<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/NCT02972931</url>
  </required_header>
  <id_info>
    <org_study_id>LoViReT</org_study_id>
    <nct_id>NCT02972931</nct_id>
  </id_info>
  <brief_title>LoViReT (Low Viral Reservoir Treated Patients)</brief_title>
  <acronym>LoViReT</acronym>
  <official_title>Impact of Antiretroviral Treatment and Predictors in Subjects With Extremely Low HIV-1 Reservoir: Optimization of New Cure Strategies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IrsiCaixa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>IrsiCaixa</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main purpose of this study is to unravel the mechanisms by which the &quot;Low Viral Reservoir&#xD;
      Treated&quot; patients (LoViReT) maintain extremely low HIV-1 DNA levels despite having initiated&#xD;
      cART during chronic HIV-1 infection. This group may have specific and different clinical,&#xD;
      virological and immunogenetical characteristics, compared to patients with regular reservoir&#xD;
      size, which might be useful to design new and more effective treatment approaches.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Combination antiretroviral therapy (cART) is highly successful suppressing HIV-1 replication&#xD;
      and clinical progression in infected patients. However, it does not hamper the establishment&#xD;
      of viral reservoirs, generating latently infected cells that provoke a quick rebound of HIV&#xD;
      viremia after treatment interruption. Different strategies to tackle HIV-1 reservoirs have&#xD;
      been suggested during last years with limited success. Actually, the few cases of described&#xD;
      HIV-1 functional cure are found in elite and post-treatment controllers. Thus, some patients&#xD;
      with regular HIV progression can control replication spontaneously, most of them after&#xD;
      receiving cART during primary HIV-1 infection. Indeed, the &quot;Mississippi baby&quot;, who was&#xD;
      treated 36h after birth, had sustained undetectable viremia for 27 months after treatment&#xD;
      interruption. Recently, it has also been proven in successfully treated patients that low&#xD;
      proviral reservoir is related to better HIV-1 control after treatment discontinuation. Thus,&#xD;
      the identification of patients with lower latent reservoir in chronic infection will allow&#xD;
      unveiling potential mechanisms to achieve a functional cure after cART withdrawal.&#xD;
&#xD;
      Our center in Badalona allocates a biological sample collection containing 72,000 specimens&#xD;
      from HIV-1-infected subjects. Samples from 319 patients under suppressive cART for more than&#xD;
      3 years have been screened using the high sensitive BioRad droplet digital Polymerase Chain&#xD;
      Reaction platform (ddPCR). Among the screened patients, a cohort of 20 &quot;Low Viral Reservoir&#xD;
      Treated&quot; patients (LoViReT) with extremely low or undetectable HIV-1 DNA levels in peripheral&#xD;
      blood despite having initiated cART during chronic HIV-1 infection have been established,&#xD;
      which is expected to be increased up to 40 patients. Discovering the factors that reduce HIV&#xD;
      reservoir and make LoViReT patients maintain extremely low levels of proviral HIV-1 DNA will&#xD;
      open new treatment strategies based on maintaining the reservoir to the lowest levels beside&#xD;
      the regular clinical marker of viral load. In addition, a further second step of controlled&#xD;
      cART interruption can be designed to evaluate the real impact of harboring extremely low&#xD;
      levels of latent reservoir for further functional HIV cure.&#xD;
&#xD;
      To unravel the mechanisms by which the LoViReT cohort maintain extremely low HIV-1 DNA levels&#xD;
      despite having initiated cART during chronic HIV-1 infection, this cohort will be studied&#xD;
      from different points of view. All the results will be compared to a control group of 40&#xD;
      individuals with standard levels of total HIV DNA (reservoir). Three mayor aims will be&#xD;
      addressed to then extrapolate our results to larger chronic HIV-1-infected populations:&#xD;
&#xD;
        -  To investigate the role of cART on the suppression of the HIV reservoir in the LoViReT&#xD;
           patients, compared to controls. To address this objective, a longitudinal analysis of&#xD;
           proviral HIV DNA for each patient will be performed, including time points previous to&#xD;
           cART. In total, 200 samples will be analyzed and dynamic models will be built for the&#xD;
           two different levels of reservoir establishment. General immune phenotype of cellular&#xD;
