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Hepatitis: HELP
Articles by Johannes Vermehren
Based on 45 articles published since 2008
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Between 2008 and 2019, J. Vermehren wrote the following 45 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2
1 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.

2 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.

3 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 --

4 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.

5 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 --

6 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.

7 Review New HCV therapies on the horizon. 2011

Vermehren, J / Sarrazin, C. ·Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität, Frankfurt am Main, Germany. ·Clin Microbiol Infect · Pubmed #21087349.

ABSTRACT: Improved understanding of the hepatitis C virus (HCV) life cycle has led to the discovery of numerous potential targets for antiviral therapy. HCV polyprotein processing and replication have been identified as the most promising viral targets. However, viral entry and fusion, RNA translation, virus assembly and release and several host cell factors may provide alternative attractive targets for future anti-HCV therapies. Inhibitors of the HCV NS3/4A protease are currently the most advanced in clinical development. Monotherapy with protease inhibitors has shown high antiviral activity, but is associated with frequent selection of resistant HCV variants, often resulting in viral breakthrough. However, there is encouraging evidence from phase 2/3 trials indicating that the addition of a protease inhibitor (e.g. telaprevir and boceprevir) to pegylated interferon-α/ribavirin substantially improves sustained virological response rates in both treatment-naïve and treatment-experienced patients with HCV genotype 1. Nucleos(t)ide inhibitors of the HCV NS5B polymerase have shown variable antiviral activity against different HCV genotypes, but seem to have a higher genetic barrier to resistance than protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. However, the development of a substance with high antiviral activity and a high genetic barrier to resistance seems to be difficult. Among the different host cell-targeting compounds in early clinical development, cyclophilin inhibitors have shown the most promising results. Although advances have also been made in improving interferons, combinations of antiviral agents with different mechanisms of action may lead to the eventual possibility of interferon-free regimens.

8 Review Treatment predictors of a sustained virologic response in hepatitis B and C. 2008

Kau, Annika / Vermehren, Johannes / Sarrazin, Christoph. ·Zentrum der Inneren Medizin, Medizinische Klinik 1, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany. ·J Hepatol · Pubmed #18715665.

ABSTRACT: Treatment predictors are important tools for the management of therapy in patients with chronic hepatitis B and C virus (HBV, HCV) infection. In chronic hepatitis B, several pretreatment parameters have been identified for prediction of virologic response to interferon alfa-based antiviral therapies or treatment with polymerase inhibitors. In interferon alfa and pegylated interferon alfa-treated patients, low baseline HBV DNA concentrations, HBV genotype A (B), and high baseline ALT levels are significantly associated with treatment response. In patients treated with nucleos(t)ide analogues, low baseline HBV DNA but not viral genotype is positively associated with virologic response. During treatment the best predictor of response is HBV DNA kinetics. Early viral suppression is associated with favourable virologic response and reduced risk for subsequent resistance mutations. For the current standard treatment with pegylated interferon alfa and ribavirin in patients with chronic hepatitis C, infection with HCV genotypes 2 and 3, baseline viral load below 400,000-800,000 IU/ml, Asian and Caucasian ethnicity, younger age, low GGT levels, absence of advanced fibrosis/cirrhosis, and absence of steatosis in the liver have been identified as independent pretreatment predictors of a sustained virologic response. After initiation of treatment, initial viral decline with undetectable HCV-RNA at week 4 of therapy (RVR) is the best predictor of sustained virologic response independent of HCV genotype.

9 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.

10 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.

11 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.

12 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.

13 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.

14 Article High efficacy of sofosbuvir/velpatasvir and impact of baseline resistance-associated substitutions in hepatitis C genotype 3 infection. 2018

von Felden, J / Vermehren, J / Ingiliz, P / Mauss, S / Lutz, T / Simon, K G / Busch, H W / Baumgarten, A / Schewe, K / Hueppe, D / Boesecke, C / Rockstroh, J K / Daeumer, M / Luebke, N / Timm, J / Schulze Zur Wiesch, J / Sarrazin, C / Christensen, S. ·Hamburg, Germany. · New York City, NY, USA. · Frankfurt, Germany. · Berlin, Germany. · Duesseldorf, Germany. · Leverkusen, Germany. · Muenster, Germany. · Herne, Germany. · Bonn, Germany. · Kaiserslautern, Germany. · Wiesbaden, Germany. ·Aliment Pharmacol Ther · Pubmed #29536554.

