HOPE in Action Trial of HIV+ Deceased Donor Liver Transplants for HIV+ Recipients

Hiv Clinical Trial

Official title:

HOPE in Action Prospective Multicenter, Clinical Trial of HIV+ Deceased Donor Liver Transplants for HIV+ Recipients

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03734393
• Other study ID #: IRB00194582
• Secondary ID: U01AI138897
• Status: Recruiting
• Phase: N/A
• Start date: January 4, 2019
• Est. completion date: June 30, 2024

Study information

• Verified date: May 2023
• Source: Johns Hopkins University
• Contact: Christine Durand, MD
• Phone: 410-955-5684
• Email: cdurand2[@]jhmi.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: June 30, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Death
• Hiv

Intervention

Other:
• HIVD+/R+
Liver from an HIV-infected deceased donor

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of Maryland, Institute of Human Virology	Baltimore	Maryland
United States	University of Alabama, Birmingham	Birmingham	Alabama
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois at Chicago	Chicago	Illinois
United States	University of Cincinnati	Cincinnati	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	University of Tennessee Health and Science Center	Memphis	Tennessee
United States	University of Miami	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	New York University School of Medicine	New York	New York
United States	Weill Cornell Medical College	New York	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	UPMC - University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	University of California, San Diego	San Diego	California
United States	University of California, San Francisco	San Francisco	California
United States	MedStar Georgetown Transplant Institute	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins University	National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Graft function as assessed by Fibrosis-4 index	Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x vALT) 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
Secondary	Graft function as assessed by Fibrosis-4 index	Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x vALT) 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
Secondary	Graft function as assessed by Fibrosis-4 index	Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x vALT) 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
Secondary	Graft function as assessed by Fibrosis-4 index	Mean calculated fibrosis-4 index (Age (years) + AST/platelet count (109/L) x vALT) 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
Secondary	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
Secondary	Graft function as assessed by liver stiffness	Mean calculated liver stiffness by transient elastography (kPA)	1 year post-transplant
Secondary	Graft function as assessed by liver stiffness	Mean calculated liver stiffness by transient elastography (kPA)	2 years post-transplant
Secondary	Graft function as assessed by liver stiffness	Mean calculated liver stiffness by transient elastography (kPA)	3 years post-transplant
Secondary	Average graft function as assessed by aspartate aminotransferase (AST)	Mean calculated AST (U/L)	1 year post-transplant
Secondary	Average graft function as assessed by AST	Mean calculated AST (U/L)	2 years post-transplant
Secondary	Average graft function as assessed by AST	Mean calculated AST (U/L)	3 years post-transplant
Secondary	Average graft function as assessed by AST	Mean calculated AST (U/L)	4 years post-transplant
Secondary	Average graft function as assessed by alanine aminotransferase (ALT)	Mean calculated ALT (U/L)	1 year post-transplant
Secondary	Average graft function as assessed by ALT	Mean calculated ALT (U/L)	2 years post-transplant
Secondary	Average Graft function as assessed by ALT	Mean calculated ALT (U/L)	3 years post-transplant
Secondary	Average graft function as assessed by ALT	Mean calculated ALT (U/L)	4 years post-transplant
Secondary	Average graft function as assessed by bilirubin	Mean calculated bilirubin (mg/dL)	1 year post-transplant
Secondary	Average graft function as assessed by bilirubin	Mean calculated bilirubin (mg/dL)	2 years post-transplant
Secondary	Average graft function as assessed by bilirubin	Mean calculated bilirubin (mg/dL)	3 years post-transplant
Secondary	Average graft function as assessed by Bilirubin	Mean calculated bilirubin (mg/dL)	4 years post-transplant
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Metabolic Outcome as assessed by Body mass index (BMI)	Mean calculated BMI (weight in kilograms/height in meters squared)	1 year post-transplant
Secondary	Metabolic Outcome as assessed by Body mass index (BMI)	Mean calculated BMI(weight in kilograms/height in meters squared)	2 years post-transplant
Secondary	Metabolic Outcome as assessed by Body mass index (BMI)	Mean calculated BMI(weight in kilograms/height in meters squared)	3 years post-transplant
Secondary	Metabolic Outcome as assessed by Body mass index (BMI)	Mean calculated BMI(weight in kilograms/height in meters squared)	4 years post-transplant
Secondary	Average hemoglobin a1c among participants at 1 year	Mean calculated hemoglobin a1c (mg/dL)	1 years post-transplant
Secondary	Average hemoglobin a1c among participants at 2 years	Mean calculated hemoglobin a1c (mg/dL)	2 years post-transplant
Secondary	Average hemoglobin a1c among participants at 3 years	Mean calculated hemoglobin a1c (mg/dL)	3 years post-transplant
Secondary	Average hemoglobin a1c among participants at 4 years	Mean calculated hemoglobin a1c (mg/dL)	4 years post-transplant
Secondary	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
Secondary	Number of opportunistic infections	Cumulative incidence of opportunistic infections	From date of transplant through end of follow-up, up to 4 years
Secondary	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
Secondary	Number of vascular complications	Number of vascular complications within 1 year of transplant, e.g. thrombosis, aneurysm	From date of transplant through year 1
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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