<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/NCT04431245</url>
  </required_header>
  <id_info>
    <org_study_id>HKUUW20-425</org_study_id>
    <nct_id>NCT04431245</nct_id>
  </id_info>
  <brief_title>Stopping Antiviral Treatment in Chronic Hepatitis B</brief_title>
  <official_title>Stopping Antiviral Treatment and Subsequent Flare in Chronic Hepatitis B Infection: Immunological and Virological Profiling</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Hong Kong</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>
      Chronic hepatitis B (CHB) infection affected 292 million individuals in the world,&#xD;
      translating to about 3.9% of global prevalence. Up to 40% of patients with CHB will develop&#xD;
      liver-related complications. Many patients require long-term oral antiviral therapy since&#xD;
      off-treatment sustained virological control can only be achieved in a minority of patients.&#xD;
      It is uncommon for patients taking long-term antivirals to be able to stop the treatment if&#xD;
      favorable factors are not present. Those include low viral load, long enough duration of&#xD;
      treatment, and absence of cirrhosis. Some studies have found that inducing a mild flare is&#xD;
      beneficial for achieving functional cure in chronic hepatitis B infection. There is lack of&#xD;
      data in the immunological and virological profile in patients who stop their long-term&#xD;
      antiviral therapy, and in those who developed flare after treatment cessation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Chronic hepatitis B infection (CHB) affected 292 million individuals in the world in 2016&#xD;
      according to the Polaris Observatory estimation, translating to about 3.9% global prevalence.&#xD;
      Up to 40% of patients with CHB will develop liver-related complications and there were&#xD;
      890,000 deaths from these complications in 2015. Current antiviral therapy is aimed to&#xD;
      achieve effective viral suppression, biochemical remission, histological improvement, and&#xD;
      risk reductions in liver-related complications including cirrhosis and liver cancer. Many&#xD;
      patients require long-term oral nucleos(t)ide analogues (NA) since off-treatment sustained&#xD;
      virological control can only be achieved in a minority of patients. For HBeAg-negative CHB&#xD;
      patients, variable rates of durable virological response were observed after cessation of NA.&#xD;
      Only a small proportion of HBeAg-negative Asian patients (&lt;10%) can successfully stop NA&#xD;
      without virological breakthrough, compared to more than 60% of Caucasian patients maintaining&#xD;
      a durable virologic response and even HBsAg seroclearance in up to 30%. Therefore, current&#xD;
      guidelines in general recommend indefinite duration of NA therapy in HBeAg-negative patients,&#xD;
      unless guaranteed close monitoring could be provided after cessation of NA in suitable&#xD;
      subjects. Favourable factors predictive of partial cure include lower baseline HBV DNA, lower&#xD;
      HBsAg titre or hepatitis B core-related antigen at NA cessation and longer duration of&#xD;
      consolidation therapy in HBeAg-negative patients. There is lack of data in the immunological&#xD;
      and virological profile in patients who stop their long-term NA, and in those who developed&#xD;
      post-NA cessation flare.&#xD;
&#xD;
      The investigators aim to study the virological and immunological profile in patients who&#xD;
      stopped long-term NA therapy, with or without post-NA cessation flare. In addition, the&#xD;
      investigators would like to investigate the effect of mild flare after monitored NA-cessation&#xD;
      on subsequent virological activity and HBsAg seroclearance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 1, 2021</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>The immunological profile in CHB patients who stopped antiviral therapy</measure>
    <time_frame>24 months</time_frame>
    <description>The investigators will perform analysis for the immunological aspects for these patients</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The virological profile in CHB patients who stopped antiviral therapy</measure>
    <time_frame>24 months</time_frame>
    <description>The investigators will perform analysis for the virological aspects for these patients</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">54</enrollment>
  <condition>Chronic Hepatitis b</condition>
  <arm_group>
    <arm_group_label>Stop antiviral</arm_group_label>
    <description>HBeAg-negative non-cirrhotic CHB patients on long-term NA ≥3 years will be identified. Only those who have undetectable serum HBV DNA by the conventional assay (Cobas Taqman, Roche Diagnostics, Branchburg, NJ) which has a lower limit of detection (LLOD) of 10 IU/mL will be recruited. CHB patients were treated with potent oral NA (i.e. tenofovir or entecavir). All recruited patients will have written informed consent for participation of study. Patients with HCC, cirrhosis, history of liver transplantation, or on immunosuppressants, will be excluded.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Entecavir</intervention_name>
    <description>Study subjects will stop the antiviral therapy. Patients will be closely monitored every 6-8 weeks for virological flare and/or biochemical flare.</description>
    <arm_group_label>Stop antiviral</arm_group_label>
    <other_name>oral nucleoside analogue</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HBeAg-negative non-cirrhotic CHB patients on long-term NA ≥3 years will be identified. Only&#xD;
        those who have undetectable serum HBV DNA by the conventional assay (Cobas Taqman, Roche&#xD;
        Diagnostics, Branchburg, NJ) which has a lower limit of detection (LLOD) of 10 IU/mL will&#xD;
        be recruited. CHB patients were treated with potent oral NA (i.e. tenofovir or entecavir).&#xD;
        All recruited patients will have written informed consent for participation of study.&#xD;
        Patients with HCC, cirrhosis, history of liver transplantation, or on immunosuppressants,&#xD;
        will be excluded.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HBeAg-negative&#xD;
&#xD;
          -  non-cirrhotic&#xD;
&#xD;
          -  on long-term NA ≥3 years (entecavir or tenofovir)&#xD;
&#xD;
          -  undetectable serum HBV DNA&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  HCC, cirrhosis, history of liver transplantation, or on immunosuppressants,&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Man-Fung Yuen, DSc, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Man Fung Yuen</name>
      <address>
        <city>Hong Kong</city>
        <state>Please Select One ...</state>
        <country>Hong Kong</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 31, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>May 8, 2023</last_update_submitted>
  <last_update_submitted_qc>May 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Professor Yuen Man Fung</investigator_full_name>
    <investigator_title>Chair Professor</investigator_title>
  </responsible_party>
  <keyword>functional cure</keyword>
  <keyword>antiviral therapy</keyword>
  <keyword>nucleoside analogue</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis B</mesh_term>
    <mesh_term>Hepatitis B, Chronic</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Hepatitis, Chronic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Entecavir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Individual participant's personal identification data will be only accessed by the PI and study team.</ipd_description>
  </patient_data>
  <!-- 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/NCT04431245
org study id: HKUUW20-425
nct id: NCT04431245
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Chronic hepatitis B (CHB) infection affected 292 million individuals in the world,
      translating to about 3.9% of global prevalence. Up to 40% of patients with CHB will develop
      liver-related complications. Many patients require long-term oral antiviral therapy since
      off-treatment sustained virological control can only be achieved in a minority of patients.
