Conditions: HIV Infections Kidney Diseases
Keywords: HIV-infected with end-stage kidney disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 97
Healthy volunteers: no

Brief summary:
Maraviroc (MVC) is a type of HIV medicine called a CCR5 inhibitor. This study will evaluate the safety and tolerability of MVC in HIV-infected adults receiving a kidney transplant.

Detailed description:
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.

Arms:
arm 1: Participants will receive MVC at the time of admission for transplantation and prior to transplant. Participants will receive MVC throughout their participation in the study, which will be 1 to 3 years depending on when they enroll. arm 2: Participants will receive placebo at the time of admission for transplantation and prior to transplant. Participants will receive placebo throughout their participation in the study, which will be 1 to 3 years depending on when they enroll.

Interventions: intervention 1: Maraviroc intervention 2: Placebo
Intervention descriptions: intervention 1: Initial dose of 300 mg twice daily (150mg twice daily if co-prescribed with a potent CYP3A inhibitor or 600mg twice daily if co-prescribed with a potent CYP3A inducer). Will be modified if GFR \< 30, if co-prescribed with a potent CYP3A inhibitor or inducer, or if the calcineurin inhibitor used for maintenance immunosuppression is changed to cyclosporine (which is only allowed for tacrolimus toxicity).

Once GFR is greater than or equal to 30, the dose should be returned to the non-renal dosage. If GFR is consistently fluctuating (especially immediately post-transplant), the site investigator may choose when to resume normal dosing of study product based on clinical assessment of stability. intervention 2: Initial dose of 300 mg twice daily (150mg twice daily if co-prescribed with a potent CYP3A inhibitor or 600mg twice daily if co-prescribed with a potent CYP3A inducer). Will be modified if GFR \< 30, if co-prescribed with a potent CYP3A inhibitor or inducer, or if the calcineurin inhibitor used for maintenance immunosuppression is changed to cyclosporine (which is only allowed for tacrolimus toxicity).

Once GFR is greater than or equal to 30, the dose should be returned to the non-renal dosage. If GFR is consistently fluctuating (especially immediately post-transplant), the site investigator may choose when to resume normal dosing of study product based on clinical assessment of stability.

Protocol document:
Prot_SAP_000.pdf: 
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients 
NCT02741323 
Protocol Version 4.0 
February 28, 2019 


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Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients 
VERSION 4.0/February 28, 2019 
IND# 129608 
Study Sponsor(s): 
 
 
 
The National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding Mechanism:  
 
U01AI118594  
DAIDS-ES #:  
 
 
 
20730 
IND Sponsor/Number:  
 
 
NIAID/DAIDS 
Study Drug Manufacturer/Provider: 
ViiV 
 
PRINCIPAL INVESTIGATOR 
Peter Stock, MD, PhD 
University of California, San Francisco 
505 Parnassus Ave., M-884 
San Francisco, CA 94143-0780 
Phone: 415-353-8617 
Fax: 415-353-8974 
E-mail: Peter.Stock@ucsf.edu 
 
DAIDS MEDICAL OFFICER 
Beverly Alston Smith, MD 
Division of AIDS, NIAID 
5601 Fishers Ln 
BG 5601FL, RM 9F50 
Rockville, MD 20852, USA 
Phone:  301-435-3773 
Fax: 301-480-4522 
E-mail: Beverly.alston@nih.gov 
DAIT MEDICAL OFFICER 
Jonah Odim, MD, PhD 
Division of Allergy, Immunology, and 
Transplantation, NIAID 
5601 Fishers Lane, Room 6B21 
Rockville, MD 20852-9827, USA  
Phone: 240-627-3540 
Fax: 240-627-3115 
E-mail: odimj@niaid.nih.gov 
DAIDS PROGRAM OFFICER 
Christine Chiou, MD.  
Division of AIDS, NIAID 
BG 5601FL RM 9F49   
5601 Fishers Lane 
Rockville, MD 20852-9830  
Phone: 240-292-4181 
E-mail: 39TU39TUchristine.chiou@nih.govU39T39T  
 
DAIDS PHARMACIST 
Katherine Shin, Pharm.D. 
Pharmaceutical Affairs Branch 
5601 Fishers Lane, Room 9D30 
Rockville, MD 20852-9829 
Phone: 240-627-3047 
Fax: 301-402-1506 
Email: KaShin@niaid.nih.gov 
BIOSTATISTICIAN 
Burc Barin 
The EMMES Corporation 
401 North Washington Suite 700 
Rockville, MD 20850-1785 
Phone: 301-251-1161 
Fax: 301-251-1355 
E-mail: bbarin@emmes.com 
UCSF PROJECT MANAGER 
Rodney Rogers 
University of California, San Francisco 
505 Parnassus Ave. M-884 
San Francisco, CA 94143-0780 
Phone: 415-514-6454 
Fax: 415-353-2233 
E-mail: Rodney.Rogers@ucsf.edu 
DAIT PROJECT MANAGER, NIAID 
Helena Chepkwurui Diop, MPH 
Division of Allergy, Immunology, and 
Transplantation, NIAID 
5601 Fishers Lane, Room 6B22 
Rockville, MD 20852-9827, USA 
Phone:  240-627-3497 
Fax: 240-627-3115 
E-mail : dioph@niaid.nih.gov 
 
 
 


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PROTOCOL SIGNATURE PAGE 
 
Protocol: 
 
HIVTR-CCR5 
DAIDS-ES 20730 
Version/Date: 
 
Version 4.0/February 28, 2019 
 
Title:  
 
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients 
 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and Human 
Service regulations (45 CFR 46); applicable U.S. Food and Drug Administration regulations; standards of 
the International Conference on Harmonization Guideline for Good Clinical Practice (E6); Institutional 
Review Board/Ethics Committee determinations; all applicable in-country, state, and local laws and 
regulations; and other applicable requirements (e.g., US National Institutes of Health, Division of AIDS) 
and institutional policies. 
 
 
 
 
 
 
___________________________________  
Site Principal Investigator Name (Print)  
 
 
 
 
 
 
____________________________________                                    _________________  
Site Principal Investigator (Signature)                                        Date  
 
 
 
 
 
 
 
 
 


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Protocol Synopsis 
Title 
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients 
Short Title 
HIVTR CCR5 
Clinical Phase 
Phase II 
Number of Sites 
10  
IND Sponsor/Number   
NIAID DAIDS 
Study Objectives 
The primary clinical objectives are to evaluate the: 
1. Impact of CCR5 blockade (maraviroc, MVC) on renal function at week 52 
post-transplant. 
2. Overall safety and tolerability of CCR5 blockade in the HIV+ kidney 
transplant recipient. 
 
The secondary clinical objectives are to evaluate the: 
1. Impact of CCR5 blockade (maraviroc, MVC) on inflammation in the graft 
at week 26 and week 52 post-transplant. 
2. Impact of CCR5 blockade on long term kidney function in the HIV positive 
kidney transplant recipient at months 3, 6, 9 and years 1, 2, 3. 
3. Impact of the addition of CCR5 blockade to cART and immunosuppression 
on HIV persistence following kidney transplantation 
4. Impact of CCR5 blockade on the incidence and severity of rejection 
5. Incidence of HIV infection/HIV nephropathy (HIVAN) in the kidney 
allograft 
6. Safety profiles with use of CCR5 blockade 
7. Pharmacokinetics and impact of CCR5 blockade exposure to CNIs 
 
The primary mechanistic objectives are to: 
1. Define immunologic parameters associated with rejection in the HIV 
positive recipient (versus HIV+ non-rejectors)  
2. Determine the impact of CCR5 blockade on the immunologic profiles in 
the HIV positive recipient.  
Study Design 
Prospective, multi-center, double-blind phase II study 
Primary Clinical 
Endpoints 
1. Measured glomerular filtration rate at 52 weeks by iohexol clearance. 
2. Graft loss, toxicities ≥ Grade 3 and/or permanent treatment 
discontinuation within the first 52 weeks post-transplant. 
Secondary Clinical 
Endpoints  
1. Inflammation in the graft 
a. CD45 gene expression (PTPRC) on the FFPE kidney biopsy sample 
at 26 weeks post-transplant. 
b. CD45 quantitative IHC on the FFPE sample at 26 weeks post-
transplant. 


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c. Gene expression profiling using the 11-gene tCRM module on 
FFPE biopsy shaves at 26 weeks and the 11-gene uCRM module 
on urine cell pellets at 26 weeks and 52 weeks post-transplant. 
2. Measures of Renal Function and Injury (months 3, 6, 9, years 1, 2, 3) 
a. Proportion of participants with eGFR by CKD-EPI, cystatin C, and 
CKD-cystatin C, < 60 mL/min/1.73 mP2
P. 
b. Proportion of participants with defined CKD stage 4 or 5. 
c. Mean calculated eGFR by CKD-EPI, cystatin C, and CKD-cystatin C. 
d. The slope of eGFR by CKD-EPI, cystatin C, and CKD-cystatin C 
variable models over time based on serum creatinine. 
3. HIV persistence 
a. HIV reactivation (frequency of CD4+ T cells producing HIV multiply 
spliced RNAs upon TCR stimulation) 
b. HIV DNA and RNA in peripheral blood CD4+ T cells 
c. Plasma HIV RNA levels (single copy assay) 
4. Histologic and Serologic Evidence of Rejection  
a. Incidence of clinically suspected and biopsy proven acute 
rejection within the first 52 weeks and 156 weeks  as defined by 
histologic evidence of rejection and graft dysfunction as identified 
on central read of biopsy slides. 
b. The incidence of acute cellular rejection grade equal to or > than 
IA, by the Banff 2007 criteria, within the study period (3 years) as 
identified on central read of biopsy slides. 
c. The severity of first and highest grade of acute cellular rejection 
within the study period. 
d. The incidence of antibody mediated rejection. 
e. The prevalence of de novo anti-donor HLA antibodies at 52 
weeks. 
5. Analysis of HIV infection in the renal allograft and HIVAN 
a. Histology/in situ hybridization to assess HIV infection in the renal 
allograft 
6. Safety Profile measures 
a. Death 
b. Graft loss 
c. Incidence of all adverse events (AEs) >/= Grade 3 
d. Incidence of serious adverse events (SAEs) >/= Grade 3 
e. Incidence of opportunistic infections or neoplasms 
f. Incidence of non-opportunistic infections requiring hospitalization 
or systemic therapy 
7. Pharmacokinetics 
a. Calcineurin inhibitor trough levels and AUC for participants on 
maraviroc versus placebo 
b. AUC and trough levels of CCR5 blockade (maraviroc)  


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Mechanistic Endpoints 
1) Define immunologic parameters associated with rejection in the HIV+ 
participants by comparing the following parameters in those who 
experience acute rejection in the first 6 months and those who do not 
have acute rejections (samples collected prior to and at the time of 
rejection will be analyzed and compared): 
 
a. Circulating leukocyte subsets and their activation phenotypes  
b. Anti-donor alloimmune responses measured by frequency of total 
donor-reactive T cells and donor-reactive effector T cells 
c. Frequencies of T cells with cross-reactivity between donor 
alloantigens and HIV, CMV, and EBV antigens 
d. DSA in serum 
e. Gene expression in for-cause biopsies by RNASeq analysis 
f. Histological analysis for evidence of cellular and antibody 
mediated rejection mechanisms. 
 
2) Determine the impact of CCR5 blockade on the immunologic profiles in 
the HIV + recipients by comparing results from MVC-treated and those 
receiving standard of care (SOC).  Change of the various parameters after 
initiation of MVC or SOC will be monitored and these changes will be 
compared between the two groups (Samples collected pre transplant and 
at various time points post-transplant will be analyzed): 
a) Change in circulating leukocyte subsets and their activation 
phenotypes from pre-transplant baseline  
b) Change in CCR5 and other chemokine receptor expression on 
subsets of various circulating leukocytes from pre-transplant 
baseline 
c) Change on anti-donor alloimmune responses measured by 
frequency of total donor-reactive T cells and donor-reactive 
effector T cells 
d) Change in frequencies of T cells with cross-reactivity between 
donor alloantigens and HIV, CMV, and EBV antigens after 
transplant. 
e) DSA in serum 
f) Histological analysis of for-cause biopsies for mechanisms of 
rejection 
Accrual Objective 
130 randomized (65 maraviroc and 65 placebo)  
Study Duration 
5 years (all participants followed for 1 – 3 years depending on enrollment 
date) 


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Treatment Description  
Prior to transplantation, participants should be on a stable non-protease 
inhibitor-based regimen. At the time of transplantation, eligible participants 
will be randomized 1:1 to add maraviroc or placebo. Initiation of study drug 
will occur during the admission for transplantation, prior to transplant. 
Arm 1: Maraviroc  
Arm 2: Placebo  
Dose: Initial dose of 300 mg twice daily (150mg twice daily if co-prescribed 
with a potent CYP3A inhibitor or 600mg twice daily if co-prescribed with a 
potent CYP3A inducer). Will be modified if GFR < 30, if co-prescribed with a 
potent CYP3A inhibitor or inducer, or if the calcineurin inhibitor used for 
maintenance immunosuppression is changed to cyclosporine (which is only 
allowed for tacrolimus toxicity). Once GFR >= 30, the dose should be returned 
to the non-renal dosage. If GFR is consistently fluctuating (especially 
immediately post-transplant), the site investigator may choose when to 
resume normal dosing of study products based on clinical assessment of 
stability. 
Inclusion Criteria  
1) Participant is able to understand and  provide informed consent 
2) Documented HIV infection (by any licensed ELISA and confirmation by 
Western Blot, positive HIV ab IFA, or documented history of detectable 
HIV-1 RNA). 
 
3) Participant is ≥ 18 years old. 
 
4) CD4+ T-cell count >/= 200/µL at any time in the 26 weeks prior to 
enrollment. 
 
5) Most recent HIV-1 RNA < 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 
cART regimen to become study eligible must also have an eligible HIV-1 
RNA result post change in cART.  
 
6) Participant meets standard listing criteria for placement on transplant 
waiting list.  
 
7) For participants with an HIV+ deceased donor: 
 
a) No active opportunistic infections. 
b) Concurrence by the study team that based on medical history and 
ART, viral suppression can be achieved in the recipient post-
transplant.   
c) Must be enrolled in an IRB approved research protocol that fulfills the 
requirements of the DHHA Hope Act Policy (see section 9.1.2). 


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d) HIV+ deceased donor must have no evidence of invasive opportunistic 
complications of HIV infection, and must have a pre-implant biopsy. 
 
8) 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.   
 
9) No known allergy or intolerance to components of MVC or its formulation. 
 
10) No known contraindication to MVC. 
 
11) Female participants of child-bearing potential must have a negative serum 
beta-HCG pregnancy test within 30 days of randomization.  
 
Exclusion Criteria  
1. Participant is currently on maraviroc. 
2. Participant needs multi-organ transplant. 
3. Participant has a live donor who is HIV+. 
4. Participant is unable to switch to a non-protease inhibitor-based cART 
regimen. 
5. Participant has received immunosuppressant medication in the 6 months 
prior to enrollment. Note: Low dose maintenance steroids (</= 10 mg per 
day of prednisone, or equivalent strength steroid) will not be considered 
immunosuppression. 
6. Opportunistic Complication History: Any history of progressive multifocal 
leukoencephalopathy  (PML), chronic intestinal cryptosporidiosis of > 1 
month duration, or primary CNS lymphoma. Note: History of pulmonary 


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coccidiodomycosis will be treated per local site policy regarding this 
infection in HIV negative transplant candidates, generally requiring a 5-year 
disease-free interval. 
7. 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.  
8. Substance use that in the opinion of the investigator would interfere with 
compliance with the study requirements. 
9. 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. 
10. Participant has used IL-2 or GM-CSF in the prior six months. 
11. Participant has received interferon-alpha therapy in the prior 12 weeks. 
12. Use of investigational drugs within 4 weeks of enrollment. 
13. 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.  
Participant Stopping 
Rules 
Treatment discontinuation 
1. Participant meets criteria to discontinue study treatment (MVC or 
placebo) 
2. The investigator no longer believes continuing study treatment is in 
the best interest of the participant. 
3. Participant refuses to continue study treatment. 
4. Treatment is held or discontinued for clinical reasons for greater than 
60 days. 
Study discontinuation 
1. The participant elects to withdraw consent from all future study 
activities, including follow-up. 
2. The participant is “lost to follow-up” (i.e., no further follow-up is 
possible because attempts to reestablish contact with the participant 
have failed).  
3. For those on the waiting list, confirmed or predicted failure to receive 
transplant by the end of year 4. 


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4. Study closed by sponsor or FDA. 
5. Despite being randomized and receiving study treatment, participant 
did not receive a transplant as expected.  
Study Stopping Rules 
The study may be discontinued at any time by the EC/IRB, NIAID, the 
pharmaceutical supporter(s) or designee, the FDA, or other government 
entities as part of their duties to ensure that research participants are 
protected. 
In addition, the incidence of specific safety-related events of particular 
concern will be continuously monitored throughout the study to determine if 
any of their observed subject-based incidence rates exceed a threshold 
incidence rate of concern pre-specified for each particular event.  
 
These events and their corresponding thresholds of concern are:  
 
1. During year 1 of follow-up, death due to any reason except accidental 
death above 10%.  
2. During year 1 of follow-up, graft loss due to any reason except 
accidental death above 16%.  
3. During year 1 of follow-up, site-reported treated acute rejection 
above 35% 
 
 
 
 


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Contents 
Glossary of Abbreviations ..................................................................................................................................................... 15 
Study Definitions Page .......................................................................................................................................................... 17 
1 
Study Hypotheses/Objectives ....................................................................................................................................... 19 
1.1 
Hypotheses............................................................................................................................................................ 19 
1.2 
Objectives .............................................................................................................................................................. 19 
2 
Background and Rationale ............................................................................................................................................ 20 
2.1 
Background and Scientific Rationale ..................................................................................................................... 20 
2.2 
Rationale for Selection of Investigational Product or Intervention ...................................................................... 20 
2.3 
Preclinical Experience ........................................................................................................................................... 21 
2.4 
Clinical Studies ...................................................................................................................................................... 22 
2.5 
Rationale for studying the impact of maraviroc on the reservoir ........................................................................ 24 
3 
Study Design .................................................................................................................................................................. 26 
3.1 
Description of Study Design .................................................................................................................................. 26 
3.1.1 
Treatment Arms 1 and 2: HIV+...................................................................................................................... 27 
3.2 
Primary Clinical Endpoint ...................................................................................................................................... 27 
3.3 
Secondary Clinical Endpoints ................................................................................................................................ 27 
3.4 
Primary Mechanistic Endpoints ............................................................................................................................ 28 
3.5 
Stratification, Randomization, and Blinding/Masking .......................................................................................... 28 
3.5.1 
Procedure for Unblinding/Unmasking .......................................................................................................... 29 
4 
Selection of Participants ............................................................................................................................................... 30 
4.1 
Rationale for Study Population ............................................................................................................................. 30 
4.2 
Inclusion Criteria ................................................................................................................................................... 30 
4.3 
Exclusion Criteria ................................................................................................................................................... 31 
5 
Known and Potential Risks and Benefits to Participants .............................................................................................. 32 
5.1 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert................. 32 
5.2 
Risks of Study Procedures ..................................................................................................................................... 33 
5.2.1 
Collection of Blood: ....................................................................................................................................... 33 
5.2.2 
Kidney Biopsy: ............................................................................................................................................... 33 
5.2.3 
Internet-Based Data Collection ..................................................................................................................... 33 
5.3 
Participant risks associated with kidney transplant from HIV+ donors ................................................................ 33 
5.3.1 Acute Rejection (AR). ............................................................................................................................................ 33 
5.3.2 Recurrent HIV-Associated Nephropathy (HIV-AN)................................................................................................ 33 


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5.3.3 Infections and Hospitalizations. ............................................................................................................................ 34 
5.3.4 HIV superinfection (HIV-SI). .................................................................................................................................. 34 
5.4 
Potential Benefits .................................................................................................................................................. 34 
6 
Study Drug /Device/Intervention .................................................................................................................................. 35 
6.1 
Study Treatment ................................................................................................................................................... 35 
6.2 
Regimens, Administration, and Duration.............................................................................................................. 35 
6.2.1 
Initial Dosage Regimen .................................................................................................................................. 35 
6.2.2 
Modified Dosage Regimen ............................................................................................................................ 36 
6.2.3 
Administration .............................................................................................................................................. 38 
6.2.4 
Duration ........................................................................................................................................................ 38 
6.3 
Study Drug Formulation and Preparation ............................................................................................................. 38 
6.4 
Pharmacy: Product Supply, Distribution, and Accountability ............................................................................... 38 
6.4.1 
Study Drug Acquisition/Distribution ............................................................................................................. 38 
6.4.2 
Study Drug Accountability ............................................................................................................................. 38 
6.5 
Premature Discontinuation of Study Drug ............................................................................................................ 38 
7 
Clinical Management Issues .......................................................................................................................................... 39 
7.1 
Toxicity Management ........................................................................................................................................... 39 
7.1.1 
Grade 1 or 2 .................................................................................................................................................. 39 
7.1.2    Grade 3 .............................................................................................................................................................. 39 
7.1.3    Grade 4 .............................................................................................................................................................. 39 
7.1.4    AST or ALT Elevations ........................................................................................................................................ 40 
7.1.5      Calculated Creatinine Clearance (CrCl) Decline ............................................................................................... 40 
7.1.6    Postural Hypotension ........................................................................................................................................ 40 
7.1.7    Allergic Reaction ................................................................................................................................................ 41 
7.1.8    Rash ................................................................................................................................................................... 41 
7.1.9 
HIV Persistent Virologic Failure ..................................................................................................................... 41 
7.2 
Pregnancy .............................................................................................................................................................. 41 
8 
Other Medications ........................................................................................................................................................ 43 
8.1 
Combination Antiretroviral Therapy (cART) ......................................................................................................... 43 
8.2 
Immunosuppression ............................................................................................................................................. 43 
8.2.1 
Rejection Treatment Protocol ....................................................................................................................... 43 
8.2.2 
Definition of Rejection .................................................................................................................................. 43 
8.3 
Prophylactic Medications ...................................................................................................................................... 43 


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9 
Study Procedures .......................................................................................................................................................... 44 
9.1 
Screening/Baseline Visit ........................................................................................................................................ 44 
9.1.1 
Living donors ................................................................................................................................................. 44 
9.1.2 
HIV+ donors ................................................................................................................................................... 44 
9.2 
Participant Enrollment .......................................................................................................................................... 45 
9.3 
Pre-Transplant On-Going Eligibility Monitoring for Segment B ............................................................................ 45 
9.4 
Randomization and Post-Transplant Study Visits ................................................................................................. 45 
9.5 
Visit Windows ....................................................................................................................................................... 46 
10 
Mechanistic Assays ................................................................................................................................................... 47 
10.1 
Samples ................................................................................................................................................................. 47 
10.1.1 
Recipient Samples: ........................................................................................................................................ 47 
10.1.2 
Donor samples: ............................................................................................................................................. 48 
10.2 
HIV persistence analyses ....................................................................................................................................... 48 
10.3 
Alloimmune analyses ............................................................................................................................................ 51 
10.3.1 
Overview ....................................................................................................................................................... 51 
10.3.2 
Assays ............................................................................................................................................................ 51 
10.3.3 
Alloimmune assay data analysis plan ............................................................................................................ 58 
10.4 
Pharmacokinetic Analysis ..................................................................................................................................... 60 
10.4.1 
Pharmacokinetic studies ............................................................................................................................... 60 
10.4.2 
Analysis of blood samples ............................................................................................................................. 61 
10.4.3 
Pharmacokinetic analysis .............................................................................................................................. 61 
10.5 
APOL1 .................................................................................................................................................................... 61 
11 
Biospecimen Storage................................................................................................................................................. 62 
12 
Criteria for Participant and Study Completion and Premature Study Termination.................................................. 63 
12.1 
Participant Completion ......................................................................................................................................... 63 
12.2 
Participant Stopping Rules and Withdrawal Criteria ............................................................................................ 63 
12.2.1 
Treatment discontinuation ........................................................................................................................... 63 
12.2.2 
Study discontinuation ................................................................................................................................... 63 
12.3 
Participant Replacement ....................................................................................................................................... 63 
12.4 
Study Stopping Rules............................................................................................................................................. 63 
12.4.1 
Continuous Monitoring of Specific Events .................................................................................................... 63 
13 
Safety Monitoring and Reporting ............................................................................................................................. 66 
13.1 
Overview ............................................................................................................................................................... 66 


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13.2 
Definitions ............................................................................................................................................................. 66 
13.2.1 
Adverse Event (AE) ........................................................................................................................................ 66 
13.2.2 
Unexpected Adverse Event ........................................................................................................................... 66 
13.2.3 
Serious Adverse Event (SAE) ......................................................................................................................... 67 
13.3 
Grading and Attribution of Adverse Events .......................................................................................................... 67 
13.3.1 
Grading Criteria ............................................................................................................................................. 67 
13.3.2 
Causality Assessment .................................................................................................................................... 67 
13.4 
Collection and Recording of Adverse Events ........................................................................................................ 68 
13.4.1 
Collection Period ........................................................................................................................................... 68 
13.4.2 
Collecting Adverse Events ............................................................................................................................. 68 
13.4.3 
Recording Adverse Events and Serious Adverse Events ............................................................................... 68 
13.4.4 
Adverse Events and Serious Adverse Events Exempt from Reporting .......................................................... 69 
13.4.5 
Special Adverse Events requiring reporting .................................................................................................. 69 
13.4.6 
Reporting of Adverse Events to IRBs/IECs .................................................................................................... 69 
13.5 
Expedited Adverse Event Reporting to DAIDS ...................................................................................................... 69 
13.5.1 
Expedited Reporting Requirements for this Study ....................................................................................... 69 
13.5.2 
Expedited AE Reporting Period ..................................................................................................................... 69 
13.6 
Pregnancy Reporting ............................................................................................................................................. 70 
13.7 
Reporting of Other Safety Information ................................................................................................................. 70 
14 
DSMB Review ............................................................................................................................................................ 71 
14.1 
Planned DSMB Reviews ........................................................................................................................................ 71 
14.2 
Ad hoc DSMB Reviews .......................................................................................................................................... 71 
14.3 
Temporary Suspension of enrollment/drug dosing for ad hoc DSMB Safety Review .......................................... 71 
15 
Clinical Site Monitoring ............................................................................................................................................. 72 
16 
Statistical Considerations and Analytical Plan .......................................................................................................... 73 
16.1 
Overview ............................................................................................................................................................... 73 
16.2 
Measures to Minimize Bias ................................................................................................................................... 73 
16.3 
Endpoint Assessments .......................................................................................................................................... 73 
16.3.1 
Primary Analysis of Primary Efficacy Endpoint ............................................................................................. 73 
16.3.2 
Supportive Analyses of Primary Efficacy Endpoints ...................................................................................... 73 
16.3.3 
Primary Safety Endpoint ............................................................................................................................... 74 
16.3.4 
Secondary Clinical Endpoints ........................................................................................................................ 74 
16.3.5 
Secondary Mechanistic Endpoints ................................................................................................................ 76 


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16.3.6 
Descriptive Analyses ..................................................................................................................................... 76 
16.3.7 
Safety Analysis............................................................................................................................................... 76 
16.4 
Interim Analyses .................................................................................................................................................... 76 
16.5 
Sample Size Considerations .................................................................................................................................. 76 
16.6 
Missing Data Conventions ..................................................................................................................................... 77 
17 
Identification and Access to Source Data ................................................................................................................. 78 
18 
Ethical Considerations and Compliance with Good Clinical Practice ........................................................................ 79 
18.1 
Statement of Compliance ..................................................................................................................................... 79 
18.2 
Informed Consent ................................................................................................................................................. 79 
18.3 
Informed Consent Process .................................................................................................................................... 79 
18.4 
Privacy and Confidentiality ................................................................................................................................... 80 
19 
References ................................................................................................................................................................ 81 
Appendix 1.  Schedule of Events ........................................................................................................................................... 86 
Appendix 2.  Schedule of Events (Donor) ............................................................................................................................. 89 
Appendix 3.  Schedule of Events Associated with Suspected Rejection ............................................................................... 90 
Appendix 4.  Reduced Follow-up Schedule for Participants who Prematurely Discontinue Study Treatment .................... 91 
 


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Glossary of Abbreviations 
3TC 
lamivudine, EPIVIR 
Ab 
Antibody 
ABC 
abacavir sulfate, ZIAGEN 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
AUC 
Area under the curve 
BID 
Twice a day 
BKV 
BK Polyoma Virus 
cART 
Combination antiretroviral therapy 
CCR5-Δ 32 
CCR5 delta 32 
CFR 
Code of Federal Regulations 
CKD 
Chronic Kidney Disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration equation 
CMV 
Cytomegalovirus 
CNI 
Calcineurin inhibitor 
CNS 
Central nervous system 
CRF 
Case Report Form 
CRM 
Common Response Module 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS 
DAIT 
Division of Allergy, Immunology, and Transplantation 
dd-cfDNA 
Donor Derived Cell Free DNA 
Dolutegravir 
Tivicay 
DSMB 
Data Safety Monitoring Board 
eGFR 
estimated glomerular filtration rate 
EBV 
Epstein Barr Virus 
EMMES IDES 
EMMES internet data entry system 
ESRD 
End-stage renal disease 
FDA 
Food and Drug Administration 
FTC 
embricitabine, EMTRIVA 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 


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HBV 
Hepatitis B 
HCV 
Hepatitis C 
HIV 
Human immunodeficiency virus 
HIV VL 
Human immunodeficiency virus viral load 
HIVAN 
HIV Associated Nephropathy 
HLA 
Human leukocyte antigen 
ICH 
International Conference on Harmonization 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
kSORT 
Kidney Solid Organ Rejection Test 
MAC 
Mycobacterium avium complex 
MOP 
Manual of Procedures 
MMF 
Mycophenolate mofetil 
MVC 
Maraviroc 
NIAID 
National Institute of Allergy and Infectious Diseases 
NNRTI 
Non-nucleoside reverse transcriptase inhibitors 
NRTI 
Nucleoside/nucleotide reverse transcriptase inhibitor 
PCP 
Pneumocystis carinii pneumonia 
PI 
[Site] Principal Investigator 
PK 
Pharmacokinetic 
PPD 
Tuberculosis skin test 
PPSC 
Publications and Presentations Sub-committee 
Pre-tx 
Pre-transplant 
QD 
Once daily 
Raltegravir 
ISENTRESS 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SOC 
Standard of care 
SOP 
Standard Operating Procedure 
SUSAR 
Serious Unexpected Suspected Adverse Reaction 
TDF 
tenofovir, VIREAD 
uPRO 
Urine Proteins 


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Study Definitions Page 
Acute Rejection 
Banff grade of greater than or equal to 1A with or without clinical symptoms. 
Antibody Mediated 
Rejection (AMR) 
Diffusely positive staining for C4d, presence of circulating anti-donor 
antibodies, and morphologic evidence of acute tissue injury. 
Banff 2007 criteria 
The Banff classification for assessment of renal allograft biopsies was 
introduced as a standardized international classification of renal allograft 
pathology and acute rejection. Subsequent debate and evaluation studies 
have attempted to develop and refine the classification.0T0T 0T0TThe 2007 version is 
the most current. 
CKD Stage 4 
Decrease in the glomerular filtration rate (GFR) to 15-30 ml/min 
CKD Stage 5 
End stage renal disease (ESRD) with a glomerular filtration rate (GFR) of 15 
ml/min or less. 
Cystatin C 
a protein encoded by the CST3 gene, mainly used as a biomarker of kidney 
function. 
Graft loss 
For protocol, defined as the first observation of any of the following events: 
death, retransplantation, or initial return to chronic dialysis. Chronic dialysis 
is defined as 30 days or a treatment plan of permanent ongoing dialysis 
support. 
HIV breakthrough 
2 consecutive plasma HIV viral load > 200 copies/mL or one HIV viral load > 
1000 copies/mL after a period of virologic control post-transplant. 
HIV persistent virologic 
failure 
HIV Viral load > 1000 copies/mL for more than 90 days that is not the result 
of an investigator/physician approved interruption in antiretroviral 
treatment.  
Iohexol 
Radiographic contrast agent whose clearance from serum can be used to 
estimate GFR (kidney function) 
MDRD4 variable model 
The most recently advocated formula for calculating the GFR is the one that 
was developed by the0T0T 0T0TModification of Diet in Renal Disease Study Group.P1
P 
The most commonly used formula is the “4-variable MDRD,” which estimates 
GFR using four variables: serum creatinine, age, ethnicity, and gender. P2 
 
P1
PNational Kidney Foundation (February 2002). “K/DOQI clinical practice 
guidelines for chronic kidney disease: evaluation, classification, and 
stratification”. American Journal of Kidney Diseases 39 (2 Suppl 1): S1–266.  
P2
PLevey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (March 1999). “A 
more accurate method to estimate glomerular filtration rate from serum 
creatinine: a new prediction equation. Modification of Diet in Renal Disease 
Study Group”. Annals of Internal Medicine 130 (6): 461–70. 
Neoplasm 
An abnormal mass of tissue that results when cells divide more than they 
should or do not die when they should. Neoplasms may be benign (not 
cancer), or malignant (cancer). Also called tumor. 


