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96 weeks of pegylated-interferon-alpha-2a plus tenofovir or placebo for the treatment of hepatitis delta: the HiDiT-2 study
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Reported by Jules Levin
AASLD 2013 Nov 1-5 Wash DC
HiDiT-2 study group
Heiner Wedemeyer1, 14, Cihan Yurdaydin2, Stefanie Ernst3, Florin A. Caruntu4, Manuela G. Curescu5, Kendal Yalcin6, Ulus S. Akarca7, Selim Gurel8, Stefan Zeuzem9, Andreas Erhardt10, Stefan Lüth11, George V. Papatheodoridis12, Onur Keskin2, Kerstin Port1, Mustafa K. Celen6, Judith Stift13, Benjamin Heidrich14, 1, ingmar Mederacke14, Svenja Hardtke14, 1, Armin Koch3, Hans P. Dienes13, 14, Michael P. Manns 1, 14
1. Gastroenterology,Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
2. Medical Faculty, gastroenterology, Ankara University, Ankara, Turkey.
3. Biometry, Hannover Medical School, Hannover, Germany.
4. infectious disease, Matei Bals infectious Diseases institute , Bucharest, Romania.
5. Clinic of infectious Diseases , University of Medicine and Pharmacy Timisoara , Timisoara, Romania.
6. Gastroenterology, Dicle University School of Medicine , Diyarbakir, Turkey.
7. Gastroenterology, Ege University Medical School , izmir, Turkey.
8. Gastroenterology, Uludag University, Bursa, Turkey.
9. Department of internal Medicine i, J.W. Goethe University Hospital , Frankfurt, Germany.
10. Gastroenterology, Hepatology and infectiology , Heinrich-Heine-University , Düsseldorf, Germany.
11. Dept. of Medicine i , University Medical Center Hamburg-Eppendorf , Hamburg, Germany.
12. 2nd Department of internal Medicine, Athens University Medical School , Athen, Greece.
13. University of Vienna, Vienna, Austria.
14. German Liver Foundation, HepNet Study-House, Hannover, Germany.
Hepatitis delta is the most severe form of chronic viral hepatitis. approximately 15-20 Million individuals world-wide are anti-HDV
positive.
Yurdaydin J Viral Hepatitis 2010,
Wedemeyer & Manns Nat Rev Gastroenterol 2010
Hughes et al., Lancet 2011
HBV polymerase inhibitors are ineffective against HDV. 48-72 weeks of pegylated interferon alfa therapy was effective in previous studies in 25-30% of patients. Combination of PEG-iFNa with HBV polymerase inhibitors has been suggested to increase HBsAg decline which would be of particular importance in HDV infection.
www.hepatitis-delta.org
The aim of the investigator-initiated Hep-Net- international Delta Hepatitis intervention-Trial (HiDiT)-2 was to investigate the efficacy of 96 weeks of PEG-iFNa-2a therapy plus tenofovir or placebo in patients with hepatitis delta.We report the primary efficacy analysis after 96w of treatment.
120 HDV-RNA-positive patients were recruited from 14 centers in 4 countries (Turkey n=50,Germany n=46,Romania n=19,Greece n=5).
Patients were randomized to receive either 180 µg PEG-iFNa-2a weekly plus tenofovir disoproxil fumarate (300mg once daily; TDFarm A, n=59) or 180 µg PEG-iFNa-2a weekly plus placebo (PBOarm B; n=61).
Predefined efficacy endpoints were HDV-RNA negativity, HBsAg loss, an HBsAg decline of at least 0.5log iU/ml and ALT normalization.
inclusion criteria: adults with chronic delta hepatitis, compensated liver disease, HBsAg + for at leaf 6 months, anti D + for at least 3 months, HDV RNA positive by PCR, ALT > /= ULN to < / =10x ULN, Negative tests for HCV-RNA & anti-HiV, No treatment for hepatitis D in the prior 6 months
Results
The majority of patients were male 79/120 (66%) with an overall mean age of 40±11 years at randomization. 54 patients (45%) had liver cirrhosis. 15 patients (9 TDFarm, 6 PBOarm) discontinued treatment prematurely. Serious adverse events affected a similar number of patients in both arms (TDF 18 vs. PBO 14) including one death in each group. Overall, 846 adverse events were documented (440 TDF and 456 PBO).
Median baseline HDV RNA 5.15 log10 cop/ml; median HBV DNA about 2.65 log10 iU/ml. Median baseline HBsAg about 3.94 log10 iU/ml.
Mean HDV RNA levels declined until week 96 by 2.79 log copies/ml in TDF-treated patients ([2.24;3.34];p<0.001) and by 2.31 log copies/ml in the PBOarm ([1.87 ;2.76];p<0.001). After 96 weeks HDV RNA was negative in 28 patients (47%) receiving combination therapy and in 20 patients (33%) receiving PEG-iFNa-2a and placebo (iTT analysis). Logistic regression adjusted for country,gender and previous iFN therapy revealed an odds ratio for the treatment effect PBO vs. TDF of 0.54 [0.26; 1.16] (iTT, p=0.115).
HBsAg became negative in 3/59 patients in the TDF arm (5.1%) and in 5/61 patients receiving PBO (8.2%). An HBsAg decline of >0.5 log iU/ml was observed in 19 patients in each arm (32% vs. 31%). ALT levels normalized until week 96 in 28 (48%) and 22 (36%) of TDF- and PBO-treated patients (p=0.203).Mean ALT levels decline was from about 120 to 60-75 for both arms.
Factors associated with HDV RNA negativity at week 96 include -- treatment arm, placebo vs tenofovir OR 0.496, pvalue 0.074; female vs male: OR 2.385 (pvalue 0.037;
Summary & Conclusions:
This is the largest prospective and randomized treatment trial in hepatitis delta, demonstrating that prolonged administration of PEG-iFNa-2a and TDF for 96 weeks is safe in HDV-infected patients. Combination therapy and PEG-iFNa-2a alone showed similar efficacy concerning HDV RNA suppression, HBsAg reduction and ALT normalization. Combination therapy with tenofovir does not provide obvious benefits in hepatitis delta patients with low baseline HBV-DNA levels. Stopping rules need to be determined to avoid unnecessary therapies and optimal individual PEG-iFNa treatment durations. More than one third of patients experience a post-treatment relapse despite prolonged therapy. Alternative treatment options are urgently needed for HDV-infected patients. Final analysis of data is ongoing. Patients will be followed for 5 years after the end of therapy.
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