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Öğe 96 weeks of pegylated-Interferon- alpha-2? plus tenofovir or placebo for the treatment of hepatitis delta: the HIDIT-2 study(Wiley-Blackwell, 2013) Wedemeyer, Heiner; Yurdaydin, Cihan; Ernst, Stefanie; Caruntu, Florin A.; Curescu, Manuela G.; Yalcin, Kendal; Akarca, Ulus S.[Abstract Not Available]Öğe Five years follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D(Elsevier, 2023) Anastasiou, Olympia Aevdoxia; Caruntu, Florin Alexandru; Curescu, Manuela Gabriela; Yalcin, Kendal; Akarca, Ulus S.; Gurel, Selim; Zeuzem, Stefan[Abstract Not Available]Öğe Five-year follow-up of 96 weeks peginterferon plus tenofovir disoproxil fumarate in hepatitis D(John Wiley and Sons Inc, 2024) Anastasiou, Olympia E.; Caruntu, Florin A.; Curescu, Manuela G.; Yalçın, Kendal; Akarca, Ulus S.; Gürel, Selim; Çelen, Mustafa KemalBackground & Aims: Until recently, pegylated interferon-alfa-2a (PEG-IFNa) therapy was the only treatment option for patients infected with hepatitis D virus (HDV). Treatment with PEG-IFNa with or without tenofovir disoproxil fumarate (TDF) for 96 weeks resulted in HDV RNA suppression in 44% of patients at the end of therapy but did not prevent short-term relapses within 24 weeks. The virological and clinical long-term effects after prolonged PEG-IFNa-based treatment of hepatitis D are unknown. Methods: In the HIDIT-II study patients (including 40% with liver cirrhosis) received 180 μg PEG-IFNa weekly plus 300 mg TDF once daily (n = 59) or 180 μg PEG-IFNa weekly plus placebo (n = 61) for 96 weeks. Patients were followed until week 356 (5 years after end of therapy). Results: Until the end of follow-up, 16 (13%) patients developed liver-related complications (PEG-IFNa + TDF, n = 5 vs PEG-IFNa + placebo, n = 11; p =.179). Achieving HDV suppression at week 96 was associated with decreased long-term risk for the development of hepatocellular carcinoma (p =.04) and hepatic decompensation (p =.009). Including complications irrespective of PEG-IFNa retreatment status, the number of patients developing serious complications was similar with (3/18) and without retreatment with PEG-IFNa (16/102, p >.999) but was associated with a higher chance of HDV-RNA suppression (p =.024, odds ratio 3.9 [1.3–12]). Conclusions: Liver-related clinical events were infrequent and occurred less frequently in patients with virological responses to PEG-IFNa treatment. PEG-IFNa treatment should be recommended to HDV-infected patients until alternative therapies become available. Retreatment with PEG-IFNa should be considered for patients with inadequate response to the first course of treatment. Clinical Trial registration: NCT00932971.Öğe Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial(Elsevier Sci Ltd, 2019) Wedemeyer, Heiner; Yurdaydin, Cihan; Hardtke, Svenja; Caruntu, Florin Alexandru; Curescu, Manuela G.; Yalcin, Kendal; Akarca, Ulus S.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. Copyright (c) 2019 Elsevier Ltd. All rights reserved.Öğe Pegylated-Interferon-a-2a plus Tenofovir or Placebo for the treatment of hepatitis delta: First results of the HIDIT-2 study(Wiley-Blackwell, 2012) Yurdaydin, Cihan; Wedemeyer, Heiner; Caruntu, Florin A.; Curescu, Manuela G.; Yalcin, Kendal; Akarca, Ulus S.; Gurel, Selim[Abstract Not Available]Öğe Real-world efficacy and safety of Ledipasvir + Sofosbuvir and Ombitasvir/Paritaprevir/Ritonavir ± Dasabuvir combination therapies for chronic hepatitis C: A Turkish experience(Aves, 2020) Değertekin, Bülent; Demir, Mehmet; Akarca, Ulus S.; Kani, Haluk Tarık; Uçbilek, Enver; Yıldırım, Emre; Güzelbulut, Fatih; Balkan, Ayhan; Vatansever, Sezgin; Danış, Nilay; Demircan, Melek; Soylu, Aliye; Yaras, Serkan; Kartal, Aysun; Kefeli, Ayşe; Gündüz, Feyza; Yalçın, Kendal; Erarslan, Elife; Aladag, Murat; Harputluoğlu, Murat; Özakyol, Aysegül; Temel, Tuncer; Akarsu, Mesut; Sümer, Hale; Akın, Mete; Albayrak, Bülent; Şen, İlker; Alkım, Hüseyin; Uyanıkoğlu, Ahmet; Irak, Kader; Öztaşkın, Sinem; Uğurlu, Çağrı