ABSTRACT: BACKGROUND: Twelve weeks of the pangenotypic direct-acting antiviral (DAA) combination sofosbuvir/velpatasvir (SOF/VEL) was highly efficient in patients with hepatitis C virus (HCV) genotype 3 (GT3) infection in the ASTRAL-3 approval study. However, presence of resistance-associated substitutions (RASs) in the HCV nonstructural protein 5A (NS5A) was associated with lower treatment response. AIM: To assess the efficacy and safety of SOF/VEL ± ribavirin (RBV) and the impact of NS5A RASs and RBV use on treatment outcome in HCV GT3 infection in a real-world setting. METHODS: In this multicentre cohort study, GT3 patients from ten treatment centres across Germany were included. Sustained virological response was assessed 12 weeks after end-of-treatment (SVR12) in modified intention-to-treat (mITT) and per-protocol analysis (PP). NS5A RASs were tested by population-based sequencing. RESULTS: A total of 293 GT3 patients were included. The median age was 48 years, 70% were male, 25.3% were cirrhotic, 9.2% were HCV/HIV co-infected and 21.8% were treatment-experienced, including 4.1% with DAA experience. Baseline NS5A RASs (Y93H, A30K, L31M) were detected in 11.2%. RBV was added in 5% of noncirrhotic and 58.9% of cirrhotic patients, respectively. SVR12 rates for SOF/VEL±RBV were 95.9% (mITT) and 99.5% (PP), respectively. Only 1 virological relapse occurred in a cirrhotic patient previously treated with SOF/RBV. No treatment-related major adverse events occurred. CONCLUSION: Twelve weeks of SOL/VEL±RBV was safe and highly efficient in HCV GT3 across a diverse patient population. Baseline NS5A RASs were rarely observed and presence did not seem to impact SVR, regardless of the use of RBV.

15 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 / Anonymous5030927. ·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.

16 Article Liver transplantation for chronic hepatitis C virus infection in the United States 2002-2014: An analysis of the UNOS/OPTN registry. 2017

Dultz, Georg / Graubard, Barry I / Martin, Paul / Welker, Martin-Walter / Vermehren, Johannes / Zeuzem, Stefan / McGlynn, Katherine A / Welzel, Tania M. ·University Hospital Frankfurt, Frankfurt am Main, Germany. · Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America. · Hepatology Division, University of Miami, Miami, FL, United States of America. · HREB, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America. ·PLoS One · Pubmed #29088255.

ABSTRACT: Chronic hepatitis C virus (HCV) infection is a leading cause for orthotopic liver transplantation (OLT) in the U.S. We investigated characteristics of HCV-infected patients registered for OLT, and explored factors associated with mortality. Data were obtained from the United Network for Organ Sharing and Organ Procurement and Transplantation network (UNOS/OPTN) registry. Analyses included 41,157 HCV-mono-infected patients ≥18 years of age listed for cadaveric OLT between February 2002 and June 2014. Characteristics associated with pre- and post-transplant survival and time trends over the study period were determined by logistic and Cox proportional hazard regression analyses and Poisson regressions. Most patients were white (69.1%) and male (70.8%). At waitlist registration, mean age was 54.6 years and mean MELD was 16. HCC was recorded in 26.9% of the records. A total of 51.2% of the patients received an OLT, 21.0% died or were too sick; 15.6% were delisted and 10.4% were still waiting. Factors associated with increased waitlist mortality were older age, female gender, blood type 0, diabetes, no HCC and transplant region (p<0.001). OLT recipient characteristics associated with increased risk for post OLT mortality were female gender, age, diabetes, race (p<0,0001), and allocation MELD (p = 0.005). Donor characteristics associated with waitlist mortality included age, ethnicity (p<0.0001) and diabetes (p<0.03). Waitlist registrations and OLTs for HCC significantly increased from 14.4% to 37.3% and 27.8% to 38.5%, respectively (p<0.0001). Pre- and post-transplant survival depended on a variety of patient-, donor-, and allocation- characteristics of which most remain relevant in the DAA-era. Still, intensified HCV screening strategies and timely and effective treatment of HCV are highly relevant to reduce the burden of HCV-related OLTs in the U.S.

