<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/NCT04480554</url>
  </required_header>
  <id_info>
    <org_study_id>R01DA048728</org_study_id>
    <nct_id>NCT04480554</nct_id>
  </id_info>
  <brief_title>Anti-retroviral Therapy, Medications for Opioid Use Disorder, Opioids and HIV Infection - Study 1</brief_title>
  <acronym>AMOHI-1</acronym>
  <official_title>Effects of Mu-opiate Receptor Engagement on Microbial Translocation and Residual Immune Activation in HIV-infected, ART Suppressed Opioid Use Disorder Patients Initiating Medication-assisted Treatment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pennsylvania</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Drug Abuse</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Wistar Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Institute of Applied Medicine and Epidemiology (IMEA)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ho Chi Minh City CDC</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pennsylvania</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</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>
      HIV infection, as well as exposure to opioids (including heroin), are associated with&#xD;
      systemic immune activation including increased microbial translocation from the gut. The&#xD;
      overall objective of this study is to define the impact of long-term mu-opiate receptor&#xD;
      stimulation or blockage with medication for opiate use disorder (i.e, methadone,&#xD;
      buprenorphine/naloxone, or extended-release naltrexone) on the kinetics and extent of immune&#xD;
      reconstitution on HIV-1 infected people who inject opiate and initiating antiretroviral&#xD;
      therapy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The use of intravenous opioids (e.g., heroin) has been shown to impair the immune&#xD;
      reconstitution outcomes of combined antiretroviral therapy (cART) in HIV-1-infected&#xD;
      individuals. People who inject opioid drugs (PWID) have lower CD4 count recovery and&#xD;
      sustained cellular activation and inflammation compared to non-opioid users. The pathogenesis&#xD;
      of this phenomenon remains understudied. Notably, the effect of oral μ-opioid receptor (MOR)&#xD;
      full agonists (e.g., methadone) or partial agonist (e.g., buprenorphine), which are widely&#xD;
      used as medications for opioid use disorder treatment, on cART-mediated immune reconstitution&#xD;
      is also unknown, limiting the information available to healthcare providers on immune or&#xD;
      viral outcomes associated with MOR agonists or antagonists (e.g., naltrexone) in HIV-infected&#xD;
      PWIDs. The primary objective of this proposal is to establish the extent and pathogenesis of&#xD;
      residual immune activation/inflammation, levels of immune reconstitution, and HIV measures in&#xD;
      HIV-1-infected PWID who start cART concomitant with medication for opioid use disorder in an&#xD;
      addiction clinic with three strategies: a) integrated treatment program (ITP) with oral&#xD;
      methadone maintenance, or b) ITP with oral buprenorphine, or c) ITP with extended-release&#xD;
      naltrexone.&#xD;
&#xD;
      The primary hypothesis is that PWIDs receiving MOR agonists (i.e. methadone maintenance) will&#xD;
      have impaired cART-mediated immune reconstitution outcomes and/or higher levels of systemic&#xD;
      immune activation and cell-associated HIV as compared to PWIDs receiving MOR partial agonist&#xD;
      (i.e., buprenorphine/naloxone) or antagonist (i.e., extended-release naltrexone).&#xD;
&#xD;
      The investigators will test these hypotheses in the following specific aims:&#xD;
&#xD;
      Specific Aim 1: To define the impact of sustained MOR stimulation on the kinetics and extent&#xD;
      of immune reconstitution and activation in HIV-1-infected PWID who are starting cART. To this&#xD;
      end, the investigators will compare long-term changes in immune activation and senescence,&#xD;
      systemic inflammation, and biological immune reconstitution parameters in a cohort of PWID&#xD;
      with chronic HIV infection initiating ART, randomized 1:1:1 to either methadone,&#xD;
      buprenorphine/naloxone or extended-release naltrexone.&#xD;
&#xD;
      Specific Aim 2: To define the clinical and virological correlates of long-term treatment with&#xD;
      MOR full agonist (methadone), partial agonist (buprenorphine/naloxone) and antagonist&#xD;
      (extended-release naltrexone), by analysis of clinical outcomes (CD4 count), adherence to&#xD;
      ART, and retention in care. Viral measures will focus on the changes in persistent HIV&#xD;
      reservoir measures on ART (i.e., characterization of cell-associated viral RNA and DNA&#xD;
      species in PBMC).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 30, 2023</start_date>
