Updates on Chronic HBV: Current Challenges and Future Goals

  • Hannah M. LeeEmail author
  • Bubu A. Banini
Liver (J Bajaj, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Liver


Purpose of Review

Chronic HBV (CHB) remains a global public health problem with over 257 million people chronically infected worldwide. Without appropriate management, 20% of individuals infected with CHB will die from complications of cirrhosis, liver failure, or hepatocellular carcinoma (HCC). Despite an effective vaccination to prevent infection, HBV has yet to be successfully eradicated globally. Current treatments can only control and suppress the virus but cannot cure. Updates in the management of chronic HBV will be reviewed, including latest treatments and treatment strategies as well as potential curative therapeutic agents in clinical trial.

Recent Findings

A new nucleotide analogue drug, tenofovir alafenamide fumarate (TAF), has been added to the HBV therapeutic armamentarium. A more potent drug showing non-inferiority, TAF has shown to improve renal and bone laboratory safety parameters compared to TDF. In addition, new treatment recommendations have been made for both general and special populations including pregnancy and HBV reactivation. There is growing data supporting the importance of antiviral therapy in patients with advanced liver disease and liver decompensation which has resulted in improved outcomes. In addition, at least 30 potential therapeutics are in clinical trials in the pursuit of curative treatments for chronic HBV with the goal of “functional cure.”


CHB remains a global public health problem with complications including cirrhosis, liver failure, and HCC. Current antiviral therapy can cause reversal of liver disease, improve outcomes, and prevent complications such as reactivation but still requires long-term use. Curative treatments for HBV are greatly needed with promising curative drugs in early phase studies.


Chronic hepatitis B Antiviral therapy Nucleoside analogue Functional cure Reactivation Perinatal transmission 


Author Contributions

Authored first draft (HL) (pregnancy, future therapeutics—BB)

Critical revision (HL/BB)

Approved final draft (HL)

