is a major health problem worldwide and the main risk factor for metabolic-associated fatty liver disease (MAFLD). Established treatment options are lifestyle interventions facilitating dietary change and increased physical activity. Here, we tested the effect of a telemonitoring-supported intervention on liver parameter of inflammation and fibrosis in individuals with MetS.

Methods: This was a prospective, randomized, parallel-group, and assessor-blind study performed in workers of the main Volkswagen factory (Wolfsburg, Germany). Volunteers with diagnosed MetS were randomly assigned (1:1) to a 6-month lifestyle intervention focusing on supervised, activity-tracker-guided exercise or to a waiting-list control group. This secondary analysis assessed the effect of the intervention on liver enzymes and MAFLD-related parameters.

Results: We screened 543 individuals between October 10, 2017, and February 27, 2018, of whom 314 were randomly assigned to the intervention group (n = 160) or control group (n = 154). Liver transaminases, alkaline phosphatase, and gamma-glutamyl transferase significantly decreased after 6 months in the intervention group compared with the CG. Furthermore, an aspartate aminotransferase-to-platelet ratio index score as a marker for liver fibrosis significantly decreased in the intervention group. These improvements were associated with changes in obesity and exercise capacity.

Discussion: A 6-month lifestyle intervention based on exercise training with individualized telemonitoring-based supervision led to improvements of liver inflammation and fibrosis in employees with MetS. Therefore, this intervention shows therapeutic potential for individuals at high risk of MAFLD (ClinicalTrials.gov Identifier: NCT03293264).
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http://dx.doi.org/10.14309/ctg.0000000000000371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216678PMC
June 2021

Hepatitis C virus: Current steps toward elimination in Germany and barriers to reaching the 2030 goal.

Health Sci Rep 2021 Jun 4;4(2):e290. Epub 2021 Jun 4.

First Department of Medicine University Medical Centre of the Johannes Gutenberg-University Mainz Germany.

Hepatitis C virus (HCV) affects over 70 million people globally, with an estimated 399 000 HCV-related deaths in 2016. The World Health Organization (WHO) has set a goal to eliminate HCV by 2030. Despite the availability of direct-acting antivirals-highly effective and well-tolerated therapies for HCV-many patients infected with HCV in Germany have not initiated treatment, including a majority of those who are aware of their positive diagnosis. Barriers to screening, diagnosis, and treatment are major factors taking many countries off track for HCV elimination by 2030. Identifying country-specific barriers and challenges, particularly in at-risk populations such as people who inject drugs or men who have sex with men, has the potential to create tailored programs and strategies to increase access to screening or treatment and engage at-risk populations. This review aims to report the current steps toward HCV elimination in Germany, the country-specific barriers and challenges that will potentially prevent reaching the 2030 HCV elimination goal and describe good practice examples to overcome these barriers.
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http://dx.doi.org/10.1002/hsr2.290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177898PMC
June 2021

Hippo Pathway Counter-Regulates Innate Immunity in Hepatitis B Virus Infection.

Front Immunol 2021 25;12:684424. Epub 2021 May 25.

Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Whether hepatitis B virus (HBV) activates or represses innate immunity continues to be debated. Toll-like receptor (TLR) 2 has been identified to recognize HBV particles in human hepatocytes. The Hippo pathway, known for growth control, is suggested to play a vital role in immune regulation. Here, molecular interactions between HBV-triggered TLR signaling and the Hippo pathway were comprehensively investigated. Reanalysis of GSE69590 data, in which human hepatocytes have been treated with cell culture-derived HBV particles, identified changes in Hippo and NF-κB signaling. Immunocytochemical staining and western blotting revealed time-dependent nuclear translocation of YAP and NF-κB in HBV-exposed primary human and murine hepatocytes (PMH). Analysis of PMH isolated from MyD88- or IRAK4-deficient mice and the inhibition of TLR2 and MST1/2 confirmed the relation between TLR2 and Hippo signaling in HBV-induced immunity. Loss and gain of function experiments implied that Hippo-downstream effector YAP directly regulated IκBα expression. Functional investigations confirmed the regulation of promoter activity by the YAP/TEAD4 transcription factor complex. Administration of TLR ligands to mice highlighted the relevance of the TLR2-MyD88-IRAK4-Hippo axis in hepatic immunity. Interestingly, reanalysis of gene expression pattern in liver biopsies of patients chronically infected with HBV (GSE83148, GSE65359) indicated an activation of TLR2 and however, an MST1-dominated Hippo control in the immune clearance phase of patients with chronic HBV infection. We demonstrated that MyD88-dependent TLR signaling activates NF-κB and Hippo signaling, with YAP prompting the IκBα-mediated negative feedback, alongside NF-κB. Imbalance between immune induction and Hippo activation may have implications for the safety of novel HBV cure strategies interfering with pathogen recognition receptors.
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http://dx.doi.org/10.3389/fimmu.2021.684424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185339PMC
May 2021

Increasing Number of Individuals Receiving Hepatitis B nucleos(t)ide Analogs Therapy in Germany, 2008-2019.

Front Public Health 2021 21;9:667253. Epub 2021 May 21.

Department of Infectious Disease Epidemiology, Robert Koch Institute, Berlin, Germany.

Germany is a low prevalence country for hepatitis B virus (HBV) infection with higher prevalence in vulnerable groups. The number of treated chronic hepatitis B (CHB) patients is unknown. We aimed to determine the number of CHB patients treated with nucleos(t)ide analogs (NUCs), the treatment costs within the statutory health insurance (SHI) in Germany and per patient per month. Data on pharmacy bills of NUCs to patients with SHI between 2008 and 2019 were purchased from Insight Health™ and described. Negative binomial regression was used for trend analysis. Number of patients increased between 2008 and 2019 (4.9% per year) with little changes in treatment options. Overall prescription costs were increasing (6.7% per year on average) until the introduction of tenofovir and entecavir generics in 2017 after which costs decreased by 31% in 2019. Average therapy costs peaked at 498 Euro per patient per month in 2016 and decreased to 214 Euro in 2019. Prescriptions changed from 30 to 90 pills per pack over time. HBV therapy was prescribed to 97% by three medical specialist groups, mainly specialists in internal medicine (63%), followed by hospital-based outpatient clinics (20%) and general practitioners (15%). Contrary to guideline recommendation, adefovir was still prescribed after 2011 for 1-5% of patients albeit with decreasing tendency. Prescriptions per 100,000 inhabitants were highest in Berlin and Hamburg. Our data shows, that the number of treated CHB patients increased steadily, while NUC therapy costs decreased. We recommend continued testing and treatment for those eligible to prevent advanced liver disease and possibly decrease further transmission of HBV.
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http://dx.doi.org/10.3389/fpubh.2021.667253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175796PMC
June 2021

Natural Killer Cells Regulate the Maturation of Liver Sinusoidal Endothelial Cells Thereby Promoting Intrahepatic T-Cell Responses in a Mouse Model.

Hepatol Commun 2021 May 5;5(5):865-881. Epub 2021 Feb 5.

Department of Infectious Diseases Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China.

