Browsing by Author "Zeuzem, Stefan"
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Publication A transient early hbv-dna increase during peg-ifnα therapy of hepatitis d indicates loss of infected cells and is associated with hdv-rna and hbsag reduction(Wiley, 2020-12-12) Anastasiou, Olympia E.; Yurdaydin, Cihan; Maasoumy, Benjamin; Hardtke, Svenja; Caruntu, Florin Alexandru; Curescu, Manuela G.; Yalcin, Kendal; Akarca, Ulus S.; Zeuzem, Stefan; Erhardt, Andreas; Luth, Stefan; Papatheodoridis, George, V; Radu, Monica; Liebig, Stephanie; Bantel, Heike; Bremer, Birgit; Manns, Michael P.; Cornberg, Markus; Wedemeyer, Heiner; Gürel, Selim; GÜREL, SELİM; Bursa Uludağ Üniversitesi/Tıp Fakültesi; HLH-8209-2023HBV-DNA levels are low or even undetectable in the majority HDV-infected patients. The impact of PEG-IFN alpha on HBV-DNA kinetics in HDV-infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV-RNA-positive patients were randomized to receive PEG-IFN alpha-2a plus tenofovir-disoproxil-fumarate (PEG-IFN alpha/TDF, n = 59) or placebo (PEG-IFN alpha/PBO; n = 61) for 96 weeks. At week 96, HBV-DNA was still quantifiable in 71% of PEG-IFN alpha/PBO-treated patients but also in 76% of PEG-IFN alpha/TDF-treated patients, despite low HBV-DNA baseline values. Surprisingly, a transient HBV-DNA increase between weeks 12 and 36 was observed in 12 in PEG-IFN alpha/TDF-treated and 12 PEG-IFN alpha/PBO-treated patients. This increase was positively associated with HBsAg loss [(P = 0.049, odds ratio (OR) 5.1] and HDV-RNA suppression (P = 0.007, OR 4.1) at week 96. Biochemical markers of cell death (M30 and ALT) were higher during the HBV-DNA peak but no distinct systemic immune pattern could be observed by screening 91 soluble inflammatory markers. In conclusion, an early increase in HBV-DNA during PEG-IFN alpha-2a therapy occurred in more than 20% of patients, even in TDF-treated patients. This transient HBV-DNA rise may indicate PEG-IFN alpha-induced cell death and lead to long-term HDV-RNA suppression and HBsAg loss.Item Anti-HDV immunoglobulin M testing in hepatitis delta revisited: Correlations with disease activity and response to pegylated interferon-alpha 2a treatment(Int Medical, 2012) Mederacke, Ingmar; Yurdaydın, Cihan; Dalekos, George N.; Bremer, Birgit; Erhardt, Andreas; Çakaloğlu, Yılmaz; Yalçın, Kendal; Zeuzem, Stefan; Zachou, Kalliopi; Bozkaya, Hakan; Dienes, Hans Peter; Manns, Michael P.; Wedemeyer, Heiner; Gürel, Selim; Uludağ Üniversitesi/Tıp Fakültesi/Gastroenteroloji Anabilim Dalı.; 7003706434Background: The role of anti-HDV immunoglobulin M (IgM) testing in patients receiving pegylated interferon-alpha therapy for hepatitis delta is unknown. We performed anti-HDV IgM testing in a well defined cohort of HDVinfected patients who were treated with pegylated interferon-alpha 2a plus adefovir, or either drug alone. Methods: Sera from 33 HDV-RNA-positive patients from the international HIDIT-1 trial were available for anti-HDV IgM testing (ETI-DELTA-IGMK-2 assay, DiaSorin, Saluggia, Italy) before therapy, at treatment weeks 24 and 48, and at 24 weeks after the end of treatment. Results: Anti-HDV IgM tested positive in 31 out of the 33 patients (94%) prior to treatment. HDV IgM levels correlated with histological inflammatory activity (r= 0.51, P<0.01) and were higher in patients with alanine aminotransferase and gamma-glutamyl transpeptidase levels above the median (P<0.05). Quantitative anti-HDV IgM values declined in patients responding to antiviral therapy, however anti-HDV IgM remained positive after treatment in the majority of virological responders. Conclusions: We suggest that anti-HDV IgM testing might give additional useful information to determine disease activity in hepatitis delta and to predict treatment response to antiviral therapy with type I interferons. However, determination of anti-HDV IgM can not substitute HDV RNA testing, which remains the primary virological marker for response to therapy.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.Item Efficacy of pegylated interferon-based treatment in patients with cirrhosis due to chronic delta hepatitis: Comparison with non-cirrhotic patients(Wiley, 2009-10) Yurdaydın, Cihan; Kobacam, Gökhan; Cakaloğlu, Yılmaz; Erhardt, Andreas; Değertekin, Halil; Zeuzem, Stefan; Dalekos, George N.; Bozkaya, Hakan; Dienes, Hans P.; Manns, Michael P.; Wedemeyer, Heiner; Gürel, Selim; Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı/Gastroenteroloji Bilimdalı.Item A multicenter randomised study comparing the efficacy of pegylated interferon-alfa-2a plus adevofir dipivoxil vs. pegylated interferon-alfa-2a plus placebo vs. adevofir dipivoxil for the treatment of chronic delta hepatitis: The hep-net/international delta hepatitis intervention trial (HID-IT)(Wiley, 2006-10) Yurdaydın, Cihan; Wedemeyer, Heiner; Dalekos, George; Erhardt, Alexander; Çakaloğlu, Y.; Değertekin, H.; Zeuzem, Stefan; Zachou, Kalliopi; Bozkaya, Hakan; Gürel, S.; Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı/Gastroenteroloji Bilim Dalı.