Compliance with Ethical Standards

Conflict of Interest

Hannah Lee declares that she has no conflict of interest. Bubu Banini declares that she has no conflict of interest.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    WHO. Hepatitis B. 2018. Accessed 11 Jan 2019.
  2. 2.
    WHO. Global hepatitis report. 2017. Accessed 11 Jan 2019.
  3. 3.
    Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386(10003):1546–55. Scholar
  4. 4.
    Kowdley KV, Wang CC, Welch S, Roberts H, Brosgart CL. Prevalence of chronic hepatitis B among foreign-born persons living in the United States by country of origin. Hepatology. 2012;56(2):422–33. Scholar
  5. 5.
    Weinbaum CM, Williams I, Mast EE, Wang SA, Finelli L, Wasley A, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1–20.Google Scholar
  6. 6.
    Konerman MA, Lok AS. Interferon treatment for hepatitis B. Clin Liver Dis. 2016;20(4):645–65. Scholar
  7. 7.
    Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1(3):185–95. Scholar
  8. 8.
    Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1(3):196–206. Scholar
  9. 9.
    Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99. Scholar
  10. 10.
    Lee JK, Shim JH, Lee HC, Lee SH, Kim KM, Lim YS, et al. Estimation of the healthy upper limits for serum alanine aminotransferase in Asian populations with normal liver histology. Hepatology. 2010;51(5):1577–83. Scholar
  11. 11.
    Ruhl CE, Everhart JE. Upper limits of normal for alanine aminotransferase activity in the United States population. Hepatology. 2012;55(2):447–54. Scholar
  12. 12.
    Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1–10.CrossRefGoogle Scholar
  13. 13.
    Lok AS, McMahon BJ, Brown RS Jr, Wong JB, Ahmed AT, Farah W, et al. Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology. 2016;63(1):284–306. Scholar
  14. 14.
    Jang JW, Choi JY, Kim YS, Woo HY, Choi SK, Lee CH, et al. Long-term effect of antiviral therapy on disease course after decompensation in patients with hepatitis B virus-related cirrhosis. Hepatology. 2015;61(6):1809–20. Scholar
  15. 15.
    • Flemming JA, Kim WR, Brosgart CL, Terrault NA. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology. 2017;65(3):804–12. A population-based study evaluating the era of DAA therapy and decreasing liver transplant wait list for decompensated HCV and HBV.
  16. 16.
    Varbobitis I, Papatheodoridis GV. The assessment of hepatocellular carcinoma risk in patients with chronic hepatitis B under antiviral therapy. Clin Mol Hepatol. 2016;22(3):319–26. Scholar
  17. 17.
    Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol. 2015;62(4):956–67. Scholar
  18. 18.
    Yeo W, Lam KC, Zee B, Chan PS, Mo FK, Ho WM, et al. Hepatitis B reactivation in patients with hepatocellular carcinoma undergoing systemic chemotherapy. Ann Oncol. 2004;15(11):1661–6. Scholar
  19. 19.
    Jang JW, Choi JY, Bae SH, Yoon SK, Chang UI, Kim CW, et al. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology. 2006;43(2):233–40. Scholar
  20. 20.
    Hui CK, Cheung WW, Zhang HY, Au WY, Yueng YH, Leung AY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006;131(1):59–68. Scholar
  21. 21.
    Hsiao LT, Chiou TJ, Liu JH, Chu CJ, Lin YC, Chao TC, et al. Extended lamivudine therapy against hepatitis B virus infection in hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant. 2006;12(1):84–94. Scholar
  22. 22.
    Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148(7):519–28.CrossRefGoogle Scholar
  23. 23.
    Paul S, Saxena A, Terrin N, Viveiros K, Balk EM, Wong JB. Hepatitis B virus reactivation and prophylaxis during solid tumor chemotherapy: a systematic review and meta-analysis. Ann Intern Med. 2016;164(1):30–40. Scholar
  24. 24.
    Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125(6):1742–9.CrossRefGoogle Scholar
  25. 25.
    Huang YH, Hsiao LT, Hong YC, Chiou TJ, Yu YB, Gau JP, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31(22):2765–72. Scholar
  26. 26.
    Lee YH, Bae SC, Song GG. Hepatitis B virus reactivation in HBsAg-positive patients with rheumatic diseases undergoing anti-tumor necrosis factor therapy or DMARDs. Int J Rheum Dis. 2013;16(5):527–31. Scholar
  27. 27.
    Mori S, Fujiyama S. Hepatitis B virus reactivation associated with antirheumatic therapy: risk and prophylaxis recommendations. World J Gastroenterol. 2015;21(36):10274–89. Scholar
