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Hepatitis: HELP
Articles by Johannes Vermehren
Based on 49 articles published since 2010
(Why 49 articles?)
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Between 2010 and 2020, Johannes Vermehren wrote the following 49 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Challenges and perspectives of direct antivirals for the treatment of hepatitis C virus infection. 2018

Vermehren, Johannes / Park, James S / Jacobson, Ira M / Zeuzem, Stefan. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. Electronic address: Johannes.vermehren@kgu.de. · Hepatology Section, Division of Gastroenterology, Department of Medicine, New York University School of Medicine and NYU Langone Health, New York, USA. · Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. ·J Hepatol · Pubmed #30006068.

ABSTRACT: Treatment of chronic hepatitis C virus infection has been revolutionised by the development of direct-acting antivirals (DAAs). All-oral, once-daily, 8- to 12-week treatment regimens are now standard of care, with viral eradication possible in >95% of patients across different populations. Despite these advances, several unresolved issues remain, including treatment of patients with hepatitis C virus genotype 3, chronic kidney disease, and those in whom DAA therapy has previously failed. Glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are the most recently approved DAA regimens. Given the overwhelming success of modern DAA-based therapies, glecaprevir/pibrentasvir and sofosbuvir/velpatasvir/voxilaprevir are also likely to represent the last DAAs to be approved. Both are pangenotypic, once-daily, all-oral DAA combinations that have the potential to close the gaps in the current DAA treatment portfolio. Herein, we review the challenges associated with current DAAs and how these two regimens may be implemented in existing treatment algorithms.

2 Review Hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C: a systematic review and meta-analysis. 2018

Mücke, Marcus M / Backus, Lisa I / Mücke, Victoria T / Coppola, Nicola / Preda, Carmen M / Yeh, Ming-Lun / Tang, Lydia S Y / Belperio, Pamela S / Wilson, Eleanor M / Yu, Ming-Lung / Zeuzem, Stefan / Herrmann, Eva / Vermehren, Johannes. ·Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany. · Department of Veterans Affairs, Population Health Services, Palo Alto Health Care System, Palo Alto, CA, USA. · Department of Mental Health and Public Medicine, University of Campania, Naples, Italy. · Gastroenterology and Hepatology Department, Fundeni Clinical Institute, Bucharest, Romania. · Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. · Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA. · Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA; Division of Infectious Diseases, Department of Medicine, VA Maryland Health Care System, Baltimore, MD, USA. · Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, Frankfurt am Main, Germany. · Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany. Electronic address: johannes.vermehren@kgu.de. ·Lancet Gastroenterol Hepatol · Pubmed #29371017.

ABSTRACT: BACKGROUND: Direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection might pose a risk for hepatitis B virus (HBV) reactivation in patients coinfected with chronic or resolved HBV infection. The need for HBV antiviral prophylaxis during DAA treatment remains controversial. We aimed to analyse the absolute risk of HBV reactivation in patients with active or resolved HBV infection treated with DAAs for HCV infection. METHODS: For this systematic review and meta-analysis, we searched PubMed, Ovid MEDLINE, the Cochrane Central Register of Controlled Trials, and Web of Science from Oct 1, 2010, to Sept 30, 2017, to identify studies of patients with chronic or resolved HBV infection at baseline treated with DAAs for chronic HCV infection. Conference proceedings, abstract books, and references from relevant reviews were also examined for potential studies. Two independent researchers extracted data and assessed quality and risk of bias. Data were pooled by use of random-effects models. The primary outcome was HBV reactivation defined by standardised nomenclature. This study is registered with PROSPERO, number CRD42017065882. FINDINGS: We identified 17 observational studies involving 1621 patients with chronic (n=242) or resolved (n=1379) HBV infection treated with different DAAs. The pooled proportion of patients who had HBV reactivation was 24% (95% CI 19-30) in patients with chronic HBV infection and 1·4% (0·8-2·4) in those with resolved HBV infection. In patients with chronic HBV infection, the pooled proportion of patients with HBV-reactivation-related hepatitis was 9% (95% CI 5-16) and the relative risk (RR) of HBV-reactivation-related hepatitis was significantly lower in patients with HBV DNA below the lower limit of quantification at baseline than in those with quantifiable HBV DNA (RR 0·17, 95% CI 0·06-0·50; p=0·0011). Three major clinical events related to HBV reactivation in patients with chronic HBV infection were reported (one patient had liver decompensation and two had liver failure, one of whom required liver transplantation). In patients with resolved HBV infection, no HBV-reactivation-related hepatitis was reported. INTERPRETATION: HBV reactivation occurs frequently in patients with chronic HBV and HCV coinfection receiving DAA therapy but is rare among patients with resolved HBV infection. Use of antiviral prophylaxis might be warranted in patients who test positive for hepatitis B surface antigen (HBsAg), particularly those with quantifiable HBV DNA. FUNDING: None.

3 Review Diagnostics in hepatitis C: The end of response-guided therapy? 2016

Maasoumy, Benjamin / Vermehren, Johannes. ·Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany. · Universitätsklinikum Frankfurt, Medizinische Klinik 1, Frankfurt am Main, Germany. Electronic address: Johannes.vermehren@kgu.de. ·J Hepatol · Pubmed #27641989.

ABSTRACT: On-treatment hepatitis C virus (HCV) RNA has been used to predict response to interferon (IFN)-based therapy. The concept of response-guided treatment (RGT) was established to determine optimal treatment duration and to early identify patients not responding to futile therapies. RGT helped to improve sustained virologic response (SVR) rates and lower the rates of adverse effects. RGT was of particular importance for telaprevir- and boceprevir-based triple therapies. RGT strategies are dependent on highly sensitive and reproducible HCV RNA quantification. However, different HCV RNA assays are used in routine clinical practice and these differ significantly in their performance characteristics. The development of IFN-free therapies has fundamentally changed the role of on-treatment HCV RNA for SVR prediction. Given the high efficacy and excellent tolerability of IFN-free regimens, the interest in treatment individualization has decreased. However, shorter treatment durations may still be desirable, particularly with respect to the high costs of current IFN-free direct-acting antiviral agents (DAAs). Moreover, some difficult-to-treat patients remain, e.g., those infected with HCV genotype 3 in whom the current standard of care may not always be sufficient to achieve SVR, especially in treatment-experienced patients with cirrhosis. Here, a RGT extension may be feasible. However, current data on the predictive value of on-treatment HCV RNA are limited and have shown conflicting results. As more potent DAAs become available, the role of response prediction may diminish further. Currently, shorter treatment duration is only based on baseline HCV RNA whereas no RGT strategy is recommended for any of the approved DAA regimens available.

