Comparison of clinical practice guidelines for chronic hepatitis B: natural history classification and treatment initiation

Abstract

International and regional clinical practice guidelines (CPGs) for chronic hepatitis B (CHB) have recently been updated to incorporate evolving clinical evidence. This review compares the latest major CPGs regarding natural history classification, treatment initiation, and selection of antiviral agents, specifically focusing on updates from the Korean Association for the Study of the Liver-East Asia Liver Alliance (KASL-EALA), the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL), and the World Health Organization (WHO). While all guidelines recognize the heterogeneous and dynamic nature of CHB, managing patients in the “grey zone” or indeterminate phase remains a major challenge. The KASL–EALA 2026 guideline introduces a novel framework based primarily on hepatitis B virus (HBV) DNA levels—independent of alanine aminotransferase criteria—eliminating the indeterminate category to better align with hepatocellular carcinoma risks and simplify treatment decision-making. In contrast, AASLD 2025, EASL 2025, and WHO 2024 retain conventional immunological phase-based classifications for natural history. For treatment indications, all four guidelines advocate broader access to antiviral therapy despite their divergent structural approaches. AASLD suggests shared decision-making, EASL emphasizes individualized risk assessment, and WHO 2024 abandons the phase-based framework for treatment decisions entirely. Understanding these key similarities and differences will help clinicians optimize patient care and inform future efforts toward global harmonization in CHB management.

INTRODUCTION

Chronic hepatitis B (CHB) remains a premier global public health challenge, affecting approximately 240 million individuals worldwide and serving as a leading driver of cirrhosis, hepatic decompensation, and hepatocellular carcinoma (HCC) [1,2]. In 2024, an estimated 1.1 million people died from hepatitis B virus (HBV)-related liver diseases, marking a 17% increase since 2015 [2]. Despite the widespread availability of potent antiviral therapies, global treatment coverage remains critically low; in 2024, fewer than 5% of infected individuals received treatment, largely due to suboptimal diagnosis rates and restrictive eligibility criteria [2,3].

Clinical practice guidelines (CPGs) are central to CHB management by standardizing diagnostic, monitoring, and therapeutic frameworks. CPGs traditionally stratify the natural history of CHB into distinct phases based on viral replication and host immune responses to recommend treatment thresholds [4]. By synthesizing virologic, biochemical, and histological parameters alongside patient-specific risk factors—such as age, sex, and comorbidities—guidelines help clinicians identify at-risk individuals and determine the optimal timing for intervention [5]. As clinical evidence and scientific understanding evolve, these frameworks undergo frequent revisions to refine patient care and improve their long-term outcomes.

Recently, several major international and regional CPGs have been updated, including those from the Korean Association for the Study of the Liver-East Asia Liver Alliance (KASL-EALA, 2026), the American Association for the Study of Liver Diseases (AASLD, 2025), the European Association for the Study of the Liver (EASL, 2025), and the World Health Organization (WHO, 2024) (Table 1) [3,6-8]. While these societies share the unified objective of preventing HCC and reducing liver-related mortality, they diverge substantially in their nomenclature, natural history phase definitions, and treatment indications [9]. These discrepancies stem from variations in regional epidemiology, resource accessibility, and the clinical interpretation of data—particularly regarding alanine aminotransferase (ALT) thresholds, viral load cutoffs, and the management of patients who fall outside conventional phase definitions (the “grey zone” or indeterminate phase) [9].

Table 1.

Comparative overview of major clinical practice guidelines for chronic hepatitis B

Guidelines	KASL-EALA	AASLD	EASL	WHO
Year	2026	2025	2025	2024
Journal	Clinical and Molecular Hepatology	Hepatology	Journal of Hepatology	WHO
Evidence grading system	GRADE	GRADE	OCEBM	GRADE
Target population	Korean, East Asian	American	European	Global
Natural history framework	Viral load-based	Immunological	Immunological	Immunological
ALT criterion	Not included	Included	Included	Included
Indeterminate phase	Absent	Present	Present	Present

AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; EALA, East Asia Liver Alliance; EASL, European Association for the Study of the Liver; GRADE, Grading of Recommendations Assessment, Development and Evaluation; KASL, Korean Association for the Study of the Liver; OCEBM, Oxford Centre for Evidence-Based Medicine; WHO, World Health Organization.

This review comprehensively compares the latest KASL-EALA, AASLD, EASL, and WHO guidelines. By systematically evaluating their differences and similarities in natural history classification, treatment thresholds, and first-line antiviral selection, we aim to provide clinical insights that optimize contemporary CHB management and inform future pathways toward global guideline harmonization.

NATURAL HISTORY CLASSIFICATION

KASL-EALA 2026 guideline

The most significant update in the KASL-EALA 2026 guideline is the introduction of a novel natural history framework based primarily on viral load (Fig. 1) [8]. This new schema directly addresses the limitations of conventional, immunologically-driven classifications—specifically, their reliance on ALT levels and the inevitable presence of an indeterminate “grey zone”. Approximately 30% of CHB patients fall into this grey zone, which typically includes individuals with moderate viral loads and normal ALT levels, or low viral loads and elevated ALT levels [10]. This diagnostic ambiguity arises because traditional phases require the simultaneous evaluation of both markers. However, in the natural history of CHB, fluctuations in viral load and ALT do not always synchronize; indeed, shifts in viral replication frequently precede changes in ALT. Furthermore, the guideline highlights that ALT levels demonstrate limited sensitivity and specificity in accurately reflecting underlying histological changes, immunological disease activity, and long-term risk for HCC and disease progression [11,12].

