Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Current Hepatology Reports
Published in: Current Hepatology Reports 3/2020

01-09-2020 | Hepatitis B | Hepatitis B (JK Lim, Section Editor)

Role of Core/Capsid Inhibitors in Functional Cure Strategies for Chronic Hepatitis B

Authors: Rex Wan-Hin Hui, Lung-Yi Mak, Wai-Kay Seto, Man-Fung Yuen

Published in: Current Hepatology Reports | Issue 3/2020

Login to get access

Abstract

Purpose of Review

Functional cure of chronic hepatitis B (CHB), defined as sustained hepatitis B surface antigen (HBsAg) seroclearance, is associated with favourable clinical outcomes. Nonetheless, the functional cure is rarely achievable by current treatment modalities. Core/capsid inhibitors (core protein allosteric modulators, CpAMs) are a novel drug class that targets the hepatitis B core protein and may have a potential impact on the functional cure. This article reviews the preclinical and clinical results of CpAMs.

Recent Findings

CpAMs interfere with the hepatitis B virus (HBV) nucleocapsid assembly and also exert a secondary action on covalently closed circular DNA replenishment. CpAMs are able to sustainably suppress hepatitis B viral load and viral antigens in in vivo studies. In phase I/II clinical trials, CpAMs are well tolerated and are efficacious in suppressing viral replication. CpAMs also have synergistic antiviral effects when combined with nucleoside analogues or pegylated interferon. The clinical data has yet to demonstrate the capability of CpAMs in inducing HBsAg seroclearance, possibly due to the short follow-up period of current studies. There is emerging data showing initial viral antigen reduction with the continuation of CpAMs for more than 24 weeks.

