Browsing by Author "Heidrich, Benjamin"
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Publication 96 weeks of pegylated-interferon- alpha-2α plus tenofovir or placebo for the treatment of hepatitis delta: The hidit-2 study(Wiley-blackwell, 2013-10-01) Wedemeyer, Heiner; Yurdaydin, Cihan; Ernst, Stefanie; Caruntu, Florin A.; Curescu, Manuela G.; Yalcin, Kendal; Akarca, Ulus S.; Zeuzem, Stefan; Erhardt, Andreas; Lueth, Stefan; Papatheodoridis, George; Keskin, Onur; Port, Kerstin; Celen, Mustafa K.; Stift, Judith; Heidrich, Benjamin; Mederacke, Ingmar; Hardtke, Svenja; Koch, Armin; Dienes, Hans P.; Manns, Michael P.; Gürel, Selim; GÜREL, SELİM; Bursa Uludağ Üniversitesi/Tıp Fakültesi; HLH-8209-2023Publication A novel non-invasive fibrosis score based on cytokines and clinical parameters for the use in chronic hepatitis delta(Wiley-blackwell, 2013-10-01) Heidrich, Benjamin; Wranke, Anika; Yurdaydin, Cihan; Stift, Judith; Caruntu, Florin A.; Curescu, Manuela G.; Yalcin, Kendal; Zeuzem, Stefan; Erhardt, Andreas; Lueth, Stefan; Papatheodoridis, George V.; Bremer, Birgit; Grabowski, Jan; Kirschner, Janina; Port, Kerstin; Cornberg, Markus; Christine, Falk; Dienes, Hans Peter; Hardtke, Svenja; Manns, Michael P.; Wedemeyer, Heiner; Gurel, Selim; GÜREL, SELİM; Bursa Uludağ Üniversitesi/Tıp Fakültesi; HLH-8209-2023Publication Anti-HDV IgM as a marker of disease activity in hepatitis delta(Public Library Science, 2014-07-29) Wranke, Anika; Heidrich, Benjamin; Ernst, Stefanie; Serrano, Beatriz Calle; Caruntu, Florin Alexandru; Curescu, Manuela Gabriela; Yalcin, Kendal; Gürel, Selim; Zeuzem, Stefan; Erhardt, Andreas; Lueth, Stefan; Papatheodoridis, George V.; Bremer, Birgit; Stift, Judith; Grabowski, Jan; Kirschner, Janina; Port, Kerstin; Cornberg, Markus; Falk, Christine S.; Dienes, Hans-Peter; Hardtke, Svenja; Manns, Michael P.; Yurdaydin, Cihan; Wedemeyer, Heiner; HIDIT-2 Study Grp; GÜREL, SELİM; Uludağ Üniversitesi/Tıp Fakültesi.; HLH-8209-2023Background: Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker.Methods: Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6-12).Results: Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05).Conclusions: Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.Publication Anti-hdv-igm levels as a marker of disease activity and response to pegylated interferon-α based therapy in hepatitis delta(Wiley-blackwell, 2013-10-01) Wranke, Anika; Yurdaydin, Cihan; Heidrich, Benjamin; Ernst, Stefanie; Koch, Armin; Serrano, Beatriz Calle; Caruntu, Florin A.; Curescu, Manuela G.; Yalçın, Kendal; Zeuzem, Stefan; Erhardt, Andreas; Lueth, Stefan; Papatheodoridis, George V.; Bremer, Birgit; Stift, Judith; Kirschner, Janina; Port, Kerstin; Cornberg, Markus; Dienes, Hans P.; Hardtke, Svenja; Manns, Michael P.; Wedemeyer, Heiner; Gurel, Selim; GÜREL, SELİM; Bursa Uludağ Üniversitesi/Tıp Fakültesi; HLH-8209-2023Item Anti-hdv-igm testing in hepatitis delta revisited: Correlations with disease activity and response to pegylated interferon alfa-2a treatment(Elsevier, 2010) Mederacke, Ingmar; Yurdaydın, Cihan; Bremer, Birgit; Çakaloğlu, Yılmaz; Erhardt, A.; Yalçın, Kendal; Zachou, Kalliopi; Heidrich, Benjamin; Dalekos, Georgios N.; Dienes, Hans P.; Manns, M. P.; Wedemeyer, Heiner; Gürel, Selim; Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı.Item Association between level of hepatitis d virus RNA at week 24 of pegylated interferon therapy and outcome(Elsevier, 2015-12) Keskin, Onur; Wedemeyer, Heiner; Tüzün, Ali; Zachou, Kalliopi; Deda, Xheni; Dalekos, George N.; Heidrich, Benjamin; Pehlivan, Selcen; Zeuzem, Stefan; Yalçın, Kendal; Tabak, Fehmi; İdilman, Ramazan; Bozkaya, Hakan; Manns, Michael; Yurdaydın, Cihan; Gürel, Selim; Uludağ Üniversitesi/Tıp Fakültesi/Gastroenteroloji Anabilim Dalı.; 7003706434BACKGROUND & AIMS: Interferon is the only effective treatment for chronic hepatitis D virus (HDV) infection. No rules have been set for stopping treatment based on viral kinetics. We analyzed data from an international study of hepatitis D treatment to