<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/NCT02995824</url>
  </required_header>
  <id_info>
    <org_study_id>2008-4248</org_study_id>
    <nct_id>NCT02995824</nct_id>
  </id_info>
  <brief_title>Effectiveness of Raltegravir-Based Antiretroviral Therapy in HIV-HCV Coinfected Liver Transplant Recipients</brief_title>
  <acronym>RAL-LT-HIV</acronym>
  <official_title>Effectiveness of Raltegravir-Based Antiretroviral Therapy in HIV-HCV Coinfected Liver Transplant Recipients: Retrospective Analysis in a Prospective National Cohort Study (RAL-LT-HIV)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Clinic of Barcelona</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital Clinic of Barcelona</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a retrospective observational multicenter cohort study based on 271 consecutive&#xD;
      HIV-HCV coinfected patients who underwent liver transplantation (LT) between 2002 and 2012 in&#xD;
      23 centers from Spain and who were prospectively followed until January 2016. The main&#xD;
      objective of this study is to analyze the effectiveness and safety of 2 nucleoside reverse&#xD;
      transcriptase inhibitors (NRTIs) plus Raltegravir (RAL)- based antiretroviral therapy (ART)&#xD;
      compared to other antiretroviral regimens in liver transplant (LT) HIV-HCV co-infected&#xD;
      recipients. In addition, the investigators want to know the rejection rates in patients&#xD;
      taking RAL-based ART in comparison with other ART-regimens and to know the efficacy and&#xD;
      safety of direct antiviral agents (DAAs) against HCV in HIV-infected liver transplant&#xD;
      recipients taking RAL-based ART.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      With the advent of combined antiretroviral therapy (cART), patients infected with human&#xD;
      immunodeficiency virus type 1 (HIV) are now living longer and dying of illnesses other than&#xD;
      acquired immunodeficiency syndrome.&#xD;
&#xD;
      Although outcome of liver transplantation (LT) in HIV and hepatitis C virus (HCV)-coinfected&#xD;
      recipients was poorer than in HIV-negative recipients in the pre-HAART era, more recent&#xD;
      evidence has demonstrated comparable results in both populations [Roland ME (2006), Terrault&#xD;
      N (2012)]. Currently, LT can be performed safely in selected HIV-1-infected patients [Miro JM&#xD;
      (2012)]. However, a number of issues persist regarding patient selection, postoperative&#xD;
      management, treatment of post-LT HCV recurrence and interactions between antiretroviral and&#xD;
      immunosuppressive agents. A key challenge in the post-transplant period is the management of&#xD;
      pharmacokinetic interactions between immunosuppressive and antiretroviral drugs, particularly&#xD;
      ritonavir-boosted HIV protease inhibitors (PIs), which involve a higher risk of allograft&#xD;
      rejection and drug toxicity [van Maarseveen EM (2012)].&#xD;
&#xD;
      Frequent monitoring of the levels of calcineurin inhibitors (e.g., tacrolimus or cyclosporine&#xD;
      A) is necessary when PIs are introduced or withdrawn in HIV-infected SOT recipients, because&#xD;
      they are strong CYP450 inhibitors.&#xD;
&#xD;
      Furthermore, the pharmacokinetics of corticosteroids and mTOR inhibitors can be affected by&#xD;
      PIs. In contrast, non-nucleoside reverse transcriptase inhibitors (NNRTI), which are also&#xD;
      commonly used in HAART regimens, are CYP450 inducers and may decrease serum levels of&#xD;
      calcineurin inhibitors, with the result that it is necessary to increase their dose to&#xD;
      prevent allograft rejection. Raltegravir (RAL) is the first HIV-1 integrase inhibitor&#xD;
      approved for clinical practice [Powderly WG (2010)]. It was shown to be highly effective and&#xD;
      well tolerated in phase III clinical trials in multidrug-experienced HIV- infected patients&#xD;
      and as initial therapy in treatment-naïve patients [Powderly WG (2010)]. RAL is metabolized&#xD;
      primarily in the liver via glucuronidation mediated by the UDP glucuronosyltransferase 1A1&#xD;
      (UGT1A1) isoenzyme, although a small percentage is cleared via the kidneys [Kassahun K&#xD;
      (2007), Brainard DM (2011)]. RAL is not a substrate of CYP450 and is neither an inducer nor&#xD;
      an inhibitor of the main CYP450 enzymes or P-glycoprotein- mediated transport. A favorable&#xD;
      pharmacokinetic profile has been demonstrated in HIV-infected LT recipients co-treated with&#xD;
      RAL and calcineurin inhibitors (cyclosporine, tacrolimus), mTOR inhibitors, and&#xD;
      corticosteroids [van Maarseveen EM (2012), Tricot L (2009)], indicating that RAL is probably&#xD;
      well tolerated and efficacious in HIV-infected SOT recipients [Tricot L (2009)]. Preliminary&#xD;
      data at the Hospital Clinic of Barcelona (Spain) also suggest that no clinically relevant PK&#xD;
      interactions between RAL and mycophenolic acid (MPA), another widely used immunosuppressant&#xD;
      [Miro JM et al. (2011)]. Moreover, RAL has few interactions with the new direct acting agents&#xD;
      (DAAs) against hepatitis C that may be used in the post-transplant period in order to treat&#xD;
      HCV recurrence. The most adequate antiretroviral regimen for HIV-HCV coinfected patients&#xD;
      undergoing SOT has not been established. However, switching protease inhibitors or&#xD;
      NNRTI-based regimens for a RAL-based regimen at the time of transplantation may be an option&#xD;
      to be considered.&#xD;
&#xD;
      Population: Multicenter cohort study based on 271 consecutive HIV-HCV coinfected patients who&#xD;
      underwent LT between 2002 and 2012 in 23 centers from Spain who were prospectively followed&#xD;
      until January 2016. The study started at 2006 and, for patients who underwent LT between 2002&#xD;
      and 2005, the information was gathered retrospectively and all participants were followed&#xD;
      until January 2016.&#xD;
&#xD;
      Antiretroviral treatment was given by the doctors in charge of patients based on their best&#xD;
      clinical judgment. Therefore, this is not a clinical trial. Fifty-two percent (142) of&#xD;
      HIV-HCV coinfected LT recipients were treated after LT with RAL plus 2 nucleoside reverse&#xD;
      transcriptase inhibitors (NRTI) [lamivudine (3TC) or emtricitabine.(FTC) plus abacavir (ABC)&#xD;
      or tenofovir (TDF)] [Group 1] and 48% of participants (129) were treated with other ART&#xD;
      regimens including boosted PI or NNRTIs [Group 2].&#xD;
&#xD;
      Clinical Outcomes and Measurements:&#xD;
&#xD;
        1. HIV-related: incidence of plasma RNA HIV viral rebound, levels of CD4+ T cells,&#xD;
           incidence of opportunistic infections after LT at weeks 48, 96,132 and 240;&#xD;
&#xD;
        2. LT-related: incidence of acute or chronic rejection (biopsy-proven), liver&#xD;
           re-transplantation or death at weeks 48, 96, 132 and 240.&#xD;
&#xD;
        3. HCV-related: incidence of progression to F3/F4 (diagnosed by liver biopsy or liver&#xD;
           elastography), clinical decompensation of liver cirrhosis at weeks 48,96,132 and 240 or&#xD;
           plasma RNA HCV recurrence and DAAs-based HCV treatment outcome (12 weeks-sustained&#xD;
           virological response [SVR12]);&#xD;
&#xD;
      All outcomes will be compared between Group 1 and Group 2.&#xD;
&#xD;
      The clinical evaluation, the laboratory tests (including cyclosporine and tacrolimus serum&#xD;
      levels), the CD4/CD8 subsets and plasma RNA HIV viral load was collected every 12 weeks up to&#xD;
      144 weeks in accordance with routine clinical practice.&#xD;
&#xD;
        -  Study start date: 1st January 2017&#xD;
&#xD;
        -  Study end date: 31st July 2017&#xD;
&#xD;
        -  First Patient in: 1st Jan 2002&#xD;
&#xD;
        -  Last patient out: 31st Nov 2012&#xD;
&#xD;
        -  Enrollment period already closed 31-12-2011.&#xD;
&#xD;
        -  Ongoing active follow-up. Last visit: January 2016.&#xD;
&#xD;
      Planned duration of current analysis: 6 months (3 months: collecting data; 2 months: data&#xD;
      management and analysis; 1 month: manuscript preparation).&#xD;
&#xD;
      The simple size was calculated based on the two primary endpoints (incidence of acute or&#xD;
      chronic rejection at 48 weeks and death during the whole follow-up period) and preliminary&#xD;
      data observed in solid organ transplant HIV-infected recipients at the Hospital Clinic of&#xD;
      Barcelona, Spain [Manzardo C et al. (2015)]. Accepting an alpha risk of 0.05 in a two-sided&#xD;
      test with 142 subjects in Group 1 and 129 in Group 2, the statistical power for the two&#xD;
      primary endpoints will be: 81%, expecting 25% of chronic or acute rejection at 48 weeks in&#xD;
      Group 1 and 41% in Group 2; and 98%, expecting 13% of death in Group 1 and 33% in Group 2, at&#xD;
      the end of the whole follow-up.&#xD;
&#xD;
      Categorical variables will be expressed as a frequency (percentage). Continuous variables&#xD;
      will be expressed as means ± standard deviation or median [interquartile range] according to&#xD;
      normal or non-normal distributions. A negative binomial or Poisson regression will be&#xD;
      performed to compare the incidence of outcomes in groups of interest. To compare the levels&#xD;
      of CD4+ T cells in groups of interest a lineal regression will be performed. All statistical&#xD;
      analysis will be carried out using Stata version 13 (StataCorp. 2013. Stata: Release 13.&#xD;
      Statistical Software. College Station, TX: StataCorp LP).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2002</start_date>
  <completion_date type="Actual">December 31, 2019</completion_date>
  <primary_completion_date type="Actual">December 2019</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>Incidence of plasma RNA HIV viral rebound in plasma after liver transplantation</measure>
    <time_frame>Through study completion, an average of 3 years</time_frame>
    <description>Plasma HIV viral load above 50 copies/mL</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CD4+ T cell evolution after liver transplantation</measure>
    <time_frame>Through study completion, an average of 3 years</time_frame>
    <description>CD4+ T cell count below 100 cells/mm3</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of acute rejection after liver transplantation</measure>
    <time_frame>Up to 24 weeks</time_frame>
    <description>Biopsy-proven acute rejection (yes or not)</description>
  </secondary_outcome>
  <enrollment type="Actual">271</enrollment>
  <condition>Liver Transplantation</condition>
  <condition>HIV Infections</condition>
  <condition>Antiretroviral Therapy</condition>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Raltegravir-based antiretroviral therapy</intervention_name>
    <description>To analyze retrospectively the efficacy and safety of raltegravir plus 2 nucleoside reverse transcriptase inhibitors (NRTI) [lamivudine (3TC) or emtricitabine.(FTC) plus abacavir (ABC) or tenofovir (TDF)] [Group 1] versus other ART regimens including boosted PI or NNRTIs [Group 2] in 271 HIV/HCV-coinfected patients who underwent liver transplantation between 2002 and 2012 and were followed until December 2016.</description>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Multicenter cohort study based on 271 consecutive HIV-HCV coinfected patients who underwent&#xD;
        LT between 2002 and 2012 in 23 centers from Spain who were prospectively followed until&#xD;
        January 2016. The study started at 2006 and, for patients who underwent LT between 2002 and&#xD;
        2005, the information was gathered retrospectively and they were followed until January&#xD;
        2016. HIV-HCV coinfected LT recipients were treated after LT, with RAL plus 2 nucleoside&#xD;
        reverse transcriptase inhibitors (NRTI) [lamivudine (3TC) or emtricitabine.(FTC) plus&#xD;
        abacavir (ABC) or tenofovir (TDF)] [Group 1] or other ART regimens including boosted PI or&#xD;
        NNRTIs [Group 2].&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV-infected patients who underwent liver transplantation between 2002 and 2012 in 23&#xD;
             centers from Spain who were prospectively followed until January 2016&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  None&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jose M Miro, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Clinic, Barcelona, Spain</affiliation>
  </overall_official>
  <reference>
    <citation>Roland ME, Barin B, Huprikar S, Murphy B, Hanto DW, Blumberg E, Olthoff K, Simon D, Hardy WD, Beatty G, Stock PG; HIVTR Study Team. Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls. AIDS. 2016 Jan 28;30(3):435-44. doi: 10.1097/QAD.0000000000000934.</citation>
    <PMID>26765937</PMID>
  </reference>
  <reference>
    <citation>Terrault NA, Roland ME, Schiano T, Dove L, Wong MT, Poordad F, Ragni MV, Barin B, Simon D, Olthoff KM, Johnson L, Stosor V, Jayaweera D, Fung J, Sherman KE, Subramanian A, Millis JM, Slakey D, Berg CL, Carlson L, Ferrell L, Stablein DM, Odim J, Fox L, Stock PG; Solid Organ Transplantation in HIV: Multi-Site Study Investigators. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl. 2012 Jun;18(6):716-26. doi: 10.1002/lt.23411.</citation>
    <PMID>22328294</PMID>
  </reference>
  <reference>
    <citation>Miro JM, Montejo M, Castells L, Rafecas A, Moreno S, Aguero F, Abradelo M, Miralles P, Torre-Cisneros J, Pedreira JD, Cordero E, de la Rosa G, Moyano B, Moreno A, Perez I, Rimola A; Spanish OLT in HIV-Infected Patients Working Group investigators. Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study. Am J Transplant. 2012 Jul;12(7):1866-76. doi: 10.1111/j.1600-6143.2012.04028.x. Epub 2012 Apr 4.</citation>
    <PMID>22471341</PMID>
  </reference>
  <reference>
    <citation>van Maarseveen EM, Rogers CC, Trofe-Clark J, van Zuilen AD, Mudrikova T. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review. AIDS Patient Care STDS. 2012 Oct;26(10):568-81. doi: 10.1089/apc.2012.0169.</citation>
    <PMID>23025916</PMID>
  </reference>
  <reference>
    <citation>Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection. J Antimicrob Chemother. 2010 Dec;65(12):2485-8. doi: 10.1093/jac/dkq350. Epub 2010 Sep 18.</citation>
    <PMID>20852268</PMID>
  </reference>
  <reference>
    <citation>Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, Azrolan N, Iwamoto M, Wagner JA, Wenning LA. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007 Sep;35(9):1657-63. doi: 10.1124/dmd.107.016196. Epub 2007 Jun 25.</citation>
    <PMID>17591678</PMID>
  </reference>
  <reference>
    <citation>Brainard DM, Wenning LA, Stone JA, Wagner JA, Iwamoto M. Clinical pharmacology profile of raltegravir, an HIV-1 integrase strand transfer inhibitor. J Clin Pharmacol. 2011 Oct;51(10):1376-402. doi: 10.1177/0091270010387428. Epub 2011 Jan 5.</citation>
    <PMID>21209233</PMID>
  </reference>
  <reference>
    <citation>Tricot L, Teicher E, Peytavin G, Zucman D, Conti F, Calmus Y, Barrou B, Duvivier C, Fontaine C, Welker Y, Billy C, de Truchis P, Delahousse M, Vittecoq D, Salmon-Ceron D. Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs. Am J Transplant. 2009 Aug;9(8):1946-52. doi: 10.1111/j.1600-6143.2009.02684.x. Epub 2009 Jun 10.</citation>
    <PMID>19519819</PMID>
  </reference>
  <reference>
    <citation>Miro JM, et al. Combination of Raltegravir (RAL) plus Lamivudine (3TC) or Emtricitabine (FTC) plus Abacavir (ABV) or Tenofovir (TDF) is Safe, Effective and Prevents Pharmacokinetic (PK) Interactions with Immunosuppressive Drugs (IS) in HIV-1-infected Solid Organ Transplant (SOT) Recipients. 18th Conference on Retroviruses and Opportunistic Infections (CROI). Boston, MA. February 27- March 2, 2011. Abstract #644</citation>
  </reference>
  <reference>
    <citation>Manzardo C, et al. Raltegravir (RAL) Based Antiretroviral Therapy (ART) in HIV-infected Solid Organ Transplant (SOT) Recipients: a Single Center Experience. 15th EACS Conference. Barcelona, Spain. October 21- 24 2015. Abstract #PE8/68.</citation>
  </reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>November 27, 2016</study_first_submitted>
  <study_first_submitted_qc>December 14, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 16, 2016</study_first_posted>
  <last_update_submitted>February 15, 2020</last_update_submitted>
  <last_update_submitted_qc>February 15, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 18, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital Clinic of Barcelona</investigator_affiliation>
    <investigator_full_name>Jose M. Miro</investigator_full_name>
    <investigator_title>Senior Consultant, Infectious Diseases</investigator_title>
  </responsible_party>
  <keyword>Liver transplantation</keyword>
  <keyword>HIV infection</keyword>
  <keyword>Antiretroviral therapy</keyword>
  <keyword>Raltegravir</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Raltegravir Potassium</mesh_term>
    <mesh_term>Anti-Retroviral Agents</mesh_term>
  </intervention_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/NCT02995824
org study id: 2008-4248
nct id: NCT02995824
lead sponsor: 
has dmc: No
This is a retrospective observational multicenter cohort study based on 271 consecutive
      HIV-HCV coinfected patients who underwent liver transplantation (LT) between 2002 and 2012 in
      23 centers from Spain and who were prospectively followed until January 2016. The main
      objective of this study is to analyze the effectiveness and safety of 2 nucleoside reverse
      transcriptase inhibitors (NRTIs) plus Raltegravir (RAL)- based antiretroviral therapy (ART)
      compared to other antiretroviral regimens in liver transplant (LT) HIV-HCV co-infected
      recipients. In addition, the investigators want to know the rejection rates in patients
      taking RAL-based ART in comparison with other ART-regimens and to know the efficacy and
      safety of direct antiviral agents (DAAs) against HCV in HIV-infected liver transplant
      recipients taking RAL-based ART.
With the advent of combined antiretroviral therapy (cART), patients infected with human
      immunodeficiency virus type 1 (HIV) are now living longer and dying of illnesses other than
      acquired immunodeficiency syndrome.

