Novel developments of hepatitis B: treatment goals, agents and monitoring tools

References

• Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection. Nat Rev Dis Primers. 2018;4:18035.
   PubMed Web of Science ®Google Scholar
• Polaris Observatory C. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018;3(6):383–403.
   PubMed Web of Science ®Google Scholar
• Lai CL, Yuen MF. The natural history and treatment of chronic hepatitis B: a critical evaluation of standard treatment criteria and end points. Ann Intern Med. 2007;147(1):58–61.
   PubMed Web of Science ®Google Scholar
• World Health Organization. Global hepatitis report 2017. Geneva: World Health Organization; 2017.
   Google Scholar
• Seeff LB, Beebe GW, Hoofnagle JH, et al. A serologic follow-up of the 1942 epidemic of post-vaccination hepatitis in the United States Army. N Engl J Med. 1987;316(16):965–970.
   PubMed Web of Science ®Google Scholar
• Stevens CE, Beasley RP, Tsui J, et al. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med. 1975;292(15):771–774.
   PubMed Web of Science ®Google Scholar
• Thio CL, Guo N, Xie C, et al. Global elimination of mother-to-child transmission of hepatitis B: revisiting the current strategy. Lancet Infect Dis. 2015;15(8):981–985.
   PubMed Web of Science ®Google Scholar
• Publication WHO. Hepatitis B vaccines: WHO position paper–recommendations. Vaccine. 2010;28(3):589–590.
   PubMedGoogle Scholar
• Bruce MG, Bruden D, Hurlburt D, et al. Antibody levels and protection after hepatitis B vaccine: results of a 30-year follow-up study and response to a booster dose. J Infect Dis. 2016;214(1):16–22.
   PubMed Web of Science ®Google Scholar
• Schonberger K, Riedel C, Ruckinger S, et al. Determinants of long-term protection after hepatitis B vaccination in infancy: a meta-analysis. Pediatr Infect Dis J. 2013;32(4):307–313.
   PubMed Web of Science ®Google Scholar
• Zou H, Chen Y, Duan Z, et al. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral Hepat. 2012;19(2):e18–25.
   PubMed Web of Science ®Google Scholar
• Brown RS Jr., McMahon BJ, Lok AS, et al. Antiviral therapy in chronic hepatitis B viral infection during pregnancy: a systematic review and meta-analysis. Hepatol. 2016;63(1):319–333.
   PubMed Web of Science ®Google Scholar
• Wichajarn K, Kosalaraksa P, Wiangnon S. Incidence of hepatocellular carcinoma in children in Khon Kaen before and after national hepatitis B vaccine program. Asian Pac J Cancer Prev. 2008;9(3):507–509.
   PubMedGoogle Scholar
• Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst. 2009;101(19):1348–1355.
   PubMedGoogle Scholar
• Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatol. 2018;67(4):1560–1599.
   PubMed Web of Science ®Google Scholar
• U.S. Food & Drug Administration. Approval letter – hepatitis B vaccine (recombinant, adjuvanted) – HEPLISAV-B. [cited 2018 Sept 16].  Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM584820.pdf
   Google Scholar
• Jackson S, Lentino J, Kopp J, et al. Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults. Vaccine. 2018;36(5):668–674.
   PubMed Web of Science ®Google Scholar
• European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L: EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–398.
   PubMed Web of Science ®Google Scholar
• Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468–475.
   PubMed Web of Science ®Google Scholar
• Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatol. 2010;52(3):886–893.
   PubMed Web of Science ®Google Scholar
• Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351(15):1521–1531.
   PubMed Web of Science ®Google Scholar
• Manolakopoulos S, Triantos C, Theodoropoulos J, et al. Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension. J Hepatol. 2009;51(3):468–474.
   PubMed Web of Science ®Google Scholar
• Yuen MF, Seto WK, Chow DH, et al. Long-term lamivudine therapy reduces the risk of long-term complications of chronic hepatitis B infection even in patients without advanced disease. Antivir Ther. 2007;12(8):1295–1303.
   PubMed Web of Science ®Google Scholar
• Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatol. 2013;58(1):98–107.
   PubMed Web of Science ®Google Scholar
• Coffin CS, Rezaeeaval M, Pang JX, et al. The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy. Aliment Pharmacol Ther. 2014;40(11–12):1262–1269.
   PubMed Web of Science ®Google Scholar
• Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy. Hepatol. 2013;57(1):399–408.
   PubMed Web of Science ®Google Scholar
• Lin CW, Huang XL, Liu HL, et al. Interactions of hepatitis B virus infection with nonalcoholic fatty liver disease: possible mechanisms and clinical impact. Dig Dis Sci. 2015;60(12):3513–3524.
