A meta-analysis of the antiviral activity of the HBV-specific immunotherapeutic TG1050 confirms its value over a wide range of HBsAg levels in a persistent HBV pre-clinical model

References

• Martin P, Dubois C, Jacquier E, Dion S, Mancini-Bourgine M, Godon O, Kratzer R, Lelu-Santolaria K, Evlachev A, Meritet JF, et al. TG1050, an immunotherapeutic to treat chronic hepatitis B, induces robust T cells and exerts an antiviral effect in HBV-persistent mice. Gut. 2015;64:1961–71. doi:10.1136/gutjnl-2014-308041. PMID:25429051.
   PubMed Web of Science ®Google Scholar
• World Health Organization. http://www.who.int/mediacentre/factsheets/fs204/en/. 2017.
   Google Scholar
• Brahmania M, Feld J, Arif A, Janssen HL. New therapeutic agents for chronic hepatitis B. Lancet Infect Dis. 2016;16:e10–21. doi:10.1016/S1473-3099(15)00436-3. PMID:26795693.
   PubMed Web of Science ®Google Scholar
• Rehermann B. Pathogenesis of chronic viral hepatitis: differential roles of T cells and NK cells. Nat Med. 2013;19:859–68. doi:10.1038/nm.3251. PMID:23836236.
   PubMed Web of Science ®Google Scholar
• Jaroszewicz J, Calle Serrano B, Wursthorn K, Deterding K, Schlue J, Raupach R, Flisiak R, Bock CT, Manns MP, Wedemeyer H, et al. Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective. J Hepatol. 2010;52:514–22. doi:10.1016/j.jhep.2010.01.014. PMID:20207438.
   PubMed Web of Science ®Google Scholar
• Dion S, Bourgine M, Godon O, Levillayer F, Michel ML. Adeno-associated virus-mediated gene transfer leads to persistent hepatitis B virus replication in mice expressing HLA-A2 and HLA-DR1 molecules. J Virol. 2013;87:5554–63. doi:10.1128/JVI.03134-12. PMID:23468504.
   PubMed Web of Science ®Google Scholar
• Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Statistical Software. 2010;36:1–48. doi:10.18637/jss.v036.i03.
   Web of Science ®Google Scholar
• Kondo Y, Ninomiya M, Kakazu E, Kimura O, Shimosegawa T. Hepatitis B surface antigen could contribute to the immunopathogenesis of hepatitis B virus infection. ISRN Gastroenterol. 2013;2013:935295. PMID:23401786.
   PubMedGoogle Scholar
• Zhu D, Liu L, Yang D, Fu S, Bian Y, Sun Z, Zhang L, Peng H, Fu YX. Clearing persistent extracellular antigen of hepatitis B Virus: An immunomodulatory strategy to reverse tolerance for an effective therapeutic vaccination. J Immunol. 2016;196:3079–87. doi:10.4049/jimmunol.1502061. PMID:26936879.
   PubMed Web of Science ®Google Scholar
• Chen GY, Zhu MF, Zheng DL, Bao YT, Wang J, Zhou X, Lou GQ. Baseline HBsAg predicts response to pegylated interferon-alpha2b in HBeAg-positive chronic hepatitis B patients. World J Gastroenterol. 2014;20:8195–200. doi:10.3748/wjg.v20.i25.8195. PMID:25009392.
   PubMed Web of Science ®Google Scholar
• Li MH, Zhang L, Qu XJ, Lu Y, Shen G, Wu SL, Chang M, Liu RY, Hu LP, Li ZZ, et al. Kinetics of hepatitis B surface antigen level in chronic hepatitis B patients who achieved hepatitis B surface antigen loss during Pegylated Interferon Alpha-2a treatment. Chin Med J (Engl). 2017;130:559–65. doi:10.4103/0366-6999.200554. PMID:28229987.
   PubMed Web of Science ®Google Scholar
• Rijckborst V, Hansen BE, Cakaloglu Y, Ferenci P, Tabak F, Akdogan M, Simon K, Akarca US, Flisiak R, Verhey E, et al. Early on-treatment prediction of response to peginterferon alfa-2a for HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatology. 2010;52:454–61. doi:10.1002/hep.23722. PMID:20683945.
   PubMed Web of Science ®Google Scholar
• Sonneveld MJ, Rijckborst V, Boucher CA, Hansen BE, Janssen HL. Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. Hepatology. 2010;52:1251–7. doi:10.1002/hep.23844. PMID:20830787.
   PubMed Web of Science ®Google Scholar
• Backes S, Jager C, Dembek CJ, Kosinska AD, Bauer T, Stephan AS, Dišlers A, Mutwiri G, Busch DH, Babiuk LA, et al. Protein-prime/modified vaccinia virus Ankara vector-boost vaccination overcomes tolerance in high-antigenemic HBV-transgenic mice. Vaccine. 2016;34:923–32. doi:10.1016/j.vaccine.2015.12.060. PMID:26776470.