4 Review New HCV Therapies and Liver Transplantation. 2016

Werner, Jens M / Vermehren, Johannes. ·1 Department of Surgery, University Hospital Regensburg, Regensburg, Bavaria, Germany. 2 Department of Internal Medicine, University Hospital Frankfurt, Frankfurt, Germany. ·Transplantation · Pubmed #26813409.

ABSTRACT: -- No abstract --

5 Review The role of resistance in HCV treatment. 2012

Vermehren, Johannes / Sarrazin, Christoph. ·Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ·Best Pract Res Clin Gastroenterol · Pubmed #23199507.

ABSTRACT: The recent development of small molecule compounds that directly inhibit the viral life cycle represents a major milestone for the treatment of chronic hepatitis C virus (HCV) infection. These new drugs that are collectively termed direct-acting antivirals (DAA) include a range of inhibitors of the non-structural (NS) 3/4A protease, NS5B polymerase and NS5A protein. Two NS3/4A protease inhibitors (boceprevir and telaprevir) in combination with pegylated interferon and ribavirin have now been approved for the treatment of chronic HCV genotype 1 infection and cure rates could be increased by 20-30%. However, the majority of DAAs is still in early clinical development. The rapid replication rate of HCV, along with the error-prone polymerase activity leads to a high genetic diversity among HCV virions that includes mutants with reduced susceptibility to DAA-therapy. These resistance-associated variants often occur at very low frequencies. However, during DAA-based treatment, rapid selection of resistance mutations may occur, eventually leading to viral break-through. A number of variants with different levels of resistance have been described in vitro and in vivo for virtually all DAAs. We review the parameters that determine DAA resistance as well as the clinical implications of resistance testing. In addition, the most recent literature and conference data on resistance profiles of DAAs in clinical development and future strategies to avoid the emergence of viral resistance are also discussed.

6 Review [Chronic hepatitis C: improved cure rates with new approved medications]. 2012

Grammatikos, Georgios / Vermehren, Johannes / Zeuzem, Stefan. ·Medizinische Klinik I, Gastroenterologie/Hepatologie Klinikum der J.W. Goethe-Universität Frankfurt, Frankfurt am Main. Georgios.Grammatikos@kgu.de ·MMW Fortschr Med · Pubmed #22916428.

ABSTRACT: -- No abstract --

7 Review New hepatitis C therapies in clinical development. 2011

Vermehren, Johannes / Sarrazin, Christoph. ·Medizinische Klinik 1, Klinikum der J.W. Goethe-Universität, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ·Eur J Med Res · Pubmed #21813371.

ABSTRACT: With the current standard of care for the treatment of chronic hepatitis C, a combination of pegylated interferon alfa and ribavirin, sustained virologic response rates can be achieved in approximately 50% of patients only. - Improved understanding of the viral life cycle has led to the identification of numerous potential targets for novel, direct-acting antiviral compounds. Inhibitors of the NS3/4A protease are currently the most advanced in clinical development. Recently completed phase 3 studies of the two protease inhibitors telaprevir and boceprevir, each given in combination with standard of care, yielded sustained virologic response rates in the range of 66-75% in treatment-naive patients and 59-66% in treatment-experienced patients with HCV genotype 1 infection. Studies of second-generation protease inhibitors, with the potential advantage of improved potency, drug metabolism and pharmacokinetics profile, are already underway. - Inhibitors of the HCV NS5A protein and NS5B polymerase are potentially active across different HCV genotypes and have shown promising antiviral efficacy in early clinical studies. Other emerging mechanisms include silymarin components and inhibitors of cell proteins required for HCV replication. - While improved formulations of current HCV therapies are also being developed, future hopes lie on the combination of direct-acting antivirals with the eventual possibility of interferon-free treatment regimens.

8 Clinical Trial Role of telaprevir plasma levels for predicting response to antiviral therapy in patients with hepatitis C virus genotype 1 infection. 2014

Farnik, Harald / Ferreirós, Nerea / Labocha, Sandra / Geisslinger, Gerd / Zeuzem, Stefan / Sarrazin, Christoph / Vermehren, Johannes. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt , Theodor-Stern-Kai 7, 60590 Frankfurt am Main , Germany. ·Scand J Gastroenterol · Pubmed #25384840.

ABSTRACT: OBJECTIVE: Telaprevir (TVR)-based triple therapy has substantially improved cure rates of hepatitis C virus (HCV) genotype 1 infection but side effects are frequent and often severe. Therefore, response predictors are needed for early identification of patients not responding to TVR-based triple therapy. MATERIAL AND METHODS: Forty-five patients (mean age: 54 ± 13 years; male gender: 60%; treatment-experienced: 82%; cirrhosis: 58%) with HCV genotype 1 infection were treated with a TVR-based triple-therapy regimen. TVR plasma levels were analyzed by liquid chromatography electrospray-ionization-tandem mass spectrometry at weeks 2, 4, 8, and 12 of antiviral therapy. On-treatment HCV RNA response was assessed at weeks 4, 12, and 24 by real-time polymerase chain reaction. RESULTS: An extended rapid virological response (eRVR) and sustained virological response (SVR) was achieved in 21 of 45 patients (47%) and 36 of 45 (80%) patients, respectively. Mean ± standard deviation TVR plasma levels at week 2 were 3.4 ± 0.2 log10 ng/ml and did not differ over time (when assessed at weeks 4, 8, and 12). TVR plasma levels at week 2 were significantly higher in patients who achieved an eRVR compared to those who did not achieve eRVR (3.5 ± 0.1 vs. 3.3 ± 0.2 log10 ng/ml; p = 0.003) but were neither associated with SVR nor with treatment-related anemia. CONCLUSION: TVR plasma levels are associated with on-treatment response but not with overall treatment efficacy. Given the high overall response rates to TVR-based triple therapy, our data suggest that TVR trough levels may not be a useful predictor of treatment response, and routine drug-level monitoring is not required.

