<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/NCT02989285</url>
  </required_header>
  <id_info>
    <org_study_id>15/277</org_study_id>
    <secondary_id>APP1105808</secondary_id>
    <nct_id>NCT02989285</nct_id>
  </id_info>
  <brief_title>Identification and Quantification of HIV CNS Latency Biomarkers</brief_title>
  <official_title>The Identification and Quantification of HIV CNS Latency Biomarkers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>St Vincent's Hospital, Sydney</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>St Vincent's Hospital, Sydney</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Human Immunodeficiency Virus (HIV) remains in infected patients receiving highly active&#xD;
      antiretroviral therapy (HAART) for many years. Stopping HAART usually leads to re-emergence&#xD;
      of small reservoirs of latent (inactive) HIV that reside inside certain types of infected&#xD;
      cells, that can replicate and cause a full HIV infection. Chronic HIV infection also leads to&#xD;
      long-term immune activation which is associated with higher incidence of serious non-AIDS&#xD;
      events including cardiovascular disease and cancers. Thus HIV+ patients must remain on HAART&#xD;
      indefinitely or replication-competent latent HIV reservoirs must be eradicated.&#xD;
&#xD;
      The central nervous system (CNS) is a sanctuary site for latent HIV. For example,&#xD;
      HIV-associated neurocognitive disorders (HAND) develop and persist in about 40% of HIV+&#xD;
      persons despite long-term HAART and viral suppression in blood and cerebrospinal fluid (CSF).&#xD;
      Continued CSF immune activation is also frequently observed despite viral suppression. Both&#xD;
      of these are likely to indicate ongoing low-level HIV replication in the CNS.&#xD;
&#xD;
      Several strategies to eradicate latent HIV are being explored. One of these, known as &quot;shock&#xD;
      and kill&quot; involves &quot;awakening&quot; latent HIV and inducing replication to make it more&#xD;
      susceptible to host immune responses and HAART. However, there are several major caveats to&#xD;
      its application in the CNS such as the risk of triggering a serious immunoinflammatory&#xD;
      response (e.g., meningoencephalitis) that cannot be easily controlled by HAART. Other&#xD;
      eradication strategies may also be problematic given that many latency-reversing agents have&#xD;
      limited penetration of the blood brain barrier and limited efficacy in astrocyte cells. To&#xD;
      improve the effectiveness of new eradication therapies it will be crucial to develop better&#xD;
      methods to identify and quantify latent HIV reservoir sites with greater precision.&#xD;
&#xD;
      To identify potential HIV latency biomarkers in the CNS, the investigators will study HIV+&#xD;
      patients stable on HAART and virally-suppressed in blood and CSF over 24 months. Because such&#xD;
      a marker should be associated with HAND or its development without changing significantly&#xD;
      with HAND progression, half of the sample will have HAND at study entry and half will not.&#xD;
      Patients will undergo neuropsychological testing and give blood and CSF samples every 6&#xD;
      months to identify candidate biomarkers and track them prospectively against HAND development&#xD;
      and progression. MRI brain scan will also occur at study entry and after 24 months.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>July 2016</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2020</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>Change in Mean CSF BCL11b levels at 24 months (latency burden biomarker)</measure>
    <time_frame>Baseline and 24 months</time_frame>
    <description>BCL11b is a C2H5 zinc-finger DNA binding protein that is expressed in the brain and immune system and inhibits HIV gene transcription by recruiting chromatin modifiers and establishing a heterochromatic environment in HIV-infected microglia. It is a promising candidate biomarker for latent HIV infection in the brain. Change in CSF BCL11b levels from baseline at 24 months will be reported. BCL11b will also be tracked against HAND development/progression at each visit to determine its suitability as a marker of latent HIV reservoir size.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Mean Level of 1H-MRS Myo-Inositol in Frontal White Matter at 24 months (latency burden biomarker)</measure>
    <time_frame>Baseline and 24 months</time_frame>