  28. 28.
    Yang C, Qin B, Yuan Z, Chen L, Zhou HY. Meta-analysis of prophylactic entecavir or lamivudine against hepatitis B virus reactivation. Ann Hepatol. 2016;15(4):501–11.Google Scholar
  29. 29.
    Yu S, Luo H, Pan M, Luis AP, Xiong Z, Shuai P, et al. Comparison of entecavir and lamivudine in preventing HBV reactivation in lymphoma patients undergoing chemotherapy: a meta-analysis. Int J Clin Pharm. 2016;38(5):1035–43. Scholar
  30. 30.
    Cerva C, Colagrossi L, Maffongelli G, Salpini R, Di Carlo D, Malagnino V, et al. Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor. Clin Microbiol Infect. 2016;22(11):946 e1–8. Scholar
  31. 31.
    Liu WP, Wang XP, Zheng W, Ping LY, Zhang C, Wang GQ, et al. Hepatitis B virus reactivation after withdrawal of prophylactic antiviral therapy in patients with diffuse large B cell lymphoma. Leuk Lymphoma. 2016;57(6):1355–62. Scholar
  32. 32.
    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):370–98. Scholar
  33. 33.
    Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, et al. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology. 2008;47(3):844–53. Scholar
  34. 34.
    Tamori A, Koike T, Goto H, Wakitani S, Tada M, Morikawa H, et al. Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts. J Gastroenterol. 2011;46(4):556–64. Scholar
  35. 35.
    Papa A, Felice C, Marzo M, Andrisani G, Armuzzi A, Covino M, et al. Prevalence and natural history of hepatitis B and C infections in a large population of IBD patients treated with anti-tumor necrosis factor-alpha agents. J Crohns Colitis. 2013;7(2):113–9. Scholar
  36. 36.
    Morisco F, Guarino M, La Bella S, Di Costanzo L, Caporaso N, Ayala F, et al. Lack of evidence of viral reactivation in HBsAg-negative HBcAb-positive and HCV patients undergoing immunosuppressive therapy for psoriasis. BMC Gastroenterol. 2014;14:214. Scholar
  37. 37.
    Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148(1):221–44 e3. Scholar
  38. 38.
    Zhang MY, Zhu GQ, Shi KQ, Zheng JN, Cheng Z, Zou ZL, et al. Systematic review with network meta-analysis: comparative efficacy of oral nucleos(t)ide analogues for the prevention of chemotherapy-induced hepatitis B virus reactivation. Oncotarget. 2016;7(21):30642–58. Scholar
  39. 39.
    Nakaya A, Fujita S, Satake A, Nakanishi T, Azuma Y, Tsubokura Y, et al. Delayed HBV reactivation in rituximab-containing chemotherapy: how long should we continue anti-virus prophylaxis or monitoring HBV-DNA? Leuk Res. 2016;50:46–9. Scholar
  40. 40.
    Bersoff-Matcha SJ, Cao K, Jason M, Ajao A, Jones SC, Meyer T, et al. Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug Administration adverse event reporting system. Ann Intern Med. 2017;166(11):792–8. Scholar
  41. 41.
    Liu CJ, Chen PJ, Chen DS. Dual chronic hepatitis B virus and hepatitis C virus infection. Hepatol Int. 2009;3(4):517–25. Scholar
  42. 42.
    Tyson GL, Kramer JR, Duan Z, Davila JA, Richardson PA, El-Serag HB. Prevalence and predictors of hepatitis B virus coinfection in a United States cohort of hepatitis C virus-infected patients. Hepatology. 2013;58(2):538–45. Scholar
  43. 43.
    Bini EJ, Perumalswami PV. Hepatitis B virus infection among American patients with chronic hepatitis C virus infection: prevalence, racial/ethnic differences, and viral interactions. Hepatology. 2010;51(3):759–66. Scholar
  44. 44.
    Wang C, Ji D, Chen J, Shao Q, Li B, Liu J, et al. Hepatitis due to reactivation of hepatitis B virus in endemic areas among patients with hepatitis C treated with direct-acting antiviral agents. Clin Gastroenterol Hepatol. 2017;15(1):132–6. Scholar
  45. 45.
    Tamori A, Abiru S, Enomoto H, Kioka K, Korenaga M, Tani J, et al. Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy. J Viral Hepat. 2018;25(5):608–11. Scholar
  46. 46.
    • Liu CJ, Chuang WL, Sheen IS, Wang HY, Chen CY, Tseng KC, et al. Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected with HBV. Gastroenterology. 2018;154(4):989–97. This is the only prospective and largest study to date evaluating HBV reactivation in DAA therapy and its outcomes.
  47. 47.
    AASLD, IDSA. HCV guidance: recommendations for testing, managing, and treating hepatitis C. 2017. Accessed 20 Jan 2019.
  48. 48.
