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Clinical Trial 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.


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of the levels of calcineurin inhibitors (e.g., tacrolimus or cyclosporine A) is necessary when PIs are introduced or withdrawn in HIV-infected SOT recipients, because they are strong CYP450 inhibitors.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


Study Design


Related Conditions & MeSH terms


NCT number NCT02995824
Study type Observational
Source Hospital Clinic of Barcelona
Contact
Status Completed
Phase
Start date January 2002
Completion date December 31, 2019

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