    <description>Myo-Inositol (mIo) is a brain metabolic marker measured by 1H-Magnetic Resonance Spectroscopy (MRS) that is thought to reflect astroglia and microglia activation in cognitively-impaired individuals. The finding that mIo in the frontal white matter is elevated in HIV+ individuals and remains elevated with HAND progression while other metabolite levels fluctuate, supports its possibility as a HIV latency biomarker. Change in 1H-MRS mIo levels in the FWM from baseline at 24 months will be reported. mIo will also be tracked against HAND development/progression to determine its suitability as a marker of latent HIV reservoir size.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Mean CSF HIV RNA by Single Copy Assay at 24 months (latency significance biomarker)</measure>
    <time_frame>Baseline and 24 months</time_frame>
    <description>Single copy assay (SCA) of CSF HIV RNA will allow for precise detection of intermittent HIV brain infection productivity at low levels. This assay is highly sensitive and can measure levels of HIV RNA as low as 0.3 copies per ml. Change in CSF HIV RNA levels from baseline at 24 months will be reported. Detectability of CSF HIV RNA by SCA is related to increased risk of HAND development in asymptomatic patients suggesting that it may reflect a marker of latent HIV reservoir significance (i.e., the potential for latent HIV replication that is not defective). Such a marker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Mean CSF HIV tat at 24 months (latency significance biomarker)</measure>
    <time_frame>Baseline and 24 months</time_frame>
    <description>Tat is a post-transcriptional regulatory protein that promotes inflammation and enhances the effectiveness of HIV transcription to neighbouring cells. Therefore it may act as a latency significance biomarker. Change in CSF HIV tat levels from baseline at 24 months will be reported. HIV tat will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Mean CSF neopterin at 24 months (latency significance biomarker)</measure>
    <time_frame>Baseline and 24 months</time_frame>
    <description>Neopterin is an immune activation biomarker that is elevated in almost all persons with HAND on antiretroviral medication and in some without HAND, supporting its possible role as a latency significance marker. Change in CSF neopterin levels from baseline at 24 months will be reported. CSF neopterin will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Mean CSF MCP-1 at 24 months (latency significance biomarker)</measure>
    <time_frame>Baseline and 24 months</time_frame>
    <description>CSF MCP-1 is an immune activation biomarker that has been found to correlate with change in HAND status. Therefore it may be a latency significance marker. Change in CSF MCP-1 levels from baseline at 24 months will be reported. CSF MCP-1 will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Mean CSF NFL at 24 months (latency significance biomarker)</measure>
    <time_frame>Baseline and 24 Months</time_frame>
    <description>CSF NFL is a marker of neuronal injury. It has been shown to correlate with HAND severity and predict its development, suggesting that it is likely to serve as a latency significance biomarker. Change in CSF NFL levels from baseline at 24 months will be reported. CSF NFL will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation between CSF HIV tat, neurocognitive global deficit score, neopterin, and MCP-1 at 24 months</measure>
    <time_frame>Baseline and 24 months</time_frame>
    <description>Cumulative levels of HIV tat in CSF will be quantified from baseline to 24 months as per primary outcome #4. They will then be correlated against HAND development/progression as quantified by neurocognitive global deficit score (GDS), and levels of inflammatory markers neopterin and MCP-1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Role of Pre-Integration-Targeting HAART in Reducing HIV Latency Burden</measure>
    <time_frame>Baseline and 6 months, 12 months, 18 months, and 24 months</time_frame>
    <description>Cumulative HAART history will be recorded and scored as follows: drugs that target the pre-integration/integration phase of HIV replication will be given a score of 1; other drugs will be given a score of 0. Total scores will then be correlated with CSF BCL11b levels and any other CNS latency marker that is identified during primary outcome analyses.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">70</enrollment>
  <condition>HIV</condition>
  <condition>HIV-associated Neurocognitive Disorder (HAND)</condition>
  <arm_group>
    <arm_group_label>HIV+ cognitively impaired (HAND)</arm_group_label>