Summary

CpAMs have shown promising preclinical and phase I/II clinical data. Data from long-term phase III trials and from combination therapies with other antiviral agents are keenly anticipated.
Literature
1.
Polaris Observatory Collaborators. Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study. Lancet Gastroenterol Hepatol. 2018;3(6):383–403.
2.
Seto WK, Lo YR, Pawlotsky JM, Yuen MF. Chronic hepatitis B virus infection. Lancet. 2018;392(10161):2313–24.PubMed
3.
The Lancet. Towards elimination of viral hepatitis by 2030. Lancet. 2016;388(10042):308.PubMed
4.
5.
• Mak LY, et al. Fibrosis evolution in chronic hepatitis B e antigen-negative patients across a 10-year interval. J Viral Hepat. 2019;26(7):818–27. Study demonstrating fibrosis regression after functional cure of heaptitis B.PubMed
6.
• Yuen MF, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008;135(4):1192–9. Study demonstrating reduced risk of hepatocellular carcinoma after functional cure of heaptitis B.PubMed
7.
Kim G-A, Lim YS, An J, Lee D, Shim JH, Kim KM, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut. 2014;63(8):1325–32.PubMed
8.
Gish RG, Chang TT, Lai CL, de Man R, Gadano A, Poordad F, et al. Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. J Viral Hepat. 2010;17(1):16–22.PubMed
9.
Mak LY, Seto WK, Yuen MF. Future therapies for functional cure of chronic HBV: review of investigational drugs in phase 1 and 2 development. Curr Hepatol Rep. 2019;18(4):503–11.
10.
Zlotnick A, Venkatakrishnan B, Tan Z, Lewellyn E, Turner W, Francis S. Core protein: a pleiotropic keystone in the HBV lifecycle. Antivir Res. 2015;121:82–93.PubMed
11.
Ceres P, Zlotnick A. Weak protein-protein interactions are sufficient to drive assembly of hepatitis B virus capsids. Biochemistry. 2002;41(39):11525–31.PubMed
12.
Ryu DK, Ahn BY, Ryu WS. Proximity between the cap and 5’ epsilon stem-loop structure is critical for the suppression of pgRNA translation by the hepatitis B viral polymerase. Virology. 2010;406(1):56–64.PubMed
13.
Kock J, et al. Hepatitis B virus nucleocapsids formed by carboxy-terminally mutated core proteins contain spliced viral genomes but lack full-size DNA. J Virol. 2004;78(24):13812–8.PubMedPubMedCentral
14.
Cui X, Ludgate L, Ning X, Hu J. Maturation-associated destabilization of hepatitis B virus nucleocapsid. J Virol. 2013;87(21):11494–503.PubMedPubMedCentral
15.
Huovila AP, Eder AM, Fuller SD. Hepatitis B surface antigen assembles in a post-ER, pre-Golgi compartment. J Cell Biol. 1992;118(6):1305–20.PubMed
16.
Bock CT, Schwinn S, Locarnini S, Fyfe J, Manns MP, Trautwein C, et al. Structural organization of the hepatitis B virus minichromosome. J Mol Biol. 2001;307(1):183–96.PubMed
17.
Pollicino T, Belloni L, Raffa G, Pediconi N, Squadrito G, Raimondo G, et al. Hepatitis B virus replication is regulated by the acetylation status of hepatitis B virus cccDNA-bound H3 and H4 histones. Gastroenterology. 2006;130(3):823–37.PubMed
18.
Guo YH, Li YN, Zhao JR, Zhang J, Yan Z. HBc binds to the CpG islands of HBV cccDNA and promotes an epigenetic permissive state. Epigenetics. 2011;6(6):720–6.PubMed
19.
Gruffaz M, Testoni B, Luangsay S, Ait-Goughoulte M, Petit MA, Ma H, et al. Hepatitis B core (HBc) protein is a key and very early negative regulator of the interferon response. J Hepatol. 2013;58:S155–6.
20.
Du J, et al. Hepatitis B virus core protein inhibits TRAIL-induced apoptosis of hepatocytes by blocking DR5 expression. Cell Death Differ. 2009;16(2):219–29.PubMed
21.
Mohamadkhani A, Jazii FR, Poustchi H, Nouraein O, Abbasi S, Sotoudeh M, et al. The role of mutations in core protein of hepatitis B virus in liver fibrosis. Virol J. 2009;6:209.PubMedPubMedCentral
22.
Kim JH, Kang S, Kim J, Ahn BY. Hepatitis B virus core protein stimulates the proteasome-mediated degradation of viral X protein. J Virol. 2003;77(13):7166–73.PubMedPubMedCentral
23.
Gai X, Zhao P, Pan Y, Shan H, Yue X, du J, et al. Hepatitis B virus core protein enhances human telomerase reverse transcriptase expression and hepatocellular carcinoma cell proliferation in a c-Ets2-dependent manner. Int J Biochem Cell Biol. 2013;45(7):1174–85.PubMed
24.
Sung FY, et al. Hepatitis B virus core variants modify natural course of viral infection and hepatocellular carcinoma progression. Gastroenterology. 2009;137(5):1687–97.PubMed
25.
Zhu Y, Jin Y, Cai X, Bai X, Chen M, Chen T, et al. Hepatitis B virus core protein variations differ in tumor and adjacent nontumor tissues from patients with hepatocellular carcinoma. Intervirology. 2012;55(1):29–35.PubMed
26.
