What is the treatment endpoint for patients with chronic hepatitis B?

Treatment Endpoints for Chronic Hepatitis B

The ideal treatment endpoint for chronic hepatitis B is sustained off-therapy HBsAg loss (with or without anti-HBs seroconversion), which represents a functional cure and is associated with complete remission of disease activity and improved long-term outcomes including reduced mortality and hepatocellular carcinoma risk. 1

Hierarchy of Treatment Endpoints

Primary (Ideal) Endpoint

• HBsAg loss is the ultimate goal for all patients with chronic hepatitis B, representing functional cure 1
• This endpoint is associated with complete and definitive remission of chronic hepatitis B activity and improved long-term outcomes including survival and reduced HCC risk 1
• However, this endpoint is infrequently achievable with currently available antiviral agents (occurring in only 0-4% of patients at one year depending on the agent used) 1

Secondary (Realistic) Endpoints

For HBeAg-Positive Patients:

• Sustained off-therapy HBeAg seroconversion (HBeAg loss with anti-HBe gain) combined with HBV DNA <2000 IU/mL and ALT normalization is a satisfactory endpoint 1
• This endpoint is associated with improved prognosis and allows consideration of treatment discontinuation 1
• For patients who achieve HBeAg seroconversion, nucleoside analogue therapy can be stopped 6-12 months after seroconversion 1

For HBeAg-Negative Patients:

• Sustained off-therapy virological response (HBV DNA <2000 IU/mL, ideally undetectable) with ALT normalization is the satisfactory endpoint 1
• However, sustained virological responses off-therapy are rare in HBeAg-negative patients, making this a difficult endpoint to achieve 1

Tertiary (On-Treatment) Endpoint

• Maintained virological remission (undetectable HBV DNA by sensitive PCR assay) under long-term antiviral therapy is the next most desirable endpoint when off-therapy endpoints cannot be achieved 1
• This applies to HBeAg-positive patients who do not achieve anti-HBe seroconversion and all HBeAg-negative patients 1
• Long-term (potentially lifelong) therapy is typically required for HBsAg-positive patients until HBsAg loss is achieved 2

Specific Virological Thresholds

For Nucleoside/Nucleotide Analogue Therapy:

• Virological response is defined as undetectable HBV DNA by sensitive PCR assay (typically <10-15 IU/mL detection limit) 1
• This should be evaluated every 3-6 months during therapy 1, 2
• HBV DNA levels should be as low as possible, ideally undetectable, to ensure full prevention of liver disease progression and emergence of resistance 1

For Interferon/Pegylated Interferon Therapy:

• Virological response is defined as HBV DNA <2000 IU/mL 1
• Sustained off-treatment virological response is defined as HBV DNA <2000 IU/mL for at least 12 months after end of therapy 1

Biochemical and Histological Endpoints

• 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 1
• Histological improvement should accompany virological suppression, as this lessens the risk of cirrhosis and decreases HCC risk particularly in non-cirrhotic patients 1

Critical Caveats

Important Pitfall: The FDA label for tenofovir explicitly states that "the optimal duration of treatment is unknown" and "the relationship between response and long-term prevention of outcomes such as hepatocellular carcinoma is not known" 3

Treatment Duration Considerations:

• Treatment should not be discontinued without first informing the physician, as severe acute exacerbations of hepatitis have been reported after discontinuation 3
• Even after HBsAg loss, patients with significant fibrosis or cirrhosis at baseline require lifelong HCC screening 2
• For HBeAg-negative patients on nucleoside analogues, guidelines for treatment discontinuation have not been clearly defined 1

Monitoring Requirements:

• If treatment is stopped, healthcare providers must check patient health often and perform blood tests regularly to monitor for HBV reactivation 3
• Transient ALT elevations (usually ≤3 months duration) may occur within the first year after treatment discontinuation before long-term biochemical remission; additional close follow-up of at least 2 years is reasonable in such cases 1