What are the stages of hepatitis B?

Stages of Hepatitis B Infection

Chronic HBV infection is divided into five distinct phases based on HBeAg status, HBV DNA levels, ALT values, and liver inflammation, though not all patients experience these phases sequentially. 1

The Five Phases of Chronic HBV Infection

Phase 1: HBeAg-Positive Chronic HBV Infection (formerly "Immune Tolerant")

• Characterized by HBeAg positivity, very high levels of HBV DNA, and normal ALT levels 1
• Minimal or no liver necroinflammation despite high viral load 1
• More common and prolonged in patients infected perinatally (can last for decades) 1
• Low rate of spontaneous HBeAg loss 1
• Patients are highly contagious due to high HBV DNA levels 1

Phase 2: HBeAg-Positive Chronic Hepatitis B (Immune Clearance)

• Characterized by HBeAg positivity, high but relatively lower HBV DNA levels compared to phase 1, and elevated ALT 1
• Moderate to severe liver necroinflammation with accelerated fibrosis progression 1
• May occur after several years of the immune tolerant phase 1
• More frequently and rapidly reached in those infected during adulthood 1
• Variable outcomes: most patients achieve HBeAg seroconversion and enter phase 3, while others progress to phase 4 1

Phase 3: HBeAg-Negative Chronic HBV Infection (formerly "Inactive Carrier")

• Characterized by HBeAg negativity, anti-HBe positivity, low or undetectable HBV DNA (<2,000 IU/ml), and normal ALT 1
• Minimal hepatic necroinflammatory activity and low fibrosis 1
• Low risk of progression to cirrhosis or HCC if patients remain in this phase 1
• Spontaneous HBsAg loss and seroconversion may occur in 1-3% of cases per year 1
• Some patients may have HBV DNA levels between 2,000-20,000 IU/ml with persistently normal ALT 1

Phase 4: HBeAg-Negative Chronic Hepatitis B (Immune Escape)

• Characterized by HBeAg negativity, moderate to high HBV DNA levels (>2,000 IU/ml), and elevated ALT 1
• Active liver inflammation with risk of progressive disease 1
• Often results from mutations in the precore or basal core promoter regions that prevent HBeAg production 1
• Higher risk of progression to cirrhosis and HCC compared to inactive carriers 1

Phase 5: HBsAg-Clearance Phase

• Characterized by HBsAg negativity, anti-HBc positivity, with or without anti-HBs 1, 2
• Undetectable HBV DNA in serum, though HBV DNA may persist in liver tissue 1, 3
• Normal ALT levels 1, 2
• Improved long-term outcomes, though risk of HCC remains in patients with cirrhosis 2, 3

Clinical Implications and Monitoring

• Regular monitoring of HBeAg, HBV DNA, and ALT is essential to determine the phase of infection and guide management decisions 1, 2
• Monitoring frequency should be every 3-6 months for liver function tests and HBV DNA in compensated patients 2
• Transition between phases is not always sequential and may be influenced by host and viral factors 1
• Patients in phases 2 and 4 (with elevated ALT and HBV DNA) are candidates for antiviral therapy 2, 4

Prognostic Factors

• High serum HBV DNA levels are associated with increased risk of cirrhosis, hepatocellular carcinoma, and liver-related mortality 2, 5
• HBV genotype C (common in Asian patients) is associated with lower rates of HBeAg seroconversion, more rapid progression to cirrhosis and HCC 1, 5
• Basal core promoter mutations and pre-S deletions are associated with increased risk of HCC 5, 6
• Multiple hepatitis flares during the immune clearance phase accelerate progression to cirrhosis 5

Important Caveats

• Some patients may not fit neatly into a single phase and require individualized assessment 1
• A single measurement of viral markers and ALT is often insufficient to classify patients; serial monitoring is required 1
• The risk of progression to cirrhosis and HCC varies significantly between phases, with phases 2 and 4 carrying the highest risk 1, 5
• Early HBeAg seroconversion typically confers a favorable outcome, while late or absent seroconversion after multiple flares accelerates disease progression 5