ABSTRACT
As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.
-
Keywords: Chronic hepatitis B; HBsAg; Consensus; Antiviral Agents; Immunologic Factors
INTRODUCTION
Owing to the substantial global progress towards hepatitis B virus (HBV) elimination goals, the worldwide prevalence of chronic HBV infection declined over time [
1], particularly in children younger than 5 years. However, chronic hepatitis B (CHB) and its complications, cirrhosis and hepatocellular carcinoma (HCC), remain a significant public health threat globally, with 254 million people chronically infected and 1.1 million HBV-related deaths worldwide as of the latest estimates [
2]. Currently, the landscape for chronic HBV therapy is evolving. The primary focus of HBV treatment is to achieve sustained off-treatment clearance of hepatitis B surface antigen (HBsAg), a milestone generally signifying a functional cure of HBV infection. Functional cure is recognized as the clinically optimal treatment goal for CHB due to its association with improved clinical outcomes, and is the only practically achievable endpoint that allows for the discontinuation of treatment. Research to achieve a functional cure for HBV infection includes exploring combinations of existing or new agents that target different steps of the viral life cycle or enhance the host’s antiviral immune response. Moreover, standardized and validated assays for novel virologic and immunologic markers toward better elucidating the mechanisms of action, defining HBV cure, measuring efficacy or predicting response are approved or in development. These studies provide the evidence for updating recommendations. This current version updates previous guidance [
3] after rigorous review of the latest available evidence.
DEFINITION OF FUNCTIONAL CURE AND ITS KEY CHALLENGES
Clinical significance of functional cure for chronic hepatitis B
The clinical significance of a “functional cure” for CHB is immense, given the long-term adverse outcomes of chronic HBV infection. Chronic HBV infection is a major cause of liver cirrhosis and HCC worldwide. Successful treatment can lead to regression of liver fibrosis and even partial reversal of cirrhosis, especially if the intervention occurs in the early stage of liver disease. A functional cure would prevent the disease progression of the advanced stages of liver disease [
4], thereby reducing the risk of liver-related morbidity and mortality and improving long-term outcomes. CHB patients require long-term management, including regular monitoring, medication, and potentially liver transplantation in advanced cases. A functional cure would thus substantially reduce the economic burden on healthcare systems and patients by eliminating the need for ongoing treatment and hospitalization [
5]. HBV infection is particularly prevalent in regions with inadequate access to healthcare and vaccination programs. Achieving a functional cure would contribute to the global effort to eliminate CHB as a public health threat by reducing the pool of infected individuals and preventing new infections. In addition, a functional cure could help reduce social stigma and promote greater acceptance and inclusion of individuals living with HBV. To sum up, the clinical significance of functional cure for CHB includes profound clinical, social, and economic benefits, offering hope for millions of individuals affected by this virus.
Current anti-HBV therapy can improve serologic, virologic, and histologic endpoints but is not considered curative. HBV cure is categorized as complete sterilizing cure, functional cure, and partial cure. The sterilizing cure, representing the ultimate therapeutic goal for CHB, is characterized by the complete elimination of both episomal covalently-closed-circular DNA (cccDNA) and integrated viral DNA fragments. However, the eradication of HBV remains elusive due to the lack of therapies that effectively target the cccDNA. Functional cure or clinical cure of CHB is defined as sustained HBsAg loss and undetectable serum HBV DNA, with or without hepatitis B surface antibody (HBsAb) seroconversion 24 weeks after the completion of treatment. Although cccDNA may still be present, it is not transcriptionally active [
6]. Guidance reported by EASL-AASLD HBV Treatment Endpoints Conference Faculty has recommended sustained HBsAg loss in addition to HBV DNA less than the lower limit of quantitation 24 weeks off-treatment as the preferred primary endpoint for phase III trials of chronic HBV treatment [
7,
8]. The advancements in understanding of HBV molecular biology and antiviral immune responses have shed light on novel approaches and combinations to treat CHB. Functional cure of CHB is becoming a realistic and feasible therapeutic goal with the treatment concept of integrating the suppression of HBV replication and viral protein production, with restoration of the host immune response to HBV. Partial cure of CHB, defined as off-treatment sustained hepatitis B e antigen (HBeAg) negative and undetectable HBV DNA with HBsAg positive at low levels (HBsAg level <100 IU/mL), is considered an acceptable intermediate endpoint on the pathway to a functional cure.
1. The optimal and achievable goal and primary endpoint for anti-HBV treatment is functional cure, which is defined as sustained serum HBsAg loss and undetectable serum HBV DNA, with or without HBsAb seroconversion 24 weeks after the completion of antiviral therapy.
Obstacles to curing hepatitis B from the virological and immunologic perspectives
Chronic HBV infection results from a complex interplay between viruses and the host immunity. HBV genome forms an episomal mini-chromosome, the so-called cccDNA in the nucleus of infected hepatocytes. cccDNA serves as the reservoir of chronic HBV infection and can be established by both de novo infection and intracellular replenishment of relaxed circular DNA (rcDNA). The half-life of cccDNA varies from a few weeks to several years depending on multiple factors including the micro-environment of the infected hepatocytes. Accumulating evidence indicates low-level ongoing HBV infection in the liver under nucleos(t) ide analogue (NA) treatment. HBV DNA, particularly the S fragments, have been observed to integrate into the host genome [
9]. The integration occurs early in infection and is involved in HBV pathogenesis depending on the integration site on host cell genome. Notably, a significant proportion of serum HBsAg is now known to be generated from the integrated HBV S gene fragment in CHB patients, particularly in HBeAg negative individuals. Elimination of HBV cccDNA and integrated HBV DNA fragment would lead to complete HBV cure, but it remains challenging and is an elusive therapeutic goal [
10,
11].
The liver is a tolerogenic organ where persistent viral infection can easily establish. HBV does not induce innate immune-related genes during entry and expansion, suggesting it is a stealth virus [
12]. Consistently, HBV core proteins cannot activate Toll-like receptors (TLRs) [
13]. Although there are a large amount of HBsAg empty particles in the blood of CHB patients [
14], these circulating HBsAg do not stimulate peripheral blood mononuclear cells to express antiviral cytokines [
15]. HBsAg is thought to suppress host immune responses. It can promote autophagic degradation of intrahepatic TAK1 and TAB2, resulting in inhibition of NF-κB signaling [
16]. HBsAg negatively regulates downstream signaling of TLR2, TLR3 and TLR9 in dendritic cells, monocytes, and macrophages [
17-
20]. Moreover, weakened natural killer cell function is caused by HBsAg in CHB patients via downregulation of stimulator of IFN genes [
21,
22].
The liver is regarded as a “graveyard” for T cells, as it represents a specific site for T cell dysfunction and exhaustion [
23]. HBV core or polymerase-specific CD8+ T cells are classically maintaining exhausted phenotype [
24]. Mechanistically, hepatocyte-primed T cells differentiate into exhausted cells rather than effector cells [
25]. Of note, the frequency of HBsAg-specific CD8+ T cells is decreased in CHB patients after they reach adulthood [
26]. Correspondingly, HBsAg-induced monocytic myeloid-derived suppressor cells were found to mediate thymic clonal deletion of these T cells [
27]. As thymic tolerance is established in children with vigorous thymus, this might be a potential mechanism for age-related outcome of HBV exposure. Peripheral B cell subsets showed low expression of TLR9 in CHB patients [
28]. In these patients, HBsAg-specific B cells were demonstrated as an atypical memory B (atMB) phenotype, which lost the capability to differentiate into plasma cells and to secrete antibodies [
29,
30]. In these atMB cells, CD138 and B cell maturation antigen that are crucial for plasma cell survival are not detected, but B-cell receptor signaling, endoplasmic reticulum pressure and apoptotic pathways are significantly upregulated [
31].
Immune exhaustion, a phenomenon commonly observed in chronic HBV infection, is regarded as a significant host barrier to achieving a functional cure of CHB. This phenotype of exhaustion, which arises from persistent antigen exposure, is marked by the expression of checkpoint receptors and a progressive loss of effector functions [
32]. Understanding the mechanisms underlying immune exhaustion in CHB is crucial for developing novel immunotherapeutic strategies [
33].
Currently, antiviral regimen includes two classes of drugs: immunomodulators, such as pegylated interferon-a (PegIFN), and directly acting antivirals (DAA), such as NAs [
34-
37]. Although potent NA can achieve virologic response during therapy, the response is generally not sustained off-treatment. Due to the tenacity of cccDNA and absence of direct effect of NA on cccDNA, CHB patients face a high risk of relapse after NA withdrawal, which in turn may deteriorate to hepatic decompensation or even catastrophic life-threatening events without close monitoring and timely retreatment. Therefore, lifelong treatment may be required to maintain viral suppression in the majority of patients, particularly in HBeAg-negative patients. However, there are concerns with indefinite NA therapy, for example, financial burden and medication adherence. Peg-IFN exerts dual effects, through promoting the activity of host immune cells and inducing the production of interferon-stimulated genes, which encode direct antiviral effector proteins [
38]. Furthermore, Peg-IFN can also inhibit HBV transcription and reduce the production of viral antigens through enhancing degradation of HBV pregenomic RNA (pgRNA) and core particles or by modifying epigenetic regulation of cccDNA [
39,
40]. The finite duration of Peg-IFN treatment can result in modest reduction in serum HBsAg concentration and durable off-treatment response, however, only in a proportion of patients.
Effective and coordinated innate and adaptive branches of immunity is indispensable for the control of HBV infection [
41], therefore, a promising target for therapeutic strategies is immune modulation to restore dysfunctional HBV-specific immunity. Persistent exposure to high HBV viremia and antigen burden creates a tolerogenic intrahepatic and extrahepatic environment in CHB [
42]. The duration of HBsAg exposure associates with the level of anti-HBV immune response, strategies to restore anti-HBV immune responses should consider younger patients [
26]. Therapeutic reduction of viral load and antigenemia by effective DAA may provide a window of opportunity to break the immune tolerance and mobilize the immune response against HBV, subsequently, the administration of immunomodulators restores the exhausted immune responses. The suppression of viral load induced by NAs may restore the impaired adaptive immune response, and leverage the immunomodulatory effects of Peg-IFN [
43-
46]. This mechanism provides a rationale for combining Peg-IFN and NA to generate additive or synergistic effects, potentially leading to a functional cure of hepatitis B [
43,
47,
48].
2. The major challenges of HBV cure include the lack of available drugs to eliminate cccDNA and integrated HBV DNA, and host’s inability to restore the exhaustion of HBV-specific immunity.
3. The mechanistic rationale for combining direct-acting antivirals (e.g., NAs) and immunomodulators (e.g., Peg-IFN) is that these two classes of drugs have differential antiviral mechanisms, and that viral suppression mediated by NAs subsequently enhances the immunologic response to Peg-IFN.
TREATMENT STRATEGIES AND ROADMAP FOR FUNCTIONAL CURE OF CHB
Combining Peg-IFN and oral antiviral therapy
As aforementioned, a combination therapy with oral NAs and Peg-IFN is an interesting modality to accelerate functional cure. Peg-IFN can enhance the immune system in CHB patients and reduce HBV replication from NAs effects, consequently eliminating the cccDNA from liver. There are several treatment strategies of a combination therapy including “de novo strategy”, “add-on combination” or “switch-to therapy”.
As shown in
Table 1, the “de novo” combination of PegIFN and low potency NAs in naïve CHB patients had no additional advantages over Peg-IFN monotherapy. Interestingly, a combination of Peg-IFN with potent NA such as tenofovir demonstrated a better response compared with Peg-IFN monotherapy [
49]. Moreover, patients with genotype A achieved the highest rates of HBsAg loss with this combination therapy. However, current guidelines do not recommend the “de novo” combination therapy for CHB patients.
Most of studies of “add-on” strategy, as shown in
Table 1 [
50-
62], provide the benefit of a declination of HBsAg level. However, the HBsAg clearance rate is still low in a short-term follow-up. The “switch-to” strategy, also highlighted in
Table 1, had benefits in finite treatment duration and may potentiate HBsAg loss. However, favorable parameters in the candidates are the pre-requisite, this includes low baseline HBsAg level and low on-treatment HBsAg level. The major drawback is the concern of HBV flare after treatment cessation, particular in those with advanced fibrosis or cirrhosis.
Meta-analyses indicated that combination therapy with Peg-IFN and NA could significantly improve the probability of HBsAg loss compared to NA monotherapy [
63,
64]. However, one showed that combination therapy failed to induce higher HBsAg loss rates compared to IFN monotherapy, and the other suggested that sequential strategy was more superior than de novo strategy in achieving HBsAg loss. A prospective randomized controlled trial in HBeAg-positive naïve patients showed that compared with tenofovir disoproxil fumarate (TDF) alone and de novo combination, the addition of Peg-IFN in TDF-treated group might be an effective strategy for HBsAg loss [
65]. This finding supports the clinical benefit of sequential administration of NA followed by Peg-IFN in CHB patients.
Efforts have also been made to determine the best approach using Peg-IFN for those already on stable NA. A previous study in HBeAg-negative NA-treated patients suggested that the “switch to” strategy might be superior to the “add-on” strategy in reducing HBsAg levels. NA cessation in the “switch-to” strategy might activate the host immune response, which could help boost the effects of Peg-IFN [
66]. A meta-analysis showed that the pooled estimates of HBsAg loss rate for “switch-to” strategy were significantly higher than that of “add-on” strategy [
64]. SWAP trial suggests that add-on Peg-IFN regimen is preferred to switch-to due to the improved safety and similar efficacy. Both strategies achieved comparable HBsAg loss in the HBeAg-negative participants, but switch arm demonstrated a higher risk of viral reactivation and clinical relapse (13.6% overall, 27% in HBeAg-positive), making this strategy inadvisable for HBeAg positive patients [
67]. A recent randomized controlled trial of HBeAg-positive entecavir (ETV)-treated patients with HBsAg <3,000 IU/mL, HBeAg <200 signal-to-cutoff ratio (S/CO) reported that switch-to or add-on Peg-IFN led to comparable HBsAg reduction at week 48 [
68]. In a study investigating factors associated with virological relapse after switching to Peg-IFN in ETV-treated patients, HBeAg positivity rate was significantly higher in patients with virological relapse than in those without [
69]. Collectively, add-on Peg-IFN may be preferable to switch-to Peg-IFN in NA-treated CHB patients, especially HBeAg-positive patients.
4. Sequential combination therapy using potent NA followed by Peg-IFN improves the HBsAg loss rate in patients with detectable HBV DNA compared to NA monotherapy.
5. For virally-suppressed patients on stable NA therapy, add-on Peg-IFN may be preferred over switch-to Peg-IFN, as it has similar HBsAg loss rates and reduces the risk of relapse in NA-treated patients with chronic hepatitis B, particularly in those who are HBeAg-positive.
Treatment navigation for functional cure by combination of NA and Peg-IFN
Based on the latest evidence, we propose an updated treatment navigation for sequential combination therapy with DAA (e.g., NA) and immunomodulator (e.g., Peg-IFN), which integrates strategies of baseline-guided therapy and response-guided therapy (
Fig. 1). Specifically [
70,
71], for patients with high HBsAg levels (>3,000 IU/mL) and detectable HBV DNA, NA should be initiated first to suppress viral replication, thereby reducing viral load burden. Once the patients achieve undetectable HBV DNA, low HBsAg levels, especially ≤1,500 IU/mL, and negative HBeAg, PegIFN can be subsequently administered to restore anti-HBV immunity. At week 24 of Peg-IFN-based treatment, individuals with HBsAg levels of ≥200 IU/mL or decline of <1 log
10 IU/mL had a minimal chance of achieving HBsAg loss, therefore, stopping Peg-IFN therapy or alternative treatment may be considered.
Although the durability of HBsAg loss is generally high, there exists a debate about whether and when the treatment can be stopped in the patients with HBsAg loss. A long-term follow-up study showed that at year 5 of followup, 18% of patients treated with Peg-IFN and NA combination therapy had durable HBsAg loss and 88% of them had developed HBsAb [
72]. Controversy remains over whether HBsAb development is requisite for functional cure, as HBsAg loss is sustained in most patients with or without HBsAb seroconversion in follow-up with currently approved therapies but will need to be confirmed with therapies in development [
8]. High level of HBsAb (>100 U/mL) is strongly associated with low risk of recurrence [
73,
74]. Studies have shown that a consolidation Peg-IFN treatment of ≥12–24 weeks after HBsAg loss may improve the durability of this response [
75]. Therefore, once HBsAg loss is achieved without HBsAb seroconversion, a consolidation Peg-IFN treatment or additional therapy such as hepatitis B vaccine [
76,
77] may be considered to maintain the HBsAg loss and improve HBsAb responses, eventually leading to a stable functional cure. For patients experiencing recurrence after cessation of Peg-IFN-based therapy, retreatment may be effective and HBsAg loss rate has been shown to be 80% [
73].
6. The roadmap integrating strategies of baseline- and response-guided therapy based upon HBsAg kinetics can guide treatment decision on combination therapy with NA and Peg-IFN.
7. Low baseline HBsAg level (<1,500 IU/mL) and HBeAg loss under NA therapy, as well as early on-treatment HBsAg decline may predict which patients are likely to achieve HBsAg loss with combination treatment.
8. Individuals with HBsAg levels of ≥200 IU/mL or decline of <1 log10 IU/mL at week 24 had a minimal chance of achieving HBsAg loss, therefore, stopping Peg-IFN therapy or alternative treatment may be considered.
9. Once HBsAg loss is achieved without HBsAb development, a consolidation Peg-IFN treatment ≥12 weeks or additional therapy such as vaccine may be considered to maintain the HBsAg loss and achieve a stable functional cure.
Discontinuation of NA in selected patients
Several trials, including FINITE study etc., have shown that finite NA therapy prior to HBsAg loss in non-cirrhotic HBeAg-negative patients is a feasible approach to functional cure with definite treatment [
78-
81]. A study in non-cirrhotic HBeAg-negative patients showed that discontinuation of ETV therapy led to more 5-year cumulative incidences of HBsAg loss (13%) without an increased risk of HCC compared to those continuing ETV. The best candidates for NA withdrawal are virally suppressed, HBeAg-negative, noncirrhotic patients with low HBsAg levels, specifically Caucasians with <1,000 IU/mL and Asians with <100 IU/mL [
82]. Although study proposed that NA discontinuation-associated relapse may be an integral part of the stop-to-cure approach and ultimately triggers HBsAg loss [
83], cessation of NA therapy prior to HBsAg loss will expose patients to the risk of off-treatment relapse, or even decompensation, such treatment decision should be made with caution, and based upon a full assessment of the individual patient’s benefit/risk [
84]. Strict surveillance and long-term follow-up after the discontinuation of NA therapy are recommended to prevent deterioration. Further studies are needed to fine-tuning the strategy, including research for the optimal duration of consolidation therapy, timing to stop, and timing to start retreatment.
10. Cessation of long-term NA therapy prior to HBsAg clearance in HBeAg-negative patients with low HBsAg levels (<100 IU/mL) may be an alternative approach to functional cure. However, such treatment decision should be made with caution, and strict surveillance and long-term follow-up after the discontinuation of NA therapy is recommended to prevent deterioration.
New treatment approaches and potentially curative regimens
Although sequential combination therapy with Peg-IFN and NA improves HBsAg loss rates compared to NA monotherapy, this benefit is largely limited to selected patients, specifically those with low HBsAg levels. The way to achieve functional cure is by using direct antiviral agents to reduce the circulatory HBsAg to an undetectable level, thereby allowing reawakening of the dysfunctional immune system in the hosts (
Fig. 2). Novel DAAs acting against different viral replicative steps have been explored. The foremost ones are HBV RNA interfering agents including small interfering RNA (siRNA) and antisense oligonucleotide (ASO) [
85]. They knock down HBV gene expression through degradation of the pgRNA and mRNAs for HBV DNA and viral protein syntheses mediated by the RNA induced silencing complex and RNase H1, respectively. Because of the overlapping genomic arrangement of HBV, a single trigger usually targeting the X genomic region is able to knock down all the HBV RNA activities. The currently active investigational siRNAs include AB-729 (Imdusiran), JNJ-3989, RG-6346 (Xalnesiran), and VIR-2218. When they were given 4–8 weekly for 12 to 48 weeks, there was >1 log
10 IU/mL HBsAg reduction in 90% of subjects and reaching the nadir HBsAg <100 IU/mL in 50% of subjects [
86-
88]. These HBsAg reductions were sustainable up to 48 weeks or longer after the treatments were stopped. However, all studies using siRNAs have not been associated with HBsAg loss. On the other hand, short term treatment of an ASO (Bepivirosen) given for 4 weeks has already been shown to be associated with transient loss of HBsAg in 4 out of 16 patients (treatment-naïve/NA-treated) [
89]. The follow-up phase II study of this agent showed that 9% of NA-treated and 10% of treatment-naïve patients achieved HBsAg seroclearance after 24 weeks of treatment [
90]. Alanine transaminase (ALT) flares, usually followed by HBsAg reduction signifying immune mediated response, were observed in both siRNA and ASO treatments.
Another group of DAAs is the core protein allosteric modulators (CpAMs). They affect the viral nucleocapsid assembly which is essential for pgRNA encapsidation. Hence, they have dual modes of action, i.e., depletion of complete virion formation and depletion of replenishment of cccDNA in the nucleus of hepatocytes. There are two classes of CpAMs: Class I (class A) CpAMs form aberrant nucleocapsids; Class II (class E) CpAMs form empty nucleocapsids. Many studies have shown that CpAMs were able to exert greater HBV DNA reduction when combined with NAs compared to NAs alone [
91,
92]. Additionally, CpAMs have a profound reduction of HBV RNA levels. In the early generation of CpAMs, there was very minimal/ modest HBsAg reduction in treatment-naïve HBeAg positive patients [
91,
92]. These early generation CpAMs may also have the concern of drug resistance development when they were given without NAs [
91]. The latest more potent CpAMs, e.g., ALG 000184, were associated with a clinically meaningful HBsAg reduction [
93] in HBeAg positive treatment-naïve patients without emergence of drug resistance when they were given without NAs.
In addition to the above two novel classes of DAAs, there are two other different classes of DAAs with different mechanisms of action, namely the virus entry inhibitor, e.g., bulevirtide (Myrcludex B), and the viral protein export inhibitor, e.g., nucleic acid polymers (NAPs) - REP-2139 and REP-2165. The former competes with the pre-S2 sequence of HBV for engaging the sodium taurocholate co-transporting polypeptide, the main hepatocyte receptor for viral entry. HBsAg reduction effect was mainly seen in the 48-week study using bulevirtide and Peg-IFN where 24.4% of patients achieved HBsAg decline by >1 log
10 IU/mL or HBsAg loss in HBV HDV co-infected population [
94]. However, when it was given alone, there was no significant reduction of HBsAg at week 48 in HBV-HDV co-infected patients [
95]. NAP also showed HBsAg responses when combined with Peg-IFN and tenofovir [
96]. With 48 weeks of this triple therapy, 87.5% of patients achieved HBsAg reduction >1 log
10 IU/mL and, 60% achieved HBsAg seroconversion.
There are several novel agents targeting different immune cells or pathways which are rendered defective by HBV. TLR agonists, e.g., TLR7 and TLR8 agonists, have been tried under different regimens. Vesatolimod (TLR7 agonist) treated for 12 weeks did not result in HBV DNA and HBsAg reduction [
97]. Ruzotolimod, another TLR7 agonist given every other day for a total of 42 days, showed mild mean reduction of 0.14 log IU/mL in HBsAg levels in NA-treated patients [
98]. Selgantolimod, a TLR8 agonist treated for 24 weeks in NA-treated patients, was associated with 5% (2/39) of HBsAg seroconversion [
99].
Targeting Programmed Death-1 (PD-1) or its ligand, Programmed Death-Ligand 1 (PD-L1), is another possible treatment to enhance the adaptive immunity through T cell activation. Initial positive results were seen in a study using 2 doses of nivolumab (anti-PD-1) with/without therapeutic vaccine [
100]. Subsequent study using an anti-PD-L1, envafolumab given biweekly for 24 weeks in patients with baseline HBsAg levels <100 IU/mL was associated with HBsAg reduction of >1 log
10IU/mL in 42.1% of patients and with HBsAg loss in 21.1% of patients [
101].
Not until recently, therapeutic vaccine stimulating host immune responses against HBV has revived its attention in the field. Novel therapeutic vaccines including BRII-179 comprised of HBsAg, Pre-S1 and Pre-S2; and VTP-300 comprised of HBsAg, Pre-S1, Pre-S2, modified polymerase and core have shown some positive results. Treatment using BRII-179 with or without IFN was associated with restoration of IFN-gamma production and mounting of HBsAb response although there was no observable HBsAg reduction [
102]. On the other hand, VTP-300 given with or without nivolumab were associated with meaningful HBsAg reduction in patients with lower baseline HBsAg <100 IU/mL [
103].
Another novel group of immunomodulatory agents is monoclonal antibodies e.g., VIR-3434. One dose of VIR3434 was associated with immediately HBsAg reduction of 2 log IU/mL [
104]. However, HBsAg rebound was seen early at day 29 after single dosing. VIR-3434 is postulated to have several actions including inhibition of viral entry, enhanced virus delivery to dendritic cells and enhanced T cell presentation and stimulation.
In addition, a possible immunotherapeutic approach to create a functionally intact population of HBV-specific T cells against HBV may be T cell engineering through T cell receptor gene transfer or use of chimeric antigen receptor T cells [
105,
106].
To date, single novel DAA has not yet resulted in high rate of functional cure. There are many ongoing studies combining different DAAs with or without immunomodulators. Examples of these include combination of Imdusiran (siRNA) with VTP-300 (therapeutic vaccine) [
107], VIR 2218 (siRNA) with Peg-IFN [
108], Xalnesiran (siRNA) with Peg-IFN or with Ruzotolimod (TLR-7 agonist) [
109]; and Bepirovirsen followed by Peg-IFN [
110]. In general, the HBsAg loss could be achieved in approximately 15–23% at 24-week post-treatment by the latter 3 regimens. However, the higher efficacy is usually observed in patients with lower baseline HBsAg levels, i.e., <1,000 IU/mL. More future studies using different agents and combination strategies to achieve a higher functional cure rate inclusive of patients with high baseline HBsAg levels are urgently needed.
The curative strategy has been explored in special populations infected with chronic HBV including those with low-level viremia, metabolic dysfunction-associated steatotic liver disease (MASLD), liver cirrhosis, HCC, renal impairment, coinfections and children (
Table 2) [
111-
160]. Shared decision making, following comprehensive discussions outlining the potential benefits and risks of Peg-IFN-based curative therapy, is advised for all candidate patients in the special populations.
Clinicians should be aware of the contraindications to Peg-IFN-based therapy prior to its initiation. Peg-IFN use in patients with decompensated cirrhosis may precipitate hepatic failure or severe bacterial infections, thus is absolutely contraindicated [
161]. Although the impact of IFN on pregnancy is controversial [
162], female patients of childbearing age should undergo a pregnancy test before Peg-IFN-based therapy. Furthermore, patients with active psychiatric disorders, a history of suicidal ideation, autoimmune diseases, or other severe systemic illnesses are contraindicated. Given the significant potential for adverse effects associated with Peg-IFN, thorough patient counseling and shared decision making are recommended to facilitate the development of individualized treatment plans for all patients.
11. Shared decision making, following comprehensive discussions outlining the potential benefits and risks of Peg-IFN-based curative therapy, is advised for all candidate patients in the special populations.
12. Patients with decompensated cirrhosis, pregnancy, active psychiatric disorders, a history of suicidal ideation, autoimmune diseases, or other severe systemic illnesses are contraindicated to Peg-IFN-based curative therapy and NA monotherapy should be recommended.
MONITORING AND LONG-TERM FOLLOW-UPS
Predictor and monitoring
Serum HBsAg level may reflect active cccDNA and is a reliable marker to optimize Peg-IFN use. HBsAg kinetics within the first 24 weeks of Peg-IFN-based therapy are predictive of HBsAg loss and sustained response. Low baseline [
163] and on-treatment [
164,
165] HBsAg levels, or early strong HBsAg reductions [
166] could help identify patients with a high probability of achieving HBsAg loss both in HBeAg-positive and HBeAg-negative patients [
167]. ETV-treated patients with HBeAg loss and HBsAg <1,500 IU/mL at baseline had high chance of achieving HBsAg loss [
59]. On-treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from Peg-IFN add-on and could be used as a potential response-guided strategy and stopping-rule for Peg-IFN therapy [
164]. Different components of HBsAg, namely the large and medium HBsAg, decrease earlier than total HBsAg before HBsAg loss, and thus might be biomarker candidates for predicting cure of HBV infection [
168]. Several studies demonstrated a correlation of ALT flares and HBsAg loss during Peg-IFN therapy [
169,
170]. ALT ≤40 U/L at baseline or ALT levels ≥80 U/L at week 12 of Peg-IFN therapy was associated with HBsAg loss at week 24 post-treatment [
171]. In a post hoc analysis of randomized trials [
170], ALT flares during Peg-IFN treatment are associated with subsequent HBsAg decline and may predict HBsAg loss. Flares rarely occurred during Peg-IFN add-on therapy. A study developed scoring system integrating baseline HBsAg level <1,000 IU/mL, HBsAg decline >0.5 log
10 IU/mL at week 12 and ALT flare at week 12 to predict HBsAg loss either by add-on or switch-to Peg-IFN in NA-suppressed patients [
172]. End of treatment (EOT) HBsAg levels may predict HBsAg loss during post-treatment follow-up. EOT HBsAg level <10 IU/mL was predictive of HBsAg loss (52%) at 3-year post-treatment [
173]. EOT HBsAb level may be correlated with sustained off-treatment HBsAg loss [
174,
175]. EOT HBsAb levels >2 log
10IU/L and hepatitis B core-related antigen (HBcrAg) levels <4 log
10U/ml were associated with durable HBsAg loss at 24 weeks post-treatment [
74]. A retrospective study indicated that HBeAg [
176] negativity at EOT was associated with lower incidence of HBsAg reversion after Peg-IFN discontinuation, which is consistent with the findings from a prospective study [
75] in HBeAg positive CHB patients.
During long-term NA therapy, HBsAg level or its trajectories can predict HBsAg loss [
177,
178]. HBsAg decline of ≥1 log
10 IU/mL at week 24 independently predicts HBsAg loss in HBeAg-positive patients treated with up to 5 years of TDF treatment [
179]. EOT HBsAg thresholds are identified to determine when NA treatment can be ended with low risk of relapse and high probability of HBsAg loss [
82,
180].
Novel HBV biomarkers are in development to understand the natural history of HBV, improve the management of CHB patients, and to predict disease outcomes of CHB. The utility of these biomarkers in predicting HBsAg loss is shown in
Table 3 [
181-
221].
Before initiating Peg-IFN based therapy, measurement of key baseline parameters is required, such as HBsAg, HBeAg, and HBV DNA levels, routine blood test and biochemical markers, liver ultrasound and transient elastography, thyroid function, mental condition, autoimmune antibodies, fundus examination, a pregnancy test and routine diagnostic tests to exclude other conditions or comorbidities that could contraindicate Peg-IFN therapy, which is significant for determining the appropriate therapy and predicting treatment response. Monitoring these parameters shall be carried out periodically to assess adverse events and treatment effectiveness during therapy, which is essential for evaluating the severity of adverse events and whether there is response to therapy.
Consensus statement:
13. Before initiating combination therapy, measurement of key baseline parameters is required to guide the treatment decision and predict efficacy and safety. Monitoring needs to be carried out periodically to assess adverse events and treatment effectiveness during therapy.
Long-term follow-up
HBsAg loss is associated with favorable long-term outcomes and reduces the risk of HCC and liver-related complications [
4,
222,
223]. Although HBsAg loss typically demonstrates durability, HBsAg reversion or recurrence may occur in approximately 6% of the patients. Notably, the recurrence rate tends to be slightly higher at the 1-year follow-up than the overall recurrence rate [
224]. Closer attention should be paid to patients with cirrhosis, older than 50 years at the time of HBsAg loss. Therefore, periodic followup visits should be performed once every 3 months in the beginning after cessation of treatment, and the time interval of the follow-up visits may be gradually extended. Furthermore, HBsAg and HBV DNA reversion can occur owing to reduced immune control of HBV infection. Patients with HBsAg loss should be evaluated annually for their HBsAg, HBV DNA, and ALT levels. Retreatment remains effective in these cases although HBsAg reversion is not a target for immediate re-treatment unless it is accompanied by elevated HBV DNA and ALT levels.
Although HBsAg loss can significantly reduce the risk of HCC, HCC can still develop in patients after HBsAg loss, even in those without cirrhosis, possibly due to occult HBV infection or HBV DNA integration. Closer attention should be paid to patients with cirrhosis because those patients who achieve HBsAg loss have a higher subsequent risk of HCC than those without cirrhosis (risk of 0.54% vs. 0.13% annually) [
225]. Moreover, old age, sex, family history of HCC, alcohol consumption, diabetes, cirrhosis, albumin, and low platelet count may be independent risk factors for HCC after HBsAg loss [
225-
227]. Surveillance for HCC should be performed every 3–6 months using alpha-fetoprotein and ultrasound, computed tomography or magnetic resonance imaging if necessary, and for esophageal varices using endoscopy if varices are detected at pre-treatment endoscopy. Patients with preexisting cofactors for liver disease (including alcohol consumption, obesity, and/or type 2 diabetes, and significant liver disease) may require additional assessments.
HBsAg loss can also significantly reduce liver-related complications. The incidence of hepatic decompensation decreases over time in patients after HBsAg loss owing to the regression of cirrhosis. However, the regression takes time, and a significant reduction in the risk of hepatic decompensation is observed after several years of HBsAg loss [
225,
228].
HBsAg-negative, anti-HBc-positive patients receiving immunosuppressive agents and antitumor chemotherapy are at risk of HBV reactivation [
35]. ALT, HBV DNA, and HBsAg levels should be assessed before initiating such treatments and closely monitored during and after treatment.
14. Despite HBsAg loss, it is essential to monitor HBsAg recurrence, HCC surveillance, and hepatic events. Regular assessment of HBV-related markers, including ALT, HBV DNA, and HBsAg levels, is necessary, especially when there is concern for HBV reactivation.
FUTURE PERSPECTIVES
Treatment thresholds in CHB are changing across all the major liver disease organizations driven by the overarching aim to reduce morbidity and mortality associated with chronic infection. The urgency of this unmet clinical need is underlined by the projected doubling of HBV-related HCC deaths by 2040 [
229]. While broadening of treatment candidacy can mitigate the complications of CHB, and a growing body of cost-effective analyses support early treatment as a strategy to avert the development of HCC [
230,
231], functional cure remains the ultimate therapeutic goal.
This consensus update focuses on the latest developments in the functional cure program and illustrates the complex interplay between viral factors and immune dynamics to achieve HBsAg loss. We demonstrate that PegIFN still has an important role in achieving HBsAg loss in selected virally suppressed patients on NA therapy, while NA withdrawal can be an effective approach in those noncirrhotic patients with low levels of HBsAg. However, the greatest focus is on the multifaceted strategy of depleting viral antigen with siRNA or ASO and creating the ideal immunological milieu to re-invigorate the host immunity [
232]. We discussed the lead candidates from the latest clinical trials and the rationale for various combination regimens is deliberated. The progress made with novel HBV therapies over recent years has been made in tandem with our broader understanding of virological markers; HBcrAg, HBV RNA and HBcAb; and novel immunological parameters. These developments are critical for the progress of the field as these novel tools are likely to signpost the functional cue program. Finally, we acknowledge the changing clinical landscape ahead and in particular the management of multimorbid patients and specifically how MASLD may represent a new challenge in the management of CHB and potentially a barrier to functional cure. Future studies will need to examine the impact of MASLD, both in isolation and with other metabolic risk factors, on CHB management and functional cure.
FOOTNOTES
-
Authors’ contribution
Conceptualization, QN and MFY; writing—original draft preparation, DW, JHK, TP, XJW, PTFK, MO, SHA, YT, GQW, ZHY, WHL, AK, FSW, MFY, and QN; writing—review and editing, all authors; supervision, QN and MFY; funding acquisition, DW and QN; All authors have read and agreed to the published version of the manuscript.
-
Acknowledgements
The authors would like to thank Dr. Liang Chen, Xinyue Chen, Yongping Chen, Cunliang Deng, Xiaoguang Dou, Zhongping Duan, Hainv Gao, Ying Han, Jinlin Hou, Jidong Jia, Jiaji Jiang, Lanjuan Li, Jiabin Li, Jun Li, Taisheng Li, Zhiwei Li, Qing Mao, Qinghua Meng, Yuqiang Mi, Yuemin Nan, Jie Peng, Jia Shang, Jifang Sheng, Deming Tan, Hong Tang, Lai Wei, Xiaoping Wu, Qing Xie, Hong You, Yanyan Yu, Xinxin Zhang, Yuexin Zhang, Caiyan Zhao, Hong Zhao and Yingren Zhao for their contribution in the preparation of previous versions of the consensus.
The National Key Research and Development Program of China (2023YFC2308600); National Natural Science Foundation of China (No.82202502). Chinese National Thirteenth-Five Years Project in Science and Technology (2017ZX10202201).
-
Conflicts of Interest
DW: Nothing to disclose. JHK: Nothing to disclose. TP: Research grants: Roche Diagnostic, Janssen, VIR, GSK, Sysmex; Honoraria: Roche, Takeda, DKSH, Viatris, Eisai, Astra Zeneca, Sysmex and American Taiwan Biopharm. XJW: Nothing to disclose. PTFK: Research grants: VIR Biotechnology Inc and Gilead Sciences; Consulting fees: Abbott Diagnostics, Aligos, BlueJay, Gilead Sciences, GSK, and Assembly Biosciences; Honoraria: Gilead Sciences and GSK. MO: Nothing to disclose. SHA: Nothing to disclose. YT: Research grants: Gilead Sciences, FUJIREBIO Inc, Sysmex Corp, Janssen Pharmaceutical K.K. and GSK; Honoraria: Gilead Sciences, GSK, and HU frontier. GQW: Nothing to disclose. ZHY: Nothing to disclose.
WHL: Nothing to disclose. YSL: Research grants, consulting fees and honoraria: Gilead Sciences. JQN: Nothing to disclose. FML: Nothing to disclose. WHZ: Nothing to disclose. ZLG: Nothing to disclose. AK: Research grants: Roche, Roche Diagnostics, and Abbott Laboratories; Honoraria: Roche, Roche Diagnostics, Abbott Laboratories, and Esai. MFH: Nothing to disclose. WMY: Nothing to disclose. HR: Nothing to disclose. PH: Nothing to disclose. SNS: Nothing to disclose. PYK: Research grants: Altimmune, Arrowhead, Gilead, Novo Nordisk, Target Registries, Ultragenyx, Salix, Madrigal, Ausper Bio, Takeda; Consulting fees: Abbvie, Aligos, Ausper Bio, Durect, Generon, Genentch, Gilead, Drug Farm, HepQuant, Inventiva, Mallinckrodt, Mirum, NovoNordisk, Surrozen. FSW: Nothing to disclose. MFY: Research grants: AbbVie, Assembly Biosciences, Arrowhead Pharmaceuticals, Fujirebio Incorporation, Gilead Sciences, Immunocore, Sysmex Corporation and Roche; Consulting fees: AbbVie, Abbott Diagnotics, Aligos Therapeutics, AiCuris, Antios Therapeutics, Arbutus Biopharma, Arrowhead Pharmaceuticals, Assembly Biosciences, Clear B Therapeutics, Dicerna Pharmaceuticals, Finch Therapeutics, Fujirebio Incorporation, GlaxoSmith-Kline, Gilead Sciences, Immunocore, Janssen, Precision BioSciences, Roche, Sysmex Corporation, Tune Therapeutics, Vir Biotechnology and Visirna Therapeutics; Honoraria: Fujirebio Incorporation, Gilead Sciences, Roche, Sysmex Corporation. QN: Research grants: MSD, Roche, NOVARTIS, BMS, Gilead Sciences and GSK; Consulting fees: MSD, Roche, NOVARTIS, BMS, Gilead Sciences and GSK.
Figure 1.Navigation for combination of NA and Peg-IFN towards functional cure of hepatitis B.
Figure 2.Proposed navigations for novel combination towards functional cure of hepatitis B. NA, nucleos(t)ide analogue; Peg-IFN, pegylated interferon-a; siRNA, small interfering RNA; ASO, antisense oligonucleotide; CpAM, core protein allosteric modulator; PD-1, Programmed Death-1, PD-L1, Programmed Death-Ligand 1; NAP, nucleic acid polymer; TLR, Toll-like receptor; HBsAg, hepatitis B surface antigen; HBeAg; hepatitis B e antigen; HBsAb, hepatitis B surface antibody.
Table 1.Combination strategies with Peg-IFN and NA
Table 1.
|
Regimen |
Study design |
Participants |
HBsAg response |
|
De novo strategy |
|
HBeAg-positive CHB patients |
Peg-IFN-2a alone (n=271), |
Multicenter, double-blind, randomised controlled trial [50] |
814 patients with HBeAgpositive chronic hepatitis B, mostly from Asian (87%) |
HBsAg seroconversion after 24 weeks of follow-up: |
|
Peg-IFN-2a plus lamivudine (n=271), |
Peg-IFN-2a alone: 2.95% |
|
Peg-IFN-2a in combination with lamivudine: 2.95% |
|
lamivudine alone (n=272) for 48 weeks |
lamivudine monotherapy: 0.00% |
|
(P=0.004 for both comparisons with lamivudine) |
|
Peg-IFN-2b plus lamivudine (n=130), |
Multicenter, double-blind, randomised controlled trial [51] |
307 HBeAg-positive patients with chronic hepatitis B |
HBsAg loss at the end of treatment (week 52): |
|
combination therapy: 7% |
|
Peg-IFN-2b monotherapy (n=136), for 52 weeks |
monotherapy group: 5% |
|
(comparison was not significant) |
|
HBeAg-negative CHB patients |
Peg-IFN-2a alone (n=177), |
Multicenter, double-blind, randomised controlled trial [52] |
537 HBeAg-negative chronic hepatitis B |
HBsAg loss after 24 weeks of follow-up, |
|
Peg-IFN-2a plus lamivudine (n=179), |
combination therapy: 2.79% |
|
Peg-IFN-2a alone: 3.95% |
|
lamivudine alone (n=181) for 48 weeks |
lamivudine alone: 0.00% |
|
(both comparisons with lamivudine were significant) |
|
Both HBeAg-positive and negative CHB patients |
Tenofovir disoproxil fumarate (TDF) plus Peg-IFN for 48 weeks (group A) (n=186) |
Multinational, open-label, randomized, controlled trial [49] |
740 HBeAg-positive or -negative patients with chronic hepatitis B, with three-quarter Asian patients |
HBsAg loss at week 72, |
|
group A: 9.1% |
|
group B: 2.8% |
|
TDF plus Peg-IFN for 16 weeks followed by TDF for 32 weeks (group B) (n=184) |
group C: 0.0% |
|
group D: 2.8% |
|
group A vs. group B (P=0.002), or group C (P<0.001) or group D (P=0.003) |
|
TDF for 120 weeks (group C) (n=185) |
group B vs. group C (P=0.466) or group D (P=0.883) |
|
Peg-IFN for 48 weeks (group D) (n=185) |
In the genotype A, CHB patients had the highest HBsAg loss and trended toward to HBeAg-positive patients. |
|
A post hoc analysis study at week 120 follow-up [53] |
|
HBsAg loss at week 120: |
|
group A:10.4% |
|
group B: 3.5% |
|
group C (120-week tenofovir): 0.0% |
|
group D: 3.5% |
|
group A vs. group C (P<0.001) or group D (P=0.002) |
|
Peg-IFN plus TDF for 48 weeks (n=104) |
Real-world clinical cohort of Chinese patients with CHB [54] |
330 patients with CHB |
HBsAg loss at week 72: |
|
Peg-IFN plus TDF: 11.5% |
|
Peg-IFN alone for 48 weeks (n=106) |
Peg-IFN: 5.7% |
|
TDF: 0.0% |
|
TDF alone for 144 weeks (n=120) |
Peg-IFN plus TDF vs. Peg-IFN (P=0.143) |
|
Peg-IFN plus TDF or Peg-IFN alone vs. TDF (P=0.000 or P=0.010) |
|
A reduction of HBsAg level >1.5 log10IU/mL at week 24 from baseline can predict the 72-week HBsAg loss with an AUROC curve of 0.846 |
|
Add-on strategy |
|
Early “add-on” Peg-IFN to NA (Defined as starting NA before Peg-IFN less than 1 year) |
|
HBeAg-positive CHB patients |
started on entecavir monotherapy and then were randomized to: |
Open-label, multicenter, randomized controlled trial (ARES study) [55] |
175 HBeAg-positive CHB patients |
During randomized therapy from week 24 to 48, decline in HBsAg: |
|
add-on arm: –0.3 log IU/mL |
|
Peg-IFN add-on therapy from week 24 to 48 (n=85) entecavir monotherapy (n=90) |
Entecavir monotherapy: –0.01 log IU/mL (P<0.001) |
|
During long-term follow-up, [55] add-on therapy group had a reduction of HBsAg level more than 1 log significantly higher than entecavir group (59% vs. 28%, P=0.02) |
|
Late “add-on” Peg-IFN to NA (Defined as starting NA before Peg-IFN more than 1 year) |
|
HBeAg-positive CHB patients |
48 weeks of Peg-IFN add-on therapy (n=39) |
Open-label, multicenter, randomized, controlled trial (PEGON) [56] |
77 HBeAg-positive patients with compensated liver disease who were treated with entecavir/tenofovir for >12 months and had an HBV DNA load of <2,000 IU/mL |
A decline in the HBsAg level of >0.5 log IU/mL at week 72: |
|
NA monotherapy (n=38) |
Peg-IFN add-on group: 26% |
|
NA monotherapy: 8% (P=0.038) |
|
HBeAg-negative CHB patients |
48 weeks of Peg-IFN-2a plus NA (n=90) |
Open-label, multicenter, randomised, controlled trial from French [57] |
183 HBeAg-negative CHB and negative HBV DNA while on stable NA for at least 1 year |
HBsAg loss at week 96 |
|
Peg-IFN-2a plus NA: 7.8 |
|
NA only (n=93) |
NA only: 3.2% (P=0.15) |
|
The baseline HBsAg level correlated with HBsAg clearance. |
|
Both HBeAg-positive and negative CHB patients |
Peg-IFN-2a was added for 48 weeks in the add-on arm (n=32) |
Prospective cohort study from Japan [58] |
83 CHB Patients receiving maintenance TDF therapy with HBsAg level >800 IU/mL |
A rapid decrease in HBsAg at 96 weeks: |
|
add-on arm: 41% |
|
TDF monotherapy (n=51) |
TDF monotherapy: 2% (P<0.001) |
|
Switch-to strategy |
|
HBeAg-positive CHB patients |
Peg-IFN-2a (n=94) |
open-label, multicenter, randomized controlled trial (OSST study) [59] |
197 HBeAg-positive CHB patients who had received entecavir for 9–36 months, with HBeAg <100 PEIU/ml and HBV DNA ≤1,000 copies/mL |
HBsAg loss at week 48: |
|
entecavir (n=98) for 48 weeks |
Peg-IFN-2a: 8.5% |
|
Entecavir: 0.0% |
|
In entecavir-treated patients with HBeAg loss and had HBsAg <1,500 IU/mL at time of switching had a higher chance of HBsAg loss (22.2%). |
|
On-treatment predictors, HBsAg levels at 12 weeks after switching <200 IU/mL predicted great chance of HBsAg loss (77.8%), HBsAg level ≥1,500 IU/mL predict poor response (1.7%) after switch therapy. |
|
A 1-year follow-up of the OSST study reported sustained HBsAg loss was documented in 6 of 7 (85.7%) patients 1-year post-treatment. [60] |
|
HBeAg-negative CHB patients |
Peg-IFN-2a for 48 weeks (n=153) |
Open-label, multicenter, randomized, controlled trial (New Switch Study) |
303 HBeAg-positive patients who achieved HBeAg loss and HBV DNA <200 IU/mL with previous NA treatment |
HBsAg loss at the end of treatment: |
|
Peg-IFN-2a for 96 weeks (n=150) |
48-week Peg-IFN treatment duration: 14.4% |
|
96-week Peg-IFN treatment duration: 20.7% (P=0.1742) |
|
HBsAg loss at the end of 48-week follow-up: |
|
48-week Peg-IFN treatment duration: 9.8% |
|
96-week Peg-IFN treatment duration: 15.3% (P=0.1670) |
|
Baseline HBsAg <1,500 IU/mL and week 24 HBsAg <200 IU/mL were associated with the highest rates of HBsAg loss at the end of both 48- and 96-week treatment (51.4% and 58.7%, respectively). [61] |
|
HBeAg-negative CHB patients |
entecavir (group I) (n=27) |
Open-label, multicenter, randomised, controlled trial (Endeavor study) [62] |
92 Patients who achieved virological suppression and HBeAg loss with entecavir treatment |
HBsAg loss at week 48 |
|
IFN for 48 weeks (group II) (n=33) |
group I: 3.70% |
|
IFN+vaccine for 48 weeks+interleukin-2 for 12 weeks (group III) (n=32) |
group II: 3.03% |
|
group III: 9.38% |
|
the comparison was not statistically |
|
HBsAg decline at week 48: |
|
group I: 0.13 log 10 IU/mL |
|
group II: 0.74 log10 IU/mL |
|
group III:0.85 log 10 IU/mL |
|
P<0.05 for group1 vs. group 2 or group 3 |
Table 2.The potential curative strategy for hepatitis B virus infection in special populations
Table 2.
|
Special populations |
Relevant studies |
|
Inactive HBsAg carriers (IHCs), CHB patients with low-level viremia, and indeterminatephase or Grey Zone patients |
• |
Although “inactive carrier” disease phase is associated with a favorable prognosis, it has been replaced by other terms in several current guidelines, as the risk of spontaneous reactivation and the potential risk of disease progression and HCC development are not negligible. [111] |
|
• |
Current guidelines do not recommend antiviral therapy for IHCs. However, IHCs may achieve high rates of HBsAg loss, whether receiving Peg-IFN therapy alone or in combination with NA. [112-114] Thus, Peg-IFN-based treatment is a therapeutic option to achieve functional cure. |
|
• |
A five-year follow-up study showed that HBsAg loss over time in HBeAg-negative patients with HBV DNA <20,000 IU/mL was not influenced by combination treatment with NA and Peg-IFN. [115] |
|
• |
Persistent low-level viremia during NA monotherapy is associated with a higher risk of liver cirrhosis or HCC. [116-118] Therefore, treatment adjustments such as switching to or adding another preferred NA that can induce maintained virological response, or adding Peg-IFN can be considered. |
|
• |
In some HBeAg-negative patients with low-level viremia, transcriptionally active HBV integration may lead to ubiquitous HBsAg expression independent of HBV replication. [119] |
|
• |
HCC risk in persistently indeterminate CHB was substantially higher than inactive CHB. [120] Antiviral treatment could reduce the risk of HCC and liver-related mortality among CHB patients in the indeterminate phase. [121] |
|
CHB in children and adolescents |
• |
Blocking mother-to-child transmission has significantly reduced HBV infection prevalence in children. [122,123] However, less developed countries indicate a significant burden of HBV infection among children. |
|
• |
The chronicity of HBV infection is much higher in children than in adults following acute HBV infection. [124] Previous guidelines recommended antiviral therapy for children with active hepatitis B, whereas no therapeutic interventions have been recommended for pediatric immune-tolerant CHB. |
|
• |
The functional cure rate in HBeAg-positive CHB children significantly decreases with increasing age when they receive antiviral therapy. [125-127] |
|
• |
The recently released expert consensus recommends initiating antiviral treatment as early as possible for children with CHB, [128] aiming to slow disease progression and reduce the disease burden in China. |
|
Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) |
• |
HBV infection and MASLD are two major causes leading to liver cirrhosis and HCC. [129-131] In Asia, there is a growing trend towards coexistence of MASLD in individuals with CHB. [131] |
|
• |
Concurrent MASLD may enhance HBsAg seroclearance and suppress HBV replication, irrespective of antiviral therapy. [132-138] However, the potential long-term adverse effects of hepatic steatosis on the liver, such as the development of liver fibrosis or HCC [130,139] should not be overlooked. |
|
• |
The impact of hepatic steatosis on efficacy of antiviral therapy for CHB is controversial. Several studies have demonstrated that hepatic steatosis may diminish the effectiveness of antiviral treatment and is significantly associated with treatment failure, [140,141] but others suggest that hepatic steatosis does not affect treatment response. [142,143] |
|
• |
Existing clinical studies on the functional cure of CHB have often excluded patients with concurrent MASLD, resulting in a lack of scientific data tailored to the treatment of this specific population. Comprehensive evaluations are essential to delineate the effects of concurrent MASLD on the functional cure in CHB patients receiving combination therapy. |
|
• |
The management of these patients should aim not only for a functional cure for HBV but also the effective control of MASLD. A recent study indicates that chronic hepatitis B and C outweigh MASLD in the associated risk of cirrhosis and HCC. This underscores the need to prioritize treatment of chronic viral hepatitis before addressing MASLD. [139] |
|
CHB patients with liver cirrhosis |
• |
Among CHB patients with liver cirrhosis, the primary therapeutic objective centers on reducing subsequent complications such as HCC development or mortality, rather than achieving functional cure. [144] |
|
• |
For patients with decompensated cirrhosis, immediate initiation of indefinite NA is strongly advised, while the use of Peg-IFN is contraindicated due to safety concerns. |
|
• |
In patients with compensated cirrhosis, NA is indicated for those with detectable serum HBV DNA levels; however, the long-term benefits of adjunctive Peg-IFN therapy remain uncertain. |
|
• |
Additionally, for well-compensated cirrhotic patients undergoing combination therapy, the optimal timing for discontinuing NA remains indeterminate. While a recent retrospective study suggests that withdrawal of NA monotherapy in cirrhotic patients may potentially facilitate HBsAg loss and enhance overall survival, [145] caution is warranted due to residual confounding factors [146] and the risk of serious adverse events such as acute flares, [147] necessitating further studies to validate the benefits of ceasing NA therapy prior to HBsAg loss in cirrhotic patients undergoing combination therapy. |
|
CHB with HCC |
• |
Patients with HCC due to underlying CHB should continue or receive lifelong prophylactic therapy with preferred NA through and following systemic anticancer therapies or potentially curative HCC therapy including liver transplantation. [148] |
|
• |
Patients who developed HCC after HBsAg loss were found to have comparable biological functions of HBV integration to HBsAg-positive patients with HCCs, with continuing pro-oncogenic effects of HBV integration. Therefore, CHB patients should remain under surveillance for HCC even after achieving HBsAg loss. [149] |
|
• |
Immune checkpoint inhibitors including anti-PD-1 and anti-PD-L1 may accelerate HBsAg loss in patients with cancer or HCC and baseline HBsAg <100 IU/mL. [150] |
|
CHB patients with renal impairment |
• |
Renal abnormalities are prevalent among the CHB population, emphasizing the necessity for regular renal assessment in these patients. [151] |
|
• |
Patients with suspected HBV-related renal involvement, [152] including membranous nephropathy, membranoproliferative glomerulonephritis, polyarteritis nodosa, and mesangial proliferative glomerulonephritis, should promptly receive antiviral therapy. |
|
• |
Although the data regarding the optimal anti-HBV therapy for this subset of patients is limited, [153] add-on Peg-IFN to ETV seemed not to exacerbate renal function decline. Moreover, those with a baseline HBsAg level of less than 250 IU/mL may experience improved renal function following 48 weeks of therapy. [154] |
|
• |
Given the potential pathophysiological mechanisms involving viral antigens and immune complex deposition in HBV-related renal dysfunction, curative combination therapy should be considered in appropriate CHB patients with renal involvement to optimize therapeutic outcomes. |
|
Patients with HBV-hepatitis C virus (HCV) coinfection |
• |
The prevalence of HBV-HCV coinfection is expected to decline due to the favorable efficacy and safety profile of pan-genotypic DAAs against HCV. |
|
• |
Given the high rates of sustained virologic response (SVR), [155] immediate initiation of DAA therapy in those with detectable HCV RNA is justified. |
|
• |
Peg-IFN-based regimens are no longer recommended as the first-line therapy for those with HBV-HCV coinfection. However, following successful achievement of SVR for HCV, Peg-IFN-based curative therapy for HBV remains an aggressive approach aimed at functional cure. |
|
• |
Prophylactic NA during anti-HCV therapy is recommended because of the high risk of hepatitis B reactivation. [156] |
|
• |
Further investigation is necessary to ascertain whether the continuation rather than cessation of NA therapy, followed by add-on Peg-IFN, constitutes a safe and efficacious strategy for achieving HBsAg loss in patients with HBV-HCV coinfection who have completed anti-HCV therapy. |
|
Patients with HBV-hepatitis D virus (HDV) coinfection |
• |
Approximately 5% of individuals infected with HBV are coinfected with HDV, [157] however, only approximately 20% to 50% of them have been diagnosed. [158] Therefore, universal HDV screening is recommended for all patients who are positive for HBsAg. [159] |
|
• |
Chronic HBV-HDV coinfection leads to more rapidly progressive liver disease than chronic HBV monoinfection. |
|
• |
HBsAg loss sustained 24 weeks after the end of therapy with HBV DNA negativity is considered a functional cure for HBV-HDV coinfection. Therapeutic strategies leading to functional cure of HBV are ideal for HBV-HDV coinfection. [8,160] |
|
• |
Peg-IFN is the current treatment of choice in HBV-HDV co-infected patients with compensated liver disease. |
|
• |
Entry-inhibitor Bulevirtide (BLV) is approved in Europe for the treatment of chronic hepatitis D. |
|
• |
Bulevirtide as well as prenylation inhibitor lonafarnib plus ritonavir with or without Peg-IFN have shown higher virological response rates but seldom lead to functional cure. [158,160] |
Table 3.Predictive potential of novel markers for HBsAg loss
Table 3.
|
Novel markers |
Characteristics |
Predictive potential for HBsAg loss |
|
Virological markers |
|
|
|
HBcrAg |
HBcrAg consists of HBeAg, HBcAg in Dane particles, and a truncated 22 kDa precore protein (p22cr) and phosphorylated HBcAg (pHBcAg) in empty Dane-like particles. [181] The levels of HBcrAg reflect HBV DNA levels in serum and liver, and cccDNA in the liver, thus HBcrAg may serve as a surrogate marker for predicting viral relapse after stopping NAs therapy. [182-185] |
Combining HBsAg (<10, 10–100 or >100 IU/mL) and HBcrAg (<2 log vs. ≥2 log) levels improved prediction of HBsAg loss after NA cessation. [186] |
|
Recently developed highly sensitive HBcrAg could be suitable in predicting HBsAg loss after NA cessation. [187] |
|
EOT HBsAb levels >2 log10IU/L and HBcrAg levels <4 log10U/mL were associated with durable HBsAg loss induced by Peg-IFN based therapy at 24 weeks post-treatment. [74] |
|
HBV RNA |
Serum HBV RNA is encapsidated pgRNA and can be used as a potential biomarker reflecting the active transcription of intrahepatic cccDNA. [188] |
Serum HBV RNA may be a potential predictor of viral rebound and HBsAg loss post NA treatment withdrawal. [188,189] |
|
A post hoc analysis of a randomized clinical trial of Peg-IFN based therapy indicated that HBV RNA and HBcrAg were weak predictors of HBsAg loss. [165] |
|
HBcrAg and HBV RNA have a limited role in improving the prediction of HBsAg loss in CHB patients upon readily available markers. [190] |
|
Quantitative anti‐HBc |
The quantification of anti‐HBc levels plays an important role in the diagnosis and treatment monitoring of CHB. [191] Anti‐ HBc may be used as a marker for significant histological inflammation diagnosis, [192] natural history differentiation, [193,194] HBeAg seroconversion, [195-197] and clinical relapse after NA discontinuation therapy. [198] |
Low levels of anti-HBc may be associated with HBsAg loss. Anti-HBc levels <3 log IU/mL was associated with undetectable HBV DNA and HBsAg loss occurred within 10 years in HBeAg negative patients. [199] |
|
Lower level of anti-HBc IgG (<11 relative light unit) at baseline was associated with HBsAg loss during long-term NA therapy. [200] |
|
Patients with lower baseline anti-HBc (<0.1 IU/mL) had a significantly higher rate of HBsAg loss under Peg-IFN add-on treatment. [201] |
|
Immunological markers |
|
|
|
Immunological markers |
The HBV-induced host immune response is pivotal in determining the outcome of HBV infection, progression of the disease, and the response to antiviral therapy. [202-206] |
On-treatment development of anti-IFNα neutralizing antibodies during Peg-IFN treatment was associated with reduced quantitative HBsAg and qHBeAg declines. [207] |
|
Changes of NK-cell phenotype were associated with HBsAg seroconversion in patients treated with NA. [208] |
|
Several immunological markers associated with HBV control or viral relapse upon NA discontinuation have been proposed. [209,210] |
|
The presence of functional HBV-specific T cells has been suggested as a candidate immunological biomarker for the safe discontinuation of NA. [211] |
|
HBV-specific CD4+ T-cell responses induced by the targeted peptide possess specificities for HBsAg loss in CHB patients undergoing NA discontinuation. [212] Successful response to Peg-IFN correlates with an early significant restoration of impaired immune responses. [213] |
|
An inverse relationship was observed between the trends of sPD-1/sPD-L1 and HBsAg loss during IFN and NAs combination treatment. [214] |
|
Baseline HBsAb-specific B cells might be a predictive biomarker of HBsAg seroconversion in CHB patients treated with Peg-IFN. [215] |
|
Genetic markers |
|
|
|
Single nucleotide polymorphisms |
Host genetic variations can affect the outcome of CHB patients. |
HBeAg-negative CHB patients carrying rs9277535 non-GG genotype had a higher likelihood of spontaneous HBsAg loss compared to those carrying G alleles. [216] |
|
Patients with S267F variant on NTCP gene tended to have more sustained response with HBsAg loss at 24 weeks following Peg-IFN treatment. [217] |
|
In HBeAg-positive genotype B patients, rs7574865 in STAT4 was found to be associated with functional cure of CHB by Peg-IFN treatment. [218] |
|
IL28B polymorphisms may predict IFN-related HBsAg loss in genotype D HBeAg-negative patients. [219] |
|
Rs7519753 C allele was associated with an increased probability of HBsAg loss in CHB patients post Peg-IFN treatment. [220] |
|
Combination of the IFN lambda 4 rs368234815 and rs117648444 genotypes predicted HBsAg clearance in HBeAg-negative CHB patients post IFN treatment. [221] |
Abbreviations
antisense oligonucleotide
covalently-closed-circular DNA
core protein allosteric modulator
directly acting antivirals
hepatitis B core-related antigen
hepatitis B surface antibody
hepatitis B surface antigen
metabolic dysfunction-associated steatotic liver disease
Programmed Death-Ligand 1
Tenofovir disoproxil fumarate
REFERENCES
- 1. GBD 2019 Hepatitis B Collaborators. Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol 2022;7:796-829.
- 2. WHO. Hepatitis B. WHO web site, <https://www.who.int/news-room/fact-sheets/detail/hepatitis-b> Accessed 1 Jan 2025.
- 3. Ning Q, Wu D, Wang GQ, Ren H, Gao ZL, Hu P, et al. Roadmap to functional cure of chronic hepatitis B: An expert consensus. J Viral Hepat 2019;26:1146-1155.
- 4. Yip TC, Wong GL, Chan HL, Tse YK, Lam KL, Lui GC, et al. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues. J Hepatol 2019;70:361-370.
- 5. Kim MA, Kim SU, Sinn DH, Jang JW, Lim YS, Ahn SH, et al. Discontinuation of nucleos(t)ide analogues is not associated with a higher risk of HBsAg seroreversion after antiviral-induced HBsAg seroclearance: a nationwide multicentre study. Gut 2020;69:2214-2222.
- 6. Fung S, Choi HSJ, Gehring A, Janssen HLA. Getting to HBV cure: The promising paths forward. Hepatology 2022;76:233-250.
- 7. Cornberg M, Lok AS, Terrault NA, Zoulim F; 2019 EASL-AASLD HBV Treatment Endpoints Conference Faculty. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. Hepatology 2019 Nov 12. doi: 10.1002/hep.31030.
- 8. Ghany MG, Buti M, Lampertico P, Lee HM; 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference Faculty. Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference. J Hepatol 2023;79:1254-1269.
- 9. Tu T, Budzinska MA, Shackel NA, Urban S. HBV DNA integration: Molecular mechanisms and clinical implications. Viruses 2017;9:75.
- 10. Tang LSY, Covert E, Wilson E, Kottilil S. Chronic hepatitis B infection: A review. JAMA 2018;319:1802-1813.
- 11. Petersen J, Thompson AJ, Levrero M. Aiming for cure in HBV and HDV infection. J Hepatol 2016;65:835-848.
- 12. Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A 2004;101:6669-6674.
- 13. Lee BO, Tucker A, Frelin L, Sallberg M, Jones J, Peters C, et al. Interaction of the hepatitis B core antigen and the innate immune system. J Immunol 2009;182:6670-6681.
- 14. Ganem D, Prince AM. Hepatitis B virus infection--natural history and clinical consequences. N Engl J Med 2004;350:1118-1129.
- 15. Fang Z, Li J, Yu X, Zhang D, Ren G, Shi B, et al. Polarization of monocytic myeloid-derived suppressor cells by hepatitis B surface antigen is mediated via ERK/IL-6/STAT3 signaling feedback and restrains the activation of T cells in chronic hepatitis B virus infection. J Immunol 2015;195:4873-4883.
- 16. Deng F, Xu G, Cheng Z, Huang Y, Ma C, Luo C, et al. Hepatitis B surface antigen suppresses the activation of nuclear factor kappa B pathway via interaction with the TAK1-TAB2 complex. Front Immunol 2021;12:618196.
- 17. Jiang M, Broering R, Trippler M, Poggenpohl L, Fiedler M, Gerken G, et al. Toll-like receptor-mediated immune responses are attenuated in the presence of high levels of hepatitis B virus surface antigen. J Viral Hepat 2014;21:860-872.
- 18. Real CI, Lu M, Liu J, Huang X, Trippler M, Hossbach M, et al. Hepatitis B virus genome replication triggers toll-like receptor 3-dependent interferon responses in the absence of hepatitis B surface antigen. Sci Rep 2016;6:24865.
- 19. Xu Y, Hu Y, Shi B, Zhang X, Wang J, Zhang Z, et al. HBsAg inhibits TLR9-mediated activation and IFN-alpha production in plasmacytoid dendritic cells. Mol Immunol 2009;46:2640-2646.
- 20. Woltman AM, Op den Brouw ML, Biesta PJ, Shi CC, Janssen HL. Hepatitis B virus lacks immune activating capacity, but actively inhibits plasmacytoid dendritic cell function. PLoS One 2011;6:e15324.
- 21. Tjwa ET, Zoutendijk R, van Oord GW, Biesta PJ, Verheij J, Janssen HL, et al. Intrahepatic natural killer cell activation, but not function, is associated with HBsAg levels in patients with HBeAg-negative chronic hepatitis B. Liver Int 2014;34:396-404.
- 22. Liu Y, Zheng J, Liu Y, Wen L, Huang L, Xiang Z, et al. Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection. Cell Mol Immunol 2018;15:827-837.
- 23. Zheng M, Tian Z. Liver-mediated adaptive immune tolerance. Front Immunol 2019;10:2525.
- 24. Hoogeveen RC, Robidoux MP, Schwarz T, Heydmann L, Cheney JA, Kvistad D, et al. Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. Gut 2019;68:893-904.
- 25. Bénéchet AP, De Simone G, Di Lucia P, Cilenti F, Barbiera G, Le Bert N, et al. Dynamics and genomic landscape of CD8+ T cells undergoing hepatic priming. Nature 2019;574:200-205.
- 26. Le Bert N, Gill US, Hong M, Kunasegaran K, Tan DZM, Ahmad R, et al. Effects of hepatitis B surface antigen on virus-specific and global T cells in patients with chronic hepatitis B virus infection. Gastroenterology 2020;159:652-664.
- 27. Fang Z, Zhang Y, Zhu Z, Wang C, Hu Y, Peng X, et al. Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV. J Exp Med 2022;219:e20211838.
- 28. Tout I, Gomes M, Ainouze M, Marotel M, Pecoul T, Durantel D, et al. Hepatitis B virus blocks the CRE/CREB complex and prevents TLR9 transcription and function in human B cells. J Immunol 2018;201:2331-2344.
- 29. Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, Swadling L, et al. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Invest 2018;128:4588-4603.
- 30. Salimzadeh L, Le Bert N, Dutertre CA, Gill US, Newell EW, Frey C, et al. PD-1 blockade partially recovers dysfunctional virus-specific B cells in chronic hepatitis B infection. J Clin Invest 2018;128:4573-4587.
- 31. Qi R, Fu R, Lei X, He J, Jiang Y, Zhang L, et al. Therapeutic vaccine-induced plasma cell differentiation is defective in the presence of persistently high HBsAg levels. J Hepatol 2024;80:714-729.
- 32. Thimme R, Bertoletti A, Iannacone M. Beyond exhaustion: the unique characteristics of CD8+ T cell dysfunction in chronic HBV infection. Nat Rev Immunol 2024;24:775-776.
- 33. Costa JP, de Carvalho A, Paiva A, Borges O. Insights into immune exhaustion in chronic hepatitis B: A review of checkpoint receptor expression. Pharmaceuticals (Basel) 2024;17:964.
- 34. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1-98.
- 35. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-1599.
- 36. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-398.
- 37. Hou J, Wang G, Wang F, Cheng J, Ren H, Zhuang H, et al. Guideline of prevention and treatment for chronic hepatitis B (2015 update). J Clin Transl Hepatol 2017;5:297-318.
- 38. Sadler AJ, Williams BR. Interferon-inducible antiviral effectors. Nat Rev Immunol 2008;8:559-568.
- 39. Wieland SF, Eustaquio A, Whitten-Bauer C, Boyd B, Chisari FV. Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proc Natl Acad Sci U S A 2005;102:9913-9917.
- 40. Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, et al. IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest 2012;122:529-537.
- 41. Thimme R, Wieland S, Steiger C, Ghrayeb J, Reimann KA, Purcell RH, et al. CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection. J Virol 2003;77:68-76.
- 42. Dembek C, Protzer U, Roggendorf M. Overcoming immune tolerance in chronic hepatitis B by therapeutic vaccination. Curr Opin Virol 2018;30:58-67.
- 43. Thimme R, Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B? J Hepatol 2013;58:205-209.
- 44. Gill US, Kennedy PTF. The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics. J Viral Hepat 2019;26:4-15.
- 45. Tan AT, Hoang LT, Chin D, Rasmussen E, Lopatin U, Hart S, et al. Reduction of HBV replication prolongs the early immunological response to IFNα therapy. J Hepatol 2014;60:54-61.
- 46. Boni C, Laccabue D, Lampertico P, Giuberti T, Viganò M, Schivazappa S, et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012;143:963-973.e9.
- 47. Gill US, Kennedy PTF. Current therapeutic approaches for HBV infected patients. J Hepatol 2017;67:412-414.
- 48. Cho EJ, Lee JH, Yoon JH. Combination of pegylated interferon and nucleos(t)ide therapy: Toward a cure of hepatitis B virus infection? Gut Liver 2016;10:497-498.
- 49. Marcellin P, Ahn SH, Ma X, Caruntu FA, Tak WY, Elkashab M, et al. Combination of tenofovir disoproxil fumarate and peginterferon α-2a increases loss of hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology 2016;150:134-144 e10.
- 50. Lau GK, Piratvisuth T, Luo KX, Marcellin P, Thongsawat S, Cooksley G, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med 2005;352:2682-2695.
- 51. Janssen HL, van Zonneveld M, Senturk H, Zeuzem S, Akarca US, Cakaloglu Y, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005;365:123-129.
- 52. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004;351:1206-1217.
- 53. Ahn SH, Marcellin P, Ma X, Caruntu FA, Tak WY, Elkhashab M, et al. Hepatitis B surface antigen loss with tenofovir disoproxil fumarate plus peginterferon Alfa-2a: Week 120 analysis. Dig Dis Sci 2018;63:3487-3497.
- 54. Hu C, Song Y, Tang C, Li M, Liu J, Liu J, et al. Effect of pegylated interferon plus tenofovir combination on higher hepatitis B surface antigen loss in treatment-naive patients with hepatitis B e antigen -positive chronic hepatitis B: A real-world experience. Clin Ther 2021;43:572-581.e3.
- 55. van Campenhout MJH, Brouwer WP, Xie Q, Guo S, Chi H, Qi X, et al. Long-term follow-up of patients treated with entecavir and peginterferon add-on therapy for HBeAg-positive chronic hepatitis B infection: ARES long-term follow-up. J Viral Hepat 2019;26:109-117.
- 56. Chi H, Hansen BE, Guo S, Zhang NP, Qi X, Chen L, et al. Pegylated interferon Alfa-2b add-on treatment in hepatitis B virus envelope antigen-positive chronic hepatitis B patients treated with nucleos(t)ide analogue: A randomized, controlled trial (PEGON). J Infect Dis 2017;215:1085-1093.
- 57. Bourlière M, Rabiega P, Ganne-Carrie N, Serfaty L, Marcellin P, Barthe Y, et al. Effect on HBs antigen clearance of addition of pegylated interferon alfa-2a to nucleos(t)ide analogue therapy versus nucleos(t)ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained undetectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial. Lancet Gastroenterol Hepatol 2017;2:177-188.
- 58. Matsumoto A, Nishiguchi S, Enomoto H, Tanaka Y, Shinkai N, Okuse C, et al. Pilot study of tenofovir disoproxil fumarate and pegylated interferon-alpha 2a add-on therapy in Japanese patients with chronic hepatitis B. J Gastroenterol 2020;55:977-989.
- 59. Ning Q, Han M, Sun Y, Jiang J, Tan D, Hou J, et al. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol 2014;61:777-784.
- 60. Han M, Jiang J, Hou J, Tan D, Sun Y, Zhao M, et al. Sustained immune control in HBeAg-positive patients who switched from entecavir therapy to pegylated interferon-α2a: 1 year follow-up of the OSST study. Antivir Ther 2016;21:337-344.
- 61. Hu P, Shang J, Zhang W, Gong G, Li Y, Chen X, et al. HBsAg loss with Peg-interferon alfa-2a in hepatitis B patients with partial response to nucleos(t)ide analog: New switch study. J Clin Transl Hepatol 2018;6:25-34.
- 62. Wu D, Wang P, Han M, Chen Y, Chen X, Xia Q, et al. Sequential combination therapy with interferon, interleukin-2 and therapeutic vaccine in entecavir-suppressed chronic hepatitis B patients: the Endeavor study. Hepatol Int 2019;13:573-586.
- 63. Liu J, Wang T, Zhang W, Cheng Y, He Q, Wang FS. Effect of combination treatment based on interferon and nucleos(t)ide analogues on functional cure of chronic hepatitis B: a systematic review and meta-analysis. Hepatol Int 2020;14:958-972.
- 64. Qiu K, Liu B, Li SY, Li H, Chen ZW, Luo AR, et al. Systematic review with meta-analysis: combination treatment of regimens based on pegylated interferon for chronic hepatitis B focusing on hepatitis B surface antigen clearance. Aliment Pharmacol Ther 2018;47:1340-1348.
- 65. Li J, Qu L, Sun X, Liu Y, Gong Q, Yu D, et al. Peg-interferon alpha add-on Tenofovir disoproxil fumarate achieved more HBsAg loss in HBeAg-positive chronic hepatitis B naïve patients. J Viral Hepat 2021;28:1381-1391.
- 66. Tatsukawa Y, Tsuge M, Kawakami Y, Hiyama Y, Murakami E, Kurihara M, et al. Reduction of hepatitis B surface antigen in sequential versus add-on pegylated interferon to nucleoside/nucleotide analogue therapy in HBe-antigen-negative chronic hepatitis B patients: a pilot study. Antivir Ther 2018;23:639-646.
- 67. Lim SG, Yang WL, Ngu JH, Chang J, Tan J, Ahmed T, et al. Switching to or add-on peginterferon in patients on nucleos(t) ide analogues for chronic hepatitis B: The SWAP RCT. Clin Gastroenterol Hepatol 2022;20:e228-e250.
- 68. Hu Q, Qi X, Yu Y, Gao Y, Zhang X, Wang Q, et al. The efficacy and safety of adding on or switching to peginterferon α-2b in HBeAg-positive chronic hepatitis B patients with long-term entecavir treatment: a multicentre randomised controlled trial. Aliment Pharmacol Ther 2022;56:1394-1407.
- 69. Huang D, Yan W, Han M, Yuan W, Wang P, Chen Y, et al. Insufficient immunity led to virologic breakthrough in NAstreated chronic hepatitis B patients switching to Peg-IFN-ɑ. Antiviral Res 2022;197:105220.
- 70. Moini M, Fung S. HBsAg loss as a treatment endpoint for chronic HBV infection: HBV cure. Viruses 2022;14:657.
- 71. Lim SG, Baumert TF, Boni C, Gane E, Levrero M, Lok AS, et al. The scientific basis of combination therapy for chronic hepatitis B functional cure. Nat Rev Gastroenterol Hepatol 2023;20:238-253.
- 72. Stelma F, van der Ree MH, Jansen L, Peters MW, Janssen HLA, Zaaijer HL, et al. HBsAg loss after peginterferon-nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow-up. J Viral Hepat 2017;24:1107-1113.
- 73. Lin X, Song A, Lu J, Zheng S, Hu Z, Ma L, et al. Study on the retreatment, outcome, and potential predictors of recurrence in patients with recurrence of hepatitis B after functional cure. Front Immunol 2022;13:879835.
- 74. Huang D, Wu D, Wang P, Wang Y, Yuan W, Hu D, et al. End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after Peg-IFN-based therapy in patients with CHB. J Hepatol 2022;77:42-54.
- 75. Li M, Sun F, Bi X, Lin Y, Yang L, Lu Y, et al. Consolidation treatment needed for sustained HBsAg-negative response induced by interferon-alpha in HBeAg positive chronic hepatitis B patients. Virol Sin 2022;37:390-397.
- 76. Liu Y, Ren S, Ma L, Lin X, Lu J, Cao Z, et al. Peg-IFNα combined with hepatitis B vaccination contributes to HBsAg seroconversion and improved immune function. Virol J 2024;21:77.
- 77. Lee JH, Lee YB, Cho EJ, Yu SJ, Yoon JH, Kim YJ. Entecavir plus pegylated interferon and sequential hepatitis B virus vaccination increases hepatitis B surface antigen seroclearance: A randomized controlled proof-of-concept study. Clin Infect Dis 2021;73:e3308-e3316.
- 78. Hadziyannis SJ, Sevastianos V, Rapti I, Vassilopoulos D, Hadziyannis E. Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir. Gastroenterology 2012;143:629-636.e1.
- 79. Berg T, Simon KG, Mauss S, Schott E, Heyne R, Klass DM, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. J Hepatol 2017;67:918-924.
- 80. Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2018;68:425-434.
- 81. Buti M, Wong DK, Gane E, Flisiak R, Manns M, Kaita K, et al. Safety and efficacy of stopping tenofovir disoproxil fumarate in patients with chronic hepatitis B following at least 8 years of therapy: a prespecified follow-up analysis of two randomised trials. Lancet Gastroenterol Hepatol 2019;4:296-304.
- 82. Hirode G, Choi HSJ, Chen CH, Su TH, Seto WK, Van Hees S, et al. Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: An International, Multicenter, Multiethnic Cohort (RETRACT-B Study). Gastroenterology 2022;162:757-771.e4.
- 83. Berg T, Lampertico P. The times they are a-changing - A refined proposal for finite HBV nucleos(t)ide analogue therapy. J Hepatol 2021;75:474-480.
- 84. Wang CC, Kao JH. The role of hepatitis B surface antigen in nucleos(t)ide analogue cessation among Asian chronic hepatitis B patients: Friend or foe? Hepatology 2019;69:1843.
- 85. Hui RW, Mak LY, Seto WK, Yuen MF. RNA interference as a novel treatment strategy for chronic hepatitis B infection. Clin Mol Hepatol 2022;28:408-424.
- 86. Gane E, Lim YS, Kim JB, Jadhav V, Shen L, Bakardjiev AI, et al. Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials. J Hepatol 2023;79:924-932.
- 87. Gane EJ, Kim W, Lim TH, Tangkijvanich P, Yoon JH, Sievert W, et al. First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection. J Hepatol 2023;79:1139-1149.
- 88. Yuen MF, Asselah T, Jacobson IM, Brunetto MR, Janssen HLA, Takehara T, et al. Efficacy and safety of the siRNA JNJ-73763989 and the capsid assembly modulator JNJ-56136379 (bersacapavir) with nucleos(t)ide analogues for the treatment of chronic hepatitis B virus infection (REEF-1): a multicentre, double-blind, active-controlled, randomised, phase 2b trial. Lancet Gastroenterol Hepatol 2023;8:790-802.
- 89. Yuen MF, Heo J, Jang JW, Yoon JH, Kweon YO, Park SJ, et al. Safety, tolerability and antiviral activity of the antisense oligonucleotide bepirovirsen in patients with chronic hepatitis B: a phase 2 randomized controlled trial. Nat Med 2021;27:1725-1734.
- 90. Yuen MF, Lim SG, Plesniak R, Tsuji K, Janssen HLA, Pojoga C, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection. N Engl J Med 2022;387:1957-1968.
- 91. Janssen HLA, Hou J, Asselah T, Chan HLY, Zoulim F, Tanaka Y, et al. Randomised phase 2 study (JADE) of the HBV capsid assembly modulator JNJ-56136379 with or without a nucleos(t)ide analogue in patients with chronic hepatitis B infection. Gut 2023;72:1385-1398.
- 92. Sulkowski MS, Agarwal K, Ma X, Nguyen TT, Schiff ER, Hann HL, et al. Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection. J Hepatol 2022;77:1265-1275.
- 93. Hou JL, Ding YH, Liang XE, Xu J, Yuen MF, Gane EJ, et al. Prolonged (> 24 week) dosing with the oral cam-E Compound Alg-000184 results in multi-log reductions in hepatitis B surface antigen, HBV DNA, and HBV RNA levels in untreated E antigen positive subjects with chronic hepatitis B. Hepatology 2023;78(Suppl 1):S583-S585.
- 94. Wedemeyer H, Schöneweis K, Bogomolov PO, Chulanov V, Stepanova T, Viacheslav M, et al. 48 weeks of high dose (10 mg) bulevirtide as monotherapy or with peginterferon alfa2a in patients with chronic HBV/HDV co-infection. J Hepatol 2020;73:S52-S53.
- 95. Wedemeyer H, Aleman S, Brunetto MR, Blank A, Andreone P, Bogomolov P, et al. A Phase 3, randomized trial of bulevirtide in chronic hepatitis D. N Engl J Med 2023;389:22-32.
- 96. Bazinet M, Pântea V, Placinta G, Moscalu I, Cebotarescu V, Cojuhari L, et al. Safety and efficacy of 48 weeks REP 2139 or REP 2165, tenofovir disoproxil, and pegylated interferon alfa-2a in patients with chronic HBV infection naïve to nucleos(t)ide therapy. Gastroenterology 2020;158:2180-2194.
- 97. Agarwal K, Ahn SH, Elkhashab M, Lau AH, Gaggar A, Bulusu A, et al. Safety and efficacy of vesatolimod (GS-9620) in patients with chronic hepatitis B who are not currently on antiviral treatment. J Viral Hepat 2018;25:1331-1340.
- 98. Yuen MF, Balabanska R, Cottreel E, Chen E, Duan D, Jiang Q, et al. TLR7 agonist RO7020531 versus placebo in healthy volunteers and patients with chronic hepatitis B virus infection: a randomised, observer-blind, placebo-controlled, phase 1 trial. Lancet Infect Dis 2023;23:496-507.
- 99. Gane EJ, Dunbar PR, Brooks AE, Zhang F, Chen D, Wallin JJ, et al. Safety and efficacy of the oral TLR8 agonist selgantolimod in individuals with chronic hepatitis B under viral suppression. J Hepatol 2023;78:513-523.
- 100. Gane E, Verdon DJ, Brooks AE, Gaggar A, Nguyen AH, Subramanian GM, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: A pilot study. J Hepatol 2019;71:900-907.
- 101. Wang G, Cui Y, Hu G, Fu L, Lu J, Chen Y, et al. HBsAg loss in chronic hepatitis B patients after 24-week treatment with subcutaneously administered PD-L1 antibody ASC22 (Envafolimab): interim results from a phase IIb extension cohort. Hepatology 2023;78(Suppl 1):abs5052.
- 102. Ma H, Lim TH, Leerapun A, Weltman M, Jia J, Lim YS, et al. Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study. JHEP Rep 2021;3:100361.
- 103. Tak WY, Chuang WL, Chen CY, Tseng KC, Lim YS, Lo GH, et al. Phase Ib/IIa randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with CHB. J Hepatol 2024;81:949-959.
- 104. Agarwal A, Yuen RMF, Wedemeyer H, Cloutier D, Shen L, Arizpe A, et al. Dose-dependent durability of hepatitis B surface antigen reductions following administration of a single dose of VIR-3434, a novel neutralizing vaccinal monoclonal antibody. J Hepatol 2022;77(Suppl 1):S831-S832.
- 105. Wisskirchen K, Kah J, Malo A, Asen T, Volz T, Allweiss L, et al. T cell receptor grafting allows virological control of Hepatitis B virus infection. J Clin Invest 2019;129:2932-2945.
- 106. Krebs K, Böttinger N, Huang LR, Chmielewski M, Arzberger S, Gasteiger G, et al. T cells expressing a chimeric antigen receptor that binds hepatitis B virus envelope proteins control virus replication in mice. Gastroenterology 2013;145:456-465.
- 107. Yuen M, Agarwal K, Roberts S, Lo G, Hsu C, Chuang W, et al. Preliminary pharmacodynamics and safety of repeat dosing of imdusiran (AB-729) followed by VTP-300 or placebo in virally-suppressed, non-cirrhotic subjects with chronic hepatitis B (CHB). Paper presented at: The AASLD Liver Meeting; 2023 Nov 10-14; Boston, MA, USA. Abs 5036.
- 108. Yuen MF, Lim YS, Yoon KT, Lim TH, Heo J, Tangkijvanich P, et al. VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study. Lancet Gastroenterol Hepatol 2024;9:1121-1132.
- 109. Hou J, Zhang W, Xie Q, Hua R, Tang H, Morano Amado LE, et al. Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B. N Engl J Med 2024;391:2098-2109.
- 110. Buti M, Heo J, Tanaka Y, Andreone P, Atsukawa M, Cabezas J, et al. Pegylated interferon reduces relapses following bepirovirsen treatment in participants with chronic hepatitis B virus infection on nucleos(t) ide analogues: end of study results from the phase 2b B-together study. Hepatology 2023;78(Suppl 1):S49-S53.
- 111. Koffas A, Kumar M, Gill US, Jindal A, Kennedy PTF, Sarin SK. Chronic hepatitis B: the demise of the ‘inactive carrier’ phase. Hepatol Int 2021;15:290-300.
- 112. Cao Z, Liu Y, Ma L, Lu J, Jin Y, Ren S, et al. A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha. Hepatology 2017;66:1058-1066.
- 113. Ning H, Li K, Peng Z, Jin H, Zhao H, Shang J. The efficacy and safety of pegylated interferon α-2b-based immunotherapy for inactive hepatitis B surface antigen carriers. Eur J Gastroenterol Hepatol 2023;35:1216-1223.
- 114. Wu F, Lu R, Liu Y, Wang Y, Tian Y, Li Y, et al. Efficacy and safety of peginterferon alpha monotherapy in Chinese inactive chronic hepatitis B virus carriers. Liver Int 2021;41:2032-2045.
- 115. Erken R, Loukachov VV, de Niet A, Jansen L, Stelma F, Helder JT, et al. A prospective five-year follow-up after peginterferon plus nucleotide analogue treatment or no treatment in HBeAg negative chronic hepatitis B patients. J Clin Exp Hepatol 2022;12:735-744.
- 116. Kim JH, Sinn DH, Kang W, Gwak GY, Paik YH, Choi MS, et al. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment. Hepatology 2017;66:335-343.
- 117. Zhang Q, Peng H, Liu X, Wang H, Du J, Luo X, et al. Chronic hepatitis B infection with low level viremia correlates with the progression of the liver disease. J Clin Transl Hepatol 2021;9:850-859.
- 118. Sun Y, Wu X, Zhou J, Meng T, Wang B, Chen S, et al. Persistent low level of hepatitis B virus promotes fibrosis progression during therapy. Clin Gastroenterol Hepatol 2020;18:2582-2591 e6.
- 119. Meier MA, Calabrese D, Suslov A, Terracciano LM, Heim MH, Wieland S. Ubiquitous expression of HBsAg from integrated HBV DNA in patients with low viral load. J Hepatol 2021;75:840-847.
- 120. Huang DQ, Li X, Le MH, Le AK, Yeo YH, Trinh HN, et al. Natural history and hepatocellular carcinoma risk in untreated chronic hepatitis B patients with indeterminate phase. Clin Gastroenterol Hepatol 2022;20:1803-1812.e5.
- 121. Huang DQ, Tran A, Yeh ML, Yasuda S, Tsai PC, Huang CF, et al. Antiviral therapy substantially reduces HCC risk in patients with chronic hepatitis B infection in the indeterminate phase. Hepatology 2023;78:1558-1568.
- 122. Zou H, Chen Y, Duan Z, Zhang H, Pan C. Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers. J Viral Hepat 2012;19:e18-25.
- 123. Wen WH, Chang MH, Zhao LL, Ni YH, Hsu HY, Wu JF, et al. Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention. J Hepatol 2013;59:24-30.
- 124. Indolfi G, Easterbrook P, Dusheiko G, Siberry G, Chang MH, Thorne C, et al. Hepatitis B virus infection in children and adolescents. Lancet Gastroenterol Hepatol 2019;4:466-476.
- 125. Li J, Fan P, Xu Z, Dong Y, Wang F, Hong W, et al. Functional cure of chronic hepatitis B with antiviral treatment in children having high-level viremia and normal or mildly elevated serum aminotransferase. J Clin Transl Hepatol 2023;11:1011-1022.
- 126. Zhang M, Li J, Xu Z, Fan P, Dong Y, Wang F, et al. Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B. Hepatol Int 2024;18:435-448.
- 127. Zhu S, Dong Y, Wang L, Liu W, Zhao P. Early initiation of antiviral therapy contributes to a rapid and significant loss of serum HBsAg in infantile-onset hepatitis B. J Hepatol 2019;71:871-875.
- 128. Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association; Group of Infectious Diseases, Chinese Pediatric Society, Chinese Medical Association; National Clinical Research Center for Infectious Diseases (Beijing). Research progress on clinical antiviral treatment of chronic hepatitis B in children. Zhonghua Gan Zang Bing Za Zhi 2024;32:435-448.
- 129. Alberts CJ, Clifford GM, Georges D, Negro F, Lesi OA, Hutin YJ, et al. Worldwide prevalence of hepatitis B virus and hepatitis C virus among patients with cirrhosis at country, region, and global levels: a systematic review. Lancet Gastroenterol Hepatol 2022;7:724-735.
- 130. Liu Z, Lin C, Mao X, Guo C, Suo C, Zhu D, et al. Changing prevalence of chronic hepatitis B virus infection in China between 1973 and 2021: a systematic literature review and meta-analysis of 3740 studies and 231 million people. Gut 2023;72:2354-2363.
- 131. Li J, Zou B, Yeo YH, Feng Y, Xie X, Lee DH, et al. Prevalence, incidence, and outcome of non-alcoholic fatty liver disease in Asia, 1999-2019: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2019;4:389-398.
- 132. Mak LY, Hui RW, Fung J, Liu F, Wong DK, Cheung KS, et al. Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B. J Hepatol 2020;73:800-806.
- 133. Hui RWH, Seto WK, Cheung KS, Mak LY, Liu KSH, Fung J, et al. Inverse relationship between hepatic steatosis and hepatitis B viremia: Results of a large case-control study. J Viral Hepat 2018;25:97-104.
- 134. Wang MM, Wang GS, Shen F, Chen GY, Pan Q, Fan JG. Hepatic steatosis is highly prevalent in hepatitis B patients and negatively associated with virological factors. Dig Dis Sci 2014;59:2571-2579.
- 135. Huang SC, Su TH, Tseng TC, Chen CL, Hsu SJ, Liu CH, et al. Metabolic dysfunction-associated steatotic liver disease facilitates hepatitis B surface antigen seroclearance and seroconversion. Clin Gastroenterol Hepatol 2024;22:581-590.e6.
- 136. Mao X, Cheung KS, Peng C, Mak LY, Cheng HM, Fung J, et al. Steatosis, HBV-related HCC, cirrhosis, and HBsAg seroclearance: A systematic review and meta-analysis. Hepatology 2023;77:1735-1745.
- 137. Choi HSJ, Brouwer WP, Zanjir WMR, de Man RA, Feld JJ, Hansen BE, et al. Nonalcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B. Hepatology 2020;71:539-548.
- 138. Huang Y, Gan Q, Lai R, Wang W, Guo S, Sheng Z, et al. Application of fatty liver inhibition of progression algorithm and steatosis, activity, and fibrosis score to assess the impact of non-alcoholic fatty liver on untreated chronic hepatitis B patients. Front Cell Infect Microbiol 2022;11:733348.
- 139. Lee MH, Chen YT, Huang YH, Lu SN, Yang TH, Huang JF, et al. Chronic viral hepatitis B and C outweigh MASLD in the associated risk of cirrhosis and HCC. Clin Gastroenterol Hepatol 2024;22:1275-1285.e2.
- 140. Jin X, Chen YP, Yang YD, Li YM, Zheng L, Xu CQ. Association between hepatic steatosis and entecavir treatment failure in Chinese patients with chronic hepatitis B. PLoS One 2012;7:e34198.
- 141. Chen J, Wang ML, Long Q, Bai L, Tang H. High value of controlled attenuation parameter predicts a poor antiviral response in patients with chronic hepatits B. Hepatobiliary Pancreat Dis Int 2017;16:370-374.
- 142. Charatcharoenwitthaya P, Pongpaibul A, Kaosombatwattana U, Bhanthumkomol P, Bandidniyamanon W, Pausawasdi N, et al. The prevalence of steatohepatitis in chronic hepatitis B patients and its impact on disease severity and treatment response. Liver Int 2017;37:542-551.
- 143. Chen YC, Jeng WJ, Hsu CW, Lin CY. Impact of hepatic steatosis on treatment response in nuclesos(t)ide analogue-treated HBeAg-positive chronic hepatitis B: a retrospective study. BMC Gastroenterol 2020;20:146.
- 144. Su TH, Hu TH, Chen CY, Huang YH, Chuang WL, Lin CC, et al. Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients. Liver Int 2016;36:1755-1764.
- 145. Jeng WJ, Chien RN, Chen YC, Lin CL, Wu CY, Liu YC, et al. Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis. Hepatology 2024;79:690-703.
- 146. Dongelmans EJ, Sonneveld MJ, Janssen HLA. Letter to the Editor: Benefits of stopping therapy in patients with cirrhotic hepatitis B, true effect or residual confounding? Hepatology 2024;79:E95-E96.
- 147. Hirode G, Hansen BE, Chen CH, Su TH, Wong G, Seto WK, et al. Incidence of hepatic decompensation after nucleos(t)ide analog withdrawal: Results from a large, international, multiethnic cohort of patients with chronic hepatitis B (RETRACT-B Study). Am J Gastroenterol 2023;118:1601-1608.
- 148. Hwang JP, Feld JJ, Hammond SP, Wang SH, Alston-Johnson DE, Cryer DR, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol 2020;38:3698-3715.
- 149. Jang JW, Kim JS, Kim HS, Tak KY, Nam H, Sung PS, et al. Persistence of intrahepatic hepatitis B virus DNA integration in patients developing hepatocellular carcinoma after hepatitis B surface antigen seroclearance. Clin Mol Hepatol 2021;27:207-218.
- 150. Mon HC, Lee PC, Hung YP, Hung YW, Wu CJ, Lee CJ, et al. Functional cure of hepatitis B in patients with cancer undergoing immune checkpoint inhibitor therapy. J Hepatol 2025;82:51-61.
- 151. Amet S, Bronowicki JP, Thabut D, Zoulim F, Bourliere M, Mathurin P, et al. Prevalence of renal abnormalities in chronic HBV infection: the HARPE study. Liver Int 2015;35:148-155.
- 152. Lai KN, Li PK, Lui SF, Au TC, Tam JS, Tong KL, et al. Membranous nephropathy related to hepatitis B virus in adults. N Engl J Med 1991;324:1457-1463.
- 153. Fu B, Ji Y, Hu S, Ren T, Bhuva MS, Li G, et al. Efficacy and safety of anti-viral therapy for Hepatitis B virus-associated glomerulonephritis: A meta-analysis. PLoS One 2020;15:e0227532.
- 154. Peng MJ, Guo XQ, Zhang WL, Chen J, Kang W, Yang XF, et al. Effect of pegylated interferon-α2b add-on therapy on renal function in chronic hepatitis B patients: A real-world experience. Front Microbiol 2022;13:980250.
- 155. Liu CJ, Chuang WL, Sheen IS, Wang HY, Chen CY, Tseng KC, et al. Efficacy of ledipasvir and sofosbuvir treatment of HCV infection in patients coinfected with HBV. Gastroenterology 2018;154:989-997.
- 156. Cheng PN, Liu CJ, Chen CY, Tseng KC, Lo CC, Peng CY, et al. Entecavir prevents HBV reactivation during direct acting antivirals for HCV/HBV dual infection: A randomized trial. Clin Gastroenterol Hepatol 2022;20:2800-2808.
- 157. Urban S, Neumann-Haefelin C, Lampertico P. Hepatitis D virus in 2021: virology, immunology and new treatment approaches for a difficult-to-treat disease. Gut 2021;70:1782-1794.
- 158. Negro F, Lok AS. Hepatitis D: A review. JAMA 2023;330:2376-2387.
- 159. Pan C, Gish R, Jacobson IM, Hu KQ, Wedemeyer H, Martin P. Correction to: Diagnosis and management of hepatitis delta virus infection. Dig Dis Sci 2023;68:4062-4063.
- 160. Tan YC, Lee GH, Huang DQ, Lim SG. Future anti-HDV treatment strategies, including those aimed at HBV functional cure. Liver Int 2023;43:1157-1169.
- 161. Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology 1993;104:1116-1121.
- 162. Zhang M, Fu S, Ren D, Wu Y, Yao N, Ni T, et al. Maternal and fetal outcomes after interferon exposure during pregnancy: A systematic review with meta-analysis. Front Reprod Health 2021;3:702929.
- 163. Takkenberg RB, Jansen L, de Niet A, Zaaijer HL, Weegink CJ, Terpstra V, et al. Baseline hepatitis B surface antigen (HBsAg) as predictor of sustained HBsAg loss in chronic hepatitis B patients treated with pegylated interferon-α2a and adefovir. Antivir Ther 2013;18:895-904.
- 164. Farag MS, van Campenhout MJH, Sonneveld MJ, Fung S, van Erpecum KJ, Wong DK, et al. Addition of PEG-interferon to long-term nucleos(t)ide analogue therapy enhances HBsAg decline and clearance in HBeAg-negative chronic hepatitis B: Multicentre Randomized Trial (PAS Study). J Viral Hepat 2024;31:197-207.
- 165. Lim SG, Phyo WW, Ling JZJ, Cloherty G, Butler EK, Kuhns MC, et al. Comparative biomarkers for HBsAg loss with antiviral therapy shows dominant influence of quantitative HBsAg (qHBsAg). Aliment Pharmacol Ther 2021;53:172-182.
- 166. Li GJ, Yu YQ, Chen SL, Fan P, Shao LY, Chen JZ, et al. Sequential combination therapy with pegylated interferon leads to loss of hepatitis B surface antigen and hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B patients receiving long-term entecavir treatment. Antimicrob Agents Chemother 2015;59:4121-4128.
- 167. Lee IC, Yang SS, Lee CJ, Su CW, Wang YJ, Lan KH, et al. Incidence and predictors of HBsAg loss after peginterferon therapy in HBeAg-negative chronic hepatitis B: A multicenter, long-term follow-up study. J Infect Dis 2018;218:1075-1084.
- 168. Pfefferkorn M, Schott T, Böhm S, Deichsel D, Felkel C, Gerlich WH, et al. Composition of HBsAg is predictive of HBsAg loss during treatment in patients with HBeAg-positive chronic hepatitis B. J Hepatol 2021;74:283-292.
- 169. Wong D, Littlejohn M, Edwards R, Jackson K, Revill P, Gaggar A, et al. ALT flares during nucleotide analogue therapy are associated with HBsAg loss in genotype A HBeAg-positive chronic hepatitis B. Liver Int 2018;38:1760-1769.
- 170. Choi HSJ, Sonneveld MJ, Farag MS, Brouwer WP, Brakenhoff SM, Hirode G, et al. Effects of on-treatment ALT flares on serum HBsAg and HBV RNA in patients with chronic HBV infection. J Viral Hepat 2021;28:1729-1737.
- 171. Tang Q, Ye J, Zhang Y, Zhang P, Xia G, Zhu J, et al. Establishment of a multi-parameter prediction model for the functional cure of HBeAg-negative chronic hepatitis B patients treated with pegylated interferonα and decision process based on response-guided therapy strategy. BMC Infect Dis 2023;23:456.
