<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/NCT03280940</url>
  </required_header>
  <id_info>
    <org_study_id>INTATTI</org_study_id>
    <nct_id>NCT03280940</nct_id>
  </id_info>
  <brief_title>Impact of Different Integrase Inhibitor Based Regimen on Immune Activation Among HIV naïve Patient (INTATTI)</brief_title>
  <acronym>INTATTI</acronym>
  <official_title>Impact of Different Integrase Inhibitor Based Regimen on Markers of Inflammation and Immune Activation Among HIV naïve Patient During the First Year of Effective First-line Combination</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Low viral replication persistence and immune activation remain important therapeutic&#xD;
      challenge in the new HAART era. They are associated with more rapid disease progression,&#xD;
      increased risk of mortality and non-AIDS defining events. Soluble biomarkers are a convenient&#xD;
      way of assessing immune activation and inﬂammation in HIV-infected patients receiving&#xD;
      effective treatment. There are limited data describing the different effects of currently&#xD;
      recommended antiretroviral regimens on immune activation and inﬂammation during HIV&#xD;
      infection. Several studies have shown that raltegravir (the first approved drug from&#xD;
      integrase inhibitor class) seems to have more impact on decreasing systemic inflammation&#xD;
      compared with other drug classes. Integrase inhibitors may decrease inflammation and immune&#xD;
      activation more than other antiretroviral drugs, because they are more lipid friendly and may&#xD;
      concentrate better in enterocytes. The aim of this observational study is to compare the&#xD;
      impact of different integrase inhibitor based regimen on changes in markers of inflammation&#xD;
      (Il-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) during the first&#xD;
      year of effective first-line combination. This is a 48-week observational retrospective&#xD;
      study, to compare the change in infiammatory markers between naïve patients who start INI&#xD;
      based regimen. Participants will be recruited from the HIV outpatient clinic. The study&#xD;
      compare the impact of commonly used first-line antiretroviral drugs on soluble markers of&#xD;
      inflammation and immune activation. The study is conducted on treatment-naive HIV-infected&#xD;
      patients who experience a rapid and persistent virological response and that do not switch&#xD;
      their initial regimen for at least 1 years. The analyses will be adjusted for baseline&#xD;
      characteristics that might influence the choice of cART regimen or affect biomarker levels,&#xD;
      such as age, smoking status, CD4 cell count, plasma HIV-1 viral load. Investigators enroll&#xD;
      patients with a rapid and persistent virological response and that do not experience any&#xD;
      blips. Cryopreserved plasma sample are obtained at baseline and at month 6 and 12 after&#xD;
      treatment starting. Two NRTI backbone combinations (TDF/FTC vs ABC/3TC) and three third&#xD;
      agents (RAL vs ELV vs DTG) will be compared in a factorial design. The results will be&#xD;
      expressed as the estimated percentage difference between the mean fold changes observed with&#xD;
      a given drug, using TDF/FTC and RAL as the reference groups for the comparison.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      INTRODUCTION AND BACKGROUND Combination antiretroviral therapy (cART) controls HIV-1 plasma&#xD;
      viral load in most patients, leading to a reduction in morbidity and mortality [Egger M, BMJ&#xD;
      1997; Detels R, JAMA 1998].&#xD;
&#xD;
      Despite efficient treatment persistent low-level viral replication and immune activation&#xD;
      remain an important therapeutic challenge. Immune activation is associated with more rapid&#xD;
      disease progression and with less efﬁcient CD4+ cell recovery during cART [Hunt PW, J Infect&#xD;
      Dis 2003; Lederman MM, J Infect Dis 2011], while plasma biomarkers of inﬂammation have been&#xD;
      linked to a risk of mortality and non-AIDS-deﬁning events such as cardiovascular disease and&#xD;
      non-AIDS-deﬁning cancers [Kuller LH, PLoS Med. 2008; Ipp H, Clin Chim Acta. 2013].&#xD;
&#xD;
      A potential link between HIV-associated inﬂammation and disease progression and mortality was&#xD;
      shown for the first time in a randomized clinical trial of continuous versus intermittent&#xD;
      antiretroviral therapy (the Strategies for Management of Antiretroviral Therapy study - SMART&#xD;
      study) [Neuhaus J, J Infect Dis 2010]. In this study HIV-infected persons were randomized to&#xD;
      continuous antiretroviral therapy (ART) or CD4- T cell count- driven ART. Subjects randomized&#xD;
      to the second arm had a higher risk of morbidity and mortality. ART interruption resulted in&#xD;
      a rapid increase in inﬂammation- and coagulation-associated biomarkers that were associated&#xD;
      with increased risks of death, AIDS, and cardiovascular disease (CVD).&#xD;
&#xD;
      Further studies have confirmed that HIV-infected individuals have elevated levels of&#xD;
      inﬂammatory and cellular activation markers and suppression of viral replication by ART&#xD;
      decreases, but does not normalize those markers [Regidor DL, AIDS 2011; Widney DP, J&#xD;
      Interferon Cytokine Res 2005; Kaplan RC, J Acquir Immune Deficiency Syndr 2012].&#xD;
&#xD;
      Soluble biomarkers are a convenient way of assessing immune activation and inﬂammation in&#xD;
      HIV-infected patients receiving cART. Interleukin-6 (IL-6) is a biomarker of inﬂammation and&#xD;
      was found to be associated with all-cause mortality and cardiovascular diseases in the SMART&#xD;
      study [Neuhaus J, J Infect Dis 2010]. Interferon-γ-inducible protein-10 (IP-10) and monokine&#xD;
