HOPE in Action Prospective Multicenter, Clinical Trial of Deceased HIVD+ Kidney Transplants for HIV+ Recipients

Study Overview
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Brief Summary
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The primary objective of this study is to determine if an HIV-infected deceased kidney donor (HIVD+) transplant is safe with regards to major transplant-related and HIV-related complications.

Detailed Description
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This study will evaluate if receiving a kidney transplant from an HIV-infected deceased kidney donor is safe with regards to survival and major transplant-related and HIV-related complications compared to receiving a kidney from an HIV-uninfected deceased kidney donor (HIVD-). Those participants who have accepted an HIVD- organ will be randomized to be followed in the full study or followed in the nested observational group.

Official Title
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HOPE in Action Prospective Multicenter, Clinical Trial of Deceased HIVD+ Kidney Transplants for HIV+ Recipients

Conditions
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Hiv

Intervention / Treatment
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* Other: HIV D+/R+


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant meets the standard criteria for kidney transplant at the local center. Participant is able to understand and provide informed consent. Participant meets with an independent advocate per the HIV Organ Policy Equity (HOPE) Act Safeguards. Documented HIV infection (by any licensed assay, or documented history of detectable HIV-1 RNA). No living donor available. Participant is ≥18 years old. Opportunistic complications: if prior history of an opportunistic infection, the participant has received appropriate therapy and has no evidence of active disease. Cluster of Differentiation 4 (CD4)+ T-cell: ≥200/µL within 16 weeks of transplant. HIV-1 is below 50 copies RNA/mL. Viral blips between 50-400 copies allowed as long as there are not consecutive measurements >200 copies/mL. Participant is willing to comply with all medication related to their transplant and HIV management. For participant with a history of aspergillus colonization or disease, no evidence of active disease. The participant must have, or be willing to start seeing, a primary medical care provider with expertise in HIV management. All participants participating in sexual activity that could lead to pregnancy must use an FDA approved method of birth control. Participant is not suffering from significant wasting (e.g. body mass index <21) thought to be related to HIV disease. Exclusion Criteria: Participant has a history of progressive multifocal leukoencephalopathy (PML) or primary central nervous system (CNS) lymphoma. Participant is pregnant or breastfeeding. 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 or may impact the quality or interpretation of the data obtained from the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV D+/R+<br>HIV-infected individuals that accept an organ from an HIV-infected deceased donor - enrollment 80 | Other: HIV D+/R+<br>* Kidney from an HIV-infected deceased donor<br>|
| No Intervention: HIV D-/R+<br>HIV-infected individuals that accept an organ from an HIV-uninfected deceased donor -enrollment 80 | |
| No Intervention: HIV D-/R+ (observational)<br>HIV-infected individuals that accept an organ from an HIV-uninfected deceased donor and randomized to observational group - enrollment 200 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite event, time to first death or graft failure or serious adverse event (SAE) or HIV breakthrough or opportunistic infection | Time to first of any of the following events: death or graft failure or serious adverse event (SAE) or HIV breakthrough or opportunistic infection | From date of transplant through administrative censorship at study completion, up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-transplant mortality | Time to mortality while enrolled before transplant (survival framework) | From date of enrollment to date of transplant or death of any cause, whichever comes first, assessed up to 4 years | 
| Graft failure | Time to mortality or re-transplant or return to maintenance dialysis (survival framework) | From date of transplant through administrative censorship at study completion, up to 4 years | 
| Rate of serious adverse events | Count of post-transplant serious adverse events per person-year as assessed by Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 | From date of transplant through graft failure or administrative censorship at study completion, up to year 4 | 
| 6-month acute rejection | Proportion of recipients who experience acute rejection as measured by biopsy using Banff 2015 criteria: Borderline changes: 'Suspicious' for acute T-cell mediated rejection.This category is used when no intimal arteritis is present, but there are foci of mild tubulitis (t1, t2, or t3) with minor interstitial infiltration (i0 or i1) or interstitial infiltration (i2, i3) with mild (t1) tubulitis. Acute T-cell mediated rejection:Grade from IA defined as cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2) to III defined as cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3) | From date of transplant to end of month 6 | 
| 1-year acute rejection | Proportion of recipients who experience acute rejection as measured by biopsy using Banff 2015 criteria: Borderline changes: 'Suspicious' for acute T-cell mediated rejection.This category is used when no intimal arteritis is present, but there are foci of mild tubulitis (t1, t2, or t3) with minor interstitial infiltration (i0 or i1) or interstitial infiltration (i2, i3) with mild (t1) tubulitis. Acute T-cell mediated rejection:Grade from IA defined as cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2) to III defined as cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3) | From date of transplant to end of year 1 | 
