Anti-HBV drugs: Progress, unmet needs, and new hope

Viruses

Volumn 7, Issue 9, 2015, Pages 4960-4977

  Kang, Lei ^a   Pan, Jiaqian ^a   Wu, Jiaofen ^b   Hu, Jiali ^c   Sun, Qian ^a   Tang, Jing ^a  

^a SHANGHAI JIAO TONG UNIVERSITY   (China)

^b Ningbo Lihuili Hospital (Ningbo Medical Centre)   (China)

^c The Third Staff Hospital of Baogang Group   (China)

Author keywords

Anti HBV drugs; Guidelines; Hepatitis B virus; Research and development

Indexed keywords

ADEFOVIR; ANAPHASE PROMOTING COMPLEX SUBUNIT 8; CYTOKINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; ENTECAVIR; HEPATITIS B SURFACE ANTIGEN; INTERFERON; IPILIMUMAB; LA ANTIGEN; LAMIVUDINE; MICRORNA; NIVOLUMAB; PEMBROLIZUMAB; PROGRAMMED DEATH 1 RECEPTOR; TELBIVUDINE; TENOFOVIR; THYMOSIN ALPHA1; TOLL LIKE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR RECEPTOR ASSOCIATED DEATH DOMAIN DEATH DOMAIN PROTEIN; UNCLASSIFIED DRUG; VIRUS PROTEIN; ANTIVIRUS AGENT;

CAENORHABDITIS ELEGANS; CRASSULACEAE; DNA DEGRADATION; DRUG GRANULE; DRUG RESISTANCE; FEVER; GENE EXPRESSION; HAIR LOSS; HEPATITIS B; HEPATITIS B VIRUS; HUMAN; IMMUNE SYSTEM; INFLAMMATION; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER INJURY; NEPHROTOXICITY; REVIEW; SEDUM SARMENTOSUM GRANULE; SOPHORA; DRUG APPROVAL; DRUG DEVELOPMENT; DRUG EFFECTS; HEPATITIS B, CHRONIC; ISOLATION AND PURIFICATION; PRACTICE GUIDELINE; TRENDS;

ANTIVIRAL AGENTS; DRUG APPROVAL; DRUG DISCOVERY; HEPATITIS B VIRUS; HEPATITIS B, CHRONIC; HUMANS; PRACTICE GUIDELINES AS TOPIC;

EID: 84941686701     PISSN: None     EISSN: 19994915     Source Type: Journal    
DOI: 10.3390/v7092854     Document Type: Review

References (97)