    Peng S, Wan Z, Liu T, Wang Y, Chen H, Li X, et al. Quantitative hepatitis B surface antigen predicts hepatitis B transmission in infants born to e antigen-positive mothers. J Clin Gastroenterol. 2018.
  49. 49.
    Pan CQ, Duan Z, Dai E, Zhang S, Han G, Wang Y, et al. Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med. 2016;374(24):2324–34. Scholar
  50. 50.
    Thompson ND, Perz JF, Moorman AC, Holmberg SD. Nonhospital health care-associated hepatitis B and C virus transmission: United States, 1998-2008. Ann Intern Med. 2009;150(1):33–9.CrossRefGoogle Scholar
  51. 51.
    Soldan K, Ramsay M, Collins M. Acute hepatitis B infection associated with blood transfusion in England and Wales, 1991-7: review of database. BMJ. 1999;318(7176):95.CrossRefGoogle Scholar
  52. 52.
    Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral Hepat. 2012;19(2):e18–25. Scholar
  53. 53.
    Yu MM, Jiang Q, Ji Y, Wu KH, Ju LL, Tang X, et al. Comparison of telbivudine versus lamivudine in interrupting perinatal transmission of hepatitis B virus. J Clin Virol. 2014;61(1):55–60. Scholar
  54. 54.
    Zhang H, Pan CQ, Pang Q, Tian R, Yan M, Liu X. Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice. Hepatology. 2014;60(2):468–76.CrossRefGoogle Scholar
  55. 55.
    Greenup AJ, Tan PK, Nguyen V, Glass A, Davison S, Chatterjee U, et al. Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus. J Hepatol. 2014;61(3):502–7. Scholar
  56. 56.
    Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98. Scholar
  57. 57.
    •• Brown RS Jr, McMahon BJ, Lok AS, Wong JB, Ahmed AT, Mouchli MA, et al. Antiviral therapy in chronic hepatitis B viral infection during pregnancy: a systematic review and meta-analysis. Hepatology. 2016;63(1):319–33. A meta-analysis of 26 studies involving 3622 pregnant women aimed to study the efficacy and safety of antiviral therapy given during pregnancy. Telbivudine, lamivudine, and tenofovir all appeared to be safe with no increase in maternal or fetal complications.
  58. 58.
    Chen HL, Lee CN, Chang CH, Ni YH, Shyu MK, Chen SM, et al. Efficacy of maternal tenofovir disoproxil fumarate in interrupting mother-to-infant transmission of hepatitis B virus. Hepatology. 2015;62(2):375–86. Scholar
  59. 59.
    •• Jourdain G, Ngo-Giang-Huong N, Harrison L, Decker L, Khamduang W, Tierney C, et al. Tenofovir versus placebo to prevent perinatal transmission of hepatitis B. N Engl J Med. 2018;378(10):911–23. A multicenter, double-blind clinical trial in which 331 HBeAg-positive pregnant women were randomized to TDF or placebo, with infants receiving HBIG at birth and HBV vaccine at 0, 1, 2, 4, and 6 months. TDF in combination with HBIG/HBV vaccination led to 0% transmission rate in infants, compared to a 2% transmission rate in the group receiving HBIG/HBV vaccination alone.
  60. 60.
    • Chen T, Liu J, Yu Q, Yao N, Yang Y, Wu Y, et al. Tenofovir plus hepatitis B immunoglobulin treatment resulted in a rapid HBV DNA load decline in high-risk pregnant women who missed the optimal time window of antiviral prophylaxis. Antivir Ther. 2018. A prospective study in which 48 pregnant women with chronic hepatitis B who missed the optimal time window for antiviral prophylaxis received TDF plus HBIG vs. TDF alone. Results showed reduced mother-to-infanct transmission with combination treatment.
  61. 61.
    APR. Antiretroviral Pregnancy Registry Interim Report for 1 January 1989 through 31 July 2017. Wilmington, NC. Accessed 20 Jan 2019.
  62. 62.
    Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology. 2015;479-480:672–86. Scholar
  63. 63.
    Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM. The entry inhibitor myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol. 2013;58.
  64. 64.
    Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65.
  65. 65.
    Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65.
  66. 66.
    Wang XJ, Hu W, Zhang TY, Mao YY, Liu NN, Wang SQ. Irbesartan, an FDA approved drug for hypertension and diabetic nephropathy, is a potent inhibitor for hepatitis B virus entry by disturbing Na(+)-dependent taurocholate cotransporting polypeptide activity. Antivir Res. 2015;120:140–6. Scholar
  67. 67.
    Gish RG, Yuen MF, Chan HL, Given BD, Lai CL, Locarnini SA. Synthetic RNAi triggers and their use in chronic hepatitis B therapies with curative intent. Antivir Res. 2015;121.