      induced by interferon-γ (MIG) are two chemokines produced by different cells and target&#xD;
      lymphocytes, particularly activated T cells. Elevated plasma IP-10 levels during the primary&#xD;
      phase of HIV-1 infection were predictive of earlier decline in the CD4 cell count in a recent&#xD;
      study [Liovat AS, PLOS One 2012; Jiao Y, Viral Immunology 2012; N. Noel, IAS 2013]. Soluble&#xD;
      CD14 (sCD14) is a marker of monocyte activation that binds to lipopolysaccharides in plasma.&#xD;
      Plasma levels of sCD14 are an independent predictor of mortality among HIV-infected patients&#xD;
      [D Sandler et al , JID 2011; E Krastinova, J Infect Dis. 2015] .&#xD;
&#xD;
      There are limited data describing the differential effects of currently recommended&#xD;
      antiretroviral regimens on immune activation and inﬂammation during HIV infection. As long as&#xD;
      viral suppression remains the goal of HIV treatment, choosing ART with the least long -term&#xD;
      toxicity and highest beneﬁt is of great priority in the management of this chronic illness.&#xD;
&#xD;
      Understanding how different ART regimens reduce chronic immune activation and inflammation in&#xD;
      treated HIV-infected patients is an ongoing interesting research.&#xD;
&#xD;
      Several studies have shown that raltegravir (the first approved drug from integrase inhibitor&#xD;
      class) seems to have more impact on decreasing systemic inflammation compared with drugs from&#xD;
      protease inhibitor or non-nucleside transcriptase inhibitor classes [Asmuth DM, AIDS 2012;&#xD;
      Massanella M, AIDS 2012; Asmuth DM, AIDS 2014], both in naïve or treated-virologically&#xD;
      suppresed patients [Gupta SK, J Acquir Immune Defic Syndr. 2013; Lake JE, HIV Medicine 2014].&#xD;
&#xD;
      It is plausible that drugs from integrase inhibitor class may decrease inflammation and&#xD;
      immune activation more than other antiretroviral classes, because they are more lipid&#xD;
      friendly and may concentrate better in enterocytes [ Martinez E, AIDS 2010] [Patterson KB,&#xD;
      AIDS 2013].&#xD;
&#xD;
      The aim of this observational study is to compare the impact of different INI based regimen&#xD;
      on changes in markers of inflammation (Il-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP ,&#xD;
      sVCAM, LPS, D-dimer) during the first year of effective first-line combination.&#xD;
&#xD;
      OBJECTIVES The primary objective is to evaluate the changes in markers of inflammation (Il-2,&#xD;
      IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) in patients who receive&#xD;
      first line INI-based therapy.&#xD;
&#xD;
      METHODS This is a 48-week observational retrospective study, to compare the change in&#xD;
      infiammatory markers between naïve patients who start INI based regimen. Participants will be&#xD;
      recruited from the HIV outpatient clinic.&#xD;
&#xD;
      STUDY DESIGN The study will compare the impact of commonly used first-line antiretroviral&#xD;
      drugs on soluble markers of inflammation and immune activation. In order to avoid the&#xD;
      influence of previous ARV exposure, active viral replication and treatment switches, the&#xD;
      analysis is limited to a homogenous group of treatment-naive HIV-infected patients who&#xD;
      experience a rapid and persistent virological response and remain on their initial regimen&#xD;
      for 1 years. The evaluation of biomarkers of inflammation is not a part of rourtine analysis,&#xD;
      so investigators will enrolled patients who have plasma samples stored before ART initiation,&#xD;
      6 month and 1 year later.&#xD;
&#xD;
      The analyses will be adjusted for baseline characteristics that might influence the choice of&#xD;
      cART regimen or affect biomarker levels, such as age, smoking status, CD4 cell count, plasma&#xD;
      HIV-1 viral load. Patients who had a rapid and persistent virological response (defined by a&#xD;
      plasma HIV-1 viral load (VL) below 400 copies/mL at 6 months and below 50 copies/mL at 12&#xD;
      months), with no values above 1000 copies/ml between month 6 and month 12 are enrolled in&#xD;
      this study, in order to control potential causes of inflammation/activation due to persistent&#xD;
      plasma viral replication Inclusion criteria&#xD;
&#xD;
      1) Naïve patients having documented HIV-1 infection, of age 18 years and older Exclusion&#xD;
      criteria&#xD;
&#xD;
        1. Patients with diagnosed CVD, diabetes, uncontrolled hypertension (screening systolic&#xD;
           blood pressure &gt;160 mm Hg or diastolic pressure &gt;90 mm Hg),&#xD;
&#xD;
        2. other systemic inflammatory disease (hepatitis B or C coinfection was allowed)&#xD;
&#xD;
        3. estimated creatinine clearance &lt;70 mL/min;&#xD;
&#xD;
        4. HIV-1 RNA level of &lt;1000 copies/mL,&#xD;
&#xD;
        5. prior ART use&#xD;
&#xD;
        6. estimated glomerular filtration rate (eGFR) of &lt;70 mL/min by the Cockcroft-Gault&#xD;
           equation&#xD;
&#xD;
        7. liver transaminase levels &lt;5 times the upper limit of normal&#xD;
&#xD;
        8. absolute neutrophil count of &lt;1000 neutrophils/mm3&#xD;
&#xD;
        9. platelet count of ≥50 000 platelets/mm3,&#xD;
&#xD;
       10. hemoglobin level of ≥8.5 g/dL,&#xD;
&#xD;
       11. use of lipid-lowering drugs&#xD;
&#xD;
       12. life expectancy of ≥1 year from the time of enrollment&#xD;
&#xD;
       13. AIDS-defining conditions diagnosed within 30 days&#xD;
&#xD;
       14. active infection or malignancy&#xD;
&#xD;
       15. current alcohol or substance use judged to potentially interfere with study compliance&#xD;
           Markers of Inflammation and Immune Activation Cryopreserved plasma sample were obtained&#xD;
