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Novel Combination Strategies With Investigational Agents for Functional Cure of Chronic Hepatitis B Infection

  • Hepatitis B (JK Lim, Section Editor)
  • Published:
Current Hepatology Reports Aims and scope Submit manuscript

Abstract 

Purpose of Review

Functional cure, defined as sustained seroclearance of hepatitis B surface antigen (HBsAg), is a favorable treatment endpoint in chronic hepatitis B (CHB). As current drugs rarely induce functional cure, investigational agents with different modes of action are being developed. Combination of investigational agents may synergistically induce functional cure, and we reviewed the evidence on novel combination strategies for CHB.

Recent Findings

Combination strategies involving novel virus-targeting agents with immunomodulators can target both the virus and the host. In particular, potent HBsAg suppression with seroclearance has been reported with combinations of pegylated interferon alpha with small-interfering RNAs (siRNAs), nucleic acid polymers (NAPs), and entry inhibitors, respectively. Conversely, the combinations of virus-targeting agents or the combinations of immunomodulators have yielded mixed results.

Summary

Combination strategies involving both virus-targeting agents and immunomodulators have demonstrated encouraging data in phase I/II trials. Further studies are warranted to confirm the efficacy and safety of combination regimens.

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Abbreviations

ASO:

Antisense oligonucleotide

ASPIN:

Active site polymerase inhibitor nucleotide

cccDNA:

Covalently-closed circular DNA

CHB:

Chronic hepatitis B

CpAM:

Core protein allosteric modulator

FXR:

Farnesoid X receptor

HBcAg:

Hepatitis B core antigen

HBV:

Hepatitis B virus

HBsAg:

Hepatitis B surface antigen

IAP:

Inhibitor of apoptosis protein

ImmTAV:

Immune-mobilizing monoclonal T-cell receptors against virus

mRNA:

Messenger RNA

NA:

Nucleos(t)ide analogue

NAP:

Nucleic acid polymer

NOD2:

Nucleotide-binding oligomerization domain-containing protein 2

NTCP:

Sodium taurocholate co-transporting polypeptide

PD1:

Programmed cell death protein 1

Peg-IFNα:

Pegylated interferon alpha

rcDNA:

Relaxed-circular DNA

RIG-I:

Retinoic acid-inducible gene I

siRNA:

Small-interfering RNA

TLR:

Toll-like receptor

WHO:

World Health Organization

References 

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

  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. https://doi.org/10.1016/s2468-1253(18)30056-6.

    Article  Google Scholar 

  2. •• Seto WK, Lo YR, Pawlotsky JM, Yuen MF. Chronic hepatitis B virus infection. Lancet. 2018;392(10161):2313–24. https://doi.org/10.1016/s0140-6736(18)31865-8. (Comprehensive review article on the virology and treatment of chronic hepatitis B)

    Article  PubMed  Google Scholar 

  3. Lancet T. Towards elimination of viral hepatitis by 2030. Lancet. 2016;388(10042):308. https://doi.org/10.1016/s0140-6736(16)31144-8.

    Article  Google Scholar 

  4. World Health Organization: Global hepatitis report 2017. https://www.who.int/publications/i/item/global-hepatitis-report-2017 (2017). Accessed January 9 2022.

  5. • Hui RW-H, Mak LY, Seto W-K, Yuen M-F. Assessing the developing pharmacotherapeutic landscape in hepatitis B treatment: a spotlight on drugs in phase II clinical trials. Expert Opinion on Emerging Drugs. 2022:1–14. https://doi.org/10.1080/14728214.2022.2074977. (Comprehensive review article on emerging novel drugs for chronic hepatitis B)

  6. Mak LY, Seto WK, Hui RW, Fung J, Wong DK, Lai CL, 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. https://doi.org/10.1111/jvh.13095.

    Article  CAS  PubMed  Google Scholar 

  7. Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008;135(4):1192–9. https://doi.org/10.1053/j.gastro.2008.07.008.

