Minimising Risk in CHB Management: A Zero-Risk Approach

Hepatitis B infection is associated with significant morbidity and mortality and represents a major global health problem. In 2019, the World Health Organization (WHO) estimated that 296 million people were living with chronic hepatitis B (CHB) infection, resulting in an estimated 820,000 deaths per year, mostly from cirrhosis and hepatocellular carcinoma (HCC) [1]. Although hepatitis B virus (HBV) can be prevented with a safe and effective vaccine, there are still an estimated 1.5 million new infections each year. Only 8% of the eligible population, and less than 3% of the total HBV-infected population, were reported to be on treatment in 2022. This special supplement considers the latest evidence for changing CHB management and what we refer to as a zero-risk approach to ensure improved disease outcomes.

The WHO has set an ambitious target for HBV elimination by 2030, aiming to reduce the number of new cases of hepatitis B infection by 90% and its related mortality by 65% [2]. This will be achieved using a strategy focused on a series of interventions. A 2022 modelling study suggested that 258 million individuals are still living with CHB. However, one of the major gains towards the WHO elimination targets is that 85% of infants globally have been vaccinated against HBV, with current global HBV prevalence among children aged 5 years and younger of only 0.7% [3]. In this special supplement, Von Cuang et al. reported on the latest developments towards HBV global elimination. Although major progress has been made to control the burden of CHB globally, this progress has been made mainly in high-income countries when compared to low- and middle-income areas with higher HBV prevalence, such as Africa, confirming geographical disparities in the work towards hepatitis B elimination [4-8].

Several interventions to accelerate HBV elimination have been adopted in most countries and, ultimately, should help achieve the HBV global elimination targets. Prevention of Mother-to-Child Transmission (PMTCT) including timely hepatitis B birth dose vaccine (HepB-BD) and antiviral prophylaxis in pregnant women should be improved further to decrease infection rates. Case finding, diagnosis and treatment, as well as the management of children and adolescents, are crucial interventions to meet the proposed targets [9]. Moreover, strengthening data collection systems should be established to age-stratified serosurveys for the prevalence of HBV [10, 11]. Establishing funding and political support in resource-limited countries is also an important and challenging strategy for achieving global elimination [12, 13]. As reported by Von Cuang, these effective interventions could make global HBV elimination possible in those regions with significant disparities.

Hepatitis B virus is a non-cytopathic virus, and the cross-talk between the virus and the human immune response determines the outcome of HBV infection. In this supplement, Antonio Bertoletti summarised the latest insights into host immune–HBV interaction, which might also determine the different clinical phases of HBV infection and therapeutic consequences. Antiviral immunity in CHB is characterised by a lack of both robust innate and virus-specific adaptive immunity.

The triggering of innate activation is notably absent during the early stage of acute HBV infection, and the levels of pro-inflammatory cytokines in serum display a delayed kinetic [14, 15], which might be linked to the slow viral replication kinetics [16] and the lack of upregulation of Type I IFN genes in hepatocytes [17]. Therefore, HBV is sensitive to the inhibitory effect of Type I IFNs and other pro-inflammatory cytokines, which makes the use of IFN-α a feasible therapeutic strategy [18, 19]. Inhibition of innate immunity in HBV infection might also be induced by the action of HBV proteins (HBsAg and HBeAg), which are actively secreted during the HBV replication cycle. Persistent exposure to these soluble virus antigens can inhibit the function of antigen-presenting cells and consequently hinder the induction of HBV-specific T cells [20-23]. Whether NK cells, the essential component of innate immunity, are directly involved in acute HBV infection remains unclear. In CHB, NK cells predominantly work as ‘immune regulators’ that selectively lyse ‘hyperactivated’ HBV-specific CD8+ T cells expressing the TRAIL-2 death receptor present in patients with active hepatitis [24], rather than exerting direct antiviral effects on HBV-infected hepatocytes.

The adaptive immune response is crucial in HBV clearance, especially in acute HBV infection. However, HBV-specific T cells in patients with CHB display heterogeneity in the expression level of exhaustion markers and demonstrate defects in the proliferation and production of cytokines [25, 26], in addition to metabolic and functional impairments [27, 28]. However, the restoration of T-cell response has been observed in patients with spontaneous or treatment-related HBeAg or HBsAg clearance. HBs-specific B cells also display deficiencies in maturing towards antibody-producing B cells [29]. Hence, the restoration and coordinated activation of both humoral and cellular HBV-specific immunity could lead to HBV control, which might become a feasible approach for immunological therapies in patients with CHB. Furthermore, Antonio Bertoletti pointed out that the clinical management and novel therapies to stratify patients with CHB need to integrate not only clinical and virological parameters but also a comprehensive profile of HBV-related immunity.

Age-related changes in the immune system might have a profound impact on the immunological profile of patients with CHB in distinctive disease phases and can affect their responsiveness to different therapeutic approaches. According to the immunological characteristics of CHB, some patients with chronic infection have lifelong quiescent disease and do not require antiviral therapy. In contrast, a substantial proportion of patients develop active inflammation or an active hepatitis with complications such as progressive liver disease, cirrhosis, liver failure and HCC. Nevertheless, the natural disease course of CHB is dynamic, reflecting the balance between host immune responses and HBV replication [30, 31]. This clinical course is categorised into five disease phases, based on HBV replication (HBsAg and HBeAg status, HBV DNA), disease activity (ALT level) and stage of liver damage. Because the course of CHB is characterised by fluctuations in HBV replication and liver inflammation, long-term monitoring of patients with CHB is required. However, not all patients go through the classical disease phases, resulting in a significant proportion of patients falling into an ‘indeterminate phase’ or a ‘grey zone’. For example, patients with HBV-DNA > 2000 IU/mL yet normal ALT levels, or conversely, patients with HBV-DNA ≤ 2000 IU/mL but elevated ALT levels, which might be caused by co-existing liver disease, such as steatosis and alcohol use, are considered to be in an ‘indeterminate phase’ or a ‘grey zone’. Liver biopsy would aid diagnosis by establishing the degree of fibrosis and the main driver of liver disease, be that CHB or another aetiology, but patient refusal to undergo biopsy or other contraindications limit its utility. Recent studies showed as many as 30%–50% of patients with CHB are in an indeterminate phase [32-34] and might still be at risk of fibrosis progression, HCC and liver-related complications. In this edition, Lung-Yi Mak and colleagues holistically summarised current data on the clinical course of patients in the indeterminate phase, including the risk of HCC, by analysing the available evidence of HBV DNA integration into the host genome, chromosomal translocations and immune activation in this special group [35-38]. Another group from Korea, Young-Suk Lim, summarised their research and other existing evidence of the association between HCC risk with baseline serum HBV DNA levels and the potential mechanisms of hepatocarcinogenesis in chronic HBV infection.

In the absence of functional cure, the goals of CHB treatment are long-term suppression of HBV replication [39, 40], which can avert the development of cirrhosis and reversal of liver fibrosis, even in patients with established cirrhosis, thus reducing the risk of liver failure and HCC [39, 41]. Clinical response to antiviral therapy is assessed by ALT normalisation, undetectable HBV DNA, HBeAg seroconversion and even HBsAg loss, although this is a rare event with current antiviral agents. However, a sustained on-treatment virological response reducing liver inflammation and the risks of disease progression to cirrhosis and HCC is readily achievable.

