- Email: [email protected]
45 IMMUNE EVASION OF HEPATITIS DELTA FROM CD8+ T CELL IMMUNE RESPONSE
ORAL PRESENTATIONS 45 IMMUNE EVASION OF HEPATITIS DELTA FROM CD8+ T CELL IMMUNE RESPONSE H. Karimzadeh1 , A. Kosinska1 , B. Budeus2 , M. Fiedler1 , M. Homs3 , A. Olivero4 , M. Buti3 , H. Keyvani5 , F. Rodr´ıguez Fr´ıas3 , S.M. Alavian5 , D. Hoffmann2 , A. Smedile4 , M. Rizzetto4 , H. Wedemeyer6 , J. Timm1 , M. Roggendorf1 . 1 Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany; 2 Department of Bioinformatics, University of Duisburg-Essen, Essen, Germany; 3 Department of Biochemistry, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Research Institute (VHIR) University Aut` onoma de Barcelona (UAB), Barcelona, Spain; 4 Department of Internal Medicine, University of Turin, Turin, Italy; 5 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, 6 Department of Gastroenterology, Hepatology and Endocrinology, Medical School of Hannover, Hannover, Germany E-mail: [email protected] Background and Aims: The immunopathology of hepatitis delta virus (HDV) infection remains unclear. However, CD8+ T cell response seems to play a key role in the infection’s outcome, as it does in many other viral infections. A high genetic diversity was observed in the genotypes. In the presence of cytotoxic T lymphocyte (CTL) immune response, those viruses with mutations within MHC class I restricted epitopes are able to evade effector T cell recognition, establishing chronic infection. In the light of these observations, the aims of the study were: analysis of the genotype(s); characterization of the variability of the large hepatitis delta antigen (L-HDAg); identification of the immune escape of HDV from CD8+ T cell response and, finally, a thorough comprehension of the immunopathogenesis of HDV and the role of selected mutants under immune pressure. Methods: 130 chronically infected HDV patients from 6 different collaborating centers were enrolled in this study. The whole large hepatitis delta antigen (L-HDAg) of these patients was amplified, sequenced and genotyped. HLA typing of the subjects and computational prediction of the potential epitopes within the L-HDAg were performed. The mutation rates in the predicted and previously identified epitopes were compared in the presence and the absence of the given HLA allele. Results: All sequences were branched under genotype one. HLA typing of PCR positive patients showed normal allele distribution, compared with the frequency of HLA class I alleles in the general European population. Preliminary results indicate a higher frequency of mutations in an identified HLA-A02 epitope and in a predicted HLA-A24 epitope in HLA-A02 and HLA-A24 positive patients, respectively, than in negative ones. Currently we are analyzing the sequential samples of some chosen patients to determine the adaptation of the virus to the host over time. Conclusions: The results suggest that CD8+ T cell responseassociated selection pressure plays an important role in the infection’s progression to the chronic phase and in the evolution of circulating HDV isolates. Genetic diversity, resulting in rapid mutations over a short period of time, has hampered attempts to develop potential therapeutic vaccines for use in the chronic phase of HDV infection.
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46 LONG-TERM FOLLOW-UP AFTER PEG-IFNa2a-BASED THERAPY OF CHRONIC HEPATITIS DELTA 3 B. Heidrich1,2 , C. Yurdaydın3 , G. Kabacam ¸ , K. Zachou1,4 , B. Bremer1 , G.N. Dalekos4 , A. Erhardt5 , Y. Cakalo˘glu6 , K. Yalcin7 , S. Gurel ¨ 8, 9 10 3 1,2 S. Zeuzem , T. Bock , R. Idilman , M.P. Manns , H. Wedemeyer1,2 . 1 Department of Gastroenterology, Hepatology and Endocrinology, 2 Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany; 3 Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey, 4 Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece, 5 Heinrich Heine University, D¨ usseldorf, Germany; 6 Memorial Hospital Istanbul, Istanbul, 7 Division of Hepatology, Dicle University, School of Medicine, Diyarbakir, 8 University of Uluda˘g Medical School, Bursa, Turkey, 9 Johann Wolfgang Goethe University, Frankfurt, 10 Robert Koch Institute, Berlin, Germany E-mail: [email protected] Background: Interferon alpha is the only effective treatment option for hepatitis delta. Recent trials investigating the efficacy of pegylated interferon alfa (PEG-IFNa) showed HDV-RNA negativity rates of 25–30% 24 weeks after therapy. However, the clinical and virological long-term outcome of HDV-infected patients treated with PEG-IFNa is unknown. Methods: We performed a retrospective-prospective follow-up of patients treated in the HIDIT-1 trial (NEJM 2011;364:322–31). Patients had been treated for 48 weeks with either PEG-alfa-2a plus adefovir dipivoxil (ADV) (Group-I), PEG-IFN-alfa-2a alone (GroupII), or adefovir dipivoxil alone (Group-III). Long-term follow-up data of patients who completed 24 weeks of post-treatment observation in the HIDIT-1 trial were available for 18 (75%), 19 (76%), and 21 (81%) of patients in groups I, II and III with a median time of follow-up of 3.9 (0.5–5.3), 4.2 (0.4–5.4), and 4.2 (0.4–5.5) years. Results: Clinical endpoints (death, liver transplantation, hepatic decompensation, HCC) during post-treatment follow-up were observed in 2 (11%), 1 (5%), and 3 (14%) patients, respectively with an overall annual event rate of 2.4%. Patients in group-III received significantly more often (re-) treatment with PEG-IFNa (n = 10; 48%) than patients in group I and II (17% and 26%; p = 0.04). Patients initially treated in the PEG-IFNa arms had significantly more often low HBV-DNA levels at the last follow-up visit compared to patients treated with ADV alone (94% and 58% vs. 43%; p = 0.012). HBsAg tested negative in 6 patients until the end-of follow-up (4 group-I, 2 group-II). 16 patients who were HDV-RNA negative 6 months after PEG-IFNa treatment entered the follow-up study (8 Group-I and 8 Group-II). Out of these, 8 individuals (3 group-I and 5 groupII)) tested HDV-RNA positive at least once during further follow-up with 7 patients being HDV-RNA positive at the most recent visit. Conclusions: The annual post-treatment rate of clinical events in hepatitis delta patients eligible for PEG-IFNa therapy is about 2–3%. A close monitoring after therapy is recommended even in patients being HDV-RNA negative 6 months after PEG-IFNa-based treatment as late relapses may occur. We are currently investigating if these cases represent real late HDV-RNA relapses or de novo infections.