9 Clinical Trial High prevalence of anti-HCV antibodies in two metropolitan emergency departments in Germany: a prospective screening analysis of 28,809 patients. 2012

Vermehren, Johannes / Schlosser, Beate / Domke, Diana / Elanjimattom, Sandra / Müller, Christian / Hintereder, Gudrun / Hensel-Wiegel, Karin / Tauber, Rudolf / Berger, Annemarie / Haas, Norbert / Walcher, Felix / Möckel, Martin / Lehmann, Ralf / Zeuzem, Stefan / Sarrazin, Christoph / Berg, Thomas. ·Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität, Frankfurt am Main, Germany. Johannes.Vermehren@kgu.de ·PLoS One · Pubmed #22848445.

ABSTRACT: BACKGROUND AND AIMS: The prevalence of hepatitis C virus (HCV) antibodies in Germany has been estimated to be in the range of 0.4-0.63%. Screening for HCV is recommended in patients with elevated ALT levels or significant risk factors for HCV transmission only. However, 15-30% of patients report no risk factors and ALT levels can be normal in up to 20-30% of patients with chronic HCV infection. The aim of this study was to assess the HCV seroprevalence in patients visiting two tertiary care emergency departments in Berlin and Frankfurt, respectively. METHODS: Between May 2008 and March 2010, a total of 28,809 consecutive patients were screened for the presence of anti-HCV antibodies. Anti-HCV positive sera were subsequently tested for HCV-RNA. RESULTS: The overall HCV seroprevalence was 2.6% (95% CI: 2.4-2.8; 2.4% in Berlin and 3.5% in Frankfurt). HCV-RNA was detectable in 68% of anti-HCV positive cases. Thus, the prevalence of chronic HCV infection in the overall study population was 1.6% (95% CI 1.5-1.8). The most commonly reported risk factor was former/current injection drug use (IDU; 31.2%) and those with IDU as the main risk factor were significantly younger than patients without IDU (p<0.001) and the male-to-female ratio was 72% (121 vs. 46 patients; p<0.001). Finally, 18.8% of contacted HCV-RNA positive patients had not been diagnosed previously. CONCLUSIONS: The HCV seroprevalence was more than four times higher compared to current estimates and almost one fifth of contacted HCV-RNA positive patients had not been diagnosed previously.

10 Clinical Trial Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir. 2011

Susser, Simone / Vermehren, Johannes / Forestier, Nicole / Welker, Martin Walter / Grigorian, Natalia / Füller, Caterina / Perner, Dany / Zeuzem, Stefan / Sarrazin, Christoph. ·Klinikum der Goethe Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ·J Clin Virol · Pubmed #21924672.

ABSTRACT: BACKGROUND: Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance. OBJECTIVES: Potential persistence of resistance mutations during long-term follow-up should be analyzed. STUDY DESIGN: Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment. RESULTS: After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients. For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4-9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1-10%) while in one patient additionally a combined variant (T54S+R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up. CONCLUSIONS: In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.

11 Article Resistance-associated substitutions in patients with chronic hepatitis C virus genotype 4 infection. 2020

Dietz, Julia / Kalinina, Olga V / Vermehren, Johannes / Peiffer, Kai-Henrik / Matschenz, Katrin / Buggisch, Peter / Niederau, Claus / Schattenberg, Jörn M / Müllhaupt, Beat / Yerly, Sabine / Ringelhan, Marc / Schmid, Roland M / Antoni, Christoph / Müller, Tobias / Schulze Zur Wiesch, Julian / Piecha, Felix / Moradpour, Darius / Deterding, Katja / Wedemeyer, Heiner / Moreno, Christophe / Berg, Thomas / Berg, Christoph P / Zeuzem, Stefan / Welsch, Christoph / Sarrazin, Christoph / Anonymous2711198. ·Department of Internal Medicine 1, University Hospital, Goethe University, Frankfurt, Germany. · German Center for Infection Research (DZIF). · Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI),Saarbrücken, Germany and Medical Faculty, Saarland University, Homburg, Germany. · Institute for Interdisciplinary Medicine IFI, Hamburg, Germany. · St. Josef-Hospital, Katholisches Klinikum, Oberhausen, Germany. · Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. · Swiss Hepato-Pancreato-Biliary Center, Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland. · Laboratory of Virology, University Hospital Geneva, University of Geneva, Geneva, Switzerland. · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Medicine II, Heidelberg University Hospital at Mannheim, Mannheim, Germany. · Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. · Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Division of Gastroenterology and Hepatology, University Hospital Lausanne, Lausanne, Switzerland. · Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany. · Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany. · Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. · Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany. · Department of Internal Medicine I, University of Tübingen, Tübingen, Germany. · Medizinische Klinik II, St. Josefs-Hospital, Wiesbaden, Germany. ·J Viral Hepat · Pubmed #32396998.

ABSTRACT: Data on the prevalence of resistance-associated substitutions (RASs) and their implications for treatment with direct acting antivirals (DAAs) is sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4-infected patients were collected in the European Resistance Database andinvestigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively.After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA-naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs versus no or one RAS, respectively, P<0.0001).RASsL28V, L30R and M31L pre-existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain1a of NS5A, close to membrane-interaction and protein-protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n=2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%).In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance-tailored retreatment using first and second generation DAAs was highly effective with SVR rates ≥ 90% acrossall subtypes and first-line treatment regimens.

12 Article Diminished hepatic IFN response following HCV clearance triggers HBV reactivation in coinfection. 2020

Cheng, Xiaoming / Uchida, Takuro / Xia, Yuchen / Umarova, Regina / Liu, Chun-Jen / Chen, Pei-Jer / Gaggar, Anuj / Suri, Vithika / Mücke, Marcus Maximilian / Vermehren, Johannes / Zeuzem, Stefan / Teraoka, Yuji / Osawa, Mitsutaka / Aikata, Hiroshi / Tsuji, Keiji / Mori, Nami / Hige, Shuhei / Karino, Yoshiyasu / Imamura, Michio / Chayama, Kazuaki / Liang, T Jake. ·Liver Diseases Branch, National Institute of Diabetes and Digestive and Kid, National Institutes of Health, Bethesda, United States of America. · Department of Gastroenterology and Metabolism, Graduate School of Biomedica, Hiroshima University, Hiroshima, Japan. · Graduate Institute of Clinical Medicine, Hepatitis Research Center and Depa, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. · Liver Diseases, Gilead Sciences, Inc., Foster City, United States of America. · Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany. · Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. · Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan. · Department of Hepatology, Sapporo Kosei General Hospital, Hokkaido, Japan. ·J Clin Invest · Pubmed #32163375.

