Evaluation and treatment of chronic hepatitis B

Abstract

A method is provided herein for administering hepatitis B virus surface antigen (HBsAg) to subjects having chronic hepatitis B, distinguishing between responsive subjects who respond to HBsAg administration with an increase in HBV antibody levels and non-responsive subjects, and treating chronic hepatitis B in responsive subjects with HBV treatment. A method for excluding non-responsive subjects from a clinical study is also provided. According to one embodiment of the present disclosure, a method is provided for treating hepatitis B virus (HBV) infection in subjects having chronic hepatitis B, the method comprising the steps of a) administering HBV surface antigen (HBsAg) to the subject; and b) administering an HBV treatment other than HBsAg to the subject at least four weeks after the initial dose of HBsAg.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 522,851, filed on Jun. 23, 2023, the content of which is incorporated herein by reference in its entirety.

[0002] <​​​​​​​​​​​​​​​Current treatments for CHB suppress HBV viral DNA, but rarely eradicate the virus. These treatments include (i) nucleoside / nucleotide reverse transcriptase inhibitors (NrtIs) (e.g., lamivudine, entecavir, tenofovir alafenamide, tenofovir disoproxil fumarate, adefovir dipivoxil, and terbivudine); and (ii) immunomodulatory agents such as PEG-IFNα. Long-term treatment with NrtIs has led to the emergence of HBV strains that confer resistance to NrtIs. Furthermore, HBV cccDNA is not removed from infected cells even with NrtI treatment, and viral protein production, particularly the production of HBV surface antigen (HBsAg), can persist as measured in the blood (Scaglione and Lok, 2012, Gastroenterology 142:1360-1368). PEG-IFNα therapy has a limited treatment course, and while some PEG-IFNα responders may maintain virological or serological responses, such as serum HBsAg clearance, after discontinuation of the drug, unfortunately, the response rate to PEG-IFNα therapy is relatively low. The inability of NrtI treatment to achieve functional cure, and the limitations of PEG-IFNα treatment, highlight the need for effective and well-tolerated HBV treatment. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Ye et al., 2015, Cell Death & Disease, 6(3):e1694 [Non-Patent Document 2] Scaglione and Lok, 2012, Gastroenterology 142:1360-1368 [Overview of the project] [Means for solving the problem]

[0006] Abstract According to one embodiment of the present disclosure, a method is provided for treating a hepatitis B virus (HBV) infection in a subject having chronic hepatitis B, the method comprising the steps of: a) administering to the subject an HBV surface antigen (HBsAg); and b) administering to the subject an HBV treatment other than HBsAg at least four weeks after the initial dose of HBsAg.

[0007] In some embodiments, the initial dose of the HBV treatment is administered at least two doses of HBsAg, or at least three, four, or five doses of HBsAg. In some embodiments, the initial dose of the HBV treatment is administered at least eight weeks after the initial dose of HBsAg, or at least nine, ten, eleven, twelve, thirteen, fourteen, or fifteen weeks after the initial dose of HBsAg.

[0008] In some embodiments, the subjects have not been treated with HBV treatment prior to the administration of HBsAg. In some embodiments, the subjects have not been treated with interferon prior to the administration of HBsAg. In some embodiments, the subjects have not been treated for HBV infection prior to the administration of HBsAg.

[0009] In some embodiments, the HBsAg is administered at a dose of 20 μg to 100 μg once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0010] In some embodiments, the HBV treatment is selected from the group consisting of anti-HBsAg siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAbs, and combinations thereof.

[0011] In some embodiments, the HBV treatment comprises anti-HBsAg siRNA. In some embodiments, the anti-HBsAg siRNA is administered at a dose of 100 mg to 400 mg every two weeks (Q2W), every three weeks (Q3W), every four weeks (Q4W), every five weeks (Q5W), or every six weeks (Q6W).

[0012] In some embodiments, the HBV treatment further comprises PEG-IFNα. In some embodiments, the PEG-IFNα is administered once a week at doses of 50-500 μg, 100-300 μg, or 180 μg.

[0013] In one embodiment, a method is provided for treating a hepatitis B virus (HBV) infection in a subject having chronic hepatitis B, the method comprising administering to the subject 20 μg to 100 μg / dose of HBV surface antigen (HBsAg) once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W), and 100 mg to 400 mg / dose of anti-HBsAg siRNA once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W), wherein the treatment comprises steps comprising at least four (or five, six, seven, eight, or ten) doses of each of the HBsAg and the siRNA.

[0014] In some embodiments, the HBsAg comprises virus-like particles (VLPs) containing Pre-S1, Pre-S2, or S, which are HBV surface envelope proteins. In some embodiments, the VLPs comprise Pre-S1, Pre-S2, and S, which are HBV surface envelope proteins.

[0015] In some embodiments, the siRNA is erebsilane.

[0016] In some embodiments, the subject is further administered a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI). In some embodiments, the method further comprises the step of stopping the administration of the NrtI if the subject meets one or more of the stopping criteria. In some embodiments, the stopping criteria include (a) HBsAg < LLOQ (lower limit of quantification), (b) HBV DNA < LLOQ, (c) undetectable HBeAg, and (d) ALT (alanine aminotransferase) ≤ 2 × ULN (upper limit of normal).

[0017] In one aspect, a method for excluding subjects with chronic hepatitis B (CHB) from a clinical study, the method comprising: (a) screening a group of CHB subjects by administering HBV surface antigen (HBsAg) to the CHB subjects, wherein each CHB subject has a predetermined baseline HBV antibody concentration prior to administration of the HBsAg, and each CHB subject who does not respond to the administration of the HBsAg with a post-baseline HBV antibody concentration higher than their baseline HBV antibody concentration is excluded from the clinical study; and (b) conducting the clinical study, wherein HBV treatment is administered to CHB subjects not excluded from the clinical study. A method as provided herein is provided.

[0018] In some embodiments, each CHB subject who does not respond to the administration of the HBsAg with a post-baseline HBV antibody concentration five times higher than their baseline HBV antibody concentration is excluded from the clinical study.

[0019] In some embodiments, (i) for each CHB subject having a predetermined baseline HBV antibody concentration at or below the lower limit of detection (e.g., ≤2 IU / L), the CHB subject is excluded from the clinical trial unless the post-baseline HBV antibody concentration of the CHB subject exceeds the lower limit of detection (e.g., >2 IU / L), and (ii) for each CHB subject having a predetermined baseline HBV antibody concentration above the lower limit of detection (e.g., >2 IU / L), the CHB subject is excluded from the clinical trial unless the post-baseline HBV antibody concentration of the subject is at least two-fold higher than their predetermined baseline HBV antibody concentration.

[0020] In some embodiments, a CHB subject is excluded from the clinical trial unless the CHB subject has a post-baseline HBV antibody concentration higher than 4 IU / L, higher than 5 IU / L, higher than 10 IU / L, higher than 12 IU / L, higher than 15 IU / L, higher than 20 IU / L, higher than 25 IU / L, higher than 30 IU / L, higher than 50 IU / L, higher than 100 IU / L, higher than 150 IU / L, higher than 200 IU / L, higher than 250 IU / L, or higher than 300 IU / L.

[0021] In some embodiments, the CHB subject is virally suppressed with a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) prior to administration of the HBsAg.

[0022] In some embodiments, the HBV antibody concentration is the serum anti-HBs concentration.

[0023] In some embodiments, the HBV treatment excludes the HBsAg.

[0024] In one aspect, a method for selecting a subject having chronic hepatitis B (CHB) for hepatitis B virus (HBV) treatment, the method comprising: (a) determining a baseline HBV antibody concentration in a subject having CHB before administering HBV surface antigen (HBsAg) to the subject; (b) administering the HBsAg to the subject; (c) determining a post-baseline HBV antibody concentration in the subject after administering the HBsAg, wherein the subject is selected for HBV treatment if the post-baseline HBV antibody concentration is higher than the baseline HBV antibody concentration, and otherwise, the subject is excluded from the HBV treatment; and (d) administering the HBV treatment to the selected subject, is provided herein.

[0025] In some embodiments, the subject is selected for HBV treatment if the post-baseline HBV antibody concentration is 5-fold higher than the baseline HBV antibody concentration, and otherwise, the subject is excluded from the HBV treatment.

[0026] In some embodiments, the subject is selected for HBV treatment if (i) the baseline HBV antibody concentration of the subject is at or below the lower limit of detection (e.g., ≤2 IU / L) and the post-baseline HBV antibody concentration of the subject is above the lower limit of detection (e.g., >2 IU / L), or (ii) the baseline HBV antibody concentration of the subject is above the lower limit of detection (e.g., >2 IU / L) and the post-baseline HBV antibody concentration of the subject is at least 2-fold higher than the baseline HBV antibody concentration of the subject, and otherwise, the subject is excluded from the HBV treatment.

[0027] In some embodiments, the subject is virally suppressed with a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) prior to administration of the HBsAg.

[0028] In some embodiments, the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject. In some embodiments, the HBV treatment excludes HBsAg. In some embodiments, the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAbs, or a combination thereof.

[0029] In one aspect, the present invention provides a method for treating HBV infection in a subject having chronic hepatitis B, the method comprising the step of administering an HBV treatment to the subject, wherein it is determined that the baseline HBV antibody concentration in the subject after administration of HBsAg is higher than the baseline HBV antibody concentration in the subject before administration of HBsAg.

[0030] In some embodiments, the HBV treatment is administered when it is determined that the baseline HBV antibody concentration in the subject after administration of HBsAg is five times higher than the baseline HBV antibody concentration in the subject before administration of HBsAg.

[0031] In some embodiments, the HBV treatment is administered to a subject if (i) the subject's baseline HBV antibody concentration is below or equal to the lower limit of detection (e.g., ≤2 IU / L) and the subject's post-baseline HBV antibody concentration is above the lower limit of detection (e.g., >2 IU / L), or (ii) the subject's baseline HBV antibody concentration is above the lower limit of detection (e.g., >2 IU / L) and the subject's post-baseline HBV antibody concentration is at least twice as high as the subject's baseline HBV antibody concentration.

[0032] In some embodiments, the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject. In some embodiments, the HBV treatment excludes HBsAg. In some embodiments, the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAbs, or a combination thereof.

[0033] A method for treating an HBV infection in a subject diagnosed with or suspected of having an HBV infection in one context is provided herein, the method comprising: (a) administering HBsAg to the subject; (b) determining the baseline HBV antibody concentration in a serum sample collected from the subject after administration of HBsAg; and (c) administering HBV treatment to the subject if the baseline HBV antibody concentration is higher than the baseline HBV antibody concentration in a serum sample collected from the subject before administration of HBsAg.

[0034] In some embodiments, the HBV treatment is administered when it is determined that the baseline HBV antibody concentration in the subject after administration of HBsAg is five times higher than the baseline HBV antibody concentration in the subject before administration of HBsAg.

