Peginterferon alfa-2a plus tenofovir disoproxil fumarate for hepatitis D (HIDIT-II): a randomised, placebo controlled, phase 2 trial

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 (TD...

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Published in:The Lancet infectious diseases 2019-03, Vol.19 (3), p.275-286
Main Authors: Wedemeyer, Heiner, Yurdaydin, Cihan, Hardtke, Svenja, Caruntu, Florin Alexandru, Curescu, Manuela G, Yalcin, Kendal, Akarca, Ulus S, Gürel, Selim, Zeuzem, Stefan, Erhardt, Andreas, Lüth, Stefan, Papatheodoridis, George V, Keskin, Onur, Port, Kerstin, Radu, Monica, Celen, Mustafa K, Idilman, Ramazan, Weber, Kristina, Stift, Judith, Wittkop, Ulrike, Heidrich, Benjamin, Mederacke, Ingmar, von der Leyen, Heiko, Dienes, Hans Peter, Cornberg, Markus, Koch, Armin, Manns, Michael P
Format: Article
Language:English
Subjects:
Adolescent
Adult
Aged
Aged, 80 and over
Alanine
Alanine transaminase
Alanine Transaminase - blood
Antiretroviral drugs
Antiviral Agents - administration & dosage
Antiviral Agents - adverse effects
Chronic infection
Cirrhosis
Clinical trials
Double-Blind Method
Drug Therapy, Combination - adverse effects
Drug Therapy, Combination - methods
Drug-Related Side Effects and Adverse Reactions - epidemiology
Drug-Related Side Effects and Adverse Reactions - pathology
Europe
Fatigue
Genotype & phenotype
Hematology
Hepatitis
Hepatitis B surface antigen
Hepatitis D - drug therapy
Hepatitis delta virus
Hepatitis Delta Virus - genetics
Humans
Infections
Infectious diseases
Influenza
Interferon
Interferon-alpha - administration & dosage
Interferon-alpha - adverse effects
Liver
Liver cirrhosis
Liver diseases
Male
Middle Aged
Nucleoside analogs
Nucleotide analogs
Patients
Placebos - administration & dosage
Platelet Count
Polyethylene Glycols - administration & dosage
Polyethylene Glycols - adverse effects
Randomization
Recombinant Proteins - administration & dosage
Recombinant Proteins - adverse effects
Recurrence
Ribonucleic acid
RNA
RNA viruses
RNA, Viral - blood
Studies
Tenofovir
Tenofovir - administration & dosage
Tenofovir - adverse effects
Therapy
Treatment Outcome
Viruses
Young Adult
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Summary: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. 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. 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, influ
ISSN:1473-3099
1474-4457
DOI:10.1016/S1473-3099(18)30663-7