Serum Hepatitis B Surface Antigen Levels to Guide the Stopping of Entecavir in HBeAg-negative Chronic Hepatitis B
Serum Hepatitis B Surface Antigen Levels to Guide the Stopping of Entecavir in HBeAg-negative Chronic Hepatitis B
This will be a multi-center study in Hong Kong. This is a retrospective-prospective study in
 HBeAg-negative chronic hepatitis B patients. HBeAg-negative patients on entecavir followed up
 in the liver clinics will be identified from the existing database. All patients had HBV DNA
 testing every 6 months as a clinic routine. Serum HBsAg levels will be tested in the residual
 serum samples at the pre-treatment and last follow-up visits. Eligible patients will be
 discussed on the plan of stopping entecavir therapy. All patients will have written informed
 consent before recruited into this study. All patients will be followed up for 12 months
 after stopping entecavir treatment. As entecavir is most commonly used antiviral drug in Hong
 Kong and in the Western countries, the investigators aim to investigate and validate the use
 of serum HBsAg quantification to guide the timing of stopping entecavir in HBeAg-negative
 patients. The results of this study will provide scientific evidence on the use of this new
 serum marker to predict sustained remission after stopping entecavir. In the long-run, it can
 improve patient compliance, reduce the need of long-term antiviral and reduce the drug cost
 in the management of HBeAg-negative chronic hepatitis B.

 All patients will stop entecavir according to the Asian Pacific guideline with written
 informed consent and close subsequent monitoring. In the protocol, there is a safety net for
 re-treatment. There will not be any invasive procedure. There is no major ethical issue.
Chronic hepatitis B is the commonest cause of liver cirrhosis and hepatocellular carcinoma in
 Hong Kong. Approximately 50% of patients had negative hepatitis B e antigen (HBeAg), which
 indicates an escape of host immune clearance by the host. Oral antiviral drugs are very
 effective in suppressing viral replication and inducing biochemical remission [1]. However,
 the timing to stop oral antiviral agents is controversial. Hepatitis B surface antigen
 (HBsAg) seroclearance has been recommended as the best time for drug cessation for
 HBeAg-negative patients [2,3], but its occurrence is very uncommon especially among Asian
 patients. The Asian Pacific guideline recommended stopping treatment when serum HBV DNA
 became undetectable for three times within 12 months [4], but approximately 50% of patients
 will experience virologic relapse post-treatment [5,6].

 HBsAg quantification has been shown to correlate with the concentration of covalently closed
 circular DNA in the liver [7]. In a Hong Kong study among 53 HBeAg-negative patients who
 stopped lamivudine, HBsAg ≤ 100 IU/ml and/or reduction of > 1 log at the end of treatment
 could predict sustained response up to 5 years post-treatment [8]. In other words, it is
 probable that patients who have a lower serum HBsAg level, which may reflect a lower
 concentration of virus inside the liver, have a lower risk of viral relapse after stopping
 antiviral therapy.
Inclusion Criteria:

 1. HBeAg-negative patients on entecavir monotherapy for at least 24 months

 2. Undetectable HBV DNA by PCR-based assay on 3 separate occasions 6 months apart (as per
 Asian Pacific guideline in 2008).

 3. Normal ALT levels according to the local laboratory reference value on 2 separate
 occasions 6 months apart

 Exclusion Criteria:

 1. Patients previously or currently on interferon therapy

 2. Patients who have experienced another antiviral agent besides entecavir

 3. Patients with hepatitis C virus infection as indicated by a positive anti-HCV serology
 test

 4. Patients with Child's B liver cirrhosis, cirrhotic complications or hepatocellular
 carcinoma

 5. Patients with organ transplantation

 6. Serious medical illnesses or malignancy

 7. Age < 18 years or > 65 years

 8. No patient consent