Nailah Blair

Background: Hepatitis B is a potentially chronic virus of the liver causing inflammation, fibrosis, cirrhosis, and even hepatocellular carcinoma if unsuccessfully treated. ^1,2. There are currently two families of medications widely being used to treat chronic HBV: Nucleoside/tide analogs, which inhibit the production of daughter virions, and interferons (IFN), which have the added ability of inhibiting the closed covalent circular DNA (cccDNA) of HBV and thus potentiating functional cure for its users. ^2,3 The mechanisms of interferon action on HBV are not well known, and outcomes of interferon use are greatly inconsistent. This paper stands to connect the mechanisms of interferon, as well as look into potential patient outcome trends and markers of successful interferon use for patients battling chronic HBV.

Objective(s): The purpose of this narrative review is to define the method of chronic Hepatitis B neutralization utilized by interferon. This review also explores potential trends and biomarkers that correlate with positive HBV patient outcomes in regards to interferon use.

Search Methods: Documents were selected via the PubMed database and were selected under the pretenses of a 2017-2023 publication date and including one or more of the following keywords: “Hepatitis B”, “Interferon”, “HBV”, “IFN”.

Results: Research studies showed that IFN has an indirect effect on the TRIM14 gene via a Jak/STAT signaling cascade—TRIM14 directly inhibits replication of HBV by post-translationally binding to the viral HBx protein and preventing it from forming a complex with DDB1 (DNA damage binding protein 1) and ubiquitinating the anti-viral Smc (structural maintenance of chromosome 5/6) protein. ⁴ It was also found that IFN has a higher potential for seroconversion and functional cure than nucleoside/tide analog treatment alone, with more successful long-term outcomes and lack of relapse seen with patients who entered IFN treatment with HB surface antigens <500 IU/ml, HB core antigens <4 log10 IU/ml, and HB surface antibodies >2 log10 IU/ml. ^5,6 IFN not only inhibits HBV, but can also contrastingly promote relapse as well as T and Natural Killer (NK) cell inhibition through its activation of CD24⁺CD38^hi B cells. ⁸ IFN use was also negatively associated with potentially serious side effects such as allergic rash, malaise, aches, and fatigue. ⁷

Conclusion: It was found that IFN has a dual-sided  immunomodulatory effect on the immune system that both promotes the eradication of HBV and its cccDNA in hepatocytes but also limits its positive effects by promoting relapse, T cell and NK cell inhibition via IFN-induced CD24⁺CD38^hi B cells. This may explain the inconsistency in HBV patient outcomes for IFN users. By monitoring both the levels of ⁺CD38^hi B cells as well as HB surface antigens, HB core antigens and HB surface antibodies, physicians can better modify the treatment plans of their chronic HBV patients to allow for the highest chance of long-term seroconversion and functional cure. Shortcomings of these studies include limited study populations as well as a lack of available research on IFN-only based treatment plans rather than transition therapies from previous nucleoside/tide analog treatment. Further research can be done to determine modified treatment plans that lessen the negative mechanisms and side-effects of IFN use to allow for more consistency in patient outcomes.

Works Cited:

1. Li Q, Sun B, Zhuo Y, et al. Interferon and interferon-stimulated genes in HBV treatment. Front Immunol. 2022;13:1034968. doi: 10.3389/fimmu.2022.1034968.
2. Tang LSY, Covert E, Wilson E, Kottilil S. Chronic hepatitis B infection: A review. JAMA. 2018;319(17):1802-1813. doi: 10.1001/jama.2018.3795.
3. Yeh M, Huang J, Dai C, Yu M, Chuang W. Pharmacokinetics and pharmacodynamics of pegylated interferon for the treatment of hepatitis B. Expert Opin Drug Metab Toxicol. 2019;15(10):779-785. doi: 10.1080/17425255.2019.1678584.
4. Tan G, Xu F, Song H, et al. Identification of TRIM14 as a type I IFN-stimulated gene controlling hepatitis B virus replication by targeting HBx. Front Immunol. 2018;9:1872. doi: 10.3389/fimmu.2018.01872.
5. Chan HLY, Chan FWS, Hui AJ, et al. Switching to peginterferon for chronic hepatitis B patients with hepatitis B e antigen seroconversion on entecavir – A prospective study. J Viral Hepat. 2019;26(1):126-135. doi: 10.1111/jvh.13000.
6. Huang D, Wu D, Wang P, et al. End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after peg-IFN-based therapy in patients with CHB. J Hepatol. 2022;77(1):42-54. doi: 10.1016/j.jhep.2022.01.021.
7. Zhou Y, Yan R, Ru GQ, Yu LL, Yao J, Wang H. Pegylated-interferon consolidation treatment versus nucleos(t)ide analogue consolidation treatment in non-cirrhotic hepatitis B patients with hepatitis B e antigen seroconversion: An open-label pilot trial. Hepatol Int. 2019;13(4):422-430. doi: 10.1007/s12072-019-09957-0.
8. Fu B, Wang D, Shen X, et al. Immunomodulation induced during interferon-α therapy impairs the anti-HBV immune response through CD24(+)CD38(hi) B cells. Front Immunol. 2020;11:591269. doi: 10.3389/fimmu.2020.591269.