Figure 1.

Viral load-based natural history framework in the KASL-EALA guideline. The dashed line indicates the HBeAg-negative moderate viremic phase, observed in approximately 20% of patients. The shaded area represents the potential variability of HBV DNA levels within the moderate viremic phase. ALT, alanine aminotransferase; cccDNA, covalently closed circular DNA; EALA, East Asia Liver Alliance; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; KASL, Korean Association for the Study of the Liver.

Therefore, this viral load-based framework classifies patients into four distinct phases: high viremic; moderate viremic, HBeAg-positive; low viremic; and moderate viremic, HBeAg-negative (Table 2). The high and low viremic phases are defined by HBV DNA levels of >8 log₁₀ IU/mL and <2,000 IU/mL, respectively, whereas the moderate viremic phases comprise HBV DNA levels between ≥2,000 IU/mL and ≤8 log₁₀ IU/mL. This classification is supported by recent novel findings that the association between HBV viral load and HCC risk is not linear but parabolic, and HCC risk peaks in patients with moderate viremia [13-19]. Mechanistically, this heightened risk is driven by the integration of HBV DNA into the host genome and the clonal expansion of hepatocytes expressing lower levels of HBV antigens under immune pressure; this process reflects ongoing liver injury [20-23]. Furthermore, studies indicate that moderate viremia serves as an independent risk factor for significant histological liver injury—including hepatic inflammation and fibrosis—irrespective of ALT levels [24,25]. The >8 log₁₀ IU/mL threshold for high viremia was established based on a meta-analysis showing that HCC risk decreases markedly above this level. By relying primarily on the objective parameter of HBV DNA, this viral load-based model reduces ambiguity in phase classification and eliminates room for the indeterminate grey zone, simplifying clinical decision-making while aligning closely with patient prognosis and treatment indications.

Table 2.

Phase definitions in the natural history of chronic hepatitis B

KASL-EALA 2026
Phases	High viremic	Moderate viremic, HBeAg-positive	Low viremic	Moderate viremic, HBeAg-negative	HBsAg seroclearance
HBV DNA (IU/mL)	>8 log10	2,000–8 log10	<2,000	2,000–8 log10	Not detected
ALT	Not used as a criterion
HBeAg	Positive		Negative
Risk of HCC and disease progression	Low	High	Low	High	Very low
Treatment indication	Conditional*	Treat	Do not treat	Treat	Do not treat
AASLD 2025
Phases	Immune-tolerant CHB	Immune-active HBeAg-positive CHB	Inactive CHB	Immune-active HBeAg-negative CHB	HBsAg loss
HBV DNA (IU/mL)	>10,000,000	>20,000	<2,000	>2,000	Undetectable
ALT	Normal	>2× ULN	Normal	>2× ULN	-
HBeAg	Positive		Negative
Risk of HCC and disease progression	Low	High	Low	High	Very low
Treatment indication	Conditional†	Treat	Do not treat	Treat	Do not treat
EASL 2025
Phases	HBeAg-positive chronic infection	HBeAg-positive chronic hepatitis	HBeAg-negative chronic infection	HBeAg-negative chronic hepatitis	-
HBV DNA (IU/mL)	High, usually >107	Moderate to high, usually 104 –107	Usually <2,000	Usually >2,000	-
ALT	Normal	Elevated	Normal	Elevated	-
HBeAg	Positive		Negative
Risk of HCC and disease progression	Low	High	Low	High	-
Treatment indication	Conditional‡	Treat	Do not treat	Treat	-
WHO 2024
Phases	HBeAg-positive infection	HBeAg-positive disease	HBeAg-negative infection	HBeAg-negative disease	Occult hepatitis B
HBV DNA (IU/mL)	Typically, >107	Typically, >105 to 107	<103	Typically, 103 to 105	Low at detection limit
ALT	Around ULN	Raised	Around ULN	Raised	Around ULN
HBeAg	Positive		Negative
Risk of HCC and disease progression	Low	High	Low	High	Very low
Treatment indication	Conditional§	Treat	Do not treat§	Treat	-

AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; CHB, chronic hepatitis B virus; EALA, East Asia Liver Alliance; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; KASL, Korean Association for the Study of the Liver; ULN, upper limit of normal; WHO, World Health Organization.

^*Treat if ALT >ULN, age >30 years, or significant fibrosis (≥F2).

^†Treat selected patients with age ≥40 years and consider shared decision-making for age <40 years.

^‡Treat selected patients with risk factor for HCC, extrahepatic manifestation, immunosuppression, or risk for HBV transmission.

^§Treat selected patients with coinfection, family history of liver cancer or cirrhosis, comorbidities, immunosuppression, or extrahepatic manifestations.