•• Mak LY, et al. Hepatitis B core protein as a therapeutic target. Expert Opin Ther Targets. 2017;21(12):1153–9. Review on the biochemistry of the hepatitis B core protein and its potential as a therapeutic target.PubMed
27.
Zlotnick A, Ceres P, Singh S, Johnson JM. A small molecule inhibits and misdirects assembly of hepatitis B virus capsids. J Virol. 2002;76(10):4848–54.PubMedPubMedCentral
28.
Bourne C, Lee S, Venkataiah B, Lee A, Korba B, Finn MG, et al. Small-molecule effectors of hepatitis B virus capsid assembly give insight into virus life cycle. J Virol. 2008;82(20):10262–70.PubMedPubMedCentral
29.
Stray SJ, Bourne CR, Punna S, Lewis WG, Finn MG, Zlotnick A. A heteroaryldihydropyrimidine activates and can misdirect hepatitis B virus capsid assembly. Proc Natl Acad Sci U S A. 2005;102(23):8138–43.PubMedPubMedCentral
30.
Stray SJ, Zlotnick A. BAY 41-4109 has multiple effects on hepatitis B virus capsid assembly. J Mol Recognit. 2006;19(6):542–8.PubMed
31.
Weber O, Schlemmer KH, Hartmann E, Hagelschuer I, Paessens A, Graef E, et al. Inhibition of human hepatitis B virus (HBV) by a novel non-nucleosidic compound in a transgenic mouse model. Antivir Res. 2002;54(2):69–78.PubMed
32.
Wu G, Liu B, Zhang Y, Li J, Arzumanyan A, Clayton MM, et al. Preclinical characterization of GLS4, an inhibitor of hepatitis B virus core particle assembly. Antimicrob Agents Chemother. 2013;57(11):5344–54.PubMedPubMedCentral
33.
Wang X-Y, 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.PubMed
34.
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.PubMed
35.
• Zhou X, et al. In vitro and in vivo antiviral characterization of RO7049389, a novel small molecule capsid assembly modulator for the treatment of chronic hepatitis B. J Hepatol. 2018;68:S770. Mechanistic study demonstrating that core/capsid inhibitors can sustainably suppress hepatitis B viral load and viral antigens.
36.
Katen SP, Chirapu SR, Finn MG, Zlotnick A. Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators. ACS Chem Biol. 2010;5(12):1125–36.PubMedPubMedCentral
37.
Feld JJ, Colledge D, Sozzi V, Edwards R, Littlejohn M, Locarnini SA. The phenylpropenamide derivative AT-130 blocks HBV replication at the level of viral RNA packaging. Antivir Res. 2007;76(2):168–77.PubMed
38.
Delaney WEt, et al. Phenylpropenamide derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine-resistant strains of hepatitis B virus in vitro. Antimicrob Agents Chemother. 2002;46(9):3057–60.PubMed
39.
Yang L, Wang YJ, Chen HJ, Shi LP, Tong XK, Zhang YM, et al. Effect of a hepatitis B virus inhibitor, NZ-4, on capsid formation. Antivir Res. 2016;125:25–33.PubMed
40.
Yang L, Shi LP, Chen HJ, Tong XK, Wang GF, Zhang YM, et al. Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation. Acta Pharmacol Sin. 2014;35(3):410–8.PubMedPubMedCentral
41.
Campagna MR, Liu F, Mao R, Mills C, Cai D, Guo F, et al. Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids. J Virol. 2013;87(12):6931–42.PubMedPubMedCentral
42.
Mani N, Cole AG, Phelps JR, et al. Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation. Antimicrob Agents Chemother. 2018;62(6):e00082–18.
43.
Lam AM, et al. Preclinical characterization of NVR 3-778, a first-in-class capsid assembly modulator against hepatitis B virus. Antimicrob Agents Chemother. 2018;63(1):e01734–18.PubMedPubMedCentral
44.
Klumpp K, et al. Efficacy of NVR 3-778, alone and in combination with pegylated interferon, vs entecavir in uPA/SCID mice with humanized livers and HBV infection. Gastroenterology. 2018;154(3):652–662.e8.PubMed
45.
Berke JM, et al. Capsid assembly modulator JNJ-56136379 prevents de novo infection of primary human hepatocytes with hepatitis B virus. Hepatology. 2016;64((S1)):124A.
46.
Vaine M, Dellisola V, Clugston S, Cao H, Gao X, Kass J, et al. EDP-514, a novel HBV core inhibitor with potent antiviral activity both in vitro and in vivo. J Hepatol. 2019;70(1):e474–5.
47.
Debing Y, Jekle A, Vendeville S, et al. Preclinical assessment of a novel capsid assembly modulator, ALG-001075, demonstrates best-in-class in vitro potency and in vivo antiviral efficacy. Hepatology. 2019;70(S1):437A.
48.
Jekle A, Debing Y, Vendeville S, et al. Preclinical assessment of potency and efficacy of a novel class-II capsid assembly modulator ALG-001024. Hepatology. 2019;70(S1):439A.
49.
Berke JM, Dehertogh P, Vergauwen K, et al. Capsid assembly modulators have a dual mechanism of action in primary human hepatocytes infected with hepatitis B virus. Antimicrob Agents Chemother. 2017;61(8):e00560–17.
50.
