Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

MVC is a CCR5 inhibitor that may have a positive role in modulating the immune response following transplantation. The purpose of this study is to evaluate the safety and tolerability of MVC in HIV-infected adults in need of a kidney transplant. The study will also evaluate whether using both immunosuppressant drugs and MVC will improve kidney function after a kidney transplant.

This study will enroll HIV-infected adults on combination antiretroviral therapy (cART) who need a kidney transplant. At the time of their kidney transplant, study participants will be randomly assigned to receive either MVC or placebo as an addition to their cART regimen. (MVC or placebo will be provided by the study. However, the HIV medicines in their cART regimens will not be provided by the study.) Participants will receive MVC or placebo throughout their participation in the study, which will be 1 to 3 years depending on when they enroll in the study.

Study visits will occur at enrollment (Day 0) and post-transplant Weeks 1, 2, 4, 8, 13, 26, 39, 52, 78, 104, 130, and 156. Study visits may include a physical examination, blood collection, lymph node collection, urine sample collection, and a kidney biopsy. During the study, participants will also be monitored closely for evidence of drug toxicities, HIV treatment failure and rejection.

Inclusion criteria

• Participant is able to understand and provide informed consent.
• Documented HIV infection (by any licensed enzyme-linked immunosorbent assay [ELISA] and confirmation by Western Blot, positive HIV antibody (ab) indirect fluorescent antibody (IFA), or documented history of detectable HIV-1 RNA).
• Participant is 18 years of age or older.
• CD4+ T-cell count greater than or equal to 200/µL at any time in the 26 weeks prior to enrollment.
• Most recent HIV-1 RNA less than 50 copies RNA/mL. Eligibility at the time of enrollment will be determined based on the most recent HIV-1 RNA, not more than 26 weeks prior to enrollment. Subjects who require a switch in combination antiretroviral therapy (cART) regimen to become study eligible must also have an eligible HIV-1 RNA result post change in cART.
• Participant meets standard listing criteria for placement on transplant waiting list.
• For participants with an HIV+ deceased donor:

• No active opportunistic infections.
• Concurrence by the study team that based on medical history and ART, viral suppression can be achieved in the recipient post-transplant.
• Must be enrolled in an Institutional Review Board (IRB) approved research protocol that fulfills the requirements of the DHHA Hope Act Policy (see the protocol for more information).
• HIV+ deceased donor must have no evidence of invasive opportunistic complications of HIV infection, and must have a pre-implant biopsy.
• Antiretroviral (ARV) Use: Participant is on a stable cART regimen for at least 3 months prior to enrollment (unless changes are made due to toxicity, drug interactions, convenience or to an eligible non-protease inhibitor-based regimen). Switch should not be due to virologic failure. A regimen consisting of 2 NTRTIs and an integrase inhibitor is preferred due to minimal drug interaction but any non-protease inhibitor regimen may be used.

• If on a protease inhibitor based regimen, participant must be switched to a non-protease inhibitor-based regimen based on lack of any prior drug resistance or antiretroviral-treatment failure, and be willing to remain on indefinitely unless a change is medically necessary. Participants who need to be switched must have been on a stable cART regimen for at least 3 months prior, and must have an eligible HIV-1 RNA result post change in cART.
• If already on a stable non-protease inhibitor-based regimen, participant is willing to remain on this regimen indefinitely unless a change in regimen is medically indicated.
• If untreated, must initiate and be willing to remain on indefinitely a non-protease inhibitor-based antiretroviral regimen unless a change is medically necessary.
• No known allergy or intolerance to components of maraviroc (MVC) or its formulation.
• No known contraindication to MVC.
• Female participants of child-bearing potential must have a negative serum beta-human chorionic gonadotropin (HCG) pregnancy test within 30 days of randomization.

Exclusion criteria

• Participant is currently on MVC.
• Participant needs multi-organ transplant.
• Participant has a live donor who is HIV+.
• Participant is unable to switch to a non-protease inhibitor-based cART regimen.
• Participant has received immunosuppressant medication in the 6 months prior to enrollment. Note: Low dose maintenance steroids (less than or equal to 10 mg per day of prednisone, or equivalent strength steroid) will not be considered immunosuppression.
• Opportunistic Complication History: Any history of progressive multifocal leukoencephalopathy (PML), chronic intestinal cryptosporidiosis of greater than 1 month duration, or primary central nervous system (CNS) lymphoma. Note: History of pulmonary coccidioidomycosis will be treated per local site policy regarding this infection in HIV negative transplant candidates, generally requiring a 5-year disease-free interval.
• Participant has a history of any neoplasm except for the following: resolved kaposi's sarcoma, in situ anogenital carcinoma, adequately treated basal or squamous cell carcinoma of the skin, solid tumors (except primary CNS lymphoma) treated with curative therapy and disease free for more than 5 years. History of renal cell carcinoma requires disease-free state for 2 years. History of leukemia and disease-free duration will be per site policy.
• Substance use that in the opinion of the investigator would interfere with compliance with the study requirements.
• Participant is pregnant or breastfeeding. Note: Participants who become pregnant post-transplant will continue to be followed in the study and will be managed per local site practice. Women that become pregnant should not breastfeed.
• Participant has used interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in the prior six months.
• Participant has received interferon-alpha therapy in the prior 12 weeks.
• Use of investigational drugs within 4 weeks of enrollment.
• Past or current medical problems or findings from medical history, physical examination, or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study.