AASLD 2025 guideline

The AASLD framework stratifies CHB into five distinct phases based on a combination of HBeAg status, HBV DNA levels, and ALT thresholds (Table 2) [7]. These include the immune-tolerant; HBeAg-positive immune-active; inactive; HBeAg-negative immune-active; and hepatitis B surface antigen (HBsAg)-negative immune clearance phases. Specifically, the immune-tolerant phase is defined by HBeAg positivity, HBV DNA >10⁷ IU/mL, and normal ALT—with the upper limit of normal (ULN) set at <35 U/L for males and <25 U/L for females. The HBeAg-positive immune-active phase requires HBeAg positivity, ALT >2× ULN, and HBV DNA >20,000 IU/mL. Conversely, the HBeAg-negative immune-active phase is characterized by HBeAg negativity, ALT >2× ULN, and HBV DNA >2,000 IU/mL. The inactive phase presents with HBeAg negativity, normal ALT, and HBV DNA <2,000 IU/mL. These phases reflect the complex interplay between viral replication and host immunity, and the framework notes that patients frequently transition between these states over time. Notably, the AASLD estimates that approximately 40% of adult CHB patients fail to meet any strict phase criteria and are instead classified into “indeterminate phases”, a clinical scenario significantly more prevalent among HBeAg-negative individuals.

EASL 2025 guideline

The EASL framework classifies CHB into four primary categories based on the presence of hepatitis, rather than “immune” labels: HBeAg-positive chronic infection, HBeAg-positive chronic hepatitis, HBeAg-negative chronic infection, and HBeAg-negative chronic hepatitis (Table 2) [6]. The HBeAg-positive chronic infection phase features a very high viral load (typically >10⁷ IU/mL), normal ALT, and high HBsAg levels. Conversely, HBeAg-positive chronic hepatitis involves elevated ALT coupled with moderate-to-high viral loads (typically 10⁴ to 10⁷ IU/mL) and intermediate-to-high HBsAg. For HBeAg-negative states, chronic infection is defined by a low viral load (<2,000 IU/mL), normal ALT, and low HBsAg, whereas chronic hepatitis presents with elevated ALT, a viral load >2,000 IU/mL, and intermediate HBsAg. Acknowledging CHB as a highly dynamic condition where patients transition between phases over time, the 2025 update expands its classification system to address the substantial proportion of individuals who historically fell into unclassified categories. Rather than relying on the traditional “grey zone” or “indeterminate phase” nomenclature, the guideline introduces clinically specific designations for research and management. These include “impending phase transition” for dynamic HBeAg-positive infections and “compensated advanced chronic liver disease” (cACLD) across both HBeAg-positive and HBeAg-negative phenotypes to better capture underlying disease progression.

WHO 2024 guideline

The WHO 2024 guideline defines the natural history of CHB by synthesizing virological, serological, clinical, and histological characteristics, combining HBeAg status, ALT levels, HBV DNA concentrations, and non-invasive biomarkers [3]. The framework outlines six distinct clinical phenotypes: HBeAg-positive infection, HBeAg-positive disease, HBeAg-negative infection, HBeAg-negative disease, occult HBV infection, and an indeterminate “grey zone” (Table 2). Specifically, HBeAg-positive infection features high levels of viral replication (typically >10⁷ IU/mL) alongside ALT levels around the ULN. HBeAg-positive disease is marked by raised ALT levels, persistent HBeAg positivity, and moderate-to-high viral loads generally ranging between 10⁵ and 10⁷ IU/mL. In HBeAg-negative states, chronic infection presents with ALT levels around the ULN and low viral replication (<2,000 IU/mL), whereas chronic disease exhibits elevated ALT and viral loads typically between 10³ and 10⁵ IU/mL. Furthermore, occult HBV infection is defined by the persistence of HBV DNA in the liver or serum despite undetectable circulating HBsAg. Patients who do not fit cleanly into any defined category are relegated to the grey zone. The WHO 2024 guideline emphasizes that CHB progresses non-linearly, meaning transitions between these phases are highly dynamic and not necessarily sequential. Ultimately, the guideline views these phases less as rigid barriers to care and more as indicators of clinical phenotypes to guide therapeutic expansion.

Comparison of natural history classifications across guidelines

Defining the natural history of CHB is foundational to effective risk stratification and therapeutic decision-making. Despite disparate terminologies and thresholds, all four societies converge on the understanding that CHB is a highly dynamic disease characterized by frequent transitions between clinical states. However, notable divergences exist in both the nomenclature and the diagnostic thresholds used to define these phases. Structurally, the WHO framework delineates phases using the terms “infection” versus “disease,” whereas EASL distinguishes between “infection” and “hepatitis.” In contrast, the AASLD remains rooted in immunological status, utilizing “immune-active” and “inactive” designations. Beyond variations in what constitutes a “normal” ALT upper limit, the actual ALT and viral load combinations required to define specific phases differ considerably. For instance, to define the HBeAg-positive immune-active hepatitis phase, AASLD mandates an ALT >2× ULN alongside an HBV DNA >20,000 IU/mL, whereas EASL broadly defines the corresponding state by elevated ALT (>ULN) and moderate-to-high viral replication (10⁴ to 10⁷ IU/mL). Accommodating patients who fall into an indeterminate “grey zone” remains another pervasive clinical challenge [26]; data suggest that approximately 30% to 40% of the global CHB population do not fit clearly into traditional phase definitions, significantly complicating management strategies [25-29].

Diverging from these multi-parametric approaches, the KASL-EALA framework prioritizes a virological paradigm that directly reflects HCC risk across distinct HBV DNA strata. Notably, by removing ALT criteria entirely from its phase definitions, this model minimizes room for the indeterminate grey zone and avoids ambiguity. This shift from an immunologically-driven to a strictly virological classification represents a major clinical milestone—minimizing diagnostic ambiguity, refining risk stratification, and facilitating more proactive treatment strategies.

