Evaluation of Donor Specific Immune Senescence and Exhaustion as Biomarkers of Tolerance Post Liver Transplantation

Participants are considered as successfully withdrawn from immunosuppression if they remain off immunosuppression for at least 52 weeks without evidence of rejection since enrollment and have a liver biopsy at 52 weeks following completion of immunosuppression withdrawal demonstrating histological stability and the absence of rejection per Banff global assessment criteria. This biopsy is assessed by the central pathologist. All participants who fail to complete immunosuppression withdrawal, regardless of reason, or fail to have a biopsy 52 weeks after completion of immunosuppression withdrawal will be considered to have failed.

HLA is a molecule formed by a complex of genes which encode cell-surface proteins responsible for the regulation of the immune system. This molecule is unique for each individual. HLA molecules are present in all cells and are responsible for helping the immune system distinguish between your own cells and foreign cells (like pathogens). However, when our immune system encounters HLA molecules from another individual (like during pregnancy, after blood transfusions or transplantation) it recognizes this as foreign and can generate anti-HLA antibodies. These anti-HLA antibodies could cause harm to the transplanted organ by recognizing its cells as foreign triggering the immune system to attack. This endpoint looks at the development of newly developed donor-specific antibodies (DSA). DSA are a subset of anti-HLA antibodies that are specific against the donor organ. These anti-HLA antibodies are categorized into two classes-class I and class II. The data shown is only for class II DSA.

Incidence will be measured as the proportion of participants who have acute rejection (per Banff criteria), steroid resistant rejection (rejection requiring antibody treatment), and chronic rejection (per Banff criteria), separately. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Severity is based on the Banff global assessment grade according to the central pathology reading of the liver biopsy. For an individual subject, the worst severity is reported. Acute rejection is categorized into mild (rejection infiltrate in a minority of triads that is generally mild and confined within the portal spaces), moderate (rejection infiltrate expanding most or all of the triads), or severe (rejection infiltrate expanding most or all of the triads with spillover into periportal areas and moderate to severe perivenular inflammation that extends into the hepatic parenchyma and is associated with perivenular hepatocyte necrosis). Chronic rejection is categorized into early (bile duct atrophy/loss and foam cell obliterative arteriopathy in <50% of the portal tracts) or late (early criteria but >50% of the portal tracts) stage. Steroid resistant rejection is always considered severe. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

Time is measured as the time (in days) from the initiation of immunosuppression withdrawal to the time of the first biopsy showing rejection (per Banff criteria).

Fibrosis of the liver is the formation of an excessive accumulation of scar tissue in the liver. Graft fibrosis was measured two ways by the ISHAK scale and by Liver Allograft Fibrosis Score (LAFSc) via a liver biopsy. Both scales range from 0 to 6, with a higher score indicating more severe fibrosis. A subject is considered as having graft fibrosis if the score is greater than or equal to 2 at their last available biopsy after the initiation of immunosuppression withdrawal.

Fibrosis of the liver is the formation of an excessive accumulation of scar tissue in the liver. Graft fibrosis was measured two ways by the ISHAK scale and by Liver Allograft Fibrosis Score (LAFSc) via a liver biopsy. Both scales range from 0 to 6, with a higher score indicating more severe fibrosis. Progression was calculated as the final available biopsy score minus the baseline biopsy score. A positive value indicates a worsening of fibrosis.

A participant is considered to have graft loss when the donated liver needs to be removed and the participant is retransplanted with another donor liver or the participant is listed for retransplant. The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.

This number reflects all deaths observed in all participants in the study period, regardless of the cause. The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.

An adverse event is considered a serious adverse event (SAE) if it results it any one of the following: death, life-threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substation disruption to conduct normal life functions, congenital anomaly or birth defect, or an important medical event. The event is considered study related if the medical monitor deems it to be at least possibly or definitely related to any of the study interventions/procedures (immunosuppression withdrawal, the blood draw, or the liver biopsy). The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.

Participants are considered operationally tolerant if they remain off immunosuppression for at least 52 weeks without evidence of rejection since enrollment and have a liver biopsy at 52 weeks following completion of immunosuppression withdrawal demonstrating histological stability and the absence of rejection per Banff global assessment criteria (as assessed by the central pathologist). This number reflects the participants that continue to show the absence of rejection per the Banff global assessment criteria (as assessed by the central pathologist) in the 3 years following completion of immunosuppression withdrawal. The endpoint will be summarized with a two-sided, 95% exact binomial confidence interval.

Glomerular filtration rate (GFR) is a measure of kidney function and helps determine the stage of kidney disease. A value less than 15 indicates kidney failure, 15 to 29 indicates severe loss of kidney function, 30 to 44 indicates moderate to severe loss of kidney function, 45 to 59 mild to moderate loss of kidney function, 60 to 89 indicates mild loss of kidney function, and 90 or higher indicates normal kidney function. The equation developed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) is used to estimate GFR from serum creatinine. The baseline value was selected as the value collected immediately prior to the initiation of immunosuppression withdrawal. The year 1, 2, and 3, values are the values closest to and within 2 months of the expected date. Change was calculated as the year 1, 2, or 3 value minus baseline. A positive value indicates an increase in kidney function.

NIDDK Liver Transplantation Database Quality of Life Form is a patient-reported survey of patient health. The questionnaire is summarized into five domains-measures of disease (ranges from 0-21 with higher score indicating worse quality), psychological status (ranges from 0-5 with higher score indicating worse quality), personal function (ranges from 0-4 with higher score indicating better quality), social and role function (ranges from 0 to 20 with higher score indicating worse quality), and general health perception (ranges from 0 to 10 with higher score indicating better quality). Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and the questionnaire completed closest to the end of study participation. This change was calculated separately for tolerant and non-tolerant subjects.

SF-36 is a patient-reported survey of patient health. There are eight different scales that can be summarized into two summary scores-Mental Component Score and Physical Component Score. Each score ranges from 0-100, with a higher score indicating a better quality of life. Change was calculated as the difference between the questionnaire completed at the initiation of withdrawal and the questionnaire completed closest to the end of study participation. This change was calculated separately for tolerant and non-tolerant subjects.

Time post-transplant is calculated as time in years from transplant to enrollment. Participants are considered operationally tolerant if they remain off immunosuppression for at least 52 weeks without evidence of rejection since enrollment and have a liver biopsy at 52 weeks following completion of immunosuppression withdrawal demonstrating histological stability and the absence of rejection per Banff global assessment criteria (as assessed by the central pathologist). The odds ratio and corresponding 95% confidence interval are presented. The odds ratio represents the probability of achieving operational tolerance per year increase in time post-transplant. An odds ratio greater than 1 means that as the factor increases, operational tolerance is more likely to occur. Whereas less than 1 means operational tolerance is less likely to occur. Since the confidence interval contains 1, this means that as the corresponding factor increases, the likelihood of tolerance does not change.

Recipient age is the age at the time of enrollment. Participants are considered operationally tolerant if they remain off immunosuppression for at least 52 weeks without evidence of rejection since enrollment and have a liver biopsy at 52 weeks following completion of immunosuppression withdrawal demonstrating histological stability and the absence of rejection per Banff global assessment criteria (as assessed by the central pathologist). The odds ratio and corresponding 95% confidence interval are presented. The odds ratio represents the probability of achieving operational tolerance per year increase in recipient age. An odds ratio greater than 1 means that as the factor increases, operational tolerance is more likely to occur. Whereas less than 1 means operational tolerance is less likely to occur. Since the confidence interval contains 1, this means that as the corresponding factor increases, the likelihood of tolerance does not change.