    Article  CAS  PubMed  Google Scholar 

  8. Yeo YH, Ho HJ, Yang HI, Tseng TC, Hosaka T, Trinh HN, et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology. 2019;156(3):635-46.e9. https://doi.org/10.1053/j.gastro.2018.10.027.

    Article  CAS  PubMed  Google Scholar 

  9. Seto WK, Cheung KS, Wong DK, Huang FY, Fung J, Liu KS, et al. Hepatitis B surface antigen seroclearance during nucleoside analogue therapy: surface antigen kinetics, outcomes, and durability. J Gastroenterol. 2016;51(5):487–95. https://doi.org/10.1007/s00535-015-1128-2.

    Article  CAS  PubMed  Google Scholar 

  10. Yuen MF, Lai CL. Hepatitis B in 2014: HBV research moves forward-receptors and reactivation. Nat Rev Gastroenterol Hepatol. 2015;12(2):70–2. https://doi.org/10.1038/nrgastro.2014.226.

    Article  PubMed  Google Scholar 

  11. Watashi K, Urban S, Li W, Wakita T. NTCP and beyond: opening the door to unveil hepatitis B virus entry. Int J Mol Sci. 2014;15(2):2892–905. https://doi.org/10.3390/ijms15022892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mouzannar K, Fusil F, Lacombe B, Ollivier A, Ménard C, Lotteau V, et al. Farnesoid X receptor-α is a proviral host factor for hepatitis B virus that is inhibited by ligands in vitro and in vivo. Faseb j. 2019;33(2):2472–83. https://doi.org/10.1096/fj.201801181R.

    Article  CAS  PubMed  Google Scholar 

  13. Erken R, Andre P, Roy E, Kootstra N, Barzic N, Girma H, et al. Farnesoid X receptor agonist for the treatment of chronic hepatitis B: a safety study. J Viral Hepat. 2021;28(12):1690–8. https://doi.org/10.1111/jvh.13608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wooddell CI, Yuen MF, Chan HL, Gish RG, Locarnini SA, Chavez D, 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). https://doi.org/10.1126/scitranslmed.aan0241.

  15. Hui RW-H, Mak L-Y, Seto W-K, Yuen M-F. RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin Mol Hepatol. 2022;28(3):408–24. https://doi.org/10.3350/cmh.2022.0012.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Jiang B, Hildt E. Intracellular trafficking of HBV particles. Cells. 2020;9(9). https://doi.org/10.3390/cells9092023.

  17. 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. https://doi.org/10.1016/j.antiviral.2016.07.004.

    Article  CAS  PubMed  Google Scholar 

  18. Köck J, Nassal M, Deres K, Blum HE, von Weizsäcker F. 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. https://doi.org/10.1128/jvi.78.24.13812-13818.2004.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hui RW, Mak LY, Seto WK, Yuen MF. Role of core/capsid inhibitors in functional cure strategies for chronic hepatitis B. Curr Hepat Rep. 2020;19(3):293–301. https://doi.org/10.1007/s11901-020-00523-z.

    Article  Google Scholar 

  20. Mak LY, Seto WK, Lai CL, Yuen MF. DNA polymerase inhibitors for treating hepatitis B: a safety evaluation. Expert Opin Drug Saf. 2016;15(3):383–92. https://doi.org/10.1517/14740338.2016.1139573.

    Article  CAS  PubMed  Google Scholar 

  21. Clark DN, Hu J. Unveiling the roles of HBV polymerase for new antiviral strategies. Future Virol. 2015;10(3):283–95. https://doi.org/10.2217/fvl.14.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Menéndez-Arias L, Álvarez M, Pacheco B. Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase: mechanism of action and resistance. Curr Opin Virol. 2014;8:1–9. https://doi.org/10.1016/j.coviro.2014.04.005.

    Article  CAS  PubMed  Google Scholar 

  23. Megahed FAK, Zhou X, Sun P. The interactions between HBV and the innate immunity of hepatocytes. Viruses. 2020;12(3). https://doi.org/10.3390/v12030285.

  24. Park JJ, Wong DK, Wahed AS, Lee WM, Feld JJ, Terrault N, et al. Hepatitis B virus-specific and global T-cell dysfunction in chronic hepatitis B. Gastroenterology. 2016;150(3):684-95.e5. https://doi.org/10.1053/j.gastro.2015.11.050.