TREATMENT INITIATION

Rationale for the shift in treatment indications

Long-term suppression of HBV replication using oral nucleos(t)ide analogue (NA) therapies normalizes ALT levels, alleviates hepatic inflammation, reverses fibrosis, and significantly reduces the risks of HCC and liver-related mortality [30-32]. Historically, however, concerns regarding antiviral resistance and suboptimal efficacy of first-generation NAs, such as lamivudine, restricted treatment eligibility. Furthermore, direct evidence supporting the impact of antiviral therapy on long-term HCC risk in CHB patients was limited. Consequently, CHB was managed primarily as an inflammatory liver disease, with therapeutic initiation strictly anchored to concurrent elevations in both ALT and HBV DNA levels.

Robust contemporary evidence has thoroughly reshaped this conservative framework. First, large-scale longitudinal studies and randomized controlled trials have demonstrated that long-term antiviral therapy with current first-line NAs, especially with tenofovir alafenamide (TAF), has a negligible risk of drug resistance, significantly reduces HCC incidence, halts progression to cirrhosis, and decreases liver-related mortality, even in patients with normal ALT levels. Notably, the first interim analysis of the ATTENTION randomized trial offers early supportive evidence for this expanded approach [33]. Although these interim findings warrant cautious interpretation pending the final, fully powered analysis, among non-cirrhotic adult CHB patients with moderate viremia and normal or mildly elevated ALT, early initiation of TAF was associated with a lower risk of serious clinical events—including HCC, hepatic decompensation, transplantation, and death (hazard ratio [HR] 0.21). Second, data reveal that HBV-driven oncogenic processes—such as viral DNA integration into the host genome, clonal expansion of hepatocytes, and the maintenance of a chronically suppressive intrahepatic immune microenvironment—persist unabated despite normal ALT levels [12,33]. ALT is an insensitive marker of active necroinflammation and underlying hepatocarcinogenic potential. Lastly, up to 60% of patients who ultimately develop HCC fall completely outside the treatment eligibility criteria mandated by older major guidelines.5,34 Collectively, these insights underpin the global transition across recent international frameworks away from inflammation-driven thresholds and toward more proactive, virus- and HCC risk-driven therapeutic paradigms.

Divergence in treatment eligibility

Although all four updated guidelines converge on expanding the scope of antiviral treatment, the specific strategies they adopt differ substantively (Table 3 and Fig. 2).

Table 3.

Treatment indications across four major chronic hepatitis B guidelines (2024–2026)

Item	KASL-EALA 2026	AASLD 2025	EASL 2025	WHO 2024
Classification framework	Viral load–based (high/moderate/low viremia)	5 phases (including indeterminate)	4 phases (grey zone acknowledged)	Phase concept abandoned
ALT ULN (M/F)	34/30 U/L (only for high viremic phase)	35/25 U/L	Not universally defined; ≥40 U/L conventional, 30/19 cited as evidence	30/19 U/L
HBeAg+, no cirrhosis	High viremia (>8 log10 IU/mL): treat if age >30, ALT >ULN, or significant fibrosis (LoE: moderate, strong recommendation)	IA: ALT ≥2× ULN+HBV DNA ≥20,000 IU/mL (LoE: high, strong recommendation); immune-tolerant: SDM if <40 yr or treat if ≥40 yr or ≥F2 (LoE: very low, conditional recommendation)	HBV DNA ≥2,000 IU/mL+ALT >ULN±significant fibrosis (HBeAg-agnostic; LoE 1, strong recommendation).	4 eligibility options (HBeAg-agnostic): (i) ≥F2 (APRI >0.5 or TE >7 kPa; LoE: moderate, strong recommendation); (ii) HBV DNA >2,000 IU/mL+ALT >ULN (LoE: high for DNA >20,000 and low for DNA 2,000–20,000 IU/mL, strong recommendation); (iii) coinfection, family hx HCC/cirrhosis, comorbidities (DM, MASLD), immunosuppression, or extrahepatic manifestations (LoE: moderate; strong recommendation); (iv) (conditional, if HBV DNA testing unavailable) persistently elevated ALT alone (LoE: very low, conditional recommendation)
	Moderate viremia (2,000–8 log10 IU/mL): treat (LoE: moderate, strong recommendation)		HBeAg+chronic infection <30 yr without risk factors: defer; low DNA+persistent ALT↑: consider other causes
HBeAg−, no cirrhosis	Low viremia (<2,000 IU/mL): monitor (LoE: moderate, strong recommendation)	IA: ALT ≥2× ULN+HBV DNA ≥2,000 IU/mL (LoE: high, strong recommendation); indeterminate: treat via SDM (LoE: very low, conditional recommendation)
Cirrhosis	Treat if HBV DNA detectable	Treat regardless of HBV DNA/ALT	Treat if HBV DNA detectable	Treat regardless
Estimated real-world eligibility*	54%	32.20%	37.30%	70.50%
Underlying framework	Evidence-based, ALT-independence	Evidence-graded SDM	Risk-based individualization	Public health simplification

AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; DM, diabetes mellitus; EALA, East Asia Liver Alliance; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; hx, history; IA, immune-active; KASL, Korean Association for the Study of the Liver; LoE, level of evidence; MASLD, metabolic dysfunction–associated steatotic liver disease; SDM, shared decision-making; ULN, upper limit of normal; WHO, World Health Organization.

^*Eligibility proportions for AASLD 2025, EASL 2025, and WHO 2024 are from the multicenter Chinese cohort of 15,763 treatment-naïve patients with CHB; the KASL-EALA 2026 proportion is from a Korean modelling simulation study.