| Incidence of graft rejection | Cumulative incidence of acute rejection (survival framework) as measured by biopsy using Banff 2015 criteria: Borderline changes: 'Suspicious' for acute T-cell mediated rejection.This category is used when no intimal arteritis is present, but there are foci of mild tubulitis (t1, t2, or t3) with minor interstitial infiltration (i0 or i1) or interstitial infiltration (i2, i3) with mild (t1) tubulitis. Acute T-cell mediated rejection:Grade from IA defined as cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3) and foci of moderate tubulitis (t2) to III defined as cases with 'transmural' arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3) | From date of transplant through administrative censorship, up to 4 years | 
| Graft function - Proportion eGFR <60 mL/min/1.73 m2 | Proportion of transplant recipients with glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 60 mL/min/1.73 m2 | 3 months post-transplant | 
| Graft function - Proportion eGFR <60 mL/min/1.73 m2 | Proportion of transplant recipients with glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 60 mL/min/1.73 m2 | 6 months post-transplant | 
| Graft function - Proportion eGFR <60 mL/min/1.73 m2 | Proportion of transplant recipients with glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 60 mL/min/1.73 m2 | 9 months post-transplant | 
| Graft function - Proportion eGFR <60 mL/min/1.73 m2 | Proportion of transplant recipients with glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 60 mL/min/1.73 m2 | 1 year post-transplant | 
| Graft function - Proportion eGFR <60 mL/min/1.73 m2 | Proportion of participants with glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 60 mL/min/1.73 m2 | 2 years post-transplant | 
| Graft function - Proportion eGFR <60 mL/min/1.73 m2 | Proportion of participants with glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 60 mL/min/1.73 m2 | 3 years post-transplant | 
| Graft function -mean eGFR | Mean calculated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 3 months post-transplant | 
| Graft function-mean eGFR | Mean calculated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 6 months post-transplant | 
| Graft function-mean eGFR | Mean calculated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 9 months post-transplant | 
| Graft function-mean eGFR | Mean calculated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 1 year post-transplant | 
| Graft function-mean eGFR | Mean calculated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 2 years post-transplant | 
| Graft function-mean eGFR | Mean calculated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | 3 years post-transplant | 
| Graft function - slope eGFR | The slope of glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) over time (longitudinal analysis) | From date of transplant to end of follow-up, up to 4 years | 
| Incidence of non-HIV renal disease | Cumulative incidence of non HIV-related renal disease as measured by biopsy, e.g. focal segmental glomerulosclerosis | 6 months post-transplant | 
| Incidence of non-HIV renal disease | Cumulative incidence of non HIV-related renal disease as measured by biopsy, e.g. focal segmental glomerulosclerosis | 1 year post-transplant | 
| Incidence of HIV-related renal disease | Cumulative incidence of non HIV-related renal disease as measured by biopsy, e.g. HIV-associated nephropathy | 6 months post-transplant | 
| Incidence of HIV-related renal disease | Cumulative incidence of non HIV-related renal disease as measured by biopsy, e.g. HIV-associated nephropathy | 1 year post-transplant | 
| Donor and recipient apolipoprotein L1 (APOL1) | Proportion of transplant recipients with at least 1 apolipoprotein L1 (APOL1) risk variant in donor and recipient | Baseline | 
| HIV infection of renal allografts | Proportion of recipients with HIV seen in laser capture microdissection of renal biopsy | 6 months post-transplant | 
| Trajectory of recipient plasma HIV RNA over time | Analysis of repeated measures of plasma HIV RNA (longitudinal model) | From date of transplant through end of follow-up, up to 4 years | 
| Trajectory of recipient Cluster of Differentiation (CD4) count over time | Analysis of repeated measures of Cluster of Differentiation 4 (CD4) count (longitudinal model) | From date of transplant through end of follow up, up to 4 years | 
| Incidence of antiretroviral resistance | Measured by local sites' Clinical Laboratory Improvement Amendments (CLIA) certified lab with episode of HIV breakthrough defined as 2 consecutive plasma HIV viral loads >200 copies/mL or one HIV viral load >1000 copies/mL after a period of virologic control post-transplant | From date of transplant through end of follow-up, up to 4 years | 
| Incidence of X4 tropic virus | Measured by local sites' Clinical Laboratory Improvement Amendments (CLIA) certified lab with episode of HIV breakthrough defined as 2 consecutive plasma HIV viral loads >200 copies/mL or one HIV viral load >1000 copies/mL after a period of virologic control post-transplant | From date of transplant through end of follow-up, up to 4 years | 
| Incidence of opportunistic infection | Cumulative incidence of opportunistic infections | From date of transplant through end of follow-up, up to 4 years | 
| Incidence of surgical complications | Number of surgical complications within 1 year of transplant, e.g. delayed closure, wound dehiscence | From date of transplant through year 1 | 
| Incidence of vascular complications | Number of vascular complications within 1 year of transplant | From date of transplant through year 1 | 
| Incidence of viral-related malignancies | Number of malignancies as determined by local pathology | From date of transplant through end of follow-up, up to 4 years | 
| Incidence of the formation of de novo donor-specific human leukocyte antigen(HLA) antibodies | Proportion of participants with a de novo donor-specific HLA antibody as measured and reported by local sites' lab | From date of transplant through end of year 1 | 
| Composite event, time to first | Time to first of any of these events: all-cause-mortality or graft failure or renal allograft rejection or HIV breakthrough or HIV virologic failure or AIDS defining illness | From date of transplant through end of follow-up, up to 4 years |