Available antiviral therapies for HBV include pegylated interferon alfa (PEG-IFN−α) and high genetic barrier nucleos(t)ide analogues (NAs). Although PEG-IFN−α has moderate antiviral activity and can enhance the degradation of cccDNA and boost the host immune response against HBV, NAs are considered the current standard of care for patients with CHB worldwide. NAs act by inhibiting reverse transcription of pregenomic RNA to HBV DNA, but have no direct effect on cccDNA; thus, although effective in suppressing HBV replication, leading to significant histological improvement and decreasing risk of cirrhosis and HCC, HBsAg loss is rarely achieved. Currently, all guidelines recommend that antiviral treatment should be given to all patients with liver cirrhosis and detectable HBV DNA regardless of HBeAg status or ALT level, acute liver failure or the severity of CHB presentation. Among non-cirrhotic patients, treatment is recommended for those with HBeAg-positive or negative ‘immune-active’ phases of CHB. Patients with a family history of HCC could also be considered for treatment even if HBV DNA or ALT levels are within normal levels [39-41]. Conversely, patients in immune-tolerant and immune-control phases are not recommended for antiviral treatment, but disease monitoring is mandated. However, a substantial proportion of patients with CHB fall into the ‘indeterminate phase’ or ‘grey zone’ and remain untreated. Both groups, Lung-Yi Mak et al. and Professor Young-Suk Lim, analysed the limitations of current guidelines in defining CHB phases and the criteria for antiviral treatment by guideline recommendations. Both manuscripts emphasised the risk of HCC in patients with CHB in the indeterminate phase and the potential role of antiviral therapy in reducing HCC risk among those patients.

Lung-Yi Mak et al. summarised the potential benefits of antiviral therapy in reducing HCC risk among patients in the indeterminate phase by reducing the hepatocarcinogenic mechanisms, reflected in a reduction of fibrosis and HCC risk. Young-Suk Lim also listed research, which suggested that antiviral treatment could reduce both HBV DNA integration and hepatocyte clonal expansion, further highlighting the benefit of starting antiviral treatment as early as possible, even in patients with normal ALT. Furthermore, the cost-effectiveness data presented make a robust case for starting treatment in the immune-tolerant phase, especially with increasing HCC risk, decreasing drug costs and considering productivity loss. They provide important suggestions that treating all non-cirrhotic individuals with a viral load above 2000 IU/mL regardless of HBeAg status and ALT levels, as well as all patients with cirrhosis regardless of HBV viral load, instead of the current available guidance, could avert considerable cases of decompensated cirrhosis and HCC [42-44].

The economic argument, specifically the cost of lifelong or indeterminate NAs therapy, has often been cited as a reason against CHB treatment simplification and expansion. Simplifying treatment guidelines could save costs by reducing diagnostics and increasing equitable access to HBV treatment, especially in countries with limited access to laboratory tests. Although the expansion of treatment will ostensibly result in higher treatment costs, it will also result in reduced costs by preventing disease progression as cases of late-stage liver disease will be averted. In this supplement, Devin Razavi-Shearer summarised the current research on treatment simplification and expansion from an economic perspective to better guide decision-making in future. The published research from both high-income countries, such as the United Kingdom, Korea and the United States [42, 45-47], and those from low- and middle-income countries (LMICs), including China and Uzbekistan [48-50], together with several unpublished analyses from Brazil, Colombia, Ethiopia and Kazakhstan are consistent, despite the vast increase in the number of treated individuals, the potential economic savings from averting late-stage liver disease result in the most highly cost-effective approach to CHB management and even cost-saving. It should be noted that China, which constitutes almost one-third of the global HBV-infected population, already acts as a pioneer in developing its own guidelines, which have recently expanded treatment to everyone with a positive HBsAg and HBV-DNA PCR without viral load thresholds or liver function test requirements [51], following the evidence that found this approach to be cost-effective [48]. Other liver associations are likely to follow the same approach.

Progress in research, diagnostics and treatment of CHB has driven the need for updated clinical practice guidelines to ensure optimal patient care and public health impact [52]. The WHO recently revised its HBV guidelines, focusing on simple and accessible recommendations, especially in LMICs [53]. This latest guidance aims to accelerate the global momentum towards eliminating HBV by 2030, emphasising expanded screening, treatment and surveillance. The updated WHO guidelines introduce lower thresholds for non-invasive tests (NITs) to define significant fibrosis (≥ F2) and the initiation of antiviral therapy regardless of HBV DNA or ALT levels. Treatment is also indicated for patients with persistently abnormal ALT levels in the absence of HBV DNA testing. These changes broaden antiviral treatment coverage, aiming to improve access to antiviral therapy and patient outcomes, and contribute to the global HBV elimination.