Figure 2.

Proportion of treatment eligibility by guidelines. (A) KASL-EALA. *Age <30 years, ≥F2 fibrosis; ULN=34 U/L for male, 30 U/L for female. (B) AASLD. *Age ≥40 years, ≥F2 fibrosis; ^†Male sex, age >40 years, platelet counts < 180 K/mm³; ULN=35 U/L for male, 25 U/L for female. (C) EASL. *≥F2 fibrosis, risk factors for HCC, extrahepatic manifestation, risk of HBV transmission; ULN=40 U/L. (D) WHO. *≥F2 fibrosis, coinfection, family history of liver cancer or cirrhosis, comorbidities (e.g., diabetes or metabolic dysfunction–associated steatotic liver disease), extrahepatic manifestation; ULN=30 U/L for male, 19 U/L for female. AASLD, American Association for the Study of Liver Diseases; ALT, alanine aminotransferase; EALA, East Asia Liver Alliance; EASL, European Association for the Study of the Liver; HBeAg, hepatitis B e antigen; HCC, hepatocellular carcinoma; KASL, Korean Association for the Study of the Liver; LLOQ, lower limit of quantification; ULN, upper limit of normal; WHO, World Health Organization.

The KASL-EALA 2026 framework provides a viral load–based classification—categorized into high, moderate, and low viremia—to define the natural history of CHB [8]. Its signature recommendation mandates antiviral therapy for all patients with moderate viremia (HBV DNA levels 2,000 IU/mL to 8 log₁₀ IU/mL), a cohort structurally linked to a high risk of HCC. Notably, this intervention is recommended completely independent of ALT levels with the explicit goal of minimizing long-term oncogenic risk. This proactive approach is strongly supported by the KASL committee’s systematic review and meta-analysis, together with interim data from the ATTENTION trial [33]. For patients with high viremia (>8 log₁₀ IU/mL), treatment initiation remains conditional, requiring the presence of age >30 years, elevated ALT, or significant fibrosis. Among the four major frameworks, KASL-EALA stands out as the only guideline to recommend default treatment for moderate-viremia patients presenting with normal ALT.

The AASLD 2025 framework retains a phase-based classification system, defining its core phenotypes alongside the indeterminate category, with the ALT ULN set at 35 U/L for men and 25 U/L for women [7]. Standard therapeutic initiation for immune-active disease requires an ALT ≥2× ULN combined with an HBV DNA ≥20,000 IU/mL for HBeAg-positive patients, or ≥2,000 IU/mL for HBeAg-negative individuals. Beyond these traditional boundaries, two notable updates expand treatment eligibility, both operationalized through shared decision-making (SDM). First, for HBeAg-positive, immune-tolerant patients, antiviral therapy is now conditionally recommended for those older than 40 years or with evidence of significant inflammation (grade ≥2) or fibrosis (≥F2). Younger patients lacking significant fibrosis who desire earlier intervention can also opt for treatment via SDM. Second, for HBeAg-negative patients in the indeterminate phase, treatment may now be actively considered through SDM, directly reversing the 2018 position that mandated monitoring alone. By positioning structured clinician-patient consultation—rather than universal default treatment—as its primary mechanism for therapeutic expansion, the AASLD maintains a relatively conservative stance that reflects the low certainty of evidence available in these specific clinical settings. These differences extend to the strength and certainty of the underlying evidence. As KASL-EALA, AASLD, and WHO apply GRADE while EASL uses OCEBM, a strict numerical comparison is not feasible (Table 3); still, AASLD frames its expanded immune-tolerant and indeterminate indications around low-certainty evidence and SDM, whereas KASL-EALA grades its recommendation on its own systematic review and meta-analysis together with the interim ATTENTION data.

The EASL 2025 framework similarly retains a four-phase classification but introduces a highly progressive foundational principle: in principle, all HBsAg-positive individuals with detectable HBV DNA are candidates for antiviral therapy [6]. While EASL specifies an HBV DNA ≥2,000 IU/mL coupled with an ALT >ULN or significant fibrosis as its standard treatment threshold, it uniquely declines to mandate a universal ALT ULN. Instead, the guideline references ≥40 U/L as the conventional standard, noting sex-specific thresholds (30 U/L for men and 19 U/L for women) only as evidence-supported benchmarks rather than strict mandates. Furthermore, the guideline explicitly underscores that a normal ALT level alone does not preclude the need for antiviral therapy, enumerating an extensive array of additional indications based on host, viral, and environmental risk factors. Through this flexible architecture, EASL achieves therapeutic expansion via highly individualized risk assessment rather than relying on rigid, prescriptive criteria.

The WHO 2024 framework represents the most radical departure from traditional paradigms, effectively abandoning the conventional phase-based concept entirely. Instead, it applies four streamlined treatment eligibility options to all HBsAg-positive adults and adolescents:

1. Significant fibrosis, defined as an Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) score >0.5 or a transient elastography measurement >7 kPa (F2).

2. An HBV DNA >2,000 IU/mL combined with an elevated ALT (ULN defined strictly as 30 U/L for men and 19 U/L for women).

3. The presence of clinical or demographic risk factors, including human immunodeficiency virus (HIV) or hepatitis C virus coinfections, significant comorbidities, a family history of HCC or cirrhosis, immunosuppression, or extrahepatic manifestations.

