HOPE in Action Trial of HIV+ Deceased Donor Liver 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 donor liver (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 liver transplant from an HIV-infected deceased liver donor is safe with regards to survival and major transplant-related and HIV-related complications compared to receiving a liver from an HIV-uninfected deceased liver 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 HIV+ Deceased Donor Liver Transplants for HIV+ Recipients

Conditions
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Hiv

Intervention / Treatment
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* Other: HIVD+/R+


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant meets the standard criteria for liver transplant at the local center. Participants being listed for a simultaneous liver kidney (SLK) are eligible if participants meet the standard criteria for both organs. Participant is able to understand and provide informed consent. Participant meets with an independent advocate per the HIV Organ Policy Equity (HOPE) Act Safeguards and Research Criteria. Documented HIV infection (by any licensed assay or documented history of detectable HIV-1 RNA).* Participant is ≥ 18 years old. Opportunistic complications: prior history of certain opportunistic infections is not an exclusion if the participant has received appropriate therapy and has no evidence of active disease. Medical record documentation should be provided whenever possible. CD4+ T-cell count: ≥ 100/µL within 16 weeks prior to transplant if no history of AIDS-defining infection; or ≥ 200 μL if history of opportunistic infection is present. HIV-1 RNA is below 50 RNA/mL.* Viral blips between 50-400 copies will be allowed as long as there are not consecutive measurements > 200 copies/mL. *Organ recipients who are unable to tolerate anti-retroviral therapy (ART) due to organ. failure or recently started ART may be eligible despite a detectable viral load if safe and effective ART to be used by the recipient after transplantation is described. Participant must have or be willing to start seeing a primary medical care provider with expertise in HIV management. Participant is willing to comply with all medications related to participant's transplant and HIV management. For participants with a history of aspergillus colonization or disease, no current clinical evidence of active disease. Agreement to use contraception. 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. (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.) 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.

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: 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 40 | Other: HIVD+/R+<br>* Liver from an HIV-infected deceased donor<br>|
| No Intervention: HIVD-/R+<br>HIV-infected individuals that accept an organ from an HIV-uninfected deceased donor and are randomized to participate in the full study arm, which includes research sample collection -enrollment 40 | |
| No Intervention: HIVD-/R+ (observational)<br>HIV-infected individuals that accept an organ from an HIV-uninfected deceased donor and randomized to observational group with limited data collection - enrollment 120 | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first death or graft failure or serious adverse event (SAE) or HIV breakthrough or opportunistic infection as a composite measure | Time (in days) to first of any of the following events: death or graft failure or 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 |
| --- | --- | --- |
| Time to Pre-transplant mortality | Time (in days) 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 as assessed by Time to first occurrence of mortality or re-transplant or return to maintenance dialysis | Time (in days) 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 | 
| 1-year acute liver rejection | Proportion of recipients who experience acute rejection as measured by biopsy using Banff 2016 comprehensive Update for antibody mediated rejection and Banff 1997 criteria for acute cellular rejection, liver. | From date of transplant to end of year 1 | 
| 2-year acute liver rejection | Proportion of recipients who experience acute rejection as measured by biopsy using Banff 2016 comprehensive Update for antibody mediated rejection and Banff 1997 criteria for acute cellular rejection, liver. | From date of transplant to end of year 2 | 
| 3-year acute liver rejection | Proportion of recipients who experience acute rejection as measured by biopsy using Banff 2016 comprehensive Update for antibody mediated rejection and Banff 1997 criteria for acute cellular rejection, liver. | From date of transplant to end of year 3 | 
| Number of graft rejections in liver transplant | Cumulative incidence of acute rejection (survival framework) as measured by biopsy using Banff 2016 comprehensive Update for antibody mediated rejection and Banff 1997 criteria for acute cellular rejection, liver. | From date of transplant to end of year 3 | 
| 6-month acute kidney rejection in simultaneous liver/kidney transplant recipients | 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 6 months post transplant | 
| 1-year acute kidney rejection in simultaneous liver/kidney transplant recipients only | 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 | 
| Number of Non-alcoholic fatty liver (NAFL) | Cumulative incidence of NAFL as measured by biopsy and transient elastography with controlled attenuation parameter for steatosis | From date of transplant through end of follow-up, up to 3 years | 
