Withdrawal of Therapy After Long-Term Antiviral Treatment for Chronic Hepatitis B

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

Background:

- Chronic infection with the hepatitis B virus may lead to cirrhosis, liver disease, and cancer of the liver. There is no cure for the infection, but several drugs have been approved to treat it. These drugs can keep the virus levels low. They seem to be safe for short-term use. But the drugs have not yet been approved for long-term use because some of them can have serious side effects. However, stopping treatment too soon can make the infection worse and may lead to more serious forms of liver disease. Researchers have not been able to determine a when to stop treatment. They want to study people with chronic hepatitis B infection to find out the best time to stop treatment and prevent the disease from causing further liver damage.

Objectives:

• To study the safety and effectiveness of withdrawing antiviral treatment for chronic hepatitis B after at least 4 years of treatment.
• To determine whether stopping long-term antiviral treatment for chronic hepatitis B makes the infection worse.

Eligibility:

- People who are at least 18 years of age; have been taking antiviral drugs to treat chronic hepatitis B for at least 4 years; and are being evaluated to stop treatment.

Design:

• Those in the study will be screened with a physical exam, medical history, questionnaire, and blood tests. They will remain under the care of their regular doctor during the study.
• They will have an abdominal ultrasound to study scarring in the liver, if they have not had one in the past year.
• Those without detectable levels of the hepatitis B virus in their blood will stop antiviral treatment. They will have monthly blood tests for the first 6 months to check virus levels, and then every 3 months afterward.
• Those whose blood tests show an increase in virus levels will restart antiviral treatment as directed by the study doctors and their personal doctor.
• All those in the study will be monitored until the end of the study.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis B e Antigen Positive; Chronic Hepatitis B e Antigen Negative

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 15

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Liver clinic population and community

Description

• 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 months

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.

EXCLUSION CRITERIA:

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Patients with HBeAg negative chronic hepatitis B; Patients with HBeAg 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.
Patients with HBeAG positive chronic hepatitis B; Patients with HBeAg positive 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who maintain an HBV DNA <1.5 X the upper limit of normal one year off therapy	Proportion of patients who maintain an HBV DNA <1,000 IU/ml, and a serum ALT or AST <1.5 X the upper limit of normal one year off therapy	One year after stopping therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients who maintain HBeAg loss and clear HBsAg one year off therapy	Proportion of patients who maintain HBeAg loss and clear HBsAg	One year after stopping therapy
Number of ALT or AST flares	Number of ALT or AST flares	One year after stopping therapy

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Investigators: Principal Investigator: Marc G Ghany, M.D., National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2011

Study Registration Dates

• First Submitted: April 19, 2012
• First Submitted That Met QC Criteria: April 19, 2012
• First Posted (Estimated): April 20, 2012

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: June 30, 2023

More Information

Terms related to this study

• Keywords: Treatment; Natural History; Hepatitis B; Nucleoside/Nucleotide Analogue
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Disease Attributes; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Chronic Disease; Hepatitis B; Hepatitis; Hepatitis A; Hepatitis B, Chronic; Hepatitis, Chronic
• Other Study ID Numbers: 110151; 11-DK-0151

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No