           at baseline (prior to ART initiation) and at month 6 and 12 after treatment starting&#xD;
           from 30 patients participating at MASTER (Management of Standardized Evaluation of&#xD;
           Retroviral HIV Infection) group, an ongoing prospective multicentre cohort that includes&#xD;
           the major Italian clinical centres involved in HIV infection care.&#xD;
&#xD;
      Thawed samples will stained for this circulating inflammatory markers [high sensitivity&#xD;
      C-reactive protein (hsCRP), serum interleukin-6 (IL-6), interleukin-2 (IL-2), soluble tumor&#xD;
      necrosis factor-[alpha] receptors I and II (sTNFRI and sTNFRII), endothelial markers (soluble&#xD;
      vascular cell adhesion molecule-1,), markers of monocyte/macrophage activation [soluble CD14&#xD;
      (sCD14), soluble CD163 (sCD163)], D-dimer.&#xD;
&#xD;
      Statistical analysis The aim of this exploratory study is to evaluate the effect of a new&#xD;
      integrase inhibitor on serum level of inflammatory markers.&#xD;
&#xD;
      Two NRTI backbone combinations (TDF/FTC vs ABC/3TC) and three third agents (RAL vs ELV vs&#xD;
      DTG) will be compared in a factorial design. Baseline characteristics will be compared&#xD;
      between treatment groups by using the Wilcoxon and chi-squared tests in order to identify&#xD;
      variables associated with the choice of treatment. Because the marker values isn't normally&#xD;
      distributed, they will be log e-transformed for analysis. For each marker, changes between&#xD;
      D0, M6 and M12 (mean fold change) will be expressed as the geometric mean of their ratio&#xD;
      after log-e transformation. A paired one-sample t test will be used to identify significant&#xD;
      differences in the overall changes in each marker. Linear regression models will be used to&#xD;
      investigate the impact of the different NRTI backbones and the different third agents on the&#xD;
      biomarker changes. The results will be expressed as the estimated percentage difference&#xD;
      between the mean fold changes observed with a given drug, using TDF/FTC and RAL as the&#xD;
      reference groups for the comparison. Relationships between baseline covariables and changes&#xD;
      in each biomarker will be examined in univariable linear regression models. These covariables&#xD;
      will be sex, age, body mass index, smoking status, prior AIDS-defining events, and the&#xD;
      pre-ART CD4 cell count and viral load. Baseline covariables associated with changes in at&#xD;
      least one biomarker (p &lt; 0.10) and viral blips above 50 copies/ml between M6 and M12 will be&#xD;
      retained in all multivariable linear regression models in order to control for factors that&#xD;
      might have influenced the choice of cART regimen or affected biomarker levels. Age and&#xD;
      smoking status will be included in the multivariable model since these variables are known to&#xD;
      influence marker levels. Interaction terms between the NRTI backbone and the third agent will&#xD;
      be tested for each marker. Sensitivity analyses will conduct. Statistical analyses will run&#xD;
      on STATA 12 software, and p values &lt;0.05 were considered statistically significant.&#xD;
&#xD;
      Ethics This study will be conducted in accordance with the ethical principles that have their&#xD;
      origin in the Declaration of Helsinki and will be consistent with Good Clinical Practice&#xD;
      (GCP) and applicable regulatory requirements.&#xD;
&#xD;
      The study will be conducted in compliance with the protocol. The protocol and any amendments&#xD;
      and the patient informed consent will receive Ethics Committee (EC) approval/favourable&#xD;
      opinion prior to initiation of the study.&#xD;
&#xD;
      Freely given written informed consent must be obtained from every patient or their legally&#xD;
      acceptable representative prior to clinical trial participation, including informed consent&#xD;
      for any screening procedures conducted to establish patient eligibility for the trial.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Actual">March 1, 2018</completion_date>
  <primary_completion_date type="Actual">March 1, 2018</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>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Inflammation outcomes 48 week</measure>
    <time_frame>48 week</time_frame>
    <description>Evaluate the changes from baseline to week 48 in level of markers of inflammation (IL-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) in patients who receive first line antiretroviral therapy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Inflammation outcomes 24 week</measure>
    <time_frame>24 week</time_frame>
    <description>Evaluate the changes from baseline to week 24 in level of markers of inflammation (IL-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) in patients who receive first line antiretroviral therapy</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">40</enrollment>
  <condition>HIV Infections</condition>
  <arm_group>
    <arm_group_label>Dolutegravir treatment group</arm_group_label>
    <description>Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a dolutegravir containing regimen</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Raltegravir treatment group</arm_group_label>
    <description>Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a raltegravir containing regimen</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Elvitegravir treatment group</arm_group_label>
    <description>Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a elvitegravir containing regimen</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Protease inhibitors treatment group</arm_group_label>
    <description>Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a protease inhibitors containing regimen</description>