Functional maturation of liver sinusoidal endothelial cells (LSECs) plays an important role in intrahepatic T-cell activation and control of viral infections. Natural killer (NK) cells have been reported to prompt the maturation of antigen-presenting cells (APCs), especially for dendritic cells (DCs), but the interaction between NK cells and LSECs is elusive. Here, we investigated whether and how NK cells are involved in regulating LSEC maturation and if this has a role in controlling hepatitis B virus (HBV) infection in a mouse model. A chronic HBV replication mouse model was established by hydrodynamic injection (HI) of 6 µg adeno-associated virus plasmid (pAAV)/HBV 1.2. The nucleotide-binding oligomerization domain-containing protein 1 (NOD1) ligand diaminopemelic acid (DAP) was imported into liver by HI at day 14 after plasmid injection. We found that HI of DAP recruited conventional NK cells (cNK) into the liver and promoted tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ) production of NK cells in a chemokine (C-X-C motif) receptor 3 (CXCR3)-dependent manner. Importantly, the maturation of LSECs and the anti-HBV effects of DAP were impaired in CXCR3 mice; this possibly was associated with the decreased number of intrahepatic cNK cells. Consistently, depleting cNK cells but not liver-resident NK cells also impaired the maturation and antigen-presenting function of LSECs, which reduced intrahepatic HBV-specific T-cell responses and thus inhibited HBV clearance both in wild-type and in Rag1 mice. Moreover, TNF-α or IFN-γ stimulation as well as coculture with intrahepatic NK cells partly promoted LSEC phenotypic and functional maturation . NOD1-triggered NK cell activation may lead to the enhancement of intrahepatic T-cell responses by promoting maturation of LSECs through soluble cytokines and cell-cell contact, thereby controlling HBV replication and expression.
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http://dx.doi.org/10.1002/hep4.1676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122378PMC
May 2021

Only partial improvement in health-related quality of life after treatment of chronic hepatitis C virus infection with direct acting antivirals in a real-world setting-results from the German Hepatitis C-Registry (DHC-R).

J Viral Hepat 2021 Aug 8;28(8):1206-1218. Epub 2021 Jun 8.

Kreiskliniken Altötting-Burghausen, Burghausen, Germany.

Improvement of health-related quality of life (HRQoL) is frequently reported as a benefit when treating hepatitis C virus infection (HCV) with direct acting antivirals (DAA). As most of the available data were obtained from clinical trials, limited generalizability to the real-world population might exist. This study aimed to investigate the impact of DAA therapy on changes in HRQoL in a real-world setting. HRQoL of 1180 participants of the German Hepatitis C-Registry was assessed by Short-Form 36 (SF-36) questionnaires. Scores at post-treatment weeks 12-24 (FU12/24) were compared to baseline (BL). Changes of ≥2.5 in mental and physical component summary scores (MCS and PCS) were defined as a minimal clinical important difference (MCID). Potential predictors of HRQoL changes were analysed. Overall, a statistically significant increase in HRQoL after DAA therapy was observed, that was robust among various subgroups. However, roughly half of all patients failed to achieve a clinically important improvement in MCS and PCS. Low MCS (p < .001, OR = 0.925) and PCS (p < .001, OR = 0.899) BL levels were identified as predictors for achieving a clinically important improvement. In contrast, presence of fatigue (p = .023, OR = 1.518), increased GPT levels (p = .005, OR = 0.626) and RBV containing therapy regimens (p = .001, OR = 1.692) were associated with a clinically important decline in HRQoL after DAA therapy. In conclusion, DAA treatment is associated with an overall increase of HRQoL in HCV-infected patients. Nevertheless, roughly half of the patients fail to achieve a clinically important improvement. Especially patients with a low HRQoL seem to benefit most from the modern therapeutic options.
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http://dx.doi.org/10.1111/jvh.13546DOI Listing
August 2021

Hepatitis E: An update on One Health and clinical medicine.

Liver Int 2021 07 19;41(7):1462-1473. Epub 2021 May 19.

Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany.

