Τίτλος:
Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2019 Elsevier Ltd
Συγγραφείς:
Wedemeyer, H.
Yurdaydin, C.
Hardtke, S.
Caruntu, F.A.
Curescu, M.G.
Yalcin, K.
Akarca, U.S.
Gürel, S.
Zeuzem, S.
Erhardt, A.
Lüth, S.
Papatheodoridis, G.V.
Keskin, O.
Port, K.
Radu, M.
Celen, M.K.
Idilman, R.
Weber, K.
Stift, J.
Wittkop, U.
Heidrich, B.
Mederacke, I.
von der Leyen, H.
Dienes, H.P.
Cornberg, M.
Koch, A.
Manns, M.P.
HIDIT-II study team
Περιοδικό:
The Lancet Infectious Diseases
Εκδότης:
The Lancet Publishing Group
Λέξεις-κλειδιά:
alanine aminotransferase; albumin; aspartate aminotransferase; bilirubin; creatinine; gamma glutamyltransferase; hepatitis B surface antigen; hepatitis B(e) antigen; peginterferon alpha2a; tenofovir disoproxil; virus DNA; virus RNA; alanine aminotransferase; alpha interferon; antivirus agent; macrogol; peginterferon alpha2a; placebo; recombinant protein; tenofovir; virus RNA, abdominal pain; adult; alanine aminotransferase blood level; albumin blood level; alopecia; anemia; antiviral therapy; Article; aspartate aminotransferase blood level; asthenia; bilirubin blood level; body weight loss; breast disease; chronic hepatitis; clinical outcome; combination drug therapy; compensated liver cirrhosis; connective tissue disease; controlled study; coughing; creatinine blood level; decreased appetite; delta agent hepatitis; diarrhea; dizziness; double blind procedure; drug efficacy; drug safety; dyspepsia; endocrine disease; epistaxis; eye disease; fatigue; female; fever; flu like syndrome; follow up; gamma glutamyl transferase blood level; gastrointestinal disease; genital system disease; Germany; Greece; headache; hematologic disease; hepatobiliary disease; human; immunopathology; infection; infestation; intention to treat analysis; leukopenia; long term care; lymphatic system disease; major clinical study; male; mediastinum disease; mental disease; metabolic disorder; multicenter study; musculoskeletal disease; nausea; neurologic disease; neutropenia; nutritional disorder; oropharynx pain; phase 2 clinical trial; platelet count; priority journal; prothrombin time; pruritus; randomized controlled trial; respiratory tract disease; Romania; side effect; skin disease; subcutaneous tissue; thorax disease; thrombocytopenia; treatment duration; treatment response; Turkey (republic); virus load; xerostomia; adolescent; adverse drug reaction; adverse event; aged; blood; clinical trial; combination drug therapy; delta agent hepatitis; Europe; genetics; Hepatitis delta virus; middle aged; pathology; procedures; recurrent disease; treatment outcome; very elderly; young adult, Adolescent; Adult; Aged; Aged, 80 and over; Alanine Transaminase; Antiviral Agents; Double-Blind Method; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Europe; Hepatitis D; Hepatitis Delta Virus; Humans; Interferon-alpha; Male; Middle Aged; Placebos; Platelet Count; Polyethylene Glycols; Recombinant Proteins; Recurrence; RNA, Viral; Tenofovir; Treatment Outcome; Young Adult
DOI:
10.1016/S1473-3099(18)30663-7
