Efficacy of HBV Vaccine in Consolidation of Nucleos(t)Ide Analogues Therapy

July 28, 2019 updated by: Chang Gung Memorial Hospital

Efficacy of HBV Therapeutic Vaccine in Consolidation of Nucleos(t)Ide Analogues Therapy: a Pilot Study

Background and aims: Nucleos(t)ide analogues may suppress HBV DNA to undetectable level, but only about 30-40% remain sustained response 1-3 years after discontinued therapy. The investigators will try to improve the sustained response rate by given a course of HBV vaccination during the last 6 months on patients receiving a 3-year entecavir or tenofovir therapy.

Rational: The host may response to HBV vaccine when HBV DNA and immune tolerance are suppressed during entecavir or tenofovir therapy.

Patients: Patients who have been receiving entecavir or tenofovir therapy for at least 30 months will be invited to this study. The case group will receive 5 Engerix-B injections during the last 6 months of entecavir or tenofovir therapy. Arm A-entecavir pretreated group: 75 cases will be enrolled to receive Engerix-B injection and compared with histological non-vaccine treated controls; Arm B-tenofovir pretreated group: 50 patients will be randomized into case (vaccine) and control group according to age, gender, pretreatment HBV DNA level.

Therapy: Both case and control groups will receive a 3 year or longer entecavir or tenofovir therapy. Patients will be screen at 24-30 months and enrolled at 30 months after entecavir or tenofovir therapy. They will receive 5 Engerix-B injections at 0,1st ,2nd,3rd and 6th month [30-36 +/-1 month post nucleos(t)ide therapy] post enrollment. Both drugs will be discontinued after completed therapy.

Follow-up: Both groups will be monitoring by biochemistry, alpha-fetoprotein, quantitative HBsAg, HBV DNA levels and immunological parameter periodically for 2 years after therapy.

Efficacy: Those patients with persistent normal ALT and HBV DNA lower than 1*100000 cps/mL after discontinued nucleos(t)ide analogues therapy will be considered to have sustained response. Patients with transient elevation of HBV DNA and ALT, but normalized spontaneously without further therapy will be defined as delayed response. Patients with persistent HBV DNA greater than 1*100000 cps/mL will be considered to have non-sustained response.

Study duration: The enrollment will be completed in one year and keep on observation for additional 2 years.

Expected goals of the study: HBV vaccine and nucleos(t)ide analogues combination therapy may decrease the HBV relapse rate at 1 and 2 year after completed therapy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Introduction Chronic hepatitis B virus (HBV) infection is a widely prevalent global health problem with estimate 350-400 million chronic HBV carriers worldwide. In China, Southeast Asia and sub-Saharan Africa, as many as 10-15% of the population are chronically infected with HBV. In North America and North Europe, HBV chronic carrier rates are much lower, usually below 1%. Intermediate HBV carrier rates of 1-7% are found in parts of Southern and Eastern Europe, Central America, the Middle East and parts of Japan (1-4).

HBV is highly infectious; many chronic HBsAg carriers were infected in their family shortly after birth or in early childhood (5-7). Recent genome-wide association studies revealed antigen presenting molecules, Human leukocyte antigen-DP (HLA-DP) and HLA-DQ, are associated with persistence HBV infection (8-10). HBV is actively replicated in chronic carriers during the initial immune tolerance phase (11). Impaired innate and adaptive immune responses to HBV can be found during this stage (12-16). They are generally asymptomatic until the immune clearance phase developed. At this stage, innate immunity, HBV-specific and non-specific T cells and other immune cells may orchestra an immune response and hepatic necroinflammation to clear HBV (17-19). The immune clearance phase is critical to the outcome of chronic HBsAg carriers. Those patients with prolonged HBV replication and repeated hepatic inflammation will run into liver cirrhosis and /or hepatocellular carcinoma (HCC) (20-23). How to terminate HBV replication is an important issue in management of chronic HBsAg carriers.

1.1 Therapy for chronic hepatitis B In the past 20 years, significant improvements in treatment of chronic hepatitis B (CHB) have been achieved by introducing regimen of interferon derivatives and nucleotide/nucleoside analogues (NA) (24-26). Interferon is a T helper cell type 1 cytokine that promotes immunity of host to clear HBV (27,28). NA inhibit HBV DNA synthesis by termination the nascent proviral DNA chain. About 30% patients may have complete response with normalization alanine aminotransferase (ALT) and HBV DNA lower than 10000 cps/mL one to three year after discontinued therapy (10,29-31). For the rest of patients a flare-up HBV replication occurred (10,29-31), a life-long therapy may be needed to eliminate covalently closed circular DNA (cccDNA) pool and achieved a sustained therapeutic response (32). Unfortunately, the prolonged use of NA need a lot of budgets and carried a substantial risk for emerging drug resistance mutants (33). The interferon derivatives regimens have similar efficacy with significant side effects (27,28). Therefore, Development of a safe and affordable anti-HBV agent/strategy is needed to further improve outcomes (34).