1. Grimm, D.; Thimme, R.; Blum, H.E. HBV life cycle and novel drug targets. Hepatol. Int. 2011, 5, 644–653.
2. Stein, L.L.; Loomba, R. Drug targets in hepatitis B virus infection. Infect. Disord. Drug Targets 2009, 9, 105–116.
3. WHO. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Available online: http://www.who.int/hiv/pub/hepatitis/hepatitis-b-guidelines/en/ (accessed on 8 July 2015).
4. Lu, F.M.; Zhuang, H. Management of hepatitis B in China. Chin. Med. J. 2009, 122, 3–4.
5. Bhattacharya, D.; Thio, C.L. Review of hepatitis B therapeutics. Clin. Infect. Dis. 2010, 51, 1201–1208.
6. Lozano, R.; Naghavi, M.; Foreman, K.; Lim, S.; Shibuya, K.; Aboyans, V.; Abraham, J.; Adair, T.; Aggarwal, R.; Ahn, S.Y.; et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the global burden of disease study 2010. Lancet 2012, 380, 2095–2128.
7. Chen, A.; Panjaworayan, T.T.N.; Brown, C.M. Prospects for inhibiting the post-transcriptional regulation of gene expression in hepatitis B virus. World J. Gastroenterol. 2014, 20, 7993–8004.
8. Levrero, M.; Pollicino, T.; Petersen, J.; Belloni, L.; Raimondo, G.; Dandri, M. Control of cccDNA function in hepatitis B virus infection. J. Hepatol. 2009, 51, 581–592.
9. Bharadwaj, M.; Roy, G.; Dutta, K.; Misbah, M.; Husain, M.; Hussain, S. Tackling hepatitis B virus-associated hepatocellular carcinoma—The future is now. Cancer Metastasis Rev. 2013, 32, 229–268.
10. Singer, G.A.; Zielsdorf, S.; Fleetwood, V.A.; Alvey, N.; Cohen, E.; Eswaran, S.; Shah, N.; Chan, E.Y.; Hertl, M.; Fayek, S.A. Limited hepatitis b immunoglobulin with potent nucleos(t)ide analogue is a cost-effective prophylaxis against hepatitis b virus after liver transplantation. Transplant. Proc. 2015, 47, 478–484.
11. Seeger, C.; Mason, W.S. Molecular biology of hepatitis b virus infection. Virology 2015, 479–480, 672–686.
12. Zhao, Z.M.; Jin, Y.; Gan, Y.; Zhu, Y.; Chen, T.Y.; Wang, J.B.; Sun, Y.; Cao, Z.G.; Qian, G.S.; Tu, H. Novel approach to identifying the hepatitis B virus pre-s deletions associated with hepatocellular carcinoma. World J. Gastroenterol. 2014, 20, 13573–13581.
13. Yan, H.; Zhong, G.; Xu, G.; He, W.; Jing, Z.; Gao, Z.; Huang, Y.; Qi, Y.; Peng, B.; Wang, H.; et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and d virus. eLife 2012, 1, e00049.
14. Chua, P.K.; Wang, R.Y.; Lin, M.H.; Masuda, T.; Suk, F.M.; Shih, C. Reduced secretion of virions and hepatitis B virus (HBV) surface antigen of a naturally occurring HBV variant correlates with the accumulation of the small s envelope protein in the endoplasmic reticulum and golgi apparatus. J. Virol. 2005, 79, 13483–13496.
15. Gaggar, A.; Coeshott, C.; Apelian, D.; Rodell, T.; Armstrong, B.R.; Shen, G.; Subramanian, G.M.; McHutchison, J.G. Safety, tolerability and immunogenicity of gs-4774, a hepatitis B virus-specific therapeutic vaccine, in healthy subjects: A randomized study. Vaccine 2014, 32, 4925–4931.
16. Jiang, W. Blockade of b7-h1 enhances dendritic cell-mediated T cell response and antiviral immunity in HBV transgenic mice. Vaccine 2012, 30, 758–766.
17. Tian, Y.; Chen, W.L.; Ou, J.H. Effects of interferon-alpha/beta on HBV replication determined by viral load. PLoS Pathog. 2011, 7, e1002159.
18. Liaw, Y.F.; Kao, J.H.; Piratvisuth, T.; Chien, R.N. Asian-pacific consensus statement on the management of chronic hepatitis B: A 2012 update. Hepatol. Int. 2012, 6, 531–561.
