<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/NCT03800407</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201801820 TB/HIV - N</org_study_id>
    <secondary_id>2R01HD071779</secondary_id>
    <secondary_id>5R01HD071779-10</secondary_id>
    <nct_id>NCT03800407</nct_id>
  </id_info>
  <brief_title>Contributing Factors for Poor HIV Treatment Response in Children With TB/HIV Coinfection</brief_title>
  <official_title>Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Florida</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Efavirenz (EFV)-based antiretroviral therapy (ART) remains the preferred regimen in human&#xD;
      immunodeficiency virus (HIV)-infected children aged 3 years or older on rifampin-containing&#xD;
      antituberculosis (anti-TB) therapy. This is because drug interactions between first-line&#xD;
      anti-TB therapy with protease inhibitors (PIs) are more severe to adjust for, and&#xD;
      interactions with integrase strand transfer inhibitors (INSTIs) are not well studied in that&#xD;
      age group. Although, current weight-based EFV dosing recommendation is not optimal in some&#xD;
      children, pharmacokinetic-treatment response (PK-PD) data to guide optimal dosing of EFV&#xD;
      during concurrent rifampin-containing therapy in children is very limited. The study team&#xD;
      propose that EFV concentrations outside the optimal therapeutic range in children will be&#xD;
      associated with virologic failure due to lack of efficacy because of low concentrations or&#xD;
      increased central nervous system (CNS) toxicities from high concentrations leading to poor&#xD;
      medication adherence. The study will determine virological suppression rates in HIV-infected&#xD;
      children with and without TB coinfection treated with standard efavirenz-based therapy and&#xD;
      examine the factors contributing to poor virologic response.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In a previous study, the study team found that first-line anti-TB therapy had minimal effect&#xD;
      on EFV pharmacokinetics (PK) at the population level, but children with TB/HIV coinfection on&#xD;
      anti-TB therapy had a trend towards worse virologic outcome compared to those with only HIV&#xD;
      infection. Due to the small sample size, the study team were unable to examined the patient&#xD;
      factors contributing to the poor virologic response. The study team hypothesized that&#xD;
      virologic suppression rates on EFV-based therapy is significantly lower in children with&#xD;
      TB/HIV coinfection compared to those with HIV alone. In addition, virologic response will be&#xD;
      dependent EFV plasma concentrations, CYP2B6 516 G&gt;T genotype and/or adherence level. This&#xD;
      hypothesis is based on the premise that extremes (low and high EFV concentration,&#xD;
      respectively) could lead to virologic failure because of lack of efficacy or intolerable side&#xD;
      effects leading to poor adherence. The current study will investigate the effect of anti-TB&#xD;
      therapy, CYP2B6 genotype and pharmacokinetically determined adherence level on virologic&#xD;
      response in children with TB/HIV coinfection treated with EFV-based ART.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 28, 2019</start_date>
  <completion_date type="Anticipated">November 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>TB coinfection status and HIV RNA &lt; 200 copies/mL on EFV-based ART in HIV-infected children.</measure>
    <time_frame>At week 24 of HIV therapy.</time_frame>
    <description>The proportion of children with TB/HIV coinfection with virological suppression (HIV RNA &lt; 200 copies/mL) on EFV-based ART and anti-TB therapy compared to that in children with only HIV infection on EFV-based therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efavirenz plasma mid-dose concentration and HIV RNA suppression &lt; 200 copies/mL.</measure>
    <time_frame>Up to week 24 of HIV therapy.</time_frame>
    <description>Relationship between EFV mid-dose concentration and HIV RNA suppression rate in the combined population of HIV-infected children with and without TB coinfection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Random efavirenz concentration below the limit of detection (poor ART adherence) and HIV RNA suppression rate.</measure>
    <time_frame>Up to week 24 of HIV therapy.</time_frame>
    <description>Relationship poor ART adherence and EFV-based ART response in the combined population of HIV-infected children with and without TB coinfection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CYP2B6 516G&gt;T genotype status and random efavirenz concentration below the limit of detection (poor ART adherence).</measure>
    <time_frame>Up to week 24 of HIV therapy.</time_frame>
    <description>Relationship between CYP2B6 516G&gt;T genotype status and likelihood of poor EFV-based ART adherence.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CYP2B6 516G&gt;T genotype status and HIV RNA suppression &lt; 200 copies/mL.</measure>
    <time_frame>Up to week 24 of HIV therapy.</time_frame>
    <description>Relationship between CYP2B6 516G&gt;T genotype status and likelihood of HIV RNA suppression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>TB coinfection status and risk of virological failure on EFV-based ART.</measure>
    <time_frame>Up to week 48 of HIV therapy.</time_frame>