   PubMed Web of Science ®Google Scholar
• Machado MV, Oliveira AG, Cortez-Pinto H. Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients. J Gastroenterol Hepatol. 2011;26(9):1361–1367.
   PubMed Web of Science ®Google Scholar
• Wong GL, Chan HL, Yu Z, et al. Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B – a prospective cohort study with paired transient elastography examinations. Aliment Pharmacol Ther. 2014;39(8):883–893.
   PubMed Web of Science ®Google Scholar
• Chan AW, Wong GL, Chan HY, et al. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B. J Gastroenterol Hepatol. 2017;32(3):667–676.
   PubMed Web of Science ®Google Scholar
• Zhang BH, Yang BH, Tang ZY. Randomized controlled trial of screening for hepatocellular carcinoma. J Cancer Res Clin Oncol. 2004;130(7):417–422.
   PubMed Web of Science ®Google Scholar
• McMahon BJ, Bulkow L, Harpster A, et al. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study. Hepatol. 2000;32(4 Pt 1):842–846.
   PubMed Web of Science ®Google Scholar
• Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98.
   PubMed Web of Science ®Google Scholar
• Wang L, Liu F, Liu YD, et al. Stringent cessation criterion results in better durability of lamivudine treatment: a prospective clinical study in hepatitis B e antigen-positive chronic hepatitis B patients. J Viral Hepat. 2010;17(4):298–304.
   PubMed Web of Science ®Google Scholar
• Kuo YH, Chen CH, Wang JH, et al. Extended lamivudine consolidation therapy in hepatitis B e antigen-positive chronic hepatitis B patients improves sustained hepatitis B e antigen seroconversion. Scand J Gastroenterol. 2010;45(1):75–81.
   PubMed Web of Science ®Google Scholar
• Van Hees S, Bourgeois S, Van Vlierberghe H, et al. Stopping nucleos(t)ide analogue treatment in caucasian hepatitis B patients after HBeAg seroconversion is associated with high relapse rates and fatal outcomes. Aliment Pharmacol Ther. 2018;47(8):1170–1180.
   PubMed Web of Science ®Google Scholar
• Seto WK, Hui AJ, Wong VW, et al. Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study. Gut. 2015;64(4):667–672.
   PubMed Web of Science ®Google Scholar
• Kranidioti H, Manolakopoulos S, Khakoo SI. Outcome after discontinuation of nucleot(s)ide analogues in chronic hepatitis B: relapse rate and associated factors. Ann Gastroenterol. 2015;28(2):173–181.
   PubMed Web of Science ®Google Scholar
• Berg T, Simon KG, Mauss S, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients – FINITE study. J Hepatol. 2017;67(5):918–924.
   PubMed Web of Science ®Google Scholar
• Hadziyannis SJ, Sevastianos V, Rapti I, et al. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterol. 2012;143(3): 629–636. e621.
   PubMed Web of Science ®Google Scholar
• Jeng WJ, Sheen IS, Chen YC, et al. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hepatol. 2013;58(6):1888–1896.
   PubMed Web of Science ®Google Scholar
• Qiu YW, Huang LH, Yang WL, et al. Hepatitis B surface antigen quantification at hepatitis B e antigen seroconversion predicts virological relapse after the cessation of entecavir treatment in hepatitis B e antigen-positive patients. Int J Infect Dis. 2016;43:43–48.
   PubMed Web of Science ®Google Scholar
• Yao CC, Lee CM, Hung CH, et al. Combining age and HBsAg level predicts post-treatment durability of nucleos(t)ide analogue-induced HBeAg seroconversion. J Gastroenterol Hepatol. 2015;30(5):918–924.
   PubMed Web of Science ®Google Scholar
• Jung KS, Park JY, Chon YE, et al. Clinical outcomes and predictors for relapse after cessation of oral antiviral treatment in chronic hepatitis B patients. J Gastroenterol. 2016;51(8):830–839.
   PubMed Web of Science ®Google Scholar
• Papatheodoridis G, Vlachogiannakos I, Cholongitas E, et al. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review. Hepatol. 2016;63(5):1481–1492.
   PubMed Web of Science ®Google Scholar
• Chu CM, Liaw YF. Hepatitis B surface antigen seroclearance during chronic HBV infection. Antivir Ther. 2010;15(2):133–143.
   PubMed Web of Science ®Google Scholar
• Liu J, Yang HI, Lee MH, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterol. 2010;139(2):474–482.