19. Xiang, X.G.; Xie, Q. IL-35: A potential therapeutic target for controlling hepatitis B virus infection. J. Dig. Dis. 2015, 16, 1–6.
20. Lai, C.L.; Dienstag, J.; Schiff, E.; Leung, N.W.; Atkins, M.; Hunt, C.; Brown, N.; Woessner, M.; Boehme, R.; Condreay, L. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin. Infect. Dis. 2003, 36, 687–696.
21. Yao, G.B.; Zhu, M.; Cui, Z.Y.; Wang, B.E.; Yao, J.L.; Zeng, M.D. A 7-year study of lamivudine therapy for hepatitis B virus E antigen-positive chronic hepatitis B patients in china. J. Dig. Dis. 2009, 10, 131–137.
22. Hou, J.; Yin, Y.K.; Xu, D.; Tan, D.; Niu, J.; Zhou, X.; Wang, Y.; Zhu, L.; He, Y.; Ren, H.; et al. Telbivudine versus lamivudine in chinese patients with chronic hepatitis B: Results at 1 year of a randomized, double-blind trial. Hepatology 2008, 47, 447–454.
23. Liaw, Y.F.; Gane, E.; Leung, N.; Zeuzem, S.; Wang, Y.; Lai, C.L.; Heathcote, E.J.; Manns, M.; Bzowej, N.; Niu, J. et al. 2-year globe trial results: Telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009, 136, 486–495.
24. Papatheodoridis, G.; Buti, M.; Cornberg, M.; Janssen, H.; Mutimer, D. Easl clinical practice guidelines: Management of chronic hepatitis B virus infection. J. Hepatol. 2012, 57, 167–185.
25. Zhang, Q.; Han, T.; Nie, C.Y.; Ha, F.S.; Liu, L.; Liu, H. Tenofovir rescue regimen following prior suboptimal response to entecavir and adefovir combination therapy in chronic hepatitis B patients exposed to multiple treatment failures. J. Med. Virol. 2015, 87, 1013–1021.
26. Yatsuji, H.; Suzuki, F.; Sezaki, H.; Akuta, N.; Suzuki, Y.; Kawamura, Y.; Hosaka, T.; Kobayashi, M.; Saitoh, S.; Arase, Y.; et al. Low risk of adefovir resistance in lamivudine-resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: Two-year follow-up. J. Hepatol. 2008, 48, 923–931.
27. Lee, J.M.; Park, J.Y.; Kim do, Y.; Nguyen, T.; Hong, S.P.; Kim, S.O.; Chon, C.Y.; Han, K.H.; Ahn, S.H. Long-term adefovir dipivoxil monotherapy for up to 5 years in lamivudine-resistant chronic hepatitis B. Antivir. Ther. 2010, 15, 235–241.
28. Ninomiya, K.; Morikawa, T.; Zhang, Y.; Nakamura, S.; Matsuda, H.; Muraoka, O.; Yoshikawa, M. Bioactive constituents from chinese natural medicines. Xxiii. Absolute structures of new megastigmane glycosides, sedumosides a(4), a(5), a(6), H, and I, and hepatoprotective megastigmanes from sedum sarmentosum. Chem. Pharm. Bull. 2007, 55, 1185–1191.
29. Lian, L.H.; Jin, X.; Wu, Y.L.; Cai, X.F.; Lee, J.J.; Nan, J.X. Hepatoprotective effects of sedum sarmentosum on d-galactosamine/lipopolysaccharide-induced murine fulminant hepatic failure. J. Pharmacol. Sci. 2010, 114, 147–157.
30. He, A.; Wang, M.; Hao, H.; Zhang, D.; Lee, K.H. Hepatoprotective triterpenes from sedum sarmentosum. Phytochemistry 1998, 49, 2607–2610.
31. Epivir-hbv Prescribing Information. GlaxoSmithKline. Available online: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2013/021003s015,021004s015lbl.pdf. 20-Dec-2013 (accessed on 16 August 2015).
32. Sebivo prescribing information. Novartis Pharmaceuticals UK Ltd. Available online: http://www.medicines.org.uk/emc/medicine/19740. 02-Feb-2015 (accessed on 16 August 2015).
33. Baraclude Prescribing Information. Bristol-Myers Squibb Pharmaceutical Limited. Available online: http://www.medicines.org.uk/emc/medicine/18377 (accessed on 16 August 2015).