4. Conditionally, in resource-limited regions where HBV DNA testing remains unavailable, persistently elevated ALT levels alone.

Interestingly, the WHO 2024 guideline explicitly acknowledges that removing the ALT criterion altogether would yield the largest absolute expansion in global treatment eligibility—resulting in an estimated 75% to 100% increase in coverage. However, the committee ultimately retained the ALT threshold due to remaining evidentiary uncertainty. This simplified, public health–oriented framework is designed explicitly to be deployable in decentralized, resource-limited settings.

A recent real-world simulation study mapping Korean and Chinese cohorts with CHB quantified the stark operational divergence among these updated frameworks (Table 3 and Fig. 2) [35,36]. Under the KASL-EALA 2026 criteria, 54.0% of the patient population was deemed eligible for antiviral therapy; this proportion dropped to 37.3% under EASL 2025 and 32.2% under AASLD 2025, but surged to 70.5% under the WHO 2024 recommendations. This eligibility variance was particularly pronounced among HBeAg-negative individuals [35]. Mechanistically, the primary drivers of the substantial coverage gap between the WHO and the AASLD/EASL frameworks were the WHO’s inclusion of metabolic comorbidities (accounting for 53.9% of discordant cases), its lower baseline ALT and HBV DNA thresholds (23.2%), and its more permissive non-invasive fibrosis cutoffs (22.9%).

KASL-EALA’s distinctive position

The clinical challenge of managing CHB independent of ALT has been addressed by EASL, the WHO, and KASL-EALA through three distinct approaches. EASL minimizes the rigidity of ALT by declining to mandate a universal cutoff, relying instead on comprehensive risk assessment and SDM [6]. The WHO retains ALT as one of four eligibility pathways but allows advanced fibrosis, metabolic comorbidities, or—where HBV DNA testing is unavailable—persistent ALT elevation alone to qualify independently [3].

By contrast, KASL-EALA establishes ALT independence as the default operational standard for the largest single subset of CHB patients: those presenting with moderate viremia. This distinctive posture is justified by data from large-scale longitudinal cohorts and interim results from the ATTENTION trial, alongside robust mechanistic evidence proving that HBV DNA integration and clonal hepatocyte expansion proceed silently in patients with normal ALT levels [5]. Consequently, KASL-EALA most clearly embodies the contemporary conceptual evolution away from treating active necroinflammatory liver injury and toward intervening directly on the underlying viral infection to maximize HCC prevention.

This paradigm shift, however, involves notable operational trade-offs. Initiating default treatment for all moderate-viremia cases substantially expands the patient population requiring indefinite NA therapy, bringing attendant challenges regarding long-term adherence, monitoring infrastructure, and financial reimbursement. KASL-EALA addresses adherence and monitoring through structured follow-up intervals. Furthermore, it integrates SDM frameworks for the niche clinical settings where watchful waiting remains reasonably—most notably in HBeAg-positive, moderate-viremia patients under 30 years of age who lack additional risk factors. Nonetheless, alignment with national insurance reimbursement policies remains the primary barrier to real-world implementation in South Korea and East Asia, highlighting a critical area requiring ongoing clinical advocacy.

Practical implications of treatment expansion

Beyond their structural and conceptual differences, all four guidelines converge on a substantial broadening of the treatment-eligible population—a shared direction that raises practical considerations extending well beyond the clinic. These trade-offs are not unique to any single framework. Larger treated populations increase the demand for long-term monitoring, adherence support, and laboratory capacity, and the cost implications differ substantially between high-income and resource-limited settings—an asymmetry that directly motivates the WHO’s public-health-oriented simplification. Although modelling suggests that earlier and broader treatment is cost-effective over the long term through HCC and mortality reduction [36], nearterm reimbursement and policy alignment remain rate-limiting for implementation, particularly where antiviral coverage is tied to legacy ALT- and DNA-based criteria.

SELECTION OF ANTIVIRAL AGENTS

KASL-EALA 2026 guideline

The KASL-EALA guideline does not recommend pegylated interferon (peg-IFN) as a preferred first-line regimen due to its low response rates, poor tolerability, and severely limited clinical availability (Table 4) [37]. Instead, high genetic barrier NAs—including TAF, tenofovir disoproxil fumarate (TDF), and entecavir (ETV)—alongside besifovir dipivoxil maleate (BSV), are recommended as preferred first-line therapies [38].

Table 4.

Treatment regimens across four major chronic hepatitis B guidelines (2024–2026)

	KASL-EALA 2026	AASLD 2025	EASL 2025	WHO 2024
1st line therapy
Nucleos(t)ide analogues	TAF, TDF, ETV, BSV	ETV, TDF, TAF	ETV, TDF, TAF	TDF, ETV
				Alternative; TDF+LMV or TDF+FTC
Peg-IFN-α
Initial treatment	Not recommended for adults	Approved, but rarely used.	Patients with favorable predictive factors	Mentioned in Table
De novo combination	Not mentioned	Not mentioned	Not generally recommended	Not mentioned
Add-on therapy	Not mentioned	Not mentioned	Selected HBeAg-negative patients undergoing NA therapy with low HBsAg levels	Not mentioned
Special population
Bone or renal disease	TAF, ETV, BSV	TAF, ETV	ETV, TAF	ETV, TAF
Pregnant or breast-feeding women	TAF, TDF	TDF>TAF	TDF, TAF	TDF
Previous exposure to NAs	TAF, TDF	TAF, TDF	TAF, TDF	TDF
Decompensated	ETV, TDF, TAF	ETV, TDF, TAF	ETV, TDF, TAF	Not mentioned
HIV	TAF, TDF	TAF, TDF	TDF, TAF	TDF with LMV or FTC
HCC	Not mentioned	Not mentioned	TDF>ETV	Not mentioned

AASLD, American Association for the Study of Liver Diseases; BSV, besifovir; EALA, East Asia Liver Alliance; EASL, European Association for the Study of the Liver; ETV, entecavir; FTC, emtricitabine; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; HIV, human immunodeficiency virus; KASL, Korean Association for the Study of the Liver; LMV, lamivudine; NA, nucleos(t)ide analogue; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization.