           populations, including also activation markers, will be also assessed in all time&#xD;
           points.&#xD;
&#xD;
        -  To investigate the integrity of HIV sequences in the LoViReT patients and its&#xD;
           relationship with pathogenesis, in comparison to controls. Genotypic HIV tropism and the&#xD;
           full viral genome will be analyzed through sequencing from DNA of patients' Peripheral&#xD;
           Blood Mononuclear Cells (PBMC). Fresh blood samples will be taken from the 40 LoViReT&#xD;
           and 40 control patients in the study. In addition, for those exerting virus production,&#xD;
           viral isolates will be used to analyze viral replication capacity and cell pathogenesis.&#xD;
&#xD;
        -  To investigate the role of immune-genetic factors that along with cART contribute to&#xD;
           reduce the HIV reservoirs in the LoViReT patients. Functional T-cell response will be&#xD;
           measured isolating CD8 T cells and measuring the inhibition capacity for HIV replication&#xD;
           in each patient. Specific HIV-related CD8 T-cell interferon production will be also&#xD;
           evaluated under epitope stimulus. Other progression associated genetic factors as Human&#xD;
           Leukocyte Antigen (HLA) type, and CCR5, CCR2 and SIGLEC-1 Single Nucleotide&#xD;
           Polymorphisms (SNPs) will be also explored.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 18, 2018</start_date>
  <completion_date type="Actual">June 20, 2019</completion_date>
  <primary_completion_date type="Actual">June 20, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Longitudinal analysis of total HIV DNA and immune-phenotype by Digital Droplet PCR and Flow Cytometry, respectively, comparing this outcome before and after cART (evaluation of cART effect on this parameters)</measure>
    <time_frame>10 months</time_frame>
    <description>To address this objective, a longitudinal analysis of proviral HIV DNA for each patient will be performed, including time points previous to cART. In total, 200 samples will be analyzed and dynamic models will be built for the two different levels of reservoir establishment. General immune phenotype of cellular populations, including also activation markers, will be also assessed in all time points.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Comparison of integrity and functionality of HIV sequences, through full viral genome sequencing, genotypic tropism and qVOA, between patients with Low (LoViReT) and Normal (controls) levels of total HIV DNA</measure>
    <time_frame>16 months</time_frame>
    <description>Genotypic HIV tropism and the full viral genome will be analyzed through sequencing from DNA of patients' PBMC. Fresh blood samples will be taken from the 40 LoViReT and 40 control patients in the study. In addition, the replication competent reservoir will be also analyzed with the gold standard quantitative viral outgrowth assay (qVOA) and, for those exerting virus production, viral isolates will be used to analyze viral replication capacity and cell pathogenesis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation and Comparison of CD8 T-cell responses, by ELISPOT and inhibition assays, between patients with Low (LoViReT) and Normal (controls) levels of total HIV DNA</measure>
    <time_frame>8 months</time_frame>
    <description>Functional T-cell response will be measured isolating CD8 T cells and measuring the inhibition capacity for HIV replication in each patient. Specific HIV-related CD8 T cell interferon production will be also evaluated under epitope stimulus.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Analysis and comparison of progression-associated genetic factors, between patients with Low (LoViReT) and Normal (controls) levels of total HIV DNA</measure>
    <time_frame>4 months</time_frame>
    <description>Different progression-associated genetic factors, such as HLA type, and CCR5, CCR2 and SIGLEC-1 SNPs will be also explored.</description>
  </primary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">54</enrollment>
  <condition>Hiv</condition>
  <arm_group>
    <arm_group_label>LoViReT</arm_group_label>
    <description>HIV-infected subjects with extremely low or undetectable HIV-1 DNA levels in peripheral blood despite having initiated cART during chronic HIV-1 infection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard Reservoir Level</arm_group_label>
    <description>HIV-infected subjects who initiated cART during chronic HIV-1 infection and that show standard HIV-1 DNA levels in peripheral blood</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        HIV-infected subjects with extremely low or undetectable HIV-1 DNA levels in peripheral&#xD;