Guo F, Zhao Q, Sheraz M, Cheng J, Qi Y, Su Q, et al. HBV core protein allosteric modulators differentially alter cccDNA biosynthesis from de novo infection and intracellular amplification pathways. PLoS Pathog. 2017;13(9):e1006658.PubMedPubMedCentral
51.
Belloni L, Palumbo GA, Li L, Chirapu SR, Calvo L, Lupacchini L, et al. Anti capsid drugs HAP12 and AT130 target HBV core protein nuclear functions. Dig Liver Dis. 2015;47:e10.
52.
Zhao N, Jia B, Zhao H, et al. A first-in-human trial of GLS4, a novel inhibitor of hepatitis B virus capsid assembly, following single- and multiple-ascending-oral-dose studies with or without ritonavir in healthy adult volunteers. Antimicrob Agents Chemother. 2020;64(1):e01686–19.
53.
Ding Y, Zhang H, Niu J, Chen H, Liu C, Li X, et al. Multiple dose study of GLS4JHS, interfering with the assembly of hepatitis B virus core particles, in patients infected with hepatitis B virus. J Hepatol. 2017;66(1):S27–8.
54.
Gane E, Yuen MF, Bo Q, Schwabe C, Tanwandee T, Das S, et al. RO7049389, a core protein allosteric modulator, demonstrates robust decline in HBV DNA and HBV RNA in chronic HBV infected patients. J Hepatol. 2019;70(1):e491.
55.
56.
57.
•• Yuen MF, et al. Safety, pharmacokinetics, and antiviral effects of ABI-H0731, a hepatitis B virus core inhibitor: a randomised, placebo-controlled phase 1 trial. Lancet Gastroenterol Hepatol. 2020;5(2):152–66. Landmark paper on a phase I trial on ABI-H0731.PubMed
58.
Ma X, Lalezari J, Nguyen T, Bae H, Schiff ER, Fung S, et al. Interim safety and efficacy results of the ABI-H0731 phase 2a program exploring the combination of ABI-H0731 with Nuc therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients. J Hepatol. 2019;70(1):e130.
59.
•• Sulkowski M, Agarwal K, Fung S, et al. Continued therapy with ABI-H0731 + NrtI results in sequential reduction/loss of HBV DNA, HBV RNA, HBeAg, HBcrAg and HBsAg in HBeAg-positive patients. Hepatology. 2019;70(6):1486A–1487A. Study demonstrating viral antigen decline with extended usage of ABI-H0731.
60.
Yuen MF, Agarwal K, Gane E, et al. The secondgeneration hepatitis B virus (HBV) core inhibitor (CI) ABI-H2158 is associated with potent antiviral activity in a 14-day monotherapy study in HBeAg-positive patients with chronic hepatitis B (CHB). Hepatology. 2019;70(6):1497A–1498A.
61.
•• Yuen MF, et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3-778 in patients with chronic HBV infection. Gastroenterology. 2019;156(5):1392–1403.e7. Landmark paper on a phase I trial on NVR 3-778.PubMed
62.
Vandenbossche J, Jessner W, van den Boer M, Biewenga J, Berke JM, Talloen W, et al. Pharmacokinetics, safety and tolerability of JNJ-56136379, a novel hepatitis B virus capsid assembly modulator, in healthy subjects. Adv Ther. 2019;36(9):2450–62.PubMed
63.
Zoulim F, et al. Safety, pharmacokinetics and antiviral activity of novel capsid assembly modulator (CAM) JNJ-56136379 (JNJ-6379) in treatment-naïve chronic hepatitis B (CHB) patients without cirrhosis. J Viral Hepat. 2018;25(S2):36.
64.
Gane E, Schwabe C, Lenz O, et al. JNJ-64530440 (JNJ-0440), a novel class N capsid assembly modulator (CAM-N): safety, tolerability, pharmacokinetics (PK), and antiviral activity of multiple ascending doses in patients with chronic hepatitis B (CHB). Hepatology. 2019;70(S1):61A.
Metadata
Title
Role of Core/Capsid Inhibitors in Functional Cure Strategies for Chronic Hepatitis B
Authors
Rex Wan-Hin Hui
Lung-Yi Mak
Wai-Kay Seto
Man-Fung Yuen
Publication date
01-09-2020
Publisher
Springer US
Published in
Current Hepatology Reports / Issue 3/2020
Electronic ISSN: 2195-9595
DOI
https://doi.org/10.1007/s11901-020-00523-z

Other articles of this Issue 3/2020

Current Hepatology Reports 3/2020 Go to the issue

Hepatitis B (JK Lim, Section Editor)

Targeting Viral cccDNA for Cure of Chronic Hepatitis B

Fatty Liver Disease (V Ajmera, Section Editor)

Cardiovascular Disease in Nonalcoholic Steatohepatitis: Screening and Management

Hepatitis B (JK Lim, Section Editor)

Management of Acute Hepatitis B Virus Infection

Portal Hypertension (J Gonzalez-Abraldes and E Tsochatzis, Section Editors)

Esophageal Varices: Primary Prophylaxis and Prevention and Management of Rebleeding

Portal Hypertension (J Gonzalez-Abraldes and E Tsochatzis, Section Editors)

Budd-Chiari Syndrome: Anticoagulation, TIPS, or Transplant

Management of the Cirrhotic Patient (A Cardenas and P Tandon, Section Editors)

Hepatopulmonary Syndrome and Portopulmonary Hypertension: Current Status and Implications for Liver Transplantation
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits