Living Donor Liver Transplantation for Hepatocellular Carcinoma Within and Outside Traditional Selection Criteria: A Multicentric North American Experience.

OBJECTIVE: To evaluate long-term oncologic outcomes of patients post-living donor liver transplantation (LDLT) within and outside standard transplantation selection criteria and the added value of the incorporation of the New York-California (NYCA) score. BACKGROUND: LDLT offers an opportunity to decrease the liver transplantation waitlist, reduce waitlist mortality, and expand selection criteria for patients with hepatocellular carcinoma (HCC). METHODS: Primary adult LDLT recipients between October 1999 and August 2019 were identified from a multicenter cohort of 12 North American centers. Posttransplantation and recurrence-free survival were evaluated using the Kaplan-Meier method. RESULTS: Three hundred sixty LDLTs were identified. Patients within Milan criteria (MC) at transplantation had a 1, 5, and 10-year posttransplantation survival of 90.9%, 78.5%, and 64.1% versus outside MC 90.4%, 68.6%, and 57.7% ( P = 0.20), respectively. For patients within the University of California San Francisco (UCSF) criteria, respective posttransplantation survival was 90.6%, 77.8%, and 65.0%, versus outside UCSF 92.1%, 63.8%, and 45.8% ( P = 0.08). Fifty-three (83%) patients classified as outside MC at transplantation would have been classified as either low or acceptable risk with the NYCA score. These patients had a 5-year overall survival of 72.2%. Similarly, 28(80%) patients classified as outside UCSF at transplantation would have been classified as a low or acceptable risk with a 5-year overall survival of 65.3%. CONCLUSIONS: Long-term survival is excellent for patients with HCC undergoing LDLT within and outside selection criteria, exceeding the minimum recommended 5-year rate of 60% proposed by consensus guidelines. The NYCA categorization offers insight into identifying a substantial proportion of patients with HCC outside the MC and the UCSF criteria who still achieve similar post-LDLT outcomes as patients within the criteria.

Psychosocial evaluation of living liver donors-State of current practices in the United States.

We surveyed living donor liver transplant programs in the United States to describe practices in the psychosocial evaluation of living donors focused on (1) composition of psychosocial team; (2) domains, workflow, and tools of the psychosocial assessment; (3) absolute and relative mental health-related contraindications to donation; and (4) postdonation psychosocial follow-up. We received 52 unique responses, representing 33 of 50 (66%) of active living donor liver transplant programs. Thirty-one (93.9%) provider teams included social workers, 22 (66.7%) psychiatrists, and 14 (42.4%) psychologists. Validated tools were rarely used, but domains assessed were consistent. Respondents rated active alcohol (93.8%), cocaine (96.8%), and opioid (96.8%) use disorder, as absolute contraindications to donation. Active suicidality (97%), self-injurious behavior (90.9%), eating disorders (87.9%), psychosis (84.8%), nonadherence (71.9%), and inability to cooperate with the evaluation team (78.1%) were absolute contraindications to donation. There were no statistically significant differences in absolute psychosocial contraindications to liver donation between geographical areas or between large and small programs. Programs conduct postdonation psychosocial follow-up (57.6%) or screening (39.4%), but routine follow-up of declined donors is rarely conducted (15.8%). Psychosocial evaluation of donor candidates is a multidisciplinary process. The structure of the psychosocial evaluation of donors is not uniform among programs though the domains assessed are consistent. Psychosocial contraindications to living liver donation vary among the transplant programs. Mental health follow-up of donor candidates is not standardized.

Practice patterns of the medical evaluation of living liver donors in the United States.

Living donor liver transplantation (LDLT) can help address the growing organ shortage in the United States, yet little is known about the current practice patterns in the medical evaluation of living liver donors. We conducted a 131-question survey of all 53 active LDLT transplant programs in the United States to assess current LDLT practices. The response rate was 100%. Donor acceptance rate was 0.33 with an interquartile range of 0.33-0.54 across all centers. Areas of high intercenter agreement included minimum age cutoff of 18 years (73.6%) and the exclusion of those with greater than Class 1 obesity (body mass index, 30.0-34.9 m/kg 2 ) (88.4%). Diabetes mellitus was not an absolute exclusion at most centers (61.5%). Selective liver biopsies were performed for steatosis or iron overload on imaging (67.9% and 62.3%, respectively) or for elevated liver enzymes (60.4%). Steatohepatitis is considered an exclusion at most centers (84.9%). The most common hypercoagulable tests performed were factor V Leiden (FVL) (88.5%), protein C (73.1%), protein S (71.2%), antithrombin III (71.2%) and prothrombin gene mutation (65.4%). At 41.5% of centers, donors were allowed to proceed with donation with FVL heterozygote status. Most programs discontinue oral contraceptive pills at least 28 days prior to surgery. At most centers, the need for cardiovascular ischemic risk testing is based on age (73.6%) and the presence of one or more cardiac risk factors (68.0%). Defining areas of practice consensus and variation underscores the need for data generation to develop evidence-based guidance for the evaluation and risk assessment of living liver donors.

The use of nondirected donor organs in living donor liver transplantation: Perspectives and guidance.

Interest in anonymous nondirected living organ donation is increasing in the United States and a small number of transplantation centers are accumulating an experience regarding nondirected donation in living donor liver transplantation. Herein, we review current transplant policy, discuss emerging data, draw parallels from nondirected kidney donation, and examine relevant considerations in nondirected living liver donation. We aim to provide a consensus guidance to ensure safe evaluation and selection of nondirected living liver donors and a schema for just allocation of nondirected grafts.

Variation in adult living donor liver transplantation in the United States: Identifying opportunities for increased utilization.

In the United States, living donor liver transplantation (LDLT) is limited to transplant centers with specific experience. However, the impact of recipient characteristics on procedure selection (LDLT vs. deceased donor liver transplant [DDLT]) within these centers has not been described. Transplant registry data for centers that performed ≥1 LDLT in 2002-2019 were analyzed using hierarchal regression modeling to quantify the impact of patient and center factors on the adjusted odds ratio (aOR) of LDLT (vs DDLT). Among 73,681 adult recipients, only 4% underwent LDLT, varying from <1% to >60% of total liver transplants. After risk adjustment, the likelihood of receiving an LDLT rose by 73% in recent years (aOR 1.73 for 2014-2019 vs. 2002-2007) but remained lower for older adults, men, racial and ethnic minorities, and obese patients. LDLT was less commonly used in patients with hepatocellular carcinoma or alcoholic cirrhosis, and more frequently in those with hepatitis C and with lower severity of illness (Model for End-Stage Liver Disease (MELD) score < 15). Patients with public insurance, lower educational achievement, and residence in the Northwest and Southeast had decreased access. While some differences in access to LDLT reflect clinical factors, further exploration into disparities in LDLT utilization based on center practice and socioeconomic determinants of health is needed.

Financial, policy, and ethical barriers to the expansion of living donor liver transplant: Meeting report from a living donor liver transplant consensus conference.

INTRODUCTION: In October 2021, the American Society of Transplantation (AST) hosted a virtual consensus conference aimed at identifying and addressing barriers to the broader, safe expansion of living donor liver transplantation (LDLT) throughout the United States (US). METHODS: A multidisciplinary group of LDLT experts convened to address issues related to financial implications on the donor, transplant center crisis management, regulatory and oversight policies, and ethical considerations by assessing the relative significance of issues in preventing LDLT growth, with proposed strategies to overcome barriers. RESULTS: Living liver donors endure multiple obstacles including financial instability, loss of job security, and potential morbidity. These concerns, along with other center, state, and federal specific policies can be perceived as significant barriers to expanding LDLT. Donor safety is of paramount importance to the transplant community; however, regulatory and oversight policies aimed at ensuring donor safety can be viewed as ambiguous and complicated leading to time-consuming evaluations that may deter donor motivation and program expansion. CONCLUSION: Transplant programs need to establish appropriate crisis management plans to mitigate potential negative donor outcomes and ensure program viability and stability. Finally, ethical aspects, including informed consent for high-risk recipients and use of non-directed donors, can be perceived as additional barriers to expanding LDLT.