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Opportunistic infection 
An infection by a microorganism that normally does not cause disease but 
becomes pathogenic when the body’s immune system is impaired and 
unable to fight off infection. 
Protocol Mandated 
Procedures 
Any procedure performed solely for the purpose of this research study, not 
considered site specific standard of care. 
Randomized 
A participant who met all eligibility criteria; met with the study investigator 
or designee to discuss the study purpose, requirements (i.e., time 
requirements, schedule of events, etc.), discussed all risks and benefits, 
signed the informed consent document and was randomly assigned to one of 
2 treatment groups. 
Study Therapy 
The investigational therapeutic regimen. 
Visit window 
2 weeks prior to time point, or after the time point up to the mid-way point 
between the target date and the subsequent study visit date. 


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1 Study Hypotheses/Objectives 
1.1 Hypotheses 
It has been established that persistent HIV infection leads to immune dysregulation, which is characterized by increased 
basal activation of T cells, B cells, and myeloid cells.  This global dysregulation can lead to augmented anti-donor 
alloimmune responses through specific expansion of donor HLA and pathogen cross-reactive cells (heterologous 
immunity) and/or non-specific expansion of effector T cells and antibody-producing B cells through homeostatic 
proliferation. CCR5 expression is increased on activated T cells, B cells, and myeloid cells and it is known to play an 
important role in orchestrating coordinated activation of immune effector functions.  In addition, CCR5 also contributes 
to the spread and maintenance of HIV reservoir by serving as a receptor for HIV entry in CD4 T cells and myeloid cells, 
thus perpetuating and exacerbating the immune dysregulation.  Therefore, we hypothesize that CCR5 contributes to the 
enhanced alloimmune responses in HIV+ participants and CCR5 blockade will be effective in reducing immunologic graft 
injury and improving long-term kidney function through reducing HIV reservoir and intercepting the vicious cycle of 
immune activation and dysregulation. Our specific hypotheses are: 
 
• 
CCR5 blockade in HIV+ renal transplant participants will minimize immunologic graft injury and improve renal 
function. The high rate of kidney transplant rejection in HIV+ patients is 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. 
• 
CCR5 blockade in combination with immunosuppressive therapy used following kidney transplantation will 
reduce HIV persistence in CD4+ T lymphocytes. 
1.2 Objectives 
 
1.2.1 
The primary clinical objectives are to evaluate the: 
1. Impact of CCR5 blockade (maraviroc, MVC) on renal function at week 52 post-transplant. 
2. Overall safety and tolerability of CCR5 blockade in the HIV+ kidney transplant recipient 
 
1.2.2 
The secondary clinical objectives are to evaluate the: 
1. Impact of CCR5 blockade (maraviroc, MVC) on inflammation in the graft at week 26 and week 52 post-
transplant. 
2. Impact of CCR5 blockade on long term kidney function in the HIV positive kidney transplant recipient at 
months 3, 6, 9 and years 1, 2, 3. 
3. Impact of the addition of CCR5 blockade to cART and immunosuppression on HIV persistence following 
kidney transplantation 
4. Impact of CCR5 blockade on the incidence and severity of rejection 
5. Incidence of HIV infection/HIV nephropathy (HIVAN) in the kidney allograft 
6. Safety profiles with use of CCR5 blockade 
7. Pharmacokinetics and impact of CCR5 blockade exposure to CNIs 
 
1.2.3 
The primary mechanistic objectives are to: 
1. Define immunologic parameters associated with rejection in the HIV positive recipient (versus HIV+ non-
rejectors)  
2. Determine the impact of CCR5 blockade on the immunologic profiles in the HIV positive recipient.  
 


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2 Background and Rationale 
2.1 Background and Scientific Rationale 
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 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 the impact on the alloimmune response is in HIV infected patients undergoing 
kidney transplantation since CCR5 inhibition with maraviroc has been effective as an antiretroviral agent that has been 
safely used as a component of cART. Furthermore, HIV infected adults have unexpectedly high rejection rates (2-3 fold 
higher than HIV uninfected recipients) [1, 2], facilitating studies exploring the immunosuppressive efficacy of CCR5 
blockade.    
HIV persists indefinitely during cART. Many mechanisms likely contribute to this persistence, including persistent 
immune activation and dysfunction, as well as persistent replenishment of the reservoir due to low-level HIV 
spread/replication. There are theoretical suggestions that CCR5 blockade may affect these pathways, leading to 
reduction in HIV reservoir. Careful measurements of HIV persistence/viral load will be performed in our study. These 
measurements are important as changes in HIV load can directly impact immune function and graft survival. Of equal 
significance, any agent that affects HIV persistence will contribute to the emerging global cure efforts.  
2.2 Rationale for Selection of Investigational Product or Intervention 
CCR5 is a chemokine receptor widely expressed on immune cells, including dendritic cells, activated macrophages [3], 
resting and activated NK cells [4], and activated Th1 and CD8 cells [5, 6]. CCR5 plays a major role in regulating immunity 
by facilitating CD4-CD8 T cell collaborations [7], serving as a co-stimulatory molecule for Th1 cell activation [8], activating 
pro-inflammatory M1 macrophages [9], and recruiting monocytes, macrophages, NK cells, and T cells to sites of 
inflammation [10].  CCR5 blockade promotes graft survival in rodent models of heart [11, 12], kidney [13], islet [14] and 
aorta transplantation [15]. Kidney transplant recipients who do not express CCR5 as a consequence of a homozygous 
CCR5 delta 32 deletion (“CCR5-Δ 32”) have significantly prolonged long term allograft survival compared to recipients 
lacking this genetic deletion [16]. Similarly, liver transplant recipients homozygous for the CCR5-Δ 32 mutation have 
reduced acute rejection rates [17]. The findings collectively support the idea that CCR5 blockade using maraviroc may be 
beneficial in kidney transplantation. Consistent with this notion, a recently concluded clinical trial in bone marrow 
transplant recipients demonstrated that maraviroc blocked lymphocyte chemotaxis and visceral graft-versus host 
disease [18]. We hypothesize that the addition of CCR5 blockade to cART in HIV+ renal transplant recipients will minimize 
immunologic graft injury and improve renal function.  
Several lines of evidence have suggested that inhibition of CCR5 could reduce the size of the reservoir during long-term 
antiretroviral therapy. Chronic inflammation and T cell activation are now well-accepted parts of HIV pathogenesis. The 
frequency of activated T cells is high during untreated disease and declines during treatment, but it rarely fully 
normalizes. Among long-term effectively treated individuals, the frequency of activated T cells is higher than normal 
[19], which is associated with risk of disease progression [20], and correlated with the size of the HIV reservoir. Chronic 
inflammation may contribute to HIV viral persistence through many mechanisms, including: 1) increased HIV production 
from CD4+ cells; 2) increased number of activated CD4+ T cells, which are the preferred target for viral replication; 3) 
homeostatic proliferation of latently infected cells; and 4) changes in immunoregulatory environment, leading to 
reduced clearance mechanisms. As binding of CCR5 on T cells to its ligands regulates chemotaxis and migration to sites 
of inflammation, inhibiting CCR5 might prevent CD4+ T cells from accumulating in areas where ongoing cell-to-cell 


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transmission of HIV occurs and alters several inflammatory pathways that lead to HIV persistence [10, 21]. Any of these 
mechanisms may have contributed to the absence of HIV viral persistence in the “Berlin patient”, the HIV+ recipient of a 
bone marrow transplant from a homozygous CCR5-Δ 32 donor [22]. We hypothesize that CCR5 blockade in combination 
with immunosuppressive therapy used following kidney transplantation will reduce HIV persistence in CD4+ T 
lymphocytes 
The finding that HIV+ patients experience three-fold more rejection than HIV- recipients not only presents an important 
clinical challenge, but also an intriguing mechanistic question which might ultimately lead to identification of novel 
interventions for the broader transplantation field.  The question which we will address in this protocol is why do HIV-
infected adults - who despite cART often have readily measured immunodeficiency - mount a stronger response to 
transplanted grafts than HIV-uninfected adults?  The answer may lie in heterologous immunity, which is emerging as a 
central focus in transplantation biology [23].  Experiments in animal models of transplantation demonstrate that 
multiple viral infections can induce the generation of memory allo-reactive T cells; this occurs as a result of cross-
reactivity between alloantigen- and pathogen-reactive T cells [24-30].  These cross-reactive memory T cells have a lower 
threshold for activation, can directly traffic to grafts, and are capable of expressing effector functions upon first 
encounter with donor antigens, all of which contribute to accelerated graft rejections and resistance to tolerance 
induction.  Cross-reactivity between human alloantigen and viral antigen-reactive T cell lines and clones has also been 
demonstrated [31].  However, association between increased heterologous immunity and enhanced graft rejection in 
transplant patients has not been documented.  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.  
2.3 Preclinical Experience 
Maraviroc is a CCR5 inhibitor that has been approved for use a component of combined antiretroviral therapy (see 
Clinical Studies).  Since CCR5 is a chemokine receptor widely expressed on immune cells, blocking this receptor has 
theoretic benefits in terms of modulating the alloimmune response by blocking the migration of pro-inflammatory cells 
to the allograft. Several pre-clinical studies have demonstrated the efficacy of CCR5 blockade in promoting allograft 
survival in rodent models of heart [11, 12], kidney [13], islet [14] and aorta transplantation [15].  
Although maraviroc has not been approved for use as an immunosuppressive agent, a recently concluded trial in bone 
marrow transplant recipients demonstrated that maraviroc blocked lymphocyte chemotaxis and visceral graft-versus-
host disease (20). Thirty-eight subjects who had undergone reduced-intensity allogeneic hematopoietic stem cell 
transplantation were treated with standard graft-versus-host disease (GVHD) prophylaxis and maraviroc 
(ClinicalTrials.gov number, NCT00948753). Among 35 evaluable subjects, the observed incidence rate of grade III or IV 
acute GVHD was far less common than that observed in historical controls. Mechanistic studies suggested that inhibition 
of lymphocyte trafficking lead to prevention of GVHD. 
The potential efficacy of CCR5blockade in terms of blocking the alloimmune response in solid organ transplantation is 
supported by the consistent observation that transplant recipients with homozygous CCR5-Δ 32 allele (no cell surface 
expression of CCR5) have significantly prolonged long term allograft survival compared to recipients with no mutations 
in CCR5; this has been shown for both kidney [16] and liver[17] transplants. The findings collectively support the idea 
that CCR5 blockade using maraviroc may be beneficial in kidney transplantation. 
 


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2.4 Clinical Studies 
Maraviroc is a member of a class of antiretroviral compounds known as small molecule CCR5 antagonists that block R5 
HIV entry into CD4 cells. Maraviroc has demonstrated selective and reversible binding to CCR5, as well as potent 
antiviral activity in vitro against a wide range of laboratory adapted strains of R5 HIV from Clades A, B, C, D, E, F, G, J and 
O. Maraviroc also retains in vitro antiviral activity against clinical isolates resistant to the existing drug classes, but has no 
activity against viruses that enter CD4+ cells using CXCR4.  When used in combination with other antiretroviral drugs in 
subjects known to lack CXCR4-utilizing viruses, maraviroc is safe, well-tolerated and results in sustained suppression of 
HIV replication. Maraviroc has been approved for the management of HIV disease sine 20XX. A recent FDA-mandated 
review of long-term (5 years) exposure to this drug in controlled studies (n=938 treated with maraviroc) found low rates 
of death, hepatic failure, malignancy, myocardial infarction and other adverse events, leading to the conclusion that the 
drug has safety provide consistent with other antiretroviral drugs [32]. 
Maraviroc is an oral medication that is rapidly absorbed when taken without food.  The standard dose is 300 mg bid 
(without concomitant potent CYP3A4 inhibitors or inducers.  Approximately 25% is excreted unchanged in the feces and 
33% is excreted unchanged in the urine, the rest being metabolized by the liver.   The drug accumulates with advanced 
renal or liver failure [33].  Maraviroc is taken up by an OATP1 uptake transporter and the homozygous 521T>C mutation 
decreases uptake by 75%.[34].  Maraviroc is metabolized by cytochrome P4503A4, and any concomitant medications 
that inhibit CYP3A4, such as tacrolimus, will increase maraviroc concentrations.  In one case report in a liver transplant 
subjects, tacrolimus AUC increased ~15%, while maraviroc AUC was approximately twice normal[35].  
With regard to our proposed study, maraviroc has no known nephrotoxicity and appears to be safe and well-tolerated in 
subjects with impaired renal function. A recent small open-label study of maraviroc in subjects with mild to severe renal 
impairment (including end-stage renal disease) found that renal function had no readily apparent effect on plasma 
concentration-time curve and no dosing adjustments among those with impaired renal function[36]. 
 UStudies in Healthy Volunteers 
In Phase 1 and 2a clinical studies conducted in healthy volunteers and HIV+ individuals, maraviroc has been 
administered as single oral doses up to 1200 mg and multiple oral doses up to 300 mg BID for 28 days, and up to 900 mg 
BID and 1200 mg QD for 7 days. Single doses up to 900mg and multiple doses up to 300mg BID were well tolerated, with 
the adverse event profile of 300mg BID being similar to placebo. Doses above 300mg (the approved dose dose) were 
associated with an increased incidence of adverse events, particularly postural hypotension, compared to placebo. The 
most common Adverse Events (AEs), regardless of causality, reported following single and multiple dosing have been 
asthenia, headache, dizziness, nausea, rhinitis and postural hypotension. Postural hypotension is potentially the dose 
limiting adverse event [37].  
No treatment related Serious Adverse Events (SAEs) were reported in the healthy volunteer (Phase 1) studies, and most 
AEs were judged to be mild to moderate in severity. Mean QTcI differences from placebo for maraviroc were not 
clinically significant for single doses up to and including 900 mg. 
UStudies in treatment-experienced subjects with R5 HIV 
Two identical phase 2B/3 registration studies of maraviroc have been completed (MOTIVATE 1 and 2). MOTIVATE 1 
enrolled 585 subjects from North America whereas MOTIVATE 2 enrolled 464 subjects from Europe, Australia and North 
America. Subjects in both studies were infected with R5 HIV-1, and have experienced more than six months treatment 
with three of four approved antiretroviral drug classes, (PIs, NRTIs, NNRTIs, and FIs) AND/OR resistance to at least one 


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member of three of the four approved classes of antiretroviral medications. Subjects were randomized (2:2:1) to receive 
optimal background therapy (OBT) plus maraviroc 300 mg QD or BID (reduced to 150 mg QD/BID in presence of a PI 
Both studies showed the reduction in HIV RNA from baseline to week 24 was statistically significantly greater in the OBT 
+ maraviroc QD or BID groups compared to the OBT + placebo group. These studies also demonstrated that maraviroc 
(QD or BID) had equivalent acceptable safety and tolerability profiles, without indications of increased risk of 
hepatotoxicity, secondary infection, malignancy or QTc interval prolongation, relative to placebo at an interim analysis 
conducted at 24 weeks [38, 39]. 
UStudies in treatment-experienced subjects with non-R5 HIV 
In cohort studies the detection of X4 virus has been associated with more rapid CD4 decline and HIV-1 disease 
progression. A safety study in treatment-experienced subjects infected with non- CCR5 tropic HIV-1 (Study A4001029) 
was conducted to address the theoretical concern that giving maraviroc to a subject with dual or mixed tropic virus 
(R5/X4) may cause a more rapid disease progression or CD4 cell loss due to the selection of X4 virus at time of virologic 
failure. Study A4001029 is an ongoing, prospective, randomized (1:1:1), double-blind, placebo controlled, multi-country, 
phase 2b clinical trial of placebo vs. a nominal dose of maraviroc 300 mg QD or BID (reduced to 150 mg QD/BID in 
presence of a PI or delavirdine) added to OBT in HIV-1-infected treatment-experienced subjects with non-R5 virus . This 
study found no apparent differences between either of the maraviroc containing groups and the placebo group in the 
reported frequency of AEs, SAEs, deaths, drug interruption or discontinuations due to AEs in A4001029. There were no 
differences in Grade 3 or 4 liver function test abnormalities (AST, ALT, total bilirubin) across the three treatment groups. 
No cases of lymphoma or other HIV associated malignancies were reported in the first 24 weeks of the A4001029 trial. 
Overall, Study A4001029 demonstrated no harm and no benefit in efficacy, safety or tolerability when maraviroc in 
subjects infected with non-R5- tropic HIV-1 (compared to OBT + placebo).   
UStudies in treatment-naive subjects with non-R5 HIV 
A registrational phase 3 study of maraviroc was performed in antiretroviral-naive subjects with R5 HIV infection 
(maraviroc versus efavirenz in Treatment-Naive Patients, or MERIT study; NCT00098293)[40]. Treatment-naïve adults 
lacking evidence of X4 infection were randomized zidovudine/lamivudine with maraviroc (300 mg once or twice daily) or 
efavirenz. The once-daily maraviroc arm was stopped early due to lack of efficacy.  At week 48, maraviroc 300 mg bid (n 
= 721) was non-inferior to maraviroc in terms of proportion with an HIV RNA level below 400 copies/mL (70.6% for 
maraviroc vs 73.1% for efavirenz) but not for <50 copies/mL (65.3% vs 69.3%). Maraviroc was associated with high rates 
of virologic failure but lower rates of premature discontinuation for adverse events. In a post-hoc reanalysis that used a 
very sensitive co-receptor tropism assay to exclude those individuals with low-level X4 viruses, the efficacy of maraviroc 
was comparable to that of efavirenz. 
UStudies of maraviroc intensification 
Given the potential immunodulatory activity of maraviroc, a series of studies have been performed in which maraviroc 
was added to a stable regimen (“intensification”) to improve immune function in antiretroviral-treated adults with 
undetectable HIV RNA levels [41-49]. These observations provide the strongest evidence that maraviroc affects immune 
function independent of its effect on HIV replication. Several studies found that maraviroc intensification lead to 
reductions in CD8+ T cell activation [46, 48, 49], but a randomized placebo-controlled study of 45 immunologic non-
responders (defined as a persistent CD4+ T cell count below < 350 cells per mmP3
P) found that compared to placebo, 
maraviroc-treated subjects experienced a greater median increase in % CD38+HLA-DR+ peripheral blood CD8+ T cells at 
week 24 (+2.2% vs -0.7%, P = .014), and less of a decline in activated CD4+ T cells (P < .001). Plasma CC chemokine 


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receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1beta) levels increased 2.4-fold during maraviroc 
intensification (P < .001) and plasma lipopolysaccharide declined[44]. In most studies, circulating CD8+ T cell counts 
increased rapidly, providing strong evidence that the drug  affects trafficking of these cells[47, 50, 51].  These 
intensification studies also provided preliminary data that maraviroc intensification reduced the size of the reservoir 
during effective cART[42, 43, 46]; this effect may be due to increased NFκB activity, which might reverse latency, leading 
to HIV production and clearance of infected cells[52]. Although the immunologic and virologic effect of maraviroc 
intensification remains controversial, these studies collectively indicate that the approach is safe and well-tolerated. 
UStudies involving the use of HIV+ donors 
The data in HIV positive donors in South Africa[53] is comparable to our data using HIV negative donors in HIV positive 
recipients[1]. Since we do not have the appropriate data in the US comparing HIV positive to HIV negative donors, we 
compiled the South African data. Despite some differences between the South African study (with HIV positive deceased 
donors, N=27) and HIVTR (with HIV negative donors, N=150) in eligibility criteria, characteristics and ARV/IS medications 
used, we compared the two studies in order to get an assessment of expected impact on the addition of HIV positive 
donors in our HIVTR-CCR5 study. The primary efficacy endpoint in HIVTR-CCR5 is the mean GFR at week 52 post-
transplant, and in the sample size considerations section, we indicate that the expected mean GFR level at week 52 for 
the control group (Arm 2), based on the data observed in HIVTR and other post-transplant studies, is 60 ml/min per 1.73 
mP2
P.   Based on Dr. Muller et al.’s NEJM 2015 publication data, the mean GFR level at week 52 was 59 ml/min per 1.73 mP2 
P, which demonstrates that use of HIV positive donors did not impact expected graft function at week 52 compared to 
the use of HIV negative donors. We have also compared some of the safety endpoints between the two studies. In 
HIVTR, the 1-year patient survival was 95% (CI 90,98) while in the South African study, the 1-year patient survival was 
84% (CI, 62, 94). The 1-year rates of acute rejection in the HIVTR and South African studies were 29% and 8%, 
respectively.  
Graft function and safety profiles with use of HIV positive deceased donors in the South African experience is very 
promising[53], and with the implementation of the HOPE Act, many centers are expected to utilize these valuable 
organs in their HIV+ kidney transplant candidates who would otherwise have long waiting times on the list. 
2.5 Rationale for studying the impact of maraviroc on the reservoir 
HIV persists indefinitely in essentially all antiretroviral-treated individuals. Several mechanisms contribute to 
persistence, including cell-to-cell transfer of virus (“replication”) and the establishment of latent (or quiescent) infection 
of long-lived memory CD4+ T cells. The latter cell population is maintained in part by homeostatic proliferation. 
The eradication of the HIV-1 reservoir resulting in the cure of the Berlin Patient in 2009 and the sustained reduction of 
the HIV-1 reservoir to undetectable levels in two infected individuals in Boston in 2012 by allogeneic hematopoietic stem 
cell transplant (HSCT) has renewed interest in novel HIV eradication strategies. [54-57] Although many factors 
contributed to these remarkable outcomes, it is noteworthy that all three individuals were heterozygous for the 
CCR5Δ32 mutation at baseline. This common genetic feature of the three individuals provides evidence that 
predisposition to HIV eradication may be linked to lower CCR5 cell surface expression. Given the central role of CCR5 in 
HIV-replication and the intriguing observations in the Berlin and Boston patients, we measured cellular HIV-1 pol and 2-
LTR circle DNA, cell-associated HIV-1 RNA, and immunologic cell surface markers in 18 CCR5 delta-32 heterozygotes and 
54 CCR5 wild type individuals on suppressive antiretroviral therapy. While no difference was observed in HIV-1 pol DNA 
levels, cell-associated HIV-1 RNA (p=0.035), RNA:DNA transcriptional ratios (p=0.013), and frequency of detectable 2-LTR 
circle DNA (p=0.013) were significantly lower in CD4+ T cells from CCR5 delta-32 heterozygotes. Cell-associated HIV-1 
RNA was significantly correlated with CCR5 cell surface expression on CD4+ T cells (rP2
P=0.136, p=0.002). Despite 


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previously reported data describing effects of CCR5-mediated signaling on HIV-1 transcription via NF-κB, NF-κB pathway 
and target genes were expressed at similar levels between genotype groups. Taken together, these data suggest that 
limited CCR5 cell surface expression impacts the stability of the HIV-1 reservoir. The mechanism for this effect is 
unknown. We will explore in this study the possibility that therapeutic manipulation of CCR5 will have a similar effect. 
Although a number of studies have investigated the impact of maravoric intensification on immune function, few have 
done detailed virologic studies. Most smaller studies that compared maraviroc-based regimens with non-maraviroc-
based regimens have failed to detect an effect [58, 59], one provocative study based in Madrid found that maraviroc 
intensification resulted in decline in level of replication-competent HIV [42] and another in Barcelona suggested the drug 
had unique virologic effects[46]. More data on this question could be informative to emerging efforts to cure HIV 
infection [60, 61] and will allow us to interpret the mechanisms whereby maraviroc might influence clinical outcomes in 
a transplant setting. 
 
 


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3 Study Design 
 
3.1 Description of Study Design  
This trial is a prospective, multi-center, double-blind phase II study of kidney transplantation in HIV+ individuals 
assessing the safety and efficacy of maraviroc or placebo given post-transplant.   Participants must be stable HIV-
infected adults in need of a kidney transplant who are on a non-protease inhibitor-based antiretroviral drug regimen. If 
not, participant must be willing and able to modify their antiretroviral regimen. This change will be initiated by the 
participant’s primary care provider at the request of the study team, and will occur prior to enrollment into the pre-
transplant phase of the study (segment A). Randomization to maraviroc or placebo and enrollment into the post-


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transplant phase of the study (segment B) will occur on the day of transplantation.  Participants will be consented and 
enrolled until 130 eligible participants are randomized.  
Major study endpoints will be determined for each participant 26 and 52 weeks after transplantation. Participants will 
be followed for a minimum of 1 year and a maximum of 3 (52 to 156 weeks). 
3.1.1 
Treatment Arms 1 and 2: HIV+ 
At the time of transplantation, eligible participants will be randomized 1:1 to add maraviroc or placebo. Initiation of 
study drug (maraviroc or placebo) will occur during the admission for transplantation, prior to transplant.  If study drug 
is not initiated prior to transplant, it must be initiated no greater than 72 hours post randomization.  
Arm 1: maraviroc  
Arm 2: placebo  
3.2 Primary Clinical Endpoint  
1. Measured glomerular filtration rate at 52 weeks by iohexol clearance. 
2. Graft loss, toxicities >/= Grade 3 and/or permanent treatment discontinuation within the first 52 weeks post-
transplant. 
3.3 Secondary Clinical Endpoints 
 
1. Inflammation in the graft 
a. CD45 gene expression (PTPRC) on the FFPE kidney biopsy sample at 26 weeks post-transplant. 
b. CD45 quantitative IHC on the FFPE sample at 26 weeks post-transplant. 
c. Gene expression profiling using the 11-gene tCRM module on FFPE biopsy shaves at 26 weeks and the 
11-gene uCRM module on urine cell pellets at 26 weeks and 52 weeks post-transplant. 
2. Measures of Renal Function and Injury (months 3, 6, 9, years 1, 2, 3) 
a. Proportion of participants with eGFR by CKD-EPI, cystatin C, and CKD-cystatin C, < 60 mL/min/1.73 mP2
P. 
b. Proportion of participants with defined CKD stage 4 or 5. 
c. Mean calculated eGFR by CKD-EPI, cystatin C, and CKD-cystatin C. 
d. The slope of eGFR by CKD-EPI, cystatin C, and CKD-cystatin C variable models over time based on serum 
creatinine. 
3. HIV persistence 
a. HIV reactivation (frequency of CD4+ T cells producing HIV multiply spliced RNAs upon TCR stimulation) 
b. HIV DNA and RNA in peripheral blood CD4+ T cells 
c. Plasma HIV RNA levels (single copy assay) 
 
4. Histologic and Serologic Evidence of Rejection  
a. Incidence of clinically suspected and biopsy proven acute rejection within the first 52 weeks and 156 
weeks  as defined by histologic evidence of rejection and graft dysfunction as identified on central read 
of biopsy slides. 
b. The incidence of acute cellular rejection grade equal to or > than IA, by the Banff 2007 criteria, within 
the study period (3 years) as identified on central read of biopsy slides. 
c. The severity of first and highest grade of acute cellular rejection within the study period. 
d. The incidence of antibody mediated rejection. 
e. The prevalence of de novo anti-donor HLA antibodies at 52 weeks. 
 