The hepatitis E virus (HEV) is one of the main causes of acute hepatitis and the de facto global burden is underestimated. HEV-related clinical complications are often undetected and are not considered in the differential diagnosis. Convincing findings from studies suggest that HEV is clinically relevant not only in developing countries but also in industrialized countries. Eight HEV genotypes (HEV-1 to HEV-8) with different human and animal hosts and other HEV-related viruses are in circulation. Transmission routes vary by genotype and location, with large waterborne outbreaks in developing countries and zoonotic food-borne infections in developed countries. An acute infection can be aggravated in pregnant women, organ transplant recipients, patients with pre-existing liver disease and immunosuppressed patients. HEV during pregnancy affects the fetus and newborn with an increased risk of vertical transmission, preterm and stillbirth, neonatal jaundice and miscarriage. Hepatitis E is associated with extrahepatic manifestations that include neurological disorders such as neuralgic amyotrophy, Guillain-Barré syndrome and encephalitis, renal injury and haematological disorders. The risk of transfusion-transmitted HEV is increasingly recognized in Western countries where the risk may be because of a zoonosis. RNA testing of blood components is essential to determine the risk of transfusion-transmitted HEV. There are currently no approved drugs or vaccines for HEV infections. This review focuses on updating the latest developments in zoonoses, screening and diagnostics, drugs in use and under development, and vaccines.
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http://dx.doi.org/10.1111/liv.14912DOI Listing
July 2021

Dulaglutide Alone and in Combination with Empagliflozin Attenuate Inflammatory Pathways and Microbiome Dysbiosis in a Non-Diabetic Mouse Model of NASH.

Biomedicines 2021 Mar 30;9(4). Epub 2021 Mar 30.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, 30625 Hannover, Germany.

Dysregulation of glucose homeostasis plays a major role in the pathogenesis of non-alcoholic steatohepatitis (NASH) as it activates proinflammatory and profibrotic processes. Beneficial effects of antiglycemic treatments such as GLP-1 agonist or SGLT-2 inhibitor on NASH in patients with diabetes have already been investigated. However, their effect on NASH in a non-diabetic setting remains unclear. With this aim, we investigated the effect of long-acting GLP1-agonist dulaglutide and SGLT-2 inhibitor empagliflozin and their combination in a non-diabetic mouse model of NASH. C57BL/6 mice received a high-fat-high-fructose (HFHC) diet with a surplus of cholesterol for 16 weeks. After 12 weeks of diet, mice were treated with either dulaglutide, empagliflozin or their combination. Dulaglutide alone and in combination with empagliflozin led to significant weight loss, improved glucose homeostasis and diminished anti-inflammatory and anti-fibrotic pathways. Combination of dulaglutide and empagliflozin further decreased MoMFLy6C and CD4Foxp3 T cells. No beneficial effects for treatment with empagliflozin alone could be shown. While no effect of dulaglutide or its combination with empaglifozin on hepatic steatosis was evident, these data demonstrate distinct anti-inflammatory effects of dulaglutide and their combination with empagliflozin in a non-diabetic background, which could have important implications for further treatment of NASH.
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http://dx.doi.org/10.3390/biomedicines9040353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066839PMC
March 2021

The impact of hepatitis B surface antigen on natural killer cells in patients with chronic hepatitis B virus infection.

Liver Int 2021 09 3;41(9):2046-2058. Epub 2021 May 3.

Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.

Background & Aims: During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB).

Methods: Eighty CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes.

Results: Compared to the healthy controls, a reshaping of NK cell pool towards more CD56 NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/mL) displayed an activated phenotype with increased expression of activation makers CD38, granzyme B and proliferation marker Ki-67 while presenting with defective functional responses (MIP-1β, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age.

Conclusions: The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance.
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http://dx.doi.org/10.1111/liv.14885DOI Listing
September 2021

[Evolution of hepatitis C virus genotype 1a vs. 1b distribution in Germany between 2004 and 2018 - An analysis of 17093 patients from different real world registries].

Z Gastroenterol 2021 Mar 8;59(3):241-249. Epub 2021 Mar 8.

Leberstiftungs-GmbH Deutschland, Hannover.

Background:  Hepatitis C virus (HCV) genotype (GT) 1 is the most common HCV GT in Western and Central Europe. The main focus of this present work is to analyze the change of baseline characteristics of 17 093 HCV-patients with genotype 1a/1b with antiviral therapy in Germany between 2004 and 2018. We analyzed five periods: (i) 2004-2007, (ii) 2008-2010, (iii) 2010-2013, (iv) 2014-2016, (v) 2017-2018.