  <completion_date type="Anticipated">June 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The study will enroll 225 HIV-positive subjects who meet DSM-5 opiate use disorder criteria and who are using opiates (primarily heroin). All subjects will receive a 48-week integrated treatment program for opiate use disorder with either (randomly assigned) daily directly observed oral methadone (MET) and buprenorphine/naloxone (BUP/NX) or monthly injection extended-release naltrexone (XR-NTX).</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in sCD14</measure>
    <time_frame>Baseline, Week-4, -8, -12, -24, -36, -48</time_frame>
    <description>Change in plasma sCD14 concentration over 48 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Marker of immune activation: Change in CD38</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -36 and -48</time_frame>
    <description>Change in CD38 concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of immune activation: HLA-DR</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -36 and -48</time_frame>
    <description>Change in HLA-DR concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of immune activation: Change in PD1</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -36 and -48</time_frame>
    <description>Change in PD1 expression in C8+ T cells over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of immune activation: Change in CD169</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -36 and -48</time_frame>
    <description>Change in CD169 expression in monocytes over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of immune activation: Change in sCD163</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -36 and -48</time_frame>
    <description>Change in plasma sCD163 concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of immune activation: Change in Type-I IFN</measure>
    <time_frame>baseline, week -12, -24, -36 and -48</time_frame>
    <description>Change in type-I IFN signature over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of inflammation: Change in Plasma hr-CRP</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -48</time_frame>
    <description>Change in plasma hr-CRP concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of inflammation: Change in d-dimer</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -48</time_frame>
    <description>Change in plasma d-dimer concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of inflammation: Change in sTNFR-1</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -48</time_frame>
    <description>Change in plasma sTNFR-1 concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of inflammation: Change in Interleukins IL-6 and IL-10</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -48</time_frame>
    <description>Change in plasma IL-6 and IL-10 concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of inflammation: Change in TGF-beta</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -48</time_frame>
    <description>Change in plasma TGF-beta concentration over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of bacterial translocation: Change in LPB</measure>
    <time_frame>Baseline, Week-48</time_frame>
    <description>Change in plasma LPB concentration at 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of bacterial translocation: Change in LPS</measure>
    <time_frame>Baseline, Week-48</time_frame>
    <description>Change in plasma LPS concentration at 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of bacterial translocation: Change in endo-CAB</measure>
    <time_frame>Baseline, Week-48</time_frame>
    <description>Change in plasma endo-CAB concentration at 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of bacterial translocation: Change in Intestinal fatty acid-binding protein (I-FABP)</measure>
    <time_frame>Baseline, Week-48</time_frame>
    <description>Change in plasma I-FABP concentration at 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of bacterial translocation: Change in Zonulin-1</measure>
    <time_frame>Baseline, Week-48</time_frame>
    <description>Change in plasma Zonulin-1 concentration at 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of bacterial translocation: Change in s16 rDNA</measure>
    <time_frame>Baseline, Week-48</time_frame>
    <description>Change in s16rDNA concentration at 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Marker of bacterial translocation: Change in bacterial butyryl-coA-coA</measure>
    <time_frame>Baseline, Week-48</time_frame>
    <description>Change in bacterial butyryl-coA-coA concentration at 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Retention in care</measure>
    <time_frame>Baseline to Week-48</time_frame>
    <description>Percentage of completed medication visits over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIV-related outcomes: Change in CD4 counts</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -36 and -48</time_frame>
    <description>Change in CD4 counts over 48 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIV-related outcomes: cART adherence</measure>
    <time_frame>baseline, Week-4, -8, -12, -24, -36 and -48</time_frame>