      It is uncommon for patients taking long-term antivirals to be able to stop the treatment if
      favorable factors are not present. Those include low viral load, long enough duration of
      treatment, and absence of cirrhosis. Some studies have found that inducing a mild flare is
      beneficial for achieving functional cure in chronic hepatitis B infection. There is lack of
      data in the immunological and virological profile in patients who stop their long-term
      antiviral therapy, and in those who developed flare after treatment cessation.
Chronic hepatitis B infection (CHB) affected 292 million individuals in the world in 2016
      according to the Polaris Observatory estimation, translating to about 3.9% global prevalence.
      Up to 40% of patients with CHB will develop liver-related complications and there were
      890,000 deaths from these complications in 2015. Current antiviral therapy is aimed to
      achieve effective viral suppression, biochemical remission, histological improvement, and
      risk reductions in liver-related complications including cirrhosis and liver cancer. Many
      patients require long-term oral nucleos(t)ide analogues (NA) since off-treatment sustained
      virological control can only be achieved in a minority of patients. For HBeAg-negative CHB
      patients, variable rates of durable virological response were observed after cessation of NA.
      Only a small proportion of HBeAg-negative Asian patients (<10%) can successfully stop NA
      without virological breakthrough, compared to more than 60% of Caucasian patients maintaining
      a durable virologic response and even HBsAg seroclearance in up to 30%. Therefore, current
      guidelines in general recommend indefinite duration of NA therapy in HBeAg-negative patients,
      unless guaranteed close monitoring could be provided after cessation of NA in suitable
      subjects. Favourable factors predictive of partial cure include lower baseline HBV DNA, lower
      HBsAg titre or hepatitis B core-related antigen at NA cessation and longer duration of
      consolidation therapy in HBeAg-negative patients. There is lack of data in the immunological
      and virological profile in patients who stop their long-term NA, and in those who developed
      post-NA cessation flare.

      The investigators aim to study the virological and immunological profile in patients who
      stopped long-term NA therapy, with or without post-NA cessation flare. In addition, the
      investigators would like to investigate the effect of mild flare after monitored NA-cessation
      on subsequent virological activity and HBsAg seroclearance.
observational model: Case-Only
time perspective: Prospective
measure: The immunological profile in CHB patients who stopped antiviral therapy
time frame: 24 months
description: The investigators will perform analysis for the immunological aspects for these patients
measure: The virological profile in CHB patients who stopped antiviral therapy
time frame: 24 months
description: The investigators will perform analysis for the virological aspects for these patients
arm group label: Stop antiviral
description: HBeAg-negative non-cirrhotic CHB patients on long-term NA ≥3 years will be identified. Only those who have undetectable serum HBV DNA by the conventional assay (Cobas Taqman, Roche Diagnostics, Branchburg, NJ) which has a lower limit of detection (LLOD) of 10 IU/mL will be recruited. CHB patients were treated with potent oral NA (i.e. tenofovir or entecavir). All recruited patients will have written informed consent for participation of study. Patients with HCC, cirrhosis, history of liver transplantation, or on immunosuppressants, will be excluded.
intervention type: Drug
intervention name: Entecavir
description: Study subjects will stop the antiviral therapy. Patients will be closely monitored every 6-8 weeks for virological flare and/or biochemical flare.
arm group label: Stop antiviral
other name: oral nucleoside analogue
Blood samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Man-Fung Yuen, DSc, MD, PhD
role: Principal Investigator
affiliation: The University of Hong Kong
facility: 
country: Hong Kong
responsible party type: Principal Investigator
investigator affiliation: The University of Hong Kong
investigator full name: Professor Yuen Man Fung
investigator title: Chair Professor
mesh term: Hepatitis A
mesh term: Hepatitis B
mesh term: Hepatitis B, Chronic
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
mesh term: Entecavir
sharing ipd: No
ipd description: Individual participant's personal identification data will be only accessed by the PI and study team.