      Although outcome of liver transplantation (LT) in HIV and hepatitis C virus (HCV)-coinfected
      recipients was poorer than in HIV-negative recipients in the pre-HAART era, more recent
      evidence has demonstrated comparable results in both populations [Roland ME (2006), Terrault
      N (2012)]. Currently, LT can be performed safely in selected HIV-1-infected patients [Miro JM
      (2012)]. However, a number of issues persist regarding patient selection, postoperative
      management, treatment of post-LT HCV recurrence and interactions between antiretroviral and
      immunosuppressive agents. A key challenge in the post-transplant period is the management of
      pharmacokinetic interactions between immunosuppressive and antiretroviral drugs, particularly
      ritonavir-boosted HIV protease inhibitors (PIs), which involve a higher risk of allograft
      rejection and drug toxicity [van Maarseveen EM (2012)].

      Frequent monitoring of the levels of calcineurin inhibitors (e.g., tacrolimus or cyclosporine
      A) is necessary when PIs are introduced or withdrawn in HIV-infected SOT recipients, because
      they are strong CYP450 inhibitors.

      Furthermore, the pharmacokinetics of corticosteroids and mTOR inhibitors can be affected by
      PIs. In contrast, non-nucleoside reverse transcriptase inhibitors (NNRTI), which are also
      commonly used in HAART regimens, are CYP450 inducers and may decrease serum levels of
      calcineurin inhibitors, with the result that it is necessary to increase their dose to
      prevent allograft rejection. Raltegravir (RAL) is the first HIV-1 integrase inhibitor
      approved for clinical practice [Powderly WG (2010)]. It was shown to be highly effective and
      well tolerated in phase III clinical trials in multidrug-experienced HIV- infected patients
      and as initial therapy in treatment-naïve patients [Powderly WG (2010)]. RAL is metabolized
      primarily in the liver via glucuronidation mediated by the UDP glucuronosyltransferase 1A1
      (UGT1A1) isoenzyme, although a small percentage is cleared via the kidneys [Kassahun K
      (2007), Brainard DM (2011)]. RAL is not a substrate of CYP450 and is neither an inducer nor
      an inhibitor of the main CYP450 enzymes or P-glycoprotein- mediated transport. A favorable
      pharmacokinetic profile has been demonstrated in HIV-infected LT recipients co-treated with
      RAL and calcineurin inhibitors (cyclosporine, tacrolimus), mTOR inhibitors, and
      corticosteroids [van Maarseveen EM (2012), Tricot L (2009)], indicating that RAL is probably
      well tolerated and efficacious in HIV-infected SOT recipients [Tricot L (2009)]. Preliminary
      data at the Hospital Clinic of Barcelona (Spain) also suggest that no clinically relevant PK
      interactions between RAL and mycophenolic acid (MPA), another widely used immunosuppressant
      [Miro JM et al. (2011)]. Moreover, RAL has few interactions with the new direct acting agents
      (DAAs) against hepatitis C that may be used in the post-transplant period in order to treat
      HCV recurrence. The most adequate antiretroviral regimen for HIV-HCV coinfected patients
      undergoing SOT has not been established. However, switching protease inhibitors or
      NNRTI-based regimens for a RAL-based regimen at the time of transplantation may be an option
      to be considered.