  </arm_group>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum (Biospecimen retained as a normal clinical practice)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Treatment-naive HIV-infected patients followed at University Division of Infectious and&#xD;
        Tropical Diseases, University of Brescia (Italy) who experience a rapid and persistent&#xD;
        virological response and remain on their initial regimen for 1 years&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Naïve patients having documented HIV-1 infection, of age 18 years and older&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with diagnosed CVD, diabetes, uncontrolled hypertension (screening systolic&#xD;
             blood pressure &gt;160 mm Hg or diastolic pressure &gt;90 mm Hg),&#xD;
&#xD;
          2. Other systemic inflammatory disease (hepatitis B or C coinfection was allowed)&#xD;
&#xD;
          3. Estimated creatinine clearance &lt;70 mL/min;&#xD;
&#xD;
          4. HIV-1 RNA level of &lt;1000 copies/mL,&#xD;
&#xD;
          5. Prior ART use&#xD;
&#xD;
          6. Estimated glomerular filtration rate (eGFR) of &lt;70 mL/min by the Cockcroft-Gault&#xD;
             equation&#xD;
&#xD;
          7. Liver transaminase levels &lt;5 times the upper limit of normal&#xD;
&#xD;
          8. Absolute neutrophil count of &lt;1000 neutrophils/mm3&#xD;
&#xD;
          9. Platelet count of ≥50 000 platelets/mm3&#xD;
&#xD;
         10. Hemoglobin level of ≥8.5 g/dL&#xD;
&#xD;
         11. Use of lipid-lowering drugs&#xD;
&#xD;
         12. Life expectancy of ≥1 year from the time of enrollment&#xD;
&#xD;
         13. AIDS-defining conditions diagnosed within 30 days&#xD;
&#xD;
         14. Active infection or malignancy&#xD;
&#xD;
         15. Current alcohol or substance use judged to potentially interfere with study compliance&#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>Eugenia Quiros Roldan, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>AO Spedali Civili di Brescia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>AO Spedali Civili di Brescia</name>
      <address>
        <city>Brescia</city>
        <state>BS</state>
        <zip>25123</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>September 11, 2017</study_first_submitted>
  <study_first_submitted_qc>September 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <last_update_submitted>January 14, 2019</last_update_submitted>
  <last_update_submitted_qc>January 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia</investigator_affiliation>
    <investigator_full_name>EUGENIA QUIROS ROLDAN</investigator_full_name>
    <investigator_title>Prof.</investigator_title>
  </responsible_party>
  <keyword>Inflammation</keyword>
  <keyword>Immune activation</keyword>
  <keyword>Integrase Inhibitors</keyword>
  <keyword>Naive patients</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03280940
org study id: INTATTI
nct id: NCT03280940
lead sponsor: 
has dmc: Yes
Low viral replication persistence and immune activation remain important therapeutic
      challenge in the new HAART era. They are associated with more rapid disease progression,
      increased risk of mortality and non-AIDS defining events. Soluble biomarkers are a convenient
      way of assessing immune activation and inﬂammation in HIV-infected patients receiving
      effective treatment. There are limited data describing the different effects of currently
      recommended antiretroviral regimens on immune activation and inﬂammation during HIV
      infection. Several studies have shown that raltegravir (the first approved drug from
      integrase inhibitor class) seems to have more impact on decreasing systemic inflammation
      compared with other drug classes. Integrase inhibitors may decrease inflammation and immune
      activation more than other antiretroviral drugs, because they are more lipid friendly and may
      concentrate better in enterocytes. The aim of this observational study is to compare the
      impact of different integrase inhibitor based regimen on changes in markers of inflammation
      (Il-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) during the first
      year of effective first-line combination. This is a 48-week observational retrospective
      study, to compare the change in infiammatory markers between naïve patients who start INI
      based regimen. Participants will be recruited from the HIV outpatient clinic. The study
      compare the impact of commonly used first-line antiretroviral drugs on soluble markers of
      inflammation and immune activation. The study is conducted on treatment-naive HIV-infected
      patients who experience a rapid and persistent virological response and that do not switch
      their initial regimen for at least 1 years. The analyses will be adjusted for baseline
      characteristics that might influence the choice of cART regimen or affect biomarker levels,
      such as age, smoking status, CD4 cell count, plasma HIV-1 viral load. Investigators enroll
      patients with a rapid and persistent virological response and that do not experience any
      blips. Cryopreserved plasma sample are obtained at baseline and at month 6 and 12 after
      treatment starting. Two NRTI backbone combinations (TDF/FTC vs ABC/3TC) and three third
      agents (RAL vs ELV vs DTG) will be compared in a factorial design. The results will be
      expressed as the estimated percentage difference between the mean fold changes observed with
      a given drug, using TDF/FTC and RAL as the reference groups for the comparison.
INTRODUCTION AND BACKGROUND Combination antiretroviral therapy (cART) controls HIV-1 plasma
      viral load in most patients, leading to a reduction in morbidity and mortality [Egger M, BMJ
      1997; Detels R, JAMA 1998].

