<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04442841</url>
  </required_header>
  <id_info>
    <org_study_id>HBV Vaccine LT</org_study_id>
    <nct_id>NCT04442841</nct_id>
  </id_info>
  <brief_title>HBV Vaccine in Anti-core Positive Donors After LT</brief_title>
  <official_title>Hepatitis B Vaccination in Liver Transplant Reecipients Who Received a Liver From an Anti-core Positive Donor. H</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Clinic of Barcelona</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Padova</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hospital Vall d'Hebron</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital Clinic of Barcelona</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Anti-HBc positive liver donors frequently have occult HBV infection, and several studies in&#xD;
      HBsAg-negative subjects have shown that there is often the detection in the liver of&#xD;
      covalently closed circular DNA (cccDNA). In the setting of liver transplantation and&#xD;
      immunosuppresion, grafts from antiHBc positive donors may cause de novo HBV infection&#xD;
      (defined by the development of positive HBsAg and/or detectable serum or liver HBV DNA in&#xD;
      previously HBsAg recipients).&#xD;
&#xD;
      Active immunization may be successful in up to 20% of patients who received an anti-HBc+&#xD;
      liver during transplantation after the first vaccination schedule, and up to 30% after a&#xD;
      second vaccination course. Responders to vaccination could safely halt nucleos(t)ide analog&#xD;
      prophylactic therapy with no risk of HBV reactivation during follow-up.&#xD;
&#xD;
      We also hypothesize that an impaired antigen-specific adaptive cell-mediated immunity at&#xD;
      baseline explain the lack of response&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
        1. To investigate the efficacy of HBV vaccination in liver transplant recipients who&#xD;
           received a liver from an anti-HBc positive donor.&#xD;
&#xD;
        2. To assess the safety of nucleos(t)ide treatment interruption in those patients achieving&#xD;
           a response to HBV vaccination&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      HYPOTHESIS The hypothesis of the study is that active immunization may be successful in up to&#xD;
      20% of patients who received an anti-HBc+ liver during transplantation after the first&#xD;
      vaccination schedule, and up to 30% after a second vaccination course. Responders to&#xD;
      vaccination could safely halt nucleos(t)ide analog prophylactic therapy with no risk of HBV&#xD;
      reactivation during follow-up.&#xD;
&#xD;
      Thus, an impaired antigen-specific adaptive cell-mediated immunity at baseline may explain&#xD;
      the lack of response.&#xD;
&#xD;
      OBJECTIVES&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
        1. To investigate the efficacy of HBV vaccination in liver transplant recipients who&#xD;
           received a liver from an anti-HBc positive donor.&#xD;
&#xD;
        2. To assess the safety of nucleos(t)ide treatment interruption in those patients achieving&#xD;
           a response to HBV vaccination&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        1. To investigate which clinical and virological variables are associated with a protective&#xD;
           response to HBV vaccination (including time from liver transplant, type of&#xD;
           immunosuppressive therapy and vaccination prior liver transplantation)&#xD;
&#xD;
        2. To assess the role of HBV specific CD8 responses in developing a protective response to&#xD;
           vaccination&#xD;
&#xD;
        3. To assess the relationship between intrahepatic cccDNA-HBV levels and the outcome after&#xD;
           vaccination&#xD;
&#xD;
           STUDY DESIGN This is a multi-center, open-label study in liver transplant recipients.&#xD;
           Four transplant centers will include non-HBV liver transplant recipients who received a&#xD;
           graft from an HBV anti-core positive donor. All patients should be under prophylactic&#xD;
           nucleos(t)ide treatment (NA). Individuals will undergo HBV vaccination with double dosis&#xD;
           vaccine (40 ug) and protective response will be evaluated at the end of a first course&#xD;
           of vaccination. Response will be defined as anti-HBs levels &gt; 100 IU/L. In patients who&#xD;
           do not respond to a first course of vaccination, a second course will be administered.&#xD;
&#xD;
           In patients achieving a protective immune response, prophylactic NA treatment will be&#xD;
           interrupted and follow-up will be extended until 2 years after treatment interruption.&#xD;
           Among those patients achieving vaccination response, a booster dose will be given if&#xD;
           antiHBs levels fall below 100 IU/L during follow-up.&#xD;
&#xD;
           Sample size calculation Sample size has been calculated in order to be able to identify&#xD;
           variables that able to predict response/non response. The estimated number of anti-core&#xD;
           positive recipients in all centers according to anti-core prevalence in general&#xD;