   PubMed Web of Science ®Google Scholar
• Ungtrakul T, Sriprayoon T, Kusuman P, et al. Role of quantitative hepatitis B surface antigen in predicting inactive carriers and HBsAg seroclearance in HBeAg-negative chronic hepatitis B patients. Med(Baltimore). 2017;96(13):e6554.
   PubMed Web of Science ®Google Scholar
• Chen YC, Jeng WJ, Chu CM, et al. Decreasing levels of HBsAg predict HBsAg seroclearance in patients with inactive chronic hepatitis B virus infection. Clin Gastroenterol Hepatol. 2012;10(3):297–302.
   PubMed Web of Science ®Google Scholar
• Hu HH, Liu J, Chang CL, et al. Level of hepatitis B (HB) core antibody associates with seroclearance of HBV DNA and HB surface antigen in HB e antigen-seronegative patients. Clin Gastroenterol Hepatol. 2018;17:172–181.
   Web of Science ®Google Scholar
• Fung J, Cheung KS, Wong DK, et al. Long-term outcomes and predictive scores for hepatocellular carcinoma and hepatitis B surface antigen seroclearance after hepatitis B e-antigen seroclearance. Hepatol. 2018;68(2):462–472.
   PubMed Web of Science ®Google Scholar
• Arase Y, Ikeda K, Suzuki F, et al. Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B. Am J Med. 2006;119(1):71e79–16.
   Google Scholar
• Yuen MF, Wong DK, Fung J, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterol. 2008;135(4):1192–1199.
   PubMed Web of Science ®Google Scholar
• Wong DK, Seto WK, Cheung KS, et al. Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA. Liver Int. 2017;37(7):995–1001.
   PubMed Web of Science ®Google Scholar
• Yan H, Zhong G, Xu G, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012;1:e00049.
   PubMed Web of Science ®Google Scholar
• Blank A, Markert C, Hohmann N, et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65(3):483–489.
   PubMed Web of Science ®Google Scholar
• Bogomolov P, Voronkova N, Allveiss L, et al. A proof-of-concept phase 2a clinical trial with HBV/HDV entry inhibitor myrcludex B: LB-20. Hepatol. 2014;60(6):1279A–1280A.
   Web of Science ®Google Scholar
• Wedemeyer H, Schoneweis K, Bogomolov PO, et al. Interim results of a multicenter, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of mycludex B in combination with peg-interferon alpha 2a in patients with chronic HBV/Hdv co-infection. Hepatol. 2018;68(1 (supp)):11A.
   Google Scholar
• Gish RG, Yuen MF, Chan HL, et al. Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent. Antiviral Res. 2015;121:97–108.
   PubMed Web of Science ®Google Scholar
• Yuen MF, Liu KS, Given B, et al. RNA interference therapy with ARC-520 injection results in long term off-therapy antigen reductions in treatment naive, HBeAg positive and negative patients with chronic HBV. J Hepatol. 2018;68(S1):S526.
   PubMedGoogle Scholar
• Streinu-Cercel A, Gane E, Cheng W, et al. A phase 2a study evaluating the multi-dose activity of ARB-1467 in HBeAg positive and negative virally suppressed patients with hepatitis B. J Hepatol. 2017;66(1):S688–S689.
   Web of Science ®Google Scholar
• Gane E, Locarnini S, Lim TH, et al. First results with RNA interference (RNAi) in chronic hepatitis B (CHB) using ARO-HBV. In: The liver meeting. San Francisco, USA; 2018.
   Google Scholar
• Wooddell CI, Yuen MF, Chan HL, et al. RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg. Sci Transl Med. 2017;9:409.
   Web of Science ®Google Scholar
• Mak LY, Wong DK, Seto WK, et al. Hepatitis B core protein as a therapeutic target. Expert Opin Ther Targets. 2017;21(12):1153–1159.
   PubMed Web of Science ®Google Scholar
• Yuen MF, Kim DJ, Weilert F, et al. NVR 3-778, a first-in-class HBV core inhibitor, alone and in combination with Peg-interferon (PEGIFN), in treatment naive HBeAg-positive patients: early reductions in HBV DNA and HbeAg. J Hepatol. 2015;62:385A.
   Google Scholar
• Yuen MF, Agarwal K, Gane E, et al. LBP-012 - Interim safety, tolerability, pharmacokinetics, and antiviral activity of ABI-H0731, a novel core protein allosteric modulator, in healthy volunteers and non-cirrhotic viremic subjects with chronic hepatitis B. J Hepatol. 2018;68(S1):S111.
   Google Scholar
• Zoulim F, Yogaratnam JZ, Vandenbossche JJ, et al. LBO-004 – Safety, pharmakokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ-56136379 (JNJ-6379) in treatment naive chronic hepatitis B (CHB) patients without cirrhosis. J Hepatol. 2018;68(S1):S102.
