Chronic hepatitis B: Is it time for expanded antiviral treatment?

Table 1 Comparison of chronic hepatitis B-related terminology and characteristics with natural history

	APASL[11]	EASL[10]	AASLD[8,9]	INASL[12]	KASL[13]	WHO[14]
Year	2016	2017	2016/2018	2018	2022	2024
Type	CPG	CPG	CPG/Guidance	CPG	CPG	CPG
Methodology	GRADE	Expert panel	GRADE/Expert	Expert	GRADE	GRADE
Formulation of questions	Process not explained	Process not explained	Questions specified a priori	Questions specified a priori	Questions specified a priori	Structured to PICO format
Target	Asia Pacific	Europe	America	India	Korea	Low to middle-income countries
Phase 1	Immune-tolerant chronic HBV infection (Immune-tolerant phase) DNA	HBeAg-positive chronic HBV infection DNA	Immune-tolerant CHB-DNA	Immune-tolerant phase DNA >107 IU/mL	Immune-tolerant phase DNA >107 IU/mL	HBeAg-positive infection (immune tolerant) DNA >107 IU/mL
Phase 2	HBeAg-positive chronic hepatitis B (Immune reactive phase) DNA	HBeAg-positive chronic HBV infection DNA	Immune active HBeAg positive CHB DNA	Immune-active HBeAg-positive phase DNA 104–107 IU/mL	Immune active (HBeAg +) phase DNA > 20000 IU/mL	HBeAg positive disease (Immune reactive phase) DNA: 105–107 IU/mL
Phase 3	Low replicative chronic HBV infection (low replicative phase) DNA	HBeAg-negative chronic HBV infection DNA	Inactive CHB DNA	Inactive carrier phase DNA < 2000 IU/mL	Immune inactive phase DNA < 2000 IU/mL	HBeAg Negative infection DNA < 103 IU/mL
Phase 4	HBeAg-negative chronic hepatitis B (reactivation phase) DNA	HBeAg-negative CHB DNA	Immune-active HBeAg-negative CHB DNA	HBeAg-negative immune reactivation phase DNA > 2000 IU/mL	Immune active (HBeAg negative) phase DNA > 2000 IU/mL	HBeAg Negative disease DNA 103–105 IU/mL
Phase 5	Resolved hepatitis B infection DNA	Resolved HBV infection	Resolved CHB (Functional cure state)	HBsAg-clearance phase DNA: Undetectable	HBsAg loss phase (Resolved CHB): DNA undetectable	Occult HBV infection DNA: Undetectable
ULN of ALT values (M/F)	40/40 IU/L	40/40 IU/L	35/25 IU/L	40/40 IU/L	34/30 IU/L	30/19 IU/L
Phase 1	HBsAg high, HBeAg positive, raised DNA, normal ALT, histological activity minimal or normal
Phase 2	HBsAg high/intermediate, HBeAg (+), raised DNA, elevated ALT, histological activity moderate/severe
Phase 3	HBsAg low, HBeAg (-), low DNA, normal ALT, histological activity minimal
Phase 4	HBsAg intermediate, HBeAg (-), raised HBV, elevated ALT, histological activity moderate/severe
Grey zone	HBsAg positive, HBeAg (-), detectable HBV DNA, ALT fluctuates around ULN, histological activity minimal or normal (Only by WHO)
Phase 5	HBsAg negative, HBeAg negative, HBV DNA undetectable, ALT normal, histological activity normal

APASL: Asian Pacific Association for the Study of the Liver; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Diseases; INASL: Indian National Association for Study of the Liver; KASL: Korean Association for the Study of the Liver; WHO: World Health Organization; CPG: Clinical practice guideline; GRADE: Grading of Recommendations Assessment, Development, and Evaluation; CHB: Chronic hepatitis B; PICO: Population, intervention, comparison, outcomes; HBV: Hepatitis B virus; ULN: Upper limit of normal; ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B surface antigen.

Table 2 Management of phases of chronic hepatitis B virus infection

	APASL[11]	EASL[10]	AASLD[8,9]	INASL[12]	KASL[13]
Monitor if	High DNA (> 2 × 106 IU/mL) and normal ALT (< 40 IU/L) if age < 30 years	High DNA (> 106 IU/mL) and normal ALT (< 40 IU/L)	High DNA (> 106 IU/mL) and normal ALT	High DNA (> 106 IU/mL) and normal ALT	High DNA (≥ 107 IU/mL) and normal ALT
Biopsy if	(1) > F2 fibrosis; (2) ALT > ULN; (3) > 35 years; and (4) Family history of cirrhosis/HCC				(1) > F2 fibrosis; (2) ALT > ULN; and (3) ≥ 30-40 years
Treat if	Biopsy shows significant inflammation or fibrosis		Biopsy shows significant inflammation or fibrosis	Extra-hepatic manifestation or, family history of cirrhosis with DNA > 2000 IU/mL	Biopsy shows significant inflammation or fibrosis
May treat if		(1) > 30 years with a family history of cirrhosis/HCC; and (2) Extra-hepatic manifestation	> 40 years and HBV DNA (> 106)	> 30 years

APASL: Asian Pacific Association for the Study of the Liver; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Diseases; INASL: Indian National Association for Study of the Liver; KASL: Korean Association for the Study of the Liver; HBV: Hepatitis B virus; ULN: Upper limit of normal; ALT: Alanine aminotransferase; HCC: Hepatocellular cancer.

Table 3 Management of phase 2 or phase 4 of chronic hepatitis B virus infection

	APASL[11]	EASL[10]	AASLD[8,9]	INASL[12]	KASL[13]
Biopsy	ALT 1-2 × ULN and significant fibrosis on non-invasive assessment	ALT 1-2 × ULN and significant fibrosis on non-invasive assessment	ALT 1-2 × ULN	HBeAg (+) with ALT between 40 and 80 IU/L and HBV DNA > 20000 IU/mL	ALT 1-2 × ULN HBeAg (-) and DNA > 2000 IU/mL
Treat	HBeAg (+) ALT > 2 × ULN HBV DNA > 20000 IU/mL	HBeAg (+) ALT > 2 × ULN, HBV DNA > 20000 IU/mL	HBeAg (+), ALT > 2 × ULN, HBV DNA > 20000 IU/mL	HBeAg (+), ALT > 80 IU/L, HBV DNA > 20000 IU/mL	HBeAg (+), ALT > 2 × ULN, HBV DNA > 20000 IU/mL
	HBeAg (-), ALT > 2 × ULN, HBV DNA > 2000 IU/mL	HBeAg (-), ALT > 40 IU/L, HBV DNA > 2000 IU/mL	HBeAg (-), ALT > 2 × ULN, HBV DNA > 2000 IU/mL	HBeAg (-), ALT > 80, HBV DNA > 2000 or > 20000 IU/mL (with normal ALT)	HBeAg (-), ALT > 2 × ULN, HBV DNA > 2000 IU/mL
		Biopsy shows inflammation (> A2) or fibrosis (≥ F2)	Biopsy shows inflammation (> A2) or fibrosis (≥ F2)	Biopsy shows inflammation (> A2) or fibrosis (≥ F2)	Biopsy shows inflammation (> A2) or fibrosis (≥ F2)
May treat			If ALT 1-2 × ULN, consider the severity of liver disease

APASL: Asian Pacific Association for the Study of the Liver; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Diseases; INASL: Indian National Association for Study of the Liver; KASL: Korean Association for the Study of the Liver; HBV: Hepatitis B virus; ULN: Upper limit of normal; ALT: Alanine aminotransferase; HBeAg: Hepatitis B e antigen; HCC: Hepatocellular cancer.

Table 4 Management of phase 3 of chronic hepatitis B virus infection

	APASL[11]	EASL[10]	AASLD[8,9]	INASL[12]	KASL[13]
Biopsy and treatment	Biopsy if ALT 1-2 × ULN or significant fibrosis on non-invasive assessment. Treat if > A2 or ≥ F2	Patients with HBeAg (-) disease and family history of HCC or cirrhosis, and extra-hepatic manifestations may be treated	Monitor	Monitor	Monitor

APASL: Asian Pacific Association for the Study of the Liver; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Diseases; INASL: Indian National Association for Study of the Liver; KASL: Korean Association for the Study of the Liver; ULN: Upper limit of normal; ALT: Alanine aminotransferase; HCC: Hepatocellular cancer.

Table 5 Management of chronic hepatitis B virus infection as per the World Health Organization[14]

Indications for anti-viral therapy in chronic hepatitis B
Evidence of significant fibrosis (≥ F2) based on an APRI score of > 0.5 or a transient elastographic value of > 7 kPa, regardless of DNA
Evidence of cirrhosis (F4) (based on clinical criteria (or an APRI score of > 1, or transient elastography value of > 12.5 kPab), regardless of HBV DNA or ALT levels
HBV DNA > 2000 IU/mL and an ALT level above the ULN on two occasions, 6 months apart
Presence of coinfections (HIV, HDV or HCV); family history of liver cancer or cirrhosis; immune suppression (such as long-term steroids, solid organ or stem cell transplant); comorbidities (such as diabetes or metabolic dysfunction–associated steatotic liver disease); or extrahepatic manifestations (such as glomerulonephritis or vasculitis), regardless of the APRI score or HBV DNA or ALT levels
In the absence of access to an HBV DNA assay persistently abnormal ALT levels (defined as 2 × ULN during a 6- to 12-month period), regardless of APRI score

HBV: Hepatitis B virus; ULN: Upper limit of normal; ALT: Alanine aminotransferase; APRI: Aspartate aminotransferase to platelet ratio; HIV: Human immunodeficiency virus; HDV: Hepatitis D virus; HCV: Hepatitis C virus.

Table 6 Hepatocellular cancer surveillance in chronic hepatitis B

	APASL[11]	EASL[10]	AASLD[8,9]	INASL[10]	KASL[13]	WHO[14]
Threshold incidence of HCC to determine the intensity of screening	Determined individually based on the economic situation of each country	Not defined	Surveillance only if the incidence is greater than 0.2%	Not defined	Not defined	Surveillance only if incidence greater than 0.2%
Use of risk scores for HCC prediction	Recommended	Recommended	Recommended	Recommends specifically the CU-HCC score	Recommended	Recommended
Mode of surveillance	USG abdomen. Serum AFP	USG abdomen. Serum AFP	USG abdomen. Serum AFP	USG abdomen. No additional benefit of AFP	USG abdomen. Serum AFP	USG abdomen. Serum AFP
Baseline CECT/MRI	All cirrhotics	Not defined	Not recommended	Not recommended	Not recommended	Not recommended
CECT/MRI	Recommended for confirmation of suspicious lesions	Recommended for confirmation of suspicious lesions	Recommended for confirmation of suspicious lesions	Recommended for confirmation of suspicious lesions	Recommended for confirmation of suspicious lesions	Recommended for confirmation of suspicious lesions
CECT/MRI in cirrhosis	Recommended for advanced cirrhosis with high-risk scores	Not recommended	Not recommended	Not addressed specifically	Not recommended	Not recommended
Screening frequency (USG/AFP)	Non-cirrhotics 6-monthly. Cirrhotics 3 monthly. High risk 3-monthly	6 monthly	6 monthly	6 monthly	6 monthly	6 monthly
Screening at the onset of therapy	Recommended	Recommended in patients with moderate to high-risk scores	Recommended	Recommended	Recommended	Recommended
During therapy	Recommended	Recommended	Recommended	Recommended	Recommended	Recommended
After therapy	Not defined	Recommended after sustained response and HBsAg loss (in high-risk patients)	Recommended after sustained response (in high-risk patients)	Recommended after sustained response (in high-risk patients)	Recommended after sustained response	Not mentioned

APASL: Asian Pacific Association for the Study of the Liver; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Diseases; INASL: Indian National Association for Study of the Liver; KASL: Korean Association for the Study of the Liver; WHO: World Health Organization; HCC: Hepatocellular cancer; CECT: Contrast-enhanced computed tomography; MRI: Magnetic resonance imaging; USG: Ultrasonography; CU-HCC: Chinese University Hepatocellular cancer; HBsAg: Hepatitis B surface antigen.

Table 7 Management of indeterminate chronic hepatitis B patients: Immune-tolerant and Immune-active

Phase	Pros of treatment	Cons of treatment
IT	Early viral suppression: Suppresses HBV replication, potentially preventing liver damage, cirrhosis, and HCC[47,48]	Limited immediate benefit: Patients in the IT phase typically have minimal liver damage, so treatment may not provide significant short-term benefits[48,82]
	Prevention of carcinogenesis: High HBV DNA levels are linked to increased HCC risk, so early intervention could reduce long-term cancer risk[47]	High cost and long duration: Long-term antiviral therapy can be costly and may require lifelong treatment[11,45]
	Reduced Transmission: Lowering viral load during the IT phase can reduce the risk of HBV transmission, important in endemic areas[45]	Treatment resistance: Prolonged antiviral use could lead to drug resistance, reducing effectiveness over time[11,45]
	Advances in understanding IT phase: New evidence suggests active immune responses in the IT phase, making treatment potentially more effective than previously thought[57]	Risk of side effects: Antiviral therapy, especially long-term, can cause adverse effects, such as renal toxicity and bone density loss[45,47]
IA	Proven effectiveness: Clear benefits of treatment, including reduced risk of cirrhosis, liver failure, and HCC[45,48]	Side effects: Long-term use of antivirals can lead to renal and bone complications, as well as other side effects[11,45]
	Improved liver function: Treatment significantly reduces liver inflammation and fibrosis, improving long-term liver function[45,47]	Monitoring required: Requires continuous monitoring of HBV DNA, liver enzymes, and liver function tests[11,82]
	Reduced mortality: Studies show that treating IA patients reduces the risk of death or liver transplantation[45,47]	Cost: Like the IT phase, long-term antiviral therapy in IA patients can be financially burdensome[11,45]
	Reduced complications: Treatment lowers the risk of liver decompensation and complications from cirrhosis[45,47]	Possible drug resistance: Prolonged use of antivirals may lead to resistance, necessitating a switch in therapy[45,82]

CHB: Chronic hepatitis B; IT: Immune-tolerant; IA: Immune-active; HCC: Hepatocellular carcinoma.