    <description>Number of prescription refills over 48-weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>HIV-related clinical outcomes: Viral load</measure>
    <time_frame>baseline, Week-12, -24, and -48</time_frame>
    <description>Percentage of participants with a suppressed viral load at Week-12, -24, and -48</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Addiction clinical outcomes: Medication for opioid use disorder (MOUD)</measure>
    <time_frame>Week 48</time_frame>
    <description>Comparison of percentage of participants who completed the treatment in each group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Addiction clinical outcomes: Change in Drug use</measure>
    <time_frame>Baseline, Week-4, -8, -12, -16, -20, -24, -28, -32, -36, -40, -44, and -48</time_frame>
    <description>Change in percentage of monthly drug use over 48 weeks</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">225</enrollment>
  <condition>Opioid-use Disorder</condition>
  <condition>HIV-1-infection</condition>
  <condition>Immune Activation</condition>
  <condition>Inflammation</condition>
  <condition>Methadone</condition>
  <condition>Buprenorphine</condition>
  <condition>Naltrexone</condition>
  <condition>Antiretroviral Treatment</condition>
  <arm_group>
    <arm_group_label>Methadone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral methadone (MET) and antiretroviral therapy (cART).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Buprenorphine/naloxone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral buprenorphine/naloxone and antiretroviral therapy (cART).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>XR-Naltrexone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with monthly injection extended-release naltrexone (XR-NTX) and antiretroviral therapy (cART).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methadone</intervention_name>
    <description>Participants will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral methadone syrup (MET), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.</description>
    <arm_group_label>Methadone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Buprenorphine/naloxone</intervention_name>
    <description>Participants will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral buprenorphine/naloxone tablets (Suboxone(R)), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.</description>
    <arm_group_label>Buprenorphine/naloxone</arm_group_label>
    <other_name>Suboxone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>XR-Naltrexone</intervention_name>
    <description>Participants will receive a 48-week integrated treatment program for opiate use disorder with monthly extended-release naltrexone (Vivitrol(R)), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.</description>
    <arm_group_label>XR-Naltrexone</arm_group_label>
    <other_name>Vivitrol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Meet DSM-5 criteria for moderate to severe opiate use disorder (as determined by DSM-5&#xD;
             checklist)&#xD;
&#xD;
          -  Opiate use with a positive urine drug screen for heroin or other opiates (other than&#xD;
             methadone, buprenorphine, buprenorphine/naloxone) at screening visit&#xD;
&#xD;
          -  Documented HIV-1 infection with CD4 less than 350 cells/ μL and VL more than 10,000&#xD;
             copies/mL&#xD;
&#xD;
          -  cART-naïve or or on cART no longer than 3 months if already started&#xD;
&#xD;
          -  Willingness to receive cART or on cART no longer than 3 months if already started&#xD;
&#xD;
          -  Willingness to be randomized to either daily methadone, buprenorphine/naloxone or&#xD;
             monthly injection of extended-release naltrexone treatment&#xD;
&#xD;
          -  Ability to understand and complete study procedures&#xD;
&#xD;
          -  Provision of adequate locator information that lists all contact information a&#xD;
             participant agrees that the research staff may use to reach him/her&#xD;
&#xD;
          -  All participants must be able to comprehend the purpose of the study and to provide&#xD;
             informed consent&#xD;
&#xD;
          -  Is, in the opinion of the study physician, in stable health as determined by pre-study&#xD;
             physical examination, medical history, ECG, and laboratory evaluations and is likely&#xD;
             to complete the study.&#xD;
&#xD;
          -  Has a total body weight of more than 50 kg (110 pounds) and a body mass index (BMI) of&#xD;
             more than 20 at screening.&#xD;
&#xD;
          -  Female subjects: Cannot be pregnant, Cannot be lactating, Must be unable to conceive&#xD;
             (i.e., surgically sterilized, sterile, or post-menopausal defined as 1 year without&#xD;
             bleeding or spotting) OR must agree to use an acceptable method of birth control&#xD;
             (e.g., birth control pills, intrauterine device [IUD], or a double barrier method of&#xD;
             birth control (condoms and spermicide together; or diaphragm, condom and spermicide&#xD;
