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.
Definition of functional cure for chronic hepatitis B and endpoints of treatment
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.
Consensus statement:
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].
Current settings of anti-HBV treatment and potential pathways to achieving HBV cure
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].
Consensus statement:
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.
Consensus statement:
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 log10 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].
Consensus statement:
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.
Consensus statement:
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 log10 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 log10 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 log10 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 log10IU/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 potential curative strategy for hepatitis B virus infection in special populations
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.
Contraindications to Peg-IFN-based therapy
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.
Consensus statement:
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 log10 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 log10IU/L and hepatitis B core-related antigen (HBcrAg) levels <4 log10U/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 log10 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.
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.
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