Table 8 Pros and cons of expanded hepatitis B treatment in different regions of the world

Region/Country	Pros of expanded HBV treatment	Cons of expanded HBV treatment	Ref.
United States and Western Europe	Reduces liver cancer (HCC) and cirrhosis risk significantly. Cost-effective long-term due to lower healthcare costs of managing advanced liver disease. High-quality healthcare infrastructure for treatment. National vaccination programs decrease new infections	High upfront costs of expanding treatment programs. A complex treatment regimen requires continuous monitoring. Antiviral drug resistance can develop. Socioeconomic disparities affect access to treatment	[83,84]
Sub-Saharan Africa	Potential to reduce high hepatitis B prevalence (8%-12% in some regions). Cost-effective in preventing liver disease. Availability of generic drugs makes treatment affordable. Could prevent mother-to-child transmission	Limited healthcare infrastructure. Poor access to diagnostic tools. Healthcare worker shortages. High upfront costs for government to scale up treatment	[85-87]
China	A large reduction in liver cancer cases due to high HBV burden. Government-subsidized treatments improve access. An effective nationwide vaccination program	High cost of treating millions of chronic HBV patients. Disparities between urban and rural healthcare access. Drug adherence and monitoring are challenging in rural areas	[88,89]
India	Reduces HBV-related mortality in a country with significant disease burden. Affordable generic antivirals are available. National initiatives to improve vaccination rates and awareness	Limited healthcare infrastructure in rural areas. Low awareness about the need for regular treatment. Cultural stigma around liver disease may hinder uptake	[51]
South-East Asia (Vietnam, Thailand)	High impact due to large HBV burden in the region. Government-funded programs and access to generics lower costs. Reduction in liver cancer and other liver-related mortality	Treatment access is limited in rural and underserved areas - Monitoring and follow-up systems are underdeveloped. High costs of diagnostic tests in some areas	[90]
Eastern Europe and Russia	Potential to reduce the growing HBV burden. Generic antivirals are available at lower costs. Could lower healthcare costs related to advanced liver disease	Insufficient healthcare infrastructure in rural areas. Limited access to quality diagnostic and monitoring tools. Economic constraints hinder government spending on healthcare	[91]
Latin America (Brazil, Argentina)	Moderate HBV prevalence with opportunity for significant impact through expanded treatment. National vaccination programs are already in place. Availability of affordable drugs	Poor healthcare infrastructure in rural areas. Budgetary constraints limit widespread access to treatment. Socioeconomic disparities affect access	[92]
Middle East (Egypt, Iran)	High impact potential due to significant HBV burden. Availability of affordable generic treatments. Could reduce complications related to liver disease	Limited diagnostic infrastructure in rural regions. Cultural and religious beliefs may affect treatment adherence. Healthcare costs are a significant burden on government budgets	[93]

HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus.

Table 9 Cost-effectiveness of expanded hepatitis B virus treatment in high and low-income countries

Ref.	Country	Expanded HBV treatment criteria	ICER/DALY averted	Cost-effectiveness threshold1
Razavi-Shearer et al[71], 2023	United States	Treat all	$41700	$65850
Sanai et al[72], 2020	Saudi Arabia	Treat all	$22500	$66150
Lim et al[73], 2022	Korea	Simplified algorithm (only HBV DNA)	$25832	$22000
Crossan et al[74], 2016	United Kingdom	Treat all	£28137	£20000
Nguyen et al[75], 2024	The Gambia	Treat all	$2149	$352

¹Cost effectiveness threshold: 0.5 × per capita GDP.

²Simplified algorithm (only DNA, no alanine aminotransferase, hepatitis B e antigen).

ICER: Incremental cost-effectiveness ratio; DALY: Disability-adjusted life year; HBV: Hepatitis B virus.

Table 10 Highlights the chemotherapeutic drugs associated with a high risk of occult hepatitis B virus infection reactivation

Drug	Mechanism of action	Ref.
Rituximab	Anti-CD20 monoclonal antibody	[111-113]
Rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone	Rituximab: Anti-CD20 monoclonal antibody	[117]
	Cyclophosphamide: Alkylating agent, inhibits protein synthesis by DNA and RNA crosslinking
	Hydroxydaunorubicin: Inhibits DNA replication and cell production
	Oncovin: Vinca alkaloid, microtubule-disrupting agent. Prednisolone: Suppression of migration of polymorphonuclear lymphocytes and reversal of increased capillary permeability
Ofatumumab; Alemtuzumab; Baricitinib	Anti-CD20 monoclonal antibody; Anti-CD52 monoclonal antibody; Janus kinase inhibitor	[111,118]