    <description>Proportion of children with TB/HIV coinfection compared to those with only HIV infection with virological failure (HIV RNA &gt; 1000 copies/mL) at 12 months of EFV-based ART.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">382</enrollment>
  <condition>Tuberculosis</condition>
  <condition>Human Immunodeficiency Virus</condition>
  <condition>Coinfection</condition>
  <arm_group>
    <arm_group_label>EFV-based ART</arm_group_label>
    <description>ART-naïve HIV-infected children aged 3 - 14 years who initiate EFV-based ART</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Concurrent EFV-based ART plus anti-TB therapy</arm_group_label>
    <description>ART-naïve HIV-infected children aged 3 - 14 years with TB coinfection who initiate EFV-based ART while receiving first-line anti-TB therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Observational study</intervention_name>
    <description>Outcome of EFV-based ART in children with TB/HIV coinfection compared to those with HIV only on EFV-based ART</description>
    <arm_group_label>Concurrent EFV-based ART plus anti-TB therapy</arm_group_label>
    <arm_group_label>EFV-based ART</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Ethylenediaminetetraacetic acid (EDTA) plasma and whole blood DNA&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Children aged 3 to 14 years old with HIV infection with or without active TB&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV seropositive children with or without active TB&#xD;
&#xD;
          -  Antiretroviral-naïve to efavirenz and meet criteria for initiation or switch to&#xD;
             efavirenz-based ART&#xD;
&#xD;
          -  Are available for follow-up until achievement of a study endpoint like completion of&#xD;
             study at 6 months or discontinuation of ART.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to obtain informed signed consent parent(s) or legal guardian&#xD;
&#xD;
          -  Have AIDS-related opportunistic infections other than TB&#xD;
&#xD;
          -  History of acute hepatitis within 30 days of study entry&#xD;
&#xD;
          -  Persistent vomiting or diarrhea at time of enrolment&#xD;
&#xD;
          -  Hemoglobin &lt; 6 g/dl, white blood cells &lt; 2500/mm3, serum creatinine &gt; 1.5 mg/dl,&#xD;
             aspartate transaminase (AST) and alanine transaminase (ALT) &gt; 2 times upper limit of&#xD;
             normal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>14 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Awewura Kwara, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Awewura Kwara, MD</last_name>
    <phone>3522739501</phone>
    <email>awewura.kwara@medicine.ufl.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Oluwayemisi Ojewale, MBChB, MPH</last_name>
    <phone>3522739446</phone>
    <email>Oluwayemisi.Ojewale@medicine.ufl.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Kwame Nkrumah University of Science and Technology</name>
      <address>
        <city>Kumasi</city>
        <country>Ghana</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sampson Antwi, MBChB</last_name>
      <phone>+233265812061</phone>
      <email>kantwi@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Anthony Enimil, MBChB</last_name>
      <phone>+233208164433</phone>
      <email>tenimil@live.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Ghana</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 3, 2019</study_first_submitted>
  <study_first_submitted_qc>January 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>May 15, 2023</last_update_submitted>
  <last_update_submitted_qc>May 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pharmacokinetic</keyword>
  <keyword>Concurrent antituberculosis therapy</keyword>
  <keyword>Efavirenz</keyword>
  <keyword>Virologic response</keyword>
  <keyword>Children</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
    <mesh_term>Coinfection</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </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/NCT03800407
org study id: IRB201801820 TB/HIV - N
secondary id: 2R01HD071779
secondary id: 5R01HD071779-10
nct id: NCT03800407
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: Yes
Efavirenz (EFV)-based antiretroviral therapy (ART) remains the preferred regimen in human
      immunodeficiency virus (HIV)-infected children aged 3 years or older on rifampin-containing
      antituberculosis (anti-TB) therapy. This is because drug interactions between first-line
      anti-TB therapy with protease inhibitors (PIs) are more severe to adjust for, and
      interactions with integrase strand transfer inhibitors (INSTIs) are not well studied in that
      age group. Although, current weight-based EFV dosing recommendation is not optimal in some
      children, pharmacokinetic-treatment response (PK-PD) data to guide optimal dosing of EFV
      during concurrent rifampin-containing therapy in children is very limited. The study team
      propose that EFV concentrations outside the optimal therapeutic range in children will be
      associated with virologic failure due to lack of efficacy because of low concentrations or
      increased central nervous system (CNS) toxicities from high concentrations leading to poor
      medication adherence. The study will determine virological suppression rates in HIV-infected
      children with and without TB coinfection treated with standard efavirenz-based therapy and
      examine the factors contributing to poor virologic response.