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5. Analysis of HIV infection in the renal allograft and HIVAN 
a. Histology/in situ hybridization to assess HIV infection in the renal allograft 
 
6. Safety Profile measures 
a. Death 
b. Graft loss 
c. Incidence of all adverse events (AEs) >/= Grade 3 
d. Incidence of serious adverse events (SAEs) >/= Grade 3 
e. Incidence of opportunistic infections or neoplasms 
f. Incidence of non-opportunistic infections requiring hospitalization or systemic therapy 
 
7. Pharmacokinetics 
a. Calcineurin inhibitor trough levels and AUC for participants on maraviroc versus placebo 
b. AUC and trough levels of CCR5 blockade (maraviroc)  
 
3.4 Primary Mechanistic Endpoints 
 
1. Define immunologic parameters associated with rejection in the HIV+ participants by comparing the following 
parameters in those who experience acute rejection in the first 6 months and those who do not have acute 
rejections (samples collected prior to and at the time of rejection will be analyzed and compared): 
 
a. Circulating leukocyte subsets and their activation phenotypes  
b. Anti-donor alloimmune responses measured by frequency of total donor-reactive T cells and donor-
reactive effector T cells 
c. Frequencies of T cells with cross-reactivity between donor alloantigens and HIV, CMV, and EBV antigens 
d. DSA in serum 
e. Gene expression in for-cause biopsies by RNASeq analysis 
f. Histological analysis for evidence of cellular and antibody mediated rejection mechanisms. 
 
2. Determine the impact of CCR5 blockade on the immunologic profiles in the HIV + recipients by comparing results 
from MVC-treated and those receiving standard of care (SOC).  Change of the various parameters after initiation 
of MVC or SOC will be monitored and these changes will be compared between the two groups (Samples 
collected pre transplant and at various time points post-transplant will be analyzed): 
a. Change in circulating leukocyte subsets and their activation phenotypes from pre-transplant baseline  
b. Change in CCR5 and other chemokine receptor expression on subsets of various circulating leukocytes 
from pre-transplant baseline 
c. Change on anti-donor alloimmune responses measured by frequency of total donor-reactive T cells and 
donor-reactive effector T cells 
d. Change in frequencies of T cells with cross-reactivity between donor alloantigens and HIV, CMV, and EBV 
antigens after transplant. 
e. DSA in serum 
f. Histological analysis of for-cause biopsies for mechanisms of rejection 
 
3.5 Stratification, Randomization, and Blinding/Masking 
Participants will be randomized in a blinded fashion to one of 2 groups (maraviroc or placebo), stratified by center and 
by donor type (HIV negative deceased, HIV negative live, HIV positive deceased), using a web-based randomization 
system. 


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3.5.1 
Procedure for Unblinding/Unmasking 
Requests can be made to unblind subjects, on a case-by-case basis immediately for emergencies or urgent situations. 
Requests should be communicated to the Project Manager or the EMMES data center, who will then contact the 
Operations Committee (See Manual of Procedures for contact information). Requests will be reviewed and approved by 
the Operations Committee (including the Medical Officer), and the IND holder as appropriate, unless an immediate life 
threatening condition has developed and the Operations Committee are not accessible.  In that case, the site 
investigator will notify the Project Manager or EMMES data center of the unblinding event on the next business day.  
All unblinding will be reported to the Data and Safety Monitoring Board (DSMB).  
Unblinding information should be shared with as few individuals as possible. The unblinding information is shared only 
on a need-to-know basis.  
A full account of the event will be recorded, including the date and time of the unblinding, the reason for the decision to 
unblind, and the name of the individual who made the decision and the names of the Medical Officer and others who 
were notified. The reasons for unblinding of a participant’s treatment will be included in the final study report. 
 


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4 Selection of Participants  
4.1 Rationale for Study Population 
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 is known to be well-tolerated in this population. This is particularly relevant since 
unexpectedly high rejection rates (2-3 fold higher than HIV uninfected recipients) were reported following kidney 
transplantation in HIV positive recipients. 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 participants on long-term antiretroviral therapy for HIV 
infection.    
4.2 Inclusion Criteria   
All individuals with end-stage kidney disease and HIV infection who meet standard clinical criteria for transplantation and 
the study inclusion and exclusion criteria will be eligible for participation in the study. All participants must meet all 
inclusion and exclusion criteria before being enrolled into segment A (pre-randomization) and at the time of enrollment 
into segment B (randomization and study drug initiation).  
1. Participant is able to understand and  provide informed consent 
2. Documented HIV infection (by any licensed ELISA and confirmation by Western Blot, positive HIV ab IFA, or 
documented history of detectable HIV-1 RNA). 
3. Participant is ≥ 18 years old. 
4. CD4+ T-cell count >/= 200/µL at any time in the 26 weeks prior to enrollment. 
5. Most recent HIV-1 RNA < 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 cART regimen to 
become study eligible must also have an eligible HIV-1 RNA result post change in cART. 
6. Participant meets standard listing criteria for placement on transplant waiting list.  
7. For participants with an HIV+ deceased donor: 
a) No active opportunistic infections. 
b) Concurrence by the study team that based on medical history and ART, viral suppression can be achieved in the 
recipient post-transplant.   
c) Must be enrolled in an IRB approved research protocol that fulfills the requirements of the DHHA Hope Act 
Policy (see section 9.1.2). 
d) HIV+ deceased donor must have no evidence of invasive opportunistic complications of HIV infection, and must 
have a pre-implant biopsy. 
8.  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 non-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 


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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. 
 
9. No known allergy or intolerance to components of MVC or its formulation. 
10. No known contraindication to MVC. 
11. Female participants of child-bearing potential must have a negative serum beta-HCG pregnancy test within 30 days of 
randomization.   
 
4.3 Exclusion Criteria  
19T19TIndividuals who meet any of these criteria are not eligible for enrollment as study participants:  
1. Participant is currently on maraviroc. 
2. Participant needs multi-organ transplant. 
3. Participant has a live donor who is HIV+. 
4. Participant is unable to switch to non-protease inhibitor-based cART regimen. 
5. Participant has received immunosuppressant medication in the 6 months prior to enrollment. Note: Low dose 
maintenance steroids (</= 10 mg per day of prednisone, or equivalent strength steroid) will not be considered 
immunosuppression. 
6. Opportunistic Complication History: Any history of progressive multifocal leukoencephalopathy  (PML), chronic 
intestinal cryptosporidiosis of > 1 month duration, or primary CNS lymphoma. Note: History of pulmonary 
coccidiodomycosis will be treated per local site policy regarding this infection in HIV negative transplant candidates, 
generally requiring a 5-year disease-free interval. 
7. 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.  
8. Substance use that in the opinion of the investigator would interfere with compliance with the study requirements. 
9. 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. 
10. Participant has used IL-2 or GM-CSF in the prior six months. 
11. Participant has received interferon-alpha therapy in the prior 12 weeks. 
12. Use of investigational drugs within 4 weeks of enrollment 
13. 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.  


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5 Known and Potential Risks and Benefits to Participants 
5.1 Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert 
 
Hepatotoxicity 
Hepatotoxicity accompanied by severe rash or systemic allergic reaction including potentially life-threatening events has 
been reported in clinical trials and post marketing. These events occurred approximately one month after starting 
treatment. Among reported cases of hepatitis, some were observed in the absence of allergic features or with no pre-
existing hepatic disease. 
Hepatic laboratory parameters including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin 
should be obtained prior to starting maraviroc and at other time points during treatment as clinically indicated. If rash or 
symptoms or signs of hepatitis or allergic reaction develop, hepatic laboratory parameters should be monitored and 
discontinuation of treatment should be considered. 
Caution should be used when administering maraviroc to patients with pre-existing liver dysfunction or who are 
coinfected with viral hepatitis B or C. The safety and efficacy of maraviroc have not been specifically studied in patients 
with significant underlying liver disorders. 
Severe skin and hypersensitivity reactions 
Severe, potentially life-threatening skin and hypersensitivity reactions have been reported in patients taking maraviroc, 
in most cases concomitantly with other drugs associated with these reactions. These include cases of Stevens-Johnson 
syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS). The 
cases were characterized by features including rash, constitutional findings, and sometimes organ dysfunction, including 
hepatic failure. Discontinue maraviroc and other suspected agents immediately if signs or symptoms of severe skin or 
hypersensitivity reactions develop. Delay in stopping treatment with maraviroc or other suspect drugs after the onset of 
rash may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and 
appropriate therapy initiated. 
Cardiovascular events 
Use with caution in patients at increased risk of cardiovascular events, because cardiovascular events, including 
myocardial ischemia and/or infarction, were observed in treatment-experienced and treatment-naïve patients who 
received maraviroc. Caution should be used when administering maraviroc in patients with a history of postural 
hypotension or who receive concomitant medication known to lower blood pressure. Patients should be advised that if 
they experience dizziness while receiving maraviroc, they should avoid driving or operating machinery. 
Postural hypotension in patients with renal impairment 
Maraviroc should not be used in patients with severe renal impairment or end-stage renal disease (ESRD) (CrCl <30 
mL/min) who are taking potent CYP3A inhibitors or inducers due to an increased risk of postural hypotension as a result 
of increased maraviroc exposure in some patients. 
Maraviroc should be used in patients with severe renal impairment or ESRD only if they are not receiving a concomitant 
potent CYP3A inhibitor or inducer and no alternative treatment options are available. If patients with severe renal 
impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience any symptoms of 
postural hypotension while taking maraviroc 300 mg twice daily, the dose should be reduced to 150 mg twice daily. 
 


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Immune reconstitution syndrome 
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, 
including maraviroc. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have 
also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and 
can occur many months after initiation of treatment. 
Potential risk of infection 
Maraviroc antagonizes the CCR5 coreceptor located on some immune cells, and therefore, could potentially increase the 
risk of developing infections. Patients should be monitored closely for evidence of infection while receiving maraviroc. 
Potential risk of malignancy 
While no increase in malignancy has been observed with maraviroc, due to this drug's mechanism of action, it could 
affect immune surveillance and lead to an increased risk of malignancy. Long-term follow-up is needed to more fully 
assess this risk. 
5.2 Risks of Study Procedures  
5.2.1 
Collection of Blood:  
Collection of blood may cause slight discomfort, pain, bleeding or bruising at the injection site.  Rarely, fainting or 
infection may occur. 
5.2.2 
Kidney Biopsy: 
The most frequent complications of a biopsy include pain and hematuria (blood in the urine). 
5.2.3 
Internet-Based Data Collection 
Data from this study will be entered into a computerized database through a secured web site.  All information will be 
saved and transmitted in a coded form.  Only authorized personnel requiring a password will be permitted to enter data.  
There is risk, although minimal, of unauthorized persons obtaining confidential information. 
5.3 Participant risks associated with kidney transplant from HIV+ donors 
5.3.1 Acute Rejection (AR).  
HIV+ recipients have been shown to have 2-4 fold higher rates of AR, in both the NIH HIV Multisite Study [1] and in the 
national experience [62]. This may be due to drug-interactions between immunosuppression and antiretroviral therapy 
or due to a dysregulated immune system from HIV infection.  Proposed interventions to address this include avoiding 
ritonavir-containing ART and induction immunosuppression. It is unknown whether AR rates will be increased in HIV-to-
HIV transplantation. 
5.3.2 Recurrent HIV-Associated Nephropathy (HIV-AN).   
There has been concern about HIV-AN recurrence after transplant; this occurred in 38% of HIV+ recipients using HIV- 
donors in a French cohort [63] but was not observed in the NIH Multisite study [1]. In South Africa, histologic changes 
consistent with HIV-AN without graft dysfunction were observed in 3 of 27 patients [53].  This risk needs to be better 
understood. 
 


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5.3.3 Infections and Hospitalizations.  
Infections requiring hospitalization have been observed in nearly 40% of HIV+ recipients using HIV- donors although 
opportunistic infections (OI) were very rare (<10%) [1]. Whether the use of HIVDD will be associated with an increased 
risk of standard OI is unknown.   
5.3.4  HIV superinfection (HIV-SI).   
HIV+ recipients of HIVDD may become superinfected, i.e. acquire a second, new HIV strain from the donor. 
Superinfection occurs at varying rates in populations with differing modes of transmission, including intravenous drug 
use (IVDU) and sexual transmission [64-66].  Although HIV+ transplant candidates are on ART [67], and HIV-SI is thought 
to occur rarely on fully suppressive ART, there is concern of increased risk of HIV-SI with an HIVDD because (i) the viral 
inoculum that occurs with transplant is likely higher than with IVDU or sexual transmission, (ii) if an HIVDD is infected 
with an ART resistant or X4 tropic virus, this might not be suppressed by the HIV+ recipient’s ART regimen [68, 69], and 
(iii) stably integrated HIV-infected resting CD4+ T-cells may be transplanted.  Additionally, ART regimens in HIV+ 
recipients ideally will avoid ritonavir-boosted protease inhibitors (PIs) [70]. However, PIs are potent and often required 
to treat drug resistant virus [71]. 
5.4 Potential Benefits 
Maraviroc is a CCR5 inhibitor that may have a positive 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 and who are already on cART (combination antiretroviral therapy).  Potential benefits 
include: 
• 
Reduction in the incidence of alloimmune rejection 
• 
Improvement in long term allograft function by blocking migration of pro-inflammatory cells to the allograft 
• 
Reduction in the size of the HIV reservoir by CCR5 blockade combined with immunosuppression. 
 
If CCR5 blockade decreases immunologic graft injury and improves long-term kidney allograft function in HIV infected 
recipients, this strategy could be applied to HIV uninfected recipients. Any impact found on HIV persistence could lead to 
further research of CCR5 blockade and immunosuppression on the eradication of HIV.  


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6 Study Drug /Device/Intervention  
 
Participants will be randomized to receive maraviroc or placebo in addition to their non-protease inhibitor-based cART 
regimen. In general, the first dose of study drug will be administered upon admission for transplantation, prior to 
transplant. Study drug and placebo will be provided by ViiV. Since the study drug is being administered to assess 
reduction in immune-mediated graft injury and is not intended as a component of antiretroviral regimen, viral tropism 
testing to confirm CCR5 status is not required. However, CCR5 tropism analysis will be done at the end of the study as 
part of the mechanistic analysis.  
6.1 Study Treatment 
Study Treatment for Arm 1 participants is maraviroc plus a non-protease inhibitor-based combination antiretroviral 
therapy (cART).  Study Treatment for Arm 2 participants is placebo for maraviroc plus non-protease inhibitor-based 
combination antiretroviral therapy (cART).  The cART is required but it will not be provided through the study. 
The study-provided drugs are maraviroc and placebo for maraviroc.   
All participants will be followed for at least 1 year after enrollment of the last participant. 
6.2 Regimens, Administration, and Duration 
6.2.1 
Initial Dosage Regimen 
At time of transplant, participants will be randomized (1:1) to Arm 1 or Arm 2 to receive one of the two blinded study 
treatment regimens while remaining on a non-protease inhibitor-based cART regimen.  The study drug will be initiated 
during admission for transplantation and prior to transplant. If study drug is not initiated prior to transplant, it must be 
initiated no greater than 72 hours post randomization. In the event a participant receives the study product upon 
admission for transplant but the transplant is cancelled, the DCC should be notified as soon as possible, and the 
participant will need to be re-randomized at the next admission for transplant. 
Treatment Arm 1: Maraviroc 
 
If co-prescribed medications that do not significantly interact with maraviroc, including tacrolimus, 
sirolimus, tipranavir/ritonavir, rilpivirine, nevirapine, raltegravir, dolutegravir, all NRTIs, and 
enfuvirtide 
300mg 
twice daily 
orally 
If co-prescribed Upotent CYP3A inhibitors*U (with or without a potent CYP3A inducer) including: 
cyclosporine, delavirdine, ketoconazole, itraconazole, clarithromycin and other potent CYP3A 
inhibitors (e.g., nefazodone, telithromycin) 
150mg 
twice daily 
orally 
If co-prescribed Upotent CYP3A inducerU (with or without a CYP3A inhibitor) including: efavirenz, 
rifampin, etravirine, carbamazepine, phenobarbital, and phenytoin 
600mg  
twice daily 
orally 
 
 
 
 
 
 
 
 
 
 


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Treatment Arm 2: Placebo for Maraviroc 
If co-prescribed medications that do not significantly interact with maraviroc, including 
tacrolimus, sirolimus, tipranavir/ritonavir, rilpivirine, nevirapine, raltegravir, dolutegravir, all 
NRTIs, and enfuvirtide 
300mg 
twice daily orally 
If co-prescribed Upotent CYP3A inhibitors*U (with or without a potent CYP3A inducer) including: 
cyclosporine, delavirdine, ketoconazole, itraconazole, clarithromycin and other potent CYP3A 
inhibitors (e.g., nefazodone, telithromycin) 
150mg 
twice daily orally 
If co-prescribed Upotent CYP3A inducerU (with or without a CYP3A inhibitor) including: efavirenz, 
rifampin, etravirine, carbamazepine, phenobarbital, and phenytoin 
600mg  
twice daily orally 
 
Decision to use maraviroc 300 mg bid 
Although the general recommendations for maraviroc dosing when given with cytochrome P450 inhibitors such as CNIs, 
or with participants with moderate reduction in renal function is 150 mg bid  
(https://rsc.niaid.nih.gov/sites/default/files/Maraviroc%20%28Selzentry%29%20PI%20dated%20July%202018.pdf U39T39T), in 
the study of CCR5 blockade by Reshef et al, the dose needed to reach the 100 ng/mL average concentration level for the 
study was 300 mg bid (see figure 2 below).[18]  For this reason, we have decided to use 300 mg bid. 
 
Figure 2: Maraviroc plasma concentrations as determined in 13 patients (300 mg twice daily [bid], n=6; 150 mg twice 
daily, n=7) on day 0 and day 12 at 0 (pre-dose), 1, 2, 3, 4, 6 and 12 hours post-dose for Blockade of Lymphocyte 
Chemotaxis in Visceral Graft-versus-Host Disease. Plasma levels were determined by high-performance liquid 
chromatography – tandem mass spectrometry.  
In the study above, all of these participants were on voriconazole, which inhibits the enzyme that metabolizes 
maraviroc, thereby raising maraviroc levels. In our previous studies, when giving two drugs that potently interact with 
each other, we either made sure that the participants always took their medications together, or we asked them to take 
the medications at least 4 hours apart, since that seems to decrease the degree of intestinal enzymatic inhibition. [72] 
 
6.2.2 
Modified Dosage Regimen 


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The study drug dose will be modified when participant’s GFR<30, if co-prescribed with a potent CYP3A inhibitor or 
inducer, or if the calcineurin inhibitor used for maintenance immunosuppression is changed to cyclosporine (which is 
only allowed for tacrolimus toxicity). Once GFR >= 30, the dose should be returned to the non-renal dosage. If GFR is 
consistently fluctuating (especially immediately post-transplant), the site investigator may choose when to resume 
normal dosing of study products based on clinical assessment of stability. 
 
Maraviroc  
Based on Renal Function 
CrCl ≥30  
CrCl <30 mL/min 
or on 
haemodialysis 
If co-prescribed medications that do not significantly interact with 
maraviroc, including tacrolimus, sirolimus, tipranavir/ritonavir, rilpivirine, 
nevirapine, raltegravir, dolutegravir,  all NRTIs, and enfuvirtide 
300 mg 
twice daily 
150 mg 
twice daily 
If co-prescribed potent CYP3A inhibitors* (with or without a potent CYP3A 
inducer) including: protease inhibitors (except tipranavir/ritonavir), 
cyclosporine, delavirdine, ketoconazole, itraconazole, clarithromycin and 
other potent CYP3A inhibitors (e.g., nefazodone, telithromycin) 
150 mg twice daily 
150 mg once daily 
If co-prescribed potent CYP3A inducer (with or without a CYP3A inhibitor) 
including: efavirenz, rifampin, etravirine, carbamazepine, phenobarbital, 
and phenytoin 
600 mg twice daily 300 mg twice daily 
 
Placebo for Maraviroc Dose  
Based on Renal Function 
CrCl ≥30  
CrCl <30 mL/min 
or on 
haemodialysis 
If co-prescribed medications that do not significantly interact with 
maraviroc, including tacrolimus, sirolimus, tipranavir/ritonavir, rilpivirine, 
nevirapine, raltegravir, dolutegravir,  all NRTIs, and enfuvirtide 
1 dose 
300 mg 
twice daily 
1 dose 
150 mg 
twice daily 
If co-prescribed potent CYP3A inhibitors* (with or without a potent CYP3A 
inducer) including: protease inhibitors (except tipranavir/ritonavir), 
cyclosporine, delavirdine, ketoconazole, itraconazole, clarithromycin and 
other potent CYP3A inhibitors (e.g., nefazodone, telithromycin) 
1 dose 
150 mg twice daily 
1 dose 
150 mg once daily 
If co-prescribed potent CYP3A inducer (with or without a CYP3A inhibitor) 
including: efavirenz, rifampin, etravirine, carbamazepine, phenobarbital, 
and phenytoin 
1 dose 
600 mg twice daily 
1 dose 
300 mg twice daily 
*For up to date lists of CYP3A4 inhibitors and inducers, we recommend checking 39Thttps://drug-
interactions.medicine.iu.edu/Main-Table.aspx. 
All participants in both Treatment Arms must receive cART based on the current local and national dosing guidelines. 
cART will not be provided by this study. Study clinicians, in conjunction with participants, should determine the optimal 
cART regimen for each participant.  Participants in both Treatment Arms will be on study drug therapy for one to three 
years. 
 
 


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6.2.3 
Administration 
Maraviroc 300 mg dose will be administered as one 300 mg tablet (OR two maraviroc 150 mg tablets) orally twice daily 
with or without food.     
 
Placebo for Maraviroc 300 mg dose will be administered as one placebo for maraviroc 300 mg tablet (OR two placebo 
for maraviroc 150 mg tablets) orally twice daily with or without food. 
 
Maraviroc 150 mg dose will be administered one 150 mg tablet orally twice daily with or without food. 
 
Placebo for Maraviroc 150 mg dose will be administered one placebo for maraviroc 150 mg tablet orally twice daily with 
or without food. 
6.2.4 
Duration 
Participants will be on the study drug for 1-3 years depending on enrollment date. 
6.3 Study Drug Formulation and Preparation 
Maraviroc 150 mg, Maraviroc 300 mg, Placebo for maraviroc 150 mg, and Placebo for maraviroc 300 mg will be supplied 
as tablets for oral administration.   
 
Store at 15° C – 30° C (59-86°F) 
6.4 Pharmacy: Product Supply, Distribution, and Accountability 
6.4.1 
Study Drug Acquisition/Distribution 
Maraviroc 150mg, maraviroc 300 mg, Placebo for maraviroc 150 mg, and Placebo for maraviroc 300 mg will be supplied 
by ViiV Healthcare Ltd. 
 
The study drugs will be available through the National Institute of Allergy and Infectious Diseases (NIAID) Clinical 
Research Products Management Center (CRPMC).  The site pharmacist can obtain the study drug for this protocol by 
following the instructions in the manual Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks in the 
Section Study Product Management Responsibilities. 
 
cART will not be provided through the study. 
6.4.2 
Study Drug Accountability 
The site pharmacist is required to maintain complete records of all study drugs received from the NIAID CRPMC and 
subsequently dispensed. All unused study drugs must be returned to the NIAID CRPMC after the study is completed, 
terminated or otherwise instructed by the study sponsor. The procedures to be followed are provided in the manual 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
6.5 Premature Discontinuation of Study Drug 
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
1. Participant meets criteria to discontinue study treatment (MVC or placebo). 
2. The investigator no longer believes continuing study treatment is in the best interest of the participant. 
3. Participant refuses to continue study treatment. 
4. Treatment is held or discontinued for clinical reasons for greater than 60 days. 
 
Participants who prematurely discontinue study treatment will be treated according to the site specific standard of care, 
and will be followed under a modified schedule post-transplant.  


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7 Clinical Management Issues 
7.1 Toxicity Management 
Only toxicities related to study medications provided through this study (MVC, placebo) will be considered in the toxicity 
management section. The grading system is located in the Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, July 2017, located at the DAIDS RSC Web Site: 
39TUhttps://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tablesU39T 
For toxicities potentially attributed to the study medication, the study medication (or the matching placebo) may be 
held. 
7.1.1 
Grade 1 or 2 
Subjects who develop a Grade 1 or 2 AE or toxicity may continue study medication without alteration of the dosage at 
the discretion of the investigators. Subjects experiencing Grade 1 or 2 AEs who choose to discontinue all study 
medication should complete the premature treatment discontinuation evaluations. The site investigator should contact 
the Operations Committee, and the subject should be encouraged to complete follow-up protocol study evaluations. 
NOTE: If subjects discontinue study medications due to Grade 1 or 2 AEs, this should be noted on the premature 
treatment discontinuation CRF as the reason for discontinuation. 
7.1.2    Grade 3 
If the investigator has evidence that the AE was NOT caused by study medication, dosing may continue. Grade 3 AE or 
toxicity must be evaluated and managed by the site investigator according to the standard of care. Discontinuation of 
study medication may be necessary. Consultation with the Operations Committee is encouraged. If study medication(s) 
are discontinued the subject should be reevaluated weekly until the AE stabilizes, returns to ≤Grade 2 or baseline. The 
study medications may be reintroduced, at the discretion of the site investigator or according to standard practice.  
If the same Grade 3 AE, excluding those AEs noted in the following sections, recurs within 4 weeks of restarting 
treatment, the study medication must be permanently discontinued. However, if the same Grade 3 AE recurs after 4 
weeks, the management scheme outlined above may be repeated. 
Participants experiencing Grade 3 AEs requiring permanent discontinuation of the study medication should be followed 
weekly until resolution or stabilization of the AE and should be encouraged to complete the premature treatment 
discontinuation evaluations and continue other study evaluations according to the protocol. The Operations Committee 
must be notified. 
7.1.3    Grade 4 
Participants who develop a Grade 4 symptomatic AE or toxicity will have all study medication permanently discontinued 
except as indicated below. Participants experiencing Grade 4 AEs requiring permanent discontinuation of study 
medication should be followed weekly until resolution or stabilization of the AE and encouraged to continue other study 
evaluations according to the protocol. Premature treatment discontinuation evaluations should be completed and 
recorded on the CRF and the core team must be notified. 
Asymptomatic Grade 4 abnormalities must be evaluated and managed by the site investigator according to the standard 
of care. Discontinuation of study medication may be necessary. Consultation with the Operations Committee is 
encouraged. The Operations Committee must be notified by e-mail regarding toxicities that result in a change in 
regimen. Participants who prematurely discontinue study treatment should continue to be followed on study. 


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7.1.4    AST or ALT Elevations 
All study medication may be continued for asymptomatic ≤Grade 3 AST/ALT elevations, at the discretion of the site 
investigator. Careful assessments should be done to rule out the use of alcohol, non-study medication-related toxicity, 
or viral hepatitis (including viral hepatitis complicated by immune reconstitution inflammatory syndrome) as the cause 
of Grade 3 elevations.  
For symptomatic Grade 3 (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia) or any Grade 4 elevations in AST or ALT, all study medication should be held and the Operations 
Committee should be consulted. In addition, for ALT ≥3 x ULN and bilirubin ≥1.5 x ULN (attempts should be made to 
fractionate the bilirubin), the study medications should be held and the Operations Committee consulted as this will 
likely result in permanent study medication discontinuation. 
Participants who develop symptomatic Grade 3 or any Grade 4 AST or ALT elevation should be followed weekly until 
stabilization or resolution to ≤Grade 2.  Subjects will be followed off study treatment, on study after study medication 
discontinuation. 
Subjects with Grade 3 or 4 AST or ALT elevation with fever, rash or eosinophilia should stop all study medications and 
not be re-challenged. These individuals should be followed weekly until stabilization or resolution to ≤Grade 2 elevation 
and should be followed off study treatment, on study. 
In consultation with the Operations Committee, careful assessments should be done to rule out the use of alcohol, non-
study medication-related toxicity, or viral hepatitis (including viral hepatitis complicated by immune reconstitution 
inflammatory syndrome) as the cause of Grade 3 or 4 AST/ ALT elevations. Evaluations to be considered (but are not 
required) include:  
•         Viral hepatitis serology including: Hepatitis A IgM antibody; Hepatitis B Surface Antigen (HBsAg) and Hepatitis B Core 
Antibody (IgM); Hepatitis C RNA; Hepatitis E IgM antibody; 
•         Cytomegalovirus IgM antibody; 
•         Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing); 
•         Syphilis screening; 
•         Drugs of abuse screen including alcohol; 
•         Serum acetaminophen test (APAP adduct test); 
•         Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH); 
•         Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney microsomal antibodies; 
•         Liver imaging to evaluate liver disease. 
7.1.5      Calculated Creatinine Clearance (CrCl) Decline 
Non-study medications should be adjusted for decline in CrCl at the discretion of the primary provider per the standard 
of care. 
 
MVC dose will be modified for CrCl <30 mL/min. See section 6.2.2 Modified Dosage Regimen.   
7.1.6    Postural Hypotension 
If a subject develops postural hypotension of any grade, the investigator should contact the Operations Committee. All 
cases of postural hypotension should also be reported as an adverse event in the EMMES IDES, regardless of grade. 


