Clinical Trial Design for Immune-Based Therapy of Hepatitis B Virus

Upkar S. Gill; Antonio Bertoletti

doi:10.1055/s-0037-1600522

Seminars in Liver Disease, Table of Contents

Semin Liver Dis 2017; 37(02): 085-094
DOI: 10.1055/s-0037-1600522

The Immune-Inflammation Connection

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA

Clinical Trial Design for Immune-Based Therapy of Hepatitis B Virus

Authors

Upkar S. Gill

¹Department of Hepatology, Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, United Kingdom

²Program Emerging Infectious Diseases, Duke-NUS Medical School, Singapore
Antonio Bertoletti

²Program Emerging Infectious Diseases, Duke-NUS Medical School, Singapore

³Infection and Immunity Program, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore

⁴Singapore Immunology Network, Singapore Agency for Science, Technology and Research (A*STAR), Singapore

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.

Keywords

chronic hepatitis B - T-cell therapy - toll-like receptor agonists - immune-tolerance - viral hepatitis

Full Text

References

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