[0035] In some embodiments, the HBV treatment is administered to the subject if (i) the subject's baseline HBV antibody concentration is below or equal to the detection limit (e.g., ≤2 IU / L) and the subject's post-baseline HBV antibody concentration is above the detection limit (e.g., >2 IU / L), or (ii) the subject's baseline HBV antibody concentration is above the detection limit (e.g., >2 IU / L) and the subject's post-baseline HBV antibody concentration is at least twice as high as the subject's baseline HBV antibody concentration. In some embodiments, the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations. In some embodiments, the subject is virally suppressed with NrtI before administration of HBsAg. In some embodiments, the HBV treatment is excluding HBsAg. In some embodiments, the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

[0036] A method for treating HBV infection in a subject having chronic hepatitis B in one aspect, wherein the HBV antibody concentration in the subject is less than 2 IU / L, and the method comprises (a) administering HBsAg to the subject; and (b) administering HBV treatment to the subject, wherein the HBV antibody concentration in the subject, after administration of HBsAg, is at least 2 IU / L, at least 5 IU / L, at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 Methods are provided herein that include a step which is determined to be IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 IU / L. In some embodiments, the subject is virally suppressed with NrtI before administration of HBsAg. In some embodiments, the HBV antibody is anti-HBs. In some embodiments, the HBV treatment is excluding HBsAg. In some embodiments, the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

[0037] A method for treating HBV infection in a subject having chronic hepatitis B in one aspect, the method comprising administering a therapeutically effective amount of HBV therapy to a subject having chronic hepatitis B, wherein, prior to the administration of the HBV therapy, the HBV antibody concentration of the subject is at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 A method comprising steps determined to be IU / L is provided herein. In some embodiments, the HBV antibody concentration of the subject is an anti-HBs concentration. In some embodiments, the HBV treatment is excluding HBsAg. In some embodiments, the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

[0038] In one aspect, an HBV surface antigen (HBsAg) for use in the manner provided herein is provided herein.

[0039] In another context, the use of HBV surface antigen (HBsAg) and HBV treatments not comprising the HBsAg for the manufacture of a kit for treating a subject having chronic hepatitis B is provided herein, wherein the subject responds to the administration of the HBV treatment with an increase in the HBV antibody concentration upon administration of the HBsAg relative to the subject's HBV antibody concentration prior to the administration of the HBsAg. In some embodiments, (i) the subject's HBV antibody concentration prior to the administration of the HBsAg is lower than 2 IU / L, or (ii) the subject responds with an increase in the HBV antibody concentration to twice the HBV antibody concentration prior to the administration of the HBsAg. In some embodiments, the subject is virally suppressed with NrtI prior to the administration of the HBsAg. In some embodiments, the HBV antibody is anti-HBs. In some embodiments, the HBV treatment described above is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAbs, or a combination thereof. [Brief explanation of the drawing]

[0040] [Figure 1] Figure 1 shows the research design scheme as discussed in Example 8.

[0041] [Figure 2] Figure 2 shows the change in HBsAg levels in patients after treatment compared to baseline.

[0042] [Figure 3] Figure 3 shows the anti-HBs antibody response after treatment. One participant withdrew from the study before Work 8 and therefore did not have available post-baseline anti-HBs data. [Modes for carrying out the invention]

[0043] Detailed explanation definition It should be noted that the terms “a” or “an” entity refer to one or more of those entities; for example, “an antibody” is understood to represent one or more antibodies. Thus, the terms “a” (or “an”), “one or more,” and “at least one” may be used interchangeably herein.

[0044] It should be further understood that, along with the wording "comprising," other similar aspects are also provided, which, whenever a situation is described herein, are always described in terms of "consisting of" and / or "consisting essentially of."

[0045] The "therapeutically effective amount," "effective dose," "effective amount," or "therapeutically effective dosage" of a therapeutic agent (e.g., anti-HBsAg siRNA) is any amount that, when used alone or in combination with another therapeutic agent, protects a subject from the development of a disease or symptom originating from CHB (e.g., liver failure or liver cancer), or promotes disease regression, as determined, for example by measuring HBV DNA levels or HBV antigen levels, by reducing the viral load, reducing the severity of disease symptoms, increasing the frequency and duration of asymptomatic periods of the disease, or preventing impairment or disability resulting from the distress of the disease. The ability of a therapeutic agent to promote disease regression can be evaluated using various methods known to those skilled in the art, such as by evaluating the activity of the agent in human subjects during clinical trials, in animal model systems for inferring efficacy in humans, or in in vitro assays.

[0046] "Subject," "individual," "animal," "patient," or "mammal" means any subject, in particular a mammalian subject, for which diagnosis, prognosis prediction, or treatment is desired. In some embodiments, the subject refers to a human. In some embodiments, the subject is a human having chronic hepatitis B (CHB) ("CHB subject").

[0047] As used herein, phrases such as “to a patient in need of treatment” or “a subject in need of treatment” include subjects (e.g., mammalian subjects) who would benefit from an administration of the compositions of this disclosure used for, for, for, detection, for, a diagnostic procedure, and / or treatment.

[0048] Evaluation and treatment of chronic HBV BRII-179 (virus-like particles (VLPs) containing HBV 3 surface envelope proteins (L, M, S)) has been found to induce a significant anti-HBs (hepatitis B surface antibody) response in some, though not all, participants with chronic HBV (cHBV) infection (Example 1). Furthermore, a potent anti-HBs response was associated with treatment with BRII-835 and PEG-IFNα combination therapy, as well as with sustained HBsAg (hepatitis B surface antigen) seroclearance after BRII-179 and PEG-IFNα add-on therapy, in a subset of CHB patients.

[0049] BRII-179 (also known as VBI-2601) is a VLP-based recombinant protein immunotherapy consisting of small, medium, and large proteins that form three HBsAg forms: HBV envelopes. The large S protein contains N-terminal preS1 and preS2 domains, as well as an adjacent small S protein. The medium S protein contains preS2 and an adjacent small S protein. The preS1 domain contains several relatively conserved B and T helper cell epitopes. Therefore, BRII-179 utilizes the PreS1, PreS2, and S protein components as immunogens in the therapeutic application of preS1 / S2-containing HBsAg. Furthermore, BRII-179 utilizes an aluminum phosphate adjuvant to produce enhanced Th1-type T cells and humoral immunity.

[0050] BRII-835 (also known as erebsilane and VIR-2218) is a synthetic ribonucleic acid interference (RNAi) therapy designed to target HBV transcripts, including a region in the HBx gene that is common to all HBV transcripts and highly conserved among HBV genotypes. It is conjugated to an N-acetylgalactosamine (GalNAc) ligand to facilitate delivery to hepatocytes via the asialoclycoprotein receptor (ASGPR).

[0051] Interferon-alpha (IFNα) is used to treat hepatitis B by inducing interferon-stimulating genes at various points in the HBV life cycle across different pathways that lead to increased degradation of viral RNA and enhanced protection against viral damage. IFNα also stimulates a cell-mediated immune response that targets infected hepatocytes, resulting in a decrease in cells containing the hepatic HBV cccDNA (covalent closed circular DNA) molecule responsible for the persistence of HBV infection. Furthermore, it can reshape the immune landscape to induce adaptive immunity by harmonizing various immune cells (including NK cells, macrophages, DCs, and T cells). PEG-IFNα allows for once-weekly injections. PEG-IFNα is associated with several side effects, including flu-like symptoms, neutropenia, thrombocytopenia, depression, and less common exacerbations or manifestations of autoimmune diseases, as well as hepatitis flares. The main advantages of PEG-IFNα in the treatment of CHB are its finite duration of treatment, lack of resistance, and the opportunity to obtain a sustained virological response off-treatment, particularly the potential for immune-mediated control of HBV infection along with the opportunity for HBsAg serum clearance in a subset of CHB patients. However, functional cure after PEG-IFNα monotherapy is confirmed in only a small percentage (<10%) of CHB patients.

[0052] As a therapeutic agent, the effect of adding BRII-179 to other HBV treatments was evaluated. As shown in Example 7, BRII-835 alone restored the HBV surface antigen-specific T cell response in a small percentage of participants (20%). The addition of BRII-179 with or without the coadjuvant IFN-α induced an improved HBV surface antigen-specific T cell response (70%). Furthermore, the combination of BRII-179 and BRII-835 resulted in a higher proportion of participants having a larger T cell response (>20 times baseline) compared to BRII-179 monotherapy (40% vs. 25%). Regarding antibody responses, BRII-835 alone did not induce an antibody response in Cohort A (Figure 3). BRII-179, with or without the adjuvant IFN-α, generally induced a potent anti-HBs response after 5 doses, with titers reaching the assay upper limit of 1000 IU / L in some participants. More than 40% of participants in cohorts B and C showed elevated anti-HBs titers (>100 IU / L) by week 40.

[0053] In certain embodiments, with regard to combination therapy including BRII-179 and one or more other HBV treatments, administration of BRII-179 may be initiated before the other treatments. Such a treatment schedule is intended not only to take advantage of synergistic effects between treatments, but also to allow the patient's response to BRII-179 to serve as a biomarker to guide subsequent treatments.

[0054] In one instance, a method for treating HBV infection in a subject diagnosed with or suspected of having HBV infection is provided herein.

[0055] In some embodiments, methods for treating CHB in subjects in need, the methods comprising the step of administering hepatitis B virus surface antigen (HBsAg) and HBV therapy to the subjects are provided herein. In some embodiments, the HBV therapy omits the administration of HBsAg to the subjects.

[0056] In some embodiments, at least a first dose of the HBsAg is administered to the subject before the HBV treatment is administered. In some embodiments, the administration of the HBV treatment is not started until after a second dose of the HBsAg. In some embodiments, the administration of the HBV treatment is not started until after a third dose of the HBsAg. In some embodiments, the administration of the HBV treatment is not started until after a fourth dose of the HBsAg. In some embodiments, the administration of the HBV treatment is not started until after a fifth dose of the HBsAg. In some embodiments, the administration of the HBV treatment is not started until the administration of the HBsAg is complete.

[0057] In some embodiments, administration of the HBV treatment is not initiated until one week after the initial dose of HBsAg. In some embodiments, administration of the HBV treatment is not initiated until two weeks after the initial dose of HBsAg. In some embodiments, administration of the HBV treatment is not initiated until at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 weeks after the initial dose of HBsAg.

[0058] In some embodiments, the subjects treated herein have not experienced any prior treatment before HBsAg administration. In other words, the subjects have not been treated with any treatment for CHB. In some embodiments, the subjects have not been treated with any treatment such as interferon. In some embodiments, the subjects have not been treated with any of the HBV treatments administered after HBsAg administration (e.g., anti-HBsAg siRNA). In some embodiments, the subjects have not been treated with either interferon or anti-HBsAg siRNA.

[0059] In some embodiments, the subjects have not been treated with a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) prior to HBsAg administration. In some embodiments, the subjects have been treated with an NrtI or are currently being treated with an NrtI.