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7.1.7    Allergic Reaction  
Subjects may continue study medication for Grade 1 or 2 allergic reactions at the discretion of the site investigator. The 
subject should be advised to contact the site investigator immediately if there is any worsening of symptoms or if further 
systemic signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed.   
Subjects with ≥Grade 3 allergic reactions that are considered to be possibly or probably related to the study medications 
should permanently discontinue the putative study medication and continue to be followed off study treatment, on 
study. The subject should not be re-challenged. The subject should be treated as clinically appropriate and followed until 
resolution of the AE.   
Allergic reactions that include but are not limited to severe rash or any rash with fever, general malaise, fatigue, muscle 
or joint aches, oral lesions, conjunctivitis, facial edema or eosinophilia should result in all study medications being 
stopped and the subject should not be re-challenged. The subject should be followed off study treatment, on study. 
All cases of allergic reaction should also be reported as an adverse event in the EMMES IDES, regardless of grade. 
7.1.8    Rash  
Hepatotoxicity accompanied by severe rash or systemic allergic reaction, including potentially life-threatening events, 
have been reported in subjects taking MVC.  Severe skin and hypersensitivity reactions including SJS and TEN have also 
been reported in subjects taking MVC. 
Subjects with an isolated Grade 1 rash may continue study medication at the site investigator’s discretion. The subject 
should be advised to contact the site investigator immediately if there is any worsening of the rash, if any systemic signs 
or symptoms worsen, or if mucosal involvement develops. 
Subjects may continue study medications for an isolated Grade 2 rash. However, study medications should be 
permanently discontinued for any ≥Grade 2 rash that is associated with an increase in ALT. The subject should be 
advised to contact the site investigator immediately if rash fails to resolve (after more than two weeks), if there is any 
worsening of the rash, if any systemic signs or allergic symptoms develop, or if mucosal involvement develops. 
Subjects should permanently discontinue study medications for an isolated Grade 3 or 4 rash, and the subject will be 
followed off study treatment, on study. Subjects should be treated as clinically appropriate and followed until resolution 
of the AE. 
If the etiology of the rash can be definitely diagnosed as being unrelated to study medications and due to a specific 
medical event or a concomitant non-study medication, routine management should be performed and documentation 
of the diagnosis provided. 
All cases of rash should also be reported as an adverse event in the EMMES IDES, regardless of grade. 
7.1.9 
HIV Persistent Virologic Failure 
HIV persistent virologic failure defined as a HIV viral load > 1000 copies/mL for more than 90 days that is not the result 
of an investigator/physician approved interruption in antiretroviral treatment should also be recorded as an adverse 
event in the EMMES IDES, regardless of grades. 
7.2 Pregnancy 


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If a woman has completed the study or chooses to discontinue from the study before the end of the pregnancy, then 
site staff should request permission to contact her regarding pregnancy outcomes at the end of pregnancy. If the 
information is obtained, pregnancy outcomes will be submitted on a CRF at the end of the pregnancy.  
5T5TThe Intrapartum complications and/or pregnancy outcome will be recorded on the CRFs. Pregnancies that occur on 
study should be reported prospectively to The Antiretroviral Pregnancy Registry. More information is available 
at  5T5T39TUwww.apregistry.comU39T5T5T. Phone: 800-258-4263; Fax: 800-800-1052.  


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8 Other Medications 
8.1 Combination Antiretroviral Therapy (cART) 
Unless a change is deemed necessary by the HIV physician, all subjects must be on a stable non-protease inhibitor-based 
maintenance cART regimen. An integrase inhibitor based 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. See the Manual of 
Procedures for more detail. 
Tenofovir and other nephrotoxic medications should be used cautiously when possible post-transplant. 
8.2 Immunosuppression 
Maintenance immunosuppressive regimen will be standard of care and may include tacrolimus, mycophenolate mofetil 
(MMF), and prednisone. Tacrolimus will be the first line calcineurin inhibitor. In the event of toxicity, cyclosporine A 
and/or sirolimus can be substituted or added. Refer to Manual of Procedures for details on the Risk Evaluation 
Management Strategy (REMS) for any participant using mycophenolate mofetil as part of maintenance 
immunosuppression. Induction with an IL-2 receptor inhibitor (anti-CD25 antibody) may be utilized and is preferred, but 
lympho depletion with thymoglobulin may be used as induction if deemed clinically indicated by the site investigators. 
Immunosuppressant doses will be modified to obtain routine trough levels standard for kidney transplants.   See the 
Manual of Procedures for more detail 
8.2.1 
Rejection Treatment Protocol 
A biopsy will be performed in all cases of suspected rejection (see the Manual of Procedures for the definition of kidney 
rejection). Treatment for rejection for > 1 day, including increases in the dose of immunosuppressive medications, 
cannot be sustained without a biopsy, unless the managing physicians believe biopsy is unsafe.  However, therapy may 
be initiated </= one day prior to the results of the biopsy if clinically indicated. Treatment of rejection episodes will be 
according to local site practices and may include sirolimus. Polyclonal anti-lymphocyte preparations have resulted in 
prolonged reduction in CD4+ counts in HIV infected transplant recipients, and there use should be restricted to 
treatment for moderate to severe rejection. TOR inhibitor agents may be added to maintenance regimens per site 
discretion. 
8.2.2 
Definition of Rejection 
The definition for kidney rejection is as defined by the NIH supported Cooperative Clinical Trials inP 
PTransplantation: 
Type I: mononuclear infiltrate in > or =5% of cortex, a total of atP 
Pleast three tubules with tubulitis in 10 
consecutive high-power fields fromP 
Pthe most severely affected areas, and at least two of the three followingP 
Pfeatures: edema, activated lymphocytes, or tubular injury.  
Type II:P 
Parterial, or arteriolar, endothelialitis with or without the precedingP 
Pfeatures.  
Type III: arterial fibrinoid necrosis or transmuralP 
Pinflammation with or without thrombosis, parenchymal necrosis, 
orP 
Phemorrhage.  
8.3 Prophylactic Medications 
See Manual of Procedures for recommended prophylaxis guidelines. 


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9 Study Procedures  
9.1 Screening/Baseline Visit 
Centers will identify potential study participants which are HIV+ kidney transplant candidates who are listed for 
transplant.  The research study will be explained in lay terms to each potential research participant, and the 
potential participant will sign an informed consent form before undergoing any study procedures. 
During the screening period for study eligibility, the study personnel will review the participant’s medical record for 
previous and current medical history, perform a physical examination, and record the participant’s demographic 
information. Screening tests indicated on the schedule of events with footnote 2 will be recorded if done as 
standard of care for transplant workup, or if the results are available in the medical record.  
The following procedures, assessments, and laboratory measures will be conducted or recorded for the baseline 
screening visit (after consent has been obtained):  
• 
Symptom & medical review plus physical exam 
• 
Record PPD (or chest x-ray if history of positive PPD) 
• 
Record Vaccination review (Pneumovax, Hepatitis A, Hepatitis B) 
• 
Record Chest x-ray result if available 
• 
Record Safety labs  
• 
Record CD4+ T-cell count 
• 
Record HIV-1 RNA 
• 
Record serologies (CMV Ab, EBV Ab, hepatitis B and C) 
The following procedures will be conducted as part of the research protocol: 
• 
Research specimens for mechanistic studies:  the collection of all baseline/screening samples are not 
necessarily drawn at initial screening for the study when all other screening laboratory measures and 
procedures are performed. All baseline/screening research specimens (blood, urine) should be collected on the 
day of transplant (day 0, visit 2) if they were not previously collected in the three months prior to transplant, 
and no more than 13 weeks prior to transplant. If the baseline research samples were not collected previously, 
or were collected more than 13 weeks prior to day of transplant, they should be collected on the day of 
transplant, prior to transplant. 
9.1.1 
Living donors 
Living donors must sign an informed consent document prior to any invasive procedures. The living donor’s decision to 
participate or not to participate in this study will not be disclosed to the recipient. 
9.1.2 
HIV+ donors 
Participants who utilize an HIV+ donor must be co-enrolled in an IRB approved research protocol that fulfills the 
requirements of the DHHS Hope Act Policy which can be found at 
https://www.federalregister.gov/documents/2015/11/25/2015-30172/final-human-immunodeficiency-virus-hiv-organ-
policy-equity-hope-act-safeguards-and-research-criteria. 
The HIVTR-CCR5 protocol will not be responsible for sample and data collection required by the policy. Sample and data 
collection and reporting to the DHHS will be the responsibility of each site’s IRB approved Hope Act protocol.  


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9.2 Participant Enrollment 
Once a participant has met all study inclusion and exclusion criteria, the participant will be assigned a unique 
participant number and will be enrolled into the Pre-Transplant (segment A) phase of the study using the EMMES 
IDES while waiting for organ availability. Enrollment into the Post-Transplant (segment B) phase of the study will 
occur on the day of transplant. 
9.3 Pre-Transplant On-Going Eligibility Monitoring for Segment B 
 
Once eligible participants have been enrolled into the Pre-Transplant (segment A) phase of the EMMES IDES, it is 
recommended that CD4+ T-cell count and HIV RNA viral load results be regularly obtained from the primary medical 
provider every 3 months if not being performed at the enrolling center as part of standard of care. This will help 
ensure documented eligibility if an organ becomes available. 
If the participant is no longer eligible for transplant or for segment B of the study, or wishes to withdraw from the 
study, the reason(s) will be recorded on the appropriate case report form. Participants in segment A may fluctuate 
between eligibility and ineligibility for segment B, but must meet study eligibility at the time of organ availability. 
Participants who withdraw their consent prior to transplant will be terminated from this study with no additional 
follow-up necessary. 
9.4 Randomization and Post-Transplant Study Visits 
 
Segment B study visits will occur at day 0, weeks 1, 2, 4, 8, 13 (month 3), 26 (month 6), 39 (month 9), 52 (year 1), 78 
(year 1.5), 104 (year 2), 130 (year 2.5), and week 156 (year 3). At each study visit, a clinical evaluation and physical 
examination will focus on signs and symptoms suggestive of HIV disease progression, impaired allograft function, 
and rejection. Clinical evaluation will concentrate on symptoms and examination findings of the oropharynx, 
respiratory, cardiac, gastrointestinal, skin, lymphatic and nervous system. Monitoring of orthostatic blood pressure 
should occur during all post-transplant visits to monitor possible hypotension. CD4+ T cell numbers and percent, 
and quantitative HIV-1 RNA by ultrasensitive bDNA or PCR assays will be determined. All necessary lab work 
outlined in the Schedule of Events should be performed.   
At each study visit, the study coordinator will collect and enter data into the web based data system, including 
medications, adverse events (AE’s)/serious adverse events (SAE’s), hospitalizations, infections, and standard of care 
labs.  
Although it is preferred that all post-transplant study visits occur at the transplant center, only the visits on weeks 4, 
13, 26, 52, and 104 (when specimen will be collected for mechanistic assays) must occur at the transplant center. If 
the participant is unable to return to the transplant center for any post-transplant study visit, a complete medical 
review should be conducted by telephone. In addition, all necessary lab work as outlined in the Schedule of Events 
should be performed locally at a CLIA-certified laboratory and the results sent to the transplant center for data 
entry along with the associated normal laboratory reference ranges. 
In addition, the following research procedures will be performed: 
• 
Protocol Biopsy: A protocol biopsy will be performed at 6 months post-transplant unless the transplant 
center already performs a 6 month post-transplant biopsy as standard of care. Slides and tissue should be 
sent to the central repository for central ready and analysis. See the laboratory manual for details. 


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• 
Iohexol clearance: Samples for iohexol study at week 52 (year 1) will be collected (2, 3 and 4 hours), 
processed, and shipped to the central repository where they will be stored and then analyzed in batch.  
• 
Collection of research bloods: Research blood will be obtained pre-transplant and at weeks 4 (month 1), 13 
(month 3), 26 (month 6), 52 (year 1), and 104 (year 2). Research blood will also be collected at the time of 
kidney rejection. These research specimens will be used primarily for the mechanistic aims of the study. 
However, some of the samples will be batch tested to address the secondary clinical aims of the trial, 
including: 
o cystatin C (months 3, 6, 9, years 1, 2, 3) 
o HLA antibodies (pre transplant, month 6, and at time of rejection) 
o KIR typing (pre transplant) 
• 
Collection of urine: 50ml – 100ml urine will be obtained at baseline, week 26 (month 6), week 52 (year 1). 
Urine will also be collected at the time of biopsy for suspected kidney rejection. Urine will be processed and 
banked at the central repository for future studies to look for HIV DNA and RNA levels if HIVAN is present 
and funding becomes available. 
• 
Pharmacokinetic Studies: Pharmacokinetic studies will be done on the first twenty UCSF participants (or all 
UCSF participants if accrual is < 20) enrolled in trial at 3 months post- transplant. PK studies will also be 
repeated on all UCSF participants if the calcineurin inhibitor used for maintenance immunosuppression is 
changed to cyclosporine (which is allowed only for tacrolimus toxicity). PK studies would be done in the 
UCSF Parnassus clinical research center.  After an overnight fast, participants would be admitted in the 
morning for a 12 hour PK study.  Samples will be collected at 0, 0.5, 1, 2, 3, 4, 6, 8 and 12 hours.  Whole 
blood samples will be frozen for tacrolimus assay and plasma samples for maraviroc assay.   
9.5 Visit Windows 
Study visits should occur within 2 weeks prior to the defined visit time point, or may occur after the defined visit 
time point up to the mid-way point between the target date and the subsequent study visit. For example, the week 
26 visit may occur up to week 31 [eg 26 + (36 – 26)/2 = 31]. 
 


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10  Mechanistic Assays 
  
Mechanistic studies will be performed on blood samples collected pre-transplant, and months 1, 3, 6, 12, 24, and at time 
of suspected kidney rejection, and on kidney biopsies collected at 6 months and time of suspected rejection.  The aims 
of the mechanistic studies are:  to define the impact of maraviroc on immune function and HIV persistence, to 
characterize the degree of immune dysregulation in HIV+ transplant recipients, and to define immunological parameters 
associated with rejection.  Comparisons will be made between those receiving maraviroc and placebo, and between 
transplant rejectors and non-rejectors. 
The goals of the mechanistic investigations associated with this trial are twofold:  
1. To determine the impact of immunosuppression and antiretroviral therapy with CCR5 blockade on HIV 
persistence in HIV+ recipients. 
2. To investigate cellular basis for enhanced graft rejection in HIV (+) recipients and to determine the impact of 
maraviroc on alloimmune responses in HIV+ recipients. 
Assays designed to achieve these goals are described below in this section. 
10.1 
Samples 
 
All recipients and donor samples will be banked and analyzed in batches. 
10.1.1 Recipient Samples: 
 
Peripheral blood mononuclear cells (PBMC) will be processed from heparinized peripheral blood and EDTA samples 
collected at pre-transplant, 1, 3, 6, 12 , and 24 months after transplant and at the time of rejection.  The samples will be 
stored in aliquots as live cells in cryopreservation medium in the vapor phase of liquid nitrogen.   
Whole blood samples collected at pre-transplant, month 6, and at the time of rejection for gene expression analysis will 
be collected directly into Paxgene tubes. 
Serum samples will be collected pre-transplant, month 6, and at the time of rejection using serum separation tubes and 
stored in -80Po
PC freezers in aliquots.   
Plasma samples will be collected at pre-transplant, 1, 3, 6, 12, and 24 months after transplant. 
Urine samples will be collected at baseline, week 26 (month 6), week 52 (year 1). Urine will also be collected at the time 
of biopsy for suspected kidney rejection. Samples will be processed into supernatant and pellet and banked at central 
repository. 
Lymph node (LN) samples will be collected during transplant and transferred in sterile organ preservation solution to 
processing laboratory. LN cells will be released using mechanical disruption.  The cells will be cryopreserved in aliquots 
using the same protocol used for PBMC. 
Graft biopsy samples will be collected at 6 months post-transplant, and at the time of all suspected rejection episodes.  
Two cores will be collected. See the Laboratory Manual for details. 
 


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10.1.2 Donor samples:   
Splenocytes from cadaveric donors or blood from living donors will also be collected at the time of the transplantation, 
processed into splenocytes or PBMC, and banked as live cells in liquid nitrogen tanks.   
10.2 
HIV persistence analyses 
 
UHighly sensitive and quantitative assay to measure replication competent HIV in T cell subsets in blood and tissues:U 
Given the extremely low frequency of reservoir cells in virally suppressed participants, precisely measuring the 
magnitude of the reservoir is challenging. HIV-1 proviral DNA and cell-associated RNA can be accurately quantified to 
provide a measurement of the total HIV burden. However, as the majority of the viral genomes detected in resting CD4P+
P 
T cells are defective, PCR based assays for HIV DNA overestimate the size of the replication competent reservoir (i.e., 
those variants which can support HIV replication in absence of therapy) [73]. Conversely, standardized viral outgrowth 
assays (VOA), which measure the cell-associated replication competent HIV pool, provide only minimal estimates of the 
frequency of resting CD4P+
P T cells harboring replication competent HIV[74]. Also, the VOA approach requires large 
numbers of freshly collected cells and is both expensive and time consuming [75]. These assays are not amenable to 
large studies such as the one proposed by this group. 
Drs. Nicholas Chomont (consultant in this trial) and his colleagues have developed a novel assay that measures the 
frequency of cells harboring inducible HIV without the limitations of the VOAs. By combining ultrasensitive detection of 
multiply-spliced RNA (msRNA) upon stimulation together with a limiting dilution assay, the “Tat/Rev Induced Limiting 
Dilution Assay (TILDA) quantifies the frequency of cells harboring transcriptionally silent – but nonetheless inducible – 
viruses. This assay can be performed with less than a million CD4P+
P T cells, as described below.  
UCell associated HIV RNA measurements by TILDA:U The frequency of cells with HIV multiply spliced (ms) RNAs will be 
measured upon activation in CD4+ T cells by using an assay developed in the laboratory of Dr. Chomont (Fig. 3). While 
unspliced HIV RNAs are frequently detected in latently infected cells in the absence of viral production, HIV msRNAs 
(tat/rev) reflect active viral production [76, 77]. These assays will take advantage of this unique feature of msRNAs in a 
limiting dilution assay to measure the frequency of cells with inducible HIV upon maximal stimulation in CD4P+
P T cells 
from the blood. Briefly, isolated CD4P+
P T cells will be stimulated for 12 hours with PMA/ionomycin. Serial dilution of the 
stimulated cells will be distributed in a 96 well plate (4 dilutions, 12 replicates each), lysed, and immediately used for RT-
PCR. msRNAs will be quantified by real time PCR [76, 78] and using the maximum likelihood method, the frequency of 
cells harboring inducible HIV msRNAs in CD4 T cells will be calculated. These experiments will determine if maraviroc 
leads to a reduction in the size of the latent (but inducible) HIV reservoir. 
 
Fig. 3: HIV RNA induction assay. Sorted CD4+ T cells are stimulated for 12 hours with PMA/ionomycin. Serial dilutions of the 
stimulated cells are distributed in a 96-well plate and digested. Multi-spliced HIV RNA are detected in a 2 step real time PCR. The 
maximum likelihood method is used to calculate the frequency of cells with inducible HIV RNA based on the number of positive 
wells. 


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In preliminary studies, the frequency of cells with inducible HIV RNA in CD4P+
P T cells from 9 HIV infected participants who 
received ART for at least 3 years was measured and compared to frequencies with integrated HIV DNA. The preliminary 
data indicate that values obtained with the two assays were strongly correlated (p = 0.002, Fig. 4A). However, the 
frequency of cells harboring integrated HIV DNA significantly exceeded the frequency of cells producing HIV RNA upon 
stimulation (median fold = 4.5, Fig. 4B). This indicated that the majority of cells harboring integrated HIV DNA do not 
produce viral RNA upon stimulation. These results confirm that the majority of HIV genomes are not replication 
competent [73] and reinforce the need for using a functional assay such as our viral induction assay to measure HIV 
latency.  
UCell Associated HIV DNA and RNA measurements:U The frequency of cells harboring total and integrated HIV DNA will be 
measured by using our well-established assays that can detect a single copy of the viral genome in 10P5
P cells [79]. While 
integrated HIV DNA is present in both latently and productively infected cells, the ratio between total and integrated has 
been recently shown to reflect residual HIV expression and de-novo reverse transcription [80]. Total and integrated HIV 
DNA will be measured in sorted CD4 T cells to determine the impact of maraviroc on this outcome measure. The 
frequency of cells expressing HIV RNA will be measured from isolated enriched CD4 T cells or pelleted cells from urine 
for single copy sensitivity qPCR assays using the AllPrep DNA/RNA kit (Qiagen, Ventura CA) as specified by the 
manufacturer. Cellular RNA will be normalized to cell equivalents based on qPCR using GAPDH mRNA expression (Life 
Technologies, Grand Island NY). Total cellular RNA is quantified with a qPCR TaqMan assay using LTR-specific primers 
F522-43 (5’ GCC TCA ATA AAG CTT GCC TTG A 3’; HXB2 522-543) and R626-43 (5’ GGG CGC CAC TGC TAG AGA 3’; 626-
643) coupled with a FAM-BQ probe (5’ CCA GAG TCA CAC AAC AGA CGG GCA CA 3) on a StepOne Plus Real-time PCR 
System (Applied Biosystems Inc, Foster City CA) using external quantitation standards prepared from full length NL4-3 
virion RNA normalization to NIH Virology Quality Assurance HIV-1 RNA standards. [81]   
UQuantifying virion HIV-1 in blood plasma:U Virion HIV-1 RNA will be quantified from blood plasma using the Abbott 
RealTime HIV-1 test modified for ultrasensitive detection. [82] Briefly, up to 30 mL plasma is layered over 0.6% OptiPrep 
Density Gradient medium cushions (Sigma Aldrich, St. Louis MO) and centrifuged for 3 hours at 4° C at 54,000 or 48,000 
x g using 10 or 30 mL ultracentrifugation tubes, respectively. Pelleted virions are resuspended in 1.0 mL Abbott lysis 
buffer, followed by RNA extraction and viral load qPCR using the m2000/rt2000 system Abbott RealTime HIV-1 assay. 
Low copy detection frequencies for large volume measurements are described [83]. For medium volume (6.0 mL) 
Fig. 4 (A-B): A: the frequency of CD4+ T cells with inducible HIV RNA is positively correlated with Integrated HIV DNA. B: However, 
integrated DNA always exceeds this frequency.  


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plasma input volumes, a probit analysis including repeat measurements of VQA virion RNA standards diluted to target 
copy numbers at 0, 1, 2, 5, 10, and 40/mL demonstrated 100% specificity (0/20 detected at 0 cps/mL). Detection 
frequencies for standards with estimated 1-40 copies/mL are as follows: 6/20 (30%) for 1 copy/mL; 11/20 (55%) for 2 
copies/mL; 19/20 (95%) for 5 copies/mL; 18/20 (90%) for 10 copies/mL; and 20/20 (100%) for 40 copies/mL.  
UViral genotype-based tropism: U HIV-1 coreceptor usage preference will be determined using ultra-deep sequencing of 
the V3 region of the HIV-1 envelope, followed by implementation of established bioinformatic prediction tools.  Ultra 
deep sequencing is critical when characterizing HIV-1 drug resistance or tropism in clinical samples, to enable sensitive 
detection of circulating minority variants.  Dr. Pillai (co-investigator on this study) has extensive experience in HIV-1 
sequencing methodology and sequence-based prediction of viral tropism.  In this study, CD4+ T cells will be negatively 
selected from PBMCs using the EasySep Human CD4+ T cell Enrichment Kit (StemCell Technologies), to enrich the 
cellular population for HIV-1 DNA.  Genomic DNA will be extracted from CD4+ T cells using the Qiagen AllPrep kit.  The 
C2-V3 region of the HIV-1 envelope will be amplified using nested PCR as previously described [84].  Illumina Nextera 
DNA sample kits will be used to prepare sequencing libraries and incorporate multiplex identifier barcodes that will 
allow pooling of 96 samples in a single deep sequencing run.  Sequencing will be performed on the Illumina MiSeq 
instrument in the Pillai Lab (2 x 250 read length).  Multiple sequence alignments of the C2-V3 region will be generated 
using hidden Markov models, and amino acid sequences of the V3 loop region will be used to predict the coreceptor 
usage of each V3 loop variant using established bioinformatics prediction tools including Wetcat [85] and Geno2pheno 
[86].  For each clinical sample, the frequencies of predicted CXCR4-tropic and CCR5-tropic clones will be reported. 
UCCR5 genotyping:U  The presence of the CCR5 delta-32 mutation will be determined in both transplant recipients and 
donors by implementing a PCR assay in the Pillai Lab as previously described [87].  Genomic DNA will be extracted from 
PBMCs using the Qiagen DNA Blood Mini Kit, according to the manufacturer’s instructions.  PCR amplification of a region 
of the CCR5 locus will be performed with the following primers: forward primer, 5’-GCTCTCTCCCAGGAATCATCTTTAC-3’; 
reverse primer 5’-TTGGTCCAACCTGTTAGAGCTACTG-3’. The thermocycler program is as follows: 95°C, 10 min, followed 
by 40 cycles of 95°C for 30 s, 62°C for 1 min, and 72°C for 1 min. The PCR yields a product of 356 bp for the wildtype 
CCR5 allele and a product of 324 bp for the CCR5 delta-32 deletion mutant. Gel visualization of PCR products is 
performed to differentiate between wild type homozygosity, CCR5 delta-32 heterozygosity, and CCR5 delta-32 
homozygosity. 
UIn Situ Hybridization (ISH).U Detection of low copy number HIV infection in tissues by immunohistochemistry (IHC) or 
immunofluorescence (IF) microscopy is hampered by low sensitivity of these methodologies. To assess low copy number 
HIV infection in formalin-fixed paraffin-embedded kidney biopsies, the Laszik lab has adapted the highly sensitive 
RNAScope® ISH platform using probes targeting multiple HIV1 clade B, A, and D strains on the coding sequence, 
including gag, pol, env, nef, tat, rev, vif and vpr. This novel ISH assay is based on a protocol of signal amplification and 
background suppression and Dr. Laszik (co-investigator on this study) has significant experience detecting low copy 
number cytokines in kidney biopsies using this technology. The HIV ISH signal will be quantitated from representative 
fields of the cortex and medulla in the glomerular, tubular, interstitial, and vascular compartments using computer-
assisted digital image analysis. The HIV ISH sections will be co-stained with multiplex IF using a panel of podocyte, 
endothelial, tubular, interstitial and inflammatory cell markers for precise quantitation of the HIV signal within various 
cellular compartments of the kidney. Preliminary results of HIV ISH show strong and specific hybridization signal in the 
podocytes from a patient with HIV nephropathy. The HIV signal is unequivocally localized to the podocytes by the HIV 
positive cells co-expressing synaptopodin on an ISH section co-stained with IF.  
 


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10.3 Alloimmune analyses 
10.3.1 Overview 
The goal of the alloimmune mechanistic assays is to define immunological parameters associated with rejection, and to 
determine the impact of maraviroc on immunological profiles.   
Our hypothesis for enhanced rejection in HIV+ recipients is that HIV+ patients have higher frequencies of allo-reactive 
memory T cells generated as a result of cross-reactivity between alloantigens and chronic viral antigens.  Experiments in 
animal models of transplantation demonstrate that multiple viral infections can induce the generation of memory allo-
reactive T cells as a result of cross-reactivity between alloantigen- and pathogen-reactive T cells [24-30]. Cross-reactivity 
between human alloantigen and viral antigen-reactive T cell lines and clones has also been demonstrated [31].  These 
viro-allo cross reactive memory T cells have a lower threshold for activation, can directly traffic to grafts, and are 
capable of expressing effector functions upon first encounter with donor antigens, all of which can contribute to 
enhanced graft rejections and resistance to tolerance induction.  Decades of chronic HIV and co-pathogen infection has 
the potential to expand viral reactive T cells and skew the immune repertoire, leading to increase in VACR memory T 
cells.  Furthermore, HIV infection can exacerbate this condition by depleting T cells.  Although T cell counts recover in 
most patients once HIV viremia is controlled by antiviral therapy, T cell receptor repertoire in patients with long-term 
HIV infection is dramatically narrower than age-matched HIV- patients. Depending on the donor allotype, a particular 
HIV+ recipient may have a narrow TCR repertoire depleted of donor-reactive T cells, whereas another recipient may 
have a narrow repertoire greatly enriched of donor reactivity due to the expansion of cross reactive memory T cells. The 
study will directly test this hypothesis by comparing frequencies of memory T cells and cross reactive T cells in samples 
collected pre-transplant in rejectors and non-rejectors.   
Memory T cells express high levels of CCR5, which facilitate CD4 and CD8 T cell cooperation and activation.  In rodent 
models of transplantation, CCR5 blockade has been shown to be beneficial for graft survival in some settings [11-15], but 
may exacerbate rejection in others [88-90].  The difference seems to reside in the mechanism of graft rejection – CCR5 
blockade was effective at blocking Th1-mediated rejection, but enhanced Th2 and antibody-mediated rejection.  
Another possible mechanism proposed for exacerbation of rejection by CCR5 blockade is the inhibition of Treg 
infiltration of the grafts [88, 91].  It is important to note that these rodent experiments used CCR5 blockade as single 
therapy [88-90] and the outcome is likely to be very different if it is combined with additional immunosuppressive 
agents as proposed in this trial.  Effect of maraviroc in kidney transplantation in patients is unknown at present time.  
Patients with CCR5d32 have less graft rejection suggesting that CCR5 plays a role in alloimmune response in humans and 
CCR5 blockage may be effective at improving transplant outcome [16, 17]. A recently concluded study in GVHD suggests 
that maraviroc is effective at restricting leukocyte trafficking to target tissues [18].  By comparing alloimmune profile in 
participants enrolled in the standard of care and maraviroc arms of this trial, the study will be able to determine the 
impact of maraviroc on alloimmune responses in humans with direct clinical relevance. 
10.3.2 Assays 
U10.3.2a Cellular assays 
U10.3.2a1 Multiparameter flow cytometric analysis (MFC)U:  HIV+ patient not only progressively lose CD4+ T cells; most of 
the immune cell subsets in patients with chronic HIV infection are dysregulated.   These changes can be detected using 
MFC.  These studies will use 4 MFC panels listed in Table 1 to assess Ccr5 expression among leukocyte subsets, 
frequencies and numbers of various subsets of regulatory cells, memory T cells, and B cell subsets in the peripheral 
blood and LN.  The data will be analyzed in conjunction with CBC+differential collected in clinical labs at the same time 
point to calculate the total number of each cells subset. In addition to enumeration of immune cell subsets, we have 


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designed the MFC panels to simultaneously analyze chemokine receptor expression on various immune cells to 
determine the impact of maraviroc on their numbers and level of chemokine receptor expression (Table 1) 
Table 1. MFC panels 
Panels 
Markers 
Rationale 
Leuk-
Ccr5 
CD3, 14, 16, 19, 45, 56, HLA-DR, Ccr5 
Enumerate T cells, B cells, subset of monocytes, dendritic cells, and 
subsets of NK cells and determine their Ccr5 expression 
T cell-
Ccr5 
CD3, 4, 8, 25, 127, 73, FOXP3, HELIOS, 
Ccr5 
Enumerate subsets of T cells and their expression of Ccr5  
Tmem 
CD3, 4, 8, 28, 45RA, 57, Ccr7, PD1 
Frequencies of naïve, memory, effector, exhausted T cells 
ChemR 
CD3, 4, 8, 25, 127, Ccr4, Ccr6, Cxcr3,  
Enumerate T cells that express various chemokine receptors found on 
Th1 (Cxcr3+), Th2 (Ccr4+), and Th17 (Ccr6+) cells 
B cell 
CD10, 19, 20, 21, 27, 95 
Frequencies of immature, transitional, naïve, activated, memory, and 
plasmablast B cells. 
 