34. Adefovir Dipivoxil Prescribing Information. SigmaPharm Laboratories, LLC. Available online: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/202051Orig1s000lbl.pdf (accessed on 16 August 2015).
35. Viread Prescribing Information. Gilead Sciences, Inc. Available online: http://www.accessdata.fda.gov/ drugsatfda_docs/label/2015/021356s049,022577s007lbl.pdf (accessed on 16 August 2015).
36. Chen, X.S.; Wang, G.J.; Cai, X.; Yu, H.Y.; Hu, Y.P. Inhibition of hepatitis b virus by oxymatrine in vivo. World J. Gastroenterol. 2001, 7, 49–52.
37. Lu, L.G.; Zeng, M.D.; Mao, Y.M.; Fang, J.Y.; Song, Y.L.; Shen, Z.H.; Cao, A.P. Inhibitory effect of oxymatrine on serum hepatitis B virus DNA in HBV transgenic mice. World J. Gastroenterol. 2004, 10, 1176–1179.
38. Lu, L.G.; Zeng, M.D.; Mao, Y.M.; Li, J.Q.; Wan, M.B.; Li, C.Z.; Chen, C.W.; Fu, Q.C.; Wang, J.Y.; She, W.M.; et al. Oxymatrine therapy for chronic hepatitis B: A randomized double-blind and placebo-controlled multi-center trial. World J. Gastroenterol. 2003, 9, 2480–2483.
39. Wang, Y.P.; Zhao, W.; Xue, R.; Zhou, Z.X.; Liu, F.; Han, Y.X.; Ren, G.; Peng, Z.G.; Cen, S.; Chen, H.S.; et al. Oxymatrine inhibits hepatitis b infection with an advantage of overcoming drug-resistance. Antivir. Res. 2011, 89, 227–231.
40. Xu, W.S.; Zhao, K.K.; Miao, X.H.; Ni, W.; Cai, X.; Zhang, R.Q.; Wang, J.X. Effect of oxymatrine on the replication cycle of hepatitis B virus in vitro. World J. Gastroenterol. 2010, 16, 2028–2037.
41. Wang, Y.P.; Liu, F.; He, H.W.; Han, Y.X.; Peng, Z.G.; Li, B.W.; You, X.F.; Song, D.Q.; Li, Z.R.; Yu, L.Y.; et al. Heat stress cognate 70 host protein as a potential drug target against drug resistance in hepatitis B virus. Antimicrob. Agents Chemother. 2010, 54, 2070–2077.
42. Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association. The guidelines of prevention and treatment for chronic hepatitis B. Zhonghua Gan Zang Bing Za Zhi 2005, 13, 881–891. (In Chinese).
43. Soon, D.K.; Lowe, S.L.; Teng, C.H.; Yeo, K.P.; McGill, J.; Wise, S.D. Safety and efficacy of alamifovir in patients with chronic hepatitis b virus infection. J. Hepatol. 2004, 41, 852–858.
44. Chan, C.; Abu-Raddad, E.; Golor, G.; Watanabe, H.; Sasaki, A.; Yeo, K.P.; Soon, D.; Sinha, V.P.; Flanagan, S.D.; He, M.M.; et al. Clinical pharmacokinetics of alamifovir and its metabolites. Antimicrob. Agents Chemother. 2005, 49, 1813–1822.
45. Ono-Nita, S.K.; Kato, N.; Shiratori, Y.; Carrilho, F.J.; Omata, M. Novel nucleoside analogue mcc-478 (ly582563) is effective against wild-type or lamivudine-resistant hepatitis B virus. Antimicrob. Agents Chemother. 2002, 46, 2602–2605.
46. Kamiya, N.; Kubota, A.; Iwase, Y.; Sekiya, K.; Ubasawa, M.; Yuasa, S. Antiviral activities of mcc-478, a novel and specific inhibitor of hepatitis B virus. Antimicrob. Agents Chemother. 2002, 46, 2872–2877.
47. Wu, T.T.; Coates, L.; Aldrich, C.E.; Summers, J.; Mason, W.S. In hepatocytes infected with duck hepatitis B virus, the template for viral RNA synthesis is amplified by an intracellular pathway. Virology 1990, 175, 255–261.
48. Locarnini, S.A.; Yuen, L. Molecular genesis of drug-resistant and vaccine-escape HBV mutants. Antivir. Ther. 2010, 15, 451–461.