| Number of steatohepatitis (NASH) | Cumulative incidence of NASH as measured by biopsy and transient elastography with controlled attenuation parameter for steatosis | From date of transplant through end of follow-up, up to 3 years | 
| Trajectory of recipient Cluster of Differentiation (CD4) count over time | Analysis of repeated measures of CD4 (cells/mm3) count (longitudinal model) | From date of transplant through end of follow up, up to 4 years | 
| Trajectory of recipient plasma HIV RNA over time | Analysis of repeated measures of plasma HIV RNA (copies/mL) longitudinal model | From date of transplant through end of follow-up, up to 4 years | 
| Graft function as assessed by Fibrosis-4 index | Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x √ALT) Fibrosis 4 index estimates the amount of scar or fibrosis in the liver without requiring a biopsy. Using a lower cutoff value of 1.45, a Fibrosis-4 score <1.45 had a negative predictive value of 90% for advanced fibrosis. In contrast, a Fibrosis-4 >3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis. In the patient cohort in which this formula was first validated, at least 70% patients had values <1.45 or >3.25. | 1 years post-transplant | 
| Graft function as assessed by Fibrosis-4 index | Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x √ALT) Fibrosis 4 index estimates the amount of scar or fibrosis in the liver without requiring a biopsy. Using a lower cutoff value of 1.45, a Fibrosis-4 score <1.45 had a negative predictive value of 90% for advanced fibrosis. In contrast, a Fibrosis-4 >3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis. In the patient cohort in which this formula was first validated, at least 70% patients had values <1.45 or >3.25. | 2 years post-transplant | 
| Graft function as assessed by Fibrosis-4 index | Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x √ALT) Fibrosis 4 index estimates the amount of scar or fibrosis in the liver without requiring a biopsy. Using a lower cutoff value of 1.45, a Fibrosis-4 score <1.45 had a negative predictive value of 90% for advanced fibrosis. In contrast, a Fibrosis-4 >3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis. In the patient cohort in which this formula was first validated, at least 70% patients had values <1.45 or >3.25. | 3 years post-transplant | 
| Graft function as assessed by Fibrosis-4 index | Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x √ALT) Fibrosis 4 index estimates the amount of scar or fibrosis in the liver without requiring a biopsy. Using a lower cutoff value of 1.45, a Fibrosis-4 score <1.45 had a negative predictive value of 90% for advanced fibrosis. In contrast, a Fibrosis-4 >3.25 would have a 97% specificity and a positive predictive value of 65% for advanced fibrosis. In the patient cohort in which this formula was first validated, at least 70% patients had values <1.45 or >3.25. | 4 years post-transplant | 
| Graft function as assessed by incidence of fibrosis | Cumulative incidence of advanced fibrosis (stage F3 or greater as defined by metavir fibrosis score) as measured on biopsy. The fibrosis score is assessed on a five point scale (F0 = no fibrosis, F1 = portal fibrosis without septa, F2 = few septa, F3 = numerous septa without cirrhosis, F4 = cirrhosis). | From date of transplant through end of follow-up, up to 3 years | 
| Graft function as assessed by liver stiffness | Mean calculated liver stiffness by transient elastography (kPA) | 1 year post-transplant | 
| Graft function as assessed by liver stiffness | Mean calculated liver stiffness by transient elastography (kPA) | 2 years post-transplant | 
| Graft function as assessed by liver stiffness | Mean calculated liver stiffness by transient elastography (kPA) | 3 years post-transplant | 
| Average graft function as assessed by aspartate aminotransferase (AST) | Mean calculated AST (U/L) | 1 year post-transplant | 
| Average graft function as assessed by AST | Mean calculated AST (U/L) | 2 years post-transplant | 
| Average graft function as assessed by AST | Mean calculated AST (U/L) | 3 years post-transplant | 
| Average graft function as assessed by AST | Mean calculated AST (U/L) | 4 years post-transplant | 
| Average graft function as assessed by alanine aminotransferase (ALT) | Mean calculated ALT (U/L) | 1 year post-transplant | 
| Average graft function as assessed by ALT | Mean calculated ALT (U/L) | 2 years post-transplant | 
| Average Graft function as assessed by ALT | Mean calculated ALT (U/L) | 3 years post-transplant | 
| Average graft function as assessed by ALT | Mean calculated ALT (U/L) | 4 years post-transplant | 
| Average graft function as assessed by bilirubin | Mean calculated bilirubin (mg/dL) | 1 year post-transplant | 
| Average graft function as assessed by bilirubin | Mean calculated bilirubin (mg/dL) | 2 years post-transplant | 
| Average graft function as assessed by bilirubin | Mean calculated bilirubin (mg/dL) | 3 years post-transplant | 
| Average graft function as assessed by Bilirubin | Mean calculated bilirubin (mg/dL) | 4 years post-transplant | 
| Graft function as assessed by Mean calculated Model for End Stage Liver Disease (MELD) score | Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease | 1 year post-transplant | 
| Graft function as assessed by Mean calculated MELD score | Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease | 2 years post-transplant | 
| Graft function as assessed by Mean calculated MELD score | Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease | 3 years post-transplant | 