Living donor liver transplantation: A multi-disciplinary collaboration towards growth, consensus, and a change in culture.

INTRODUCTION: Living donor liver transplantation (LDLT) reduces liver transplant waitlist mortality and provides excellent long-term outcomes for persons with end stage liver disease. Yet, utilization of LDLT has been limited in the United States (US). METHODS: In October 2021, the American Society of Transplantation held a consensus conference to identify important barriers to broader expansion of LDLT in the US, including data gaps, and make recommendations for impactful and feasible mitigation strategies to overcome these barriers. Domains addressed encompassed the entirety of the LDLT process. Representation from international centers and living donor kidney transplantation were included for their perspective/experience in addition to members across disciplines within the US liver transplantation community. A modified Delphi approach was employed as the consensus methodology. RESULTS: The predominant theme permeating discussion and polling results centered on culture; the beliefs and behaviors of a group of people perpetuated over time. CONCLUSIONS: Creating a culture of support for LDLT in the US is key for expansion and includes engagement and education of stakeholders across the spectrum of the process of LDLT. A shift from awareness of LDLT to acknowledgement of benefit of LDLT is the primary goal. Propagation of the maxim "LDLT is the best option" is pivotal.

A survey of transplant providers regarding attitudes, barriers, and facilitators to living donor liver transplantation in the United States.

INTRODUCTION: A successful living donor liver transplant (LDLT) is the culmination of a multifaceted process coordinated among key stakeholders. METHODS: We conducted an electronic survey of US liver transplant (LT) centers (August 26, 2021-October 10, 2021) regarding attitudes, barriers, and facilitators of LDLT to learn how to expand LDLT safely and effectively in preparation for the American Society of Transplantation Living Donor Liver Transplant Consensus Conference. RESULTS: Responses were received from staff at 58 programs (40.1% of US LT centers). There is interest in broadening LDLT (100% of LDLT centers, 66.7% of non-LDLT centers) with high level of agreement that LDLT mitigates donor shortage (93.3% of respondents) and that it should be offered to all suitable candidates (87.5% of respondents), though LDLT was less often endorsed as the best first option (29.5% of respondents). Key barriers at non-LDLT centers were institutional factors and surgical expertise, whereas those at LDLT centers focused on waitlist candidate and donor factors. Heterogeneity in candidate selection for LDLT, candidate reluctance to pursue LDLT, high donor exclusion rate, and disparities in access were important barriers. CONCLUSION: Findings from this study may help guide current and future expansion of LDLT more efficiently in the US. These efforts require clear and cohesive messaging regarding LDLT benefits, engagement of the public community, and dedicated resources to equitably increase LDLT access.

Advances and innovations in living donor liver transplant techniques, matching and surgical training: Meeting report from the living donor liver transplant consensus conference.

The practice of LDLT currently delivers limited impact in western transplant centers. The American Society of Transplantation organized a virtual consensus conference in October 2021 to identify barriers and gaps to LDLT growth, and to provide evidence-based recommendations to foster safe expansion of LDLT in the United States. This article reports the findings and recommendations regarding innovations and advances in approaches to donor-recipient matching challenges, the technical aspects of the donor and recipient operations, and surgical training. Among these themes, the barriers deemed most influential/detrimental to LDLT expansion in the United States included: (1) prohibitive issues related to donor age, graft size, insufficient donor remnant, and ABO incompatibility; (2) lack of acknowledgment and awareness of the excellent outcomes and benefits of LDLT; (3) ambiguous messaging regarding LDLT to patients and hospital leadership; and (4) a limited number of proficient LDLT surgeons across the United States. Donor-recipient mismatching may be circumvented by way of liver paired exchange. The creation of a national registry to generate granular data on donor-recipient matching will guide the practice of liver paired exchange. The surgical challenges to LDLT are addressed herein and focuses on the development of robust training pathways resulting in proficiency in donor and recipient surgery. Utilizing strong mentorship/collaboration programs with novel training practices under the auspices of established training and certification bodies will add to the breadth and depth of training.

