Standard Nomenclature for Hepatitis B
The standard nomenclature for hepatitis B follows the EASL 2017 framework, which distinguishes between "chronic HBV infection" (presence of virus without significant inflammation) and "chronic hepatitis B" (active liver disease), replacing outdated terms like "immune tolerant" with descriptive phase-based terminology. 1
Virus Name and Classification
The causative agent is Hepatitis B virus (HBV), a partially double-stranded DNA virus belonging to the Hepadnaviridae family with a 3.2 kb genome. 2, 3, 4
HBV is classified into nine genotypes (A through I) based on genome-wide nucleotide divergence of >8% in complete viral genome sequences. 1, 2
Four major serotypes exist: ayw, ayr, adw, and adr, determined by S gene sequence analysis. 4
Serologic Markers
The key serological markers used in HBV nomenclature include: 5, 6
HBsAg (Hepatitis B surface antigen): Hallmark of HBV infection; first marker to appear in acute infection (average 30 days post-exposure); persistence >6 months defines chronic infection. 7, 5
Anti-HBs (Antibody to HBsAg): Indicates recovery from infection or vaccine-induced immunity; ≥10 mIU/mL is protective. 7
Anti-HBc (Antibody to core antigen): Total anti-HBc persists for life after infection; IgM anti-HBc indicates acute or recent infection (detectable up to 6 months). 7
HBeAg (Hepatitis B e antigen): Indicates high viral replication and infectivity. 7
Anti-HBe (Antibody to HBeAg): Usually indicates decreased viral replication. 7
HBV DNA: Direct measure of viral replication; essential for diagnosis, treatment decisions, and monitoring. 1, 7
Clinical Phase Nomenclature (EASL 2017 Framework)
The EASL 2017 guidelines replaced older terminology with a five-phase system based on HBeAg status, HBV DNA levels, ALT values, and liver inflammation: 1
Phase 1: HBeAg-Positive Chronic HBV Infection
- Replaces: "Immune tolerant phase" (this term is now discouraged). 1
- Characteristics: HBeAg-positive, very high HBV DNA levels, persistently normal ALT (ULN ~40 IU/L), minimal/no liver necroinflammation or fibrosis. 1
- Clinical context: More frequent in perinatal infection; patients highly contagious; low rate of spontaneous HBeAg loss. 1
Phase 2: HBeAg-Positive Chronic Hepatitis B
- Replaces: "Immune active phase" or "immune clearance phase." 1
- Characteristics: HBeAg-positive, high HBV DNA, elevated ALT, moderate-to-severe liver necroinflammation, accelerated fibrosis progression. 1
- Clinical context: Occurs after years of Phase 1 or rapidly in adult-acquired infection; variable outcomes including HBeAg seroconversion or progression to HBeAg-negative disease. 1
Phase 3: HBeAg-Negative Chronic HBV Infection
- Replaces: "Inactive carrier state." 1
- Characteristics: HBeAg-negative, anti-HBe-positive, HBV DNA <2,000 IU/mL, persistently normal ALT, minimal liver inflammation/fibrosis. 1, 7
- Clinical context: Favorable long-term prognosis with very low risk of cirrhosis or HCC; requires lifelong monitoring as ~20% reactivate. 7
Phase 4: HBeAg-Negative Chronic Hepatitis B
- Characteristics: HBeAg-negative, anti-HBe-positive, HBV DNA ≥2,000 IU/mL, elevated or fluctuating ALT, moderate-to-severe liver inflammation. 1, 7
- Clinical context: Associated with viral mutants (basal core promoter or precore mutations); severe necroinflammation; low rates of spontaneous remission; high risk of cirrhosis and HCC. 7
Phase 5: HBsAg-Negative Phase (Resolved Infection)
- Characteristics: Previous HBV infection with anti-HBc positive, anti-HBs positive (or negative), HBsAg negative, undetectable HBV DNA, normal ALT. 1, 7
- Clinical context: Indicates functional cure; cccDNA may persist in liver with potential for reactivation under immunosuppression. 7
Disease Terminology
Chronic HBV Infection vs. Chronic Hepatitis B
- Critical distinction: The EASL 2017 nomenclature emphasizes that "chronic HBV infection" refers to persistent viral presence, while "chronic hepatitis B" (CHB) specifically denotes active liver disease with inflammation. 1
- Not all patients with chronic HBV infection have chronic hepatitis. 1
Formal Diagnostic Criteria
Chronic Hepatitis B: 1
- HBsAg-positive >6 months
- Serum HBV DNA >20,000 IU/mL (HBeAg-positive) or 2,000-20,000 IU/mL (HBeAg-negative)
- Persistent or intermittent ALT/AST elevation
- Liver biopsy showing moderate-to-severe necroinflammation (when performed)
Inactive HBsAg Carrier State: 1, 7
- HBsAg-positive >6 months
- HBeAg-negative, anti-HBe-positive
- Serum HBV DNA <2,000 IU/mL
- Persistently normal ALT/AST
- Liver biopsy confirms absence of significant hepatitis (when performed)
- Previous history of acute or chronic HBV or presence of anti-HBc ± anti-HBs
- HBsAg-negative
- Undetectable serum HBV DNA
- Normal ALT
Additional Clinical Terms
Acute exacerbation/flare: Intermittent ALT elevations >10× ULN and >2× baseline value. 1
Reactivation: Reappearance of active necroinflammatory disease in someone with inactive carrier state or resolved hepatitis B. 1
HBeAg seroconversion: Loss of HBeAg with detection of anti-HBe in previously HBeAg-positive, anti-HBe-negative person. 1
Occult HBV infection: Undetectable HBsAg but detectable HBV DNA in serum or liver tissue. 7
Antiviral Resistance Nomenclature
The standardized terminology for antiviral resistance includes: 1
Primary treatment failure (nonresponse): Inability to reduce HBV DNA by 1 log₁₀ IU/mL after 6 months of nucleos(t)ide analogue treatment. 1
Secondary treatment failure (virologic breakthrough): Increase in HBV DNA by 1 log₁₀ above nadir on two occasions 1 month apart while on treatment in a compliant patient. 1
Genotypic resistance: Detection of amino acid substitutions in the reverse transcriptase region conferring resistance in phenotypic assays. 1
Phenotypic resistance: Decreased susceptibility of HBV polymerase to an antiviral drug in vitro. 1
Cross-resistance: Decreased susceptibility to multiple antiviral drugs conferred by the same amino acid substitution(s). 1
Common Pitfalls in Nomenclature
Avoid "immune tolerant": This term is outdated and inaccurate; use "HBeAg-positive chronic HBV infection" instead, as children and young adults show less immune compromise than previously thought. 1
Serial monitoring required: A single determination of HBV DNA and ALT often cannot classify patients into a specific phase; serial monitoring over time is essential. 1
Phases are not sequential: Patients do not necessarily progress through phases in order; transitions can be bidirectional with reactivation or reversion. 1, 7
HBeAg-negative disease is not benign: HBeAg-negative chronic hepatitis B carries worse prognosis than HBeAg-positive disease despite the absence of HBeAg. 7
Distinguish infection from hepatitis: Always specify whether discussing chronic HBV infection (viral presence) or chronic hepatitis B (active liver disease), as management differs dramatically. 1