      Population: Multicenter cohort study based on 271 consecutive HIV-HCV coinfected patients who
      underwent LT between 2002 and 2012 in 23 centers from Spain who were prospectively followed
      until January 2016. The study started at 2006 and, for patients who underwent LT between 2002
      and 2005, the information was gathered retrospectively and all participants were followed
      until January 2016.

      Antiretroviral treatment was given by the doctors in charge of patients based on their best
      clinical judgment. Therefore, this is not a clinical trial. Fifty-two percent (142) of
      HIV-HCV coinfected LT recipients were treated after LT with RAL plus 2 nucleoside reverse
      transcriptase inhibitors (NRTI) [lamivudine (3TC) or emtricitabine.(FTC) plus abacavir (ABC)
      or tenofovir (TDF)] [Group 1] and 48% of participants (129) were treated with other ART
      regimens including boosted PI or NNRTIs [Group 2].

      Clinical Outcomes and Measurements:

        1. HIV-related: incidence of plasma RNA HIV viral rebound, levels of CD4+ T cells,
           incidence of opportunistic infections after LT at weeks 48, 96,132 and 240;

        2. LT-related: incidence of acute or chronic rejection (biopsy-proven), liver
           re-transplantation or death at weeks 48, 96, 132 and 240.

        3. HCV-related: incidence of progression to F3/F4 (diagnosed by liver biopsy or liver
           elastography), clinical decompensation of liver cirrhosis at weeks 48,96,132 and 240 or
           plasma RNA HCV recurrence and DAAs-based HCV treatment outcome (12 weeks-sustained
           virological response [SVR12]);

      All outcomes will be compared between Group 1 and Group 2.

