What is the treatment endpoint for an adult patient with chronic hepatitis B (CHB) and no significant comorbidities or contraindications?

Treatment Endpoints for Chronic Hepatitis B

The primary treatment endpoint for chronic hepatitis B is sustained long-term suppression of HBV DNA to undetectable levels (ideally <10-15 IU/mL by sensitive PCR assay), which represents the cornerstone of preventing cirrhosis, hepatic failure, and hepatocellular carcinoma. 1

Hierarchy of Treatment Endpoints

Optimal Endpoint: HBsAg Loss

• HBsAg loss, with or without anti-HBs seroconversion, represents the optimal endpoint as it indicates profound suppression of HBV replication and viral protein expression, associated with improved long-term survival and reduced HCC risk. 1, 2
• This endpoint is achieved in only 0-4% of patients at one year with currently available antiviral agents, making it an aspirational but infrequently attainable goal. 2
• Even after achieving HBsAg loss, patients with baseline cirrhosis or significant fibrosis require lifelong HCC surveillance. 2

Primary Endpoint: Virological Suppression

• Long-term suppression of HBV DNA to undetectable levels by sensitive PCR assay represents the main endpoint of all current treatment strategies. 1
• The level of HBV replication is the strongest single predictive biomarker for disease progression, and its suppression eliminates chronic necroinflammatory activity and progressive fibrosis in the vast majority of patients. 1
• The threshold for adequate suppression is not precisely defined, but the principle is "the lower, the better"—ideally undetectable HBV DNA (<10-15 IU/mL detection limit). 1, 2

Secondary Endpoints by HBeAg Status

For HBeAg-Positive Patients:

• HBeAg loss with or without anti-HBe seroconversion is a valuable endpoint, as it represents partial immune control of chronic HBV infection. 1
• Sustained off-therapy HBeAg seroconversion combined with HBV DNA <2000 IU/mL and ALT normalization is a satisfactory endpoint that allows consideration of treatment discontinuation. 2
• This endpoint is associated with improved prognosis and transition to a low replicative phase. 1

For HBeAg-Negative Patients:

• Sustained off-therapy virological response with HBV DNA <2000 IU/mL (ideally undetectable) and ALT normalization is the satisfactory endpoint. 2
• Treatment discontinuation guidelines for HBeAg-negative patients on nucleos(t)ide analogues remain poorly defined, and relapse is frequent even after prolonged viral suppression. 1, 2

Additional Endpoints

Biochemical Response:

• ALT normalization should be considered an additional endpoint, achieved in most patients with long-term suppression of HBV replication. 1
• Biochemical response is defined as normalization of ALT levels, confirmed with determinations at least every 3 months for a minimum of 1 year post-treatment. 2

Histological Response:

• Histological improvement should accompany virological suppression, decreasing the risk of cirrhosis and HCC, particularly in non-cirrhotic patients. 2
• Regression of fibrosis and cirrhosis can be regarded as a further goal in patients with established advanced fibrosis, though its impact on clinical outcomes requires further clarification. 1

Treatment Duration Considerations

• For patients without cirrhosis, treatment with nucleos(t)ide analogues should continue until HBsAg loss is achieved and maintained for 6-12 months. 2
• For HBeAg-positive patients, treatment may be stopped after achieving sustained HBeAg seroconversion, though close monitoring for relapse is mandatory. 1, 2
• Patients with cirrhosis require lifelong therapy in the vast majority of cases, with discontinuation only considered if HBsAg loss occurs for 6-12 months or longer. 2, 3
• If treatment is stopped, frequent monitoring with regular blood tests is essential to detect HBV reactivation, as transient ALT elevations may occur within the first year. 2

Common Pitfalls and Caveats

• Do not confuse on-therapy viral suppression with a durable cure—most patients will experience viral rebound if treatment is discontinued prematurely, particularly HBeAg-negative patients. 1
• Virological response definitions vary: complete response requires HBsAg loss, while virological response refers only to HBV DNA suppression and HBeAg loss (in HBeAg-positive patients). 1
• The ultimate goal of preventing HCC, cirrhosis, and liver-related mortality depends on the timing of therapy initiation—earlier treatment in the disease course yields better outcomes. 1
• Treatment strategies to prevent HCC development may differ from those needed to prevent fibrosis progression, requiring individualized risk assessment. 1