1. Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): A randomised, placebo controlled, phase 2 trial
- Author
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Heiko von der Leyen, Kendal Yalcin, Ingmar Mederacke, Markus Cornberg, Ramazan Idilman, Stefan Lüth, Kerstin Port, Hans Peter Dienes, Judith Stift, Ulrike Wittkop, Cihan Yurdaydin, Manuela Curescu, Mustafa Kemal Çelen, Kristina Weber, Onur Keskin, Svenja Hardtke, Selim Gürel, Hidit-Ii study team, Monica Radu, Michael P. Manns, Andreas Erhardt, Heiner Wedemeyer, Benjamin Heidrich, Armin Koch, Ulus Salih Akarca, George V. Papatheodoridis, Florin Alexandru Caruntu, Stefan Zeuzem, Bursa Uludağ Üniversitesi/Tıp Fakültesi/İç Hastalıkları Anabilim Dalı., and Gürel, Selim
- Subjects
Male ,HBsAg ,Neurologic disease ,Gamma glutamyl transferase blood level ,Procedures ,Skin disease ,Drug-related side effects and adverse reactions ,Albumin blood level ,law.invention ,Hepatobiliary disease ,0302 clinical medicine ,Eye disease ,Germany ,Pathology ,Coughing ,Treatment outcome ,Long term care ,Drug safety ,Alanine transaminase ,RNA, viral ,Aged, 80 and over ,Greece ,Clinical outcome ,Headache ,virus diseases ,Double blind procedure ,Genital system disease ,Multicenter study ,Clinical trial ,Blood ,Epistaxis ,Tenofovir disoproxil ,Randomized controlled trial ,Creatinine ,Interferon ,Infectious diseases ,030211 gastroenterology & hepatology ,Drug Therapy, Combination ,Hepatitis D virus ,Infection ,Human ,Diarrhea ,medicine.medical_specialty ,Recombinant protein ,Double-blind method ,Gamma glutamyltransferase ,Virus RNA ,Major clinical study ,Side effect ,Body weight loss ,Placebo ,Aspartate aminotransferase ,Hepatitis B(e) antigen ,Xerostomia ,Article ,Intention to treat analysis ,Mediastinum disease ,Hematologic disease ,03 medical and health sciences ,Genetics ,Humans ,Creatinine blood level ,Dyspepsia ,Tenofovir ,Aged ,Very elderly ,Follow up ,Leukopenia ,medicine.disease ,Metabolic disorder ,030104 developmental biology ,Asthenia ,Delta virus-replication ,0301 basic medicine ,Platelet count ,Aspartate aminotransferase blood level ,Weight loss ,Medizin ,Antiviral therapy ,Breast disease ,Turkey (republic) ,Placebos ,Hepatitis delta virus ,Musculoskeletal disease ,law ,Recurrence ,Recurrent disease ,Middle aged ,Fatigue ,Chronic hepatitis ,Oropharynx pain ,Priority journal ,Recombinant proteins ,Respiratory tract disease ,Polyethylene glycols ,Anemia ,Nausea ,Gastrointestinal disease ,Nutritional disorder ,Hepatitis D ,Delta agent hepatitis ,Europe ,Combination drug therapy ,Hepatitis B surface antigen ,Decreased appetite ,Combination ,Alanine aminotransferase blood level ,Female ,Drug therapy ,Viral hepatitis ,Lymphatic system disease ,Peginterferon alfa-2a ,medicine.drug ,Adult ,Adverse event ,Abdominal pain ,Neutropenia ,Adolescent ,Fever ,Infestation ,Prothrombin time ,Adverse drug reaction ,Peginterferon alpha2a ,Compensated liver cirrhosis ,Immunopathology ,Dizziness ,Alpha interferon ,Internal medicine ,Virus DNA ,medicine ,Phase 2 clinical trial ,Antivirus agent ,Endocrine disease ,Connective tissue disease ,Intention-to-treat analysis ,Bilirubin blood level ,business.industry ,Romania ,Albumin ,Pruritus ,Interferon-alpha ,Bilirubin ,Alopecia ,Mental disease ,Hepatitis Delta Virus ,Chronic Hepatitis D ,Hepatitis B ,Drug efficacy ,Antiviral agents ,Young adult ,Macrogol ,Flu like syndrome ,Alanine aminotransferase ,Virus load ,Therapy ,business ,Controlled study - Abstract
Summary 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.
- Published
- 2019