             together)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current cognitive impairment, schizophrenia, paranoid disorder, bipolar disorder not&#xD;
             compatible with study procedure (assessed by the medical director of the study)&#xD;
&#xD;
          -  Known neurological, cardiovascular, renal, or other significant medical disorder that&#xD;
             is likely to impair or make the individual's participation hazardous Active&#xD;
             Tuberculosis or other symptomatic infectious disease AIDS-defining illness&#xD;
&#xD;
          -  Current cancer or other malignancies&#xD;
&#xD;
          -  Advanced liver disease (FibroScan® METAVIR score F3-F4, liver elasticity more&#xD;
             than10kPa)&#xD;
&#xD;
          -  Use of immunomodulators&#xD;
&#xD;
          -  Meet DSM-5 criteria for any other substance use disorder (except nicotine)&#xD;
&#xD;
          -  Engagement in opiate medication treatment at baseline (methadone, buprenorphine,&#xD;
             buprenorphine/naloxone, naltrexone)&#xD;
&#xD;
          -  Pending legal charges with likely incarceration within next 6 months&#xD;
&#xD;
          -  Currently participating in another clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Luis J Montaner, DVM, D.Phil</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Wistar Institute</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>David S Metzger, PhD</last_name>
    <phone>2157467346</phone>
    <email>dsm@pennmedicine.upenn.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Cecile M Denis, PhD</last_name>
    <phone>2158981825</phone>
    <email>cdenis@pennmedicine.upenn.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Go Vap Clinic</name>
      <address>
        <city>Ho Chi Minh City</city>
        <country>Vietnam</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Thuy Huynh Thu, MD, MSc</last_name>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
    <country>Vietnam</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>July 1, 2020</study_first_submitted>
  <study_first_submitted_qc>July 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 21, 2020</study_first_posted>
  <last_update_submitted>July 6, 2023</last_update_submitted>
  <last_update_submitted_qc>July 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Opioid use disorder</keyword>
  <keyword>HIV</keyword>
  <keyword>Medication for Opioid Use Disorder</keyword>
  <keyword>Antiretroviral therapy</keyword>
  <keyword>Immune activation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Opioid-Related Disorders</mesh_term>
    <mesh_term>Substance-Related Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Naltrexone</mesh_term>
    <mesh_term>Buprenorphine</mesh_term>
    <mesh_term>Methadone</mesh_term>
    <mesh_term>Buprenorphine, Naloxone Drug Combination</mesh_term>
    <mesh_term>Naloxone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 19, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/54/NCT04480554/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04480554
org study id: R01DA048728
nct id: NCT04480554
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
HIV infection, as well as exposure to opioids (including heroin), are associated with
      systemic immune activation including increased microbial translocation from the gut. The
      overall objective of this study is to define the impact of long-term mu-opiate receptor
      stimulation or blockage with medication for opiate use disorder (i.e, methadone,
      buprenorphine/naloxone, or extended-release naltrexone) on the kinetics and extent of immune
      reconstitution on HIV-1 infected people who inject opiate and initiating antiretroviral
      therapy.
The use of intravenous opioids (e.g., heroin) has been shown to impair the immune
      reconstitution outcomes of combined antiretroviral therapy (cART) in HIV-1-infected
      individuals. People who inject opioid drugs (PWID) have lower CD4 count recovery and
      sustained cellular activation and inflammation compared to non-opioid users. The pathogenesis
      of this phenomenon remains understudied. Notably, the effect of oral μ-opioid receptor (MOR)
      full agonists (e.g., methadone) or partial agonist (e.g., buprenorphine), which are widely
      used as medications for opioid use disorder treatment, on cART-mediated immune reconstitution
      is also unknown, limiting the information available to healthcare providers on immune or
      viral outcomes associated with MOR agonists or antagonists (e.g., naltrexone) in HIV-infected
      PWIDs. The primary objective of this proposal is to establish the extent and pathogenesis of
      residual immune activation/inflammation, levels of immune reconstitution, and HIV measures in
      HIV-1-infected PWID who start cART concomitant with medication for opioid use disorder in an
      addiction clinic with three strategies: a) integrated treatment program (ITP) with oral
      methadone maintenance, or b) ITP with oral buprenorphine, or c) ITP with extended-release
      naltrexone.