1.2 Rational for combine HBV vaccine with NA therapy NA therapy may suppress Serum HBV DNA to undetectable level (29-31). These drugs are acceptable to most of the patients because they are admitted orally, once daily and without significant side effect. The main problem is HBV DNA tends to relapse in approximately 70% of patients 1-3 years after discontinued therapy (10, 29-31).

When HBV was suppressed by NA therapy, the immune tolerance may also be suppressed. The post treatment relapse is an indirect evidence of losing immune tolerance in such patients (29-31). The post treatment clinical relapse is associated with enhanced Th1 response (35-37). T regulatory (Treg) cells, macrophages and other unidentified factors may play important roles on HBV tolerance (19, 38-41). One of an important phenomenon for patients receiving NA therapy is decrease of Treg cells level (42,43). The post treatment relapse of hepatic necroinflammation is an evidence of the restored HBV specific immune response (44,45).

In addition to the relief of immune tolerance, NA may suppress the HBsAg production from free virus, but no effect is expected for those HBsAg produced by integrated HBV genome. These two types of HBsAg may have some differences on protein conformation and behavior (46,47). The vaccine is produced according to free virus. Therefore, when the HBsAg produced by free virus is suppressed by NA to a low level, the vaccine may be recognized as a new antigen. The immune response elicited by the therapeutic vaccine may have a potential on suppression of free virus.

1.3 Combined HBV vaccine and NA therapy in animal study A Woodchuck animal study suggest entecavir therapy followed by Woodchuck surface (WHs) and core (WHc) DNA vaccination 7 weeks later may induce WHc and WHs specific T cell responses. Two of the 6 animals clear Woodchuck surface antigen (WHBsAg) and product anti-WHBs (48). Similar results can be found in HBV transgenic mice model. Hepatitis B surface (HBs) and hepatitis B core (HBc) specific cellular and humoral response was identified after HBc and HBs protein vaccine therapy (49). In a mouse model with sustained HBV viremia after infection with a recombinant adeno-associated virus carrying a replicable HBV genome. Immunization with the conventional HBV vaccine in the presence of aluminum adjuvant failed to elicit an immune response,but vaccination of mice with HBsAg/CpG induced strong antibody production and T-cell responses(50)

1.4 Combined HBV vaccine and NA therapy in liver transplantation Prevention of HBV reinfection is an important issue in chronic hepatitis B received liver transplantation. HBsAg immunoglobulin (HBIG) is the choice of therapy with evident of good protection (51). However, HBIG is quite expensive and long term therapy is needed. Combination of HBV vaccine and NA therapy had been done in patients received liver transplantation. The initial reports were not good (52-54), but recent studies suggest up to 50% patients response to lamivudine and HBV vaccination combination therapy (55,56) after adjusted dose of HBIG. All these studies did not report severe adverse event using lamivudine and HBV vaccine combination therapy.

1.5 Combined HBV vaccine and NA therapy in patients with chronic hepatitis B To increase response rate many HBV vaccines has been developed by increase immune epitope or posttranslation modifications (57,58) Combination of Lamivudine with therapeutic HBsAg DNA vaccination led to the persistence of T-cell responses (59). An HBV therapeutic vaccine clinical trial studies showed a decrease of HBV replication in hepatitis B e antigen (HBeAg) positive patients received HBV vaccine and lamivudine combination therapy (60).

2. Study objectives To understand the efficacy of combining a 3-year NA and Engerix-B therapy in sustained viral suppression.

3. Investigational plan 3.1 Overall study design This trials will examine the efficacy of NA and Engerix-B combination therapy in chronic hepatitis B.

3.2 Study design Arm A-entecavir pretreated group: Case vs. histological control study. Arm B-tenofovir pretreated group: randomized case and control study. 3.3. Therapy 3.3.1 Entecavir 0.5 mg daily for at least 3 years. 3.3.2 Tenofovir 300 mg daily for at least 3 years. 3.3.3 Five doses of Engerix-B 20 ug during the last 6 month of NA therapy in case group.

Both case and control groups will complete a 3-year NA therapy. The vaccination group will receive a course of Engerix-B vaccination. They will be enrolled at the last 6 months of the NA therapy. Engerix-B will be given at the 0,1st ,2nd 3rd and 6th month after the enrollment.

Study Type

Interventional

Enrollment (Actual)

116

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Taiwan
      • Taipei, Taiwan, 10507
        • Chang Gung Memorial Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

31 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. HBeAg negative chronic hepatitis B
  2. Has been receiving a 3-year or more than 3 years entecavir or tenofovir therapy and intending to stop the treatment 6 months later.
  3. An inform consent will be obtained after well explanation.