ABSTRACT: In patients with HBV and HCV coinfection, HBV reactivation leading to severe hepatitis has been reported with the use of direct-acting antivirals (DAAs) to treat HCV infection. Here we study the molecular mechanisms behind this viral interaction. In coinfected cell culture and humanized mice, HBV replication was suppressed by HCV coinfection. In vitro, HBV suppression was attenuated when interferon signaling was blocked. In vivo, HBV viremia, after initial suppression by HCV super-infection, rebounded following HCV clearance by DAA treatment that was accompanied by a reduced hepatic interferon response. Using blood samples of coinfected patients, interferon-stimulated gene products including C-X-C motif chemokine 10 (CXCL10) and C-C motif chemokine ligand 5 (CCL5), and alanine aminotransferase (ALT) were identified to have predictive value for HBV reactivation after HCV clearance. Taken together, our data suggest that HBV reactivation is a result of diminished hepatic interferon response following HCV clearance and identifies serologic markers that can predict HBV reactivation in DAA-treated HBV-HCV coinfected persons.

13 Article Utility of the new cobas HCV test for viral load monitoring during direct-acting antiviral therapy. 2019

Mücke, Marcus M / Maasoumy, Benjamin / Dietz, Julia / Mücke, Victoria T / Simon, Christian O / Canchola, Jesse A / Cornberg, Marcus / Marins, Ed G / Manns, Michael P / Zeuzem, Stefan / Wedemeyer, Heiner / Sarrazin, Christoph / Vermehren, Johannes. ·Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · Roche Molecular Systems, Pleasanton, CA, United States of America. · Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany. · Department of Gastroenterology, St. Josefs-Hospital, Wiesbaden, Germany. ·PLoS One · Pubmed #31738773.

ABSTRACT: BACKGROUND: The COBAS AmpliPrep/COBAS TaqMan assay HCV (CAP/CTM) is widely used in clinical routine for HCV testing. Recently, the new cobas HCV test was established for high throughput testing with minimal operator intervention. As different assays may yield different quantitative/qualitative results that possibly impact treatment decisions, the aim of this study was to externally evaluate the cobas HCV test performance in comparison to CAP/CTM in a clinically relevant setting. METHODS: Serum samples were obtained from 270 patients who received direct acting antiviral therapy with different treatment regimens at two study sites (Hannover and Frankfurt) in 2016. Overall, 1545 samples (baseline, on-treatment and follow-up) were tested in parallel by both assays. RESULTS: The mean difference between cobas HCV and CAP/CTM for the quantification of HCV RNA was 0.008 log10 IU/ml HCV RNA (95% limits of agreement: -0.02-0.036) showing excellent agreement of both assays. With respect to clinical cut offs (HCV RNA detectable vs. target not detected and HCV RNA above the lower limit of quantification (LLOQ) vs. The performance of the new cobas HCV test was comparable to CAP/CTM in a clinical setting representing a large patient population with HCV GT 1 and 3 treated with DAAs.

14 Article Efficacy of Direct-acting Antivirals for Chronic Hepatitis C Virus Infection in People Who Inject Drugs or Receive Opioid Substitution Therapy: A Systematic Review and Meta-analysis. 2019

Graf, Christiana / Mücke, Marcus M / Dultz, Georg / Peiffer, Kai-Henrik / Kubesch, Alica / Ingiliz, Patrick / Zeuzem, Stefan / Herrmann, Eva / Vermehren, Johannes. ·Department of Internal Medicine, University Hospital Frankfurt, Frankfurt am Main, Germany. · Center for Infectiology, Berlin, Germany. · Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, Frankfurt am Main, Germany. ·Clin Infect Dis · Pubmed #31513710.

ABSTRACT: BACKGROUND: Treatment uptake for hepatitis C virus (HCV) infection in people who inject drugs (PWID) and patients on opioid substitution therapy (OST) is still low despite treatment guidelines that advocate the use of direct-acting antivirals (DAAs) in all patients. Our aim in this review was to investigate treatment outcomes among PWID and patients on OST in comparison to control cohorts. METHODS: A search of Embase, Medline, PubMed, and Web of Science (from October 2010 to March 2018) was conducted to assess sustained virologic response (SVR), discontinuation rates, adherence, and HCV reinfection in PWID and patients on OST. RESULTS: We identified 11 primary articles and 12 conference abstracts comprising 1702 patients on OST, 538 PWID, and 19 723 patients who served as controls. Among patients on OST, the pooled SVR was 90% (95% confidence interval [CI], 87% to 93%) and pooled treatment discontinuation rate was 7% (95% CI, 4% to 11%). Similarly, the pooled SVR was 88% (95% CI, 80% to 93%) in PWID and the pooled treatment discontinuation rate was 9% (95% CI, 5% to 15%). There was no significant difference regarding pooled rates of SVR, adherence, and discontinuation between patients on OST and controls as well as between PWID and controls. HCV reinfection rates among patients on OST ranged from 0.0 to 12.5 per 100 person-years. CONCLUSIONS: HCV treatment outcomes in PWID and patients on OST are similar to those in patients without a history of injecting drugs, supporting current guideline recommendations to treat HCV in these patient populations.

15 Article Serum sphingolipids predict de novo hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virologic response. 2019

Mücke, Victoria T / Thomas, Dominique / Mücke, Marcus M / Waidmann, Oliver / Zeuzem, Stefan / Sarrazin, Christoph / Pfeilschifter, Josef / Vermehren, Johannes / Finkelmeier, Fabian / Grammatikos, Georgios. ·Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. · Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Frankfurt am Main, Germany. · St. Josefs-Hospital, Wiesbaden, Germany. · Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany. · St. Luke's Hospital Thessaloniki, Panorama, Greece. ·Liver Int · Pubmed #31207039.