    <description>Participants will be assessed based on their performance on the neuropsychological test battery at study entry. HAND status will be diagnosed per FRASCATI research criteria and this will determine which study cohort they are allocated to. Participants will continue to receive their standard of care treatment during the study period.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV+ cognitively normal (no-HAND)</arm_group_label>
    <description>Participants will be assessed based on their performance on the neuropsychological test battery at study entry. HAND status will be diagnosed per FRASCATI research criteria and this will determine which study cohort they are allocated to. Participants will continue to receive their standard of care treatment during the study period.</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Cerebrospinal fluid and bloods&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HIV+ patients who are stable on HAART and have achieved viral suppression in blood and CSF&#xD;
        who attend outpatient hospital and primary care clinics.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV-infected&#xD;
&#xD;
          -  Aged &gt;18 years&#xD;
&#xD;
          -  On HAART with viral load suppression (&lt;50 copies / ml) in both plasma and CSF for at&#xD;
             least 6 months&#xD;
&#xD;
          -  Able to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non-HIV related neurological disorder or active CNS opportunistic infection as&#xD;
             assessed by full blood count, electrolytes, creatinine, glucose, liver function tests,&#xD;
             venereal disease reaction level (VDRL), MRI brain scan and CSF analyses for cell&#xD;
             count, protein, glucose, culture, VDRL and cryptococcal antigen&#xD;
&#xD;
          -  Psychiatric disorders on the psychotic axis, current major depression, current&#xD;
             substance use disorder and/or 12 month history of severe substance use disorder&#xD;
&#xD;
          -  Active Hepatitis C co-infection&#xD;
&#xD;
          -  History of severe traumatic brain injury (post-traumatic amnesia (PTA) duration&gt;1 day)&#xD;
             or loss of consciousness &gt; 30 minutes from other cause (e.g., hypoxic brain injury)&#xD;
&#xD;
          -  Non-proficient in English&#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>Bruce J Brew, MBBS, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>St Vincent's Hospital, Sydney</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Bruce J Brew, MBBS, MD</last_name>
    <phone>+61 2 8382 1111</phone>
    <phone_ext>4100</phone_ext>
    <email>bruce.brew@svha.org.au</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Thomas M Gates, MPsychol</last_name>
    <phone>+61 2 8382 1111</phone>
    <phone_ext>2435</phone_ext>
    <email>thomas.gates@svha.org.au</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>St Vincent's Hospital, Sydney</name>
      <address>
        <city>Darlinghurst</city>
        <state>New South Wales</state>
        <zip>2010</zip>
        <country>Australia</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sarah Barney, RN</last_name>
      <phone>+61 2 8382 4976</phone>
      <email>sarah.barney@svha.org.au</email>
    </contact>
    <investigator>
      <last_name>Bruce J Brew, MBBS, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>July 6, 2016</study_first_submitted>
  <study_first_submitted_qc>December 7, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 12, 2016</study_first_posted>
  <last_update_submitted>February 12, 2019</last_update_submitted>
  <last_update_submitted_qc>February 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>St Vincent's Hospital, Sydney</investigator_affiliation>
    <investigator_full_name>Bruce Brew</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>HIV-associated neurocognitive disorder (HAND)</keyword>
  <keyword>Neurology</keyword>
  <keyword>Latent HIV</keyword>
  <keyword>HIV Reservoirs</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurocognitive Disorders</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/NCT02989285
org study id: 15/277
secondary id: APP1105808
nct id: NCT02989285
lead sponsor: 
has dmc: Yes
Human Immunodeficiency Virus (HIV) remains in infected patients receiving highly active
      antiretroviral therapy (HAART) for many years. Stopping HAART usually leads to re-emergence
      of small reservoirs of latent (inactive) HIV that reside inside certain types of infected
      cells, that can replicate and cause a full HIV infection. Chronic HIV infection also leads to
      long-term immune activation which is associated with higher incidence of serious non-AIDS
      events including cardiovascular disease and cancers. Thus HIV+ patients must remain on HAART
      indefinitely or replication-competent latent HIV reservoirs must be eradicated.