Burak; Günes, Şevkican; Gürel, Selim; Nuriyev, Kenan; İnci, İsmail; Kaçar, Sabite; Dinçer, Dinç; Doğanay, Levent; Doğanay, Levent; Göktürk, Hüseyin Savaş; Mert, Ali; Coşar, Arif Mansur; Dursun, Hakan; Atalay, Roni; Akbulut, Sabiye; Balkan, Yasemin; Köklü, Hayrettin; Şimsek, Halis; Özdoğan, Osman; Çoban, Mehmet; Poturoğlu, Şule; Ayyıldız, Talat; Yapalı, Suna; Günsar, Fulya; Akdoğan, Meral; Özenirler, Seren; Akyıldız, Murat; Sezgin, Orhan; Özdoğan, Osman; Kaymakoğlu, Sabahattin; Beşışık, Fatih; Karasu, Zeki; İdilman, RamazanBackground/Aims: This study aimed to evaluate the real-life efficacy and tolerability of direct-acting antiviral treatments for patients with chronic hepatitis C (CHC) with/without cirrhosis in the Turkish population. Material and Methods: A total of 4,352 patients with CHC from 36 different institutions in Turkey were enrolled. They received ledipasvir (LDV) and sofosbuvir (SOF)+/- ribavirin (RBV) ombitasvir/paritaprevir/ritonavir +/- dasabuvir (PrOD)+/- RBV for 12 or 24 weeks. Sustained virologic response (SVR) rates, factors affecting SVR, safety profile, and hepatocellular cancer (HCC) occurrence were analyzed. Results: SVR12 was achieved in 92.8% of the patients (4,040/4,352) according to intention-to-treat and in 98.3% of the patients (4,040/4,108) according to per-protocol analysis. The SVR12 rates were similar between the treatment regimens (97.2%-100%) and genotypes (95.6%-100%). Patients achieving SVR showed a significant decrease in the mean serum alanine transaminase (ALT) levels (50.90 +/- 54.60 U/L to 17.00 +/- 14.50 U/L) and model for end-stage liver disease (MELD) scores (7.51 +/- 4.54 to 7.32 +/- 3.40) (p<0.05). Of the patients, 2 were diagnosed with HCC during the treatment and 14 were diagnosed with HCC 37.0 +/- 16.0 weeks post-treatment. Higher initial MELD score (odds ratio [OR]: 1.92, 95% confidence interval [CI]: 1.22-2.38; p=0.023]), higher hepatitis C virus (HCV) RNA levels (OR: 1.44, 95% CI: 1.31-2.28; p=0.038), and higher serum ALT levels (OR: 1.38, 95% CI: 1.21-1.83; p=0.042) were associated with poor SVR12. The most common adverse events were fatigue (12.6%), pruritis (7.3%), increased serum ALT (4.7%) and bilirubin (3.8%) levels, and anemia (3.1%). Conclusion: LDV/SOF or PrOD +/- RBV were effective and tolerable treatments for patients with CHC and with or without advanced liver disease before and after liver transplantation. Although HCV eradication improves the liver function, there is a risk of developing HCC.Öğe 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) Bremer, Birgit; Anastasiou, Olympia E.; Hardtke, Svenja; Caruntu, Florin Alexandru; Curescu, Manuela G.; Yalçın, Kendal; Akarca, Ulus S.; Gürel, Selim; Zeuzem, Stefan; Erhardt, Andreas; Luth, Stefan; Papatheodoridis, George, V.; Radu, Monica; Idilman, Ramazan; Manns, Michael P.; Cornberg, Markus; Yurdaydın, Cihan; Wedemeyer, HeinerThe 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.Öğe 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) Bremer, Birgit; Anastasiou, Olympia; Hardtke, Svenja; Caruntu, Florin Alexandru; Curescu, Manuela Gabriela; Yalcin, Kendal; Akarca, Ulus S.[Abstract Not Available]Öğe Ten-year follow-up of a randomized controlled clinical trial in chronic hepatitis delta(Wiley, 2020) Wranke, Anika; Hardtke, Svenja; Heidrich, Benjamin; Dalekos, George; Yalçın, Kendal; Tabak, Fehmi; Gürel, Selim; Çakaloglu, Yılmaz; Akarca, Ulus S.; Lammert, Frank; Haeussinger, Dieter; Mueller, Tobias; Woebse, Michael; Manns, Michael P.; İdilman, Ramazan; Cornberg, Markus; Wedemeyer, Heiner; Yurdaydın, CihanHepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG-interferon alpha-2a (PEG-IFN alpha-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-IFN alpha-2a plus adefovir dipivoxil (ADV) (Group I), PEG-IFN alpha-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-IFN alpha-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-IFN alpha-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-IFN alpha-2a treatment leads to improved clinical long-term outcome.