    Article  CAS  PubMed  Google Scholar 

  25. Woo ASJ, Kwok R, Ahmed T. Alpha-interferon treatment in hepatitis B. Ann Transl Med. 2017;5(7):159. https://doi.org/10.21037/atm.2017.03.69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Frontiers in Immunology. 2014;5. https://doi.org/10.3389/fimmu.2014.00461.

  27. Nie L, Xu XX, Xiang LX, Shao JZ, Chen J. Mutual regulation of NOD2 and RIG-I in zebrafish provides insights into the coordination between innate antibacterial and antiviral signaling pathways. Int J Mol Sci. 2017;18(6). https://doi.org/10.3390/ijms18061147.

  28. Yuen MF, Coffin CS, Elkhashab M, Greenbloom S, Ramji A, Chan HLY, et al. SB 9200 an oral selective immunomodulator is safe and efficacious in treatment-naive, non-cirrhotic HBV patients: results from cohort 1 of the ACHIEVE trial. Hepatology. 2017;66:22A.

    Google Scholar 

  29. Jubel JM, Barbati ZR, Burger C, Wirtz DC, Schildberg FA. The role of PD-1 in acute and chronic infection. Frontiers in Immunology. 2020;11. https://doi.org/10.3389/fimmu.2020.00487.

  30. Ebert G, Allison C, Preston S, Cooney J, Toe JG, Stutz MD, et al. Eliminating hepatitis B by antagonizing cellular inhibitors of apoptosis. Proc Natl Acad Sci U S A. 2015;112(18):5803–8. https://doi.org/10.1073/pnas.1502400112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fergusson JR, Wallace Z, Connolly MM, Woon AP, Suckling RJ, Hine DW, et al. Immune-mobilizing monoclonal T cell receptors mediate specific and rapid elimination of hepatitis B-infected cells. Hepatology. 2020;72(5):1528–40. https://doi.org/10.1002/hep.31503.

    Article  CAS  PubMed  Google Scholar 

  32. Lim SG, Agcaoili J, De Souza NNA, Chan E. Therapeutic vaccination for chronic hepatitis B: a systematic review and meta-analysis. J Viral Hepat. 2019;26(7):803–17. https://doi.org/10.1111/jvh.13085.

    Article  PubMed  Google Scholar 

  33. Beretta M, Mouquet H. Advances in human monoclonal antibody therapy for HBV infection. Curr Opin Virol. 2022;53:101205. https://doi.org/10.1016/j.coviro.2022.101205.

    Article  CAS  PubMed  Google Scholar 

  34. Yuen MF, Berliba E, Sukeepaisarnjaroen W, Tangkijvanich P, Leerapun A, Holmes JA, et al. Low HBsAg levels maintained following cessation of the GalNAc-siRNA, AB-729, in chronic hepatitis B patients on nucleos(t)ide analogue therapy. AASLD The Liver Meeting. US2021.

  35. Yuen MF, Lim TH, Kim W, Tongkijvonich P, Yoon JH, Sievert W, et al. HBV RNAi inhibitor RG6346 in Phase 1b-2a trial was safe, well tolerated, and resulted in subtantial and durable reductions in serum HBsAg levels. AASLD The Liver Meeting. US2020.

  36. Gane E, Lim YS, Cloutier D, Shen L, Cathcart A, Ding X, et al. Safety and antiviral activity of VIR-2218, an X-targeting RNAi therapeutic, in participants with chronic hepatitis B infection: week 48 follow-up results. J Hepatol. 2021;75:S287.

    Google Scholar 

  37. Gane E, Locarnini S, Lim TH, Strasser S, Sievert W, Cheng W, et al. Short interfering RNA JNJ-3989 combination therapy in chronic hepatitis B shows potent reduction of all viral markers but no correlate was identified for HBsAg reduction and baseline factors. J Hepatol. 2021;75:S289.