      The clinical evaluation, the laboratory tests (including cyclosporine and tacrolimus serum
      levels), the CD4/CD8 subsets and plasma RNA HIV viral load was collected every 12 weeks up to
      144 weeks in accordance with routine clinical practice.

        -  Study start date: 1st January 2017

        -  Study end date: 31st July 2017

        -  First Patient in: 1st Jan 2002

        -  Last patient out: 31st Nov 2012

        -  Enrollment period already closed 31-12-2011.

        -  Ongoing active follow-up. Last visit: January 2016.

      Planned duration of current analysis: 6 months (3 months: collecting data; 2 months: data
      management and analysis; 1 month: manuscript preparation).

      The simple size was calculated based on the two primary endpoints (incidence of acute or
      chronic rejection at 48 weeks and death during the whole follow-up period) and preliminary
      data observed in solid organ transplant HIV-infected recipients at the Hospital Clinic of
      Barcelona, Spain [Manzardo C et al. (2015)]. Accepting an alpha risk of 0.05 in a two-sided
      test with 142 subjects in Group 1 and 129 in Group 2, the statistical power for the two
      primary endpoints will be: 81%, expecting 25% of chronic or acute rejection at 48 weeks in
      Group 1 and 41% in Group 2; and 98%, expecting 13% of death in Group 1 and 33% in Group 2, at
      the end of the whole follow-up.