      Despite efficient treatment persistent low-level viral replication and immune activation
      remain an important therapeutic challenge. Immune activation is associated with more rapid
      disease progression and with less efﬁcient CD4+ cell recovery during cART [Hunt PW, J Infect
      Dis 2003; Lederman MM, J Infect Dis 2011], while plasma biomarkers of inﬂammation have been
      linked to a risk of mortality and non-AIDS-deﬁning events such as cardiovascular disease and
      non-AIDS-deﬁning cancers [Kuller LH, PLoS Med. 2008; Ipp H, Clin Chim Acta. 2013].

      A potential link between HIV-associated inﬂammation and disease progression and mortality was
      shown for the first time in a randomized clinical trial of continuous versus intermittent
      antiretroviral therapy (the Strategies for Management of Antiretroviral Therapy study - SMART
      study) [Neuhaus J, J Infect Dis 2010]. In this study HIV-infected persons were randomized to
      continuous antiretroviral therapy (ART) or CD4- T cell count- driven ART. Subjects randomized
      to the second arm had a higher risk of morbidity and mortality. ART interruption resulted in
      a rapid increase in inﬂammation- and coagulation-associated biomarkers that were associated
      with increased risks of death, AIDS, and cardiovascular disease (CVD).

      Further studies have confirmed that HIV-infected individuals have elevated levels of
      inﬂammatory and cellular activation markers and suppression of viral replication by ART
      decreases, but does not normalize those markers [Regidor DL, AIDS 2011; Widney DP, J
      Interferon Cytokine Res 2005; Kaplan RC, J Acquir Immune Deficiency Syndr 2012].