   Google Scholar
• Gane E, Liu A, Yuen MF, et al. LBO-003 - RO7049389, a core protein allosteric modulator, demonstrates robust anti-HBV activity in chronic hepatitis B patients and is safe and well tolerated. J Hepatol. 2018;68(S1):S101.
   Google Scholar
• Vaillant A, Bazinet M, Pantea V, et al. FRI-343 – Updated follow-up analysis in the REP 401 protocol: treatment naive HBeAg chronic hepatitis B infection with REP 2139 or REP 2165, tenofovir disoproxil fumarate and pegylated inteferon alfa-2a. J Hepatol. 2018;68(S1):S517.
   Google Scholar
• Wu J, Meng Z, Jiang M, et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatol. 2009;49(4):1132–1140.
   PubMed Web of Science ®Google Scholar
• Shin EC, Sung PS, Park SH. Immune responses and immunopathology in acute and chronic viral hepatitis. Nat Rev Immunol. 2016;16(8):509–523.
   PubMed Web of Science ®Google Scholar
• Yuen MF, Coffin CS, Elkhashab SG, et al. SB 9200 an oal selective immunomodulator is safe and efficacious in treatment-naive, non-cirrhotic HBV patients: results from cohort 1 of the ACHIEVE trial. Hepatol. 2017;66(Suppl 1):22–23A.
   Google Scholar
• Daffis S, Ramakrishnan D, Niu C, et al. In vitro and in vivo characterization of the selective toll-like receptor 8 agnist GS-9688. J Hepatol. 2017;66(1 (supplement)):S694.
   Web of Science ®Google Scholar
• Agarwal K, Ahn SH, Elkhashab M, et al. Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. J Viral Hepat. 2018;25:1331–1340.
   Web of Science ®Google Scholar
• Lok AS, Pan CQ, Han SH, 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(3):509–516.
   PubMed Web of Science ®Google Scholar
• Gane E, Gaggar A, Nguyen AH, et al. A phase 1 study evaluating anti-PD-1 treatment with or without GS-4774 in HBeAg negative chronic hepatitis B patients. J Hepatol. 2017;66:S26–S27.
   Google Scholar
• Joly S, Porcherot M, Radreau P, et al. The selective FXR agonist EYP001 is well tolerated in healthy subjects and has additive anti-HBV effect with nucleoside analogues in HepaRG cells. J hepatol. 2017;66(1 (supplement)):S690.
   Web of Science ®Google Scholar
• Lam YF, Seto WK, Wong D, et al. Seven-year treatment outcome of entecavir in a real-world cohort: effects on clinical parameters, HBsAg and HBcrAg levels. Clin Transl Gastroenterol. 2017;8(10):e125.
   PubMedGoogle Scholar
• Kimura T, Rokuhara A, Sakamoto Y, et al. Sensitive enzyme immunoassay for hepatitis B virus core-related antigens and their correlation to virus load. J Clin Microbiol. 2002;40(2):439–445.
   PubMed Web of Science ®Google Scholar
• Suzuki F, Miyakoshi H, Kobayashi M, et al. Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients. J Med Virol. 2009;81(1):27–33.
   PubMed Web of Science ®Google Scholar
• Wong DK, Tanaka Y, Lai CL, et al. Hepatitis B virus core-related antigens as markers for monitoring chronic hepatitis B infection. J Clin Microbiol. 2007;45(12):3942–3947.
   PubMed Web of Science ®Google Scholar
• Tada T, Kumada T, Toyoda H, et al. HBcrAg predicts hepatocellular carcinoma development: an analysis using time-dependent receiver operating characteristics. J Hepatol. 2016;65(1):48–56.
   PubMed Web of Science ®Google Scholar
• Cheung KS, Seto WK, Wong DK, et al. Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy. J Viral Hepat. 2017;24(8):654–661.
   PubMed Web of Science ®Google Scholar
• Seto WK, Wong DK, Chan TS, et al. Association of hepatitis B core-related antigen with hepatitis B virus reactivation in occult viral carriers undergoing high-risk immunosuppressive therapy. Am J Gastroenterol. 2016;111(12):1788–1795.
   PubMed Web of Science ®Google Scholar
• Yuen MF, Chan HLY, Liu KS, et al. Differential reductions in viral proteins expressed from cccDNA vs integrated DNA in treatment naive HBeAg positive and negative patients with chronic HBV after RNA interference therapy with ARC-520. J Hepatol. 2016;64:S390–391.
