Effectiveness of Raltegravir-Based Antiretroviral Therapy in HIV-HCV Coinfected Liver Transplant Recipients
Condition: Liver Transplantation; HIV Infections; Antiretroviral Therapy
MeSH terms: HIV Infections
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Raltegravir-based antiretroviral therapy
Intervention type(s): Other
Intervention description(s): 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.
Intervention MeSH terms: Raltegravir Potassium; Anti-Retroviral Agents
Observational model: Cohort
Time perspective: Retrospective
Sampling method: Non-Probability Sample
Study 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 they were followed until January
        2016. 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] or other ART regimens including boosted PI or
        NNRTIs [Group 2].
      
Keywords: Liver transplantation; HIV infection; Antiretroviral therapy; Raltegravir