   PubMed Web of Science ®Google Scholar
• Maini MK, Boni C, Ogg GS, King AS, Reignat S, Lee CK, Larrubia JR, Webster GJ, McMichael AJ, Ferrari C, et al. Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection. Gastroenterology. 1999;117:1386–96. doi:10.1016/S0016-5085(99)70289-1. PMID:10579980.
   PubMed Web of Science ®Google Scholar
• Korevaar DA, Hooft L, ter Riet G. Systematic reviews and meta-analyses of preclinical studies: publication bias in laboratory animal experiments. Lab Anim. 2011;45:225–30. doi:10.1258/la.2011.010121. PMID:21737463.
   PubMedGoogle Scholar
• Lélu K, Evlachev A, Kratzer R, Dion S, Mancini-Bourgine M, Godon O, Schmitt D, Dubois C, Méritet, JF, Schlesinger Y, et al. TG1050, a novel immunotherapeutic to treat chronic hepatitis B, can control HBsAg and provoke HBsAg seroconversion in HBV-persistent mouse models. 50th Annual meeting of the European Association for the Study of the Liver (EASL). Vienna, Austria: J Hepatol. 2015:S187–S931.
   Google Scholar
• Akbar S, Mishiro S, Mahtab MA, Rahman S, Aguilar J. A phase III clinical trial with a therapeutic vaccine containing both HBsAg and HBcAg administered via both mucosal and parenteral routes in patients with chronic hepatitis B. Poster presented at AASLD Liver Meeting, 2013. https://liverlearning.aasld.org/aasld/2013/thelivermeeting/35877/sheikh.mohammad.fazle.akbar.a.phase.iii.clinical.trial.with.a.therapeutic.html.
   Google Scholar
• Xu DZ, Wang XY, Shen XL, Gong GZ, Ren H, Guo LM, Sun AM, Xu M, Li LJ, Guo XH, et al. Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. J Hepatol. 2013;59:450–6. doi:10.1016/j.jhep.2013.05.003. PMID:23669281.
   PubMed Web of Science ®Google Scholar
• Lok AS, Pan CQ, Han SH, Trinh HN, Fessel WJ, Rodell T, Massetto B, Lin L, Gaggar A, Subramanian GM, et al. Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J Hepatol. 2016;65:509–16. doi:10.1016/j.jhep.2016.05.016. PMID:27210427.
   PubMed Web of Science ®Google Scholar
• Godon O, Fontaine H, Kahi S, Meritet JF, Scott-Algara D, Pol S, Michel ML, Bourgine M. Immunological and antiviral responses after therapeutic DNA immunization in chronic hepatitis B patients efficiently treated by analogues. Mol Ther. 2014;22:675–84. doi:10.1038/mt.2013.274. PMID:24394187.
   PubMed Web of Science ®Google Scholar
• Kosinska AD, Zhang E, Johrden L, Liu J, Seiz PL, Zhang X, Ma Z, Kemper T, Fiedler M, Glebe D, et al. Combination of DNA prime–adenovirus boost immunization with entecavir elicits sustained control of chronic hepatitis B in the woodchuck model. PLoS Pathog. 2013;9:e1003391. doi:10.1371/journal.ppat.1003391. PMID:23785279.
   PubMed Web of Science ®Google Scholar
• Webster GJ, Reignat S, Brown D, Ogg GS, Jones L, Seneviratne SL, Williams R, Dusheiko G, Bertoletti A. Longitudinal analysis of CD8+ T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B: implications for immunotherapy. J Virol. 2004;78:5707–19. doi:10.1128/JVI.78.11.5707-5719.2004. PMID:15140968.
   PubMed Web of Science ®Google Scholar
• Le Bert N, Rivino L, Gill U, Cheng Y, Kunasegaran K, Tan D, Koh S, Becht E, Hansi N, Foster G, et al. An immunological biomarker to predict hepatic flares upon NUC therapy discontinuation in chronic hepatits B. J Hepatol. 2016;64:S164–S5 doi:10.1016/S0168-8278(16)01672-X.
   Web of Science ®Google Scholar
• Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, Chisari FV. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol. 2003;77:68–76. doi:10.1128/JVI.77.1.68-76.2003. PMID:12477811.
   PubMed Web of Science ®Google Scholar
• Boni C, Laccabue D, Lampertico P, Giuberti T, Vigano M, Schivazappa S, Alfieri A, Pesci M, Gaeta GB, Brancaccio G, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology. 2012;143:963–73 e9. doi:10.1053/j.gastro.2012.07.014. PMID:22796241.
   PubMed Web of Science ®Google Scholar
• Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology. 2015;61:712–21. doi:10.1002/hep.27323. PMID:25048716.
   PubMed Web of Science ®Google Scholar