17 Article Hepatocellular carcinoma recurrence after direct antiviral agent treatment: A European multicentre study. 2017

Kolly, Philippe / Waidmann, Oliver / Vermehren, Johannes / Moreno, Christophe / Vögeli, Isabelle / Berg, Thomas / Semela, David / Zeuzem, Stefan / Dufour, Jean-François. ·Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland; University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland. · Department of Medicine I, Division of Gastroenterology and Hepatology, University Hospital Frankfurt, Frankfurt am Main, Germany. · Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium. · Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland. · Department of Internal Medicine, Neurology and Dermatology, Medical Clinic of Gastroenterology and Rheumatology, Section of Hepatology, University Hospital Leipzig, Leipzig, Germany. · Division of Gastroenterology and Hepatology, Cantonal Hospital St Gallen, St Gallen, Switzerland. · Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland; University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland. Electronic address: jf.dufour@insel.ch. ·J Hepatol · Pubmed #28733219.

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18 Article No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct-acting antivirals for hepatitis C in a large real-world cohort. 2017

Mücke, V T / Mücke, M M / Peiffer, K-H / Weiler, N / Welzel, T M / Sarrazin, C / Zeuzem, S / Berger, A / Vermehren, J. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. · Institut für Klinische Virologie, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. ·Aliment Pharmacol Ther · Pubmed #28627791.

ABSTRACT: BACKGROUND: Hepatitis B virus (HBV) reactivation has been observed following interferon (IFN)-based treatment in HBV/hepatitis C virus (HCV) co-infected patients. Recent reports suggest that reactivation may also occur in both hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative patients during HCV treatment with direct-acting antivirals (DAAs). AIM: To investigate the rate of patients with HBV reactivation during IFN-based and IFN-free HCV treatment in a large real-world cohort. METHODS: A total of 848 patients with chronic hepatitis C were treated with different combinations of DAAs. Among patients with available outcome and HBV data, there were 272 patients hepatitis B core antibody (HBcAb)-positive (HBsAg-positive, n=9; HBsAg-negative, n=263), and 536 were HBcAb-negative. All HBcAb-positive patients were tested for HBV DNA at the end of DAA therapy and alanine transaminase (ALT) levels were frequently measured during therapy and follow-up. RESULTS: Seventy-three percent (n=192/263) of HBsAg-negative/HBcAb-positive patients had elevated ALT levels at baseline, which declined to normal values in all but 18 patients, and no HBV reactivation was observed. Eight patients had detectable but not quantifiable HBV DNA (<20 IU/mL) at end of treatment, but none were associated with elevated ALT. Five of nine HBsAg-positive/HBcAb-positive patients experienced transient or permanent HBV reactivation, three of whom required nucleos(t)ide treatment during (n=1) or after (n=2) DAA therapy. CONCLUSIONS: HBV reactivation was not observed in HBsAg-negative/HBcAb-positive patients but common in HBsAg-positive/HBcAb-positive patients treated with different combinations of DAAs for HCV.