      The primary hypothesis is that PWIDs receiving MOR agonists (i.e. methadone maintenance) will
      have impaired cART-mediated immune reconstitution outcomes and/or higher levels of systemic
      immune activation and cell-associated HIV as compared to PWIDs receiving MOR partial agonist
      (i.e., buprenorphine/naloxone) or antagonist (i.e., extended-release naltrexone).

      The investigators will test these hypotheses in the following specific aims:

      Specific Aim 1: To define the impact of sustained MOR stimulation on the kinetics and extent
      of immune reconstitution and activation in HIV-1-infected PWID who are starting cART. To this
      end, the investigators will compare long-term changes in immune activation and senescence,
      systemic inflammation, and biological immune reconstitution parameters in a cohort of PWID
      with chronic HIV infection initiating ART, randomized 1:1:1 to either methadone,
      buprenorphine/naloxone or extended-release naltrexone.

      Specific Aim 2: To define the clinical and virological correlates of long-term treatment with
      MOR full agonist (methadone), partial agonist (buprenorphine/naloxone) and antagonist
      (extended-release naltrexone), by analysis of clinical outcomes (CD4 count), adherence to
      ART, and retention in care. Viral measures will focus on the changes in persistent HIV
      reservoir measures on ART (i.e., characterization of cell-associated viral RNA and DNA
      species in PBMC).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The study will enroll 225 HIV-positive subjects who meet DSM-5 opiate use disorder criteria and who are using opiates (primarily heroin). All subjects will receive a 48-week integrated treatment program for opiate use disorder with either (randomly assigned) daily directly observed oral methadone (MET) and buprenorphine/naloxone (BUP/NX) or monthly injection extended-release naltrexone (XR-NTX).
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in sCD14
time frame: Baseline, Week-4, -8, -12, -24, -36, -48
description: Change in plasma sCD14 concentration over 48 weeks
measure: Marker of immune activation: Change in CD38
time frame: baseline, Week-4, -8, -12, -24, -36 and -48
description: Change in CD38 concentration over 48 weeks
measure: Marker of immune activation: HLA-DR
time frame: baseline, Week-4, -8, -12, -24, -36 and -48
description: Change in HLA-DR concentration over 48 weeks
measure: Marker of immune activation: Change in PD1
time frame: baseline, Week-4, -8, -12, -24, -36 and -48
description: Change in PD1 expression in C8+ T cells over 48 weeks
measure: Marker of immune activation: Change in CD169
time frame: baseline, Week-4, -8, -12, -24, -36 and -48
description: Change in CD169 expression in monocytes over 48 weeks
measure: Marker of immune activation: Change in sCD163
time frame: baseline, Week-4, -8, -12, -24, -36 and -48
description: Change in plasma sCD163 concentration over 48 weeks
measure: Marker of immune activation: Change in Type-I IFN
time frame: baseline, week -12, -24, -36 and -48
description: Change in type-I IFN signature over 48 weeks
measure: Marker of inflammation: Change in Plasma hr-CRP
time frame: baseline, Week-4, -8, -12, -24, -48
description: Change in plasma hr-CRP concentration over 48 weeks
measure: Marker of inflammation: Change in d-dimer
time frame: baseline, Week-4, -8, -12, -24, -48
description: Change in plasma d-dimer concentration over 48 weeks
measure: Marker of inflammation: Change in sTNFR-1
time frame: baseline, Week-4, -8, -12, -24, -48
description: Change in plasma sTNFR-1 concentration over 48 weeks
measure: Marker of inflammation: Change in Interleukins IL-6 and IL-10
time frame: baseline, Week-4, -8, -12, -24, -48
description: Change in plasma IL-6 and IL-10 concentration over 48 weeks
measure: Marker of inflammation: Change in TGF-beta
time frame: baseline, Week-4, -8, -12, -24, -48
description: Change in plasma TGF-beta concentration over 48 weeks
measure: Marker of bacterial translocation: Change in LPB
time frame: Baseline, Week-48
description: Change in plasma LPB concentration at 48 weeks
measure: Marker of bacterial translocation: Change in LPS
time frame: Baseline, Week-48
description: Change in plasma LPS concentration at 48 weeks