49. Lucifora, J.; Xia, Y.; Reisinger, F.; Zhang, K.; Stadler, D.; Cheng, X.; Sprinzl, M.F.; Koppensteiner, H.; Makowska, Z.; Volz, T.; et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccdna. Science 2014, 343, 1221–1228.
50. Thomas, H.C.; Karayiannis, P.; Brook, G. Treatment of hepatitis b virus infection with interferon. Factors predicting response to interferon. J. Hepatol. 1991, 1, S4–S7.
51. Zhang, F.; Wang, G. A review of non-nucleoside anti-hepatitis B virus agents. Eur. J. Med. Chem. 2014, 75, 267–281.
52. Fattovich, G.; Giustina, G.; Favarato, S.; Ruol, A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with Alfa interferon. J. Hepatol. 1996, 24, 38–47.
53. Muckenfuss, H.; Hamdorf, M.; Held, U.; Perkovic, M.; Lower, J.; Cichutek, K.; Flory, E.; Schumann, G.G.; Munk, C. Apobec3 proteins inhibit human line-1 retrotransposition. J. Biol. Chem. 2006, 281, 22161–22172.
54. Stenglein, M.D.; Burns, M.B.; Li, M.; Lengyel, J.; Harris, R.S. Apobec3 proteins mediate the clearance of foreign DNA from human cells. Nat. Struct. Mol. Biol. 2010, 17, 222–229.
55. Carpenter, M.A.; Li, M.; Rathore, A.; Lackey, L.; Law, E.K.; Land, A.M.; Leonard, B.; Shandilya, S.M.; Bohn, M.F.; Schiffer, C.A.; et al. Methylcytosine and normal cytosine deamination by the foreign DNA restriction enzyme apobec3a. J. Biol. Chem. 2012, 287, 34801–34808.
56. Krebs, K.; Böttinger, N.; Huang, L.R.; Chmielewski, M.; Arzberger, S.; Gasteiger, G.; Jäger, C.; Schmitt, E.; Bohne, F.; Aichler, M.; et al. T cells expressing a chimeric antigen receptor that binds hepatitis b virus envelope proteins control virus replication in mice. Gastroenterology 2013, 145, 456–465.
57. Ahmed, M.; Wang, F.; Levin, A.; Le, C.; Eltayebi, Y.; Houghton, M.; Tyrrell, L.; Barakat, K. Targeting the achilles heel of the hepatitis b virus: A review of current treatments against covalently closed circular DNA. Drug Discov. Today 2015, 20, 548–561.
58. Jagya, N.; Varma, S.P.; Thakral, D.; Joshi, P.; Durgapal, H.; Panda, S.K. Rna-seq based transcriptome analysis of hepatitis e virus (HEV) and hepatitis b virus (HBV) replicon transfected huh-7 cells. PLoS ONE 2014, 9, e87835.
59. Cheng, Y.C.; Ying, C.X.; Leung, C.H.; Li, Y. New targets and inhibitors of HBV replication to combat drug resistance. J. Clin. Virol. 2005, 34, S147–S150.
60. Ying, C.; Li, Y.; Leung, C.H.; Robek, M.D.; Cheng, Y.C. Unique antiviral mechanism discovered in anti-hepatitis B virus research with a natural product analogue. Proc. Natl. Acad. Sci. USA 2007, 104, 8526–8531.
61. Janmanchi, D.; Tseng, Y.P.; Wang, K.C.; Huang, R.L.; Lin, C.H.; Yeh, S.F. Synthesis and the biological evaluation of arylnaphthalene lignans as anti-hepatitis B virus agents. Bioorg. Med. Chem. 2010, 18, 1213–1226.
62. Janmanchi, D.; Lin, C.H.; Hsieh, J.Y.; Tseng, Y.P.; Chen, T.A.; Jhuang, H.J.; Yeh, S.F. Synthesis and biological evaluation of helioxanthin analogues. Bioorg. Med. Chem. 2013, 21, 2163–2176.
63. Tseng, Y.P.; Kuo, Y.H.; Hu, C.P.; Jeng, K.S.; Janmanchi, D.; Lin, C.H.; Chou, C.K.; Yeh, S.F. The role of helioxanthin in inhibiting human hepatitis B viral replication and gene expression by interfering with the host transcriptional machinery of viral promoters. Antivir. Res. 2008, 77, 206–214.
64. Pang, R.; Tao, J.Y.; Zhang, S.L.; Chen, K.L.; Zhao, L.; Yue, X.; Wang, Y.F.; Ye, P.; Zhu, Y.; Wu, J.G. Ethanol extract from ampelopsis sinica root exerts anti-hepatitis B virus activity via inhibition of p53 pathway in vitro. Evid. Based Complement. Altern. Med. 2011, 2011, e939205.