[0060] In some embodiments, a method for treating hepatitis B virus (HBV) infection in a subject having chronic hepatitis B is provided herein, the method comprising the steps of administering to the subject 20 μg to 100 μg / dose of HBV surface antigen (HBsAg) once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W), and 100 mg to 400 mg / dose of anti-HBsAg siRNA once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W). In some embodiments, the treatment comprises at least four doses of each of the HBsAg and the siRNA. In some embodiments, the treatment comprises at least five, six, seven, eight, nine, or ten doses of each of the HBsAg and the siRNA.

[0061] In some embodiments, the following methods are provided herein, which include the step of administering hepatitis B virus (HBV) therapy to a CHB subject, wherein it is determined that the post-baseline HBV antibody concentration in the CHB subject after administration of hepatitis B virus surface antigen (HBsAg) is higher than the baseline HBV antibody concentration in the CHB subject before administration of HBsAg.

[0062] In some embodiments, a method for selecting a CHB subject for HBV treatment is provided herein, the method comprising: (a) determining a baseline HBV antibody concentration in a biological sample derived from the CHB subject; (b) administering HBsAg to the CHB subject; (c) determining a post-baseline HBV antibody concentration in a biological sample derived from the CHB subject after administration of HBsAg, wherein the subject is selected for HBV treatment if the post-baseline HBV antibody concentration is higher than the baseline HBV antibody concentration, and otherwise excluded from HBV treatment; and (d) administering the HBV treatment to the selected subject.

[0063] In some embodiments, the method includes the steps of (a) administering HBsAg to a CHB subject; (b) determining the anti-HBs concentration in a biological sample collected from the subject after administration of HBsAg; and (c) administering HBV treatment to the subject if the anti-HBs concentration in the biological sample collected from the subject after administration of HBsAg is higher than the baseline anti-HBs concentration in the biological sample collected from the subject before administration of HBsAg.

[0064] In some embodiments, methods for treating HBV infection in a CHB subject, wherein the baseline HBV antibody concentration in the CHB subject is below 2 IU / L, and the method comprises the steps of (a) administering HBsAg to the CHB subject; and (b) administering HBV treatment to the CHB subject, wherein it is determined that the post-baseline HBV antibody concentration in the subject is 2 IU / L or greater after the administration of HBsAg.

[0065] In some embodiments, methods for treating HBV infection in a CHB subject are provided herein, wherein the baseline HBV antibody concentration in the CHB subject is in the range of 0 to 4 IU / L, and the method comprises the steps of (a) administering HBsAg to the CHB subject; and (b) administering HBV treatment to the CHB subject, wherein it is determined that the post-baseline HBV antibody concentration in the subject exceeds 10 IU / L after administration of HBsAg.

[0066] In some embodiments, the baseline HBV antibody concentration in the CHB subject is in the range of 0 to 10 IU / L.

[0067] In some embodiments, a method for treating HBV infection in a CHB subject having a predetermined baseline HBV antibody concentration is provided herein, the method comprising the steps of (a) administering HBsAg to the CHB subject; and (b) administering an HBV treatment to the CHB subject, wherein it is determined that the post-baseline HBV antibody concentration in the subject after administration of HBsAg is at least 5 times higher than the predetermined baseline HBV antibody concentration.

[0068] In one aspect, a method for excluding subjects having CHB from a clinical study is provided herein. In some embodiments, the method comprises the step of screening a group of CHB subjects, where each CHB subject has a predetermined baseline HBV antibody concentration by administering HBV surface antigen (HBsAg) to the CHB subject, and CHB subjects that do not respond to HBsAg administration and have a post-baseline HBV antibody concentration higher than their baseline HBV antibody concentration are excluded from the clinical study. In certain embodiments, the method comprises the step of conducting the clinical study, where HBV treatment is administered to CHB subjects who are not excluded from the clinical study.

[0069] In some embodiments, a method for selecting subjects for a clinical study, wherein an HBV treatment is administered to the selected subjects, the method comprising the steps of (a) determining a baseline HBV antibody concentration in subjects having CHB before administering HBsAg to the subjects, (b) administering HBsAg to the subjects, (c) determining a post-baseline HBV antibody concentration in the subjects after administration of HBsAg, wherein the subjects are selected for inclusion in the clinical study if the post-baseline HBV antibody concentration is higher than the baseline HBV antibody concentration, and (d) conducting the clinical study, wherein an HBV treatment is administered to the selected subjects, is provided herein.

[0070] As used herein, the term "responder CHB subject" refers to a CHB subject that shows an increase in HBV antibody concentration after administration of HBsAg to the CHB subject.

[0071] As used herein, the term "non-responder CHB subject" refers to a CHB subject that does not show an increase in HBV antibody concentration after administration of HBsAg to the CHB subject.

[0072] Without being limited to any theory or embodiment, it is thought that HBsAg administration may induce a de novo adaptive immune response in responsive CHB subjects and / or boost existing immunological memory specific to surface antigens, thereby achieving higher efficacy of subsequent HBV treatment. Identifying non-responsive CHB subjects can avoid, for example, unnecessary costs and personal inconvenience or intolerance of being administered HBV treatment that may not be effective with respect to the treatment of CHB in non-responsive CHB subjects. An increased HBV antibody response may be a surrogate marker of intrinsic HBV-specific immunity that may positively correlate with the desired outcome of HBV treatment; conversely, a lack of HBV antibody response may suggest weak or absent HBV-specific immunity and may negatively correlate with the desired outcome of HBV treatment.

[0073] Diagnosing a subject with CHB typically requires a series of medical tests and evaluations. First, a medical professional may perform a physical examination to look for signs of liver damage (e.g., jaundice, enlarged liver or spleen, and abdominal distension). Blood tests are also commonly used to check for the presence of hepatitis B virus DNA, antigens, and antibodies, and liver function tests are similarly used to assess the liver's ability to perform its functions.

[0074] In certain embodiments of the methods provided herein, the CHB subject is virally suppressed with respect to HBV, for example, by exposure to nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) treatment. As used herein, the term "virally suppressed for HBV" means, in some embodiments, a serum HBV DNA concentration below the detection limit (which typically varies between approximately 2 IU / mL and 16 IU / mL depending on the assay system used) (see, e.g., Supplementary Table 1 and Supplementary Information in Kramvis et al., 2022, Nature Reviews Gastroenterology & Hepatology, 19: 727-745). In some embodiments, “virus suppressed with respect to HBV” means a serum HBV DNA concentration of less than 100 IU / mL, less than 90 IU / mL, less than 80 IU / mL, less than 70 IU / mL, less than 60 IU / mL, less than 50 IU / mL, less than 40 IU / mL, less than 30 IU / mL, less than 20 IU / mL, less than 15 IU / mL, less than 10 IU / mL, less than 9.6 IU / mL, less than 6.7 IU / mL, less than 2.7 IU / mL, less than 2.4 IU / mL, or less than 2 IU / mL. Testing methods for HBV DNA viral loading are well-known in the field (see, for example, Abe et al., 1999, J. Clin. Microbiol., 37(9):2899-2903; Kramvis et al., 2022, Nature Reviews Gastroenterology & Hepatology, 19: 727-745 and supplementary information). For example, specimens for HBV DNA viral loading can be tested using the Roche COBASE® HBV Quantitative Assay.

[0075] In some embodiments, the CHB subjects who will be administered the HBsAg have been exposed to NrtI treatment. NrtI treatments for treating HBV infection are known in the art and include, for example, lamivudine, entecavir, tenofovir alafenamide, tenofovir disoproxil fumarate, adefovir dipivoxil, and terbivudine.

[0076] In some embodiments, the CHB subjects have been treated with NrtI and / or interferon (e.g., interferon-alpha (IFNα) or PEG-IFNα) prior to the administration of HBsAg.

[0077] In some embodiments, the CHB subjects who are administered the HBsAg do not experience viral suppression.

[0078] In some embodiments of the methods provided herein, the CHB subject has had HBsAg persisting in its serum for at least 6 months.

[0079] In some embodiments, the CHB subject has an occult HBV infection characterized by having detectable HBV DNA in a liver specimen and being negative for serum HBsAg.

[0080] In some embodiments of the methods provided herein, it is understood that the HBsAg is administered to the subject during the diagnostic phase, whereas the HBV treatment is administered to the subject during the treatment phase. During the diagnostic phase, a biological sample may be collected from the subject to determine whether the subject responds to HBsAg administration with an increase in HBV antibody concentration, and if it does, the subject is selected for the treatment phase.

[0081] The HBV DNA S gene described above encodes three envelope / surface proteins within a single open reading frame containing three distinct in-frame start codons. This organization defines three protein domains (Pre-S1, Pre-S2, and S) that form a large ("Pre-S1"), medium-sized ("Pre-S2"), and small ("S") surface protein sharing a common C-terminal region (see, e.g., Seitz et al., 2020, Annu. Ref. Virol., 7:263-288). These three proteins form a spherical structure on the surface of the virus, which is highly antigenic. Furthermore, HBV surface proteins are typically the first serological markers to appear in serum after HBV infection and are commonly used as diagnostic tests for acute or chronic hepatitis B.

[0082] The hepatitis B surface antigen (HBsAg) administered to the subject in the methods provided herein may include, for example, any one of the large (Pre-S1), medium (Pre-S2), and small (S) HBV surface proteins, and / or parts thereof, or combinations thereof. In some embodiments, the HBsAg is recombinant HBsAg. In some embodiments, the HBsAg is derived from human plasma. In some embodiments, the HBsAg is a virus-like particle. Methods for generating HBsAg from cell cultures and generating virus-like particles are known in the art (see, for example, Wampler et al., 1985, Proc. Natl. Acad. USA, 82(20):6830-6834). Furthermore, prophylactic HBV vaccines containing HBsAg have been available for over 30 years and could, for example, be a source of HBsAg to be administered to the subject in the methods provided herein. Examples of HBV vaccines include, for example, HEPLISAV-B (Dynavax Technologies Corporation) (available in a single 0.5 mL dose containing 20 μg HBsAg and 3000 μg CpG 1018 adjuvant); ENGERIX-B (GlaxoSmithKline Biologicals SA) (available in 0.5 mL (10 μg HBsAg) and 1 mL (20 μg HBsAg) doses with aluminum hydroxide adjuvant); and PREHEVBRIO (VBI Vaccines) (containing small (S), moderate (Pre-S2), and large (Pre-S1) hepatitis B surface antigens and available as 1 mL (10 μg HBsAg) with aluminum hydroxide adjuvant).

[0083] In some embodiments, the HBsAg described above consists of a small (S) protein as the sole hepatitis B surface antigen.

