Despite considerable refinement in immunosuppressive regimens over the last 25 years and decreased rates of acute rejection following kidney transplantation, long-term transplant outcomes have not improved at the same rate and have remained stagnant. Furthermore, there has been a relative paucity in the development of new immunosuppressive strategies to minimize acute and chronic injury. Maraviroc is a CCR5 inhibitor that may have a novel role in modulating the immune response following transplantation. An ideal setting to test its impact on the alloimmune response is in HIV infected patients undergoing kidney transplantation as maraviroc has known anti-retroviral qualities. This is particularly relevant in that unexpectedly high rejection rates (2-3 fold higher than HIV uninfected recipients) have been reported following kidney transplantation in HIV positive recipients. We hypothesize that CCR5 blockade will minimize immunologic graft injury and improve long-term kidney function. This hypothesis leads to the primary aim, which is to determine the impact of a CCR5 inhibitor (maraviroc) on improving long-term kidney graft function following kidney transplantation in HIV infected recipients. Secondly, some evidence suggests that inhibition of CCR5 could reduce the size of the HIV viral reservoir during long-term antiretroviral therapy in people with HIV. We hypothesize that CCR5 blockade in combination with immunosuppressive therapy used following kidney transplantation will reduce HIV persistence in CD4+ T lymphocytes. Thus, we aim to determine the impact of maraviroc on HIV persistence. Lastly, We hypothesize that the high rate of kidney transplant rejection in HIV+ patients is be due to high frequency of heterologous memory donor-reactive T cells that arise in response to chronic infections in this population which include HIV and a multitude of other co-pathogens such as CMV, EBV, HCV, and HBV. Thus, transplantation in HIV+ patients may provide a unique opportunity to determine the importance of heterologous immunity to transplant outcomes in humans. This leads to the third aim, which is to assess the alloimmune status of HIV+ transplant patients and impact of CCR5 blockade on their alloimmune profile. To achieve these three aims, we propose a prospective, multi-center, double-blind phase II study of kidney transplantation in HIV+ individuals assessing the safety and efficacy of a maraviroc-based antiretroviral regimen given post-transplant. Subjects will be consented and enrolled until 120 eligible subjects are randomized. We will perform mechanistic analysis of the study subjects by testing collected blood samples at defined time points. The R34 grant will allow the investigators to finalize all facets of the clinical trial protocol, procedures for specimen collecion, banking and tracking, for confirming all participating centers, and preparing all necessary study documents and processes.
Maraviroc is a CCR5 inhibitor that may have a novel role in modulating the immune response following transplantation, and an ideal setting to test its effect on the transplant alloimmune response is in HIV infected patients undergoing kidney transplantation. If the unexpectedly high rejection rates seen in HIV infected patients undergoing kidney transplantation can be reduced, the approach could lead to benefits for all kidney transplant recipients. In addition, CCR5 inhibition may play a role in reducing HIV persistence for subjects on long-term antiretroviral therapy for HIV infection.