identify factors associated with outcomes of pegylated interferon treatment, with and without adefovir. METHODS: We analyzed data from the Hep-Net-International Delta Hepatitis Intervention Trial on 50 patients with compensated liver disease who tested positive for anti-HDV and HDV RNA. Subjects received pegylated interferon alpha 2a, with adefovir or placebo, or only adefovir, for 48 weeks. Twenty-four weeks after treatment ended, 41 patients were evaluated for levels of HDV RNA and DNA, liver enzymes, and hepatitis B surface antigen (HBsAg); liver biopsy specimens were analyzed for fibrosis. Response to therapy was defined as end-of-treatment response or post-treatment week 24 virologic response. In both cases virologic response was associated with undetectable HDV RNA levels. Patients with less than a 1 log decrease in HDV RNA at the end of treatment were considered null responders. RESULTS: Based on univariate and multivariate analysis, the level of HDV RNA at week 24 of treatment was associated more strongly with response to therapy than other factors analyzed. The level of HBsAg at week 24 of treatment was associated with a response to therapy only in univariate analysis. Lack of HDV RNA at week 24 of treatment, or end of treatment, identified responders with positive predicted values of 71% and 100%, respectively. At 24 weeks after treatment, a decrease in HDV RNA level of less than 1 log, combined with no decrease in HBsAg level, identified null responders with a positive predictive value of 83%. A decrease in HDV RNA level of more than 2 log at week 24 of treatment identified null responders with a negative predictive value of 95%. CONCLUSIONS: Based on an analysis of data from a large clinical trial, the level of HDV RNA at week 24 of treatment with pegylated interferon, with or without adefovir for 48 weeks, can identify patients who will test negative for HDV RNA 24 weeks after the end of treatment. This information can be used to help physicians manage patients receiving therapy for chronic hepatitis D.Publication Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta(Lippincott Williams & Wilkins, 2014-07-01) Heidrich, Benjamin; Yurdaydin, Cihan; Kabacam, Gokhan; Ratsch, Boris A.; Zachou, Kalliopi; Bremer, Birgit; Dalekos, George N.; Erhardt, Andreas; Tabak, Fehmi; Yalçın, Kendal; Gürel, Selim; Zeuzem, Stefan; Cornberg, Markus; Bock, C. -Thomas; Manns, Michael P.; Wedemeyer, Heiner; GÜREL, SELİM; Uludağ Üniversitesi/Tıp Fakültesi/Gastroenteroloji Anabilim Dalı.; HLH-8209-2023Interferon alpha is the only treatment option for hepatitis delta virus (HDV). Trials investigating the efficacy of pegylated interferon alpha (PEG-IFNa) showed HDV RNA negativity rates of 25-30% 24 weeks after therapy. However, the clinical and virological long-term outcome of HDV-infected patients treated with PEG-IFNa is unknown. We performed a retrospective-prospective follow-up of 77 patients treated for 48 weeks with either PEG-alfa-2a and adefovir (ADV) or either drug alone in the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-1) trial. Long-term follow-up data were available for 58 out of 77 patients (75%) with a median time of follow-up of 4.5 (0.5-5.5) years and a median 3 visits per patient. Patients treated with ADV alone received retreatment with PEG-IFNa (48% versus 19%; P = 0.02) more often. Hepatitis B virus surface antigen (HBsAg) became negative in six PEG-IFNa-treated patients until the end of long-term follow-up (10%). Sixteen patients tested HDV RNA-negative 6 months after PEG-IFNa treatment who were entered in the long-term follow-up study. Out of these, nine individuals tested HDV RNA-positive at least once during further long-term follow-up, with seven patients being HDV RNA-positive at the most recent visit. Clinical endpoints (liver-related death, liver transplantation, hepatic decompensation, hepatocellular carcinoma) were observed in three PEG-IFNa-treated (8%) and three ADV-treated (14%) patients during posttreatment long-term follow-up with an overall