[0084] In some embodiments, the HBsAg administered to the subject comprises small (S), medium (Pre-S2), and large (Pre-S1) proteins, as well as an aluminum phosphate adjuvant. The preparation and administration of compositions comprising HBsAg and aluminum phosphate adjuvant are described in WO 2020 / 099927 A1. In certain embodiments, the HBsAg administered to the subject is in the form of an HBsAg formulation as described in Example 1 of WO 2020 / 099927 A1 (which is incorporated herein by reference in its entirety for all purposes). In some embodiments, the HBsAg administered to the subject is in a composition comprising S protein, Pre-S1 protein, and Pre-S2 protein, as well as an aluminum phosphate adjuvant, wherein the composition contains at least 20 μg / ml of HBsAg antigen, and the amount of unadsorbed antigen is at least 30%. In a particular embodiment, the HBsAg administered to the subject is in a composition comprising virus-like particles containing small (S), medium (Pre-S2), and large (Pre-S1) proteins.

[0085] In some embodiments, the HBsAg is administered to the subject in a dose regimen in which the HBsAg dose is administered to the subject over a course of several days or several weeks. In some embodiments, the HBsAg is administered as a single dose, which, if necessary, is divided into two or more injections per day. A single dose of HBsAg may include, for example, between 1 μg and 100 μg of HBsAg. In some embodiments of the methods provided herein, the amount of HBsAg administered is between 5 and 100 μg, 5 μg and 80 μg, 10 and 100 μg, or 10 and 80 μg of HBsAg. In some embodiments, the amount of HBsAg administered to the subject is approximately 7 μg to 60 μg, approximately 8 μg to 50 μg, approximately 10 μg to 60 μg, approximately 20 μg to 60 μg, approximately 30 μg to 50 μg, approximately 35 μg to 45 μg, or approximately 10 μg to 40 μg.

[0086] In some embodiments of the methods provided herein, the HBsAg is administered as a single dose per day over a period of 2, 3, 4, 5, 6, 7, 8, 9 days or longer, the number of days being consecutive, for example, or with intervals of the following: about 1 day (e.g., every other day), about 7 days (e.g., once a week), about 14 days (e.g., every 2 weeks), about 21 days (e.g., every 3 weeks), about 28 days (e.g., every 4 weeks), about 30 days (e.g., once a month), about 35 days (e.g., every 5 weeks), about 42 days (e.g., every 6 weeks), or about 60 days (e.g., every 2 months) or once a year. In some embodiments, the HBsAg is administered once a month, for example, over a period of 4-5 months, or for up to 9 months or longer.

[0087] In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 10 to 100 μg once every 1, 2, 3, 4, or 5 weeks. In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 20 to 60 μg once every 1, 2, 3, 4, or 5 weeks. In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 30 to 50 μg once every 1, 2, 3, 4, or 5 weeks. In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 10 to 100 μg once every 3 weeks. In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 20 to 60 μg once every 3 weeks. In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 30-50 μg once every three weeks. In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 40 μg once every three weeks. In some embodiments of the methods provided herein, the HBsAg is administered as a single dose of 20-100 μg / dose once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0088] The above HBsAg may be administered, for example, intramuscularly or subcutaneously. In some embodiments, the HBsAg is administered together with an adjuvant (for example, among others, aluminum hydroxide adjuvant, CpG 1018 adjuvant, or aluminum phosphate adjuvant).

[0089] Typically, in the methods provided herein, the HBsAg is understood to be administered as a diagnostic agent to identify a responsive CHB subject before administering HBV treatment to that subject. In some embodiments of the methods provided herein, the HBsAg is administered to a subject in the absence of any additional therapeutic agents to treat hepatitis B virus infection.

[0090] In some embodiments of the methods provided herein, the HBsAg is administered to the subject simultaneously with Nrtl and / or interferon (e.g., IFN or PEG-IFN) prior to the administration of the HBV treatment.

[0091] Determining HBV antibody concentrations in subjects can be performed using assays known in the art. HBV antibodies are produced in the immune system in response to the hepatitis B virus and may include, for example, hepatitis B surface antigen antibodies (anti-HBs); hepatitis B e antigen antibodies (anti-HBe); and hepatitis B core antigen antibodies (anti-HBc). Anti-HBc may be found in IgM subtypes (which typically appear during the early stages of acute HBV infection) and IgG subtypes (which persist throughout life and are markers of past or ongoing infection).

[0092] In some embodiments of the methods provided herein, the HBV antibody comprises anti-HBs, anti-HBe, and anti-HBc. Thus, in some embodiments, the HBV antibody concentration is understood to be the concentration of anti-HBs, anti-HBe, and anti-HBe.

[0093] In some embodiments of the methods provided herein, the HBV antibody is anti-HBs. Therefore, in some embodiments, the HBV antibody concentration is understood to be the anti-HBs concentration.

[0094] The HBV antibody concentration in the subject can be determined from a biological sample collected from the subject. This biological sample may be, for example, a blood sample, a serum sample, or a plasma sample.

[0095] In some embodiments, the biological sample is a plasma sample.

[0096] In some embodiments, the biological sample is a serum sample.

[0097] In some embodiments of the methods provided herein for determining the HBV antibody concentration, the HBV antibody concentration is the serum HBV antibody concentration. In some embodiments, the HBV antibody concentration is the serum anti-HBs concentration. In some embodiments, the HBV antibody concentration is the plasma anti-HBs concentration.

[0098] Assays and kits for determining HBV antibodies are commercially available in several formats (see, for example, Supplementary Table 1 in Kramvis et al., 2022, Nature Reviews Gastroenterology & Hepatology, 19: 727-745, and Supplementary Information listing commercially available kits, which is incorporated herein by reference). Enzyme-conjugated immunosolvent assay (ELISA) kits use enzyme-based colorimetric or fluorescence detection systems to identify the presence of specific antibodies in the biological samples. Rapid diagnostic tests (RDTs) use lateral flow immunoassay techniques. Chemiluminescent immunoassay (CLIA) kits utilize chemiluminescent detection methods to measure HBV antibodies. Radioimmunoassay kits use radioactive tracers to measure the binding of HBV antibodies in biological samples. Examples of commercially available quantitative HBV antibody kits include: for example, DIASOURCE Anti-HBs Elisa (DIASoure ImmunoAssays SA, Belgium), ELECSYS® HBsAG II quant II immunoassay (Roche Diagnostics), ARCHITECT AUSAB immunoassay (Abbott Laboratories), and VITROS® Anti-HBs assay (Ortho-Clinical Diagnostics).

[0099] Depending on the specific kit or assay used, the lower limit of detection (LLOD) of the HBV antibody concentration (e.g., anti-HBs concentration) may range from 1 IU / L to 5 IU / L. Therefore, in some embodiments, the term “lower limit of detection” or “LLOD” as used herein in reference to the HBV antibody concentration (e.g., anti-HBs concentration) is 2 IU / L.

[0100] As used herein, the term “baseline” (e.g., “baseline HBV antibody concentration,” “baseline anti-HBs concentration,” “baseline plasma HBV antibody concentration,” “baseline serum HBV antibody concentration,” “baseline plasma anti-HBs concentration,” “baseline serum anti-HBs concentration,” etc.) refers to the antibody concentration determined from a biological sample collected from the subject prior to the administration of the HBsAg to the subject.

[0101] As used herein, the term “post-baseline” (e.g., “post-baseline HBV antibody concentration,” “post-baseline anti-HBs concentration,” “post-baseline plasma HBV antibody concentration,” “post-baseline serum HBV antibody concentration,” “post-baseline plasma anti-HBs concentration,” “post-baseline serum anti-HBs concentration,” etc.) refers to the antibody concentration determined from biological samples collected from the subject after HBsAg has been administered to the subject.

[0102] In some embodiments of the methods provided herein, the HBV treatment is administered to a subject having an increased HBV antibody concentration (e.g., anti-HBs concentration) after administration of HBsAg.

[0103] In some embodiments, the HBV treatment described above is administered to subjects having a post-baseline HBV antibody concentration (e.g., anti-HBs concentration) higher than 10 IU / L, 50 IU / L, 100 IU / L, 150 IU / L, 200 IU / L, 250 IU / L, or 300 IU / L.

[0104] In some embodiments of the methods provided herein, HBV treatment is administered to the subject after it has been determined that the post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is higher than the baseline HBV antibody concentration (e.g., anti-HBs concentration) for the subject.

[0105] In some embodiments of the methods provided herein, the HBV antibody concentration (e.g., anti-HBs concentration) in the subject before administration of HBsAg may be undetectable. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 0.5 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 1 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 2 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 3 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 4 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 5 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 6 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 7 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 8 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 9 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 10 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 11 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 12 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 13 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 14 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 15 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 20 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 30 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 40 IU / L.In some embodiments, the baseline HBV antibody concentration of the subject is lower than 50 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 60 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 75 IU / L. In some embodiments, the baseline HBV antibody concentration of the subject is lower than 100 IU / L.

[0106] In some embodiments of the methods provided herein, the HBV antibody concentration (e.g., anti-HBs concentration) in the subject before administration of HBsAg may be between 0 IU / L and 5 IU / L, or between 2 IU / L and 10 IU / L. In some embodiments, the baseline HBV antibody concentration in the subject is greater than 10 IU / L, greater than 25 IU / L, greater than 50 IU / L, greater than 100 IU / L, or greater than 200 IU / L.

[0107] In some embodiments of the methods provided herein, the HBV treatment is administered to the subject if (i) the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at or below the detection limit (e.g., 2 IU / L) and the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is above the detection limit (e.g., 2 IU / L); or (ii) the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is higher than the detection limit (e.g., 2 IU / L) and the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least five times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration).

[0108] In some embodiments of the methods provided herein, where the baseline HBV antibody concentration (e.g., anti-HBs concentration) of the subject is below the detection limit (e.g., 2 IU / L), the HBV treatment is performed when the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 2 IU / L, at least 5 IU / L, at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 The above-mentioned subjects are administered the drug if the concentration is IU / L or at least 1000 IU / L.

[0109] In some embodiments of the methods provided herein, where the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) exceeds the detection limit (e.g., 2 IU / L), the HBV treatment is administered to the subject if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least twice as high as the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least three times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least four times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 5 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 6 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 7 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 8 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least nine times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration).In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 10 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 11 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 12 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 13 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 14 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, the HBV treatment is administered to the subject if the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 15 times higher than the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration).

[0110] In some embodiments of the methods provided herein, the HBV treatment is administered to subjects identified as “responder subjects” during the diagnostic phase by meeting any one or more of the following criteria (A) to (C): (A) having a baseline HBV antibody concentration (e.g., anti-HBs concentration) at or below the detection limit (e.g., ≤2 IU / L) and a post-baseline HBV antibody concentration (e.g., anti-HBs concentration) of at least 5 IU / L, or at least 10 IU / L, at least 12 IU / L, at least 15 IU / L, at least 20 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, or at least 110 IU / L; (B) having a baseline HBV antibody concentration (e.g., anti-HBs concentration) above the detection limit (e.g., >2 IU / L); (C) Having a baseline HBV antibody concentration (e.g., anti-HBs concentration) of at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, or at least 7 times higher than the baseline HBV antibody concentration of the subject; or (C) having a baseline HBV antibody concentration (e.g., anti-HBs concentration) of at least 10 IU / L, at least 12 IU / L, at least 15 IU / L, at least 20 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, or at least 110 IU / L.