Journal of Hepatology 2013 vol. 58 | S1–S24
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46 LONG-TERM FOLLOW-UP AFTER PEG-IFNa2a-BASED THERAPY OF CHRONIC HEPATITIS DELTA 3 B. Heidrich1,2 , C. Yurdaydın3 , G. Kabacam ¸ , K. Zachou1,4 , B. Bremer1 , G.N. Dalekos4 , A. Erhardt5 , Y. Cakalo˘glu6 , K. Yalcin7 , S. Gurel ¨ 8, 9 10 3 1,2 S. Zeuzem , T. Bock , R. Idilman , M.P. Manns , H. Wedemeyer1,2 . 1 Department of Gastroenterology, Hepatology and Endocrinology, 2 Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany; 3 Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey, 4 Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece, 5 Heinrich Heine University, D¨ usseldorf, Germany; 6 Memorial Hospital Istanbul, Istanbul, 7 Division of Hepatology, Dicle University, School of Medicine, Diyarbakir, 8 University of Uluda˘g Medical School, Bursa, Turkey, 9 Johann Wolfgang Goethe University, Frankfurt, 10 Robert Koch Institute, Berlin, Germany E-mail: [email protected] Background: Interferon alpha is the only effective treatment option for hepatitis delta. Recent trials investigating the efficacy of pegylated interferon alfa (PEG-IFNa) showed HDV-RNA negativity rates of 25–30% 24 weeks after therapy. However, the clinical and virological long-term outcome of HDV-infected patients treated with PEG-IFNa is unknown. Methods: We performed a retrospective-prospective follow-up of patients treated in the HIDIT-1 trial (NEJM 2011;364:322–31). Patients had been treated for 48 weeks with either PEG-alfa-2a plus adefovir dipivoxil (ADV) (Group-I), PEG-IFN-alfa-2a alone (GroupII), or adefovir dipivoxil alone (Group-III). Long-term follow-up data of patients who completed 24 weeks of post-treatment observation in the HIDIT-1 trial were available for 18 (75%), 19 (76%), and 21 (81%) of patients in groups I, II and III with a median time of follow-up of 3.9 (0.5–5.3), 4.2 (0.4–5.4), and 4.2 (0.4–5.5) years. Results: Clinical endpoints (death, liver transplantation, hepatic decompensation, HCC) during post-treatment follow-up were observed in 2 (11%), 1 (5%), and 3 (14%) patients, respectively with an overall annual event rate of 2.4%. Patients in group-III received significantly more often (re-) treatment with PEG-IFNa (n = 10; 48%) than patients in group I and II (17% and 26%; p = 0.04). Patients initially treated in the PEG-IFNa arms had significantly more often low HBV-DNA levels at the last follow-up visit compared to patients treated with ADV alone (94% and 58% vs. 43%; p = 0.012). HBsAg tested negative in 6 patients until the end-of follow-up (4 group-I, 2 group-II). 16 patients who were HDV-RNA negative 6 months after PEG-IFNa treatment entered the follow-up study (8 Group-I and 8 Group-II). Out of these, 8 individuals (3 group-I and 5 groupII)) tested HDV-RNA positive at least once during further follow-up with 7 patients being HDV-RNA positive at the most recent visit. Conclusions: The annual post-treatment rate of clinical events in hepatitis delta patients eligible for PEG-IFNa therapy is about 2–3%. A close monitoring after therapy is recommended even in patients being HDV-RNA negative 6 months after PEG-IFNa-based treatment as late relapses may occur. We are currently investigating if these cases represent real late HDV-RNA relapses or de novo infections.
Journal of Hepatology 2013 vol. 58 | S1–S24