Effectiveness of Raltegravir-Based Antiretroviral Therapy in HIV-HCV Coinfected Liver Transplant Recipients: Retrospective Analysis in a Prospective National Cohort Study (RAL-LT-HIV)

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of the levels of calcineurin inhibitors (e.g., tacrolimus or cyclosporine A) is necessary when PIs are introduced or withdrawn in HIV-infected SOT recipients, because they are strong CYP450 inhibitors.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