[0111] Biological samples collected after HBsAg administration to determine HBV antibody concentration (e.g., anti-HBs concentration) can be collected at any point during the diagnostic stages described above, for example, after the first dose of HBsAg is administered (e.g., a single dose is administered here), and / or between doses of HBsAg (more than one dose is administered here), and / or after the final dose of HBsAg is administered (more than one dose is administered here).

[0112] Samples collected after HBsAg administration to determine HBV antibody concentration (e.g., anti-HBs concentration) can be collected at any time between, for example, 1 day after HBsAg administration and approximately 12 months after HBsAg administration. In some embodiments, the baseline HBV antibody concentration is determined from samples collected 2 to 8 months after HBsAg administration. In some embodiments, the baseline anti-HBV antibody concentration is determined from samples collected 3 to 6 months after HBsAg administration. In some embodiments, the baseline HBV antibody concentration is determined from samples collected 2 weeks to 6 months after HBsAg administration. In some embodiments, the baseline HBV antibody concentration is determined from samples collected 5 days to 4 months after HBsAg administration. In some embodiments, the baseline HBV antibody concentration is determined from samples collected 7 days to 3 months after HBsAg administration. In some embodiments, the baseline HBV antibody concentration is determined from samples collected 7 days to 2 months after HBsAg administration. In some embodiments, the post-baseline HBV antibody concentration is determined from samples collected 2 weeks to 1 month after HBsAg administration.

[0113] In some embodiments, the above HBV treatment is administered to a responding CHB subject in a therapeutically effective dose to treat CHB.

[0114] As used herein, the terms “treating” and “treatment” refer to the treatment of an existing HBV infection (e.g., CHB) or the prevention (i.e., prophylactic) of a serious liver disease (e.g., cirrhosis and hepatocellular carcinoma caused by CHB). Therefore, it is recognized that the treating or treatments referred herein may be prophylactic in some embodiments. In some embodiments, treating or treating an HBV infection (e.g., CHB) results in a reduction of HBV DNA, or a reduction of hepatitis B e antigen, or a reduction of serum alanine aminotransferase (ALT), or a reduction of hepatitis B s antigen, or any combination thereof. In some embodiments, treating or treating an HBV infection may be a functional cure in which HBsAg and HBV DNA are undetectable in the subject for six months in the absence of any HBV treatment. As used herein, the term “therapeutically effective amount” refers to the amount of a single treatment, alone or in combination with other treatments, used to treat HBV infection. “To treat” is as defined above.

[0115] The HBV treatment administered to the subject may be any treatment administered for the treatment of HBV infection, such as CHB.

[0116] In some embodiments, the above HBV treatment is administered in clinical studies.

[0117] In some embodiments, the HBV treatment described above is either a single treatment or a combination of treatments selected from the following HBV treatments: (i) nucleoside / nucleotide reverse transcriptase inhibitors (NrtIs) (e.g., lamivudine, entecavir, tenofovir alafenamide, tenofovir disoproxil fumarate, adefovir dipivoxil, and terbivudine); (ii) immunomodulatory factors (e.g., interferon-alpha (IFNα) and PEG-IFNα); (iii) small interfering RNAs (siRNAs) that target HBV RNA (e.g., AB-729, ALG-125755, ALG-125918, ARB-1467, ARC-520, JNJ-3989, RG-6346, VIR-2218 (BRII-835 or erebsilan), and WO 2016 / 077321 (iv) HBV neutralizing monoclonal antibodies (mAbs) (e.g., those described in WO / 2017 / 060504 A1, WO 2020 / 132091 A2, WO 2022 / 164805 A1, WO 2021 / 012135 A1, U.S. Patent No. 10,544,205 B2 (including, for example, VIR-3434 (BRII-877), HH-003, HH-006, BJT-778, and lenvervimab (GC1102))); (v) sodium / bile acid cotransporter (also known as NTCP) inhibitors (e.g., myrcludex B) (b) (such as bullevirtide); (vi) Capsid assembly regulators (e.g., ABI-HO731, ABI-H3733, NVR 3-778, RO7049389, JNJ-56136389, ALG-000184, and GLS4JHS); (vii) COPS3 inhibitors (e.g., those described in US 20230122751 A1);(viii) Store-operated calcium entry-associated regulatory factor (SARAF) inhibitors (e.g., those described in US 2023 / 0120063 A1); (ix) Antisense oligonucleotides (ASOs) (e.g., bepirobircene, GSK3389404, RO7062931, and ALG-020572); (x) Toll-like receptor (TLR) agonists (e.g., vestolimod (GS-9620; TLR7 agonist), RO7020531 (TLR7 agonist), JNJ-64794964 (TLR7 agonist), selgantolimod (GS-9688; (xi) checkpoint regulators (e.g., ASC22 (anti-PDL1), semiprimab (anti-PD1), and nivolumab (anti-PD1)); (xii) inhibitor of apoptosis protein (IAP) antagonists (e.g., APG-1387); (xiii) farnesoid X receptor (FXR) agonists (e.g., EYP001); and (xiv) therapeutic vaccines (e.g., ABX203 (HeberNasvac), GS-4774, HepTcell, AIC649, HB-110, VTP-300, JNJ-64300535, BRII-179 (VBI-2601), TG-1050, and INO-1800). ;

[0118] In some embodiments, the HBV treatment is selected from the group consisting of NrtI, siRNA, IFNα, PEG-IFNα, and HBV neutralizing mAbs, or combinations thereof. In some embodiments, the HBV treatment is selected from the group consisting of siRNA, IFNα, and PEG-IFNα, HBV neutralizing mAbs, or combinations thereof. In some embodiments, the HBV treatment is selected from the group consisting of siRNA, IFNα, and PEG-IFNα, or combinations thereof. In some embodiments, the HBV treatment is siRNA. In some embodiments, the HBV treatment is a combination of siRNA and IFNα. In some embodiments, the HBV treatment is a combination of siRNA and PEG-IFNα. In some embodiments, the HBV treatment is a combination of HBV neutralizing mAb and PEG-IFNα. In some embodiments, the HBV treatment is PEG-IFNα.

[0119] In some embodiments, the HBV treatment described above is a combination of NrtI and interferon (e.g., IFNα or PEG-IFNα).

[0120] In some embodiments, the above HBV treatment is administered in combination with HBsAg.

[0121] In some embodiments, the HBV treatment described above excludes HBsAg.

[0122] In some embodiments in which the siRNA is administered alone or in combination with HBV treatment, the siRNA is N-acetylgalactosamine (GalNAc)-conjugated HBV dsRNA as described in Table 2 of WO 2020 / 036862 A1 (which is incorporated herein by reference for all purposes). In some embodiments, the siRNA is erebsilane (CAS No. 2648009-64-5) (also known as VIR-2218 and BRII-835).

[0123] In some embodiments in which an HBV neutralizing antibody is administered alone or in combination, the HBV neutralizing antibody is VIR-3434 (BRII-877).

[0124] In some embodiments, the HBV treatment is a combination of siRNA and an HBV neutralizing antibody. In some embodiments, the HBV treatment is a combination of siRNA, an HBV neutralizing antibody, and PEG-IFNα. For example, in some embodiments, the siRNA is erebsilan (CAS No. 2648009-64-5; VIR-2218; BRII-835), and the HBV neutralizing antibody is VIR-3434 (BRII-877).

[0125] In some embodiments, the HBV treatment described above is a combination of erebsilan (CAS No. 2648009-64-5) and PEG-IFNα.

[0126] In some embodiments, the siRNA (e.g., erebsiran) is administered as a single dose per day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 29, or 20 days, or longer, the number of days may be, for example, consecutive or with intervals such as: about 1 day (e.g., every other day), about 7 days (e.g., once a week), about 14 days (e.g., every 2 weeks), about 21 days (e.g., every 3 weeks), about 28 days (e.g., every 4 weeks), about 30 days (e.g., once a month), about 35 days (e.g., every 5 weeks), about 42 days (e.g., every 6 weeks), or about 60 days (e.g., every 2 months) or once a year.

[0127] In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 20 to 500 mg once every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 30 to 400 mg once every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 40 to 250 mg once every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 50 to 200 mg once every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 75–150 mg once every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 80–120 mg once every 1, 2, 3, 4, 5, or 6 weeks.

[0128] In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 50-50 mg once every four weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 75-150 mg once every four weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 80-120 mg once every four weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of 90-110 mg once every four weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebushiran) is administered as a single dose of approximately 100 mg once every four weeks. In some embodiments of the methods provided herein, the siRNA (e.g., erebsilan) is administered as a single dose of 100 mg to 400 mg / dose, once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W).

[0129] The above-mentioned siRNA (e.g., erebsilan) can be administered, for example, intramuscularly or subcutaneously.

[0130] In some embodiments, the PEG-IFNα is administered as a single dose per day for 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 45, 48, 50, or 60 days, or longer, the number of days, which may be consecutive, for example, or may be spaced apart, for example, as follows: about 1 day (e.g., every other day), about 7 days (e.g., once a week), about 14 days (e.g., every 2 weeks), about 21 days (e.g., every 3 weeks), about 28 days (e.g., every 4 weeks), about 30 days (e.g., once a month), about 35 days (e.g., every 5 weeks), about 42 days (e.g., every 6 weeks), or about 60 days (e.g., every 2 months), or once a year.

[0131] In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 50-500 μg once every 1, 2, or 3 weeks. In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 100-300 μg once every 1, 2, or 3 weeks. In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 150-240 μg once every 1, 2, or 3 weeks. In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 170-190 μg once every 1, 2, or 3 weeks.

[0132] In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly as a single dose of 50 to 500 μg. In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly as a single dose of 100 to 300 μg. In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly as a single dose of 150 to 240 μg. In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly as a single dose of 170 to 190 μg.

[0133] The above-mentioned PEG-IFNα can be administered, for example, intramuscularly or subcutaneously.

[0134] In one aspect, compositions for use in the manner described herein are provided herein. In some embodiments, the composition is HBsAg for use in the manner described herein. A suitable HBsAg composition may be, for example, any of those described herein. In some embodiments, the composition is an HBV treatment for use in the manner described herein. A suitable HBV treatment may be, for example, any of those described herein.

[0135] In one aspect, a kit comprising HBsAg and HBV treatment for use in the manner described herein is provided herein. Suitable compositions for the above HBsAg and HBV treatment may be, for example, any of those described herein.

[0136] In some embodiments, the use of HBV surface antigen (HBsAg) and HBV treatments that do not contain the HBsAg for the manufacture of a kit for treating a subject having chronic hepatitis B is provided herein, wherein the subject responds to the administration of the HBV treatment with an increase in the serum concentration of anti-HBV antibody upon administration of the HBsAg compared to the serum concentration of anti-HBV in the subject before administration of the HBsAg to the subject.

[0137] In some embodiments, the above treatment is effective in achieving disease regression in the CHB subjects. For example, disease regression may be measured, without limitation, as a reduction in viral load or as HBV antigen serum clearance (e.g., by measuring HBV DNA levels or antigen levels).