        blood despite having initiated cART during chronic HIV-1 infection&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥ 18 years of age&#xD;
&#xD;
          -  Voluntarily signed informed consent&#xD;
&#xD;
          -  Proven HIV-1 infection&#xD;
&#xD;
          -  On stable cART regimen (antiretroviral therapy consisting of at least 3 registered&#xD;
             antiretroviral agents) for at least 3 years&#xD;
&#xD;
          -  HIV-RNA &lt;50 copies/mL during the last 3 years prior to the study&#xD;
&#xD;
          -  Proviral HIV-DNA &lt;50 copies/million PBMCs by using the ultrasensitive BioRad residual&#xD;
             ddPCR quantification platform&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  cART discontinuation between previous screening and Visit #1.&#xD;
&#xD;
          -  HIV-RNA above 50 copies/mL between previous screening to Visit #1&#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>Javier Martinez-Picado, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitari Germans Trias i Pujol</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>November 17, 2016</study_first_submitted>
  <study_first_submitted_qc>November 23, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 25, 2016</study_first_posted>
  <last_update_submitted>November 11, 2019</last_update_submitted>
  <last_update_submitted_qc>November 11, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 13, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HIV infection</keyword>
  <keyword>low HIV reservoir</keyword>
  <keyword>functional cure</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>March 3, 2020</submitted>
    <returned>March 16, 2020</returned>
  </pending_results>
  <!-- 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/NCT02972931
org study id: LoViReT
nct id: NCT02972931
lead sponsor: 
has dmc: No
The main purpose of this study is to unravel the mechanisms by which the "Low Viral Reservoir
      Treated" patients (LoViReT) maintain extremely low HIV-1 DNA levels despite having initiated
      cART during chronic HIV-1 infection. This group may have specific and different clinical,
      virological and immunogenetical characteristics, compared to patients with regular reservoir
      size, which might be useful to design new and more effective treatment approaches.
Combination antiretroviral therapy (cART) is highly successful suppressing HIV-1 replication
      and clinical progression in infected patients. However, it does not hamper the establishment
      of viral reservoirs, generating latently infected cells that provoke a quick rebound of HIV
      viremia after treatment interruption. Different strategies to tackle HIV-1 reservoirs have
      been suggested during last years with limited success. Actually, the few cases of described
      HIV-1 functional cure are found in elite and post-treatment controllers. Thus, some patients
      with regular HIV progression can control replication spontaneously, most of them after
      receiving cART during primary HIV-1 infection. Indeed, the "Mississippi baby", who was
      treated 36h after birth, had sustained undetectable viremia for 27 months after treatment
      interruption. Recently, it has also been proven in successfully treated patients that low
      proviral reservoir is related to better HIV-1 control after treatment discontinuation. Thus,
      the identification of patients with lower latent reservoir in chronic infection will allow
      unveiling potential mechanisms to achieve a functional cure after cART withdrawal.

      Our center in Badalona allocates a biological sample collection containing 72,000 specimens
      from HIV-1-infected subjects. Samples from 319 patients under suppressive cART for more than
      3 years have been screened using the high sensitive BioRad droplet digital Polymerase Chain
      Reaction platform (ddPCR). Among the screened patients, a cohort of 20 "Low Viral Reservoir
      Treated" patients (LoViReT) with extremely low or undetectable HIV-1 DNA levels in peripheral
      blood despite having initiated cART during chronic HIV-1 infection have been established,
      which is expected to be increased up to 40 patients. Discovering the factors that reduce HIV
      reservoir and make LoViReT patients maintain extremely low levels of proviral HIV-1 DNA will
      open new treatment strategies based on maintaining the reservoir to the lowest levels beside
      the regular clinical marker of viral load. In addition, a further second step of controlled
      cART interruption can be designed to evaluate the real impact of harboring extremely low
      levels of latent reservoir for further functional HIV cure.