ABSTRACT: BACKGROUND & AIMS: Curing hepatitis C virus (HCV) infection reduces the risk of hepatocellular carcinoma (HCC) development, yet HCC occurs despite sustained virologic response (SVR) in 2%-8% of cirrhotic patients. Sphingolipids (SLs) have been identified as new biomarkers of chronic liver disease and HCC. The aim of this study was to evaluate serum SLs as diagnostic HCC biomarkers in patients with HCV-associated cirrhosis at SVR12. METHODS: From 2014 to 2016, 166 patients with HCV-cirrhosis and SVR were recruited and SL profiles were measured at baseline and 12 weeks after completion of direct-acting antiviral (DAA) therapy. All patients received HCC surveillance in line with current guideline recommendations. Minimum follow-up period comprised 6 months. RESULTS: Our study included 130 (78%) patients without history of HCC, 25 (15%) with history of HCC prior DAA therapy and 11 (7%) patients with de novo HCC after FU12. In those with upcoming de novo HCC serum C24DHC (P = 0.006), C24:1DHC (P = 0.048) and C16Cer (P = 0.011) were significantly upregulated at FU12, but not AFP (P = 0.138). Contemporaneous ultrasound did not visualize HCC, at this time. C16Cer stayed sole independent predictor with high diagnostic accuracy of AFP-positive (AUC = 0.741) and -negative (AUC = 0.766) HCC development. Serum SL parameters decreased from baseline to SVR12. CONCLUSIONS: C24DHC, C24:1DHC and especially C16Cer were superior to AFP in early detection of AFP-positive and -negative de novo HCC development. We observed significant SL profile changes upon SVR. SLs may play a role in non-invasive HCC surveillance and hepatocarcinogenesis.

16 Article Performance of Three Common Hepatitis C Virus (HCV) Genotyping Assays for Identification of HCV Genotype 2/1 Chimeras. 2019

Peiffer, Kai-Henrik / Kuhnhenn, Lisa / Stelzl, Evelyn / Dietz, Julia / Susser, Simone / Tal, Andrea Oliver / Finkelmeier, Fabian / Zuckerman, Eli / Cornberg, Marcus / Barak, Mira / Piazzolla, Valeria / Mangia, Alessandra / Zeuzem, Stefan / Kessler, Harald H / Vermehren, Johannes / Sarrazin, Christoph. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany kai-henrik.peiffer@kgu.de. · Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. · Research Unit Molecular Diagnostics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria. · Liver Unit, Carmel Medical Center and Rappaport Faculty of Medicine, The Technion, Haifa, Israel. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · Haifa and Western Galilee Laboratory, Clalit Health Services, Nesher, Israel. · Liver Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. · Medizinische Klinik 2, St. Josefs Hospital, Wiesbaden, Germany. ·J Clin Microbiol · Pubmed #31043467.

ABSTRACT: Besides seven major hepatitis C virus (HCV) genotypes (GT), a number of intergenotypic recombinant strains have been described. These so-called chimeras combine genetic characteristics of different HCV genotypes. However, correct genotype classification is important, as choice and duration of direct-acting antiviral (DAA) treatment is mainly based on the viral genotype. Therefore, misclassification of chimeras might lead to suboptimal treatment of patients infected with these strains. For example, 2k/1b chimeras are typically described as HCV genotype 2 strains by commercially available hybridization assays, but real-time PCR-based tests recognizing another HCV region might be more suitable for correct chimera detection. In this study, the analytic capacity of the hybridization-assay Versant HCV Genotype 2.0 (LiPA 2.0) and the real-time PCR-based-assays cobas HCV GT and Abbott RealTime HCV Genotype II were tested in a selected cohort of 230 patients infected with HCV genotype 1 (

17 Article Efficacy and safety of direct-acting antivirals for hepatitis C in the elderly: A systematic review and meta-analysis. 2019

Mücke, Marcus M / Herrmann, Eva / Mücke, Victoria T / Graf, Christiana / Zeuzem, Stefan / Vermehren, Johannes. ·Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany. · Institute of Biostatistics and Mathematical Modeling, Goethe University, Frankfurt am Main, Germany. ·Liver Int · Pubmed #31033122.

ABSTRACT: BACKGROUND&AIMS: Since the introduction of direct-acting antivirals (DAAs) several studies have reported high efficacy and safety in Hepatitis C infected patients, even in those earlier considered difficult-to-treat. We aimed to assess the efficacy and safety of DAA therapy in elderly patients. METHODS: The PubMed MEDLINE, Embase and Cochrane databases were searched through July 2018. Two independent researchers extracted data and assessed the quality and risk of bias. Risk ratios (RRs) were pooled using random effects models. The primary outcome was efficacy of DAA therapy assessed by the RR for non-sustained virologic response (SVR) among patients aged <65 vs ≥65 years. RESULTS: Overall, we identified 63 studies including 34 082 patients treated with different DAAs. Risk for non-SVR was comparable in patients <65 and ≥65 years of age (RR 1.00, 95% CI 0.86-1.15; P = 0.979) and even lower in a subgroup analysis of cirrhotic patients ≥65 years of age (RR 0.59, 95% CI 0.35-0.99, P = 0.044). Risk for non-SVR was similar between age groups in all other subgroup analyses. Elderly patients had a significantly increased risk of adverse events (AEs) (RR 1.30, 95% CI 1.11-1.52, P = 0.001), but not for serious adverse events (P = 0.43) or treatment discontinuation (P = 0.15). Risk for anaemia if treated with additional ribavirin was 2.84 (95% CI 1.73-4.66, P < 0.001) in elderly patients compared to patients <65 years. CONCLUSION: Our results show that DAAs are highly effective and safe in elderly patients. Ribavirin should be avoided in the elderly as more AEs and particularly anaemia is observed. Further cost-effectiveness analyses are needed to evaluate the socio-economic benefit of treating elderly people without advanced liver disease.

18 Article Absence of HBV Reactivation in Patients With Resolved HBV Infection Following DAA Therapy for Hepatitis C: A 1-Year Follow-up Study. 2019

Mücke, Marcus M / Mücke, Victoria T / Peiffer, Kai-Henrik / Sarrazin, Christoph / Zeuzem, Stefan / Berger, Annemarie / Vermehren, Johannes. ·Department of Internal Medicine, University Hospital Frankfurt, Frankfurt am Main, Germany. · Department of Internal Medicine, St. Josephs-Hospital, Wiesbaden, Germany. · Institute of Clinical Virology, University Hospital Frankfurt, Frankfurt am Main, Germany. ·Open Forum Infect Dis · Pubmed #30648130.