measure: Marker of bacterial translocation: Change in endo-CAB
time frame: Baseline, Week-48
description: Change in plasma endo-CAB concentration at 48 weeks
measure: Marker of bacterial translocation: Change in Intestinal fatty acid-binding protein (I-FABP)
time frame: Baseline, Week-48
description: Change in plasma I-FABP concentration at 48 weeks
measure: Marker of bacterial translocation: Change in Zonulin-1
time frame: Baseline, Week-48
description: Change in plasma Zonulin-1 concentration at 48 weeks
measure: Marker of bacterial translocation: Change in s16 rDNA
time frame: Baseline, Week-48
description: Change in s16rDNA concentration at 48 weeks
measure: Marker of bacterial translocation: Change in bacterial butyryl-coA-coA
time frame: Baseline, Week-48
description: Change in bacterial butyryl-coA-coA concentration at 48 weeks
measure: Retention in care
time frame: Baseline to Week-48
description: Percentage of completed medication visits over 48 weeks
measure: HIV-related outcomes: Change in CD4 counts
time frame: baseline, Week-4, -8, -12, -24, -36 and -48
description: Change in CD4 counts over 48 weeks
measure: HIV-related outcomes: cART adherence
time frame: baseline, Week-4, -8, -12, -24, -36 and -48
description: Number of prescription refills over 48-weeks
measure: HIV-related clinical outcomes: Viral load
time frame: baseline, Week-12, -24, and -48
description: Percentage of participants with a suppressed viral load at Week-12, -24, and -48
measure: Addiction clinical outcomes: Medication for opioid use disorder (MOUD)
time frame: Week 48
description: Comparison of percentage of participants who completed the treatment in each group
measure: Addiction clinical outcomes: Change in Drug use
time frame: Baseline, Week-4, -8, -12, -16, -20, -24, -28, -32, -36, -40, -44, and -48
description: Change in percentage of monthly drug use over 48 weeks
arm group label: Methadone
arm group type: Experimental
description: Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral methadone (MET) and antiretroviral therapy (cART).
arm group label: Buprenorphine/naloxone
arm group type: Experimental
description: Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral buprenorphine/naloxone and antiretroviral therapy (cART).
arm group label: XR-Naltrexone
arm group type: Experimental
description: Participants in this arm will receive a 48-week integrated treatment program for opiate use disorder with monthly injection extended-release naltrexone (XR-NTX) and antiretroviral therapy (cART).
intervention type: Drug
intervention name: Methadone
description: Participants will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral methadone syrup (MET), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.
arm group label: Methadone
intervention type: Drug
intervention name: Buprenorphine/naloxone
description: Participants will receive a 48-week integrated treatment program for opiate use disorder with daily directly observed oral buprenorphine/naloxone tablets (Suboxone(R)), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.
arm group label: Buprenorphine/naloxone
other name: Suboxone
intervention type: Drug
intervention name: XR-Naltrexone
description: Participants will receive a 48-week integrated treatment program for opiate use disorder with monthly extended-release naltrexone (Vivitrol(R)), structured counseling sessions (BDRC-based) weekly for the first 3 months and monthly thereafter, and antiretroviral therapy.
arm group label: XR-Naltrexone
other name: Vivitrol
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Luis J Montaner, DVM, D.Phil
role: Principal Investigator
affiliation: The Wistar Institute
last name: David S Metzger, PhD
phone: 2157467346
email: dsm@pennmedicine.upenn.edu
last name: Cecile M Denis, PhD
phone: 2158981825
email: cdenis@pennmedicine.upenn.edu
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
country: United States
country: Vietnam
responsible party type: Sponsor
mesh term: Infections
mesh term: Inflammation
mesh term: Opioid-Related Disorders
mesh term: Substance-Related Disorders
mesh term: Naltrexone
mesh term: Buprenorphine
mesh term: Methadone
mesh term: Buprenorphine, Naloxone Drug Combination
mesh term: Naloxone
sharing ipd: No
provided document: 