Living donor liver transplant candidate and donor selection and engagement: Meeting report from the living donor liver transplant consensus conference.

INTRODUCTION: Living donor liver transplantation (LDLT) is a promising option for mitigating the deceased donor organ shortage and reducing waitlist mortality. Despite excellent outcomes and data supporting expanding candidate indications for LDLT, broader uptake throughout the United States has yet to occur. METHODS: In response to this, the American Society of Transplantation hosted a virtual consensus conference (October 18-19, 2021), bringing together relevant experts with the aim of identifying barriers to broader implementation and making recommendations regarding strategies to address these barriers. In this report, we summarize the findings relevant to the selection and engagement of both the LDLT candidate and living donor. Utilizing a modified Delphi approach, barrier and strategy statements were developed, refined, and voted on for overall barrier importance and potential impact and feasibility of the strategy to address said barrier. RESULTS: Barriers identified fell into three general categories: 1) awareness, acceptance, and engagement across patients (potential candidates and donors), providers, and institutions, 2) data gaps and lack of standardization in candidate and donor selection, and 3) data gaps regarding post-living liver donation outcomes and resource needs. CONCLUSIONS: Strategies to address barriers included efforts toward education and engagement across populations, rigorous and collaborative research, and institutional commitment and resources.

Equitable Access to Liver Transplant: Bridging the Gaps in the Social Determinants of Health.

The COVID-19 pandemic and social justice movement have highlighted the impact of social determinants of health (SDOH) and structural racism in the United States on both access to care and patient outcomes. With the evaluation for liver transplantation being a highly subjective process, there are multiple ways for SDOH to place vulnerable patients at a disadvantage. This policy corner focuses on three different methods to reverse the deleterious effects of SDOH-identify and reduce implicit bias, expand and optimize telemedicine, and improve community outreach.

Pregnancy Outcomes After Living Liver Donation: A Multi-Institutional Study.

Nearly half of living liver donors in North America are women of child-bearing age. Fetal and maternal outcomes after donation are unknown. We conducted a retrospective cohort study of female living liver donors (aged 18-50 years at donation) from 6 transplant centers. Participants were surveyed about their pregnancies and fertility. Outcomes were compared between predonation and postdonation pregnancies. Generalized estimating equations were clustered on donor and adjusted for age at pregnancy, parity, and pregnancy year. Among the 276 donors surveyed, 151 donors responded (54.7% response rate) and reported 313 pregnancies; 168/199 (68.8%) of the predonation pregnancies and 82/114 (71.9%) of the postdonation pregnancies resulted in live births, whereas 16.6% and 24.6% resulted in miscarriage, respectively. Women with postdonation pregnancies were older (32.0 versus 26.7 years; P < 0.001) and more frequently reported abnormal liver enzymes during pregnancy (3.5% versus 0.0%; P = 0.02) and delivery via cesarean delivery (35.4% versus 19.7%; P = 0.01). On adjusted analysis, there was no difference in cesarean delivery (odds ratio [OR], 2.44; 95% confidence interval [95% CI], 0.98-6.08), miscarriage (OR, 1.59; 95% CI, 0.78-3.24), combined endpoints of pregnancy-induced hypertension and preeclampsia (OR, 1.27; 95% CI, 0.36-4.49), or intrauterine growth restriction and preterm birth (OR, 0.91; 95% CI, 0.19-4.3). Of the 49 women who attempted pregnancy after donation, 11 (22.5%) self-reported infertility; however, 8/11 (72.7%) eventually had live births. Aside from increased reporting of abnormal liver enzymes and cesarean deliveries, there was no significant difference in pregnancy outcomes before and after living liver donation. One-fifth of women who attempt pregnancy after liver donation reported infertility, and although the majority went on to successful live births, further exploration is needed to understand the contributing factors. Future research should continue to monitor this patient-centered outcome across a large cohort of donors.

Pharmacokinetics and important drug-drug interactions to remember when treating advanced chronic kidney disease patients with hepatitis C direct acting anti-viral therapy.