    Google Scholar 

  38. Yuen MF, Wong DK, Schluep T, Lai CL, Ferrari C, Locarnini S, et al. Long-term serological, virological and histological responses to RNA inhibition by ARC-520 in Chinese chronic hepatitis B patients on entecavir treatment. Gut. 2021. https://doi.org/10.1136/gutjnl-2020-323445.

    Article  PubMed  Google Scholar 

  39. • Yuen MF, Lim YS, Cloutier D, Thanawala V, Shen L, Arizpe A, et al. Preliminary results from a phase 2 study evaluating VIR-2218 alone and in combination with pegylated interferon alfa-2a in participants with chronic hepatitis B infection. Hepatology. 2021;74:63A. (Key study on the combination of pegylated interferon with siRNA)

    Google Scholar 

  40. • Wedemeyer H, Schöneweis K, Bogomolov PO, Chulanov V, Stepanova T, Viacheslav M, et al. 48 weeks of high dose (10 mg) bulevirtide as monotherapy or with peginterferon alfa-2a in patients with chronic HBV/HDV co-infection. J Hepatol. 2020;73:S52–3. (Key study on the combination of pegylated interferon with entry inhibitors)

    Article  Google Scholar 

  41. • Bazinet M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, et al. Safety and efficacy of 48 Weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon alfa-2a in patients with chronic HBV infection naïve to nucleos(t)ide therapy. Gastroenterology. 2020;158(8):2180–94. https://doi.org/10.1053/j.gastro.2020.02.058. (Key study on the combination of pegylated interferon with nucleic acid polymers)

    Article  CAS  PubMed  Google Scholar 

  42. Squires KE, Mayers DL, Bluemling GR, Kolykhalov AA, Guthrie DB, Reddy P, et al. ATI-2173, a novel liver-targeted non-chain-terminating nucleotide for hepatitis B virus cure regimens. Antimicrob Agents Chemother. 2020;64(9). https://doi.org/10.1128/aac.00836-20.

  43. Mak LY, Seto WK, Yuen MF. Novel antivirals in clinical development for chronic hepatitis B infection. Viruses. 2021;13(6). https://doi.org/10.3390/v13061169.

  44. Yuen MF, Asselah T, Jacobson IM, Brunetto MR, Janssen HL, Takehara T, et al. Efficacy and safety of the siRNA JNJ-3989 and/or the capsid assembly modulator JNJ-6379 for the treatment of chronic hepatitis B virus infection: results from the phase 2b REEF-1 study. AASLD The Liver Meeting. US2021.

  45. Tan H, Kang H, Luo M, Nie Y, Pandey R, Montero SM, et al. Combination drug interactions of hepatitis B virus (HBV) small interfering RNA (siRNA) and antisense oligonucleotides (ASO) in vitro and in vivo. Journal of Hepatology. 2021;75:S720-S.

  46. Liu J, Zhang E, Ma Z, Wu W, Kosinska A, Zhang X, et al. Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection. PLoS Pathog. 2014;10(1):e1003856. https://doi.org/10.1371/journal.ppat.1003856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bunse T, Kosinska AD, Michler T, Protzer U. PD-L1 silencing in liver using siRNAs enhances efficacy of therapeutic vaccination for chronic hepatitis B. Biomolecules. 2022;12(3). https://doi.org/10.3390/biom12030470.

  48. Gane E, Verdon DJ, Brooks AE, Gaggar A, Nguyen AH, Subramanian GM, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J Hepatol. 2019;71(5):900–7. https://doi.org/10.1016/j.jhep.2019.06.028.

    Article  CAS  PubMed  Google Scholar 

  49. Evans T, Barnes E. Phase 1b/2a study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with CHB on nucleos(t)ide analogues. J Hepatol. 2022;77:S868.

    Article  Google Scholar 

  50. Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65(3):490–8. https://doi.org/10.1016/j.jhep.2016.04.016.

    Article  CAS  PubMed  Google Scholar 

  51. Yuen MF, Gane EJ, Kim DJ, Weilert F, Yuen Chan HL, Lalezari J, et al. Antiviral activity, safety, and pharmacokinetics of capsid assembly modulator NVR 3–778 in patients with chronic HBV infection. Gastroenterology. 2019;156(5):1392-403.e7. https://doi.org/10.1053/j.gastro.2018.12.023.

