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DOI: 10.1055/s-0037-1600522
Clinical Trial Design for Immune-Based Therapy of Hepatitis B Virus
Publikationsverlauf
Publikationsdatum:
31. Mai 2017 (online)
![](https://www.thieme-connect.de/media/sld/201702/lookinside/thumbnails/10-1055-s-0037-1600522_1600034-1.jpg)
Abstract
The treatment paradigm in hepatitis B virus is on the cusp of major development, with a multitude of novel agents undergoing testing for clinical efficacy. Such new immune therapies are urgently required for the treatment of chronic hepatitis B virus. The current direct antiviral therapies, although able to control viral replication and limit the progression to cirrhosis, require lifelong administration due to frequent viral rebound on treatment cessation, and immune modulation with interferon is only effective in a subpopulation of patients. Here the authors discuss novel agents in the pipeline along with whom and how best to utilize these immune therapies to achieve functional cure with defined treatment endpoints in chronic hepatitis B virus.
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References
- 1 Stanaway JD, Flaxman AD, Naghavi M. , et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet 2016; 388 (10049): 1081-1088
- 2 Liaw Y-F, Chu C-M. Hepatitis B virus infection. Lancet 2009; 373 (9663): 582-592
- 3 Ahmed F, Foster GR. Global hepatitis, migration and its impact on Western healthcare. Gut 2010; 59 (08) 1009-1011
- 4 Foster GR, Afdhal N, Roberts SK. , et al. ASTRAL-2 Investigators; ASTRAL-3 Investigators. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015; 373 (27) 2608-2617
- 5 Gish RG, Given BD, Lai C-L. , et al. Chronic hepatitis B: virology, natural history, current management and a glimpse at future opportunities. Antiviral Res 2015; 121: 47-58
- 6 Block TM, Gish R, Guo H. , et al. Chronic hepatitis B: what should be the goal for new therapies?. Antiviral Res 2013; 98 (01) 27-34
- 7 Zoulim F, Lebossé F, Levrero M. Current treatments for chronic hepatitis B virus infections. Curr Opin Virol 2016; 18: 109-116
- 8 Gill US, Zissimopoulos A, Al-Shamma S. , et al. Assessment of bone mineral density in tenofovir-treated patients with chronic hepatitis B: can the fracture risk assessment tool identify those at greatest risk?. J Infect Dis 2015; 211 (03) 374-382
- 9 Durantel D, Zoulim F. New antiviral targets for innovative treatment concepts for hepatitis B virus and hepatitis delta virus. J Hepatol 2016; 64 (1, Suppl) S117-S131
- 10 Bertoletti A, Rivino L. Hepatitis B: future curative strategies. Curr Opin Infect Dis 2014; 27 (06) 528-534
- 11 Maini MK, Gehring AJ. The role of innate immunity in the immunopathology and treatment of HBV infection. J Hepatol 2016; 64 (1, Suppl) S60-S70
- 12 Sato S, Li K, Kameyama T. , et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity 2015; 42 (01) 123-132
- 13 Lucifora J, Xia Y, Reisinger F. , et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 2014; 343 (6176): 1221-1228
- 14 Belloni L, Allweiss L, Guerrieri F. , et al. IFN-a inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest 2012; 122 (02) 529-537
- 15 McClary H, Koch R, Chisari FV, Guidotti LG. Relative sensitivity of hepatitis B virus and other hepatotropic viruses to the antiviral effects of cytokines. J Virol 2000; 74 (05) 2255-2264
- 16 Watashi K, Liang G, Iwamoto M. , et al. Interleukin-1 and tumor necrosis factor-a trigger restriction of hepatitis B virus infection via a cytidine deaminase activation-induced cytidine deaminase (AID). J Biol Chem 2013; 288 (44) 31715-31727
- 17 Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol 2013; 4: 57
- 18 Peppa D, Gill US, Reynolds G. , et al. Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion. J Exp Med 2013; 210 (01) 99-114
- 19 Fisicaro P, Valdatta C, Boni C. , et al. Early kinetics of innate and adaptive immune responses during hepatitis B virus infection. Gut 2009; 58 (07) 974-982
- 20 Webster GJ, Reignat S, Maini MK. , et al. Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms. Hepatology 2000; 32 (05) 1117-1124
- 21 Fletcher SP, Chin DJ, Gruenbaum L. , et al. Intrahepatic transcriptional signature associated with response to interferon-a treatment in the woodchuck model of chronic hepatitis B. PLoS Pathog 2015; 11 (09) e1005103-e1005131