  68. 68.
    Ko C, Michler T, Protzer U. Novel viral and host targets to cure hepatitis B. Curr Opin Virol. 2017;24:38–45. Scholar
  69. 69.
    Schluep T, Lickliter J, Hamilton J, Lewis DL, Lai CL, Lau JY, et al. Safety, tolerability, and pharmacokinetics of ARC-520 injection, an RNA interference-based therapeutic for the treatment of chronic hepatitis B virus infection, in healthy volunteers. Clin Pharmacol Drug Dev. 2017;6(4):350–62. Scholar
  70. 70.
    Flisiak R, Jaroszewicz J, Lucejko M. siRNA drug development against hepatitis B virus infection. Expert Opin Biol Ther. 2018;18(6):609–17. Scholar
  71. 71.
    Streinu-Cercel A, Gane E, Cheng W, Sievert W, Roberts S, Ahn SH et al. A phase 2a study evaluating the multi-dose activity of ARB-1467 in HBeAg positive and negative virally suppressed subjects with hepatitis B. J Hepatol. 2017;66.
  72. 72.
    Javanbakht H, Mueller H, Walther J, Zhou X, Lopez A, Pattupara T, et al. Liver-targeted anti-HBV single-stranded oligonucleotides with locked nucleic acid potently reduce HBV gene expression in vivo. Mol Ther Nucleic Acids. 2018;11:441–54. Scholar
  73. 73.
    Fung J, Lai CL, Seto WK, Yuen MF. Emerging drugs for the treatment of hepatitis B. Exp Opin Emerg Drugs. 2016;21(2):183–93. Scholar
  74. 74.
    Cai D, Mills C, Yu W, Yan R, Aldrich CE, Saputelli JR. Identification of disubstituted sulfonamide compounds as specific inhibitors of hepatitis B virus covalently closed circular DNA formation. Antimicrob Agents Chemother. 2012;56.
  75. 75.
    Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T. IFN-alpha 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.
  76. 76.
    Tropberger P, Mercier A, Robinson M, Zhong W, Ganem DE, Holdorf M. Mapping of histone modifications in episomal HBV cccDNA uncovers an unusual chromatin organization amenable to epigenetic manipulation. Proc Natl Acad Sci U S A. 2015;112.
  77. 77.
    Moyo B, Bloom K, Scott T, Ely A, Arbuthnot P. Advances with using CRISPR/Cas-mediated gene editing to treat infections with hepatitis B virus and hepatitis C virus. Virus Res. 2018;244:311–20. Scholar
  78. 78.
    Hynes RO, Coller BS, Porteus M. Toward responsible human genome editing. JAMA. 2017;317(18):1829–30. Scholar
  79. 79.
    Boucle S, Lu X, Bassit L, Ozturk T, Russell OO, Amblard F, et al. Synthesis and antiviral evaluation of novel heteroarylpyrimidines analogs as HBV capsid effectors. Bioorg Med Chem Lett. 2017;27(4):904–10. Scholar
  80. 80.
    Brezillon N, Brunelle MN, Massinet H, Giang E, Lamant C, DaSilva L, et al. Antiviral activity of Bay 41-4109 on hepatitis B virus in humanized Alb-uPA/SCID mice. PLoS One. 2011;6(12):e25096. Scholar
  81. 81.
    Wang XY, Wei ZM, Wu GY, Wang JH, Zhang YJ, Li J, et al. In vitro inhibition of HBV replication by a novel compound, GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations. Antivir Ther. 2012;17(5):793–803. Scholar
  82. 82.
    Ren Q, Liu X, Luo Z, Li J, Wang C, Goldmann S, et al. Discovery of hepatitis B virus capsid assembly inhibitors leading to a heteroaryldihydropyrimidine based clinical candidate (GLS4). Bioorg Med Chem. 2017;25(3):1042–56. Scholar
  83. 83.
    Al-Mahtab M, Bazinet M, Vaillant A. Safety and efficacy of nucleic acid polymers in monotherapy and combined with immunotherapy in treatment-naive Bangladeshi patients with HBeAg+ chronic hepatitis B infection. PLoS One. 2016;11.
  84. 84.
    Bazinet M, Pantea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L et al. Update on safety and efficacy in the REP 401 protocol: REP 2139- Mgor REP 2165-mg used in combination with tenofovir disoproxil fumarate and pegylated interferon alpha-2a in treatment naïve Caucasian patients with chronic HBeAg negative HBV infection. J Hepatol. 2017;66.
  85. 85.
    Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM. GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology. 2013;144.
  86. 86.
    Gane EJ, Lim YS, Gordon SC, Visvanathan K, Sicard E, Fedorak RN. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. J Hepatol. 2015;63.
  87. 87.
    Janssen HL, Brunetto MR, Kim YJ, Ferrari C, Massetto B, Nguyen AH et al. Safety and efficacy of GS-9620 in virally-suppressed patients with chronic hepatitis B. Hepatology. 2016;64.Google Scholar