ABSTRACT: Background: Patients with chronic hepatitis C virus (HCV) infection and active or previous hepatitis B virus (HBV) are at risk of HBV reactivation (HBV-R) during direct-acting antiviral (DAA) therapy. Recent reports suggest that HBV-R may even occur several months after completion of DAA therapy. The aim of this study was to assess the risk of HBV-R in patients with resolved HBV after successful DAA therapy during long-term follow-up (FU). Methods: Among 848 patients treated for chronic HCV, all patients with resolved HBV and long-term FU data were eligible for inclusion. Patients were HBV DNA/hepatitis B surface antigen (HBsAg)-negative at the end of therapy (EOT) and were followed for up to 52 weeks thereafter. Patients underwent regular alanine transaminase (ALT) testing, and additional HBV DNA/HBsAg testing was performed at FU week 12, end of FU, and in case of an ALT increase above the upper limit of normal (>ULN). Results: A total of 108 patients were followed up for a mean (range) of 41.5 (24-52) weeks after EOT. None of the patients experienced reverse HBsAg seroconversion or reappearance of HBV DNA. One patient received a liver transplantation; 1 patient was diagnosed with de novo hepatocellular carcinoma, and 2 patients died. Eighteen patients (16.7%) had increased ALT levels (grade 0/1). Of those, the majority were male (72.2%) and significantly more patients had cirrhosis (66.7% vs 36.2%, Conclusions: Our results indicate that the risk of HBV-R in patients with resolved HBV treated with DAAs for HCV is low during long-term follow-up.

19 Article HCV core antigen as an alternative to HCV RNA testing in the era of direct-acting antivirals: retrospective screening and diagnostic cohort studies. 2018

van Tilborg, Marjolein / Al Marzooqi, Saeed H / Wong, William W L / Maan, Raoel / Vermehren, Johannes / Maasoumy, Benjamin / Mazzulli, Tony / Bolotin, Shelly / Garber, Gary / Guerra, Fiona / Flud, Christopher R / Kowgier, Matthew / Janssen, Harry L / de Knegt, Robert J / Pawlotsky, Jean-Michel / Cloherty, Gavin A / Duarte-Rojo, Andres / Sarrazin, Christoph / Wedemeyer, Heiner / Feld, Jordan J. ·Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada; Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. · Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada. · School of Pharmacy, University of Waterloo, Waterloo, ON, Canada. · Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · Public Health of Ontario, Mount Sinai Hospital, University Health Network, University of Toronto, Toronto, ON, Canada. · Public Health of Ontario, Mount Sinai Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, ON, Canada. · Infection Protection and Control, Public Health Ontario Department of Medicine University of Ottawa and University of Toronto, Toronto, ON, Canada. · Department of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. · Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. · National Reference Center for Viral Hepatitis B C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est and INSERM U955, Créteil, France. · Abbott Laboratories, Abbott Park, IL, USA. · Department of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt, Germany; Gastroenterology and Hepatology, St Josefs-Hospital, Wiesbaden, Germany. · Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany; Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada. Electronic address: Jordan.Feld@uhn.ca. ·Lancet Gastroenterol Hepatol · Pubmed #30274834.

ABSTRACT: BACKGROUND: Direct-acting antivirals for chronic hepatitis C (HCV) infection have reduced the need for on-treatment HCV RNA monitoring. We assessed the accuracy and cost implications of using HCV core antigen testing to replace HCV RNA testing for confirmation of diagnosis, on-treatment monitoring, and determination of sustained virological response (SVR). METHODS: In a retrospective screening cohort study, de-identified residual serum from unselected samples were obtained from commercial laboratories in Ontario, Canada. Samples from each 5-year age-sex band from birth years 1945-74 collected from Aug 1, 2014, to Feb 28, 2015, were included. All samples that tested positive for HCV antibodies, and 10% of samples that tested negative for HCV antibodies, were tested for HCV core antigen and HCV RNA. A retrospective clinical cohort study was also done using blood samples from patients with confirmed HCV infection collected at four tertiary academic centres: one in Canada, two in Germany, and one in the USA. For assessment of SVR, we included samples from patients who started direct-acting antiviral-based treatment (excluding telaprevir and boceprevir) with or without peginterferon, ribavirin, or both, from Jan 1, 2014, to March 31, 2015. To ensure inclusion of adequate numbers for analysis, patients who relapsed after any treatment regimen were included. Serum samples included in the study were from baseline, week 4 on-treatment (only for patients treated with direct-acting antivirals), end of treatment, and week 12 or 24 of follow-up. The sensitivity and specificity of core antigen testing as a diagnostic tool was assessed in the screening cohort, using HCV RNA as a reference. The sensitivity and specificity of core antigen testing as well as its concordance with HCV RNA testing in the clinical cohort was assessed at baseline, week 4 on-treatment, and at weeks 12 or 24 after the end of treatment in patients undergoing therapy with direct-acting antivirals. The cost-effectiveness of core antigen testing with and without confirmatory HCV RNA testing for negative samples was also assessed. FINDINGS: From 10 006 samples in the screening cohort, 75 of 80 viraemic (HCV RNA-positive) samples tested positive for HCV core antigen (sensitivity 94%, 95% CI 86-98), and none of the 993 HCV RNA-negative samples tested positive for HCV core antigen (specificity 100%, 95% CI 94-100). The five viraemic samples that tested negative for HCV core antigen had low corresponding HCV RNA concentrations. In the clinical cohort, two (1%) of 202 baseline samples tested negative for HCV core antigen; one had a low HCV RNA concentration (468 IU/mL), the other had a high HCV RNA concentration (>2 000 000 IU/mL). By week 4 of treatment, HCV core antigen concentrations decreased in all patients but were not predictive of SVR. Although there was good concordance between HCV RNA and HCV core antigen results at 12 weeks after the end of treatment (r=0·97; p<0·0001), three of the 148 patients who achieved SVR at 12 weeks tested HCV core antigen positive. 12 weeks after the end of treatment, HCV core antigen was undetectable in one (1%) of 71 samples from patients who were identified as having relapsed according to HCV RNA detection. On-treatment and end-of-treatment testing of core antigen or HCV RNA provided little clinical value. The use of HCV core antigen testing as a confirmatory diagnostic strategy was cost saving relative to HCV RNA testing, with a reduction of CAD$0·29-3·70 per patient screened depending on whether HCV RNA testing was used to confirm HCV core antigen-negative results. INTERPRETATION: These data support the use of HCV core antigen testing to document HCV viraemia in a cost-saving diagnostic algorithm. In a treatment setting, HCV core antigen testing can be used instead of HCV RNA testing for diagnosis and documentation of treatment adherence, but it might not be adequate to determine SVR. This approach might improve access to care, particularly in low-income and middle-income countries. FUNDING: Abbott Diagnostics and Toronto Centre for Liver Disease.