   PubMed Web of Science ®Google Scholar
• Kurosaki M, Tsuchiya K, Nakanishi H, et al. Serum HBV RNA as a possible marker of HBV replication in the liver during nucleot(s)ide analogue therapy. J Gastroenterol. 2013;48(6):777–778.
   PubMed Web of Science ®Google Scholar
• Tsuge M, Murakami E, Imamura M, et al. Serum HBV RNA and HBeAg are useful markers for the safe discontinuation of nucleotide analogue treatments in chronic hepatitis B patients. J Gastroenterol. 2013;48(10):1188–1204.
   PubMed Web of Science ®Google Scholar
• Butler EK, Gersch J, McNamara A, et al. HBV serum DNA and RNA levels in nucleos(t)ide analogue-treated or untreated patients during chronic and acute infection. Hepatol. 2018;68:2106–2117.
   PubMedGoogle Scholar
• Wang J, Yu Y, Li G, et al. Natural history of serum HBV-RNA in chronic HBV infection. J Viral Hepat. 2018;25:1038–1047.
   Web of Science ®Google Scholar
• Wang J, Du M, Huang H, et al. Reply to: “Serum HBV pgRNA as a clinical marker for cccDNA activity”: consistent loss of serum HBV RNA might predict the “para-functional cure” of chronic hepatitis B. J Hepatol. 2017;66(2):462–463.
   PubMed Web of Science ®Google Scholar
• Gao Y, Li Y, Meng Q, et al. Serum Hepatitis B virus DNA, RNA, and HBsAg: which correlated better with intrahepatic covalently closed circular DNA before and after nucleos(t)ide analogue treatment? J Clin Microbiol. 2017;55(10):2972–2982.
   PubMed Web of Science ®Google Scholar
• Wang J, Shen T, Huang X, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol. 2016;65(4):700–710.
   PubMed Web of Science ®Google Scholar
• Yuen MF, Kim DJ, Weilert F, et al. NVR3-778, a first-in-class HBV core inhibitor, alone and in combination with Peg-Interferon (PegIFN), in treatment-naive HBeAg-positive patients: early reductions in HBV DNA and HBeAg. J Hepatol. 2016;64(2 (Supp)):S210–S211.
   Google Scholar
• Chu CM, Lin DY, Liaw YF. Clinical and virological characteristics post HBsAg seroclearance in hepatitis B virus carriers with hepatic steatosis versus those without. Dig Dis Sci. 2013;58(1):275–281.
   PubMed Web of Science ®Google Scholar
• Gotchev D, Gao M, Moore C, et al. Identification and charaterization of HBV RNA destabilizers in vitro and in vivo. Hepatol. 2017;66(S1):493A.
   Google Scholar
• Gallay P, Chatterji U, Bobardt MD, et al. Novel cyclophilin inhibitor CPI-431-32 shows broad spectrum antiviral action by blocking replication of HCV, HBV and HIV-1. J Hepatol. 2015;52:S677.
   Google Scholar
• Lion TCR. Pipeline. [cited 2018 Dec 18]. Available from: https://liontcr.com/pipeline/[https://liontcr.com/pipeline/
   Google Scholar
• Koh S, Tan AT, Li L, et al. Targeted therapy of hepatitis B virus-related hepatocellular carcinoma: present and future. Diseases. 2016;4:1.
   Google Scholar
• 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(2):486–491.
   PubMed Web of Science ®Google Scholar
• Yuen MF, Agarwal K, Gane E, et al. Final results of a phase 1b 28-day study of ABI-H0731, a novel core inhibitor, in non-cirrhotic viremic subjects with chronic hepatitis B. Hepatol. 2018;1(Suppl):46A.
   Google Scholar
• Zhang F, Wen Y, Guo X. CRISPR/Cas9 for genome editing: progress, implications and challenges. Hum Mol Genet. 2014;23(R1):R40–46.
   PubMed Web of Science ®Google Scholar
• Dong C, Qu L, Wang H, et al. Targeting hepatitis B virus cccDNA by CRISPR/Cas9 nuclease efficiently inhibits viral replication. Antiviral Res. 2015;118:110–117.
   PubMed Web of Science ®Google Scholar
• Lin SR, Yang HC, Kuo YT, et al. The CRISPR/Cas9 system facilitates clearance of the intrahepatic HBV templates in vivo. Mol Ther Nucleic Acids. 2014;3:e186.
   PubMedGoogle Scholar
• Ohno M, Otsuka M, Kishikawa T, et al. Novel therapeutic approaches for hepatitis B virus covalently closed circular DNA. World J Gastroenterol. 2015;21(23):7084–7088.
   PubMed Web of Science ®Google Scholar