Heiner Wedemeyer1, Cihan Yurdaydin2, Svenja Hardtke3, Florin Alexandru Caruntu4, Manuela G Curescu5, Kendal Yalcin6, Ulus S Akarca7, Selim Gürel8, Stefan Zeuzem9, Andreas Erhardt10, Stefan Lüth11, George V Papatheodoridis12, Onur Keskin13, Kerstin Port14, Monica Radu4, Mustafa K Celen6, Ramazan Idilman13, Kristina Weber15, Judith Stift16, Ulrike Wittkop17, Benjamin Heidrich3, Ingmar Mederacke14, Heiko von der Leyen18, Hans Peter Dienes16, Markus Cornberg14, Armin Koch15, Michael P Manns19. 1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infectious Disease Research, HepNet Study-House, Hannover, Germany; Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany; Medical Faculty of the University of Duisburg-Essen, Essen, Germany. Electronic address: heiner.wedemeyer@uk-essen.de. 2. Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey; Department of Internal Medicine, Koc University Medical School, Istanbul, Turkey. 3. German Center for Infectious Disease Research, HepNet Study-House, Hannover, Germany. 4. Institutul de Boli Infectioase, Bucharest, Romania. 5. Spitalul Clinic de Boli Infectioase si, Timisoara, Romania. 6. Dicle University Medical Faculty, Diyarbakir, Turkey. 7. Ege University Medical Faculty, Izmir, Turkey. 8. Uludağ University Medical Faculty, Bursa, Turkey. 9. Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany. 10. Heinrich Heine University, Düsseldorf, Germany. 11. University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. 12. School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. 13. Department of Gastroenterology, Ankara University Medical School, Ankara, Turkey. 14. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 15. Institute for Biometry, Hannover Medical School, Hannover, Germany. 16. Medical University of Vienna, Vienna, Austria. 17. Hannover Clinical Trial Center, Hannover, Germany. 18. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; Hannover Clinical Trial Center, Hannover, Germany. 19. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; German Center for Infectious Disease Research, HepNet Study-House, Hannover, Germany.
Abstract
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 μL, 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 μg 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 thepeginterferon 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. FUNDING: The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.
RCT Entities:
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 μL, 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 μg 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. FUNDING: The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.