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Withdrawal of Therapy After Long-Term Oral Nucleos(t)Ide Analogue Treatment in Patients With Chronic Hepatitis B

18 Years
Open (Enrolling)
Chronic Hepatitis B e Antigen Positive, Chronic Hepatitis B e Antigen Negative

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Trial Information

Withdrawal of Therapy After Long-Term Oral Nucleos(t)Ide Analogue Treatment in Patients With Chronic Hepatitis B

Chronic hepatitis B affects at least 1.5 million Americans and is a major cause of
cirrhosis, end-stage liver disease and hepatocellular carcinoma. Five oral antiviral agents
have been licensed for use in chronic hepatitis B in the United States. These agents are
effective at suppressing viral replication, improving liver disease and reversing cirrhosis.
The standard indications for starting antiviral therapy have been developed and widely
accepted. Less clear is how long therapy should continue and when and under what conditions
should therapy be stopped. Withdrawal after one year of therapy is commonly followed by
relapse that in rare instances is severe and can be fatal. With longer courses of therapy,
withdrawal of antiviral therapy has been associated with fewer and less severe relapses, but
the criteria for stopping treatment are still unclear.

In this study, we propose to withdraw therapy in up to 50 patients with both HBeAg positive
and negative chronic hepatitis B who have received a minimum of 4 years of oral nucleoside
therapy with a serum HBV DNA level less than 500 IU/ml in the 6 months prior to
withdrawal. After an outpatient evaluation, consenting patients will be withdrawn from
therapy and followed carefully for presence of symptoms, abnormal liver tests and HBV DNA
levels monthly for 6 months and every 3 months thereafter. Patients who relapse will be
offered retreatment. Patients without relapse will be followed for at least four years after
stopping therapy. The primary endpoint of the study will be the proportion of patients who
maintain an HBV DNA < 1,000 IU/ml, and a serum ALT or AST< 1.5 times the upper limit of
normal one year off therapy. Secondary endpoints will be the proportion of patients who
maintain HBeAg loss and clear HBsAg one year off therapy, the number of ALT or AST flares,
predictors of maintained virological suppression and HBeAg negativity and the proportion of
subjects who require re-initiation of therapy.

Inclusion Criteria


Age greater than 18 years and older, male or female

HBsAg positive for greater than 6 months

For HBeAg positive subjects, HBeAg loss with or without anti-HBe with a minimum period of
antiviral therapy for 48 weeks after HBeAg loss was first detected.

HBV DNA less than or equal to 500 IU/mL tested on at least 2 occasions over the last 6

Antiviral therapy for a minimum of 4 years

Baseline ALT or AST within the upper limit of normal.

Willing and able to provide written, informed consent.

Subjects must be eligible to enter protocol 07-DK-0207 or be willing to be treated by
their local physician should relapse or a hepatitis flare occur.


Presence of cirrhosis (Ishak fibrosis score 5 or 6) on any liver biopsy performed within
the last 4 years. In the absence of a liver biopsy then any three of the following five
variables: platelet count less than or equal to 100,000/mm(3), reversal of ALT/AST ratio,
total bilirubin greater than 2.0 mg/dL, splenomegaly on ultrasound and presence of
esophageal or gastric varices or portal hypertensive gastropathy on endoscopy

Any history of decompensated liver disease

Prior or current therapy with tenofovir or tenofovir plus emtricitabine

Renal insufficiency defined as a serum creatinine greater than 1.5 mg/dL or an estimated
glomerular filtration rate less than or equal to 50 mls/minute using the Cockroft and
Gault formula.

Anti-hepatitis C virus positivity

Anti-hepatitis D virus positivity

Anti-human immunodeficiency virus positivity

Type of Study:


Study Design:

Time Perspective: Prospective

Principal Investigator

Marc G Ghany, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)


United States: Federal Government

Study ID:




Start Date:

April 2011

Completion Date:

Related Keywords:

  • Chronic Hepatitis B e Antigen Positive
  • Chronic Hepatitis B e Antigen Negative
  • Hepatitis B
  • Treatment
  • Nucleoside/Nucleotide Analogue
  • Hepatitis
  • Hepatitis A
  • Hepatitis B
  • Hepatitis, Chronic
  • Hepatitis B, Chronic



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