      Soluble biomarkers are a convenient way of assessing immune activation and inﬂammation in
      HIV-infected patients receiving cART. Interleukin-6 (IL-6) is a biomarker of inﬂammation and
      was found to be associated with all-cause mortality and cardiovascular diseases in the SMART
      study [Neuhaus J, J Infect Dis 2010]. Interferon-γ-inducible protein-10 (IP-10) and monokine
      induced by interferon-γ (MIG) are two chemokines produced by different cells and target
      lymphocytes, particularly activated T cells. Elevated plasma IP-10 levels during the primary
      phase of HIV-1 infection were predictive of earlier decline in the CD4 cell count in a recent
      study [Liovat AS, PLOS One 2012; Jiao Y, Viral Immunology 2012; N. Noel, IAS 2013]. Soluble
      CD14 (sCD14) is a marker of monocyte activation that binds to lipopolysaccharides in plasma.
      Plasma levels of sCD14 are an independent predictor of mortality among HIV-infected patients
      [D Sandler et al , JID 2011; E Krastinova, J Infect Dis. 2015] .

      There are limited data describing the differential effects of currently recommended
      antiretroviral regimens on immune activation and inﬂammation during HIV infection. As long as
      viral suppression remains the goal of HIV treatment, choosing ART with the least long -term
      toxicity and highest beneﬁt is of great priority in the management of this chronic illness.