- 22 Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol 2016; 64 (1, Suppl) S71-S83
- 23 Shouval D, Shibolet O. Immunosuppression and HBV reactivation. Semin Liver Dis 2013; 33 (02) 167-177
- 24 Michalak TI, Pasquinelli C, Guilhot S, Chisari FV. Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 1994; 93 (01) 230-239
- 25 Liang TJ, Block TM, McMahon BJ. , et al. Present and future therapies of hepatitis B: From discovery to cure. Hepatology 2015; 62 (06) 1893-1908
- 26 Isogawa M, Robek MD, Furuichi Y, Chisari FV. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol 2005; 79 (11) 7269-7272
- 27 Guo F, Han Y, Zhao X. , et al. STING agonists induce an innate antiviral immune response against hepatitis B virus. Antimicrob Agents Chemother 2015; 59 (02) 1273-1281
- 28 Menne S, Tumas DB, Liu KH. , et al. Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B. J Hepatol 2015; 62 (06) 1237-1245
- 29 Lanford RE, Guerra B, Chavez D. , et al. GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology 2013; 144 (07) 1508-1517 , 1517.e1–1517.e10
- 30 Gane EJ, Lim Y-S, Gordon SC. , et al. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. J Hepatol 2015; 63 (02) 320-328
- 31 Li F, Wei H, Wei H. , et al. Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. Gastroenterology 2013; 144 (02) 392-401
- 32 Kimura K, Kakimi K, Wieland S, Guidotti LG, Chisari FV. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. J Virol 2002; 76 (21) 10702-10707
- 33 Ji C, Sastry KSR, Tiefenthaler G. , et al. Targeted delivery of interferon-a to hepatitis B virus-infected cells using T-cell receptor-like antibodies. Hepatology 2012; 56 (06) 2027-2038
- 34 Jo J, Tan AT, Ussher JE. , et al. Toll-like receptor 8 agonist and bacteria trigger potent activation of innate immune cells in human liver. PLoS Pathog 2014; 10 (06) e1004210
- 35 Zhang TY, Yuan Q, Zhao JH. , et al. Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen. Gut 2016; 65 (04) 658-671
- 36 Boni C, Fisicaro P, Valdatta C. , et al. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007; 81 (08) 4215-4225
- 37 Fisicaro P, Valdatta C, Massari M. , et al. Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B. Gastroenterology 2010; 138 (02) 682-693 , 693.e1–693.e4
- 38 Gehring AJ, Haniffa M, Kennedy PT. , et al. Mobilizing monocytes to cross-present circulating viral antigen in chronic infection. J Clin Invest 2013; 123 (09) 3766-3776
- 39 Mancini-Bourgine M, Fontaine H, Scott-Algara D, Pol S, Bréchot C, Michel ML. Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology 2004; 40 (04) 874-882
- 40 Vandepapelière P, Lau GKK, Leroux-Roels G. , et al. Therapeutic HBV Vaccine Group of Investigators. Therapeutic vaccination of chronic hepatitis B patients with virus suppression by antiviral therapy: a randomized, controlled study of co-administration of HBsAg/AS02 candidate vaccine and lamivudine. Vaccine 2007; 25 (51) 8585-8597
- 41 Xu D-Z, Wang X-Y, Shen X-L. , et al. YIC Efficacy Trial Study Team. 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 (03) 450-456
- 42 Godon O, Fontaine H, Kahi S. , et al. Immunological and antiviral responses after therapeutic DNA immunization in chronic hepatitis B patients efficiently treated by analogues. Mol Ther 2014; 22 (03) 675-684
- 43 Lok AS, Pan CQ, Han S-HB. , 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 (03) 509-516
- 44 Kosinska AD, Zhang E, Johrden L. , 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 (06) e1003391
- 45 Costa R, Carneiro BA, Agulnik M. , et al. Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials. Oncotarget 2016; 5. [Epub ahead of print]
- 46 Abdel-Wahab N, Shah M, Suarez-Almazor ME. Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One 2016; 11 (07) e0160221
- 47 Aya F, Gaba L, Victoria I. , et al. Life-threatening colitis and complete response with ipilimumab in a patient with metastatic BRAF-mutant melanoma and rheumatoid arthritis. ESMO Open 2016; 1 (01) e000032
- 48 Wu W, Shi Y, Li S. , et al. Blockade of Tim-3 signaling restores the virus-specific CD8+ T-cell response in patients with chronic hepatitis B. Eur J Immunol 2012; 42 (05) 1180-1191
- 49 Kurktschiev PD, Raziorrouh B, Schraut W. , et al. Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction. J Exp Med 2014; 211 (10) 2047-2059