19 Article Comparison of on-treatment HCV RNA during direct antiviral therapy using two different COBAS TaqMan HCV assays. 2017

Vermehren, Johannes / Bourlière, Marc / Pol, Stanislas / Marcellin, Patrick / Hyland, Robert H / Jiang, Deyuan / Brainard, Diana M / Zeuzem, Stefan / Welzel, Tania M. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. Electronic address: johannes.vermehren@kgu.de. · Hépato-Gastroénterologie, Hôpital-Saint Joseph, Marseille, France. · Hépatologie, Université Paris Descartes, Inserm UMS20, Institut Pasteur, Hôpital Cochin, France. · Service d'Hepatologie, Hôpital Beaujon, Clichy, France. · Liver Disease Therapeutic Area, Gilead Sciences, Foster City, CA, USA. · Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. · Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. Electronic address: tania.welzel@kgu.de. ·J Clin Virol · Pubmed #28259054.

ABSTRACT: BACKGROUND: Repeated measurements of hepatitis C virus (HCV) RNA levels during antiviral therapy are recommended to monitor treatment efficacy and adherence. Throughout most direct antiviral agent (DAA) approval studies, HCV RNA cutoffs and endpoints were established with the COBAS TaqMan assay for use with the High Pure System (HPS/CTM). Different assays used in clinical practice may yield different quantitative results and possibly impact treatment decisions. OBJECTIVES: The concordance of the fully-automated COBAS AmpliPrep/COBAS TaqMan assay (CAP/CTM) with HPS/CTM and its ability to predict response to DAA-treatment with ledipasvir/sofosbuvir was assessed in cirrhotic patients with HCV genotype-1-infection who had failed prior treatment with protease inhibitor-based regimens. STUDY DESIGN: Serum samples from patients (n=154) treated in the phase-2 SIRIUS-study were collected at baseline and during antiviral therapy (weeks 1-8), and were tested in parallel by both assays. RESULTS: The mean difference between HPS/CTM and CAP/CTM at baseline (n=153) was 0.32 log CONCLUSIONS: CAP/CTM and HPS/CTM showed significantly different response rates during the early stages of ledipasvir/sofosbuvir treatment. However, on-treatment response was not predictive of SVR with either assay, indicating that determination of on-treatment HCV RNA levels may not be useful to guide treatment decisions.

20 Article Multicenter Comparison Study of both Analytical and Clinical Performance across Four Roche Hepatitis C Virus RNA Assays Utilizing Different Platforms. 2017

Vermehren, Johannes / Stelzl, Evelyn / Maasoumy, Benjamin / Michel-Treil, Veronique / Berkowski, Caterina / Marins, Ed G / Paxinos, Ellen E / Marino, Enrique / Wedemeyer, Heiner / Sarrazin, Christoph / Kessler, Harald H. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt, Germany. · Institut für Hygiene, Mikrobiologie und Umweltmedizin, Medizinische Universität Graz, Graz, Austria. · Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany. · Covance Central Laboratory Services, Geneva, Switzerland. · Roche Molecular Systems, Pleasanton, California, USA. · Institut für Hygiene, Mikrobiologie und Umweltmedizin, Medizinische Universität Graz, Graz, Austria harald.kessler@medunigraz.at. ·J Clin Microbiol · Pubmed #28122870.

ABSTRACT: The efficacy of antiviral treatment for chronic hepatitis C virus (HCV) infection is determined by measuring HCV RNA at specific time points throughout therapy using highly sensitive and accurate HCV RNA assays. This study compared the performances of two recently developed real-time PCR HCV RNA assays, cobas HCV for use on the cobas 6800/8800 systems (cobas 6800/8800 HCV) and cobas HCV for use on the cobas 4800 system (cobas 4800 HCV), with those of two established assays, the Cobas AmpliPrep/Cobas TaqMan HCV quantitative test, version 2 (CAP/CTM v2) and the Cobas TaqMan HCV test, version 2 for use with the High Pure system (HPS/CTM v2). The limits of detection (LODs) and linearity at lower concentrations (5 to 1000 IU/ml) were assessed for cobas 6800/8800 HCV and cobas 4800 HCV using WHO standard traceable panels representing HCV genotypes (GT) 1 to 4. Pairwise assay comparisons were also performed using 245 clinical samples representing HCV GT 1 to GT 4. Results from cobas 6800/8800 HCV and cobas 4800 HCV were linear at low HCV RNA concentrations (<0.3 log

21 Article To treat or not to treat - Successful hepatitis C virus eradication in a patient with advanced hepatocellular carcinoma and complete response to sorafenib. 2017

Waidmann, Oliver / Peveling-Oberhag, Jan / Eichler, Katrin / Schulze, Falko / Vermehren, Johannes. ·Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany. · Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany. · Dr. Senckenbergisches Institut für Pathologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany. ·Z Gastroenterol · Pubmed #27806410.