  88. 88.
    Boni C, Vecchi A, Rossi M, Laccabue D, Giuberti TG, Alfieri A et al. TLR-7 agonist GS-9620 can improve HBV-specific T cell and NK cell responses in nucleos(t)ide suppressed patients with chronic hepatitis B. Hepatology. 2016;64.Google Scholar
  89. 89.
    Bam RA, Hansen D, Irrinki A, Mulato A, Jones GS, Hesselgesser J et al. TLR7 agonist GS-9620 is a potent inhibitor of acute HIV-1 infection in human peripheral blood mononuclear cells. Antimicrob Agents Chemother. 2017;61(1).
  90. 90.
    Rao M, Valentini D, Dodoo E, Zumla A, Maeurer M. Anti-PD-1/PD-L1 therapy for infectious diseases: learning from the cancer paradigm. Int J Infect Dis. 2017;56:221–8. Scholar
  91. 91.
    Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S, et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell. 2016;165(1):35–44. Scholar
  92. 92.
    Pei Y, Wang C, Yan SF, Liu G. Past, current, and future developments of therapeutic agents for treatment of chronic hepatitis B virus infection. J Med Chem. 2017;60(15):6461–79. Scholar
  93. 93.
    Kah J, Koh S, Volz T, Allweiss L, Lohse A, Lütgehetmann M. Immunotherapy using T cells redirected against HBV results in reduced viral loads and enhanced immune responses in humanized mice. J Hepatol. 2016;64.
  94. 94.
    Mueller K, von Massenhausen A, Aichele U, Starck L, Leisegang M, Uckert W, et al. Protective capacity of virus-specific T cell receptor-transduced CD8 T cells in vivo. J Virol. 2012;86(19):10866–9. Scholar
  95. 95.
    Kah J, Koh S, Volz T, Ceccarello E, Allweiss L, Lutgehetmann M, et al. Lymphocytes transiently expressing virus-specific T cell receptors reduce hepatitis B virus infection. J Clin Invest. 2017;127(8):3177–88. Scholar
  96. 96.
    Koh S, Kah J, Tham CYL, Yang N, Ceccarello E, Chia A, et al. Nonlytic lymphocytes engineered to express virus-specific T-cell receptors limit HBV infection by activating APOBEC3. Gastroenterology. 2018;155(1):180–93 e6. Scholar
  97. 97.
    Lok AS, Pan CQ, Han SB, Trinh HN, Fessel WJ, Rodell T. Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B. J Hepatol. 2016;65.
  98. 98.
    Janssen HL, Yoon SK, Yoshida EM, Trinh HN, Rodell TC, Nguyen AH et al. Safety and efficacy of GS-4774 in combination with TDF in patients with chronic hepatitis B not on antiviral medication. Hepatology. 2016;64.Google Scholar
  99. 99.
    Petersen J, Thompson AJ, Levrero M. Aiming for cure in HBV and HDV infection. J Hepatol 2016;65.
  100. 100.
    • Honer Zu Siederdissen C, Hui AJ, Sukeepaisarnjaroen W, Tangkijvanich P, Su WW, Nieto GEG, et al. Contrasting timing of virological relapse after discontinuation of tenofovir or entecavir in hepatitis B e antigen-negative patients. J Infect Dis. 2018;218(9):1480–4. A post hoc analysis of 220 HBeAg-negative patients who received the recombinant vaccine ABX203 after cessation of tenofovir vs. entecavir. Only the type of antiviral therapy was associated with virological relapse, with relapse occurring earlier in patients treated with tenofovir.
  101. 101.
    Berg T, Simon KG, Mauss S, Schott E, Heyne R, Klass DM, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients—FINITE study. J Hepatol. 2017;67(5):918–24. Scholar
  102. 102.
    Honer Zu Siederdissen C, Rinker F, Maasoumy B, Wiegand SB, Filmann N, Falk CS, 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):1492–7. Scholar
  103. 103.
    Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology. 2012;143(3):629–36.e1. Scholar
  104. 104.
    Rinker F, Zimmer CL, Honer Zu Siederdissen C, Manns MP, Kraft ARM, Wedemeyer H, et al. Hepatitis B virus-specific T cell responses after stopping nucleos(t)ide analogue therapy in HBeAg-negative chronic hepatitis B. J Hepatol. 2018;69(3):584–93. Scholar
  105. 105.
    •• Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2018;68(2):425–34. A prospective study of 691 HBeAg negative patients, who remained HBsAg positive after NA treatment for a median of 156 weeks, had treatment discontinued. Higher rates of HBsAg seroclearance after discontinuation of therapy were observed. Factors associated with off- therapy seroclearance were studied.

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University Medical CenterRichmondUSA

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