The investigators from the  UCSF core Immunology lab (under the direction of Qizhi Tang, PhD)  have used the Tmem 
panel to determine the frequencies of naïve (CD45RA+CCR7+), memory (CD45RA-CCR7+), and effector (CD45RA-CCR7-) T 
cells [92] in pre-transplant samples collected from the participants in the HIVTR trial (Fig 5A). Our analysis demonstrates 
that end-stage renal disease is associated with increased effector CD4 T cells in both of HIV+ and HIV- age-matched 
patients and HIV+ rejectors and non-rejectors had similar frequencies of effector T cells (Fig. 5B).   
 
 
 
 
 
 
Fig 5 (A-B).  Flow cytometric analysis of memory and effector T cells.  (A) Frozen PBMCs are thawed and 
stained with the Tmem panel of fluorochrome-conjugated antibodies.  The cells are then analyzed on a BD 
Fortessa flow cytometer.  CCR7 and CD45RA expression patterns of CD3+CD8+ (blue) and CD3+CD4+ (red) 
from a representative HIV(+) and an age-matched HIV(-) sample are shown on top. (B) Summary data of results 
for CD4+ T cells using samples HIV- controls without end stage renal disease (non-ESRD), HIV- controls with 
ESRD, and HIV+ non-ESRD, and pretransplant samples from HIVTR rejectors and non-rejectors. 


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Our Leuk-Ccr5 panel demonstrates that Ccr5 is primarily expressed on subset of T cells, monocytes, and dendritic cells 
(Fig 6A).  Flow cytometric analyses can have significant experiment-to-experiment variations, therefore samples to be 
directly compared, such as those collected from the same patient before and after maraviroc treatment should be 
analyzed at the same time in one experiment. The core immunology investigator Qizhi Tang plans to do this by 
cryopreserving all PBMC samples and thawing and analyzing an entire time series from pre-transplant to 1 year after 
transplant in batch.  We have determined that Ccr5 expression pattern is not affected by cryopreservation (Fig 6B), 
making batch analysis of time series possible.  
These MFC assays will be performed on PBMC samples collected at all time points and LN samples collected pre-
transplant.  
U
 
Fig 6 (A-B). Flow cytometric analysis of Ccr5 expression on various leukocyte subsets.  (A) Example of Leuk-Ccr5 panel result 
obtained using PBMC collected from a normal donor.  The result shows expression of Ccr5 on a subset of T cells and dendritic cells and 
largely absence of expression on B cells, monocytes and NK cells.  (B) Cryopreservation does not affect the quantification of Ccr5 
expression on leukocyte subsets. 
 
U10.3.2a2  Alloreactive T cell frequency assay (ATF):U Transplants induce vigorous immune responses because of the 
exceptionally high frequencies of alloantigen-reactive T cells.  Transplant immunology research in the past decade 
revealed that allo-reactive Tregs capable of suppressing rejection are also present at high frequency and the overall 
immune response toward a transplanted organ depends on the balance between the rejection-prone conventional T 
(Tconv) cells and the tolerance-prone Tregs.  The ATF assay measures the frequency of donor-reactive Tconv and Tregs.  
This assay uses highly potent CD40L-stimulated B cells (sBc) from donors to induce proliferation of donor-reactive T cells 
from recipients.  Because of the high expression of HLA and costimulative CD80 and CD86 molecules, the sBcs can 
activate Tconv and Tregs.  An established CFSE dilution method is used to record the division history of the donor-
reactive T cells, which can be analyzed using flow cytometry (along with markers to identify CD4, CD8 and Tregs) and 
used to calculate the frequency of the reactive T cells (Fig 7A).   


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The UCSF Immunology lab has used this assay to determine pre-transplant donor-reactive T cell frequencies in HIV+ 
kidney transplant recipients.  Our preliminary analysis of 8 rejectors and 8 non-rejectors shows that the rejectors have 
significantly higher donor-reactive CD8 T cells before transplant and donor-reactive CD4 Tconv and Tregs were the same 
between the two groups (Fig 7B). 
 
 
 
 
This assay will be used to measure the frequencies of donor-reactive Tregs, Tconv CD4+ T cells and CD8P+
P T cells in 
recipient PBMC samples collected at all time points and LN samples collected pre-transplant.  
U10.3.2a3  Alloreactive memory T cell assay (AMT):U  Donor reactive memory T cells pose a major threat to transplanted 
grafts because they have a lower activation threshold and are resistant to immunosuppression.  We hypothesize that 
HIV+ transplant recipients have higher memory alloreactive T cells due to heterologous immunity generated through 
their anti-viral T cells.  A hallmark of memory T cells is their ability to produce effector cytokines shortly after antigen 
encounter.  The alloreactive effector T cell assay will measure frequencies of alloantigen stimulated cytokine production 
after a short stimulation with either a panel of allogeneic sBcs (panel-reactive effector T cell assay [93]) or donor sBcs 
(donor-reactive effector T cell assay).  Cytokine secretion will be blocked during stimulation to permit the detection of 
intracellular IFNg and IL-4 using flow cytometry.  The cells will also be stained for CD3, CD4, CD8, CD45RO, 
CD19/CD14/CD16 (dump), and viability.  As a positive control, each sample will also be stimulated with PMA and 
ionomycin to determine the cytokine production potential of the cells.  Negative control will be cells incubated alone 
without stimulants (Fig 8). 
Fig 7 (A-B) Alloreactive T cell frequency assay (ATF). (A) Recipient PBMCs are labeled with CFSE and 
stimulated with donor sBc for 64 hours.  The culture is harvested and stained for CD3, CD4, CD8, Foxp3 and 
Helios and analyzed on a flow cytometer.  The CFSE profiles of CD8, CD4+ Tconv, and Tregs are used to 
calculate the frequencies of donor-reactive T cells in each of the subset (numbers in purple).  (B) Comparison 
of Donor-reactive T cell frequencies using PBMC sample collected pretransplant from HIV+ kidney transplant 
recipients who had acute cellular rejection (R, n=8) or not (NR, n=8). 


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This assay will be used to measure the frequencies of panel- and donor-reactive IFNg-producing effector cells in 
recipient PBMC samples collected at all time points and LN samples collected pre-transplant. 
U10.3.2a4  Cross reactive T cell assay (CRT):U We have developed an approach to identify T cells with allo and viral dual 
reactivities (Fig 9).  Our approach takes advantage of the potent allostimulatory activity of the sBc.  We found that after 
one round of allogeneic sBc stimulation of PBMC and 10-day expansion in IL-2, virtually 100% of the T cells in culture are 
reactive to the sBcs (data not shown).  We then restimulated the alloreactive T cell lines with various pools of viral 
peptides.  Cells reactive to viral antigens were then identified using cell surface activation marker CD98 and dilution of a 
proliferation dye CTV.  Fig 9 shows an example of identification of T cells in an HIV+ patient that are cross-reactive 
between donor alloantigens and an HIV-Pol peptide pool.  Similarly we have also identified allo-reactive T cells that can 
recognize HIV-Gag, HIV-Nef, CMV, EBV, and Flu peptide antigens.   
 
 
Fig 8.  Alloreactive memory T cell assay.  Frozen PBMCs are thawed and incubated with allogeneic sBcs 
(right), PMA and ionomycine (left, positive control), or no stimulants (middle, negative control) in the presence 
of brefeldin A.  The cells are then stained for CD3, CD4, CD8, CD45RA, CCR7, and IFNg before flow cytometric 
analysis.  Result from a healthy blood bank donor is shown.  Red numbers indicate percentages of the cells in 
the quadrant.  


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We will use this assay to measure the frequencies of cross reactive T cells in recipient PBMC and LN samples collected 
before transplant and at various time points after transplant.  
U10.3.2b Serum HLA antibodies (HLA) 
U10.3.2b1 HLA antibodies:U  Prior alloantigen exposure can lead to the formation of alloreactive memory T cells and B cells 
and presence of anti-HLA antibodies in the serum that can contribute to graft injury. In addition, lymphopenia in HIV-
infected patients has been shown to drive homeostatic proliferation of B cells and increase the frequencies of 
transitional B cells that produce cross-reactive antibodies.  We will determine if B cell dysregulation in HIV+ patients also 
leads to increased alloantibodies before and after transplant.  We will measure antibodies to class I and class II HLA 
using Luminex single antigen coated beads (LABScreen; One Lambda, Inc., Canoga Park, CA). Donor specificity of HLA 
alloantibodies will be determined by comparing the specificities with the HLA typing of the donor. 
In addition of anti-HLA antibodies, B cell dysregulation can also lead to increase of antibodies to other specificities.  
Particularly, non-HLA antibodies have been shown to mediate chronic graft injuries [94].  We will bank extra serum 
aliquots for future exploratory analysis of non-HLA antibodies. 
 
 
Fig 9.  T cell cross-reactivity assay.  (A) experiment protocol. Frozen PBMCs are thawed and expanded with anti-CD3
and CD86-expressing feeder cells (polyclonal line) or allogeneic sBcs (donor-reactive line) for 10 days.  The cells are then
labeled with cell tracker violate (CTV) and restimulated with a pooled overlapping library of peptides from HIV Pol protein.
Expression of CD98 and dilution of CTV on day 3 post restimulation were determined using flow cytometry. (B) A
representative experiment using sample from an HIVTR rejector.  Black box highlights cells that are activated by the
restimulation. The presence of HIV pol peptide activated cells in the donor-reactive line indicates cross-reactivity. 


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U10.3.2c  Histological analysis of biopsy samples using multiplex immunofluorescence (mIF) and in situ hybridization (ISH) 
Standard histopathology will be used to determine tissue integrity and the degree of inflammation. 
Quantitative mIF stains will be performed on formalin fixed paraffin-embedded tissue to detect collagen 3, leukocyte 
common antigen (LCA), and various inflammatory cell subpopulations including CD68+ macrophages, the CD4, CD8, 
CD20, NK, CXCL9/CXCL10/CCL5, PD1, PD1L1, PD1L2, FoxP3, Th17, and T-bet+ subsets of lymphocytes (Fig 10). C4d 
deposition will also be analyzed to detect antibody-mediated rejection. Quantitative image analysis will be used to 
calculate the inflammatory cell density per sq. mm for each subset and the proportion of the collagen 3+ interstitial 
compartment in the non-glomerular renal cortex. In situ hybridization (ISH) using a novel signal amplification and  
 
 
 
 
 
Fig 10. Quantitative measurement of the inflammatory cell load in the cortex by 
computer-assisted image analysis on IF stained sections. The pictures show two
consecutive biopsies from the same patient, both stained with collagen 3 (red) and leukocyte
common antigen (LCA, green).  This example shows 37.2% reduction of the inflammatory
cell load (LCA+ cells) in the 2nd biopsy 


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background suppression protocol patented by Advanced Cell Diagnostics (Hayward, CA) allows the visualization of single 
mRNA molecules per cell.  For markers that no reliable IHC protocol exists, such as IL-10, ISH can be a good alternative to 
visualize local IL-10 production and is also the preferred methodology to detect IL-6, IL-17 and GATA3. The ISH will be 
quantitated by computer assisted image analysis (Tissue Studio, Definiens) and combined with multiple IF stains 
(cytokeratin for the tubules, CD31 for endothelial cells, leukocyte common antigen for lymphocytes, CD68 for 
macrophages) for precise signal localization within various compartments of the kidney.   
Whole genome gene expression profiling: RNA deep sequencing (RNA-Seq) will be utilized as our primary method for 
defining the mechanism of graft rejection in HIV+ patients and the impact of maraviroc on the rejection mechanism. 
Transcript sequences are mapped back to a reference genome and transcriptome. Reads that map back to the reference 
are quantified to assess the level of gene expression, with the number of mapped reads being the measure of expression 
level for that gene or genomic region. Because RNA-Seq provides direct access to the sequence, it has several technical 
advantages over microarray:  Junctions between exons can be assayed without prior knowledge of the gene structure, 
RNA editing events can be detected, and knowledge of polymorphisms can provide direct measurements of allele-
specific expression. RNA-Seq can detect expressed regions of the genome that correspond to yet to be annotated genes. 
RNA-Seq can quantify transcript isoforms that result from alternative splicing, making possible the study of transcript 
isoform diversity and abundance.  
Identification of gene transcripts will be carried out by deep sequencing of the cDNA libraries reverse transcribed from 
poly(A)-tailed RNA isolated from graft biopsies.  We will use the Illumina GAIIx (Illumina Inc., San Diego, CA) platform for 
this analysis. We will use approximately 5 ug of total RNA per library preparation. We will amplify the poly(A)-tailed RNA 
isolated prior to library preparation by Ambion’s MessageAmp II aRNA Amplification Kit (Austin, TX). For each sample, 
100 ng of amplified polyA+ RNA will be used, fragmented, converted to double stranded cDNA and subjected to RNA-
Seq. We plan to barcode and sequence 5 samples in one lane on our Illumina HiSeq 2000 machine. This currently 
produces about 30M reads per sample. Since ~60% yield unique reads, we will obtain 18M mapped reads per sample. 
This is adequate for accurate monitoring of gene expression for most genes. Prior work with embryonic stem cells 
suggests that we can obtain information on approximately 80% of detectable genes with this depth. These figures are 
consistent with the results of others. Moreover, we will generate 76b paired-end reads to monitor splicing isoforms, 
though we may only cover approximately ~40% of the known variants at this depth. The results obtained from both 
arms of the patients in this trial will be compared to each other and will be compared with historical RNAsep data on 
HIV- rejection biopsies published by others and that in the Sarwal lab. 
10.3.3 Alloimmune assay data analysis plan 
Endpoints: Mechanistic endpoints will be analyzed using assays described above.  Specific measurements, both 
categorical and quantitative, to be collected from the assays are as described in Table 2. Other planned assays are for 
exploratory assessment and any statistically significant results from these tests will be reported as requiring 
independent verification and will provide a basis for further studies.   
Table 2 Endpoints measured by the assays 
Assays 
Endpoints 
MFC/Leuk-CCR5, 
T cell-Ccr5 
MFI of CCR5 on subsets of T cells, B cells, subsets of monocytes, dendritic cells, and subsets of NK 
cells 
MFC/leuk-CCR5, 
T cell-Ccr5 
Percentages and absolute numbers of subsets of  T cells, B cells, monocytes, and NK cells in circulation 
MFC/Tmem 
Percentages and absolute numbers of T cell subsets including naïve, memory, effector and exhausted 
CD4, and CD8 


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MFC/B cells 
Percentages and absolute numbers of B cell subsets including transitional, naïve, memory, and 
terminally differentiated B cells 
ATF 
Frequencies of donor-reactive CD4, CD8, and regulatory T cells at baseline and various time points 
after transplant. 
AMT (donor) 
Frequencies of donor antigen stimulated IFNg-producing CD4 and CD8 T cells at baseline and various 
times after transplant. 
AMT (PMA+I) 
Frequencies of mitogen-stimulated Th1 (IFNg-producing), Th2 (IL-4-rpoducing), and Th17 (IL17-
producing) CD4 and CD8 T cells at baseline and various time points after transplant. 
CRT 
Frequencies of T cells with cross-reactivity between donor alloantigens and HIV, CMV, and EBV 
antigens at baseline and at various time points after transplant 
HLA  
Anti-HLA antibodies, including donor-specific antibodies, in serum at baseline and various times after 
transplant; DSA MFI 
mIF/ISH 
Histological analysis for evidence of cellular and antibody mediated rejection mechanisms 
RNA-seq 
Gene expression profiling  
 
UTreatment groups and comparators:  
To define immunological parameters associated with rejection, participants will be further divided into 4 groups: HIV+ 
standard immunosuppression rejectors and non-rejectors, HIV+ maraviroc rejectors and non-rejectors.  Results obtained 
using pre-transplant samples will be compared across all four groups.  Results obtained from samples collected at the 
time of rejection (blood and graft) will be compared among HIV+ rejectors on standard immunosuppression and HIV+ 
rejectors on maraviroc to determine if rejections in the two groups have distinct or similar profiles. 
To determine the impact of maraviroc on immunological profiles, comparisons will be made between HIV+ patients 
receiving standard immunosuppression and those on maraviroc-containing regimen.  
UData integrity checks:U The first step of data analysis will be to perform data integrity checks, including checks for 
unrealistic outliers in assay measurements and missing data. Data that are not within a plausible clinical range will be 
individually checked for potential causes e.g., data entry errors; if no plausible explanation is found, they will be treated 
as missing data. 
UDescriptive analyses:U Descriptive analyses will be used to summarize participant characteristics of our study populations 
across treatment groups. Dichotomous variables will be summarized as proportions with 95% confidence intervals. 
Continuous variables will be summarized using means, standard deviations, and 95% confidence intervals if they are 
symmetric and unimodal. Otherwise, they will be summarized using the median and the interquartile range. Simple t-, 
ANOVA, chi-squared, or Fisher’s exact test, as appropriate, will be used to compare quantitative measures across 
treatment groups.  
UStatistical modeling:U Statistical analysis will be performed primarily via ANOVA, chi-squared, or Fisher’s exact test, as 
appropriate, and when warranted (in the case of repeated measurements on the same participants), using the linear 
mixed-effect model. In the case of mixed effects model, the random-effects we consider are the intercept term for the 
2-timepoint analyses and intercept plus slopes modeled for 3-timepoints. Fixed effects will include intercept, slope, 
treatment group and treatment group by time interactions. We will also consider the need for heterogeneous residual 
variance magnitude between groups (as has been observed in some of our assays). A major strength of this linear mixed-
effects modeling approach is the ability to model all of the data available for a person, regardless of length of follow-up, 
number and spacing of evaluations, and/or missing outcome data at some time points (assuming non-informative 
missingness). An additional important advantage is the enhanced power obtained by using reliable measures of the 
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UStatistical testing for hypotheses:U In the case of linear mixed effects models, hypothesis testing will use the linear mixed-
effect model to determine whether the inclusion of a treatment group variable and its interaction with time significantly 
improves the model fit for the assay response variables (conditional t-tests within linear mixed effects model fits). 
Primary focus will be on detection of a statistically significant time by treatment group interaction. We will also examine 
any effects in terms of restricted maximum likelihood point estimates and 95% confidence intervals. As far as the 
primary hypotheses are concerned, we will use a nominal significance threshold of α = 0.05. However, we will make 
adjustments for multiple comparisons when multiple pairwise assessments need to be conducted among groups. 
UAssessing normal assumption:U Many of the statistical procedures we will use, including the linear mixed-effects model, 
assume that responses follow a normal distribution. We will use standard diagnostic methods such as quantile-quantile 
plots and direct tests of normality to examine the appropriateness of this assumption.  If we detect severe departures 
from normal distributions, we will either transform the outcome to produce better approximations to normal 
distributions or apply non-linear mixed-effects modeling approaches. 
UOutliers:U We will examine plots of data and residuals from fitted models to detect potential outlying and influential 
points. If we detect such points, we will flag and check them with the sites for accuracy. If any outliers are not in error, 
then we will assess the effect of these points on the analysis by rerunning the analysis without the points. If the two sets 
of analyses differ substantially, we will report the results separately. 
UMissing data:U Every attempt will be made to determine the reason for any missing data, in particular for missing 
observations caused by loss to follow up. Individuals with missing data on key variables will be compared to those with 
complete data to assess for potential bias due to non-random missing data. If a participant’s observation is deemed 
missing at random (i.e. missing follow-up for reasons unrelated to the outcome) then we can continue to apply models 
“as is” with the missing observation simply left out of the analysis. When missing outcome data is deemed informative 
(i.e. not missing at random), we will perform sensitivity analyses. The sensitivity analysis will examine multiple 
approaches to imputing the missing data (e.g. simple carry last one forward, or advanced methods such as Expectation 
Maximization), as well as outcomes corresponding to different extreme case scenarios for the missing data mechanism.  
10.4 
Pharmacokinetic Analysis  
10.4.1 Pharmacokinetic studies 
 
PK studies will be performed on the first 20 participants enrolled at UCSF at month 3 post-transplant, and will be 
repeated on all UCSF participants in the unlikely event that the calcineurin inhibitor used for maintenance 
immunosuppression is changed to cyclosporine (which is allowed only for tacrolimus toxicity).  In the previous HIV-
transplant studies, drug regimens have been modified in response to drug side effects, low drug levels, or rejection 
episodes.   
 
Participants will be admitted to the UCSF Clinical Research Center for the pharmacokinetic studies.  According to 
previously published protocols, participants are admitted after an overnight fast, and after drawing trough blood 
samples, participants take their morning cART, maraviroc or placebo and CNI. [70] Blood samples are drawn at 0, 0.5, 1, 
2, 3, 4, 6, 8 and 12 hours.  No food is allowed for the first three hours after the study was started, and all participants eat 
a 30% fat meal at the same times relative to taking their medication.  Medications known to be strong CYP3A and P-
glycoprotein inhibitors (e.g., ketoconazole or fluconazole) are not given until after the pharmacokinetic study had been 
completed.  In general, PK studies are initiated 12 hours after the prior doses of potential concomitant ARV 
inhibitors/inducers and other prescribed medications. 
 
 


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10.4.2 Analysis of blood samples   
 
Blood samples are frozen at –80°C until analyzed.   
 
Whole blood samples are analyzed for tacrolimus (or cyclosporine or sirolimus) by a validated HPLC/MS assay in 
combination with automated online sample preparation (LC/LC-MS) (Hewlett-Packard; Palo Alto, CA).  Method 
validation has been described in detail by Christians et al.[95]  
 
We have developed an updated methodology for analysis of maraviroc.  API4000 LC/MS/MS trace from injection of 20 
pmol maraviroc.  The method is sensitive down to injections of 1 pmol.  Toronto Research Chemicals offers d6-
maraviroc, the ideal internal standard, at 175/mg. The MS method uses the MS/MS transition m/z 514.3 → 390.1.  The 
Sciex API4000 instrumental parameters (in positive ion electrospray mode) are: declustering potential = 56 V, collision 
energy = 29 V, collision cell exit potential = 22 V, entrance potential = 10.5 V, collision gas = 12, curtain gas = 16, ion 
source gas1 = 30, ion source gas2 = 40, ionspray voltage = 5500 V, temperature = 500 C.   
 
The LC method is carried out with a Shimadzu Prominence LC system including a pair of LC20-AD pumps, a SIL-20AC HT 
autosampler and a CBM-20A controller. It uses a Phenomenex Kinetex C18 50 x 4.6 mm (5 µm, 100 Å) column and the 
following gradient at a flow rate of 0.5 ml/min: 0-1 min, 10% B; 1-4 min, linear ramp to 100% B; 4-6 min, 100% B; 6-6.5 
min, linear ramp to 10% B; 6.5-10 min, 10% B, where A = 15% methanol:water, B = 100% methanol, and both A and B 
contain 0.1% formic acid, 0.1% acetonitrile and 160 mg/L ammonium acetate.  A similar method has been published by a 
group from Tandem Laboratories and Pfizer. [96] 
 
10.4.3 Pharmacokinetic analysis   
Individual whole blood concentration-time data are used for pharmacokinetic parameter estimation using 
noncompartmental methods (WinNonlin software, Professional Edition, version 5.0; Pharsight, Mountain View, CA).  
Pre-dose sample times of less than time zero are assigned values of zero.  Samples below the limit of quantitation of 
bioanalytical assays that occurred before the first quantifiable concentration was achieved are assigned a concentration 
of zero to prevent overestimation of initial area under the curve (AUC). Values below the limit of quantitation at all 
other time points are treated as missing data.  Maximum concentration (CRRmax
RR)RR 
RRand time at maximum concentration 
(TRRmax
RR) are taken as the observed values.  
 
AUCs are calculated over the dosing interval using the linear-log trapezoidal method and adjusted for both drug dose 
and patient weight.  Dividing these values into the dose yielded measures of weight adjusted apparent oral clearance 
(CL/F).  Terminal half-lives during the dosing interval [representing the multiple dosing operational half-life, are used to 
calculate the apparent oral volume of distribution: V/F = (CL/F) x (tRR1/2,op
RR/0.693)].[97] 
 
10.5 
APOL1  
Donor samples will be collected and stored to determine APOL1 polymorphisms retrospectively.  
 


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11 Biospecimen Storage 
 
Biological specimens from this study will be sent to the central repository, Precision Bioservices, where they will sent in 
batch to the core mechanistic labs for analysis. Details can be found in the Laboratory Manual. 
Biological specimens obtained under this protocol may be used in future assays to reevaluate biological responses as 
additional research tests are developed over time. These specimens will be collected at time points already scheduled 
for the core mechanistic studies, in order to allow specimens to be stored for use in new assays that have yet to be 
optimized or conceived.  Appropriate informed consent will be obtained for both the collection and storing of samples.  
The specimens from these evaluations may be stored beyond the funding period. During the funding period, samples 
will be identifiable, which means samples will be coded with a participant ID number that could be directly linked to the 
participant and the participant’s medical record.  
Study participants will be informed that they may be approached about additional clinical evaluations or studies that 
have received the full approval of the NIAID as new evaluations are identified.  If additional evaluations are determined 
to be desirable, this protocol (and other appropriate study documents, e.g., the informed consent and the statistical 
analysis plan) will be amended and submitted to the appropriate regulatory authorities, ethics committees, and IRBs for 
approval.  Each participant’s signature will be obtained on the revised informed consent form before additional 
evaluations are performed.  The specimens from these evaluations may be stored up to the end of the contract— 
approximately 5 years, or longer if the contract is extended. 
 


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12 Criteria for Participant and Study Completion and Premature Study Termination 
12.1 
Participant Completion 
Participants will have completed the study at the week 156 (year 3) study visit, or once the study has been closed. All 
participants will be followed for at least 52 weeks (1 year) post-transplant depending on enrollment date (4 years of 
accrual). 
12.2 
Participant Stopping Rules and Withdrawal Criteria 
Participants may be prematurely terminated from the study for the following reasons: 
12.2.1 Treatment discontinuation 
1. Participant meets criteria to discontinue study treatment (MVC or placebo) 
2. The investigator no longer believes continuing study treatment is in the best interest of the participant. 
3. Participant refuses to continue study treatment. 
4. Treatment is held or discontinued for clinical reasons for greater than 60 days. 
12.2.2 Study discontinuation 
1. The participant elects to withdraw consent from all future study activities, including follow-up. 
2. The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish 
contact with the participant have failed).  
3. For those on the waiting list, confirmed or predicted failure to receive transplant by the end of year 4 
4. Study closed by sponsor or FDA 
5. Despite being randomized and receiving study treatment, participant did not receive a transplant as expected. 
12.3 
Participant Replacement 
 
Participants who withdraw or are withdrawn post-transplant will not be replaced. 
12.4 
Study Stopping Rules 
The study may be discontinued at any time by the EC/IRB, NIAID, the pharmaceutical supporter(s) or designee, the 
FDA, or other government entities as part of their duties to ensure that research participants are protected.  
12.4.1 Continuous Monitoring of Specific Events  
 
In addition, the incidence of specific safety-related events of particular concern will be continuously monitored 
throughout the study to determine if any of their observed subject-based incidence rates exceed a threshold incidence 
rate of concern pre-specified for each particular event.  
 
These events and their corresponding thresholds of concern are:  
 
1. During year 1 of follow-up, death due to any reason except accidental death above 10%.  
2. During year 1 of follow-up, graft loss due to any reason except accidental death above 16%.  
3. During year 1 of follow-up, site-reported treated acute rejection above 35% 
 


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These rules will be implemented by the Emmes data center continuously monitoring the occurrence of any of these 
events to determine if the currently observed rate of each exceeds the corresponding threshold rate of concern with a 
pre-specified level of confidence. The stopping rule will be considered to be met if the lower one-sided 95% exact 
confidence limit on the observed incidence rate exceeds the corresponding threshold level of concern for that event. If 
any stopping rule is met, enrollment and randomization will be halted pending expedited DSMB review.  
 
The following two tables describe the threshold numbers of events (n) out of selected numbers of subjects randomized 
to each treatment arm (N) which, if equaled or exceeded, would satisfy the stopping rule for each event of particular 
concern.  
 
