Novel Therapies in HBV Infection

Giuseppe Foti, Vincenzo Scaglione, Carlo Torti



Current treatments for chronic hepatitis B are able to provide a sustained suppression of the viral replication (i.e., persistent undetectability of HBV DNA). This leads to improvement of liver fibrosis and reduction of clinical complications. However, hepatitis B surface antigen (HBsAg) persists in most patients, probably justifying a still increased risk of hepatocellular carcinoma. Indeed, obtaining a complete and sterilizing cure with elimination of the covalently closed circular DNA (cccDNA) or silencing its activity is still a holy grail. New molecules are under evaluation to suppress viral replication acting on multiple phases of the HBV cycle or improve specific immune response against HBV. Molecules acting on HBV cycle have already showed encouraging results, such as entry inhibitors, small interfering RNAs (siRNAs), capsid assembly modulators (CAMs), nucleic acid polymers (NAPs). Also, promising results have been observed with immune-modulators, therapeutic vaccines, and other immune-based approaches. Among these, toll-like (TLR) or anti-programmed receptor agonists antibody 1 of the cell death protein (PD1) (e.g., nivolumab) are most promising. This paper describes newer drugs appearing on the horizon, including antiviral drugs targeting different steps of the HBV life cycle and therapeutic approaches based on immune-modulation.


Antiviral Therapy; Hepatitis B Surface Antigen; Nucleos(t)ide Analogs; PEGylated Interferon; Covalently Closed Circular DNA; Immune-Modulatory Therapy