20 Article Clinical significance of detectable and quantifiable HCV RNA at the end of treatment with ledipasvir/sofosbuvir in GT1 patients. 2018

Maasoumy, Benjamin / Buggisch, Peter / Mauss, Stefan / Boeker, Klaus H W / Müller, Tobias / Günther, Rainer / Zimmermann, Tim / Manns, Michael P / Sarrazin, Christoph / Hüppe, Dietrich / Wedemeyer, Heiner / Vermehren, Johannes. ·Hannover Medical School, Hannover, Germany. · IFI-Institute for Interdisciplinary Medicine, Hamburg, Germany. · Center for HIV and Hepatogastroenterology, Duesseldorf, Germany. · Leberpraxis Hannover, Hannover, Germany. · Charité Campus Virchow-Klinikum (CVK), Berlin, Germany. · Universitätsklinikum Schleswig-Holstein, Kiel, Germany. · University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. · St. Josef-Hospital, Wiesbaden, Germany. · University Hospital Frankfurt, Frankfurt am Main, Germany. · Hepatologische Schwerpunktpraxis Herne, Herne, Germany. · Leberstiftungs-GmbH Deutschland, Hannover, Germany. · Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg Essen, Essen, Germany. ·Liver Int · Pubmed #30022590.

ABSTRACT: BACKGROUND & AIMS: AASLD/IDSA treatment guidelines for hepatitis C virus (HCV) infection state that testing for quantitative HCV RNA can be considered at the end of antiviral treatment (EOT) with interferon-free regimens. However, it remains unclear how to respond to a detectable or even quantifiable HCV RNA result. The aim of this study was to analyse the frequency and predictive value of detectable and quantifiable HCV RNA results at the EOT in patients with HCV genotype 1 infection treated with ledipasvir (LDV) and sofosbuvir (SOF) ± ribavirin (RBV) in a large real-world cohort. METHODS: A retrospective analysis of the DHC-R (Deutsches Hepatitis C-Register, German Hepatitis C-Registry) cohort was performed including all patients who were treated with LDV/SOF ± RBV and in whom HCV RNA testing was done with either the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) or the Abbott RealTime HCV assay (ART). RESULTS: The frequency of detectable HCV RNA at the EOT was 7% in this real-world study involving 471 patients. Furthermore, 3% of the patients (n = 14/471) even had quantifiable viral load at the EOT. Detectable and quantifiable results were more frequent if the ART was used for testing. However, SVR was achieved by 32/33 patients (97%) with detectable and even by all 14 patients (100%) with quantifiable HCV RNA results at the EOT. CONCLUSION: Detectable and even quantifiable HCV RNA results are quite frequent if highly sensitive HCV RNA assays are used. However, treatment prolongation is not indicated, as SVR rates remain high in these patients.

21 Article Risk of de novo Hepatocellular Carcinoma after HCV Treatment with Direct-Acting Antivirals. 2018

Finkelmeier, Fabian / Dultz, Georg / Peiffer, Kai-Henrik / Kronenberger, Bernd / Krauss, Franziska / Zeuzem, Stefan / Sarrazin, Christoph / Vermehren, Johannes / Waidmann, Oliver. ·Schwerpunkt Gastroenterologie und Hepatologie, Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. · Gastroenterologie, Hepatologie, Allgemeine Innere Medizin, Herz-Jesu-Krankenhaus Fulda, Fulda, Germany. · Schwerpunkt Gastroenterologie und Hepatologie, Medizinische Klinik 2, St. Josefs-Hospital Wiesbaden, Wiesbaden, Germany. ·Liver Cancer · Pubmed #29888208.

ABSTRACT: Background and Aims: The aim of the study was to evaluate the risk of hepatocellular carcinoma (HCC) development after treatment with direct-acting antivirals (DAAs) and to compare HCC occurrence in these patients with that among patients treated with interferon (IFN)-based therapies. Methods: We analyzed a large cohort with chronic hepatitis C virus patients for the onset of new HCC after DAA treatment. A historical IFN-treated cohort was investigated for comparison. Results: A total of 819 patients were included in the DAA group. The median follow-up period was 263 days (0-1,001). Twenty-five patients (3.6 HCCs/100 person-years; 3.1%) were diagnosed with de novo HCC within the time of observation. No patient without cirrhosis had developed HCC. Patients with newly diagnosed HCC were mostly male, older, and treatment-experienced and had a lower 12-week sustained virologic response (SVR12) rate and higher levels of liver inflammation markers. The median time to HCC was 312 days (0-880). Investigation of the subcohort of 269 cirrhotic patients yielded an HCC rate of 8.9 HCCs/100 person-years. In this cohort, non-SVR12 was an independent risk factor for de novo HCC (HR 4.48; 95% CI 1.51-13.12; Conclusion: The de novo HCC rates did not differ between the DAA-treated patients and those who received IFN. Achievement of SVR is of utmost importance for HCC prevention.

22 Article Interferon-free treatment choice according to baseline RASs leads to high SVR rates in HCV genotype 1 infected patients. 2018

Peiffer, Kai-Henrik / Vermehren, Johannes / Kuhnhenn, Lisa / Susser, Simone / Dietz, Julia / Finkelmeier, Fabian / Weiler, Nina / Welzel, Tania / Grammatikos, Georgios / Zeuzem, Stefan / Sarrazin, Christoph. ·University Hospital Frankfurt, Department of Gastroenterology and Hepatology, 60590 Frankfurt, Germany. Electronic address: kai-henrik.peiffer@kgu.de. · University Hospital Frankfurt, Department of Gastroenterology and Hepatology, 60590 Frankfurt, Germany. · University Hospital Frankfurt, Department of Gastroenterology and Hepatology, 60590 Frankfurt, Germany; St. Josefs Hospital, Department of Gastroenterology, 65189 Wiesbaden, Germany. ·J Infect Chemother · Pubmed #29628383.