Table 3: Thresholds for Meeting the Stopping Rule for Death in the First Year of Follow-up 
 
Number of Subjects 
with Event (n)  
Number of Subjects 
Randomized (N)  
Observed Incidence 
Rate (%)  
Lower 95% 
Confidence Limit 
(%)  
4  
10  
40.0  
15.0  
5  
20  
25.0  
10.4  
7 
30  
23.3  
11.5  
8  
40  
20.0  
10.4 
10 
50  
20.0  
11.3  
11 
60  
18.3  
10.6  
12 
70  
17.1 
10.2  
14  
80  
17.5 
10.9  
15 
90  
16.7  
10.6  
16 
100  
16.0  
10.3  
17 
110  
15.5  
10.1 
19  
120  
15.8  
10.6  
20 
130  
15.4  
10.4 
 
Table 4: Thresholds for Meeting the Stopping Rule for Graft Loss in the First Year of Follow-up 
 
Number of Subjects 
with Event (n)  
Number of Subjects 
Randomized (N)  
Observed Incidence 
Rate (%)  
Lower 95% 
Confidence Limit 
(%)  
5  
10  
50.0  
22.2  
7 
20  
35.0  
17.7  
9 
30  
30.0  
16.6  
11  
40  
27.5  
16.3 
13 
50  
26.0  
16.1  
15 
60  
25.0  
16.1  
17 
70  
24.3 
16.1 
19  
80  
23.8 
16.1 
21 
90  
23.3  
16.2  
23 
100  
23.0  
16.3  
25 
110  
22.7  
16.3 
27 
120  
22.5  
16.4 
29 
130  
22.3  
16.4 
 


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Table 5: Thresholds for Meeting the Stopping Rule for Treated Acute Rejection 
 
Number of Subjects 
with Event (n)  
Number of Subjects 
Randomized (N)  
Observed Incidence 
Rate (%)  
Lower 95% 
Confidence Limit 
(%)  
7  
10  
70.0  
39.3  
12 
20  
60.0  
39.4  
16 
30  
53.3  
37.0  
20  
40  
50.0  
36.1 
24 
50  
48.0  
35.7  
28 
60  
46.7  
35.6  
32 
70  
45.7 
35.5 
37  
80  
46.3 
36.7 
40 
90  
44.4  
35.6  
44 
100  
44.0  
35.6  
48 
110  
43.6  
35.6 
52 
120  
43.3  
35.7 
55 
130  
42.3  
35.0 
 


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13 Safety Monitoring and Reporting  
13.1 
Overview 
 
This section defines the types of safety data that will be collected under this protocol and outlines the procedures for 
appropriately collecting, grading, recording, and reporting those data. All grade 3 adverse events or higher will be 
reported in the EMMES IDES database. Adverse Event reporting is only required post-transplant.  In addition, adverse 
events that are classified as serious according to the definition of health authorities must be reported promptly (per 
section 13.5 Expedited Adverse Event Reporting to DAIDS) to the sponsor following Version 2.0 of the DAIDS EAE manual 
which is available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-
adverse-events-daids.  
Severity of AEs will be graded according to the “Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events” (Corrected Version 2.1, July, 2017). 
 
Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical Practice, 21CFR Parts 312 and 320. 
13.2 
Definitions 
13.2.1 Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the participant’s participation in the research, 
whether or not considered related to the participant’s participation in the research (modified from the definition of 
adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice) (from 
OHRP “Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse 
Events (1/15/07)” 39TUhttp://www.hhs.gov/ohrp/sites/default/files/ohrp/policy/advevntguid.pdf.  
For this study, an adverse event will include any untoward or unfavorable medical occurrence associated with, but not 
limited to:   
• 
Worsening (change in nature, severity, or frequency) of conditions present at the onset of the study 
• 
Intercurrent illnesses 
• 
Drug reactions or interactions of antiretroviral agents, immunosuppressant agents, or other concomitant 
medications used on study 
• 
Infections 
• 
Events related or possible related to maraviroc or concomitant medications 
• 
Abnormal laboratory values (significant shifts from baseline within the range of normal that the investigator 
considers to be clinically important) 
• 
Clinically significant abnormalities in physical examination, vital signs, weight, and/or tests and procedures 
• 
Surgical complications of kidney transplantation 
13.2.2 Unexpected Adverse Event  
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the Investigator Brochure  
or is not listed at the specificity, severity or rate of occurrence that has been observed. 


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“Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in the Investigator 
Brochure or package insert as occurring with a class of drugs or as anticipated from the pharmacological properties of 
the drug, but are not specifically mentioned as occurring with the particular drug under investigation (21 CFR 312.32(a)] 
13.2.3 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or 
Sponsor [DAIDS], it results in any of the following outcomes (21 CFR 312.32(a)): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the investigator or 
Sponsor, its occurrence places the participant at immediate risk of death. It does not include an AE or SAR that, had 
it occurred in a more severe form, might have caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions. 
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol mandated procedures are not to 
be reported as an SAE unless hospitalization is prolonged due to complications. 
13.3 
Grading and Attribution of Adverse Events 
13.3.1 Grading Criteria 
Severity of AEs will be graded according to the “Division Of AIDS Table For Grading The Severity Of Adult And Pediatric 
Adverse Events” (Corrected Version 2.1, July 2017). 
 
Adverse Events not found in the Toxicity Table will be assessed for severity and classified into one of the categories 
below: 
Grade 1 (Mild): Event requires minimal or no treatment and do not interfere with the participant’s daily 
activities. 
Grade 2 (Moderate): Event results in a low level of inconvenience or concern with the therapeutic measures.  
Moderate events may cause some interference with functioning. 
Grade 3 (Severe): Event interrupts a subject’s usual daily activity or functioning and may require systemic drug 
therapy or other treatment.  Severe events are usually incapacitating. 
Grade 4 (Potentially Life threatening):  Events causing inability to perform basic self-care functions OR Medical 
or operative intervention indicated to prevent permanent impairment, persistent disability, or death. 
Grade 5 (Death) 
13.3.2 Causality Assessment 
Causality (likelihood that the event is related to the study agent) will be assessed from the time study dosing 
begins until 30 days following the last dose considering the factors listed under the following categories:  
 


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Definitely Related  
• 
reasonable temporal relationship 
• 
follows a known response pattern 
• 
clear evidence to suggest a causal relationship 
• 
there is no alternative etiology 
 
Probably Related 
 
• 
reasonable temporal relationship 
• 
follows a suspected response pattern (based on similar agents) 
• 
no evidence of a more likely alternative etiology 
 
Possibly Related 
 
• 
reasonable temporal relationship 
• 
little evidence for a more likely alternative etiology 
 
Unlikely Related 
 
• 
does not have a reasonable temporal relationship  
OR 
• 
good evidence for a more likely alternative etiology 
 
Not Related 
 
• 
does not have a temporal relationship 
         
OR 
• 
definitely due to an alternative etiology 
 
Note:  Other factors (e.g., dechallenge, rechallenge) should also be considered for each causality category 
when appropriate. Causality assessment is based on available information at the time of the assessment of 
the AE. The Investigator may revise the causality assessment as additional information becomes available. 
13.4 
Collection and Recording of Adverse Events 
13.4.1 Collection Period 
Adverse events will be collected from the time of transplant until a participant completes study participation or until 30 
days after he/she prematurely withdraws (without withdrawing consent) or is withdrawn from the study. 
13.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
• 
Observing the participant. 
• 
Interviewing the participant [e.g., using a checklist, structured questioning, diary, etc.]  . 
• 
Receiving an unsolicited complaint from the participant. 
• 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate an adverse event, 
as defined in section 13.3 Grading and Attribution of Adverse Events. 
13.4.3 Recording Adverse Events and Serious Adverse Events 
Throughout the study, the investigator will record all adverse events and serious adverse events as described previously 
(13.2 Definitions) on the appropriate electronic case report form in the EMMES IDES regardless of the relationship to 
study therapy regimen or study procedure. 


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Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until the end of study 
participation, or until 30 days after the participant prematurely withdraws (without withdrawing consent)/or is 
withdrawn from the study, whichever occurs first. 
13.4.4 Adverse Events and Serious Adverse Events Exempt from Reporting 
• 
Elevated creatinine in the first week post-transplant if they are within expected ranges. 
• 
Decline in CD4+ T-cell counts during the first year following thymoglobulin treatment for rejection. 
• 
Elective hospitalizations or hospital admissions for the purpose of conduct of protocol mandated procedures 
are not to be reported as an SAE unless hospitalization is prolonged due to complications. 
13.4.5 Special Adverse Events requiring reporting 
Only grade 3 or higher adverse events must be recorded in the EMMES IDES. However, all cases of the following should 
be recorded in the EMMES IDES, regardless of grade: 
• 
Postural hypotension 
• 
Allergic reaction 
• 
Rash 
• 
HIV persistent virologic failure defined as an HIV viral load >1000 copies/mL for more than 90 days that is 
not the result of an investigator/physician approved interruption in antiretroviral treatment. 
13.4.6 Reporting of Adverse Events to IRBs/IECs 
All investigators shall report adverse events, including expedited reports, in a timely fashion to their 
respective IRBs/IECs in accordance with applicable regulations and guidelines. All Safety Reports to the FDA 
shall be distributed by the sponsor or designee to all participating institutions for site IRB/IEC submission. 
13.5 
Expedited Adverse Event Reporting to DAIDS 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are outlined in Version 2.0 of 
the DAIDS EAE Manual, which is available on the RSC website at 39Thttps://rsc.niaid.nih.gov/clinical-research-sites/manual-
expedited-reporting-adverse-events-daids39T. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting system, must be used for 
expedited AE reporting to DAIDS. In the event of system outages or technical difficulties, expedited AEs may be 
submitted using the DAIDS EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. 
For questions about DAERS, please contact NIAID CRMS Support at CRMSSupport@niaid.nih.gov. Please note that site 
queries may also be sent from within the DAERS application itself. 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at DAIDSRSCSafetyOffice@tech-
res.com.  
 
For questions about expedited reporting, please contact DAIDS RSC (39TUDAIDSRSCSafetyOffice@tech-res.comU39T). 
13.5.1 Expedited Reporting Requirements for this Study 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are: maraviroc (MVC) and placebo.   
 
13.5.2 Expedited AE Reporting Period 


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• 
The expedited AE reporting period for this study is per Version 2.0 of the EAE Manual. 
 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as defined in Version 2.0 of the 
EAE Manual will be reported to DAIDS if the study staff become aware of the events on a passive basis (from publicly 
available information). 
 
13.6 
Pregnancy Reporting 
All pregnancies during study enrollment should be reported in the EMMES IDES.  
All pregnancies should also be registered in “The Antiretroviral Pregnancy Registry” by a health care provider from the 
enrolling center (http://www.apregistry.com/).   
All pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and medically indicated 
abortion will be reported to the sponsor thru DAERS as outlined in Version 2.0 of the DAIDS EAE Manual.   
 
13.7 
Reporting of Other Safety Information 
An investigator shall promptly notify the site IRB as well as the Sponsor when an “unanticipated problem involving risks 
to participants or others” is identified, which is not otherwise reportable as an adverse event. 


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14 DSMB Review 
The DSMB will be chartered to perform independent oversight for the trial through regular review of enrollment and 
safety information provided in tables, listing and figures generated from the clinical database.  
14.1 
Planned DSMB Reviews  
The Data and Safety Monitoring Board (DSMB) shall review safety data at least yearly during planned DSMB Data Review 
Meetings. Data for the planned safety reviews will include, at a minimum, a listing of all reported AEs and SAEs.   
14.2 
Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews and planned safety monitoring, the DSMB may be called upon for ad hoc 
reviews. The DSMB will  review any event that potentially impacts safety at the request of the protocol chair or 
DAIDS/DAIT/NIAID. In addition, the following events will trigger an ad hoc comprehensive DSMB Safety Review:  
• 
Any death in the study which is considered possibly, probably or definitely related to study treatment 
regimen. 
• 
Non-skin cancer including post-transplant lymphoproliferative disease (PTLD). 
After review of the data, the DSMB will make recommendations regarding study conduct and/or continuation. 
14.3 
Temporary Suspension of enrollment/drug dosing for ad hoc DSMB Safety Review  
A temporary halt in study enrollment or drug dosing at all participating clinical sites may be implemented pending 
expedited review of all pertinent data by the institutional review board (IRB), the National Institute of Allergy and 
Infectious Diseases (NIAID), and the NIAID Data Safety Monitoring Board (DSMB) if any unexpected fatal or life-
threatening AE related to the study treatment occurs and the study team and DAIT/DAIDS medical officers advise to do 
so. 
A temporary halt in enrollment/drug dosing will be implemented if an ad hoc DSMB safety review is required for any 
unexpected fatal or life-threatening AE related to the study treatment.   


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15 Clinical Site Monitoring 
Site monitors under contract to the National Institute of Allergy and Infectious Diseases (NIAID) will visit 
participating clinical research sites to review participants records, including consent forms, CRFs, medical records 
(e.g., physicians’ progress notes, nurses’ notes, individuals’ hospital charts), and laboratory records to ensure 
protection of study participants, compliance with the EC/IRB approved protocol/amendments, and accuracy and 
completeness of records. The monitors will inspect sites’ regulatory files to ensure that local regulatory 
requirements, in addition to U.S. Federal regulations, are being followed. They will also inspect sites’ pharmacies to 
review product storage and management. 
 


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16 Statistical Considerations and Analytical Plan 
16.1 
Overview  
 
 
This trial is a prospective, multi-center, double-blind phase II study of kidney transplantation in HIV+ individuals 
assessing the safety and efficacy of maraviroc (Arm 1) or placebo (Arm 2) given at transplant with an antiretroviral drug 
regimen that does not include protease inhibitors. Analysis of the primary endpoint will be based on outcomes 
measured at 52 weeks post-randomization, while analyses of most secondary outcomes will be done on measurements 
taken at months 3, 6, 9, years 1, 2 and/or 3 post-randomization. The primary clinical objective is to evaluate CCR5 
blockade as a strategy to improve long term kidney function following transplantation in the HIV positive recipient. In 
addition, this study has a large number of secondary clinical and mechanistic objectives. 
16.2 
Measures to Minimize Bias  
Donor type (deceased versus live) is an important confounding factor known to impact graft function, inflammation and 
survival outcomes post kidney transplantation, and recent approval regarding the use of HIV+ donors, although not 
observed in the South Africa experience, could yield differences in outcomes compared to use of HIV- donors. Outcome 
differences may also arise due to known and unknown center-specific differences. Hence, participants will be randomized 
in a blinded fashion to one of the two treatment arms in a 1:1 ratio within each center-by-donor type stratum using a 
web-based randomization system with donor type categories being HIV negative deceased, HIV negative live, and HIV 
positive deceased. The randomization schedule will not incorporate other stratification variables. The maraviroc and 
placebo pills will be identical in appearance to maintain the masking of study participants. The masking of study and lab 
investigators to individual participant assignments will be maintained until the end of the study to avoid any bias in 
treatment or assessment. During the study, unblinded data listings can be provided to DSMB members for any scheduled 
or ad hoc reviews of safety data.  To minimize bias, central read of biopsy slides by the core renal pathologist will be 
implemented for histological endpoint assessments.  
 
For the primary and secondary endpoints on graft function, missing data can be of concern and a source of bias in the case 
of graft failures. Hence, we will consider graft failures as informed drop-outs in these analyses. Appropriate imputations 
will be implemented as explained for the primary endpoint below. For the secondary endpoints on graft function, similar 
imputations will be performed at the time of graft failure. 
16.3 
Endpoint Assessments  
16.3.1 Primary Analysis of Primary Efficacy Endpoint  
The primary efficacy endpoint is defined in section 3.2. The primary efficacy endpoint will be the 52-week GFR as 
measured by iohexol clearance. Mean GFR of maraviroc group (Arm 1) will be compared to the mean GFR of the placebo 
reference group (Arm 2) via a Wilcoxon rank-sum test. Informed drop-outs will consist only of graft failures prior to week 
52, and will be incorporated to the analysis by imputing the worst  GFR value observed at that time point in the study or 
a value of 10 ml/min/1.73mP2
P (10 being the average estimated GFR at the time of dialysis initiation in the U.S.), whichever 
is lower. Note that graft failure will be defined as the first observation of any of the following events: 1) death with a 
non-functioning graft, 2) retransplantation, or 3) initial return to chronic dialysis.  Results will be reported with p-value 
associated with the Wilcoxon rank-sum test and the estimated mean treatment difference with two-sided 95% 
confidence interval. All tests of significance will be two-tailed at the 0.05 level.  
16.3.2 Supportive Analyses of Primary Efficacy Endpoints  
We will conduct 2 sensitivity analyses for the primary efficacy endpoint: (1) include only the completers in the analysis 
(i.e., exclude all dropouts and treatment discontinuations prior to week 52); (2) impute the worst GFR value observed at 
that time point in the study or a value of 10 ml/min/1.73m2, whichever is lower, for deaths with graft function that occur 
prior to week 52. The sensitivity analyses will be included as additional secondary analyses.    


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16.3.3 Primary Safety Endpoint  
The primary safety endpoint will be the incidence of graft loss and toxicities ≥ Grade 3 and/or permanent treatment 
discontinuation within the first 52 weeks post-transplant. Cumulative incidence in maraviroc group (Arm 1) will be 
compared to the cumulative incidence in the placebo reference group (Arm 2) via a log-rank test.  Results will be 
reported with p-value associated with the log-rank test and the Kaplan-Meier estimates for each treatment group with 
two-sided 95% confidence intervals. All tests of significance will be two-tailed at the 0.05 level.  
16.3.4 Secondary Clinical Endpoints  
 
The secondary clinical endpoints are defined in section 3.3. The endpoints are to be computed and summarized by 
treatment and, in a few cases, by day/week and treatment. With the exception of specific AEs and lab parameters, 
proportions or means will be estimated for each treatment arm and tested for treatment differences through the use of 
a statistical model. The particular model to be used depends on the scale of measurement of the endpoint. The 
accompanying table lists each endpoint and its measurement scale (continuous, dichotomous, and ordinal). All tests of 
significance in all analyses will be made at the 0.05 level.  
 
Dichotomous measures of prevalence and incidence will be analyzed with log-binomial regression models, wherein 
treatment effects will be estimated as relative risk ratios; the reference group will be the Arm 2 participants. The log-
binomial model (rather than logistic regression) is applied for prevalence and incidence analyses because model-based 
estimates of relative risk (RR) are both more desirable and appropriate for non-Poisson events that are expected to 
occur more commonly than in 10% of the cases. In such cases, logistic regression-based odds ratio (OR) estimates are 
poor estimators of the relative risk [98-101]. It may be appropriate to treat some of the dichotomous outcomes as 
censored data; if this is the case, we will obtain RR estimates by fitting Cox regression models to the data [102].  
The single ordinal secondary outcome variable (Banff cell-mediated AR score) will be analyzed in a proportional odds 
model [103] which may include additional covariates and interaction terms, as appropriate.  
 
For continuous outcomes, we will test for differences in response means among the treatment arms by fitting normal 
theory analysis of variance (ANOVA) or analysis of covariance (ANCOVA) models to the original scores or to some 
normalizing-variance stabilizing transformation of them. For some endpoints, these models may be fit separately by day 
or week post-randomization (i.e., time will be treated as a by-variable and no repeated measures analysis will be 
performed). Repeated measures models will be fit to the slopes of eGFR vs. time regressions. The latter will be 
estimated in a mixed effects repeated measures model in which both treatment-group means (with 95% confidence 
limits) of the individual participant slopes and the individual participant slopes themselves will be estimated and tested 
for equality. Distributions of the individual slopes will be examined graphically and compared among the treatment 
groups. 
  
Table 6: Summary of Proposed Analyses for Primary and Secondary Clinical Response Variables 
Response type  
Response  
Measurement  
Scale  
Summary  
Statistics  
Models to test for 
treatment effects  
Primary Efficacy 
Endpoints 
Mean GFR at week 52 (based on  
iohexol clearance)   
continuous  
Mean and/or  
geometric mean + 95% CI, 
and median [IQR]   
Wilcoxon rank-
sum test 
Secondary/sensitivity 
analyses for primary 
efficacy endpoint 
Mean GFR at week 52, with dropouts 
removed  
continuous  
Mean and/or  
geometric mean + 95% CI, 
and median [IQR] 
Wilcoxon rank-
sum test 
 
Mean GFR at week 52, with a GFR 
imputation for deaths and graft 
failures 
continuous  
Mean and/or  
geometric mean + 95% CI, 
and median [IQR] 
Wilcoxon rank-
sum test 
Primary Safety 
Endpoint 
Cumulative incidence of graft loss, 
toxicities ≥ Grade 3 per the DAIDS 
toxicity table  and/or permanent 
treatment discontinuation 
continuous 
Kaplan Meier estimates by 
treatment group 
Logrank test for a 
treatment group 
difference 


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Inflammation 
Endpoints 
Mean CD45 gene expression count 
(PTPRC) at week 26 
continuous  
Mean and/or  
geometric mean + 95% CI, 
and median [IQR]   
Wilcoxon rank-
sum test 
 
Mean CD45 quantitative IHC at week 
26  
 
continuous 
Mean and/or  
geometric mean + 95% CI, 
and median [IQR]   
Wilcoxon rank-
sum test 
 
Mean tCRM score at week 26 
continuous 
Mean and/or  
geometric mean + 95% CI, 
and median [IQR]   
Wilcoxon rank-
sum test 
 
Mean uCRM score at weeks 26 and 
52 
continuous 
Mean and/or  
geometric mean + 95% CI, 
and median [IQR]   
Wilcoxon rank-
sum test 
Renal Function and 
Injury Endpoints  
Indicator of week 52 eGFR<60 
mL/min/1.7 m2 (based on CKD-EPI, 
cystatin C, and CKD-cystatin C 
equations)  
dichotomous  
Proportion  
+ 95% CI  
Log-binomial or 
Poisson regression  
 
Mean eGFR at week 52, 104 and 156  
based on CKD-EPI, cystatin C, and 
CKD-cystatin C Eqs.  
Continuous  
Mean and/or  
geometric mean + 95% CI  
Mixed Effects 
Repeated Measure 
ANCOVA  
 
Slope of eGFR vs. time Regression 
over week 13 – week 52, for each 
treatment arm, based on CKD-EPI, 
cystatin C, and CKD-cystatin C Eqs. 
Continuous  
Slope  
Mean and std. error or 
mean + 95% CI  
Mixed effects 
Repeated 
Measures ANCOVA  
Histologic Evidence 
of Rejection and 
Graft Dysfunction 
Endpoint 
Cumulative Incidence of biopsy 
proven Acute Rejection (AR) within 
the first 52, 104 and 156  weeks 
continuous  
 
Kaplan Meier estimates by 
treatment group  
 
Logrank test for a 
treatment group 
difference in 
cumulative 
incidence  
 
Severity of Rejection 
and Anti-Donor 
Reactivity Endpoints 
Banff score of the 1Pst
P observed AR 
within 52 weeks post-transplant  
 
Ordered 
categories (3 
levels)  
Proportion  
+ 95% CI  
  
Proportional Odds 
model  
 
Highest Banff score observed within 
52 weeks post-transplant  
Ordered 
categories (3 
levels)  
 
Proportion  
+ 95% CI  
Proportional Odds 
model  
 
 
Incidence of humoral rejection 
within the first 52 weeks and overall  
dichotomous  
 
Proportion  
+ 95% CI  
Log-binomial or 
Poisson regression  
 
Prevalence of  
anti-donor antibodies at week 52  
dichotomous  
 
Proportion  
+ 95% CI  
Log-binomial or 
Poisson regression  
Safety Profile 
Endpoints 
Death within the first 52 weeks and 
overall 
continuous 
Kaplan Meier estimates by 
treatment group  
Logrank test for a 
treatment group 
difference 
 
Graft loss within the first 52 weeks 
and overall 
continuous 
Kaplan Meier estimates by 
treatment group 
Logrank test for a 
treatment group 
difference 
 
Cumulative incidence of 
opportunistic infections or 
neoplasms within the first 52 weeks 
and overall 
continuous 
Kaplan Meier estimates by 
treatment group  
Logrank test for a 
treatment group 
difference in 
cumulative 
incidence  
 
Cumulative incidence of non-
opportunistic infections requiring 
continuous 
Kaplan Meier estimates by 
treatment group  
 
Logrank test for a 
treatment group 
difference in 


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hospitalization within the first 52 
weeks and overall 
cumulative 
incidence  
 
HIV persistence 
HIV msRNA 
continuous 
Mean estimate 
+ 95% CI 
Mixed Effects 
Repeated Measure 
ANCOVA 
 
HIV DNA 
continuous 
Mean estimate 
+ 95% CI 
Mixed Effects 
Repeated Measure 
ANCOVA 
16.3.5 Secondary Mechanistic Endpoints  
The primary mechanistic endpoints are defined in section 3.4.  The mechanistic assays and planned 
comparisons/analyses are detailed in Section 10. 
 
16.3.6 Descriptive Analyses 
Summary descriptive statistics for baseline and demographic characteristics will be provided for all enrolled participants. 
Demographic data will include age, race, sex, body mass index; these data will be presented in the following manner:  
 
• Continuous data (i.e., age, body mass index) will be summarized descriptively by mean, standard deviation, median, 
and range.  
• Categorical data (i.e., sex and race) will be presented as enumerations and percentages.   
 
The number and percentage of participants receiving immunosuppressive medications and certain concomitant 
medications or therapies of interest will be presented.  
 
16.3.7 Safety Analysis  
All adverse events (AEs) and serious adverse events (SAEs) will be classified by body system and preferred term 
according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs and SAEs will be summarized as the 
frequency of each event by treatment group.  
Frequency tables by treatment group and category of event (e.g., serious, related to study therapy, causing the 
discontinuation of study therapy) and by the DAIDS Toxicity Table  grade will be presented. Selected laboratory values 
will also be summarized by treatment group using the mean and standard deviation of the change from baseline at 
scheduled visits. 
16.4 
Interim Analyses 
No interim analyses are planned for this study. Unspecified interim analyses are only conducted if they will not adversely 
affect the integrity of the study or for safety reasons. The nature of the planned and ad hoc DSMB reviews is detailed in 
Section 14. 
16.5 
Sample Size Considerations 
Primary efficacy endpoints: The primary efficacy endpoint is mean glomerular filtration rate (GFR) calculated for each 
treatment group using iohexol clearance at 52 weeks. The expected mean±SD GFR level at week 52 post-transplant for 
the control group (Arm 2) was based on the data observed in HIV-TR and other post-transplant studies and assumed to 
be 60 ± 20 ml/min per 1.73 mP2
P.  Using the same SD for the maraviroc group (Arm 1) and group sample sizes of 65 with a 
8% drop-out rate at 1 year, we would achieve about 80% power to detect a difference of 10.6 ml/min per 1.73 mP2
P or 
more in mean GFR levels between the two groups (with a significance level of 0.05 using a two-sided Wilcoxon rank-sum 
test assuming that the actual distribution is normal). Average drop in GFR in patients on calcineurin inhibitors is 2ml/min 
per 1.73 mP2
P per year [104, 105]; hence, we have targeted detection of around a 10 ml/min per 1.73 mP2
P difference 


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between the two treatment groups that would be equivalent to about 5 years of difference in the life of the renal 
allograft. Note that drop-out rate is assumed to be 13%, but 5% is expected to be informed drop-outs that will be 
incorporated to the primary analyses. Hence, the adjusted drop-out rate used for this calculation is equivalent to 8%. 
 
Secondary endpoints: Based on expected rates of normal, borderline changes and acute cellular rejection in the HIV+ 
kidney transplant recipients at 26 weeks from previous studies, the expected mean ± SD CD45 gene expression count 
(PTPRC mRNA in log2 scale) for the control group (Arm 2) was assumed to be 7.9 ± 1.0.  Using the same SD for the 
maraviroc group (Arm 1) and group sample sizes of 30 (assuming enrollment of 60 HIV+ cases in the study with follow-up 
to week 26 or further), we would achieve about 80% power to detect a difference of 0.8 or more in mean CD45 gene 
expression count between the two groups (with a significance level of 0.05 using a two-sided Wilcoxon rank-sum test 
with normal actual distribution assumption). 
 
 
Another secondary endpoint of interest is the incidence of treated acute rejection at 52 weeks post-transplant.  We 
expect 1-year cumulative incidence of rejection for the placebo group to be around 0.30, based on the rate observed in 
the HIVTR study. By assuming a loss-to-follow-up rate of 0.13 and proportional hazard rates, a two-sided log rank test 
achieves at least 80% power at a 0.05 significance level to detect a reduction of 0.21 or more in the rejection rate in the 
maraviroc group. Sample size calculations were performed using PASS 2008 software. 
16.6 
Missing Data Conventions  
Except for the sensitivity analyses described for the primary endpoint in Section 16.3.2, no data imputation is planned. 
Analyses of all secondary clinical and mechanistic endpoints will be carried out on the observed, non-missing data. 
However, summary statistics will include counts of missing data, summarized by treatment arm. 


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17 Identification and Access to Source Data 
Each clinical research site is responsible for maintaining accurate clinical research records and documentation in 
compliance with DAIDS policies, ICH E6 GCP, and all other applicable regulatory and institutional requirements. 
Essential documents are clinical research records, source documents, or files that permit the evaluation of both the 
conduct of a clinical trial and the quality of the data produced. Source data are all information, original records and 
certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for 
the reconstruction and evaluation of the trial. All source documents and source data are considered essential 
documents.  
 
As part of participating in a NIAID (DAIDS)-supported and/or –sponsored clinical trial, the site investigators and site 
staff will permit authorized representatives of the sponsor(s), DAIDS, the FDA, the OHRP, and other local, US, and 
international regulatory entities, other state and local health authorities, and pharmaceutical or device companies 
and their commercial partners, and the local Institutional Review Board to examine (and when required by 
applicable law, to copy) clinical research records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety and progress.  
 