      The central nervous system (CNS) is a sanctuary site for latent HIV. For example,
      HIV-associated neurocognitive disorders (HAND) develop and persist in about 40% of HIV+
      persons despite long-term HAART and viral suppression in blood and cerebrospinal fluid (CSF).
      Continued CSF immune activation is also frequently observed despite viral suppression. Both
      of these are likely to indicate ongoing low-level HIV replication in the CNS.

      Several strategies to eradicate latent HIV are being explored. One of these, known as "shock
      and kill" involves "awakening" latent HIV and inducing replication to make it more
      susceptible to host immune responses and HAART. However, there are several major caveats to
      its application in the CNS such as the risk of triggering a serious immunoinflammatory
      response (e.g., meningoencephalitis) that cannot be easily controlled by HAART. Other
      eradication strategies may also be problematic given that many latency-reversing agents have
      limited penetration of the blood brain barrier and limited efficacy in astrocyte cells. To
      improve the effectiveness of new eradication therapies it will be crucial to develop better
      methods to identify and quantify latent HIV reservoir sites with greater precision.

      To identify potential HIV latency biomarkers in the CNS, the investigators will study HIV+
      patients stable on HAART and virally-suppressed in blood and CSF over 24 months. Because such
      a marker should be associated with HAND or its development without changing significantly
      with HAND progression, half of the sample will have HAND at study entry and half will not.
      Patients will undergo neuropsychological testing and give blood and CSF samples every 6
      months to identify candidate biomarkers and track them prospectively against HAND development
      and progression. MRI brain scan will also occur at study entry and after 24 months.
observational model: Cohort
time perspective: Prospective
measure: Change in Mean CSF BCL11b levels at 24 months (latency burden biomarker)
time frame: Baseline and 24 months
description: BCL11b is a C2H5 zinc-finger DNA binding protein that is expressed in the brain and immune system and inhibits HIV gene transcription by recruiting chromatin modifiers and establishing a heterochromatic environment in HIV-infected microglia. It is a promising candidate biomarker for latent HIV infection in the brain. Change in CSF BCL11b levels from baseline at 24 months will be reported. BCL11b will also be tracked against HAND development/progression at each visit to determine its suitability as a marker of latent HIV reservoir size.
measure: Change in Mean Level of 1H-MRS Myo-Inositol in Frontal White Matter at 24 months (latency burden biomarker)
time frame: Baseline and 24 months
description: Myo-Inositol (mIo) is a brain metabolic marker measured by 1H-Magnetic Resonance Spectroscopy (MRS) that is thought to reflect astroglia and microglia activation in cognitively-impaired individuals. The finding that mIo in the frontal white matter is elevated in HIV+ individuals and remains elevated with HAND progression while other metabolite levels fluctuate, supports its possibility as a HIV latency biomarker. Change in 1H-MRS mIo levels in the FWM from baseline at 24 months will be reported. mIo will also be tracked against HAND development/progression to determine its suitability as a marker of latent HIV reservoir size.