[0138] In some embodiments, the HBV DNA level or antigen level is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%. In some embodiments, the HBV DNA level or antigen level is reduced to a desired level for at least one week, two weeks, three weeks, four weeks, two months, three months, four months, five months, six months, one year, two years, or five years. [Examples]

[0139] Examples Example 1: Response CHB subject This example demonstrates that CHB subjects are divided into those who produce anti-HBs in response to HBsAg administration (responsive CHB subjects) and those who do not show such a response (non-responsive CHB subjects).

[0140] A clinical study administering HBsAg to non-cirrhotic CHB subjects with viral suppression under NrtI treatment was conducted as described in Ma et al., 2021, JHEP Reports, 3(3):100361. The HBsAg was BRII-179 (also known as VBI-2601), a virus-like particle containing all three types of (Pre-S1, Pre-S2, and S)HBV surface envelope proteins. Subjects were randomized to accept NrtI alone (Cohort A), 20 μg BRII-179 + NrtI (Cohort B), 20 μg BRII-179 + 3 MIU IFN + NrtI (Cohort C), 40 μg BRII-179 + NrtI (Cohort D), and 40 μg BRII-179 + 3 MIU IFN + NrtI (Cohort E). Serum HBsAg and anti-HBs antibodies were quantified using the ELECSYS HBsAg II QUANT II kit and the ELECSYS ANTI-HBs II kit / Cobas e411 / e601 (Roche Diagnostics, Germany) according to the manufacturer's instructions. The number of subjects observed to have a positive response (i.e., an increase in antibody concentration after baseline) is shown in Table 1 below. [Table 1]

[0141] Example 2: Administration of HBV treatment to a responding CHB subject This hypothetical example illustrates the exemplary administration of HBV treatment to a responding CHB subject. A responding CHB subject identified by having increased anti-HBs after HBsAg administration (e.g., the patient identified as a responding CHB subject in Example 1) may have HBV treatment administered as described below.

[0142] The above HBV treatment may be a combination of siRNA and PEG-IFNα. Specifically, the siRNA may be BRII-835 (also known as erebsilane and VIR-2218), a synthetic N-acetylgalactosamine-conjugated small ribonucleic acid designed to silence HBV transcripts across all HBV genotypes. BRII-835 has been administered in healthy subjects and subjects with chronic HBV infection at single doses up to 900 mg (see, for example, AASLD 2022, VIR-2218-1001 study: preliminary 48-week safety and efficacy data of VIR-2218 alone and in combination with PEG-IFNα in participants with chronic HBV infection; ClinicalTrials.gov identifier: NCT03672188; and Gupta et al., 2021, Drugs in R&D, 21:455-465).

[0143] Important criteria for excluding subjects from receiving the above treatment may be as follows: 1. Having received other siRNA or interferon-based treatments within 12 months before screening. 2. Marked fibrosis or cirrhosis. 3. Contraindication to the use of PEG-IFNα or inability to self-administer or co-administer PEG-IFNα (the following test abnormalities: a) Hemoglobin < 100 g / L. b) Absolute neutrophil count < 1,500 / mm3. c) Platelet count < 90,000 / mm 3 3. 4. Active HIV, HCV, or HDV infection (but not limited to these). 5. Estimated glomerular filtration rate (eGFR) ≤ 60 ml / min / 1.73 m 2 at the time of screening, indicating renal dysfunction. 6. History of intolerance or hypersensitivity to interferon / pegylated interferon.

[0144] The dosage and dosing regimen of the above HBV treatment administered to the above responsive CHB subjects may be 100 mg of BRII-835 administered subcutaneously (SC) every 4 weeks over a period of 48 weeks, and 180 μg of PEG-IFNα administered SC weekly.

[0145] CHB subjects may be monitored for HBsAg loss (< 0.05 IU / mL) and suppression of HBV DNA (< LLOQ) to evaluate efficacy.

[0146] Example 3: Administration of HBV Treatment to Responsive CHB Subjects This prospective example describes an exemplary administration of the above HBV treatment to responsive CHB subjects containing siRNA and PEG-IFNα. The dosage and dosing regimen of the above HBV treatment administered to the above responsive CHB subjects may be 200 mg of BRII-835 administered subcutaneously (SC) every 4 weeks over a period of 48 weeks, and 180 μg of PEG-IFNα administered SC weekly. CHB subjects may be monitored for HBsAg loss (< 0.05 IU / mL) and suppression of HBV DNA (< LLOQ) to evaluate efficacy.

[0147] Example 4: Administration of HBV Treatment to Responding CHB Subjects This exemplary embodiment shows an exemplary administration of the HBV treatment to responding CHB subjects comprising the HBV-neutralizing mAb and PEG-IFNα. The dosage and dosing regimen of the HBV treatment administered to the responding CHB subjects can be 300 mg of BRII-877 (HBV-neutralizing antibody also known as VIR-3434) administered by SC injection once a month for 6 months or longer, and 180 μg of PEG-IFNα administered by SC injection once a week. The CHB subjects can be monitored for loss of HBsAg (<0.05 IU / mL) and suppression of HBV DNA (<LLOQ) to evaluate efficacy.

[0148] Example 5: Administration of HBV Treatment to Responding CHB Subjects This exemplary embodiment shows an exemplary administration of the HBV treatment to responding CHB subjects comprising a combination of siRNA, HBV-neutralizing mAb and PEG-IFNα. The dosage and dosing regimen of the HBV treatment administered to the responding CHB subjects can be 100 mg or 200 mg of BRII-835 administered by SC injection every 4 weeks for a period of 48 weeks, 100 mg or 150 mg of BRII-877 administered by SC injection once a month, and 180 μg of PEG-IFNα administered by SC injection once a week. The CHB subjects can be monitored for loss of HBsAg (<0.05 IU / mL) and suppression of HBV DNA (<LLOQ) to evaluate efficacy.

[0149] Example 6: Administration of HBV Treatment to Responding CHB Subjects This exemplary embodiment shows an exemplary administration of the above HBV treatment to responder CHB subjects where the HBV treatment comprises a combination of siRNA and HBV-neutralizing mAb. The dosages and dosing regimens of the above HBV treatment administered to the above responder CHB subjects can be 100 mg or 200 mg BRII-835 administered by SC injection once every 4 weeks over a 48-week period, and 100 mg or 150 mg BRII-877 administered by SC injection once a month. CHB subjects can be monitored for HBsAg loss (<0.05 IU / mL) and suppression of HBV DNA (<LLOQ) to assess efficacy.

[0150] Example 7: Preliminary Safety and Efficacy of the Combination of BRII-835 and BRII-179 in Treating Chronic HBV Infection This example tested the safety and efficacy of a combination therapy comprising both BRII-835 and BRII-179 for treating chronic HBV infection in a Phase II trial.

[0151] Adult chronic HBV patients who had been exposed to NrtI treatment for ≥12 months with HBV DNA <LLOQ were enrolled. The above participants were enrolled in three cohorts. In cohort A, while still on NrtI treatment, each patient was administered 100 mg BRII-835 via subcutaneous injection (SC) once every 4 months for 9 times. In cohort B, while still on NrtI treatment, each patient was administered 100 mg BRII-835 every 4 weeks for 9 times; starting at the 3rd dose, the above patients also received 40 μg BRII-179 + adjuvant 3 MIU IFN-α via intramuscular injection (IM) for 9 times. Cohort C was different from cohort B in that IFN-α was not administered together with BRII-179.

[0152] In all three cohorts, at the last dose of BRII-835 and / or BRII-179, the patients were evaluated for meeting the NrtI discontinuation criteria (defined as undetectable HBsAg and HBeAg, alanine aminotransferase < 2 x upper limit of normal, and HBV DNA < LLOQ). Those who met the NrtI discontinuation criteria were eligible to withdraw from NrtI treatment, subject to 48 weeks of NrtI discontinuation monitoring. The demographics and baseline characteristics of the participants are shown in Table 2.

Table 2

[0153] The safety evaluation results (Table 3) indicate that BRII-835 was well tolerated, either alone or in combination with BRII-179 ± adjuvant IFN-α. Most of the TEAEs were grade 1 or 2 in severity; none of the grade ≥ 3 or serious TEAEs were treatment-related. The most common TEAE across the cohorts was injection site reaction (56.0%). TEAEs with a higher incidence in cohort B (i.e., headache, fatigue, myalgia, and fever) were consistent with known side effects of IFN-α.

Table 3-1

Table 3-2

[0154] Regarding efficacy, significant HBsAg reduction in the patients was observed with BRII-835 alone or in combination with BRII-179 ± adjuvant IFN-α (Figure 2 and Table 4). Also, the mean HBsAg reduction from baseline was comparable across the cohorts. Notably, as shown in Figure 2, two patients who received combination treatment achieved HBsAg ≤ LLOQ (0.05 IU / mL) by week 40.

Table 4

[0155] Regarding antibody responses, BRII-835 alone did not induce an antibody response in Cohort A (Figure 3). BRII-179 generally induced a potent anti-HBs response after 5 doses, with titers reaching the assay upper limit of 1000 IU / L in some participants. More than 40% of participants in Cohorts B and C showed elevated anti-HBs titers (>100 IU / L) by week 40.

[0156] Two early responders who reached peak antibody titers after two injections of BRII-179 were observed only in the BRII-179 + adjuvant IFN-α group (Cohort B). The combination therapy of 9 doses of BRII-179 + BRII-835 resulted in a higher percentage (44%) of participants with anti-HBs levels above 100 IU / L compared to BRII-179 monotherapy (4 doses, 17%, Figure 3).

[0157] HBV surface antigen-specific T cell responses were measured in these patients. The results are shown in Table 5. [Table 5]

[0158] As shown in the table above, BRII-835 alone restored the HBV surface antigen-specific T cell response in a small percentage of participants. BRII-179, with or without the adjuvant IFN-α, induced an improved HBV surface antigen-specific T cell response in combination with BRII-835. Comparable HBV surface antigen-specific T cell responses were observed in two combination cohorts receiving BRII-835 and BRII-179, with or without the adjuvant IFN-α.

[0159] Importantly, the combination therapy of BRII-179 + BRII-835 resulted in a higher proportion of participants with a larger T-cell response (>20 times baseline) compared to BRII-179 monotherapy (40% vs. 25%).

[0160] Example 8. Phase 2 multicenter open-label study investigating the efficacy and safety of regimens including BRII-179, BRII-835, and PEG-IFNα for the treatment of chronic hepatitis B virus (HBV) infection. This is a Phase 2 single-arm, open-label study evaluating the efficacy and safety of sequential BRII-179 treatment followed by BRII-835 and PEG-IFNα combination therapy in participants with chronic HBV infection.