      Understanding how different ART regimens reduce chronic immune activation and inflammation in
      treated HIV-infected patients is an ongoing interesting research.

      Several studies have shown that raltegravir (the first approved drug from integrase inhibitor
      class) seems to have more impact on decreasing systemic inflammation compared with drugs from
      protease inhibitor or non-nucleside transcriptase inhibitor classes [Asmuth DM, AIDS 2012;
      Massanella M, AIDS 2012; Asmuth DM, AIDS 2014], both in naïve or treated-virologically
      suppresed patients [Gupta SK, J Acquir Immune Defic Syndr. 2013; Lake JE, HIV Medicine 2014].

      It is plausible that drugs from integrase inhibitor class may decrease inflammation and
      immune activation more than other antiretroviral classes, because they are more lipid
      friendly and may concentrate better in enterocytes [ Martinez E, AIDS 2010] [Patterson KB,
      AIDS 2013].

      The aim of this observational study is to compare the impact of different INI based regimen
      on changes in markers of inflammation (Il-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP ,
      sVCAM, LPS, D-dimer) during the first year of effective first-line combination.

      OBJECTIVES The primary objective is to evaluate the changes in markers of inflammation (Il-2,
      IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) in patients who receive
      first line INI-based therapy.

      METHODS This is a 48-week observational retrospective study, to compare the change in
      infiammatory markers between naïve patients who start INI based regimen. Participants will be
      recruited from the HIV outpatient clinic.

      STUDY DESIGN The study will compare the impact of commonly used first-line antiretroviral
      drugs on soluble markers of inflammation and immune activation. In order to avoid the
      influence of previous ARV exposure, active viral replication and treatment switches, the
      analysis is limited to a homogenous group of treatment-naive HIV-infected patients who
      experience a rapid and persistent virological response and remain on their initial regimen
      for 1 years. The evaluation of biomarkers of inflammation is not a part of rourtine analysis,
      so investigators will enrolled patients who have plasma samples stored before ART initiation,
      6 month and 1 year later.

      The analyses will be adjusted for baseline characteristics that might influence the choice of
      cART regimen or affect biomarker levels, such as age, smoking status, CD4 cell count, plasma
      HIV-1 viral load. Patients who had a rapid and persistent virological response (defined by a
      plasma HIV-1 viral load (VL) below 400 copies/mL at 6 months and below 50 copies/mL at 12
      months), with no values above 1000 copies/ml between month 6 and month 12 are enrolled in
      this study, in order to control potential causes of inflammation/activation due to persistent
      plasma viral replication Inclusion criteria

      1) Naïve patients having documented HIV-1 infection, of age 18 years and older Exclusion
      criteria

        1. Patients with diagnosed CVD, diabetes, uncontrolled hypertension (screening systolic
           blood pressure >160 mm Hg or diastolic pressure >90 mm Hg),

        2. other systemic inflammatory disease (hepatitis B or C coinfection was allowed)

        3. estimated creatinine clearance <70 mL/min;

        4. HIV-1 RNA level of <1000 copies/mL,

        5. prior ART use

        6. estimated glomerular filtration rate (eGFR) of <70 mL/min by the Cockcroft-Gault
           equation

        7. liver transaminase levels <5 times the upper limit of normal

        8. absolute neutrophil count of <1000 neutrophils/mm3

        9. platelet count of ≥50 000 platelets/mm3,

       10. hemoglobin level of ≥8.5 g/dL,

       11. use of lipid-lowering drugs

       12. life expectancy of ≥1 year from the time of enrollment

       13. AIDS-defining conditions diagnosed within 30 days

       14. active infection or malignancy

       15. current alcohol or substance use judged to potentially interfere with study compliance
           Markers of Inflammation and Immune Activation Cryopreserved plasma sample were obtained
           at baseline (prior to ART initiation) and at month 6 and 12 after treatment starting
           from 30 patients participating at MASTER (Management of Standardized Evaluation of
           Retroviral HIV Infection) group, an ongoing prospective multicentre cohort that includes
           the major Italian clinical centres involved in HIV infection care.