65. Le Seyec, J.; Chouteau, P.; Cannie, I.; Guguen-Guillouzo, C.; Gripon, P. Infection process of the hepatitis b virus depends on the presence of a defined sequence in the pre-s1 domain. J. Virol. 1999, 73, 2052–2057.
66. Blanchet, M.; Sureau, C. Infectivity determinants of the hepatitis b virus pre-s domain are confined to the N-terminal 75 amino acid residues. J. Virol. 2007, 81, 5841–5849.
67. Volz, T.; Allweiss, L.; ḾBarek, M.B.; Warlich, M.; Lohse, A.W.; Pollok, J.M.; Alexandrov, A.; Urban, S.; Petersen, J.; Lütgehetmann, M.; et al. The entry inhibitor myrcludex-b efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis b virus. J. Hepatol. 2013, 58, 861–867.
68. Yan, H.; Peng, B.; Liu, Y.; Xu, G.; He, W.; Ren, B.; Jing, Z.; Sui, J.; Li, W. Viral entry of hepatitis b and d viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide. J. Virol. 2014, 88, 3273–3284.
69. Slijepcevic, D.; Kaufman, C.; Wichers, C.G.; Gilglioni, E.H.; Lempp, F.A.; Duijst, S.; de Waart, D.R.; Elferink, R.P.; Mier, W.; Stieger, B.; et al. Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice. Hepatology 2015, 62, 207–219.
70. Tsukuda, S.; Watashi, K.; Iwamoto, M.; Suzuki, R.; Aizaki, H.; Okada, M.; Sugiyama, M.; Kojima, S.; Tanaka, Y.; Mizokami, M.; et al. Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis b virus infection through modulation of sodium taurocholate cotransporting polypeptide (NTCP) expression. J. Biol. Chem. 2015, 290, 5673–5684.
71. Bouezzedine, F.; Fardel, O.; Gripon, P. Interleukin 6 inhibits HBV entry through NTCP down regulation. Virology 2015, 481, 34–42.
72. Isogawa, M.; Robek, M.D.; Furuichi, Y.; Chisari, F.V. Toll-like receptor signaling inhibits hepatitis b virus replication in vivo. J. Virol. 2005, 79, 7269–7272.
73. Lopatin, U.; Wolfgang, G.; Tumas, D.; Frey, C.R.; Ohmstede, C.; Hesselgesser, J.; Kearney, B.; Moorehead, L.; Subramanian, G.M.; McHutchison, J.G. Safety, pharmacokinetics and pharmacodynamics of gs-9620, an oral toll-like receptor 7 agonist. Antivir. Ther. 2013, 18, 409–418.
74. Lawitz, E.; Gruener, D.; Marbury, T.; Hill, J.; Webster, L.; Hassman, D.; Nguyen, A.H.; Pflanz, S.; Mogalian, E.; Gaggar, A.; et al. Safety, pharmacokinetics and pharmacodynamics of the oral toll-like receptor 7 agonist gs-9620 in treatment-naive patients with chronic hepatitis C. Antivir. Ther. 2014.
75. Gane, E.J.; Lim, Y.S.; Gordon, S.C.; Visvanathan, K.; Sicard, E.; Fedorak, R.N.; Roberts, S.; Massetto, B.; Ye, Z.; Pflanz, S.; et al. The oral toll-like receptor-7 agonist gs-9620 in patients with chronic hepatitis b virus infection. J. Hepatol. 2015, 63, 320–328.
76. Zhang, E.; Lu, M. Toll-like receptor (tlr)-mediated innate immune responses in the control of hepatitis b virus (HBV) infection. Med. Microbiol. Immunol. 2015, 204, 11–20.
77. Kapoor, R.; Kottilil, S. Strategies to eliminate hbv infection. Future Virol. 2014, 9, 565–585.
78. Tang, J.; Zhang, Z.H.; Huang, M.; Heise, T.; Zhang, J.; Liu, G.L. Phosphorylation of human la protein at ser 366 by casein kinase II contributes to hepatitis B virus replication and expression in vitro. J. Viral Hepat. 2013, 20, 24–33.
79. Tang, J.; Zhang, Z.H.; Liu, G.L. A systematic analysis of the predicted human la protein targets identified a hepatitis b virus infection signature. J. Viral Hepat. 2013, 20, 12–23.