      Categorical variables will be expressed as a frequency (percentage). Continuous variables
      will be expressed as means ± standard deviation or median [interquartile range] according to
      normal or non-normal distributions. A negative binomial or Poisson regression will be
      performed to compare the incidence of outcomes in groups of interest. To compare the levels
      of CD4+ T cells in groups of interest a lineal regression will be performed. All statistical
      analysis will be carried out using Stata version 13 (StataCorp. 2013. Stata: Release 13.
      Statistical Software. College Station, TX: StataCorp LP).
observational model: Cohort
time perspective: Retrospective
measure: Incidence of plasma RNA HIV viral rebound in plasma after liver transplantation
time frame: Through study completion, an average of 3 years
description: Plasma HIV viral load above 50 copies/mL
measure: CD4+ T cell evolution after liver transplantation
time frame: Through study completion, an average of 3 years
description: CD4+ T cell count below 100 cells/mm3
measure: Incidence of acute rejection after liver transplantation
time frame: Up to 24 weeks
description: Biopsy-proven acute rejection (yes or not)
intervention type: Other
intervention name: Raltegravir-based antiretroviral therapy
description: To analyze retrospectively the efficacy and safety of raltegravir plus 2 nucleoside reverse transcriptase inhibitors (NRTI) [lamivudine (3TC) or emtricitabine.(FTC) plus abacavir (ABC) or tenofovir (TDF)] [Group 1] versus other ART regimens including boosted PI or NNRTIs [Group 2] in 271 HIV/HCV-coinfected patients who underwent liver transplantation between 2002 and 2012 and were followed until December 2016.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Jose M Miro, MD PhD
role: Principal Investigator
affiliation: Hospital Clinic, Barcelona, Spain
citation: Roland ME, Barin B, Huprikar S, Murphy B, Hanto DW, Blumberg E, Olthoff K, Simon D, Hardy WD, Beatty G, Stock PG; HIVTR Study Team. Survival in HIV-positive transplant recipients compared with transplant candidates and with HIV-negative controls. AIDS. 2016 Jan 28;30(3):435-44. doi: 10.1097/QAD.0000000000000934.
PMID: 26765937
citation: Terrault NA, Roland ME, Schiano T, Dove L, Wong MT, Poordad F, Ragni MV, Barin B, Simon D, Olthoff KM, Johnson L, Stosor V, Jayaweera D, Fung J, Sherman KE, Subramanian A, Millis JM, Slakey D, Berg CL, Carlson L, Ferrell L, Stablein DM, Odim J, Fox L, Stock PG; Solid Organ Transplantation in HIV: Multi-Site Study Investigators. Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection. Liver Transpl. 2012 Jun;18(6):716-26. doi: 10.1002/lt.23411.
PMID: 22328294
citation: Miro JM, Montejo M, Castells L, Rafecas A, Moreno S, Aguero F, Abradelo M, Miralles P, Torre-Cisneros J, Pedreira JD, Cordero E, de la Rosa G, Moyano B, Moreno A, Perez I, Rimola A; Spanish OLT in HIV-Infected Patients Working Group investigators. Outcome of HCV/HIV-coinfected liver transplant recipients: a prospective and multicenter cohort study. Am J Transplant. 2012 Jul;12(7):1866-76. doi: 10.1111/j.1600-6143.2012.04028.x. Epub 2012 Apr 4.
PMID: 22471341
citation: van Maarseveen EM, Rogers CC, Trofe-Clark J, van Zuilen AD, Mudrikova T. Drug-drug interactions between antiretroviral and immunosuppressive agents in HIV-infected patients after solid organ transplantation: a review. AIDS Patient Care STDS. 2012 Oct;26(10):568-81. doi: 10.1089/apc.2012.0169.
PMID: 23025916
citation: Powderly WG. Integrase inhibitors in the treatment of HIV-1 infection. J Antimicrob Chemother. 2010 Dec;65(12):2485-8. doi: 10.1093/jac/dkq350. Epub 2010 Sep 18.
PMID: 20852268
citation: Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, Azrolan N, Iwamoto M, Wagner JA, Wenning LA. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007 Sep;35(9):1657-63. doi: 10.1124/dmd.107.016196. Epub 2007 Jun 25.
PMID: 17591678
citation: Brainard DM, Wenning LA, Stone JA, Wagner JA, Iwamoto M. Clinical pharmacology profile of raltegravir, an HIV-1 integrase strand transfer inhibitor. J Clin Pharmacol. 2011 Oct;51(10):1376-402. doi: 10.1177/0091270010387428. Epub 2011 Jan 5.
PMID: 21209233
citation: Tricot L, Teicher E, Peytavin G, Zucman D, Conti F, Calmus Y, Barrou B, Duvivier C, Fontaine C, Welker Y, Billy C, de Truchis P, Delahousse M, Vittecoq D, Salmon-Ceron D. Safety and efficacy of raltegravir in HIV-infected transplant patients cotreated with immunosuppressive drugs. Am J Transplant. 2009 Aug;9(8):1946-52. doi: 10.1111/j.1600-6143.2009.02684.x. Epub 2009 Jun 10.
PMID: 19519819
citation: Miro JM, et al. Combination of Raltegravir (RAL) plus Lamivudine (3TC) or Emtricitabine (FTC) plus Abacavir (ABV) or Tenofovir (TDF) is Safe, Effective and Prevents Pharmacokinetic (PK) Interactions with Immunosuppressive Drugs (IS) in HIV-1-infected Solid Organ Transplant (SOT) Recipients. 18th Conference on Retroviruses and Opportunistic Infections (CROI). Boston, MA. February 27- March 2, 2011. Abstract #644
citation: Manzardo C, et al. Raltegravir (RAL) Based Antiretroviral Therapy (ART) in HIV-infected Solid Organ Transplant (SOT) Recipients: a Single Center Experience. 15th EACS Conference. Barcelona, Spain. October 21- 24 2015. Abstract #PE8/68.
responsible party type: Principal Investigator
investigator affiliation: Hospital Clinic of Barcelona
investigator full name: Jose M. Miro
investigator title: Senior Consultant, Infectious Diseases
mesh term: HIV Infections
mesh term: Raltegravir Potassium
mesh term: Anti-Retroviral Agents
sharing ipd: No