- 50 Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol 2014; 61 (06) 1212-1219
- 51 Schurich A, Pallett LJ, Jajbhay D. , et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Reports 2016; 16 (05) 1243-1252
- 52 Bohne F, Chmielewski M, Ebert G. , et al. T cells redirected against hepatitis B virus surface proteins eliminate infected hepatocytes. Gastroenterology 2008; 134 (01) 239-247
- 53 Gehring AJ, Xue S-A, Ho ZZ. , et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J Hepatol 2011; 55 (01) 103-110
- 54 Krebs K, Böttinger N, Huang LR. , et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 2013; 145 (02) 456-465
- 55 Qasim W, Brunetto M, Gehring AJ. , et al. Immunotherapy of HCC metastases with autologous T cell receptor redirected T cells, targeting HBsAg in a liver transplant patient. J Hepatol 2015; 62 (02) 486-491
- 56 European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012; 57 (01) 167-185
- 57 Mason WS, Gill US, Litwin S. , et al. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant. Gastroenterology 2016; 151 (05) 986-998.e4
- 58 Chen C-J, Yang H-I, Su J. , et al. REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295 (01) 65-73
- 59 Zoulim F, Mason WS. Reasons to consider earlier treatment of chronic HBV infections. Gut 2012; 61 (03) 333-336
- 60 Stabenow D, Frings M, Trück C. , et al. Bioluminescence imaging allows measuring CD8 T cell function in the liver. Hepatology 2010; 51 (04) 1430-1437
- 61 Maini MK, Boni C, Lee CK. , et al. The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000; 191 (08) 1269-1280
- 62 Webster GJM, Reignat S, Brown D. , et al. 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 (11) 5707-5719
- 63 Kennedy PTF, Sandalova E, Jo J. , et al. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology 2012; 143 (03) 637-645
- 64 Kollmann TR, Levy O, Montgomery RR, Goriely S. Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly. Immunity 2012; 37 (05) 771-783
- 65 Bertoletti A, Kennedy PT. The immune tolerant phase of chronic HBV infection: new perspectives on an old concept. Cell Mol Immunol 2015; 12 (03) 258-263
- 66 Beyer M, Abdullah Z, Chemnitz JM. , et al. Tumor-necrosis factor impairs CD4(+) T cell-mediated immunological control in chronic viral infection. Nat Immunol 2016; 17 (05) 593-603
- 67 Das A, Hoare M, Davies N. , et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J Exp Med 2008; 205 (09) 2111-2124
- 68 Sandalova E, Laccabue D, Boni C. , et al. Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells. Gastroenterology 2012; 143 (01) 78-87.e3
- 69 Pallett LJ, Gill US, Quaglia A. , et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med 2015; 21 (06) 591-600
- 70 Gotto J, Webster GJM, Brown D, Jenkins J, Dusheiko GM, Bertoletti A. The impact of HBV-DNA fluctuations on virus-specific CD8+ T cells in HBeAg+ chronic hepatitis B patients treated with a steroid and lamivudine. J Viral Hepat 2006; 13 (06) 415-425
- 71 Carey I, D'Antiga L, Bansal S. , et al. Immune and viral profile from tolerance to hepatitis B surface antigen clearance: a longitudinal study of vertically hepatitis B virus-infected children on combined therapy. J Virol 2011; 85 (05) 2416-2428
- 72 Loggi E, Bihl FK, Cursaro C. , et al. Virus-specific immune response in HBeAg-negative chronic hepatitis B: relationship with clinical profile and HBsAg serum levels. PLoS One 2013; 8 (06) e65327
- 73 Tseng TC, Liu CJ, Yang HC. , et al. High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load. Gastroenterology 2012; 142 (05) 1140-1149.e3 , quiz e13–e14
- 74 Rehermann B, Bertoletti A. Immunological aspects of antiviral therapy of chronic hepatitis B virus and hepatitis C virus infections. Hepatology 2015; 61 (02) 712-721
- 75 Neumann AU, Lam NP, Dahari H. , et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 1998; 282 (5386): 103-107
- 76 Micco L, Peppa D, Loggi E. , et al. Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B. J Hepatol 2013; 58 (02) 225-233
- 77 Gill US, Peppa D, Micco L. , et al. Interferon alpha induces sustained changes in NK cell responsiveness to hepatitis B viral load suppression in vivo. PLoS Pathog 2016; 12 (08) e1005788