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18 Ethical Considerations and Compliance with Good Clinical Practice 
18.1 
Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance, and according to the criteria specified in this study protocol.  Before study 
initiation, the protocol and the informed consent documents will be reviewed and approved by the NIAID DSMB.  Any 
amendments to the protocol or to the consent materials will also be approved by the NIAID DSMB before they are 
implemented. 
18.2 
Informed Consent 
Prior to implementation of this protocol, and any subsequent full version amendments, each site must have the protocol 
and the protocol informed consent forms approved, as appropriate, by their local institutional review board (IRB)/ethics 
committee (EC) and any other applicable regulatory entity (RE). Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory 
Support Center (RSC).  The DAIDS PRO will review the submitted protocol registration packet to ensure that all of the 
required documents have been received.   
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the DAIDS PRO and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the site’s regulatory files. 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites should implement the 
amendment immediately.  Sites are required to submit an amendment registration packet to the DAIDS PRO at the RSC.  
The DAIDS PRO will review the submitted protocol registration packet to ensure that all the required documents have 
been received. Site-specific ICFs WILL NOT be reviewed and approved by the DAIDS PRO and sites will receive an 
Amendment Registration Notification when the DAIDS PRO receives a complete registration packet. A copy of the 
Amendment Registration Notification should be retained in the site’s regulatory files. 
For additional information on the protocol registration process and specific documents required for initial and 
amendment registrations, refer to the current version of the DAIDS Protocol Registration Manual. 
18.3 
Informed Consent Process 
The consent process will provide information about the study to a prospective participant and will allow adequate time 
for review and discussion prior to his/her decision.  The principal investigator or designee listed on the Investigator of 
Record form (or FDA 1572 if applicable) will review the consent and answer questions.  The prospective participant will 
be told that being in the trial is voluntary and that he or she may withdraw from the study at any time, for any reason.  
All participants (or their legally acceptable representative) will read, sign, and date a consent form before undergoing 
any study procedures.  Consent materials will be presented in participants’ primary language. A copy of the signed 
consent form will be given to the participant. 
The consent process will be ongoing. The consent form will be revised when important new safety information is 
available, the protocol is amended, and/or new information becomes available that may affect participation in the 
study. Study participants will be re-consented if new information affecting participant safety is made available.    
 


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18.4 
Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant will be assigned a 
unique identification number and these numbers rather than names will be used to collect, store, and report participant 
information.  Site personnel will not transmit documents containing personal health identifiers (PHI) to the study 
sponsor or their representatives. 


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34. 
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influenced by SLCO1B1 521 T>C polymorphism. Pharmacogenet Genomics, 2010. 20(12): p. 759-65. 
35. 
Dufty, N.E., et al., Pharmacokinetic interaction of maraviroc with tacrolimus in a patient coinfected with HIV and 
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68(4): p. 972-4. 
36. 
Vourvahis, M., et al., Pharmacokinetics, safety, and tolerability of maraviroc in HIV-negative subjects with 
impaired renal function. HIV clinical trials, 2013. 14(3): p. 99-109. 
37. 
Abel, S., et al., Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 
antagonist, in healthy volunteers. Br J Clin Pharmacol, 2008. 65 Suppl 1: p. 5-18. 
38. 
Gulick, R.M., et al., Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med, 2008. 
359(14): p. 1429-41. 
39. 
Fatkenheuer, G., et al., Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med, 
2008. 359(14): p. 1442-55. 
40. 
Cooper, D.A., et al., Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the 
treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. The Journal of infectious diseases, 
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41. 
Cuzin, L., et al., Maraviroc intensification of stable antiviral therapy in HIV-1-infected patients with poor immune 
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557-64. 
42. 
Gutierrez, C., et al., Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 
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43. 
Gutierrez, C., et al., Dynamics of the HIV-1 latent reservoir after discontinuation of the intensification of 
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44. 
Hunt, P.W., et al., The immunologic effects of maraviroc intensification in treated HIV-infected individuals with 
incomplete CD4+ T-cell recovery: a randomized trial. Blood, 2013. 121(23): p. 4635-46. 
45. 
Kawana-Tachikawa, A., et al., Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently 
HIV-1-Infected Individuals. PloS one, 2014. 9(1): p. e87334. 
46. 
Puertas, M.C., et al., Intensification of a raltegravir-based regimen with maraviroc in early HIV-1 infection. AIDS, 
2013. 
47. 
Rusconi, S., et al., Maraviroc as Intensification Strategy in HIV-1 Positive Patients with Deficient Immunological 
Response: an Italian Randomized Clinical Trial. PloS one, 2013. 8(11): p. e80157. 


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Westrop, S.J., et al., CCR5 antagonism impacts vaccination response and immune profile in HIV-1 infection. 
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Wilkin, T.J., et al., A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4+ T-
cell recovery despite sustained virologic suppression: ACTG A5256. The Journal of infectious diseases, 2012. 
50. 
Pulido, I., et al., T-cell changes after a short-term exposure to maraviroc in HIV-infected patients are related to 
antiviral activity. The Journal of infection, 2012. 64(4): p. 417-23. 
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Romero-Sanchez, M.C., et al., Effect of maraviroc on HIV disease progression-related biomarkers. Antimicrobial 
agents and chemotherapy, 2012. 56(11): p. 5858-64. 
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Madrid-Elena, N., et al. The Effect of Maraviroc on HIV Transcription in Resting CD4+ T-cells from ART-suppressed 
HIV- 1-infected Patients. in in the Program and Abstracts of the 6th HIV Persistence During Therapy Workshop, 
Miama, FL, December 3-6, 2103. Abstract 41. 
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Muller, E., et al., HIV-positive-to-HIV-positive kidney transplantation--results at 3 to 5 years. N Engl J Med, 2015. 
372(7): p. 613-20. 
54. 
Hütter, G., et al., Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. The New England 
journal of medicine, 2009. 360(7): p. 692-698. 
55. 
Henrich, T., et al., Long-term reduction in peripheral blood HIV type 1 reservoirs following reduced-intensity 
conditioning allogeneic stem cell transplantation. The Journal of infectious diseases, 2013. 207(11): p. 1694-
1702. 
56. 
Allers, K., et al., Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood, 2011. 
117(10): p. 2791-2799. 
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Berlin patient. PLoS pathogens, 2013. 9(5). 
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Ananworanich, J., et al., Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV 
reservoir seeding during acute HIV infection. PloS one, 2012. 7(3): p. e33948. 
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Markowitz, M., et al., A Randomized Open-Label Study of Three- versus Five-Drug Combination Antiretroviral 
Therapy in Newly HIV-1 Infected Individuals. Journal of acquired immune deficiency syndromes, 2014. 
60. 
Richman, D.D., et al., The challenge of finding a cure for HIV infection. Science, 2009. 323(5919): p. 1304-7. 
61. 
Deeks, S.G., et al., Towards an HIV cure: a global scientific strategy. Nature reviews. Immunology, 2012. 
62. 
Locke, J.E., et al., Immunosuppression regimen and the risk of acute rejection in HIV-infected kidney transplant 
recipients. Transplantation, 2014. 97(4): p. 446-50. 
63. 
Kopp, J.B., et al., APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. 
J Am Soc Nephrol, 2011. 22(11): p. 2129-37. 
64. 
Redd, A.D., et al., The rates of HIV superinfection and primary HIV incidence in a general population in Rakai, 
Uganda. J Infect Dis, 2012. 206(2): p. 267-74. 
65. 
Redd, A.D., T.C. Quinn, and A.A. Tobian, Frequency and implications of HIV superinfection. Lancet Infect Dis, 
2013. 13(7): p. 622-8. 
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Redd, A.D., et al., Limited HIV-1 superinfection in seroconverters from the CAPRISA 004 Microbicide Trial. J Clin 
Microbiol, 2014. 52(3): p. 844-8. 
67. 
Blumberg, E.A. and C.C. Rogers, Human immunodeficiency virus in solid organ transplantation. Am J Transplant, 
2013. 13 Suppl 4: p. 169-78. 
68. 
Smith, D.M., et al., Incidence of HIV superinfection following primary infection. JAMA, 2004. 292(10): p. 1177-8. 
69. 
Brenner, B., et al., Persistence of multidrug-resistant HIV-1 in primary infection leading to superinfection. Aids, 
2004. 18(12): p. 1653-60. 
70. 
Frassetto, L.A., et al., Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and 
kidney transplant recipients. Am J Transplant, 2007. 7(12): p. 2816-20. 
71. 
Rabi, S.A., et al., Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. J Clin 
Invest, 2013. 123(9): p. 3848-60. 
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Floren, L.C., et al., Tacrolimus oral bioavailability doubles with coadministration of ketoconazole. Clin Pharmacol 
Ther, 1997. 62(1): p. 41-9. 


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Eriksson, S., et al., Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog, 
2013. 9(2): p. e1003174. 
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Ho, Y.C., et al., Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 
Cure. Cell, 2013. 155(3): p. 540-51. 
75. 
Laird, G.M., et al., Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS 
Pathog, 2013. 9(5): p. e1003398. 
76. 
Pasternak, A.O., et al., Cellular levels of HIV unspliced RNA from patients on combination antiretroviral therapy 
with undetectable plasma viremia predict the therapy outcome. PloS one, 2009. 4(12): p. e8490. 
77. 
Lewin, S.R., et al., Use of real-time PCR and molecular beacons to detect virus replication in human 
immunodeficiency virus type 1-infected individuals on prolonged effective antiretroviral therapy. J Virol, 1999. 
73(7): p. 6099-103. 
78. 
Pasternak, A.O., et al., Highly sensitive methods based on seminested real-time reverse transcription-PCR for 
quantitation of human immunodeficiency virus type 1 unspliced and multiply spliced RNA and proviral DNA. J Clin 
Microbiol, 2008. 46(7): p. 2206-11. 
79. 
Chomont, N., et al., HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. 
Nat Med, 2009. 15(8): p. 893-900. 
80. 
Mexas, A.M., et al., Concurrent measures of total and integrated HIV DNA monitor reservoirs and ongoing 
replication in eradication trials. Aids, 2012. 26(18): p. 2295-306. 
81. 
Kumar, A.M., et al., Human immunodeficiency virus type 1 RNA Levels in different regions of human brain: 
quantification using real-time reverse transcriptase-polymerase chain reaction. J Neurovirol, 2007. 13(3): p. 210-
24. 
82. 
Yukl, S.A., et al., Modification of the Abbott RealTime assay for detection of HIV-1 plasma RNA viral loads less 
than one copy per milliliter. J Virol Methods, 2011. 175(2): p. 261-5. 
83. 
Yukl, S.A., et al., Challenges in detecting HIV persistence during potentially curative interventions: a study of the 
Berlin patient. PLoS Pathog, 2013. 9(5): p. e1003347. 
84. 
Pillai, S.K., et al., Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain, 2006. 129(7): p. 1872-83. 
85. 
Pillai, S., et al., A new perspective on V3 phenotype prediction. AIDS Res Hum Retroviruses, 2003. 19(2): p. 145-9. 
86. 
Lengauer, T., et al., Bioinformatics prediction of HIV coreceptor usage. Nat Biotechnol, 2007. 25(12): p. 1407-10. 
87. 
Raposo, R.A., et al., Increased expression of intrinsic antiviral genes in HLA-B*57-positive individuals. J Leukoc 
Biol, 2013. 94(5): p. 1051-9. 
88. 
Nozaki, T., et al., CCR5 is required for regulation of alloreactive T-cell responses to single class II MHC-
mismatched murine cardiac grafts. Am J Transplant, 2009. 9(10): p. 2251-61. 
89. 
Bickerstaff, A., et al., Acute humoral rejection of renal allografts in CCR5(-/-) recipients. Am J Transplant, 2008. 
8(3): p. 557-66. 
90. 
Nozaki, T., et al., Antibody-mediated rejection of cardiac allografts in CCR5-deficient recipients. J Immunol, 2007. 
179(8): p. 5238-45. 
91. 
Wysocki, C.A., et al., Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute 
graft-versus-host disease. Blood, 2005. 106(9): p. 3300-7. 
92. 
Sallusto, F., J. Geginat, and A. Lanzavecchia, Central memory and effector memory T cell subsets: function, 
generation, and maintenance. Annu Rev Immunol, 2004. 22: p. 745-63. 
93. 
Poggio, E.D., et al., Pretransplant cellular alloimmunity as assessed by a panel of reactive T cells assay correlates 
with acute renal graft rejection. Transplantation, 2007. 83(7): p. 847-52. 
94. 
Sigdel, T.K., et al., Non-HLA antibodies to immunogenic epitopes predict the evolution of chronic renal allograft 
injury. J Am Soc Nephrol, 2012. 23(4): p. 750-63. 
95. 
Christians, U., et al., Automated, fast and sensitive quantification of drugs in blood by liquid chromatography-
mass spectrometry with on-line extraction: immunosuppressants. J Chromatogr B Biomed Sci Appl, 2000. 748(1): 
p. 41-53. 
96. 
Brewer, E., et al., An LC-MS-MS method for quantitative determination of maraviroc (UK-427,857) in human 
plasma, urine and cerebrospinal fluid. Biomed Chromatogr, 2010. 24(12): p. 1316-23. 


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Sahin, S. and L.Z. Benet, The operational multiple dosing half-life: a key to defining drug accumulation in patients 
and to designing extended release dosage forms. Pharm Res, 2008. 25(12): p. 2869-77. 
98. 
McNutt, L.A., et al., Estimating the relative risk in cohort studies and clinical trials of common outcomes. Am J 
Epidemiol, 2003. 157(10): p. 940-3. 
99. 
Greenland, S., Model-based estimation of relative risks and other epidemiologic measures in studies of common 
outcomes and in case-control studies. Am J Epidemiol, 2004. 160(4): p. 301-5. 
100. 
Schmidt, C.a.T.K., When to use the odds ratio or the relative risk? Int. J. Public Health, 208. 53: p. 165-167. 
101. 
Zou, G., A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol, 2004. 
159(7): p. 702-6. 
102. 
Barros, A.J. and V.N. Hirakata, Alternatives for logistic regression in cross-sectional studies: an empirical 
comparison of models that directly estimate the prevalence ratio. BMC Med Res Methodol, 2003. 3: p. 21. 
103. 
Agresti, A., An Introduction to Categorical Data Analysis. 2nd Ed. ed. 2007: E. J. Wiley and Sons, NY. NY. 
104. 
Vincenti, F., et al., Three-year outcomes from BENEFIT, a randomized, active-controlled, parallel-group study in 
adult kidney transplant recipients. Am J Transplant, 2012. 12(1): p. 210-7. 
105. 
Gill, J.S., et al., The change in allograft function among long-term kidney transplant recipients. J Am Soc Nephrol, 
2003. 14(6): p. 1636-42. 
 


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Appendix 1.  Schedule of Events  
 
Years: 
Year 
0 
Year 
1 
Years 2 - 
3 
every 6 mP1 
 
Visit 1 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visits 11 - 14 
Weeks: 
Screen 
Enroll  
Pre-TX 
Segment 
A 
Day 0 
Segment 
B 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
13 
Week 
26 
Week 
39 
Week 
52 
Week 
53-156 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Symptom & Medical Review plus Physical Exam 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
STANDARD OF CARE ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of HIV infection 
X 
 
 
 
 
 
 
 
 
 
 
 
Monitor orthostatic blood pressure for hypotension 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PPDP 
P(or chest x-ray if history of positive PPD)  
XP2 
 
 
 
 
 
 
 
 
 
 
 
Vaccination Review (Pneumovax, Hep A and B) 
XP2 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
 
XP3 
 
 
 
 
 
 
 
 
 
RADIOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
CXR 
XP2 
 
 
 
 
 
 
 
 
 
 
 
SAFETY LABS  
 
 
 
 
 
 
 
 
 
 
 
 
CBC-diff 
XP2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Renal/Electrolytes/glucose/albumin 
XP2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LFTs 
XP2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting Lipid Panel (Chol, LDL, HDL, TGL) 
XP2 
 
X 
 
 
 
 
 
 
 
X 
Y2 
Immunosuppressant levels 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV LABS 
 
 
 
 
 
 
 
 
 
 
 
 
CD4+ T-cell count 
XP2 
XP4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
HIV-1 RNA (bDNA or PCR) 
XP2 
XP4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
RPR/VDRL 
XP2 
 
 
 
 
 
 
 
 
 
 
 
Toxoplasmosis QuantitativeP5 
XP2 
 
 
 
 
 
 
 
 
 
 
 
General Serology 
 
 
 
 
 
 
 
 
 
 
 
 
CMV Ab 
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 
HepBSAg 
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 


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Years: 
Year 
0 
Year 
1 
Years 2 - 
3 
every 6 mP1 
 
Visit 1 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
Visit 10 
Visits 11 - 14 
Weeks: 
Screen 
Enroll  
Pre-TX 
Segment 
A 
Day 0 
Segment 
B 
Week 
1 
Week 
2 
Week 
4 
Week 
8 
Week 
13 
Week 
26 
Week 
39 
Week 
52 
Week 
53-156 
 
HepBSAb 
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 
HepB core Ab 
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 
HepB DNA                                
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 
HCV Ab 
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 
HCV RNA                                  
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 
EBV Ab 
XP2 
 
XP2 
 
 
 
 
 
 
 
 
 
RESEARCH 
 
 
 
 
 
 
 
 
 
 
 
 
Specimen (Study Participants) 
 
 
 
 
 
 
 
 
 
 
 
 
Recipient Blood collected and shipped to central 
repository for mechanistic studies  
XP5 
 
XP6 
 
 
X 
 
X 
X 
 
X 
Y2 
Recipient urine collected and shipped to central 
repository for banking for future analysis 
XP5 
 
XP6 
 
 
 
 
 
X 
 
X 
 
Cystatin C samples collected and shipped to central 
repository for analysis  
 
 
 
 
 
 
 
X 
X 
X 
X 
Y2, Y3 
Recipient Lymph Nodes collected and shipped 
 
 
X 
 
 
 
 
 
 
 
 
 
Iohexol study samples collected, processed and 
shipped to central repository 
 
 
 
 
 
 
 
 
 
 
X 
 
Specimen (Donors) 
 
 
 
 
 
 
 
 
 
 
 
 
Living donor blood collected and shipped 
 
 
X 
 
 
 
 
 
 
 
 
 
Deceased donor spleen collected and shipped 
 
 
X 
 
 
 
 
 
 
 
 
 
Biopsy (Study Participants) 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol biopsy (or SOC if applicable per site). Slides 
and tissue to be sent to repository.  
 
 
 
 
 
 
 
 
X 
 
 
 
Pharmacokinetics        (UCSF ONLY) 
 
 
 
 
 
 
 
 
 
 
 
 
Maraviroc pK                      
 
 
 
 
 
 
 
X 
 
 
 
 
 
1. every 6 months except where indicated 
2. Record if done as standard of care. CD4+ T-cell count and HIV-1 RNA are required for eligibility and may be obtained from primary provider if not done 
locally 


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3. Must be completed no more than 30 days prior to day 0. 
4. Recommend collecting every 12 weeks from primary provider if not done locally since the protocol requires a result no more than 26 weeks prior to 
transplant, although not required. Only pre-transplant results used for study eligibility/enrollment into segment B are required. 
5. Baseline samples must be drawn not more than 13 weeks prior to day of transplant (day 0). Urine is not required in subjects with anuria. Do not draw 
baseline blood samples at screening if subject is not expected to be transplanted and randomized within the next 13 weeks. If it is not possible to 
obtain these baseline research blood samples within window, they should be drawn on the day of admission for transplant and prior to study drug 
administration and transplant. Drawing research samples on the day of transplant can be difficult logistically since samples need to be collected, 
processed and shipped to the repository, and transplant may occur with no study team present, so all attempts should be made to obtain baseline 
samples prior to day 0 if possible.  
6. If the screening samples were not previously drawn, or were drawn more than 13 weeks prior to day of transplant (day 0), redraw all screening blood 
and/or urine samples for mechanistic studies on the day of admission for transplant and prior to study drug administration and transplant. 


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Appendix 2.  Schedule of Events (Donor)  
 
Donor Type 
Day of Transplant 
Deceased Donor 
Spleen tissue, 1cmP3 
Living Donor 
50 cc blood NaHep or ACD 
 


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Appendix 3.  Schedule of Events Associated with Suspected Rejection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suspected 
Rejection 
BIOPSY 
Biopsy slides sent to repository for central review. 
X 
Biopsy tissue: 2 cores sent to repository 
X 
BLOOD 
Collected prior to treatment for rejection. 
X 
URINE 
Recipient urine collected and shipped to central repository for 
banking for future analysis. Collected prior to treatment for 
rejection. 
X 


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Appendix 4.  Reduced Follow-up Schedule for Participants who Prematurely Discontinue Study Treatment 
 
 
 
 
 
 
 
 
 
 
Safety Labs 
• At time of study drug discontinuation.  
• If study treatment discontinued due to drug toxicity, 
should have follow-up safety evaluations as deemed 
necessary by local investigators. 
• Every 6 Months Post Discontinuation if available as 
standard of care. 
 
Phone call to assess patient survival, graft 
survival, and medical diagnosis (see the Manual 
of Procedures for details) 
Every 6 Months Post Discontinuation 
Medical Record Review 
Every 6 Months Post Discontinuation 
Serious Adverse Events 
Recorded as discovered by the study site 

ICF_001.pdf: 
 
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients 
 
NCT00948753 
 
Informed Consent: Recipient  
Version 4.0 
 
February 28, 2019 


 
 
CONSENT TO BE A RESEARCH PARTICIPANT 
Version of the Informed Consent – DAIDS-ES 20730  
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients  
 
RECIPIENT CONSENT 
CONSENT VERSION 4.0 /February 28, 2019 
PROTOCOL VERSION 4.0 /February 28, 2019 
 
[NOTE: Site specific sections are identified in bold italics, and will be tailored at each center 
accordingly] 
INTRODUCTION 
 
We invite you to take part in a medical research study at the [ NAME OF CENTER]. Your study 
doctor(s) [NAMES, MD] from the [NAME OF CENTER] will explain the study to you. 
 
First, we want you to know that: 
 
• 
Taking part in this research is entirely voluntary. 
 
• 
You may choose not to take part, or you may withdraw from the study at any time. In either 
case, you will not lose any benefits to which you are otherwise entitled.. 
 
• 
You may receive no benefit from taking part. The research may give us knowledge that may 
help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). If you have such 
beliefs, please discuss them with your [NAME OF CENTER] doctors or research team before you agree 
to the study. Also, if you have a living donor, they will be informed that you are HIV-positive. 
 
 
Now we will describe this research study. Before you decide to take part, please take as much time 
as you need to ask any questions and discuss this study with anyone at [NAME OF CENTER], or 
with family, friends or your personal physician or other health professional. 
 
Study Team 
Your study team consists of doctors, nurses and other specialized medical professionals, who are 
experienced in taking care of patients with HIV. You will be interacting with some if not all of the 
study team members at specific study visits. However, a study team member will always be available 
to you if you have a question about the study, your response to treatment, or the study drugs. 
 
Why is this study being done? 
A research study is being conducted to find out if maraviroc (a drug used to treat HIV infection) and 
immunosuppressant drugs (drugs that prevent your body from attacking/rejecting your transplanted 
kidney) will prevent rejection and help HIV positive subjects keep their transplanted kidney longer. You 
are being asked to join this research study because you have HIV infection and end-stage kidney disease 


Impact of CCR5 Blockade in 
 
Page 2 of 13  
HIV+ Kidney Transplant Recipients 
RECIPIENT CONSENT 
Version 4.0   February 28, 2019 
 
and plan to have a kidney transplant.  Kidney transplantation is a good option for people with kidney 
disease but there is still a lot to learn about how to best care for the HIV infected kidney transplant 
patients.  
 
The purpose of this study is to evaluate the safety and tolerability of maraviroc in the HIV+ kidney 
transplant recipient, and to find out if using both immunosuppressant drugs and maraviroc (an HIV drug) 
will help your transplanted kidney work better. Although maraviroc is an HIV drug, it is being used to see 
if it can reduce rejection in your transplanted kidney.  
 
This research study is sponsored by the National Institute of Allergy and Infectious Disease (NIAID). The 
drug will be provided free to you by the manufacturer, ViiV Healthcare. 
 
How many people will take part in the study? 
This study will enroll about 130 participants.  [X] participants are expected be enrolled at this 
center.  
 
What will happen if you take part in this research study? 
Your participation in this study may last up to about 3 years after your kidney transplant surgery.  You 
will be assigned by chance to one of two groups. One group will receive the study drug (maraviroc) and 
one group will receive a placebo (inactive substance). You will be asked to take either maraviroc or 
placebo for the duration of the study. You have a 50/50 chance of being assigned to either group. This is 
a double-blind study, which means that neither you nor the study doctor or study staff will know which 
treatment you are receiving. However, in an emergency, the study doctor can get this information. 
 
Samples (blood, lymph nodes, biopsy slides, and tissue) are collected during the study.  Some of these 
samples will be collected as part of your standard of care if you are in the study or not, but will be 
recorded in your research record. Some samples will also be collected for research tests.  Research tests 
help us learn more about your disease, the immune system and response to drugs or treatment. The 
results of the research tests will not be shared with you.  The research samples will not identify you. 
Before any study procedures are completed, your study doctor will discuss this study with you. You will 
have the opportunity to ask questions and time to think about whether you wish to participate. Once 
you have signed this consent, you will need to come in for some tests to see if you are eligible to be in 
this study.   
 
If you have a living donor, your donor will be asked if they would like to participate in this study by 
providing a blood sample at the time of the organ donation. This blood sample will also be used to help 
us learn more about your disease, the immune system and your response to drugs or treatment.  Their 
decision to participate will not be disclosed to you.  
 
Before you begin the main part of the study… 
Before your transplant, your medical records will be reviewed and tests will be done as standard care to 
see if you can be in this study.  These are called “screening” tests.  Some of these tests will be done by 
your primary medical care provider (the person that sees you for regular visits and checkups). All test 
results that may affect your health or treatment will be discussed with the primary medical care 
provider.  The following screening procedures will be done before your transplant:  physical exam, 
medical records review, blood tests, TB screening and vaccination review, and chest x-ray.   
 


Impact of CCR5 Blockade in 
 
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HIV+ Kidney Transplant Recipients 
RECIPIENT CONSENT 
Version 4.0   February 28, 2019 
 
To be eligible to participate in this study, you will need to be on a non-protease inhibitor based HIV 
regimen (preferably an integrase-based regimen). The reason for this is that drugs classified as 
“protease inhibitors” can make it difficult to control the drug levels for some medications you will be 
taking after your transplant. Regardless of your participation in this study, it is typically advised to not be 
on a protease inhibitor based HIV regimen post-transplant. If you need to change regimens, the study 
team will discuss this with your primary care provider who will determine if it is safe for you to switch. 
Your primary provider will make the switch if they feel it is safe.   
 
Once eligible, you will be enrolled in the study. You will then have your primary provider send your HIV 
viral load and CD4 T cell counts to the study center every 3 – 4  months until you receive your transplant 
or are no longer eligible for transplant and/or the study.  Table 1 below outlines what will happen at 
each study visit.  An explanation of all the study procedures is listed in Table 2. (Description of 
Procedures) below. 
 
During the main part of the study 
After you receive your transplant you will have 12 study visits.  During these visits you will receive blood 
tests for standard of care lab results. At some visits, you will have blood drawn for research, and a 
kidney biopsy.  The biopsy will occur around 6 months after your transplant.  If you do not receive a 
biopsy as part of your regular transplant care, you will receive it for this study. You will also have a 
biopsy if your study doctor thinks you may have early signs of rejection. See Tables 1 and 2 below for 
more information. 


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Description of Procedures 
 
Medical Records 
Review/Physical Exam  
The study doctors will review all of your medical history, all the medications you 
are taking, and how your body is feeling. 
Blood Tests for standard 
of care labs.  
About 2.5 tablespoons of blood will be drawn to look at your overall health and 
how well your immune system (the body’s natural defense against illness) is 
working.  The blood tests will also look for any current or past infections. 
Tuberculosis (TB) 
Screening and Vaccination 
You will be asked to have a skin test for tuberculosis (an infection of the lungs 
and other organs) called a PPD test.  For this test, a small injection is placed just 
Table 1. Pre and Post Transplant Procedures 
Procedures 
Screening 
Day 0 
 
Week 
1 
 
Week 
2 
 
Week 
4 
 
Week 
8 
 
Week 
13 
 
Week 
26 
 
Week 
39 
 
Week 
52 
 
Years 2-3 
(53-156) 
Every 6 
months 
Visit 
1 
Visit  
2 
Visit 
3 
Visit 
4 
Visit 
5 
Visit 
6 
Visit 
7 
Visit 
8 
Visit 
9 
Visit 
10 
Visits 
11-14 
Review of 
Medical Records 
plus Physical 
Exam 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw for 
standard of care 
labs 
 
 
 
 
 
 
 
 
 
 
 
TB Screening/ 
Vaccination 
Review 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
 
 
 
 
 
 
 
 
 
 
Biopsy 
 
 
 
 
 
 
 
 
 
 
 
Iohexol GFR 
samples drawn 
 
 
 
 
 
 
 
 
 
 
 
Blood Draw for 
research studies 
 
 
 
 
 
 
 
 
 
 
Y2,Y3 
Urine collection 
for banking 
 
 
 
 
 
 
 
 
 
 
 
Lymph nodes 
collected for 
research studies 
 
 
 
 
 
 
 
 
 
 
 
[UCSF 
Participants only: 
PK Study] 
 
 
 
 
 
 
 
 
 
 
 


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Review   
 
under the skin of the arm. If you test positive, or have tested positive in the 
past and have never been treated for TB, you will begin a 9-month course of 
medications before being eligible to receive a transplant. If you have ever had a 
positive skin test for TB, you will have chest x-rays instead of a skin test. 
 