Exclusion Criteria:

  1. Pregnant woman.
  2. Hepatitis C virus, hepatitis D virus or human immunodeficient virus co-infection.
  3. Alcoholism
  4. Present with malignant tumor, decompensated liver or renal diseases, present with other major medical illness.
  5. Liver cirrhosis, child B or C.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: entecavir pretreated vaccine arm
Arm A,case group: 75 cases will be enrolled to receive Engerix-B injection and compared with histological non-vaccine treated controls
Drug: Engerix-B
The case group will receive 5 Engerix-B injections during the last 6 months of a 3-year NA therapy.
Drug: Entecavir
Both case and control will receive 0.5 mg entecavir therapy for at least 3 years
Experimental: tenofovir pretreated vaccine arm
Arm B case group: A total of 50 patients will be randomized into case (vaccine) and control group according to age, gender, pretreatment HBV DNA level.
Drug: Engerix-B
The case group will receive 5 Engerix-B injections during the last 6 months of a 3-year NA therapy.
Drug: Tenofovir
Both case and control will receive 300 mg Tenofovir for at least 3 years
Active Comparator: Entecavir pretreated control arm
Arm A control group: Age, gender and pretreatment DNA matched histological controls
Drug: Entecavir
Both case and control will receive 0.5 mg entecavir therapy for at least 3 years
Active Comparator: tenofovir pretreated control arm
Arm B control group: A total of 50 patients will be randomized into case (vaccine) and control group according to age, gender, pretreatment HBV DNA level.
Drug: Tenofovir
Both case and control will receive 300 mg Tenofovir for at least 3 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
HBV DNA levels during followup period
Time Frame: At 48th weeks of followup after completed combination therapy
  1. Non-responder: When HBV DNA levels were greater than 1*100000 cps/mL and persistence to 1 year after stopped combination therapy, or need other therapy before the end point.
  2. Delayed responder: Those patients with transient elevation of HBV DNA shortly after stopped NA therapy and then become normal ALT and HBV DNA lower than 1*100000 cps/mL without other therapy.
  3. Sustained responder:HBV DNA levels were lower than 1*100000 cps/mL and persistence to 1 year after stopped combination therapy
At 48th weeks of followup after completed combination therapy
HBV DNA levels during followup period
Time Frame: At 96th weeks of followup after completed combination therapy
  1. Non-responder: When HBV DNA levels were greater than 1*100000 cps/mL and persistence to 2 years after stopped combination therapy, or need other therapy before the end point.
  2. Delayed responder: Those patients with transient elevation of HBV DNA shortly after stopped NA therapy and then become normal ALT and HBV DNA lower than 1*100000 cps/mL without other therapy.
  3. Sustained responder:HBV DNA levels were lower than 1*100000 cps/mL and persistence to 2 years after stopped combination therapy
At 96th weeks of followup after completed combination therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Alanine aminotransferase (ALT) level during followup period
Time Frame: At 48 th week of followup after completed combination therapy
ALT level after completed therapy will be grouped into normal serum ALT level, 1-2x upper limit normal (ULN), 2-5x ULN or >5x ULN. ALT relapse is defined as ALT level >2x ULN.
At 48 th week of followup after completed combination therapy
Alanine aminotransferase (ALT) level during followup period
Time Frame: At 96th weeks of followup after completed combination therapy
ALT level after completed therapy will be grouped into normal serum ALT level, 1-2x upper limit normal (ULN), 2-5x ULN or >5x ULN. ALT relapse is defined as ALT level >2x ULN.
At 96th weeks of followup after completed combination therapy
Quantitative HBsAg (qHBsAg) level during followup period
Time Frame: At 48th week of followup after completed combination therapy
Serum qHBsAg level after completed therapy will be grouped into lower than 150 international unit (IU)/mL, 500 IU/mL, 500-1000 IU/mL and >1000 IU/mL. Those qHBsAg lower than 150 IU/mL is defined as good serological response.
At 48th week of followup after completed combination therapy
Quantitative HBsAg (qHBsAg) level during followup period
Time Frame: At 96th week of followup after completed combination therapy
Serum qHBsAg level after completed therapy will be grouped into lower than 150 international unit (IU)/mL, 500 IU/mL, 500-1000 IU/mL and >1000 IU/mL. Those qHBsAg lower than 150 IU/mL is defined as good serological response.
At 96th week of followup after completed combination therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Chang Gung Memorial Hospital

Investigators

  • Principal Investigator: Dar-In Tai, MD, PhD, Chang Gung Memorial Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2015

Primary Completion (Actual)

December 21, 2018

Study Completion (Actual)

December 21, 2018

Study Registration Dates

First Submitted

July 6, 2015

First Submitted That Met QC Criteria

July 20, 2015

First Posted (Estimate)

July 22, 2015

Study Record Updates

Last Update Posted (Actual)

July 30, 2019

Last Update Submitted That Met QC Criteria

July 28, 2019

Last Verified

December 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 104-3167C

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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