           population is 160 patients (40 patients/center). According to previous reported data,&#xD;
           around 20% would achieve a response to a first course of vaccination and an additional&#xD;
           30% would achieve response after a second course. With a confidance interval of 95% and&#xD;
           accepting a precision level of 5% and an estimated loss rate of 15%, the calculated&#xD;
           sample size would be 114 patients.&#xD;
&#xD;
           Study flowchart All patients will receive 40 ug of HBV vaccine, at 0, 1 and 3 months&#xD;
           time points.&#xD;
&#xD;
           In patients not achieving protective anti-HBs titers (≥ 100 IU/L) 1 month after the last&#xD;
           HBV vaccine dose, the same vaccine schedule will be repeated (40 ug of vaccine 0, 1 and&#xD;
           3 months).&#xD;
&#xD;
           Patients not achieving protective anti-HBs titers (≥ 100 IU/L) 1 month after last HBV&#xD;
           vaccine dose will be considered non-responders and will continue on NA therapy.&#xD;
&#xD;
           In patients achieving protective anti-HBs titers, prophylaxis with nucleoside analogues&#xD;
           will be interrupted and patients will be followed for a minimum period of 24 months.&#xD;
           Blood tests will be performed every 6 months including liver tests, markers of HBV&#xD;
           reactivation and anti-HBs. If anti-HBs levels fall below &lt;100 IU/L at any time point of&#xD;
           follow-up, a single boost (40 ug) will be repeated.&#xD;
&#xD;
           In case of HBV reactivation (HBsAg or HBV-DNA positive) during follow-up, oral NA&#xD;
           therapy will be restarted with high barrier to resistance drugs such as entecavir or&#xD;
           tenofovir.&#xD;
&#xD;
           Study procedures All patients Screening visit&#xD;
&#xD;
             -  Medical history and physical examination.&#xD;
&#xD;
             -  Review inclusion and exclusion criteria.&#xD;
&#xD;
             -  Obtain written informed consent.&#xD;
&#xD;
             -  Complete blood tets&#xD;
&#xD;
                  -  Hematology, chemistry and coagulation tests.&#xD;
&#xD;
                  -  Serologies: HBsAg, IgG HBV anti-core (HBc), anti-HBs, HIV antibody, IgG HCV&#xD;
&#xD;
                  -  HBV-DNA, HCV-RNA (only if anti-HCV positive)&#xD;
&#xD;
                  -  Liver biopsy (if the patient signs an additional inform consent)&#xD;
&#xD;
             -  Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova&#xD;
                University Hospital)&#xD;
&#xD;
             -  Liver Biopsy (Hospital Clínic Barcelona) in order to exclude the presence of liver&#xD;
                fibrosis (or other lesions) and to obtain frozen tissue and evaluate the presence&#xD;
                of cccDNA and its correlation with study outcomes.&#xD;
&#xD;
           Baseline (day 1):&#xD;
&#xD;
           The following procedures will be completed prior to treatment administration:&#xD;
&#xD;
             -  Perform a complete physical examination.&#xD;
&#xD;
             -  Extraction of 40 ml of blood to process PBMC Thereafter, the first dose of vaccine&#xD;
                (GSK 40 ug) will be administered Week 4: 2nd dose of vaccine Week 12: 3rd dose of&#xD;
                vaccine&#xD;
&#xD;
           Week 16:&#xD;
&#xD;
             -  Medical history and physical examination.&#xD;
&#xD;
             -  Complete blood tets&#xD;
&#xD;
                  -  Hematology, chemistry and coagulation tests.&#xD;
&#xD;
                  -  Serologies: HBsAg, anti-HBc, anti-HBs,&#xD;
&#xD;
                  -  HBV-DNA&#xD;
&#xD;
             -  Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova&#xD;
                University Hospital) a) Responders If anti-HBs ≥ 100 IU/L Interruption of&#xD;
                nucleoside analogue* (in patients who qualify for NA interruption, a specific&#xD;
                follow-up will continue, as described below) b) Non-responders If anti-HBs &lt; 100&#xD;
                IU/L First dose of second course of vaccination Week 20: 2nd dose of vaccine Week&#xD;
                32: 3rd dose of vaccine&#xD;
&#xD;
           Week 38:&#xD;
&#xD;
             -  Medical history and physical examination.&#xD;
&#xD;
             -  Complete blood tets o Hematology, chemistry and coagulation tests.&#xD;
&#xD;
                o Serologies: HBsAg, anti-HBc, anti-HBs,&#xD;
&#xD;
                o HBV-DNA&#xD;
&#xD;
             -  Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova&#xD;
                University Hospital)&#xD;
&#xD;
                  1. Responders If anti-HBs ≥ 100 IU/L Interruption of nucleoside analogue (in&#xD;
                     patients who qualify for NA interruption, a specific follow-up will continue,&#xD;
                     as described below)&#xD;
&#xD;
                  2. Non-responders If anti-HBs &lt; 100 IU/L will continue NA therapy&#xD;
&#xD;
                       -  Responders to vaccination and NA withdrawal: follow-up every 2 months&#xD;
                          during the first 6 months and every 6 months until 2 years of follow-up&#xD;
&#xD;
           At each visit:&#xD;
&#xD;
           Medical history and physical examination.&#xD;
&#xD;
           Complete blood tets:&#xD;