[0161] Preliminary studies have shown that an anti-HBs response is associated with the persistence of HBsAg serum clearance after end-of-treatment (EOT) in CHB patients receiving BRII-835 + PEG-IFNα combination therapy. In this study, all 4 of the 13 patients who achieved HBsAg serum clearance after 48 weeks of combination therapy had anti-HBs seroconversion. Of the participants with HBsAg serum clearance by EOT, all (4 / 4) with anti-HBs titer >500 IU / L at EOT maintained HBsAg serum clearance for 24 weeks after EOT; on the other hand, participants with anti-HBs titer <100 IU / L at EOT (3 / 3) experienced HBsAg rebound. This suggests that a high anti-HBs titer at EOT correlates with the persistence of serum clearance. Furthermore, the presence of anti-HBs-producing B cells in PBMCs at baseline in CHB patients may be an important immunological indicator for predicting the efficacy of IFNα treatment. This indicates a greater opportunity to achieve functional healing with PEG-IFNα treatment. These findings suggest that the ability to enhance humoral immune responses to HBsAg in CHB participants may be used to identify potential responders with less impaired endogenous anti-HBV immunity, enabling them to achieve and maintain sustained functional healing during therapeutic regimen treatment.

[0162] As shown in Example 1, BRII-179 induced a significant anti-HBs response in some, though not in all, chronic HBV participants, even after 9 doses. This suggests that BRII-179 could be used to identify CHB participants who may be able to induce a favorable antibody response and to increase the probability of their response to BRII-835 + PEG-IFNα. Therefore, it is proposed that a clinical study be initiated in which CHB participants receive BRII-179, followed by BRII-835 + PEG-IFNα sequentially. Participants would be evaluated to see if predetermined criteria for an anti-HBs response are met after completion of BRII-179 treatment. This study design would provide an opportunity to compare the effectiveness of a finite duration of BRII-835 + PEG-IFNα treatment between anti-HBs responders and non-responders after completion of BRII-179 treatment and to find the optimal treatment combination with a favorable benefit / risk profile.

[0163] The data from this study support further exploration of other curative treatments with finite durations in achieving clinically meaningful functional cure rates for chronic HBV infection.

[0164] Enrolled participants will receive sequential BRII-179, followed by BRII-835 and PEG-IFNα combination over a total treatment period of 64 weeks, as follows: - BRII-179 (Day 1 to Week 12): Participants will receive five doses of BRII-179 40 μg, administered every three weeks (Q3W); - BRII-835 and PEG-IFNα combination (weeks 16-64): Participants receive 13 doses of BRII-835 100 mg every four weeks (Q4W) and 48 doses of PEG-IFNα 180 μg every week (QW).

[0165] A 24-week follow-up period exists after treatment. An additional 24-week NrtI discontinuation monitoring period applies to eligible participants for discontinuing their NrtI treatment.

[0166] Participants with chronic HBV infection, either HBeAg-negative or HBeAg-positive, are eligible to participate in this study. A total of 110 participants are planned, and an additional 40 floating participants may be added. The total duration of study participation for each participant includes a screening period (up to 4 weeks), a dosing period (68 weeks), a follow-up period (24 weeks), and an NRTI discontinuation monitoring period (24 weeks if applicable). The above study design scheme is illustrated in Figure 1.

[0167] Inclusion Criteria Participants eligible to be included in the above study must meet all of the following criteria. All inspection requirements regarding inclusion, unless otherwise specified, are performed by the central laboratory: 1. Have a signed and dated written informed consent form (ICF) prior to study participation. 2. Be aged 18 (or the higher of the legal age of consent) to 60 years (inclusive at both ends). 3. Body mass index (BMI) ≥ 18 kg / m 2 and ≤ 32 kg / m 2 . 4. Have chronic HBV infection as defined by serum HBsAg positivity for ≥ 6 months prior to screening. 5. Have been exposed to NRTI treatment consisting of either entecavir, tenofovir disoproxil, tenofovir amibufenamide, or tenofovir alafenamide and have had HBV-DNA < LLOQ for at least 6 months prior to screening (local test results are acceptable). 6. Have HBsAg > 100 IU / mL and ≤ 3,000 IU / mL at screening. 7. Have HBV DNA < LLOQ at screening. 8. Have anti-HBs < 2 IU / L at screening. 9. Serum ALT and AST levels must be ≤ ULN at the time of screening. 10. Female participants must have confirmation that they have tested negative for pregnancy or are postmenopausal. 11. Male participants with a female partner of childbearing potential must agree to meet one of the following contraceptive requirements from the time of the first administration of the study drug until 48 weeks after the last administration of the study drug. 12. You agree not to donate blood during the duration of the study. 13. Willingness and ability to comply with research procedures and requirements, including discontinuing PEG-IFNα and NRTI treatment in accordance with the protocol.

[0168] The screening tests in the study may be repeated with medical monitor approval for any values ​​that the principal investigator deems suspicious.

[0169] exclusion criteria Participants will be excluded from the study if, as necessary, evidence exists at the time of screening or before randomization, if any of the following conditions are met: Medical condition 1. The principal investigator has any clinically significant chronic medical condition other than chronic HBV infection that would make the participant's participation in the above study inappropriate. 2. The patient has a fever (>38°C) or any clinically significant acute condition, such as acute respiratory illness, within 7 days of the first administration of the study drug. 3. Having significant liver fibrosis or cirrhosis as defined by having a liver stiffness test result of >9 kPa at the time of screening. 4. A history of clinically significant chronic liver disease originating from any cause other than chronic HBV infection. 5. A history of hepatic decompensation, including but not limited to ascites, hepatic encephalopathy, and / or esophageal or gastric varices. 6. Hepatocellular carcinoma must be diagnosed or suspected. Participants with an alpha-fetoprotein (AFP) concentration of ≥200 nanograms / milliliter (ng / mL) at screening should be excluded. If the above-mentioned AFP concentration at screening is ≥50 ng / mL and <200 ng / mL, the absence of liver mass must be documented by imaging at screening. 7. A history or evidence of drug abuse or alcohol abuse, as assessed by the principal investigator, within 12 months prior to screening. 8. Having a current or past history of infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis delta virus (HDV). 9. A history of thyroid disease that is not adequately controlled with prescription medication, or clinically significant signs of thyroid dysfunction as determined by the principal investigator at the time of screening. 10. Known history of immunological dysfunction, including but not limited to the following: a) Autoimmune diseases (e.g., rheumatoid arthritis, immune thrombocytopenic purpura, autoimmune hepatitis, etc.); or b) Primary immunodeficiency disorders (e.g., unclassifiable immunodeficiency, defective phagocytic cell function and neutropenia syndrome, and complement deficiency); or c) Secondary immunodeficiency disorders (e.g., acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) infection, solid organ transplantation, and splenectomy). 11. If determined by the principal investigator, having uncontrolled diabetes or uncontrolled hypertension; or having a diagnosis of advanced-stage heart failure (New York Heart Association Class III or Class IV or unstable angina). 12. Pre-existing or current mental conditions that would impede adherence to the protocol. Individuals with a serious mental disorder (including, but not limited to, schizophrenia, psychosis, severe depression, bipolar disorder, severe anxiety, ongoing suicide risk, or a history of suicide attempts or gestures within the past five years) as determined by the Principal Investigator will be specifically excluded. 13. Participants must have a history of cancer requiring treatment in a localized or systemic area within 5 years prior to randomization, or currently have the disease. Participants who have been disease-free for more than 3 years and have had a tumor completely surgically removed, or who have a history of low-risk basal cell carcinoma, are acceptable (low-risk is defined as 1) located on the trunk, arm, leg, cheek, forehead, temple, scalp, neck, or jaw; 2) being <2 cm in size; 3) nodular or superficial; 4) primary cancer that has not recurred after treatment; 5) having clear and smooth margins of the cancerous area; and 6) not located within or around a nerve). Previous / concurrent drug therapy 14. Having received any HBV vaccine (approved or experimental) within the five years prior to screening. 15. You have received any of the following procedures within the 12 months prior to screening: a) Small interfering RNA or antisense oligonucleotide b) Interferon-based treatment 16. You have received any of the following procedures within the six months prior to screening: a) Terbivudine b) Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human interleukin-11 (oprelbequin), or erythropoietin (EPO). 17. The participant has received blood products or immunoglobulins within 90 days prior to the administration of the study drug on Day 1, or may require blood products during the study. 18. Within 30 days prior to the administration of the study drug on Day 1, the patient has received one of the following treatments: a) Myelotoxic drugs such as systemic cell proliferation inhibitors (i.e., cancer chemotherapy drugs) b) Systemic immunosuppressants (including, but not limited to, corticosteroids with a prednisolone equivalent dose of >40 mg / day). c) Immunity from attenuated vaccines (e.g., mumps, measles, rubella). 19. Prior to the administration of the investigational drug at the Day 1 visit, participants must have participated in another clinical trial with the investigational drug or biologic within 30 days or within 5 drug half-lives (whichever is longer). Participants must agree not to participate in any other studies at any time while they are participating in this study (including the follow-up period and NRTI discontinuation monitoring period).

[0170] Discontinuation of NRTI treatment Upon completion of the 88-week visit, the principal investigator will assess whether the participant is eligible to discontinue NRTI treatment based on the following NrtI discontinuation criteria: - HBsAg < LLOQ and - HBV DNA < LLOQ and - Undetectable HBeAg and - ALT ≤ 2 × ULN.

[0171] Participants who meet all of the above criteria for at least two consecutive visits at week 88 are eligible to discontinue NrtI treatment. The investigator should confirm the participant's eligibility as soon as possible, within two weeks after the week 88 visit. Participants discontinuing NrtI will enter the NrtI discontinuation monitoring period of the study within one week of the investigator's eligibility confirmation. Participants will not take their NrtI drug therapy on the first day of the NrtI discontinuation monitoring period and will be followed for a further 24 weeks.

[0172] For the purpose of clarity of understanding, the embodiments described above are described in some detail by illustration and example, but it will be readily apparent to those skilled in the art that certain changes and modifications can be made without departing from the spirit or scope of the appended claims. Only the limitations that appear in the appended claims should be imposed on the nomenclature of any claim.

[0173] All publications, patents, and patent applications cited herein are incorporated herein by reference in such a way that each publication, patent, or patent application is specifically and individually indicated as being incorporated by reference.

Claims

1. A method for treating hepatitis B virus (HBV) infection in a subject with chronic hepatitis B, wherein the method is: a) The step of administering HBV surface antigen (HBsAg) to the subject; and b) A step of administering an HBV treatment other than HBsAg to the subject at least four weeks after the initial dose of HBsAg, A method of including.

2. The method according to claim 1, wherein the initial dose of the HBV treatment is administered at least two doses after the HBsAg, or at least three, four, or five doses after the HBsAg.

3. The method according to claim 2, wherein the initial dose of the HBV treatment is administered at least eight weeks after the initial dose of HBsAg, or at least nine, ten, eleven, twelve, thirteen, fourteen, or fifteen weeks after the initial dose of HBsAg.

4. The method according to any one of claims 1 to 3, wherein the subject has not been treated with the HBV treatment prior to the administration of the HBsAg.