| Graft function as assessed by Mean calculated MELD score | Mean calculated MELD score. MELD score indicates the severity of liver disease, with scores ranging from 0-40. The higher the score the more severe the disease | 4 years post-transplant | 
| Graft function as assessed by AST to Platelet Ratio (APRI) index | Mean calculated APRI index [( AST / upper limits of normal (ULN) AST ) x 100] / Platelets (109/L)] An APRI score greater than 1.0 has a sensitivity of 76% and specificity of 72% for predicting cirrhosis. In addition, APRI score greater than 0.7 has a sensitivity of 77% and specificity of 72% for predicting significant hepatic fibrosis.For detection of cirrhosis, using an APRI cutoff score of 2.0 is more specific (91%) but less sensitive (46%). The lower the APRI score (less than 0.5), the greater the negative predictive value (and ability to rule out cirrhosis) and the higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis); midrange values are less helpful. | 1 year post-transplant | 
| Graft function as assessed by AST to Platelet Ratio (APRI) index | Mean calculated APRI index [( AST / ULN AST ) x 100] / Platelets (109/L)] An APRI score greater than 1.0 has a sensitivity of 76% and specificity of 72% for predicting cirrhosis. In addition, APRI score greater than 0.7 has a sensitivity of 77% and specificity of 72% for predicting significant hepatic fibrosis.For detection of cirrhosis, using an APRI cutoff score of 2.0 is more specific (91%) but less sensitive (46%). The lower the APRI score (less than 0.5), the greater the negative predictive value (and ability to rule out cirrhosis) and the higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis); midrange values are less helpful. | 2 years post-transplant | 
| Graft function as assessed by AST to Platelet Ratio (APRI) index | Mean calculated APRI index [( AST / ULN AST ) x 100] / Platelets (109/L)] An APRI score greater than 1.0 has a sensitivity of 76% and specificity of 72% for predicting cirrhosis. In addition, APRI score greater than 0.7 has a sensitivity of 77% and specificity of 72% for predicting significant hepatic fibrosis.For detection of cirrhosis, using an APRI cutoff score of 2.0 is more specific (91%) but less sensitive (46%). The lower the APRI score (less than 0.5), the greater the negative predictive value (and ability to rule out cirrhosis) and the higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis); midrange values are less helpful. | 3 years post-transplant | 
| Graft function as assessed by AST to Platelet Ratio (APRI) index | Mean calculated APRI index [( AST / ULN AST ) x 100] / Platelets (109/L)] An APRI score greater than 1.0 has a sensitivity of 76% and specificity of 72% for predicting cirrhosis. In addition, APRI score greater than 0.7 has a sensitivity of 77% and specificity of 72% for predicting significant hepatic fibrosis.For detection of cirrhosis, using an APRI cutoff score of 2.0 is more specific (91%) but less sensitive (46%). The lower the APRI score (less than 0.5), the greater the negative predictive value (and ability to rule out cirrhosis) and the higher the value (greater than 1.5) the greater the positive predictive value (and ability to rule in cirrhosis); midrange values are less helpful. | 4 years post-transplant | 
| Metabolic Outcome as assessed by Body mass index (BMI) | Mean calculated BMI (weight in kilograms/height in meters squared) | 1 year post-transplant | 
| Metabolic Outcome as assessed by Body mass index (BMI) | Mean calculated BMI(weight in kilograms/height in meters squared) | 2 years post-transplant | 
| Metabolic Outcome as assessed by Body mass index (BMI) | Mean calculated BMI(weight in kilograms/height in meters squared) | 3 years post-transplant | 
| Metabolic Outcome as assessed by Body mass index (BMI) | Mean calculated BMI(weight in kilograms/height in meters squared) | 4 years post-transplant | 
| Average hemoglobin a1c among participants at 1 year | Mean calculated hemoglobin a1c (mg/dL) | 1 years post-transplant | 
| Average hemoglobin a1c among participants at 2 years | Mean calculated hemoglobin a1c (mg/dL) | 2 years post-transplant | 
| Average hemoglobin a1c among participants at 3 years | Mean calculated hemoglobin a1c (mg/dL) | 3 years post-transplant | 
| Average hemoglobin a1c among participants at 4 years | Mean calculated hemoglobin a1c (mg/dL) | 4 years post-transplant | 
| Number of HIV breakthroughs | 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 | 
| Number of opportunistic infections | Cumulative incidence of opportunistic infections | From date of transplant through end of follow-up, up to 4 years | 
| Number of X4 tropic virus breakthroughs | Measured by sending virus at time of breakthrough for HIV co-receptor assay | From date of transplant through end of follow-up, up to 4 years | 
| Number of vascular complications | Number of vascular complications within 1 year of transplant, e.g. thrombosis, aneurysm | From date of transplant through year 1 | 
| Number 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 | 
| Number 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 | 
| Hepatitis C (HCV) sustained viral response post-transplant | Proportion of HCV RNA positive recipients that achieve a sustained virologic response week 12 post-treatment (<15 IU/mL) with direct acting antivirals | 12 weeks HCV treatment | 
| Number 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 | 
| Time to first occurrence of all-cause-mortality or graft failure or renal allograft rejection or HIV breakthrough or HIV virologic failure or AIDS defining illness as a composite measure | 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 |