&#xD;
           o Hematology, chemistry and coagulation tests.&#xD;
&#xD;
             -  Serologies: HBsAg, Anti-HBs&#xD;
&#xD;
             -  HBV-DNA If anti-HBs &lt; 100 IU/L : a vaccine booster (40 ug) will be administered If&#xD;
                HBsAg+ or HBV-DNA+ confirmed in two occasions 2 weeks apart: NA therapy with&#xD;
                entecavir or tenofovir will be introduced.&#xD;
&#xD;
           Statistical analysis Statistical analysis will be performed using SPSS, version 22&#xD;
           (SPSS, Chicago, IL). Categorical data will be analyzed using the chi-square test;&#xD;
           continuous data will be analyzed using the Student T test. The survival rates were&#xD;
           calculated using the Kaplan-Meier method with log- rank test for significance. A P value&#xD;
           of&lt;0.05 will be considered&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">September 2020</start_date>
  <completion_date type="Anticipated">January 2023</completion_date>
  <primary_completion_date type="Anticipated">January 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Response to HBV vaccine</measure>
    <time_frame>1 month after last HBV vaccine dose</time_frame>
    <description>&gt; 100 IU/mlL anti-HBs</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of Emergent Adverse Events in case of nucleos(t)ide analogue (NUC) treatment interruption</measure>
    <time_frame>6 months after NUC interruption</time_frame>
    <description>No reactivation of HBV (negative HBV-DNA) 6-12 months after NUC interruption</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">114</enrollment>
  <condition>Hepatitis B Reactivation</condition>
  <arm_group>
    <arm_group_label>Single arm (vaccine)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>No further description</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Hepatitis B vaccine</intervention_name>
    <description>It may be GSk or MSD vaccine</description>
    <arm_group_label>Single arm (vaccine)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 18 and 75 years- old.&#xD;
&#xD;
          -  HBsAg-negative pre-transplantation&#xD;
&#xD;
          -  Liver transplant recipients; more than 2 years from the date of LT&#xD;
&#xD;
          -  Transplantation of a graft from an HBV anti-core positive donor&#xD;
&#xD;
          -  Patients should be under nucleoside analogue therapy with Lamivudine, Tenofovir or&#xD;
             Entecavir&#xD;
&#xD;
          -  Stable immunosuppressive therapy during the last 6 months&#xD;
&#xD;
          -  Baseline anti-HBs levels &lt;100 IU/L (HBV vaccination while on the waiting list is&#xD;
             allowed and will be recorded)&#xD;
&#xD;
          -  Willingness to participate in the study and written inform consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  • HBsAg positive at any time post-transplantation&#xD;
&#xD;
               -  HBV-DNA positive at any time post-transplantation&#xD;
&#xD;
               -  Any HBIG dose during the last 12 months&#xD;
&#xD;
               -  HBV vaccination after liver transplantation&#xD;
&#xD;
               -  Spontaneous or vaccine-induced post-transplant anti-HBs titers ≥ 100 UI/L&#xD;
&#xD;
               -  Any rejection episode during the last 12 months&#xD;
&#xD;
               -  Positive HCV-RNA at time of vaccination&#xD;
&#xD;
               -  HCV therapy with direct acting antivirals within the previous 12 months&#xD;
&#xD;
               -  HIV coinfection&#xD;
&#xD;
               -  Advanced fibrosis after LT (liver stiffness measurement ≥ 9.5 kPa)&#xD;
&#xD;
               -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>xavier forns</last_name>
    <phone>34932275753</phone>
    <phone_ext>34932275753</phone_ext>
    <email>xforns@clinic.cat</email>
  </overall_contact>
  <location>
    <facility>
      <name>Liver Unit, Hospital Clinic</name>
      <address>
        <city>Barcelona</city>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Xavier Forns, MD</last_name>
      <phone>34 93 227 5753</phone>
      <email>xforns@clinic.cat</email>
    </contact>
    <investigator>
      <last_name>Xavier Forns, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 19, 2020</study_first_submitted>
  <study_first_submitted_qc>June 19, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 23, 2020</study_first_posted>
  <last_update_submitted>July 30, 2020</last_update_submitted>
  <last_update_submitted_qc>July 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 31, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis B</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04442841
org study id: HBV Vaccine LT
nct id: NCT04442841
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Anti-HBc positive liver donors frequently have occult HBV infection, and several studies in
      HBsAg-negative subjects have shown that there is often the detection in the liver of
      covalently closed circular DNA (cccDNA). In the setting of liver transplantation and
      immunosuppresion, grafts from antiHBc positive donors may cause de novo HBV infection
      (defined by the development of positive HBsAg and/or detectable serum or liver HBV DNA in
      previously HBsAg recipients).

      Active immunization may be successful in up to 20% of patients who received an anti-HBc+
      liver during transplantation after the first vaccination schedule, and up to 30% after a
      second vaccination course. Responders to vaccination could safely halt nucleos(t)ide analog
      prophylactic therapy with no risk of HBV reactivation during follow-up.

      We also hypothesize that an impaired antigen-specific adaptive cell-mediated immunity at
      baseline explain the lack of response

      Primary objective:

        1. To investigate the efficacy of HBV vaccination in liver transplant recipients who
           received a liver from an anti-HBc positive donor.

        2. To assess the safety of nucleos(t)ide treatment interruption in those patients achieving
           a response to HBV vaccination
HYPOTHESIS The hypothesis of the study is that active immunization may be successful in up to
      20% of patients who received an anti-HBc+ liver during transplantation after the first
      vaccination schedule, and up to 30% after a second vaccination course. Responders to
      vaccination could safely halt nucleos(t)ide analog prophylactic therapy with no risk of HBV
      reactivation during follow-up.

      Thus, an impaired antigen-specific adaptive cell-mediated immunity at baseline may explain
      the lack of response.

      OBJECTIVES

      Primary objective:

        1. To investigate the efficacy of HBV vaccination in liver transplant recipients who
           received a liver from an anti-HBc positive donor.

        2. To assess the safety of nucleos(t)ide treatment interruption in those patients achieving
           a response to HBV vaccination

      Secondary objectives:

        1. To investigate which clinical and virological variables are associated with a protective
           response to HBV vaccination (including time from liver transplant, type of
           immunosuppressive therapy and vaccination prior liver transplantation)

        2. To assess the role of HBV specific CD8 responses in developing a protective response to
           vaccination

        3. To assess the relationship between intrahepatic cccDNA-HBV levels and the outcome after
           vaccination

           STUDY DESIGN This is a multi-center, open-label study in liver transplant recipients.
           Four transplant centers will include non-HBV liver transplant recipients who received a
           graft from an HBV anti-core positive donor. All patients should be under prophylactic
           nucleos(t)ide treatment (NA). Individuals will undergo HBV vaccination with double dosis
           vaccine (40 ug) and protective response will be evaluated at the end of a first course
           of vaccination. Response will be defined as anti-HBs levels > 100 IU/L. In patients who
           do not respond to a first course of vaccination, a second course will be administered.

           In patients achieving a protective immune response, prophylactic NA treatment will be
           interrupted and follow-up will be extended until 2 years after treatment interruption.
           Among those patients achieving vaccination response, a booster dose will be given if
           antiHBs levels fall below 100 IU/L during follow-up.

           Sample size calculation Sample size has been calculated in order to be able to identify
           variables that able to predict response/non response. The estimated number of anti-core
           positive recipients in all centers according to anti-core prevalence in general
           population is 160 patients (40 patients/center). According to previous reported data,
           around 20% would achieve a response to a first course of vaccination and an additional
           30% would achieve response after a second course. With a confidance interval of 95% and
           accepting a precision level of 5% and an estimated loss rate of 15%, the calculated
           sample size would be 114 patients.

           Study flowchart All patients will receive 40 ug of HBV vaccine, at 0, 1 and 3 months
           time points.

           In patients not achieving protective anti-HBs titers (≥ 100 IU/L) 1 month after the last
           HBV vaccine dose, the same vaccine schedule will be repeated (40 ug of vaccine 0, 1 and
           3 months).

           Patients not achieving protective anti-HBs titers (≥ 100 IU/L) 1 month after last HBV
           vaccine dose will be considered non-responders and will continue on NA therapy.