- 78 Schurich A, Pallett LJ, Lubowiecki M. , et al. The third signal cytokine IL-12 rescues the anti-viral function of exhausted HBV-specific CD8 T cells. PLoS Pathog 2013; 9 (03) e1003208
- 79 Penna A, Laccabue D, Libri I. , et al. Peginterferon-a does not improve early peripheral blood HBV-specific T-cell responses in HBeAg-negative chronic hepatitis. J Hepatol 2012; 56 (06) 1239-1246
- 80 Rehermann B, Lau D, Hoofnagle JH, Chisari FV. Cytotoxic T lymphocyte responsiveness after resolution of chronic hepatitis B virus infection. J Clin Invest 1996; 97 (07) 1655-1665
- 81 Tan AT, Hoang LT, Chin D. , et al. Reduction of HBV replication prolongs the early immunological response to IFNa therapy. J Hepatol 2014; 60 (01) 54-61
- 82 Teijaro JR, Ng C, Lee AM. , et al. Persistent LCMV infection is controlled by blockade of type I interferon signaling. Science 2013; 340 (6129): 207-211
- 83 Wilson EB, Yamada DH, Elsaesser H. , et al. Blockade of chronic type I interferon signaling to control persistent LCMV infection. Science 2013; 340 6129 202-207
- 84 Crouse J, Bedenikovic G, Wiesel M. , et al. Type I interferons protect T cells against NK cell attack mediated by the activating receptor NCR1. Immunity 2014; 40 (06) 961-973
- 85 Eberhard JM, Kummer S, Hartjen P. , et al. Reduced CD161(+) MAIT cell frequencies in HCV and HIV/HCV co-infection: Is the liver the heart of the matter?. J Hepatol 2016; 65 (06) 1261-1263
- 86 van der Molen RG, Sprengers D, Biesta PJ, Kusters JG, Janssen HLA. Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV. Hepatology 2006; 44 (04) 907-914
- 87 Tjwa ETTL, van Oord GW, Hegmans JP, Janssen HLA, Woltman AM. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. J Hepatol 2011; 54 (02) 209-218
- 88 Peppa D, Micco L, Javaid A. , et al. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS Pathog 2010; 6 (12) e1001227
- 89 Zídek Z, Franková D, Holý A. Activation by 9-(R)-[2-(phosphonomethoxy)propyl]adenine of chemokine (RANTES, macrophage inflammatory protein 1alpha) and cytokine (tumor necrosis factor alpha, interleukin-10 [IL-10], IL-1beta) production. Antimicrob Agents Chemother 2001; 45 (12) 3381-3386
- 90 Melchjorsen J, Risør MW, Søgaard OS. , et al. Tenofovir selectively regulates production of inflammatory cytokines and shifts the IL-12/IL-10 balance in human primary cells. J Acquir Immune Defic Syndr 2011; 57 (04) 265-275
- 91 Boni C, Bertoletti A, Penna A. , et al. Lamivudine treatment can restore T cell responsiveness in chronic hepatitis B. J Clin Invest 1998; 102 (05) 968-975
- 92 Boni C, Penna A, Ogg GS. , et al. Lamivudine treatment can overcome cytotoxic T-cell hyporesponsiveness in chronic hepatitis B: new perspectives for immune therapy. Hepatology 2001; 33 (04) 963-971
- 93 Boni C, Laccabue D, Lampertico P. , et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012; 143 (04) 963-73.e9
- 94 Evans A, Riva A, Cooksley H. , et al. Programmed death 1 expression during antiviral treatment of chronic hepatitis B: impact of hepatitis B e-antigen seroconversion. Hepatology 2008; 48 (03) 759-769
- 95 Chen Y, Li X, Ye B. , et al. Effect of telbivudine therapy on the cellular immune response in chronic hepatitis B. Antiviral Res 2011; 91 (01) 23-31
- 96 Wursthorn K, Jung M, Riva A. , et al. Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients. Hepatology 2010; 52 (05) 1611-1620
- 97 Guidotti LG, Inverso D, Sironi L. , et al. Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell 2015; 161 (03) 486-500
- 98 Liu J, Zhang E, Ma Z. , et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog 2014; 10 (01) e1003856
- 99 Thimme R, Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B?. J Hepatol 2013; 58 (02) 205-209
- 100 Marcellin P, Ahn SH, Ma X. , et al. Study 149 Investigators. Combination of tenofovir disoproxil fumarate and peginterferon a-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology 2016; 150 (01) 134-144.e10
- 101 Brouwer WP, Xie Q, Sonneveld MJ. , et al. ARES Study Group. Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: a multicenter randomized trial (ARES study). Hepatology 2015; 61 (05) 1512-1522
- 102 Siederdissen C Höner Zu, Rinker F, Maasoumy B. , et al. Viral and host responses after stopping long-term nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Infect Dis 2016; 214 (10) 1492-1497