Your study doctor will review your vaccination history.  Your study doctor will 
let you know if you need to get additional or new vaccinations.   
Chest X-ray 
X-rays are painless tests that use radiation to create pictures of the structures 
inside of your chest like your lungs, heart and blood vessels.  No instruments 
are inserted into your body and no surgery is done for this test. 
Pregnancy Testing 
 
If you are a female who can have children, you must have a negative pregnancy 
within 30 days prior to the transplant procedure.  If you become pregnant 
during the study you should notify the study doctor immediately.  The outcome 
of any pregnancy test will be recorded.   
Biopsy 
The biopsy site will be cleaned and a numbing medicine will be injected into the 
area where the biopsy will be done.  Usually a small cut (less than ¼ inch in size) 
is made in the skin.  A small needle is inserted just under the skin and a small 
piece of the kidney is removed.  You will be asked not to breath and to remain 
completely still during this procedure.  Medications may be given to help you 
relax.  You will be asked to sign a separate consent form for this procedure. 
Iohexol Glomerular 
Filtration Rate (GFR) 
 
GFR can tell doctors how well your kidneys are working.  The GFR test will begin 
with an injection of a dye, Iohexol, intravenously.  Iohexol is a non-toxic dye 
regularly used in special X-ray studies.  Over the course of the test, 3 blood 
samples will be collected.  To avoid multiple needle sticks, a catheter may be 
placed in a vein (intravenous catheter or IV) and used to draw blood.  The total 
amount of blood collected is no more than 2 tablespoons.  The samples taken 
will measure your kidneys’ ability to remove the contrast  
agent from your blood.  No urine samples are needed for this test. 
Blood Draw for research 
studies 
About 5 – 6 tablespoons of blood will be drawn at specified study visits to be 
used for research. You will not receive any results from these tests.  
Urine collection for 
banking 
About 50 – 100ml of urine will be collected at specified visits to be banked for 
future testing if funding becomes available. You will not receive any results 
from these tests. 
Lymph nodes collected for 
research studies 
A lymph node sample will be collected during the transplant procedure to be 
used for research. You will not receive any results from these tests. 
[UCSF Participants only: 
PK Study] 
Because we do not know how the medications you are taking will interact with 
each other, multiple blood samples will be collected during a day-long stay in 
the General Clinical Research Center (GCRC) at various times over a 12 hour 
period. This will be done 3 months after your transplant. You will be required to 
fast overnight prior to this visit. 
 
A small plastic tube will be inserted in a vein in order to avoid multiple needle 
sticks for the collection of these blood samples.  Approximately 1 teaspoonful 
of blood will be collected at each of multiple time points over 12 - 24 hours (a 
total of approximately 10 teaspoonfuls).  
 


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In addition to the visit based procedures, if you have a kidney biopsy for suspected rejection, we will 
also collect blood samples for research as well as a urine sample for future testing. 
 
Genetic information will be recorded from specimens collected for this study.  The specimens will be 
used in experiments planned for this study and with your permission for future studies not yet planned.  
Your samples will not be looked at for other genetic conditions, genetic cloning, or paternity testing.  We 
will keep all information recorded private as much as possible.  However, because genetic information is 
unique to you, complete confidentiality cannot be guaranteed.   
 
 
What side effects or risks can you expect from being in the study? 
Treatment and procedures in this research study may involve risks that are not possible to predict.  You 
will be informed of any new risks that may be identified during the study.   These unforeseen risks might 
affect you during your participation in the study and/or some point in the future. Please ask your study 
doctor or the research staff to explain any procedures or risks that you do not understand. 
 
As a result of participation in this research study, you are at risk for the following side effects.     
• 
Risk of Maraviroc (Selzentry) 
The following serious side effects have been associated with the use of MVC:  
  
Liver problems (liver toxicity) have occurred in people who took MVC. An allergic reaction may 
happen before liver problems occur. Stop taking MVC and call the study doctor right away if you 
get any of the following signs or symptoms:  
• 
Rash on your body (allergic reaction) 
• 
Yellowing of the skin or whites of your eyes 
• 
Dark urine 
• 
Vomiting 
• 
Stomach pain 
• 
If your healthcare provider informs you that you have an elevated liver-related function 
test. People who are co-infected with hepatitis B or C might be at higher risk of having 
liver problems.  
  
Heart problems, including heart attack. 
  
Low blood pressure when standing up, which can cause dizziness or fainting. People who have 
serious kidney problems may be at increased risk for dizziness and fainting.   
  
In addition to the serious side effects listed above, additional side effects include: 
• 
Colds 
• 
Cough 
• 
Fever 
• 
Rash  
• 
Diarrhea 
• 
Swelling of parts of the body 
• 
Flu and flu-like symptoms 


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• 
Muscle aches, spasms and pain  
• 
Stomach  pain and bloating 
• 
Sleeping problems 
• 
Runny, congested nose 
• 
Problems with urination 
• 
Low white blood cell counts (neutropenia) 
  
NOTE: Because of how the drug works in your body, there is a possible increased risk for getting 
other infections or cancer, although there is no evidence from the clinical trials of an increase in 
serious infections or cancer. 
 
Maraviroc contains soy lecithin. If you have a medical history of allergy to soy (soya or soybeans) 
or peanuts, you may develop an allergic reaction to maraviroc. Before starting maraviroc, you 
should inform your health care provider if you are allergic to soy or peanuts. 
 
• 
Randomization risks 
You will be assigned to a treatment program by chance. One group will receive the study drug 
(maraviroc) and one group will receive a placebo (inactive substance). The treatment you 
receive may prove to be less effective or to have more side effects than the other study 
treatment(s) or other available treatments. Neither you nor the study doctor or study staff will 
know which treatment you are receiving. However, in an emergency, the study doctor can get 
this information. 
 
• 
Use of Combination Antiretroviral Drugs 
The use of potent antiretroviral drug combinations may be associated with an abnormal 
placement of body fat and wasting. Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement” 
 
Maraviroc is not known to cause these symptoms, however. 
 
• 
Risk of blood draw 
The risks of having blood taken are discomfort, bleeding, fainting, small blood clot or swelling to 
the vein and area surrounding where the blood is drawn, bruising where the needle enters the 
skin and infection. There is also a very small chance of infection at the needle puncture site.  You 
will never have more the 10 tablespoons of blood collected during a 6-week period for research.  
• 
Risk of Biopsy 
In this study, you will have more kidney biopsies than you would usually get with standard care.  
These additional kidney biopsies will be done to look for early signs of rejection and for research 
purposes.  The risks of a kidney biopsy include bleeding, infection, pain and, very rarely, loss of 
the transplanted kidney due to hemorrhage (uncontrolled bleeding of the kidney) and bleeding 
in or around the kidney that may cause a fall in blood pressure and rise in heart rate.  In very 
rare cases, a hole between blood vessels can form, called a fistula. Complications of the biopsy 
procedure may require a blood transfusion; or very rarely this may require surgery or cause loss 
of the kidney.  Other risks include pain and bleeding at the site of biopsy, infection, discomfort, 


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and bloodstained urine.  To lessen these risks, the biopsy procedure will be done using 
ultrasound guidance.  There is a very small chance that a small scar may form. 
 
• 
Risk of Iohexol Glomerular Filtration Rate (GFR) 
The risks with the GFR test are associated with the dye injected intravenously and blood draws.  
The risks associated with the injection and blood draws are bruising, infection, redness, swelling, 
tenderness at site of the needle entry, and a remote chance of fainting. There are minimal risks 
from the dye used in the GFR test.  The most common side effects are nausea, warmth, 
headache, and dizziness.  You could also experience cough, vomiting, and anxiety.  There is a risk 
of allergic reaction, which will be treated as needed. If you experience an adverse event 
associated with this test, then the test may be stopped and you will be followed closely. 
 
• 
Risk of Chest X-Ray 
Chest x rays have few risks. The amount of radiation used in a chest x ray is very small. A lead 
apron may be used to protect certain parts of your body from the radiation.  The test gives out a 
radiation dose similar to the amount of radiation you're naturally exposed to over 10 days. 
 
• 
Risk of Privacy and Stored Samples 
There may be unknown risks associated with the storage and analysis of your samples or the 
information resulting from the analysis of your samples.  For example, if future research involves 
genetic testing there's a potential risk associated with the release of private health information, 
though every effort will be made to maintain your confidentiality. 
 
• 
Pregnancies, Birth Control  
We do not know if the drug may have bad effects on an unborn baby. It is therefore very 
important that you do not take part in this study if you are pregnant, plan to become pregnant 
within at least 1 month of the end of the study, or are breast-feeding.   
 
If you become pregnant during the study, it is important that you tell us right away. All 
pregnancies will be reported to the Antiretroviral Pregnancy Registry.  
 
WOMEN : If you become pregnant, or if you think you are pregnant, tell the study doctor 
immediately. There could be risks to an unborn child in this study. If you become pregnant 
during the study, you may be discontinued from study participation for safety reasons. If you 
become pregnant within 28 days after you have stopped taking maraviroc, we ask that you 
contact your study doctor for safety monitoring. In either case, please make your obstetrician 
aware of your study participation. Your study doctor will ask that you, or your obstetrician, 
provide updates on the progress of your pregnancy and its outcome. The study doctor will make 
this information available to the study sponsor for safety monitoring follow-up.  
 
[OPTIONAL: For sites with an IRB approved HOPE Act Protocol] 
• 
HIV+ donor 
If you are enrolled in a study at [SITE NAME] so that you can be offered a kidney from a 
deceased donor who is HIV+, you will also be required to sign a separate consent form for that 
study. You will be expected to complete all of the study visits and procedures for that study in 
addition to the study visits and procedures for this study.  
 


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The consent form for that study will explain the possible risks of accepting an HIV+ kidney. The 
main risk is that there is a chance that the transplanted organ may contain a type of HIV that 
cannot be controlled by the HIV medicines that you use now. If so, you may have to change your 
HIV medicines to control the new type of HIV, and the new medicines may interfere with the 
drugs you are taking to prevent rejection of your new organ. 
 
 
Are there benefits to taking part in the study? 
If you agree to take part in this study there may be no direct medical benefit to you. The information 
learned from this study may someday benefit future HIV positive kidney transplant recipients.  You may 
benefit by being closely followed for your health status.   
The study doctor will tell you about any new information (good or bad) that may affect your willingness 
to continue in this study. If new information is provided to you, your consent to continue participation in 
this study will be re-obtained. 
 
What other choices do you have if you do not take part in this study? 
The study doctor and/or study staff will talk with you about this study and other options available to 
you.    You may choose not to be in this research study.    Your decision to participate in this study will 
not affect your medical care. 
 
Can you stop being in the study? 
You may decide not to take part or to leave the study at any time.  If you decide to leave the study, 
there is no penalty or loss of benefits in your routine medical care or any other benefit(s) that you would 
otherwise be entitled to receive. In addition, you should talk to your study doctor who will discuss future 
treatment and procedures for your continued care.  
 
You may be discontinued from study treatment if the study doctor feels it is not in your best interest to 
continue in this study.   
 
Also, you may be removed from the study without your consent at any time.  Reasons why you may be 
removed from the study include, but are not limited to, the following:      
 
• 
You are unable to complete required study treatments and examinations. 
• 
If you are not predicted to receive a transplant by the end of year 4 of the study. 
• 
The study is stopped by the Institution, the IRB (a committee that watches over the safety and 
rights of research participants), the Sponsor(s), pharmaceutical supporter(s) or designee, or by 
the Food and Drug Administration (FDA) or other health authorities. 
 
If you are removed from the study, your study doctor will contact you to discuss stopping procedures 
and your future care.  
 
What are the costs of taking part in this study? 
Costs related to usual clinical care of your HIV infection, kidney transplant or other medical problems 
will be billed to you and/or your insurance provider(s).   Your insurance company may cover costs 
associated with standard medical care provided to you during your participation in this study. These 
costs include routine clinic visits and procedures. Some health plans will not pay the costs for people 
taking part in a research study. Please contact your insurance company to find out what they will pay. If 


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your insurance company doesn’t pay for all charges, you may be responsible for those charges. There 
will be no charge to you or your health insurance company for any costs which are directly related to 
this study. 
 
Will you be paid for taking part in this study? 
You will receive no payment for taking part in this study. 
   
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator's name(s)], if you feel 
that you have been injured because of taking part in this study. You can tell the doctor in person or call 
him/her at __________________ [telephone number]. 
Treatment and Compensation for Injury:  If you are injured as a result of being in this study, the 
[name of center] will provide necessary medical treatment.  The costs of the treatment may be 
billed to you or your insurer just like any other medical costs, or covered by the [name of 
center]  depending on a number of factors.  The [name of center]  and the study sponsor do not 
normally provide any other form of compensation for injury.  For further information about this, 
you may call the office of the Committee on Human Research at XXX- XXX-XXXX.   
In case of injury resulting from this study, you will not lose any legal rights by signing this form. 
 
The U.S. National Institutes of Health (NIH) does not have a mechanism to provide compensation for 
research related injury. 
 
How will information about you be kept confidential? 
Your medical and research records will be confidential to the extent permitted by law.  Efforts will be 
made to keep your personal information private.  However, we cannot guarantee complete 
confidentiality.   
 
You will be identified by a code, and personal information from your records will not be released 
without your written permission.  You will not be identified in any publication or in the sharing of your 
data about this study.  After the study is completed, the data may be placed in a central storage 
location.  These data will not include your name or other traditional personal identifiers.  The purpose is 
to share and make study data available to other researchers. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and 
data analysis include:   
• The Institutional Review Board involved in the approval of study conduct 
• the National Institute of Allergy and Infectious Diseases, (NIAID)   sponsor of the research ,  
•  NIAID representatives, agents, employees, contractors, and other persons assisting in 
conducting, monitoring or analyzing the study.   
• the U.S. Food and Drug Administration, 
• the OHRP, 
• other local, US and international regulatory entities,  
• other State and Local health authorities, and  
• Pharmaceutical or device companies(s) and their commercial partners may review your medical 
and research records for regulatory purposes.    


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RECIPIENT CONSENT 
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
law.  This web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results.  You can search this Web site at any time. 
 
Who can answer questions about the study? 
You can talk to your study doctor about any questions, concerns, or complaints you have about this 
study.  Contact your study doctor(s)__________________ [name(s)] at __________________ 
[telephone number(s)]. 
If you wish to ask questions about the study or your rights as a research participant to someone other 
than the researchers or if you wish to voice any problems or concerns you may have about the study, 
please call the Office of the Committee on Human Research at XXX-XXX-XXXX.   [If there are additional 
informational sources related to the study (e.g., patient representatives or individuals at other study sites 
as appropriate), list here with contact information.] 
 
Stored samples and Future Research 
The investigators conducting this study would like your permission to store and share extra/ 
leftover/unused samples and information resulting from the analysis of samples of biological specimens 
(e.g., blood, tissue, and urine) collected during the course of this study to be used in the future for tests 
that aren’t yet planned.  These tests may or may not be related to the study of HIV infection and kidney 
transplantation.   
 
Your stored samples may be used to obtain knowledge about genetic information in relation to your HIV 
infection, end stage renal disease, related diseases, and/or the immune system.  Research tests may 
include genetic tests.  Genetic tests study an individual’s inherited characteristics, found in DNA, which 
is present in each of the cells of your body.  DNA contains information needed to construct and operate 
a human body. The results of tests done on stored samples or reports resulting from the analysis of your 
samples will not be given to you or your doctor and they will not be put in your medical record.  They 
will not identify you and will not affect your routine medical care.      
 
Researchers are required to protect your privacy and to keep your information private to the extent 
permitted by the law. There may be risks in allowing the storage or analysis of samples and information.  
Once a study is complete, all personal health information (PHI) will be removed from the study database 
and sample labels.  PHI that will be removed include your initials, clinical center name and location, 
dates (i.e., date of birth and date of transplant), and study identification numbers.  Your samples will be 
randomly coded and cannot be linked to you.  Although we remove all PHI, we cannot guarantee 
confidentiality.  For example, if the research is for genetic testing it is possible that it could be traced 
back to you because your genes are specific to you.  
There is no benefit to you from the storage of samples and information.  However, the use of your 
samples and information may help researchers learn more about your disease or the genetics related to 
a specific condition.  The purpose of storage and sharing data is to make information available for use in 
health research.  Collecting, storing, sharing information and making it available for other studies may 
help people in the future.     
 
Samples will be stored at Precision Bioservices.  If you decide to allow storage, your samples and 
information may be stored for 5 years unless additional funding is available to continue storing them.   
 


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Although your stored research samples will not be sold, the information obtained from the research 
performed on your samples may in the future lead to the development of commercial products.  You 
will not receive any money from research using your stored samples and information 
There may be unknown risks associated with the storage of samples and linked information.    For 
example, if the future research involves genetic testing it is possible that it could be traced back to you 
because your genes are specific to you. We will make every attempt to protect your confidentiality and 
to make sure that your personal identity does not become known.    
You can change your mind at any time and ask to have your samples destroyed.  This request should be 
made in writing to the study doctor.  If you make this request, all remaining stored samples will be 
destroyed.  However, the results of any previous tests using your stored samples will be used.  Your 
decision regarding the storage of samples or the information resulting from the analysis of your samples 
will not affect your ability to participate in this study.  The future use of your samples and information 
may contribute to learning more about disease or help to study the genetics related to a specific 
condition.   
 
Please indicate your response below: 
I agree to the storage and sharing of samples (blood, urine and/or tissue) and information for genetic 
tests not currently planned.   
 
   Yes       
  No    
 
 
                                   _______________________ 
 
 
    Initials of Research Participant 
 
I agree to the storage and sharing of samples (blood, urine and/or tissue) and information resulting 
from the analysis of my samples for other tests not currently planned.  
 
 
   Yes       
  No    
 
 
                                    _______________________ 
 
 
      Initials of Research Participant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SIGNATURE PAGE 
 
(Site may use the site-specific signature page if required) 
 
 
Please sign below if you agree to take part in this study.  
  
• 
you have read the informed consent and/or had it explained to you 
• 
you were given the opportunity to ask questions about the information, and 
• 
you voluntarily agree to take part in the study 
 
 
 
 
 
_________________ 
         
_____________________      
 
______________ 
Research Participant’s Name 
Research Participant’s Signature             Date 
(Typed or printed) 
 
 
 
 
 
 
Signature of person explaining and obtaining the consent: 
 
 
 
 
____________________ 
____________________ 
 
_________________ 
Name and Title  
 
Signature 
 
 
 
Date 
(Typed or printed)   
  
(NOTE:  This consent form with the original signatures MUST be retained on file by the principal 
investigator.  A copy must be given to the research participant.  A copy should be placed in the research 
participant’s medical record, if applicable.)      
 


 
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients 
 
NCT00948753 
 
Informed Consent: Donor  
Version 4.0 
 
February 28, 2019 


 
 
CONSENT TO BE A RESEARCH PARTICIPANT 
Version of the Informed Consent – DAIDS-ES 20730  
Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients  
 
DONOR CONSENT 
CONSENT VERSION 4.0/February 28, 2019 
PROTOCOL VERSION 4.0 /February 28, 2019 
[NOTE: Site specific sections are identified in bold italics, and will be tailored at each center 
accordingly] 
INTRODUCTION 
 
We invite you to take part in a medical research study at the [ NAME OF CENTER]. Your study 
doctor(s) [NAMES, MD] from the [NAME OF CENTER] will explain the study to you. 
 
First, we want you to know that: 
 
• 
Taking part in this research is entirely voluntary. 
 
• 
You may choose not to take part, or you may withdraw from the study at any time. In either 
case, you will not lose any benefits to which you are otherwise entitled. 
 
• 
You may receive no benefit from taking part. The research may give us knowledge that may 
help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). If you have such 
beliefs, please discuss them with your [NAME OF CENTER] doctors or research team before you 
agree to the study. 
 
Now we will describe this research study. Before you decide to take part, please take as much time 
as you need to ask any questions and discuss this study with anyone at [NAME OF CENTER], or 
with family, friends or your personal physician or other health professional. 
 
Why is this study being done? 
A research study is being conducted to find out if maraviroc (a drug used to treat HIV infection) and 
immunosuppressant drugs (drugs that prevent the body from attacking/rejecting the transplanted 
kidney) will prevent rejection and help HIV positive subjects keep their transplanted kidney longer. You 
are being asked to join this research study because you are donating a kidney to someone that is 
enrolled in this research study. Kidney transplantation is a good option for people with kidney disease 
but there is still a lot to learn about how to best care for the HIV infected kidney transplant patients.  
 
The purpose of this study is to evaluate the safety and tolerability of maraviroc in the HIV+ kidney 
transplant recipients, and to find out if using both immunosuppressants drugs and maraviroc (an HIV 
drug) will help the transplanted kidney work better. The purpose of requesting a blood sample from you 
(the donor) is to perform research tests that will help us understand how to best care for HIV infected 
kidney transplant patients, and will be used to estimate the strength of the immune response in the 
recipient of the kidney that you donated.   
 
This research study is sponsored by the National Institute of Allergy and Infectious Disease (NIAID). 
 


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How many people will take part in the study? 
 
This study will enroll about 130 participants on the list to receive a kidney transplant.  [X] 
participants are expected be enrolled at this center.  
 
What will happen if you take part in this research study? 
 
Your participation in this study will end after your blood draw on the day of your organ donation.  These 
samples are used for research tests.  Research tests help us learn more about kidney transplant, the 
immune system and response to drugs or treatment. The results of the research tests will not be shared 
with you.  The research samples will not identify you. Before any study procedures are completed, your 
study doctor will discuss this study with you. You will have the opportunity to ask questions and time to 
think about whether you wish to participate.  
 
On the day of your organ donation (before your procedure) your blood will be drawn and your medical 
records will be reviewed.  Table 1 below outlines what will happen at each study visit.  An explanation of 
all the study procedures is listed in Table 2 below. 
 
Table 2.  Description of Procedures 
 
Medical Records Review  
The study doctors will review all of your medical history. 
Blood Tests 
About 2 – 3 tablespoons of blood will be drawn for research. 
 
Genetic information will be recorded from specimens collected for this study.  The specimens will be 
used in experiments planned for this study and with your permission for future studies not yet planned.  
Your samples will not be looked at for other genetic conditions, genetic cloning, or paternity testing.  We 
will keep all information recorded private as much as possible.  However, because genetic information is 
unique to you, complete confidentiality cannot be guaranteed.   
 
What side effects or risks can you expect from being in the study? 
 
• 
Risk of blood draw 
The risks of having blood taken are discomfort, bleeding, fainting, small blood clot or swelling to 
the vein and area surrounding where the blood is drawn, bruising where the needle enters the 
skin and infection. There is also a very small chance of infection at the needle puncture site.   
 
• 
Risk of Privacy and Stored Samples 
There may be unknown risks associated with the storage and analysis of your samples or the 
information resulting from the analysis of your samples.  For example, if future research 
involvesgenetic testing there's a potential risk associated with the release of private health 
Table 1. Procedures 
Procedures 
Day of organ donation 
Review of Medical 
Records 
 
Blood Draw 
 


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information, though every effort will be made to maintain your confidentiality. 
 
Are there benefits to taking part in the study? 
If you agree to take part in this study there may be no direct medical benefit to you. 
The information learned from this study may someday benefit future HIV positive kidney transplant 
recipients.  
 
The study doctor will tell you about any new information (good or bad) that may affect your willingness 
to continue in this study. If new information is provided to you, your consent to continue participation in 
this study will be re-obtained. 
 
What other choices do you have if you do not take part in this study? 
The study doctor and/or study staff will talk with you about this study and other options available to 
you.    You may choose not to be in this research study.    Your decision to participate in this study will 
not affect your medical care. 
 
Your decision to participate or not to participate in this study will not be disclosed to the person that 
you are donating your kidney to.  
 
Can you stop being in the study? 
 
You may decide not to take part or to leave the study at any time.  If you decide to leave the study, 
there is no penalty or loss of benefits in your routine medical care or any other benefit(s) that you would 
otherwise be entitled to receive. In addition, you should talk to your study doctor who will discuss future 
treatment and procedures for your continued care.  
 
What are the costs of taking part in this study? 
The blood draw will be provided to you at no cost.   
 
Will you be paid for taking part in this study? 
You will receive no payment for taking part in this study. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator's name(s)], if you feel 
that you have been injured because of taking part in this study. You can tell the doctor in person or call 
him/her at __________________ [telephone number]. 
Treatment and Compensation for Injury:  If you are injured as a result of being in this study, the 
[name of center] will provide necessary medical treatment.  The costs of the treatment may be 
billed to you or your insurer just like any other medical costs, or covered by the [name of 
center] depending on a number of factors.  The [name of center]  and the study sponsor do not 
normally provide any other form of compensation for injury.  For further information about this, 
you may call the office of the Committee on Human Research at XXX- XXX-XXXX.   
In case of injury resulting from this study, you will not lose any legal rights by signing this form. 
 
The U.S. National Institutes of Health (NIH) does not have a mechanism to provide compensation for 
research related injury. 


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How will information about you be kept confidential? 
Your medical and research records will be confidential to the extent permitted by law.  Efforts will be 
made to keep your personal information private.  However, we cannot guarantee complete 
confidentiality.   
 
You will be identified by a code, and personal information from your records will not be released 
without your written permission.  You will not be identified in any publication or in the sharing of your 
data about this study.  After the study is completed, the data may be placed in a central storage 
location.  These data will not include your name or other traditional personal identifiers.  The purpose is 
to share and make study data available to other researchers. 
 
Organizations that may look at and/or copy your medical records for research, quality assurance and 
data analysis include:   
• The Institutional Review Board involved in the approval of study conduct 
• the National Institute of Allergy and Infectious Diseases, (NIAID)   sponsor of the research ,  
•  NIAID representatives, agents, employees, contractors, and other persons assisting in 
conducting, monitoring or analyzing the study.   
• the U.S. Food and Drug Administration, 
• the OHRP,  
• other local, US and international regulatory entities, 
• other State and Local health authorities, and  
• Pharmaceutical or device companies and their commercial partners may review your medical 
and research records for regulatory purposes.    
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
law.  This web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results.  You can search this Web site at any time. 
 
Who can answer questions about the study? 
You can talk to your study doctor about any questions, concerns, or complaints you have about this 
study.  Contact your study doctor(s)__________________ [name(s)] at __________________ 
[telephone number(s)]. 
If you wish to ask questions about the study or your rights as a research participant to someone other 
than the researchers or if you wish to voice any problems or concerns you may have about the study, 
please call the Office of the Committee on Human Research at XXX-XXX-XXXX.   [If there are additional 
informational sources related to the study (e.g., patient representatives or individuals at other study sites 
as appropriate), list here with contact information.] 
 
Stored samples and Future Research 
The investigators conducting this study would like your permission to store and share extra/ 
leftover/unused samples and information resulting from the analysis of samples of blood collected 
during the course of this study to be used in the future for tests that aren’t yet planned.  These tests 
may or may not be related to the study of HIV infection and kidney transplantation.   
 


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Your stored samples may be used to obtain knowledge about genetic information in relation to the 
immune system.  Research tests may include genetic tests.  Genetic tests study an individual’s inherited 
characteristics, found in DNA, which is present in each of the cells of your body.  DNA contains 
information needed to construct and operate a human body. The results of tests done on stored 
samples or reports resulting from the analysis of your samples will not be given to you or your doctor 
and they will not be put in your medical record.  They will not identify you and will not affect your 
routine medical care.      
 
Researchers are required to protect your privacy and to keep your information private to the extent 
permitted by the law. There may be risks in allowing the storage or analysis of samples and information.  
Once a study is complete, all personal health information (PHI) will be removed from the study database 
and sample labels.  PHI that will be removed include clinical center name and location, dates (i.e., date 
of birth and date of transplant), and study identification numbers.  Your samples will be randomly coded 
and cannot be linked to you.  Although we remove all PHI, we cannot guarantee confidentiality.  For 
example, if the research is for genetic testing it is possible that it could be traced back to you because 
your genes are specific to you.  
 
There is no benefit to you from the storage of samples and information.  However, the use of your 
samples and information may help researchers learn more about your disease or the genetics related to 
a specific condition.  The purpose of storage and sharing data is to make information available for use in 
health research.  Collecting, storing, sharing information and making it available for other studies may 
help people in the future.     
 
Samples will be stored at Precision Bioservices.  If you decide to allow storage, your samples and 
information may be stored for 5 years, or longer if additional funding is obtained. 
 
Although your stored research samples will not be sold, the information obtained from the research 
performed on your samples may in the future lead to the development of commercial products.  You 
will not receive any money from research using your stored samples and information 
There may be unknown risks associated with the storage of samples and linked information.    For 
example, if the future research involves genetic testing it is possible that it could be traced back to you 
because your genes are specific to you. We will make every attempt to protect your confidentiality and 
to make sure that your personal identity does not become known.    
You can change your mind at any time and ask to have your samples destroyed.  This request should be 
made in writing to the study doctor.  If you make this request, efforts will be made to locate all 
remaining stored samples to be destroyed.  However, the results of any previous tests using your stored 
samples will be used.  Your decision regarding the storage of samples or the information resulting from 
the analysis of your samples will not affect your ability to participate in this study.  The future use of 
your samples and information may contribute to learning more about disease or help to study the 
genetics related to a specific condition.   
 
 
 
 
 


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Please indicate your response below: 
I agree to the storage and sharing of samples (blood) and information for genetic tests not currently planned.   
 
   Yes       
  No    
 
 
                                   _______________________ 
 
 
    Initials of Research Participant 
 
I agree to the storage and sharing of samples (blood) and information resulting from the analysis of my samples 
for other tests not currently planned.  
 
 
   Yes       
  No    
 
                                    _______________________ 
 
 
      Initials of Research Participant 
 
SIGNATURE PAGE 
 
(Site may use the site-specific signature page if required) 
 
Please sign below if you agree to take part in this study.  
  
• 
you have read the informed consent and/or had it explained to you 
• 
you were given the opportunity to ask questions about the information, and 
• 
you voluntarily agree to take part in the study 
 
 
 
 
_________________ 
         
 
______________________________ 
 
______________ 
Research Participant’s Name 
 
Research Participant’s Signature                                 Date 
(Typed or printed) 
 
 
 
Signature of person explaining and obtaining the consent: 
 
 
 
____________________  
____________________________  
_________________ 
Name and Title  
 
Signature 
 
 
 
Date 
(Typed or printed)   
 
  
(NOTE:  This consent form with the original signatures MUST be retained on file by the principal investigator.  A 
copy must be given to the research participant.  A copy should be placed in the research participant’s medical 
record, if applicable.)