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.