ABSTRACT:

22 Article Hepatitis C RNA assay differences in results: Potential implications for shortened therapy and determination of Sustained Virologic Response. 2016

Cloherty, Gavin / Chevaliez, Stephane / Sarrazin, Christoph / Herman, Christine / Holzmayer, Vera / Dawson, George / Maasoumy, Benjamin / Vermehren, Johannes / Wedemeyer, Heiner / Feld, Jordan J / Pawlotsky, Jean-Michel. ·Abbott Laboratories, Abbott Park, IL, USA. · National Reference Center for Viral Hepatitis B, C and delta, Hopital Henry Mondor, Université Paris-Est, Créteil, France. · Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. · Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany. · Toronto Centre for Liver Disease, Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON, Canada. ·Sci Rep · Pubmed #27762283.

ABSTRACT: Approval of Ledipasvir/Sofosbuvir for the treatment of chronic hepatitis C (HCV) includes the truncation of therapy from 12 to 8 weeks in treatment naïve, non-cirrhotic patients with baseline HCV RNA levels <6 million IU/mL (6.8 log10 IU/mL). The aim of this study was to evaluate this clinical cutoff with a different widely used commercially available HCV RNA test. Results from samples tested prospectively with Roche High Pure TaqMan HCV 2.0 test (HPS) were compared to those tested retrospectively with the Abbott RealTime HCV RNA test (ART). Using 6 million IU/mL as the cut-off, pre-treatment results were concordant in 70.4% of cases. When results with the same test measured at screening and baseline, clinical decisions could be impacted in 14.4% and 6.2% of cases for HPS and ART respectively. Using only HCV RNA cutoff of 6 million IU/mL, 29.55% of subjects would receive a different and potentially incorrect treatment duration based solely on HCV RNA test method used. A further 6-14% of subjects would have treatment decision change based on the day the sample was taken.

23 Article The efficacy and safety of direct acting antiviral treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection. 2016

Vermehren, J / Peiffer, K-H / Welsch, C / Grammatikos, G / Welker, M-W / Weiler, N / Zeuzem, S / Welzel, T M / Sarrazin, C. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. Johannes.Vermehren@kgu.de. · Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. ·Aliment Pharmacol Ther · Pubmed #27549000.

ABSTRACT: BACKGROUND: Direct antiviral therapies for chronic hepatitis C virus (HCV) infection have expanded treatment options for neglected patient populations, including elderly patients who are ineligible/intolerant to receive interferon (IFN)-based therapy. AIM: To investigate the efficacy, tolerability and potential for drug-drug interactions (DDIs) of IFN-free treatment in patients aged ≥65 years in a large real-world cohort. METHODS: A total of 541 patients were treated with different combinations of direct antiviral agents (DAAs: ledipasvir/sofosbuvir ±ribavirin; daclatasvir/sofosbuvir ±ribavirin; paritaprevir/ombitasvir ±dasabuvir ±ribavirin or simeprevir/sofosbuvir ±ribavirin in genotype 1/4, and daclatasvir/sofosbuvir ±ribavirin or sofosbuvir/ribavirin in genotype 2/3). Efficacy, safety and potential DDIs were analysed and compared between patients aged <65 years (n = 404) and patients aged ≥65 years (n = 137) of whom 41 patients were ≥75 years. RESULTS: Sustained virological response rates were 98% and 91% in patients aged ≥65 years and <65 years, respectively. Elderly patients took significantly more concomitant medications (79% vs. 51%; P < 0.0001). The number of concomitant drugs per patient was highest in patients ≥65 years with cirrhosis (median, three per patient; range, 0-10). Based on the hep-druginteractions database, the proportion of predicted clinically significant DDIs was significantly higher in elderly patients (54% vs. 28%; P < 0.0001). The number of patients who experienced treatment-associated adverse events was similar between the two age groups (63% vs. 65%; P = n.s.). CONCLUSIONS: Elderly patients are at increased risk for significant DDIs when treated with DAAs for chronic HCV infection. However, with careful pre-treatment assessment of concomitant medications, on-treatment monitoring or dose-modifications, significant DDIs and associated adverse events can be avoided.