    Article  CAS  PubMed  Google Scholar 

  52. Michler T, Kosinska AD, Festag J, Bunse T, Su J, Ringelhan M, et al. Knockdown of virus antigen expression increases therapeutic vaccine efficacy in high-titer hepatitis B virus carrier mice. Gastroenterology. 2020;158(6):1762-75.e9. https://doi.org/10.1053/j.gastro.2020.01.032.

    Article  CAS  PubMed  Google Scholar 

  53. Blaising J, Yu Y, Zhou X, Pedersen L, Wildum S, Ottosen S, et al. Combination treatment of liver-targeted HBV locked nucleic acid antisense oligonucleotide and TLR7 agonist RO7020531 leads to prolonged off-treatment antiviral effect in the AAV-HBV mouse model. Hepatology. 2019;70:428A-A429.

    Google Scholar 

  54. Yoo BC, Kim JH, Kim TH, Koh KC, Um SH, Kim YS, et al. Clevudine is highly efficacious in hepatitis B e antigen-negative chronic hepatitis B with durable off-therapy viral suppression. Hepatology. 2007;46(4):1041–8. https://doi.org/10.1002/hep.21800.

    Article  CAS  PubMed  Google Scholar 

  55. Jang JH, Kim JW, Jeong SH, Myung HJ, Kim HS, Park YS, et al. Clevudine for chronic hepatitis B: antiviral response, predictors of response, and development of myopathy. J Viral Hepat. 2011;18(2):84–90. https://doi.org/10.1111/j.1365-2893.2010.01281.x.

    Article  PubMed  Google Scholar 

  56. Perrillo R, Tamburro C, Regenstein F, Balart L, Bodenheimer H, Silva M, et al. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus. Gastroenterology. 1995;109(3):908–16. https://doi.org/10.1016/0016-5085(95)90401-8.

    Article  CAS  PubMed  Google Scholar 

  57. Cornberg M, Lok AS, Terrault NA, Zoulim F. Guidance for design and endpoints of clinical trials in chronic hepatitis B - report from the 2019 EASL-AASLD HBV treatment endpoints conference. Hepatology. 2019. https://doi.org/10.1002/hep.31030

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Authors and Affiliations

  1. Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, China

    Rex Wan-Hin Hui, Lung-Yi Mak, Ka-Shing Cheung, James Fung, Wai-Kay Seto & Man-Fung Yuen

  2. State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong, China

    Lung-Yi Mak, James Fung, Wai-Kay Seto & Man-Fung Yuen

  3. Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China

    Ka-Shing Cheung & Wai-Kay Seto

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Contributions

RWHH was involved in data interpretation and drafting of the manuscript. LYM, KSC, JF, and WKS were involved in the critical revision of the manuscript. MFY was involved in the study concept, critical revision of the manuscript, and overall study supervision. All authors have seen and approved the final version of the manuscript.

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Correspondence to Wai-Kay Seto or Man-Fung Yuen.

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Conflict of Interest

Rex Wan-Hin Wu, Lung-Yi Mak, Ka-Shing Cheung, and James Fung declare no conflict of interests.

Man-Fung Yuen is an advisory board member and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myer Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp, and Dohme, Clear B Therapeutics, Springbank Pharmaceuticals; and received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation, and Sysmex Corporation.

Wai-Kay Seto received speaker’s fees from AstraZeneca and Mylan, is an advisory board member of CSL Behring, is an advisory board member and received speaker’s fees from AbbVie, and is an advisory board member, received speaker’s fees and researching funding from Gilead Sciences. The remaining authors have no conflict of interest.

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Hui, R.WH., Mak, LY., Cheung, KS. et al. Novel Combination Strategies With Investigational Agents for Functional Cure of Chronic Hepatitis B Infection. Curr Hepatology Rep 21, 59–67 (2022). https://doi.org/10.1007/s11901-022-00590-4

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