measure: Change in Mean CSF HIV RNA by Single Copy Assay at 24 months (latency significance biomarker)
time frame: Baseline and 24 months
description: Single copy assay (SCA) of CSF HIV RNA will allow for precise detection of intermittent HIV brain infection productivity at low levels. This assay is highly sensitive and can measure levels of HIV RNA as low as 0.3 copies per ml. Change in CSF HIV RNA levels from baseline at 24 months will be reported. Detectability of CSF HIV RNA by SCA is related to increased risk of HAND development in asymptomatic patients suggesting that it may reflect a marker of latent HIV reservoir significance (i.e., the potential for latent HIV replication that is not defective). Such a marker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
measure: Change in Mean CSF HIV tat at 24 months (latency significance biomarker)
time frame: Baseline and 24 months
description: Tat is a post-transcriptional regulatory protein that promotes inflammation and enhances the effectiveness of HIV transcription to neighbouring cells. Therefore it may act as a latency significance biomarker. Change in CSF HIV tat levels from baseline at 24 months will be reported. HIV tat will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
measure: Change in Mean CSF neopterin at 24 months (latency significance biomarker)
time frame: Baseline and 24 months
description: Neopterin is an immune activation biomarker that is elevated in almost all persons with HAND on antiretroviral medication and in some without HAND, supporting its possible role as a latency significance marker. Change in CSF neopterin levels from baseline at 24 months will be reported. CSF neopterin will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
measure: Change in Mean CSF MCP-1 at 24 months (latency significance biomarker)
time frame: Baseline and 24 months
description: CSF MCP-1 is an immune activation biomarker that has been found to correlate with change in HAND status. Therefore it may be a latency significance marker. Change in CSF MCP-1 levels from baseline at 24 months will be reported. CSF MCP-1 will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
measure: Change in Mean CSF NFL at 24 months (latency significance biomarker)
time frame: Baseline and 24 Months
description: CSF NFL is a marker of neuronal injury. It has been shown to correlate with HAND severity and predict its development, suggesting that it is likely to serve as a latency significance biomarker. Change in CSF NFL levels from baseline at 24 months will be reported. CSF NFL will be tracked against HAND development/progression and as a latency significance biomarker would be expected to change with incident HAND/progression while having no relationship to latency burden biomarkers (i.e., BCL11b).
measure: Correlation between CSF HIV tat, neurocognitive global deficit score, neopterin, and MCP-1 at 24 months
time frame: Baseline and 24 months
description: Cumulative levels of HIV tat in CSF will be quantified from baseline to 24 months as per primary outcome #4. They will then be correlated against HAND development/progression as quantified by neurocognitive global deficit score (GDS), and levels of inflammatory markers neopterin and MCP-1.
measure: Role of Pre-Integration-Targeting HAART in Reducing HIV Latency Burden
time frame: Baseline and 6 months, 12 months, 18 months, and 24 months
description: Cumulative HAART history will be recorded and scored as follows: drugs that target the pre-integration/integration phase of HIV replication will be given a score of 1; other drugs will be given a score of 0. Total scores will then be correlated with CSF BCL11b levels and any other CNS latency marker that is identified during primary outcome analyses.
arm group label: HIV+ cognitively impaired (HAND)
description: Participants will be assessed based on their performance on the neuropsychological test battery at study entry. HAND status will be diagnosed per FRASCATI research criteria and this will determine which study cohort they are allocated to. Participants will continue to receive their standard of care treatment during the study period.
arm group label: HIV+ cognitively normal (no-HAND)
description: Participants will be assessed based on their performance on the neuropsychological test battery at study entry. HAND status will be diagnosed per FRASCATI research criteria and this will determine which study cohort they are allocated to. Participants will continue to receive their standard of care treatment during the study period.
Cerebrospinal fluid and bloods
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Bruce J Brew, MBBS, MD
role: Principal Investigator
affiliation: St Vincent's Hospital, Sydney
last name: Bruce J Brew, MBBS, MD
phone: +61 2 8382 1111
phone ext: 4100
email: bruce.brew@svha.org.au
last name: Thomas M Gates, MPsychol
phone: +61 2 8382 1111
phone ext: 2435
email: thomas.gates@svha.org.au
facility: 
status: Recruiting
contact: 
investigator: 
country: Australia
responsible party type: Principal Investigator
investigator affiliation: St Vincent's Hospital, Sydney
investigator full name: Bruce Brew
investigator title: Professor
mesh term: Neurocognitive Disorders