24 Article Regression of fibrosis and portal hypertension in HCV-associated cirrhosis and sustained virologic response after interferon-free antiviral therapy. 2016

Knop, V / Hoppe, D / Welzel, T / Vermehren, J / Herrmann, E / Vermehren, A / Friedrich-Rust, M / Sarrazin, C / Zeuzem, S / Welker, M-W. ·Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. · Institut für Biostatistik und mathematische Modellierung, Goethe-Universität Frankfurt, Frankfurt am Main, Germany. ·J Viral Hepat · Pubmed #27500382.

ABSTRACT: It is still controversial, whether and to what amount cirrhosis and portal hypertension are reversible in patients with hepatitis C virus (HCV)-associated cirrhosis and sustained virologic response (SVR) after interferon-free antiviral therapy. In this study, we prospectively evaluated dynamics of liver and spleen stiffness in HCV-infected patients with advanced liver disease and SVR after interferon-free treatment. A total of 54 patients with HCV-associated cirrhosis and SVR were included. Liver and spleen stiffness was measured at therapy baseline (BL), end of treatment (EOT) and 24 weeks after EOT (FU24) by transient liver elastography (L-TE) as well as by acoustic radiation force impulse of the liver (L-ARFI) and spleen (S-ARFI), as well as biochemical, virologic and clinical data. Improvement of liver and spleen stiffness was found in 44 of 50 (88%), 31 of 54 (57%) and 25 of 54 (46%) of patients assessed by L-TE, L-ARFI and S-ARFI between baseline and FU24. Liver stiffness assessed by L-TE improved between BL [median (range), 32.5 (9.1-75) kPa] and EOT [median (range), 21.3 (6.7-73.5) kPa; (P<.0001)], and between BL and FU24 [median (range), 21.2 (5.4-70) kPa; (P<.0001)]. Liver stiffness assessed by L-ARFI improved between BL [median (range), 2.7 (1.2-4.1) m/s] and FU24 [median (range), 2.4 (1.2-3.9) m/s; P=.002), while spleen stiffness remained unchanged. Our data suggest that improvement of liver stiffness may be rather due to reduced necroinflammation and may be due to a less extent to regression of cirrhosis, as dynamics of liver stiffness improvement was more pronounced between BL and EOT than BL and FU24.

25 Article Investigation of NS3 Protease Resistance-Associated Variants and Phenotypes for the Prediction of Treatment Response to HCV Triple Therapy. 2016

Dietz, Julia / Rupp, Daniel / Susser, Simone / Vermehren, Johannes / Peiffer, Kai-Henrik / Filmann, Natalie / Bon, Dimitra / Kuntzen, Thomas / Mauss, Stefan / Grammatikos, Georgios / Perner, Dany / Berkowski, Caterina / Herrmann, Eva / Zeuzem, Stefan / Bartenschlager, Ralf / Sarrazin, Christoph. ·Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany. · Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany. · Institute of Biostatistics and Mathematical Modeling, Goethe University Frankfurt, Frankfurt am Main, Germany. · Klinik für Gastroenterologie und Hepatologie, Universitätsspital Zürich, Zürich, Switzerland. · Zentrum für HIV und Hepatogastroenterologie, Düsseldorf, Germany. · German Center for Infection Research, Heidelberg University, Heidelberg, Germany. ·PLoS One · Pubmed #27281344.

ABSTRACT: Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR.

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