ABSTRACT: AIM: Different combinations of direct antiviral agents (DAA) lead to high SVR rates in HCV genotype 1 infected patients. However, presence of baseline resistance-associated substitutions (RASs) represents a major risk factor for treatment failure. It is unknown whether choice of treatment based on RASs has the potential to decrease virologic failure rates. METHODS: Population-based sequencing of NS3 and NS5A genes was performed in HCV genotype 1 infected patients at a German university hospital. Treatment was individually selected based on resistance analyses. RESULTS: In total, 319 patients (50% treatment-experienced and 30% with cirrhosis) were included. With the treatment choice based on the baseline NS3 and NS5A resistance profile SVR rates between 96 and 100% were observed in all subgroups, including treatment-experienced patients with cirrhosis and HCV genotype 1a infected cirrhotic patients. CONCLUSIONS: The choice of treatment based on the RASs status at baseline may be beneficial for optimizing treatment efficacy in patients with HCV genotype 1 infection and risk factors for treatment failure.

23 Article Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients. 2018

Peiffer, Kai-Henrik / Kuhnhenn, Lisa / Jiang, Bingfu / Mondorf, Antonia / Vermehren, Johannes / Knop, Viola / Susser, Simone / Walter, Dirk / Dietz, Julia / Carra, Gert / Finkelmeier, Fabian / Zeuzem, Stefan / Sarrazin, Christoph / Hildt, Eberhard. ·University Hospital Frankfurt, Department of Gastroenterology and Hepatology, Langen, Germany. · Paul Ehrlich Institute, Division of Virology, Langen, Germany. · St. Josefs Hospital, Department of Gastroenterology, Wiesbaden, Germany. · German Center for Infection Research, Germany. ·J Infect Dis · Pubmed #29528436.

ABSTRACT: Background: Hepatitis B virus (HBV) surface proteins (HBsAg) coat the viral particle and form subviral particles (SVPs). Loss of HBsAg represents a functional cure and is an important treatment goal. Methods: We analyzed the impact of the HBV genotypes A-E and pre-S mutations on SVP expression in hepatitis B virus e antigen (HBeAg)-negative chronic HBV-infected patients. A HBV genome harboring a preS1-deletion was analyzed in hepatoma cells. Results: We observed a genotype-specific ratio of the 3 surface proteins (SHBs/MHBs/LHBs), reflecting differences in the morphology and composition of SVPs. Deletions/mutations in the preS1/preS2 domain, detected in released viral genomes, did not affect the molecular weight of MHBs and LHBs in these patients. In contrast, LHB molecular weight was altered in vitro using an HBV genome harboring a preS1-deletion derived from one of these patients. Conclusion: Differences in composition of SVPs may result in genotype-specific immunogenicity and pathogenesis. In the patients with preS-mutations, secreted HBsAg and released viral genomes cannot be derived from the same genetic source. As viral genomes are derived from covalently closed circular DNA (cccDNA), HBsAg is presumably derived from integrated DNA. This important HBsAg source should be considered for novel antiviral strategies in HBeAg-negative chronic HBV-infected patients.

24 Article Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals. 2018

Dietz, Julia / Susser, Simone / Vermehren, Johannes / Peiffer, Kai-Henrik / Grammatikos, Georgios / Berger, Annemarie / Ferenci, Peter / Buti, Maria / Müllhaupt, Beat / Hunyady, Bela / Hinrichsen, Holger / Mauss, Stefan / Petersen, Jörg / Buggisch, Peter / Felten, Gisela / Hüppe, Dietrich / Knecht, Gaby / Lutz, Thomas / Schott, Eckart / Berg, Christoph / Spengler, Ulrich / von Hahn, Thomas / Berg, Thomas / Zeuzem, Stefan / Sarrazin, Christoph / Anonymous1610927. ·Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany, German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany. · Institute for Medical Virology, University Hospital Frankfurt, Frankfurt, Germany. · Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Hospital Universitario Valle Hebron and Ciberehd del Instituto Carlos III, Barcelona, Spain. · Swiss Hepato-Pancreato-Biliary Center and Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland. · Somogy County Kaposi Mór Teaching Hospital, Kaposvár, Hungary. · Practice of Gastroenterology, Kiel, Germany. · Practice of Gastroenterology, Düsseldorf, Germany. · Institute for Interdisciplinary Medicine IFI, Hamburg, Germany. · Practice of Hepatology, Herne, Germany. · Infektiologikum, Frankfurt, Germany. · Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. · Department of Internal Medicine I, University of Tübingen, Tübingen, Germany. · Department of Internal Medicine I, University of Bonn, Bonn, Germany. · Department of Gastroenterology, Hepatology and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Germany. · Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany. · Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt, Germany, German Center for Infection Research (DZIF), External Partner Site Frankfurt, Germany; Medizinische Klinik II, St. Josefs-Hospital, Wiesbaden, Germany. Electronic address: sarrazin@em.uni-frankfurt.de. ·Gastroenterology · Pubmed #29146520.

ABSTRACT: BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

25 Article Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C. 2018

Buggisch, Peter / Vermehren, Johannes / Mauss, Stefan / Günther, Rainer / Schott, Eckart / Pathil, Anita / Boeker, Klaus / Zimmermann, Tim / Teuber, Gerlinde / Vornkahl, Heike-Pfeiffer / Simon, Karl-Georg / Niederau, Claus / Wedemeyer, Heiner / Zeuzem, Stefan. ·ifi-institute for Interdisciplinary Medicine, Hamburg, Germany. Electronic address: buggisch@ifi-medizin.de. · University Hospital Frankfurt, Frankfurt am Main, Germany. · Center for HIV and Hepatogastroenterology, Duesseldorf, Germany. · Universitätsklinikum Schleswig-Holstein (UKSH), Campus Kiel, Kiel, Germany. · Charité Campus Virchow-Klinikum (CVK), Berlin, Germany. · University Hospital Heidelberg, Heidelberg, Germany. · Hepatologische Praxis, Hannover, Germany. · University Hospital Mainz, Mainz, Germany. · Hepatologische Praxis, Frankfurt, Germany. · e.factum GmbH, Butzbach, Germany. · Hepatologische Praxis, Leverkusen, Germany. · St. Josef-Hospital, Katholisches Klinikum Oberhausen, Oberhausen, Germany. · Hannover Medical School, Hannover, Germany. · University Hospital Frankfurt, Frankfurt am Main, Germany. Electronic address: Zeuzem@em.uni-frankfurt.de. ·J Hepatol · Pubmed #29133244.

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

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