annual event rate of 2.5% (4.9% in cirrhosis). Sequencing confirmed the reappearance of pretreatment virus strains in all cases. Conclusion: Late HDV RNA relapses may occur after PEG-IFNa therapy of hepatitis delta and thus the term sustained virological response should be avoided in HDV infection. The annual posttreatment rate of clinical events in hepatitis delta patients eligible for PEG-IFNa therapy is about 2.5% and 4.9% in patients with cirrhosis.Item Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): A randomised, placebo controlled, phase 2 trial(Elsevier, 2019-03) Wedemeyer, Heiner; Yurdaydin, Cihan; Hardtke, Svenja; Caruntu, Florin Alexandru; Curescu, Manuela G.; Yalcin, Kendal; Akarca, Ulus S.; Erhardt, Andreas; Lueth, Stefan; Papatheodoridis, George V.; Keskin, Onur; Port, Kerstin; Radu, Monica; Celen, Mustafa K.; Idilman, Ramazan; Weber, Kristina; Stift, Judith; Wittkop, Ulrike; Heidrich, Benjamin; Zeuzem, Stefan; Gürel, Selim; Bursa Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı.; 7003706434Abstract Background Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25-30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. Methods We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per mu L, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 mu g of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659. Findings Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1.84, 95% CI 0.86-3.91, p=0.12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Interpretation Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D.Item Pegylated-Interferon-a-2a plus Tenofovir or Placebo for the treatment of hepatitis delta: First results of the HIDIT-2 study(Wiley, 2012-10) Yurdaydın, Cihan; Wedemeyer, Heiner; Caruntu, Florin A.; Curescu, Manuela G.; Yalçın, Kendal; Akarca, Ulus S.; Zeuzem, Stefan; Erhardt, Andreas; Lueth, Stefan; Papatheodoridis, George V.; Port, Kerstin; Keskin, Onur; Radu, Monica N.; Çelen, Mustafa K.; İdilman, Ramazan; Stift, Judith; Mederacke, Ingmar; Heidrich, Benjamin; Manns, Michael P.; Dienes, Hans Peter; Gürel, Selim; Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı.; 0000-0002-7279-2161; EYK-5719-2022Item Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta(Wiley, 2020-07-24) Wranke, Anika; Hardtke, Svenja; Heidrich, Benjamin; Dalekos, George; Yalçın, Kendal; Tabak, Fehmi; Çakaloğlu, Yılmaz; Akarca, Ulus S.; Lammert, Frank; Haeussinger, Dieter; Mueller, Tobias; Woebse, Michael; Manns, Michael P.; Idilman, Ramazan; Cornberg, Markus; Wedemeyer, Heiner; Yurdaydın, Cihan; Gürel, Selim; Bursa Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı.; EYK-5719-2022; 7003706434Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG-interferon alpha-2a (PEG-IFNα-2a) is the only effective treatment but its long-term clinical impact is unclear. The aim of this study was to investigate the long-term outcome after 48 weeks of pegylated interferon alpha-2a therapy. We performed a retrospective follow-up study of the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-I trial). Patients had received 48 weeks of treatment with either PEG-IFNα-2a plus adefovir dipivoxil (ADV) (Group I), PEG-IFNα-2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver-related complications were defined as liver-related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child-Pugh scores B or C or an increase in Model for End-stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG-IFNα-2a. Follow-up data (at least 1 visit beyond post-treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow-up was 8.9 (1.6 - 13.4) years. 19 patients were retreated with IFN-based therapy: 42% (n = 8) in PEG-IFNα-2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long-term follow-up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. The annual event-free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long-term follow-up of a large randomized clinical trial suggests that off-treatment HDV RNA response to PEG-IFNα-2a treatment leads to improved clinical long-term outcome.