Methods:  The present analysis is based on five German non-interventional registry studies and comprises data on 17 093 HCV-GT1 patients documented between 2004 and 2018 [ML17071, ML19464, ML21645, ML25724 (Peginterferon alfa-2a non-interventional study [PAN]) and the German Hepatitis C-Registry (DHC-R).

Findings:  Overall, 7662 patients were infected with HCV GT1a and 9431 patients with HCV GT1b. GT1a patients were younger (46.5 years vs. 51.2 years) and more often male (70 % vs. 52 %). Previous or ongoing drug abuse was documented more frequently for GT1a patients throughout the study periods with highest frequencies in the most recent period (2017-2018; 44 % for GT1a and 10.3 % for GT1b). Metabolic comorbidities, such as those who are overweight and those with diabetes mellitus, were associated with HCV GT1b-infected women. The GT1a ratio increased from 33.6 % (2004-2007) to 50 % (2017-2018). A relevant change in the GT1a/1b ratio was observed over time in men (2004-2007: 38 %/63 %; 2017-2018: 59 %/41 %). In contrast, only 30 % of women had GT1a infection throughout all study periods without relevant changes. There were no regional differences within Germany in HCV GT1a/1b distribution despite a higher proportion of GT1b-infected women in East Germany in 2004-2007 (86 %).

Conclusion:  A marked increase of GT1a infection associated with drug use was observed in men, but not women, in Germany between 2004 and 2018. The present data show a fundamental change in HCV epidemiology, which has an impact on therapy management and general care of hepatitis C patients in Germany.
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http://dx.doi.org/10.1055/a-1332-2214DOI Listing
March 2021

Significant compartment-specific impact of different RNA extraction methods and PCR assays on the sensitivity of hepatitis E virus detection.

Liver Int 2021 08 22;41(8):1815-1823. Epub 2021 Mar 22.

Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.

Background: RNA detection in plasma/stool is the gold-standard for diagnosis of hepatitis E virus (HEV) infection. The impact of viral extraction methods on HEV RNA detection is poorly investigated.

Methods: We determined the limit of detection of the RealStar HEV RT-PCR V2.0 Kit (altona Diagnostics, RS) utilizing 3 RNA extraction methods (COBAS AmpliPrep Total Nucleic Acid Isolation Kit, TNAi Roche; MagNA Pure 96 DNA, Viral NA SV Kit, MgP; QIAamp Viral RNA mini Kit Qiagen; VRK) in plasma and stool. The most sensitive method was evaluated in a total of 307 longitudinal samples of patients with HEV infection (acute = 18/chronic = 36) and compared to results with the former diagnostic standard of our centre (TNAi/FastTrack Diagnostic; FTD).

Results: The plasma-LOD was 49, 94 and 329 IU/mL for extraction with MgP, VRK and TNAi respectively. In stool, the LOD was 21 IU/mL, 528 IU/mL and indefinable for extraction with TNAi, VRK and MgP respectively. Utilizing longitudinal patient plasma samples, MgP/RS revealed 56 HEV RNA-positive samples in 158 negative samples as determined by TNAi/FTD. In stool, from 37 HEV negative samples (TNAi/FTD), 15 were positive with TNAi/RS. At end of treatment, 8 out of 27 chronically infected patients were RNA positive with MgP/RS, while classified negative with TNAi/FTD. A relapse occurred in 3 of these patients.

Conclusion: Different methods for RNA extraction and quantification have a significant, compartment-specific impact on the sensitivity of HEV detection. Knowledge about the favourable combinations of extraction and quantification has important implications for diagnosis and patients receiving antiviral therapy.
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http://dx.doi.org/10.1111/liv.14870DOI Listing
August 2021
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