- 172. Ren P, Li H, Huang Y, Jiang J, Guo S, Cao Z, et al. A simple-to-use tool for predicting response to peginterferon in HBV DNA suppressed chronic hepatitis B patients in China. Antiviral Res 2021;194:105163.
- 173. Brunetto MR, Moriconi F, Bonino F, Lau GK, Farci P, Yurdaydin C, et al. Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B. Hepatology 2009;49:1141-1150.
- 174. Li MH, Yi W, Zhang L, Lu Y, Lu HH, Shen G, et al. Predictors of sustained functional cure in hepatitis B envelope antigen-negative patients achieving hepatitis B surface antigen seroclearance with interferon-alpha-based therapy. J Viral Hepat 2019;26 Suppl 1:32-41.
- 175. Pan CQ, Li MH, Yi W, Zhang L, Lu Y, Hao HX, et al. Outcome of Chinese patients with hepatitis B at 96 weeks after functional cure with IFN versus combination regimens. Liver Int 2021;41:1498-1508.
- 176. Guo Y, Han J, Zhang Y, Jin C, Zhang Y, He J, et al. End-of-treatment anti-HBs levels and HBeAg status identify durability of HBsAg loss after PEG-IFN discontinuation. Front Cell Infect Microbiol 2023;13:1120300.
- 177. Caviglia GP, Troshina Y, Garro E, Gesualdo M, Aneli S, Birolo G, et al. Usefulness of a hepatitis B surface antigen-based model for the prediction of functional cure in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogues: A real-world study. J Clin Med 2021;10:3308.
- 178. Fan R, Zhao S, Niu J, Ma H, Xie Q, Yang S, et al. High accuracy model for HBsAg loss based on longitudinal trajectories of serum qHBsAg throughout long-term antiviral therapy. Gut 2024;73:1725-1736.
- 179. Marcellin P, Buti M, Krastev Z, de Man RA, Zeuzem S, Lou L, et al. Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate. J Hepatol 2014;61:1228-1237.
- 180. Sonneveld MJ, Chiu SM, Park JY, Brakenhoff SM, Kaewdech A, Seto WK, et al. HBV DNA and HBsAg levels at 24 weeks off-treatment predict clinical relapse and HBsAg loss in HBeAg-negative patients who discontinued antiviral therapy. Gastroenterology 2024;166:168-177.e8.
- 181. Hadziyannis E, Laras A. Viral biomarkers in chronic HBeAg negative HBV infection. Genes (Basel) 2018;9:469.
- 182. Rokuhara A, Tanaka E, Matsumoto A, Kimura T, Yamaura T, Orii K, et al. Clinical evaluation of a new enzyme immunoassay for hepatitis B virus core-related antigen; a marker distinct from viral DNA for monitoring lamivudine treatment. J Viral Hepat 2003;10:324-330.
- 183. Wong DK, Seto WK, Cheung KS, Chong CK, Huang FY, Fung J, et al. Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA. Liver Int 2017;37:995-1001.
- 184. Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res 2020;50:892-923.
- 185. Kaewdech A, Tangkijvanich P, Sripongpun P, Witeerungrot T, Jandee S, Tanaka Y, et al. Hepatitis B surface antigen, core-related antigen and HBV RNA: Predicting clinical relapse after NA therapy discontinuation. Liver Int 2020;40:2961-2971.
- 186. Sonneveld MJ, Chiu SM, Park JY, Brakenhoff SM, Kaewdech A, Seto WK, et al. Probability of HBsAg loss after nucleo(s) tide analogue withdrawal depends on HBV genotype and viral antigen levels. J Hepatol 2022;76:1042-1050.
- 187. Inoue T, Kusumoto S, Iio E, Ogawa S, Suzuki T, Yagi S, et al. Clinical efficacy of a novel, high-sensitivity HBcrAg assay in the management of chronic hepatitis B and HBV reactivation. J Hepatol 2021;75:302-310.
- 188. Wang J, Shen T, Huang X, Kumar GR, Chen X, Zeng Z, et al. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol 2016;65:700-710.
- 189. Xia M, Chi H, Wu Y, Hansen BE, Li Z, Liu S, et al. Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment. Aliment Pharmacol Ther 2021;54:709-714.
- 190. Ghany MG, King WC, Hinerman AS, Lok AS, Lisker-Melman M, Chung RT, et al. Use of HBV RNA and to predict change in serological status and disease activity in CHB. Hepatology 2023;78:1542-1557.
- 191. Li A, Yuan Q, Huang Z, Fan J, Guo R, Lou B, et al. Novel double-antigen sandwich immunoassay for human hepatitis B core antibody. Clin Vaccine Immunol 2010;17:464-469.
- 192. Zhang C, Liu Y, Li J, Liu H, Shao C, Liu D, et al. Doseresponse relationship between qAnti-HBc and liver inflammation in chronic hepatitis B with normal or mildly elevated alanine transaminase based on liver biopsy. J Med Virol 2022;94:3911-3923.
- 193. Chi Z, Zhao W, Li JW, Liu H, Shao C, Zhao H, et al. Combination of quantitative hepatitis B core antibody (qHBcAb) and aspartate aminotransferase (AST) can accurately diagnose immune tolerance of chronic hepatitis B virus infection based on liver biopsy. Clin Res Hepatol Gastroenterol 2021;45:101563.
- 194. Song LW, Liu PG, Liu CJ, Zhang TY, Cheng XD, Wu HL, et al. Quantitative hepatitis B core antibody levels in the natural history of hepatitis B virus infection. Clin Microbiol Infect 2015;21:197-203.
- 195. Fan R, Sun J, Yuan Q, Xie Q, Bai X, Ning Q, et al. Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues. Gut 2016;65:313-320.
- 196. Hou FQ, Song LW, Yuan Q, Fang LL, Ge SX, Zhang J, et al. Quantitative hepatitis B core antibody level is a new predictor for treatment response in HBeAg-positive chronic hepatitis B patients receiving peginterferon. Theranostics 2015;5:218-226.
- 197. Chen HS, Wu JF, Su TH, Chen HL, Hsu HY, Xia NS, et al. Baseline level of hepatitis B core antibody predicts spontaneous hepatitis B e antigen (HBeAg) seroconversion in HBeAg-positive children with a normal alanine aminotransferase level. Hepatology 2019;70:1903-1912.
- 198. Chi H, Li Z, Hansen BE, Yu T, Zhang X, Sun J, et al. Serum level of antibodies against hepatitis B Core protein is associated with clinical relapse after discontinuation of nucleos(t)ide analogue therapy. Clin Gastroenterol Hepatol 2019;17:182-191.e1.
- 199. Hu HH, Liu J, Chang CL, Jen CL, Lee MH, Lu SN, et al. Level of hepatitis B (HB) core antibody associates with seroclearance of HBV DNA and HB surface antigen in HB e antigen-seronegative patients. Clin Gastroenterol Hepatol 2019;17:172-181 e1.
- 200. Kim S, Yoo S, Lee JI, Kim S, Chang HY, Kim D, et al. AntiHBc IgG levels: A predictor of HBsAg seroclearance in chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroclearance. Dig Dis Sci 2022;67:321-328.
- 201. Wang WX, Jia R, Gao YY, Liu JY, Luan JQ, Qiao F, et al. Quantitative anti-HBc combined with quantitative HBsAg can predict HBsAg clearance in sequential combination therapy with PEG-IFN-α in NA-suppressed chronic hepatitis B patients. Front Immunol 2022;13:894410.
- 202. Rehermann B, Nascimbeni M. Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005;5:215-229.
- 203. Zhang Z, Zhang JY, Wang LF, Wang FS. Immunopathogenesis and prognostic immune markers of chronic hepatitis B virus infection. J Gastroenterol Hepatol 2012;27:223-230.
- 204. Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol 2016;64(1 Suppl):S71-S83.
- 205. Maini MK, Peppa D. NK cells: a double-edged sword in chronic hepatitis B virus infection. Front Immunol 2013;4:57.
- 206. Xiao L, Tang K, Fu T, Yuan X, Seery S, Zhang W, et al. Cytokine profiles and virological markers highlight distinctive immune statuses, and effectivenesses and limitations of NAs across different courses of chronic HBV infection. Cytokine 2024;173:156442.
- 207. Zahoor MA, Feld JB, Lin HS, Mosa AI, Salimzadeh L, Perrillo RP, et al. Neutralizing antibodies to interferon alfa arising during peginterferon therapy of chronic hepatitis B in children and adults: Results from the HBRN Trials. Hepatology 2025;81:254-268.
- 208. Boni C, Lampertico P, Talamona L, Giuberti T, Invernizzi F, Barili V, et al. Natural killer cell phenotype modulation and natural killer/T-cell interplay in nucleos(t)ide analogue-treated hepatitis e antigen-negative patients with chronic hepatitis B. Hepatology 2015;62:1697-1709.
- 209. Kranidioti H, Manolakopoulos S, Kontos G, Breen MS, Kourikou A, Deutsch M, et al. Immunological biomarkers as indicators for outcome after discontinuation of nucleos(t)ide analogue therapy in patients with HBeAg-negative chronic hepatitis B. J Viral Hepat 2019;26:697-709.
- 210. Zeng G, Koffas A, Mak LY, Gill US, Kennedy PTF. Utility of novel viral and immune markers in predicting HBV treatment endpoints: A systematic review of treatment discontinuation studies. JHEP Rep 2023;5:100720.
- 211. Rivino L, Le Bert N, Gill US, Kunasegaran K, Cheng Y, Tan DZ, et al. Hepatitis B virus-specific T cells associate with viral control upon nucleos(t)ide-analogue therapy discontinuation. J Clin Invest 2018;128:668-681.
- 212. Li Y, Wen C, Gu S, Wang W, Guo L, Li CK, et al. Differential response of HBV envelope-specific CD4 + T cells is related to HBsAg loss after stopping nucleos(t)ide analogue therapy. Hepatology 2023;78:592-606.
- 213. Yan W, Wu D, Wang X, Chen T, Lai Q, Zheng Q, et al. Upregulation of NKG2C+ natural killer cells, TLR-2 expression on monocytes and downregulation of regulatory T-cells influence PEG-IFN treatment efficacy in entecavir-suppressed patients with CHB. Antivir Ther 2015;20:591-602.
- 214. Chen X, Zhang B, Song X, Qian T, Zheng X, Zhang Y, et al. Serum sPD-1 and sPD-L1 as predictive biomarkers for HBsAg clearance in HBeAg-negative CHB patients undergoing IFN-based therapy. Aliment Pharmacol Ther 2024;60:593-603.
- 215. Yin S, Wan Y, Issa R, Zhu Y, Xu X, Liu J, et al. The presence of baseline HBsAb-Specific B cells can predict HBsAg or HBeAg seroconversion of chronic hepatitis B on treatment. Emerg Microbes Infect 2023;12:2259003.
- 216. Cheng HR, Liu CJ, Tseng TC, Su TH, Yang HI, Chen CJ, et al. Host genetic factors affecting spontaneous HBsAg seroclearance in chronic hepatitis B patients. PLoS One 2013;8:e53008.
- 217. Thanapirom K, Suksawatamnuay S, Sukeepaisarnjaroen W, Treeprasertsuk S, Tanwandee T, Charatcharoenwitthaya P, et al. Association of the S267F variant on NTCP gene and treatment response to pegylated interferon in patients with chronic hepatitis B: a multicentre study. Antivir Ther 2018;23:67-75.
- 218. Chen H, Sun J, Zhou B, Xie Q, Liang X, Fan R, et al. Variants in STAT4 associated with cure of chronic HBV infection in HBeAg-positive patients treated with pegylated interferonalpha. Clin Gastroenterol Hepatol 2020;18:196-204.e8.
- 219. Lampertico P, Viganò M, Cheroni C, Facchetti F, Invernizzi F, Valveri V, et al. IL28B polymorphisms predict interferonrelated hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology 2013;57:890-896.
- 220. Guan G, Zhang T, Ning J, Tao C, Gao N, Zeng Z, et al. Higher TP53BP2 expression is associated with HBsAg loss in peginterferon-α-treated patients with chronic hepatitis B. J Hepatol 2024;80:41-52.
- 221. Galmozzi E, Facchetti F, Grossi G, Loglio A, Viganò M, Lunghi G, et al. IFNL4 rs368234815 and rs117648444 variants predict off-treatment HBsAg seroclearance in IFN-treated HBeAg-negative chronic hepatitis B patients. Liver Int 2018;38:417-423.
- 222. Anderson RT, Choi HSJ, Lenz O, Peters MG, Janssen HLA, Mishra P, et al. Association between seroclearance of hepatitis B surface antigen and long-term clinical outcomes of patients with chronic hepatitis B virus infection: Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2021;19:463-472.
- 223. Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg Seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135:1192-1199.
- 224. Song A, Wang X, Lu J, Jin Y, Ma L, Hu Z, et al. Durability of hepatitis B surface antigen seroclearance and subsequent risk for hepatocellular carcinoma: A meta-analysis. J Viral Hepat 2021;28:601-612.
- 225. Yip TC, Wong VW, Lai MS, Lai JC, Hui VW, Liang LY, et al. Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss. J Hepatol 2023;78:524-533.
- 226. Yang H, Bae SH, Nam H, Lee HL, Lee SW, Yoo SH, et al. A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Hepatol 2022;77:632-641.
- 227. Hur MH, Yip TC, Kim SU, Lee HW, Lee HA, Lee HC, et al. A machine learning model to predict liver-related outcomes after the functional cure of chronic hepatitis B. J Hepatol 2025;82:235-244.
- 228. Lee HW, Yip TC, Tse YK, Wong GL, Kim BK, Kim SU, et al. Hepatic Decompensation in cirrhotic patients receiving antiviral therapy for chronic hepatitis B. Clin Gastroenterol Hepatol 2021;19:1950-1958.e7.
- 229. Foreman KJ, Marquez N, Dolgert A, Fukutaki K, Fullman N, McGaughey M, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016- 40 for 195 countries and territories. Lancet 2018;392:2052-2090.
- 230. Lee H, Kim BK, Jang S, Ahn SH. Cost-effectiveness analysis of antiviral therapy for untreated minimally active chronic hepatitis B to prevent liver disease progression. Clin Transl Gastroenterol 2021;12:e00299.
- 231. Zhang S, Wang C, Liu B, Lu QB, Shang J, Zhou Y, et al. Cost-effectiveness of expanded antiviral treatment for chronic hepatitis B virus infection in China: an economic evaluation. Lancet Reg Health West Pac 2023;35:100738.
- 232. Wu D, Chen Y, Huang D, Yuan Z, Wu W, Yuan W, et al. Combination therapy with TLR7 agonist TQ-A3334 and ANTI-PD-L1 TQ-B2450 enhance HBsAg decline in virally-suppressed patients with chronic hepatitis B: Oceancure05 study. Hepatology 2024;80(Suppl 1):abst321.
, Qin Ning1