To evaluate long-term outcomes, the KASL-EALA guideline committee conducted a network meta-analysis involving 37 studies and 243,577 patients to compare the real-world clinical performance of TAF, TDF, and ETV. Compared to ETV, statistically significant reductions in HCC incidence were observed for TAF (HR 0.65; 95% confidence interval [CI] 0.49–0.86), and TDF (HR 0.80; 95% CI 0.70–0.91) [8].

However, rigorous quality assessment revealed that a low-to-moderate risk of confounding remained across these comparative studies. This was primarily due to their retrospective designs, which relied heavily on propensity score matching or inverse probability of treatment weighting to adjust for baseline imbalances. Because of these methodological limitations, the guideline committee voted against explicitly recommending tenofovir over ETV for HCC prevention. Despite this formal neutrality, a preference for tenofovir is indirectly communicated by listing TAF and TDF ahead of ETV in the preferred drug hierarchy, despite ETV possessing the longest track record of real-world use.

AASLD 2025 guideline

The AASLD guideline affirms that two distinct therapeutic modalities—NA and peg-IFN-alpha—are approved for the management of chronic HBV infection (Table 4) [7]. However, the panel notes that peg-IFN-alpha is rarely utilized in contemporary practice due to significant challenges regarding its clinical applicability, safety profile, and patient tolerability. Consequently, the framework recommends three highbarrier NAs as preferred first-line therapies: ETV, TDF, and TAF. Drug selection among these preferred choices is tailored to individualized patient profiles, dictated by local availability and cost, patient age, and specific clinical cofactors. Clinicians are advised to avoid TDF in patients with pre-existing renal or bone disease, and to avoid ETV during pregnancy. Furthermore, ETV should be avoided in patients with HIV coinfection unless their HIV RNA is fully suppressed on a concurrent antiretroviral regimen, as well as in individuals with a history of prior treatment that includes lamivudine exposure.

EASL 2025 guideline

The EASL 2025 guideline recommends two distinct therapeutic pathways for CHB: NAs and peg-IFN-alpha (Table 4) [6]. The panel emphasizes that the selection between these modalities as a first-line approach requires a comprehensive evaluation of each agent’s clinical profile alongside individual patient preferences. Notably, EASL provides an extensive, four-paragraph discussion on peg-IFN-alpha therapy, highlighting data that demonstrates a lower incidence of HCC in interferon-treated cohorts compared to untreated controls [39-41]. In particular, the text cites two retrospective Asian studies suggesting that peg-IFN-alpha may offer a superior reduction in HCC risk compared directly to NA therapy [42,43].

For patients initiating oral therapy, EASL strongly recommends ETV, TDF, or TAF as preferred first-line NAs. The guideline stresses that agent selection among these three must be tailored to specific patient cofactors—including advanced age, prior antiviral exposure, and concomitant settings such as childbearing potential or pregnancy—as well as metabolic comorbidities, particularly baseline renal insufficiency or decreased bone mineral density.

Regarding the ongoing clinical debate over the comparative oncogenic efficacy of oral agents, the guideline reviews multiple retrospective cohorts and meta-analyses examining HCC incidence between TDF and ETV but concludes that the current data remains insufficient to declare a definitive superiority. However, EASL introduces a nuanced, setting-specific recommendation: it positions TDF as the preferred NA for patients with HBV-related HCC who have undergone curative interventions, such as surgical resection, local ablation, or liver transplantation (level of evidence 2, weak recommendation, strong consensus). This targeted preference is supported by several retrospective studies consistently linking TDF to a significantly lower risk of post-treatment tumor recurrence and improved overall survival [44-46].

WHO 2024 guideline

The WHO 2024 guideline designates TDF and ETV as its primary first-line therapeutic recommendations (Table 4) [3]. Notably, the framework omits peg-IFN-alpha as a primary recommendation, acknowledging it only within a comparative table alongside NAs [3]. Although peg-IFN-alpha achieves higher functional cure rates than oral NAs, its subcutaneous route of administration, low efficacy, profound adverse event profile, and high cost present significant implementation barriers. Given the WHO’s overarching objective of global hepatitis elimination, the guideline prioritizes therapeutic accessibility within low- and middle-income countries (LMICs) [47], emphasizing cost-effectiveness and scalability over complex resource-intensive regimens. Driven by this public health mandate, the WHO 2024 guideline classifies TAF as an alternative rather than a firstline option, citing its relative financial premium and a lack of long-term safety data comparable to TDF or ETV. Interestingly, based on an incorporated network meta-analysis, the guideline also suggests the fixed-dose HIV combination tablets TDF plus lamivudine (3TC) and TDF plus emtricitabine as acceptable alternative regimens [3]. This pragmatic inclusion stems from the fact that mass-produced HIV dual therapies are frequently more accessible and affordable than single-agent TDF or ETV monotherapy in highly endemic regions. Among specific patient populations, TAF is recommended as an alternative for individuals with baseline bone or renal disease (where ETV is preferred over TAF) or those with prior NA exposure (where TDF is preferred over TAF); however, due to residual safety data gaps, TDF remains the sole recommended agent during pregnancy.