In a previous study, the study team found that first-line anti-TB therapy had minimal effect
      on EFV pharmacokinetics (PK) at the population level, but children with TB/HIV coinfection on
      anti-TB therapy had a trend towards worse virologic outcome compared to those with only HIV
      infection. Due to the small sample size, the study team were unable to examined the patient
      factors contributing to the poor virologic response. The study team hypothesized that
      virologic suppression rates on EFV-based therapy is significantly lower in children with
      TB/HIV coinfection compared to those with HIV alone. In addition, virologic response will be
      dependent EFV plasma concentrations, CYP2B6 516 G>T genotype and/or adherence level. This
      hypothesis is based on the premise that extremes (low and high EFV concentration,
      respectively) could lead to virologic failure because of lack of efficacy or intolerable side
      effects leading to poor adherence. The current study will investigate the effect of anti-TB
      therapy, CYP2B6 genotype and pharmacokinetically determined adherence level on virologic
      response in children with TB/HIV coinfection treated with EFV-based ART.
observational model: Cohort
time perspective: Prospective
measure: TB coinfection status and HIV RNA < 200 copies/mL on EFV-based ART in HIV-infected children.
time frame: At week 24 of HIV therapy.
description: The proportion of children with TB/HIV coinfection with virological suppression (HIV RNA < 200 copies/mL) on EFV-based ART and anti-TB therapy compared to that in children with only HIV infection on EFV-based therapy.
measure: Efavirenz plasma mid-dose concentration and HIV RNA suppression < 200 copies/mL.
time frame: Up to week 24 of HIV therapy.
description: Relationship between EFV mid-dose concentration and HIV RNA suppression rate in the combined population of HIV-infected children with and without TB coinfection.
measure: Random efavirenz concentration below the limit of detection (poor ART adherence) and HIV RNA suppression rate.
time frame: Up to week 24 of HIV therapy.
description: Relationship poor ART adherence and EFV-based ART response in the combined population of HIV-infected children with and without TB coinfection.
measure: CYP2B6 516G>T genotype status and random efavirenz concentration below the limit of detection (poor ART adherence).
time frame: Up to week 24 of HIV therapy.
description: Relationship between CYP2B6 516G>T genotype status and likelihood of poor EFV-based ART adherence.
measure: CYP2B6 516G>T genotype status and HIV RNA suppression < 200 copies/mL.
time frame: Up to week 24 of HIV therapy.
description: Relationship between CYP2B6 516G>T genotype status and likelihood of HIV RNA suppression.
measure: TB coinfection status and risk of virological failure on EFV-based ART.
time frame: Up to week 48 of HIV therapy.
description: Proportion of children with TB/HIV coinfection compared to those with only HIV infection with virological failure (HIV RNA > 1000 copies/mL) at 12 months of EFV-based ART.
arm group label: EFV-based ART
description: ART-naïve HIV-infected children aged 3 - 14 years who initiate EFV-based ART
arm group label: Concurrent EFV-based ART plus anti-TB therapy
description: ART-naïve HIV-infected children aged 3 - 14 years with TB coinfection who initiate EFV-based ART while receiving first-line anti-TB therapy
intervention type: Other
intervention name: Observational study
description: Outcome of EFV-based ART in children with TB/HIV coinfection compared to those with HIV only on EFV-based ART
arm group label: Concurrent EFV-based ART plus anti-TB therapy
arm group label: EFV-based ART
Ethylenediaminetetraacetic acid (EDTA) plasma and whole blood DNA
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 3 Years
maximum age: 14 Years
healthy volunteers: No
last name: Awewura Kwara, MD
role: Principal Investigator
affiliation: University of Florida
last name: Awewura Kwara, MD
phone: 3522739501
email: awewura.kwara@medicine.ufl.edu
last name: Oluwayemisi Ojewale, MBChB, MPH
phone: 3522739446
email: Oluwayemisi.Ojewale@medicine.ufl.edu
facility: 
status: Recruiting
contact: 
contact backup: 
country: Ghana
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Coinfection
sharing ipd: Undecided