      Thawed samples will stained for this circulating inflammatory markers [high sensitivity
      C-reactive protein (hsCRP), serum interleukin-6 (IL-6), interleukin-2 (IL-2), soluble tumor
      necrosis factor-[alpha] receptors I and II (sTNFRI and sTNFRII), endothelial markers (soluble
      vascular cell adhesion molecule-1,), markers of monocyte/macrophage activation [soluble CD14
      (sCD14), soluble CD163 (sCD163)], D-dimer.

      Statistical analysis The aim of this exploratory study is to evaluate the effect of a new
      integrase inhibitor on serum level of inflammatory markers.

      Two NRTI backbone combinations (TDF/FTC vs ABC/3TC) and three third agents (RAL vs ELV vs
      DTG) will be compared in a factorial design. Baseline characteristics will be compared
      between treatment groups by using the Wilcoxon and chi-squared tests in order to identify
      variables associated with the choice of treatment. Because the marker values isn't normally
      distributed, they will be log e-transformed for analysis. For each marker, changes between
      D0, M6 and M12 (mean fold change) will be expressed as the geometric mean of their ratio
      after log-e transformation. A paired one-sample t test will be used to identify significant
      differences in the overall changes in each marker. Linear regression models will be used to
      investigate the impact of the different NRTI backbones and the different third agents on the
      biomarker changes. The results will be expressed as the estimated percentage difference
      between the mean fold changes observed with a given drug, using TDF/FTC and RAL as the
      reference groups for the comparison. Relationships between baseline covariables and changes
      in each biomarker will be examined in univariable linear regression models. These covariables
      will be sex, age, body mass index, smoking status, prior AIDS-defining events, and the
      pre-ART CD4 cell count and viral load. Baseline covariables associated with changes in at
      least one biomarker (p < 0.10) and viral blips above 50 copies/ml between M6 and M12 will be
      retained in all multivariable linear regression models in order to control for factors that
      might have influenced the choice of cART regimen or affected biomarker levels. Age and
      smoking status will be included in the multivariable model since these variables are known to
      influence marker levels. Interaction terms between the NRTI backbone and the third agent will
      be tested for each marker. Sensitivity analyses will conduct. Statistical analyses will run
      on STATA 12 software, and p values <0.05 were considered statistically significant.

      Ethics This study will be conducted in accordance with the ethical principles that have their
      origin in the Declaration of Helsinki and will be consistent with Good Clinical Practice
      (GCP) and applicable regulatory requirements.

      The study will be conducted in compliance with the protocol. The protocol and any amendments
      and the patient informed consent will receive Ethics Committee (EC) approval/favourable
      opinion prior to initiation of the study.

      Freely given written informed consent must be obtained from every patient or their legally
      acceptable representative prior to clinical trial participation, including informed consent
      for any screening procedures conducted to establish patient eligibility for the trial.
observational model: Cohort
time perspective: Retrospective
measure: Inflammation outcomes 48 week
time frame: 48 week
description: Evaluate the changes from baseline to week 48 in level of markers of inflammation (IL-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) in patients who receive first line antiretroviral therapy
measure: Inflammation outcomes 24 week
time frame: 24 week
description: Evaluate the changes from baseline to week 24 in level of markers of inflammation (IL-2, IL-6, sTNFR-1, sCD14, sCD163, sICAM, hsRCP , sVCAM, LPS, D-dimer) in patients who receive first line antiretroviral therapy
arm group label: Dolutegravir treatment group
description: Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a dolutegravir containing regimen
arm group label: Raltegravir treatment group
description: Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a raltegravir containing regimen
arm group label: Elvitegravir treatment group
description: Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a elvitegravir containing regimen
arm group label: Protease inhibitors treatment group
description: Naïve patients having documented HIV-1 infection and starting their first antiretroviral treatment with a protease inhibitors containing regimen
Serum (Biospecimen retained as a normal clinical practice)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Eugenia Quiros Roldan, Prof
role: Principal Investigator
affiliation: AO Spedali Civili di Brescia
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia
investigator full name: EUGENIA QUIROS ROLDAN
investigator title: Prof.
mesh term: HIV Infections
sharing ipd: No