Comparative summary of frontline antiviral agent selection

Traditionally, the treatment of CHB has largely been recommended to consist of IFN-based injectable therapy and oral NAs. Peg-IFN-alpha offers the advantage of a finite, defined-duration treatment regimen and remains an important therapeutic option in selected patient populations—particularly younger individuals with preserved hepatic function and in treatment strategies aimed at achieving functional cure. Strategic positions regarding peg-IFN-alpha slightly vary among international frameworks. The EASL guideline recommends finite-duration peg-IFN-alpha as a primary option for patients exhibiting strong predictors of response—such as a low baseline viral load, high ALT levels, and infection with genotypes A or B—with the explicit goal of achieving HBsAg clearance. Conversely, while the AASLD conditionally suggests peg-IFN-alpha for noncirrhotic or compensated cirrhotic cohorts, it acknowledges that real-world utilization remains low due to poor tolerability and strict compliance barriers. The WHO framework largely sidelines the agent, restricting its mention to summary comparative tables.

Uniquely, the KASL-EALA guideline omits peg-IFN-alpha from its first-line recommendations entirely. This omission is directly tied to suboptimal treatment outcomes and high adverse event risks within the Korean and East Asian CHB demographic, where the vast majority of patients are infected with the treatment-resistant HBV genotype C [37]. Nevertheless, given contemporary interest in add-on or switching strategies for patients under sustained oral NA suppression, the clinical relevance of peg-IFN-alpha may re-emerge pending future new drug development [48-50].

With the exception of the WHO, all societies universally recommend high genetic barrier NAs—specifically TAF, TDF, and ETV—as preferred first-line therapies. Structurally, the KASL-EALA framework expands this list by adding BSV as a primary frontline agent. In contrast, the WHO designates TAF strictly as an alternative option, restricting its use to explicit sub-populations with pre-existing bone or renal diseases, or prior NA experience, while maintaining TDF as the exclusive first-line recommendation during pregnancy.

Potential differences in HCC risk reduction among these high-barrier NAs are explicitly discussed only by KASL-EALA and EASL. KASL-EALA’s underlying network metaanalysis identified a significantly lower incidence of HCC among patients treated with TDF or TAF compared to ETV.8 Nonetheless, the committee abstained from making a definitive preferential recommendation. This decision stems from the moderate certainty of the available data, which relies heavily on retrospective observational studies prone to unmeasured confounding. Similarly, EASL notes that due to conflicting clinical data and the absence of a clear biological mechanism, there is currently no justification to favor TDF over ETV for primary oncogenic prevention. However, for the prevention of tumor recurrence after curative HCC treatment (resection or ablation), the EASL framework identifies TDF as the preferred NA choice.

CONCLUSIONS

The recent cycle of updates from major international and regional liver societies marks a definitive global paradigm shift toward expanding antiviral treatment eligibility for patients with CHB. Despite differences in specific treatment algorithms, these guidelines share a common direction: a coordinated expansion of the candidate population eligible for antiviral therapy. Within this evolving landscape, the KASL-EALA 2026 guideline distinguishes itself through the removal of traditional ALT-based criteria and the introduction of an innovative natural history framework based primarily on HBV DNA strata. This approach eliminates the clinical uncertainty associated with the so-called indeterminate or grey-zone population and aligns disease classification more closely with the risks of HCC. Furthermore, this framework strengthens its clinical persuasiveness by anchoring therapeutic initiation directly to robust evidence of HCC risk. Compared with other contemporary guidelines, the KASL–EALA approach occupies a pragmatic middle ground. It is more proactive than the phase-based strategies retained by the EASL and AASLD guidelines, while remaining more structured than the simplified public health approach adopted by the WHO. The continued broadening of treatment eligibility represents an important milestone in the management of CHB. Wider implementation of these evolving strategies has the potential to reduce the global burden of HBV-related HCC and mortality and diminish long-term healthcare expenditure, while contributing to the accelerated achievement of the WHO goal of hepatitis B elimination as a public health threat.

Abbreviations

AASLD

American Association for the Study of Liver Diseases

ALT

alanine aminotransferase

APRI

Aspartate Aminotransferase-to-Platelet Ratio Index

BSV

besifovir dipivoxil maleate

cccDNA

covalently closed circular DNA

CHB

chronic hepatitis B

CI

confidence interval

CPGs

clinical practice guidelines

HBeAg

hepatitis B e antigen

HBsAg

hepatitis B surface antigen

EALA

East Asia Liver Alliance

EASL

European Association for the Study of the Liver

ETV

entecavir

FTC

emtricitabine

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HIV

human immunodeficiency virus

HR

hazard ratio

KASL

Korean Association for the Study of the Liver

MASLD

metabolic dysfunction-associated steatotic liver disease

LoE

level of evidence

LMICs

low- and middle-income countries

NA

nucleos(t)ide analogue

Peg-IFN

pegylated interferon

SDM

shared decision-making

TAF

tenofovir alafenamide

TDF

tenofovir disoproxil fumarate

ULN

upper limit of normal

WHO

World Health Organization