China has already updated its CHB guidelines in 2022, recommending more extensive screening, active prevention and broader treatment coverage [51]. The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) are also in the process of updating their CHB clinical practice guidelines, which are expected to be published later in 2024 or 2025. Grace Wong, in this special supplement, compared the updated guidelines for the prevention and management of CHB between WHO 2024 and China 2022 HBV guidelines.

Both WHO 2024 and China 2022 HBV treatment guidelines align in several key areas. They emphasise the importance of HBV screening, particularly for pregnant women, high-risk populations and individuals receiving immunosuppressive treatment or on direct-acting antivirals for chronic hepatitis C virus infection. Universal HBV vaccination is strongly recommended, including timely administration of the birth dose within 24 hours, followed by additional doses. Both guidelines highlight the importance of ensuring high vaccination coverage and timely administration of the HBV vaccine. In addition, both guidelines gave comparable recommendations for initiating antiviral treatment on the basis of ALT and HBV DNA levels, favouring newer generation of NAs like Tenofovir and Entecavir as first-line treatment. Antiviral prophylaxis during pregnancy and administering hepatitis B immunoglobulin (HBIG) and HBV vaccine to newborns for PMTCT was emphasised. Similarly, both guidelines also stressed the need for a long-term follow-up with the regular assessment of liver enzymes, HBV DNA levels and monitoring of disease progression.

Despite these alignments, there are some notable distinctions between both guidelines, particularly in treatment eligibility criteria and antiviral treatment options. The WHO guidelines adopt a simpler, more straightforward approach to determine treatment eligibility, primarily based on ALT and the presence of significant fibrosis, with or without HBV DNA, to reflect the difficulties in accessing HBV DNA in some LMICs. In contrast, the Chinese guidelines provide more detailed and specific criteria, taking into account a detectable HBV DNA result as the key determinant for starting antiviral treatment. This difference leads to varying proportions of patients requiring antiviral treatment and those falling into a ‘grey zone’ or ‘indeterminate phase’, fulfilling only one but not all treatment indications. As for antiviral treatment, the WHO guidelines place a stronger emphasis on the use of NAs, such as Tenofovir and Entecavir, whereas China's guidelines recommend a broader range of antiviral agents, including PEG-IFNα and NAs, including tenofovir alafenamide (TAF), a prodrug of tenofovir, as a recommended treatment option. The WHO guidelines also allow flexibility in terms of monitoring and follow-up on the basis of local resources, whereas the Chinese guidelines offer more specific recommendations, including schedules for laboratory testing and liver imaging. Additionally, China's guidelines incorporate the aMAP score (age-Male-ALBI-Platelets score) for risk-stratified HCC surveillance, advocating for a shorter surveillance interval for high-risk groups, suitable for managing their large disease burden.

The overall alignment between the WHO and China HBV guidelines contributes to a more harmonised global approach to HBV management, which is a welcome development. However, distinctions among the guidelines highlight the need for tailored approaches that consider local epidemiology, healthcare infrastructure, and available resources.

In conclusion, all contributing authors in this special supplement have provided a strong rationale for the earlier initiation of antiviral treatment in patients with CHB, especially patients formerly considered to be in the ‘grey zone’ or ‘indeterminate disease phase’ to reduce the risk of fibrosis progression and HCC development. By detailing the latest molecular, clinical and economic data, this special supplement provides essential evidence for clinicians to consider the early initiation of antiviral treatment according to HBV DNA level, serum ALT level or the presence of fibrosis, thus reducing the complications of CHB and in particular the risk of HCC. The expansion and simplification of the CHB treatment guidelines can shift the dial to a ‘zero-risk’ approach in managing patients with CHB.¹

Professor Kennedy has acted as a consultant/advisor or received speaker fees from Aligos, Assembly Biosciences, Gilead Sciences, GlaxoSmithKline and Bluejay. He has received educational grants from Aligos, Gilead Sciences and Vir Biotechnology. He is the current Chair of the British Viral Hepatitis Group.