           In patients achieving protective anti-HBs titers, prophylaxis with nucleoside analogues
           will be interrupted and patients will be followed for a minimum period of 24 months.
           Blood tests will be performed every 6 months including liver tests, markers of HBV
           reactivation and anti-HBs. If anti-HBs levels fall below <100 IU/L at any time point of
           follow-up, a single boost (40 ug) will be repeated.

           In case of HBV reactivation (HBsAg or HBV-DNA positive) during follow-up, oral NA
           therapy will be restarted with high barrier to resistance drugs such as entecavir or
           tenofovir.

           Study procedures All patients Screening visit

             -  Medical history and physical examination.

             -  Review inclusion and exclusion criteria.

             -  Obtain written informed consent.

             -  Complete blood tets

                  -  Hematology, chemistry and coagulation tests.

                  -  Serologies: HBsAg, IgG HBV anti-core (HBc), anti-HBs, HIV antibody, IgG HCV

                  -  HBV-DNA, HCV-RNA (only if anti-HCV positive)

                  -  Liver biopsy (if the patient signs an additional inform consent)

             -  Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova
                University Hospital)

             -  Liver Biopsy (Hospital Clínic Barcelona) in order to exclude the presence of liver
                fibrosis (or other lesions) and to obtain frozen tissue and evaluate the presence
                of cccDNA and its correlation with study outcomes.

           Baseline (day 1):

           The following procedures will be completed prior to treatment administration:

             -  Perform a complete physical examination.

             -  Extraction of 40 ml of blood to process PBMC Thereafter, the first dose of vaccine
                (GSK 40 ug) will be administered Week 4: 2nd dose of vaccine Week 12: 3rd dose of
                vaccine

           Week 16:

             -  Medical history and physical examination.

             -  Complete blood tets

                  -  Hematology, chemistry and coagulation tests.

                  -  Serologies: HBsAg, anti-HBc, anti-HBs,

                  -  HBV-DNA

             -  Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova
                University Hospital) a) Responders If anti-HBs ≥ 100 IU/L Interruption of
                nucleoside analogue* (in patients who qualify for NA interruption, a specific
                follow-up will continue, as described below) b) Non-responders If anti-HBs < 100
                IU/L First dose of second course of vaccination Week 20: 2nd dose of vaccine Week
                32: 3rd dose of vaccine

           Week 38:

             -  Medical history and physical examination.

             -  Complete blood tets o Hematology, chemistry and coagulation tests.

                o Serologies: HBsAg, anti-HBc, anti-HBs,

                o HBV-DNA

             -  Extraction of 40 ml of blood to process PBMC (Hospital Clínic Barcelona and Padova
                University Hospital)

                  1. Responders If anti-HBs ≥ 100 IU/L Interruption of nucleoside analogue (in
                     patients who qualify for NA interruption, a specific follow-up will continue,
                     as described below)

                  2. Non-responders If anti-HBs < 100 IU/L will continue NA therapy

                       -  Responders to vaccination and NA withdrawal: follow-up every 2 months
                          during the first 6 months and every 6 months until 2 years of follow-up

           At each visit:

           Medical history and physical examination.

           Complete blood tets:

           o Hematology, chemistry and coagulation tests.

             -  Serologies: HBsAg, Anti-HBs

             -  HBV-DNA If anti-HBs < 100 IU/L : a vaccine booster (40 ug) will be administered If
                HBsAg+ or HBV-DNA+ confirmed in two occasions 2 weeks apart: NA therapy with
                entecavir or tenofovir will be introduced.

           Statistical analysis Statistical analysis will be performed using SPSS, version 22
           (SPSS, Chicago, IL). Categorical data will be analyzed using the chi-square test;
           continuous data will be analyzed using the Student T test. The survival rates were
           calculated using the Kaplan-Meier method with log- rank test for significance. A P value
           of<0.05 will be considered
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Response to HBV vaccine
time frame: 1 month after last HBV vaccine dose
description: > 100 IU/mlL anti-HBs
measure: Incidence of Emergent Adverse Events in case of nucleos(t)ide analogue (NUC) treatment interruption
time frame: 6 months after NUC interruption
description: No reactivation of HBV (negative HBV-DNA) 6-12 months after NUC interruption
arm group label: Single arm (vaccine)
arm group type: Experimental
description: No further description
intervention type: Biological
intervention name: Hepatitis B vaccine
description: It may be GSk or MSD vaccine
arm group label: Single arm (vaccine)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: xavier forns
phone: 34932275753
phone ext: 34932275753
email: xforns@clinic.cat
facility: 
status: Recruiting
contact: 
investigator: 
country: Spain
responsible party type: Sponsor
mesh term: Hepatitis B
mesh term: Hepatitis