      To unravel the mechanisms by which the LoViReT cohort maintain extremely low HIV-1 DNA levels
      despite having initiated cART during chronic HIV-1 infection, this cohort will be studied
      from different points of view. All the results will be compared to a control group of 40
      individuals with standard levels of total HIV DNA (reservoir). Three mayor aims will be
      addressed to then extrapolate our results to larger chronic HIV-1-infected populations:

        -  To investigate the role of cART on the suppression of the HIV reservoir in the LoViReT
           patients, compared to controls. To address this objective, a longitudinal analysis of
           proviral HIV DNA for each patient will be performed, including time points previous to
           cART. In total, 200 samples will be analyzed and dynamic models will be built for the
           two different levels of reservoir establishment. General immune phenotype of cellular
           populations, including also activation markers, will be also assessed in all time
           points.

        -  To investigate the integrity of HIV sequences in the LoViReT patients and its
           relationship with pathogenesis, in comparison to controls. Genotypic HIV tropism and the
           full viral genome will be analyzed through sequencing from DNA of patients' Peripheral
           Blood Mononuclear Cells (PBMC). Fresh blood samples will be taken from the 40 LoViReT
           and 40 control patients in the study. In addition, for those exerting virus production,
           viral isolates will be used to analyze viral replication capacity and cell pathogenesis.

        -  To investigate the role of immune-genetic factors that along with cART contribute to
           reduce the HIV reservoirs in the LoViReT patients. Functional T-cell response will be
           measured isolating CD8 T cells and measuring the inhibition capacity for HIV replication
           in each patient. Specific HIV-related CD8 T-cell interferon production will be also
           evaluated under epitope stimulus. Other progression associated genetic factors as Human
           Leukocyte Antigen (HLA) type, and CCR5, CCR2 and SIGLEC-1 Single Nucleotide
           Polymorphisms (SNPs) will be also explored.
observational model: Case-Control
time perspective: Retrospective
measure: Longitudinal analysis of total HIV DNA and immune-phenotype by Digital Droplet PCR and Flow Cytometry, respectively, comparing this outcome before and after cART (evaluation of cART effect on this parameters)
time frame: 10 months
description: To address this objective, a longitudinal analysis of proviral HIV DNA for each patient will be performed, including time points previous to cART. In total, 200 samples will be analyzed and dynamic models will be built for the two different levels of reservoir establishment. General immune phenotype of cellular populations, including also activation markers, will be also assessed in all time points.
measure: Comparison of integrity and functionality of HIV sequences, through full viral genome sequencing, genotypic tropism and qVOA, between patients with Low (LoViReT) and Normal (controls) levels of total HIV DNA
time frame: 16 months
description: Genotypic HIV tropism and the full viral genome will be analyzed through sequencing from DNA of patients' PBMC. Fresh blood samples will be taken from the 40 LoViReT and 40 control patients in the study. In addition, the replication competent reservoir will be also analyzed with the gold standard quantitative viral outgrowth assay (qVOA) and, for those exerting virus production, viral isolates will be used to analyze viral replication capacity and cell pathogenesis.
measure: Evaluation and Comparison of CD8 T-cell responses, by ELISPOT and inhibition assays, between patients with Low (LoViReT) and Normal (controls) levels of total HIV DNA
time frame: 8 months
description: Functional T-cell response will be measured isolating CD8 T cells and measuring the inhibition capacity for HIV replication in each patient. Specific HIV-related CD8 T cell interferon production will be also evaluated under epitope stimulus.
measure: Analysis and comparison of progression-associated genetic factors, between patients with Low (LoViReT) and Normal (controls) levels of total HIV DNA
time frame: 4 months
description: Different progression-associated genetic factors, such as HLA type, and CCR5, CCR2 and SIGLEC-1 SNPs will be also explored.
arm group label: LoViReT
description: HIV-infected subjects with extremely low or undetectable HIV-1 DNA levels in peripheral blood despite having initiated cART during chronic HIV-1 infection
arm group label: Standard Reservoir Level
description: HIV-infected subjects who initiated cART during chronic HIV-1 infection and that show standard HIV-1 DNA levels in peripheral blood
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Javier Martinez-Picado, PhD
role: Principal Investigator
affiliation: IrsiCaixa AIDS Research Institute, Hospital Universitari Germans Trias i Pujol
facility: 
country: Spain
responsible party type: Sponsor
sharing ipd: No
submitted: March 3, 2020
returned: March 16, 2020