Full Text



  • WHO Global Health Estimates 2015. Deaths by cause, age, sex, by country and by region, 2000-2015. Geneva: World Health Organization, 2016
  • EASL. Clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67: 370-98;
  • Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63: 261-83;
  • Lok AS, Zoulim F, Dusheiko G, et al. Hepatitis B cure: from discovery to regulatory approval. J Hepatol 2017; 67: 847-61;
  • Zoulim F. Inhibition of hepatitis B virus gene expression: a step towards functional cure. J Hepatol 2018; 68: 386-8;
  • Marcellin P, Bonino F, Yurdaydin C, et al. Hepatitis B surface antigen levels: association with 5 year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol Int 2013; 7: 88-97;
  • Kao JH. HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated interferon? Liver International 2014; 35 (Supp. 1): 112-9;
  • Marcellin P, Asselah T. Long‐term therapy for chronic hepatitis B: hepatitis B virus DNA suppression leading to cirrhosis reversal. J Gastroenterol Hepatol 2013; 28: 912-23;
  • Ni Y, Lempp FA, Mehrle S, et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocyte. Gastroenterology 2014; 146: 1070-83;
  • Schulze A, Gripon P, Urban S. Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparansulfateproteoglycans. Hepatology 2007; 46: 1759-68;
  • Schieck A, Schulze A, Gähler C, et al. Hepatitis B virus hepatotropism is mediated by specific receptor recognition in the liver and not restricted to susceptible hosts. Hepatology 2013; 58: 43-53;
  • Bogomolov P, Alexandrov A, Voronkova N, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: First results of a phase Ib/IIastudy. J Hepatol 2016; 65: 490-8;
  • Blank A, Markert C, Hohmann N, et al. First-in-human application of the first-in-class hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 2016; 65; 483-9;
  • Wedemeyer H, Bogomolov P, Blank A, et al. Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection. J Hepatology 2018; 68 (Suppl 1): s3; Abstr GS-005;
  • Wedemeyer H, Schöneweis K, Bogomolov P, et al. Interim Results of a Multicentre, Open-Label Phase 2 Clinical Trial (MYR203) to Assess Safety and Efficacy of Myrcludex B in Combination with Peg-Interferon Alpha 2a in Patients with Chronic HBV/HDV Co-Infection. Hepatology 2018; 68 (Suppl): Abstract 16;
  • Haag M, Hofmann U, Mürdter TE, et al. Quantitative bile acid profiling by liquid chromatography quadrupole time-offlight mass spectrometry: monitoring hepatitis B therapy by a novel Na-taurocholatecotransporting polypeptide inhibitor. Anal Bioanal Chem 2015; 407: 6815-25;
  • Blank A, Eidam A, Haag M, et al. The NTCP - inhibitor myrcludex B: effects on bile acid disposition and tenofovir pharmacokinetics. Clin Pharmacol Ther 2018; 103: 341-8;
  • Yuen MF, Locarnini S, Lim TH, et al. Short term RNA interference therapy in chronic hepatitis B using JNJ-3989 brings majority of patients to HBsAg< 100IUml threshold [abstract PS-080]. J Hepatol 2019; 70: e51;
  • Agarwal K. Bi- weekly dosing of ARB-1467 LNP siRNA in HBeAg negative, virally suppressed patients with chronic HBV infection leads to deeper declines in HBsAg and potential association with IL28b [abstract]. Hepatology 2017; 66: LB17
  • Yuen MF, Agarwal K, Gane EJ, 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. Hepatology 2018; 68 (S1): Abstract 73;
  • Zoulim F, Yogaratnam J, Vandenbossche JJ, et al. Safety, pharmacokinetics and antiviral activity of a novel hepatitis b virus (HBV) capsid assembly modulator, JNJ-56136379, in Patients with Chronic Hepatitis B (CHB). Hepatology 2018; 68 (S1): Abstract 74;
  • 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 Hepatology 2016; 64 (Suppl): S210-S211; Abstract LBO6;
  • Vaillant A, Bazinet M, Pantea V, et al. Updated follow-up analysis in the REP 401 protocol: Treatment HBeAg negative chronic hepatitis B infection with REP 2139 or REP 2165, tenofovir disoproxil fumarate and pegylated interferon alfa-2a. J Hepatol 2018; 68 (Suppl 1): S517; Abstract FRI-343;
  • Vaillant A. Nucleic acid polymers: Broad spectrum antiviral activity, antiviral mechanisms and optimization for the treatment of hepatitis B and hepatitis D infection. Antiviral Res 2016; 133: 32-40;
  • Bazinet M, Pântea V, Cebotarescu V, et al. Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol 2017; 2: 877-89;
  • Königer C, Wingert I, Marsmann M, et al. Involvement of the host DNA- repair enzyme TDP2 in formation of the covalently closed circular DNA persistence reservoir of hepatitis B viruses. Proc Natl Acad Sci USA 2014; 111: 4244-53;
  • Long Q, Yan R, Hu J, et al. The role of host DNA ligases in hepadnavirus covalently closed circular DNA formation. PLOS Pathog 2017; 13: e1006784;
  • Seeger C, Sohn, JA. Complete spectrum of CRISPR/Cas9-induced mutations on HBV cccDNA. Mol Ther 2016; 7: 1258-66;
  • Kennedy EM, Bassit LC, Mueller H, et al. Suppression of hepatitis B virus DNA accumulation in chronically infected cells using a bacterial CRISPR/Cas RNA-guided DNA endonuclease. Virology 2015; 476: 196-205;
  • Sekiba K, Otsuka M, Ohno M, et al. Inhibition of HBV transcription from cccDNA with nitazoxanide by targeting the HBx-DDB1 interaction. Cell Mol Gastroenterol Hepatol 2019; 7: 297-312;
  • Sekiba K, Otsuka M, Ohno M, et al. Pevonedistat, a Neuronal Precursor Cell-Expressed Developmentally Down-Regulated Protein 8-Activating Enzyme Inhibitor, Is a Potent Inhibitor of Hepatitis B Virus. Hepatology 2019; 69: 1903-15;
  • Rossignol JF, Bréchot C. A Pilot Clinical Trial of Nitazoxanide in the Treatment of Chronic Hepatitis B. Hepatol Commun 2019; 3: 744-7;
  • Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 2015; 64: 1972-84;
  • 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: 123-32;
  • Yuen MF, Chen CY, Liu CJ, et al. Ascending dose cohort study of inarigivir - a novel RIG I agonist in chronic HBV patients: final results of the ACHIEVE trial [abstract GS-12]. J Hepatol 2019; 70: e47-e48;
  • Yuen MF, Elkhashab M, Chen CY, et al. Inarigivir demonstrates potent dose dependent anti-viral activity in HBV treatment-naïve patients: role of HBeAg status and baseline HBsAg in anti-viral response. Hepatology 2018; 68 (S1): Abstract 75
  • 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: 1237-45;
  • Gane EJ, Lim YS, 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: 320-8;
  • Boni C, Vecchi A, Rossi M, et al. TLR7 agonist increases responses of hepatitis B virus- specific T cells and natural killer cells in patients with chronic hepatitis B treated with nucleos(t)ide analogues. Gastroenterology 2018; 154: 1764-77;
  • Gane E, Kim HJ, Visvanathan K, et al. Safety, pharmacokinetics and pharmacodynamics of oral TLR8 agonist GS-9688 in patients with chronic hepatitis B: a randomized, placebo-controlled, double-blind Phase 1b study. Hepatology 2018; 68 (S1): Poster #0401
  • 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 Hepatology 2016; 65: 509-16;
  • Gane E, Gaggar A, Nguyen AH, et al. A phase1 study evaluating anti-PD-1 treatment with or without GS-4774 in HBeAg negative chronic hepatitis B patients. J Hepatology 2017; 66 (Supplement): S26-S27;
  • Gane E, Verdon DJ, Brooks AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study. J Hepatology 2019; 71: 900-7;
  • Cerino A, Mantovani S, Mele D, et al. Human Monoclonal Antibodies as Adjuvant Treatment of Chronic Hepatitis B Virus Infection. Front Immunol 2019; 10: 2290;
  • Zhang T-Y, Yuan Q, Zhao J-H, 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: 658-71;
  • Li D, He W, Liu X, et al. A potent human neutralizing antibody Fc-dependently reduces established HBV infections. Elife 2017; 6: e26738;
  • Bertoletti A, Tan AT, Koh S. T-cell therapy for chronic viral hepatitis. Cytotherapy 2017; 19: 1317-24;
  • Boni C, Barili V, Acerbi G, et al. HBV Immune-Therapy: From Molecular Mechanisms to Clinical Applications. Int J Mol Sci 2019; 20: pii: E2754;


Abstract: 351 views
HTML: 178 views
PDF: 199 views


  • There are currently no refbacks.

© SEEd srl