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 Renal function during treatment with adefovir plus peginterferon alfa-2a vs either drug alone in hepatitis B/D co-infection(Wiley, 2012-06) Mederacke, Ingmar; Yurdaydın, Cihan; Grosshennig, Anika; Erhardt, Andreas; Çakaloğlu, Yılmaz; Yalçın, Kendal; Zeuzem, Stefan; Zachou, Kalliopi; Chatzikyrkou, Christos; Bozkaya, Hakan; Dalekos, George Nikolaos; Manns, Michael Peter; Wedemeyer, Heiner; Gürel, Selim; Uludağ Üniversitesi/Tıp Fakültesi.; 7003706434Long-term safety of treatment with hepatitis B virus (HBV) polymerase inhibitors is a concern. Adefovir dipivoxil (ADV) therapy has previously been associated with impairment of renal function. Limited data are available on the safety of combination therapy with nucleos(t)ide analogues and interferon alfa (IFNa). The aim of this analysis was to assess the renal function during combination therapy with peginterferon alfa-2a (PegIFNa-2a) plus ADV vs either drug alone in patients with hepatitis B/D co-infection. We performed a retrospective analysis of renal function data of patients treated in the Hep-Net/International Delta Hepatitis Intervention Trial 1(HIDIT-1-trial), a European multicenter study to investigate the efficacy of 48 weeks of therapy with PegIFNa-2a+ADV vs either drug alone in 90 patients with chronic hepatitis B/D co-infection. Glomerular filtration rates (GFR) were calculated by CockcroftGault (CG), abbreviated Modification of Diet in Renal Disease (MDRD) study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. After 48 weeks of therapy GFR values were significantly lower in patients receiving adefovir-containing treatment vs PegIFNa-2a alone [mean difference 16.1 mL/min (CG) and 10.2 mL/min (MDRD), respectively, P < 0.05] while no differences were observed between patients receiving adefovir alone vs combination treatment. Twenty-four weeks after treatment GFR values did not differ between treatment arms. A decrease in GFR =20% was observed more often in patients during adefovir-containing treatment vs PegIFNa-2a alone (P < 0.05) which was confirmed by KaplanMeier analysis. Adefovir-containing but not PegIFNa-2a treatment was associated with a decrease in GFR values in about one-fifth of patients. Combination treatment of PegIFNa-2a+ADV in chronic hepatitis B/D co-infection did not lead to any further impairment of kidney function.Item Residual low HDV viraemia is associated HDV RNA relapse after PEG-IFNa-based antiviral treatment of hepatitis delta: Results from the HIDIT-II study(Wiley, 2020-11-20) Bremer, Birgit; Anastasiou, Olympia E.; Hardtke, Svenja; Caruntu, Florin A.; Curescu, Manuela G.; Yalçın, Kendal; Akarca, Ulus S.; Zeuzem, Stefan; Erhardt, Andreas; Luth, Stefan; Papatheodoridis, George V.; Radu, Monica; İdilman, Ramazan; Manns, Michael P.; Cornberg, Markus; Yurdaydın, Cihan; Wedemeyer, Heiner; Gürel, Selim; Bursa Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları.; HLH-8209-2023; 7003706434The role of low levels of HDV-RNA during and after interferon therapy of hepatitis D is unknown. We re-analysed HDV RNA in 372 samples collected in the HIDIT-2 trial (Wedemeyer et al, Lancet Infectious Diseases 2019) with the Robogene assay (RA; Jena Analytics). Data were compared with the previously reported in-house assay (IA). We detected HDV-RNA in one-third of samples previously classified as undetectable using the highly sensitive RA. Low HDV viraemia detectable at week 48 or week 96 was associated with a high risk for post-treatment relapse, defined as HDV RNA positivity in both assays at week 120. HDV RNA relapses occurred in 10/15 (67%) patients with detectable low HDV RNA at week 48 and in 10/13 (77%) patients with low viraemia samples at week 96. In contrast, the post-treatment relapse rate was lower in patients with undetectable HDV RNA in both assays during treatment.Publication Residual low hdv viremia is associated with hdv rna relapse after peg-ifna-based antiviral treatment of hepatitis d (delta): Results from the hidit-ii study(Elsevier, 2020-08-01) Bremer, Birgit; Anastasiou, Olympia; Hardtke, Svenja; Caruntu, Florin Alexandru; Curescu, Manuela Gabriela; Yalcin, Kendal; Akarca, Ulus S.; Idilman, Ramazan; Zeuzem, Stefan; Erhardt, Andreas; Lueth, Stefan; Papatheodoridis, George; Radu, Monica; Manns, Michael P.; Cornberg, Markus; Yurdaydın, Cihan; Wedemeyer, Heiner; Gürel, Selim; GÜREL, SELİM; Bursa Uludağ Üniversitesi/Tıp Fakültesi.; HLH-8209-2023Item Significance of HDV-RNA and HBsAg levels in delta hepatitis: First data of the HEP-NET/International HDV Intervention Trial(Elsevier, 2006) Zachou, K.; Yurdaydin, C.; Dienes, H.; Dalekos, G.; Erhardt, Angelika; Çakaloğlu, Yılmaz; Değertekin, H.; Zeuzem, Stefan; Bozkaya, H.; Bock, Tim; Schlaphoff, Verena; Manns, M.; Wedemeyer, Heiner; Gürel, Selim; Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı/Gastroenteroloji Bilim Dalı.Bu çalışma, 26-30 Nisan 2006 tarihleri arasında Vienna[Avustralya]’da düzenlenen 41. Annual Meeting of the European-Association-for-the-Study-of-the-Liver’da bildiri olarak sunulmuştur.