80. Heise, T.; Guidotti, L.G.; Chisari, F.V. Characterization of nuclear rnases that cleave hepatitis B virus RNA near the la protein binding site. J. Virol. 2001, 75, 6874–6883.
81. Tang, J.; Huang, Z.M.; Chen, Y.Y.; Zhang, Z.H.; Liu, G.L.; Zhang, J. A novel inhibitor of human la protein with anti-HBV activity discovered by structure-based virtual screening and in vitro evaluation. PLoS ONE 2012, 7, e36363.
82. Yu, X.; Guo, R.; Ming, D.; Deng, Y.; Su, M.; Lin, C.; Li, J.; Lin, Z.; Su, Z. The tgf-beta1/il-31 pathway is up-regulated in patients with acute-on-chronic hepatitis b liver failure and is associated with disease severity and survival. Clin. Vaccine Immunol. 2015, 22, 484–492.
83. Qi, P.; Chen, Y.M.; Wang, H.; Fang, M.; Ji, Q.; Zhao, Y.P.; Sun, X.J.; Liu, Y.; Gao, C.F. ´509c > t polymorphism in the tgf-beta1 gene promoter, impact on the hepatocellular carcinoma risk in Chinese patients with chronic hepatitis b virus infection. Cancer Immunol. Immunother. 2009, 58, 1433–1440.
84. Wu, Y.; Zhao, J.; He, M. Correlation between tgf-beta1 gene 29 t > c single nucleotide polymorphism and clinicopathological characteristics of osteosarcoma. Tumour Biol. 2015, 36, 5149–5156.
85. Yin, W.; Zhao, Y.; Ji, Y.J.; Tong, L.P.; Liu, Y.; He, S.X.; Wang, A.Q. Serum/plasma micrornas as biomarkers for HBV-related hepatocellular carcinoma in China. Biomed. Res. Int. 2015, 2015.
86. Webster, R.M. The immune checkpoint inhibitors: Where are we now? Nat. Rev. Drug Discov. 2014, 13, 883–884.
87. Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012, 12, 252–264.
88. Wolchok, J.D.; Kluger, H.; Callahan, M.K.; Postow, M.A.; Rizvi, N.A.; Lesokhin, A.M.; Segal, N.H.; Ariyan, C.E.; Gordon, R.A.; Reed, K.; et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 2013, 369, 122–133.
89. Barakat, K. Immune checkpoints: The search for a single antiviral-anticancer magic bullet. J. Pharma Care Health Syst. 2015, 2, e125.
90. Gao, X.; Zhu, Y.; Li, G.; Huang, H.; Zhang, G.; Wang, F.; Sun, J.; Yang, Q.; Zhang, X.; Lu, B. Tim-3 expression characterizes regulatory t cells in tumor tissues and is associated with lung cancer progression. PLoS ONE 2012, 7, e30676.
91. Barakat, K. Do we need small molecule inhibitors for the immune checkpoints? J. Pharma Care Health Syst. 2014, 1.
92. Viricel, C.; Ahmed, M.; Barakat, K. Human pd-1 binds differently to its human ligands: A comprehensive modeling study. J. Mol. Graph. Model. 2015, 57, 131–142.
93. Barakat, K. Computer-aided drug design. J. Pharma Care Health Syst. 2014, 1.
94. Barakat, K.H.; Jordheim, L.P.; Perez-Pineiro, R.; Wishart, D.; Dumontet, C.; Tuszynski, J.A. Virtual screening and biological evaluation of inhibitors targeting the xpa-ercc1 interaction. PLoS ONE 2012, 7, e51329.
95. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 2013, 342, 1432–1433.
96. Chang, T.T.; Lai, C.L.; Kew Yoon, S.; Lee, S.S.; Coelho, H.S.; Carrilho, F.J.; Poordad, F.; Halota, W.; Horsmans, Y.; Tsai, N.; et al. Entecavir treatment for up to 5 years in patients with hepatitis b e antigen-positive chronic hepatitis B. Hepatology 2010, 51, 422–430.
97. Heathcote, E.J.; Marcellin, P.; Buti, M.; Gane, E.; De Man, R.A.; Krastev, Z.; Germanidis, G.; Lee, S.S.; Flisiak, R.; Kaita, K.; et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011, 140, 132–143.