5. The method according to claim 4, wherein the subject has not been treated with interferon prior to the administration of HBsAg.

6. The method according to claim 4 or 5, wherein the subject has not been treated for the HBV infection prior to the administration of the HBsAg.

7. The method according to claim 6 or 7, wherein the HBsAg is administered at a dose of 20 μg to 100 μg once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

8. The HBV treatment is the method according to any prior claim, selected from the group consisting of anti-HBsAg siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, and combinations thereof.

10. The method according to claim 9, wherein the HBV treatment comprises anti-HBsAg siRNA.

11. The method according to claim 10, wherein the anti-HBsAg siRNA is administered at a dose of 100 mg to 400 mg once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W).

12. The method according to claim 10 or 11, wherein the HBV treatment further comprises PEG-induced interferon-alpha (PEG-IFNα).

13. The method according to claim 12, wherein the PEG-IFNα is administered once a week in an amount of 50 to 500 μg, 100 to 300 μg, or 180 μg.

14. A method for treating hepatitis B virus (HBV) infection in a subject having chronic hepatitis B, the method comprising the steps of administering to the subject 20 μg to 100 μg / dose of HBV surface antigen (HBsAg) once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W), and 100 mg to 400 mg / dose of anti-HBsAg siRNA once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W), wherein the treatment comprises at least four doses of each of the HBsAg and the siRNA.

15. The method according to any one of claims 1 to 14, wherein the HBsAg comprises virus-like particles (VLPs) containing Pre-S1, Pre-S2, or S, which are HBV surface envelope proteins.

16. The method according to claim 15, wherein the VLP comprises Pre-S1, Pre-S2, and S, which are HBV surface envelope proteins.

17. The method according to any one of claims 8 to 16, wherein the siRNA is erebsilane.

18. The method according to any one of claims 1 to 17, wherein the subject is further administered a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI).

19. The method according to claim 18, further comprising the step of discontinuing the administration of NrtI if the subject meets one or more of the discontinuation criteria.

20. The method according to claim 19, wherein the discontinuation criteria include (a) HBsAg < LLOQ (lower limit of quantification), (b) HBV DNA < LLOQ, (c) undetectable HBeAg, and (d) ALT (alanine aminotransferase) ≤ 2 × ULN (upper limit of normal).

21. A method for excluding subjects with chronic hepatitis B (CHB) from clinical research, wherein the method is: (a) A step of screening a group of CHB subjects by administering HBV surface antigen (HBsAg) to the CHB subjects, wherein each CHB subject has a predetermined baseline HBV antibody concentration prior to the administration of HBsAg, and each CHB subject that does not respond to the administration of HBsAg and has a post-baseline HBV antibody concentration higher than their baseline HBV antibody concentration is excluded from the clinical study, and (b) The step of conducting the clinical study, wherein the HBV treatment is administered to CHB subjects who are not excluded from the clinical study. A method of including.

22. The method according to claim 21, wherein each CHB subject that does not respond to HBsAg administration and has a post-baseline HBV antibody concentration five times higher than their baseline HBV antibody concentration is excluded from the clinical study.

23. The method according to claim 21, wherein (i) with respect to each CHB subject having a predetermined baseline HBV antibody concentration at or below the detection limit (e.g., ≤2 IU / L), the CHB subject is excluded from the clinical trial unless the CHB subject's post-baseline HBV antibody concentration is above the detection limit (e.g., >2 IU / L), and (ii) with respect to each CHB subject having a predetermined baseline HBV antibody concentration above the detection limit (e.g., >2 IU / L), the CHB subject is excluded from the clinical trial unless the subject's post-baseline HBV antibody concentration is at least twice as high as their predetermined baseline HBV antibody concentration.

24. The method according to any one of claims 21 to 23, wherein the CHB subject is subjected to viral suppression with a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) before administration of HBsAg.

25. The method according to any one of claims 21 to 24, wherein the HBV antibody concentration is the serum anti-HBs concentration.

26. The HBV treatment is the method according to any one of claims 21 to 25, excluding the HBsAg.

27. A method for selecting subjects with chronic hepatitis B (CHB) for the treatment of hepatitis B virus (HBV), wherein the method is: a) A step of determining the baseline HBV antibody concentration in a subject having CHB before administering HBV surface antigen (HBsAg) to the subject; b) The step of administering the HBsAg to the subject; c) A step of determining the baseline HBV antibody concentration in the subject after administration of HBsAg, wherein the subject is selected for HBV treatment if the baseline HBV antibody concentration is higher than the baseline HBV antibody concentration, and otherwise the subject is excluded from HBV treatment; and d) The step of administering the HBV treatment to the selected subject, A method of including.

28. The method according to claim 27, wherein if the subject's post-baseline HBV antibody concentration is five times higher than the baseline HBV antibody concentration, the subject is selected for HBV treatment; otherwise, the subject is excluded from HBV treatment.

29. The aforementioned subject is (i) If the baseline HBV antibody concentration of the subject is at or below the lower limit of detection (e.g., ≤2 IU / L), and the post-baseline HBV antibody concentration of the subject is above the lower limit of detection (e.g., >2 IU / L), (ii) If the baseline HBV antibody concentration of the subject is above the lower limit of detection (e.g., >2 IU / L), and the post-baseline HBV antibody concentration of the subject is at least twice as high as the baseline HBV antibody concentration of the subject, Regarding the aforementioned HBV treatment, Otherwise, the subject is excluded from the HBV treatment, the method according to claim 27.

30. The method according to any one of claims 27 to 29, wherein the subject is subjected to viral suppression with a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) before administration of HBsAg.

31. The method according to any one of claims 27 to 31, wherein the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject.

32. The HBV treatment is the method according to any one of claims 27 to 31, excluding the HBsAg.

33. The method according to any one of claims 27 to 32, wherein the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

34. A method for treating HBV infection in a subject with chronic hepatitis B, wherein the method is: a) A step of administering HBV treatment to the subject, wherein it is determined that the baseline HBV antibody concentration in the subject after administration of HBsAg is higher than the baseline HBV antibody concentration in the subject before administration of HBsAg. A method of including.

35. The method according to claim 34, wherein the HBV treatment is administered when it has been determined that the baseline HBV antibody concentration in the subject after administration of HBsAg is five times higher than the baseline HBV antibody concentration in the subject before administration of HBsAg.

36. The method according to claim 34, wherein the HBV treatment is administered to the subject if (i) the subject's baseline HBV antibody concentration is below or equal to the lower limit of detection (e.g., ≤2 IU / L) and the subject's post-baseline HBV antibody concentration is above the lower limit of detection (e.g., >2 IU / L), or (ii) the subject's baseline HBV antibody concentration is above the lower limit of detection (e.g., >2 IU / L) and the subject's post-baseline HBV antibody concentration is at least twice as high as the subject's baseline HBV antibody concentration.

37. The method according to any one of claims 34 to 36, wherein the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject.

38. The HBV treatment is the method according to any one of claims 34 to 37, excluding the HBsAg.

39. The method according to any one of claims 34 to 38, wherein the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

40. A method for treating HBV infection in a subject diagnosed with or suspected of having HBV infection, wherein the method is: a) A step of administering HBsAg to the subject; b) A step of determining the baseline HBV antibody concentration in serum samples collected from the subject after administration of HBsAg; and c) If the HBV antibody concentration after baseline is higher than the baseline HBV antibody concentration in the serum sample collected from the subject before administration of HBsAg, the step of administering HBV treatment to the subject. A method of including.

41. The method according to claim 40, wherein the HBV treatment is administered in step (c) when the post-baseline HBV antibody concentration is five times higher than the baseline HBV antibody concentration in the serum sample collected from the subject before administration of the HBsAg.

42. The method according to claim 40, wherein the HBV treatment is administered to the subject if (i) the subject's baseline HBV antibody concentration is below or equal to the lower limit of detection (e.g., ≤2 IU / L) and the subject's post-baseline HBV antibody concentration is above the lower limit of detection (e.g., >2 IU / L), or (ii) the subject's baseline HBV antibody concentration is above the lower limit of detection (e.g., >2 IU / L) and the subject's post-baseline HBV antibody concentration is at least twice as high as the subject's baseline HBV antibody concentration.

43. The method according to any one of claims 40 to 42, wherein the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations.

44. The method according to any one of claims 40 to 43, wherein the subject is subjected to viral suppression with NrtI before administration of HBsAg.

45. The HBV treatment is the method according to any one of claims 40 to 44, excluding the HBsAg.

46. The method according to any one of claims 40 to 45, wherein the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

47. A method for treating HBV infection in a subject with chronic hepatitis B, wherein the HBV antibody concentration in the subject is less than 2 IU / L, and the method is a) A step of administering HBsAg to the subject; b) The process includes administering HBV treatment to the subject, The HBV antibody concentration in the subject has been determined to be at least 2 IU / L, at least 5 IU / L, at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 IU / L after administration of HBsAg. method.

48. The method according to claim 47, wherein the subject is subjected to viral suppression with NrtI before administration of HBsAg.

49. The method according to any one of claims 47 to 48, wherein the HBV antibody is anti-HBs.

50. The HBV treatment is the method according to any one of claims 47 to 49, excluding the HBsAg.

51. The method according to any one of claims 47 to 50, wherein the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

52. A method for treating HBV infection in a subject having chronic hepatitis B, the method comprising the step of administering a therapeutically effective amount of HBV therapy to a subject having chronic hepatitis B, wherein, prior to the administration of the HBV therapy, the subject's HBV antibody concentration is at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 A method in which the concentration is determined to be IU / L, at least 900 IU / L, or at least 1000 IU / L.

53. The method according to claim 52, wherein the HBV antibody concentration of the subject is the anti-HBs concentration.

54. The HBV treatment is the method according to any one of claims 52 to 53, excluding HBsAg.

55. The method according to any one of claims 52 to 54, wherein the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

56. HBV surface antigen (HBsAg) for use in the method according to any one of claims 1 to 35.

57. Use of HBV surface antigen (HBsAg) and HBV treatment without HBsAg for the manufacture of a kit for treating a subject having chronic hepatitis B, wherein the subject responds to the administration of HBsAg with an increase in HBV antibody concentration upon administration of HBsAg to the subject's HBV antibody concentration prior to the administration of HBsAg to the subject.

58. The use according to claim 57, wherein (i) the HBV antibody concentration of the subject prior to administration of the HBsAg to the subject is less than 2 IU / L, or (ii) the subject responds with an increase at an HBV antibody concentration twice as high as the HBV antibody concentration prior to administration of the HBsAg.

59. The use according to any one of claims 57 to 58, wherein the subject is subjected to viral suppression with NrtI before administration of HBsAg.

60. The use according to any one of claims 57 to 59, wherein the HBV antibody is anti-HBs.

61. The use according to any one of claims 57 to 60, wherein the HBV treatment is siRNA, interferon-alpha (IFNα), PEG-IFNα, HBV neutralizing mAb, or a combination thereof.

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