Hepatitis C direct acting antiviral (DAA) therapy has evolved so that infected patients with advanced chronic kidney disease (CKD) can now anticipate the opportunity for sustained virologic response equivalent to that of the broader population of patients with hepatitis C. This has revolutionized the field of transplantation as it relates to renal transplant candidates with hepatitis C and the use of grafts from hepatitis C virus (HCV) viremic donors. In treating this population of patients, special consideration must be given to the timing of anti-viral therapy and drug-drug interactions. Herein we review the pharmacokinetics of HCV DAA therapy in the setting of CKD and chronic renal replacement therapy. Highlighted are drug/drug interactions with special attention to therapies utilized in advanced CKD and immunosuppressants.

Management of Chronic Hepatitis C in End-stage Renal Disease.

Treatment for chronic viral hepatitis C has advanced dramatically to current standard of care all-oral direct-acting antiviral regimens with relatively short treatment duration and high efficacy. Patients with comorbid end-stage renal disease have constituted a "special patient population" with data and treatment options lagging behind that of the broader population of patients with chronic hepatitis C until recently. Herein we review the current evidence base for direct-acting antiviral therapy in this population. We provide a suggested algorithm for the evaluation of such patients for therapy. We highlight special considerations in regards to the choice of regimen, duration, and timing in regards to potential kidney transplantation.

Successful treatment of primary donor-derived human herpesvirus-8 infection and hepatic Kaposi Sarcoma in an adult liver transplant recipient.

Kaposi sarcoma (KS) may rarely occur in transplant recipients through primary human herpesvirus-8 (HHV-8) infection from a seropositive donor. This report describes a patient who developed hepatic KS after receiving a split liver transplant from an HHV-8-positive donor. The recipient was treated with liposomal doxorubicin after reduction in immunosuppression led to acute cellular rejection. This treatment achieved regression of KS while preserving allograft function, demonstrating a successful therapeutic strategy for this malignancy.

Solid organ transplantation of viral hepatitis C positive donor organs into viral hepatitis C negative recipients.

PURPOSE OF REVIEW: Strategies are needed to reduce waitlist mortality and increase transplantation rates. Advances in hepatitis C therapy has allowed the transplant community to look toward utilization of grafts from hepatitis C viremic donors to expand the organ pool. Use of such grafts for hepatitis C-negative patients is being evaluated and debated, and early trial data are emerging. RECENT FINDINGS: Both hepatitis C antibody-positive/nucleic acid test-negative and viremic donors are currently underutilized. Outcomes for viral hepatitis C (HCV) viremic transplant recipients are improving in the setting of direct-acting antiviral therapy. Optimization of graft utilization from HCV 'positive' donors and expansion to use of viremic donors for HCV-negative recipients will likely reduce waitlist mortality and result in net overall reduction in healthcare expenditures. SUMMARY: Herein, we provide a review of recent advancements relating to hepatitis C in solid organ transplant and outline future directions. A primary future focus will be data collection of outcomes of transplantation of grafts from HCV 'viremic' donors to nonviremic recipients in formal clinical trial protocols.

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study.

BACKGROUND: Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS: In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS: 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION: Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING: Merck Sharp & Dohme Corp.

Safety and efficacy of sofosbuvir-containing regimens in hepatitis C-infected patients with impaired renal function.

BACKGROUND & AIMS: Renal clearance is the major elimination pathway for sofosbuvir (SOF). We assessed the safety and efficacy of SOF-containing regimens in patients with varying baseline estimated glomerular filtration rate (eGFR). METHODS: HCV-TARGET database is a multicentre, longitudinal 'real-world' treatment cohort. RESULTS: A total of 1789 patients [genotypes 1 (72%), 2 (17%) 3 (9%), 4-6 (2%)] had baseline eGFR determination: 73 with eGFR≤45 (18 with eGFR≤30, 5 on dialysis) were compared to 1716 with eGFR>45 ml/min/1.73 m(2) . Patients with baseline eGFR≤45 vs. >45 differed in being female (55% vs. 36%), age ≥65 years (24% vs. 16%), Black race (22% vs. 12%), having cirrhosis with decompensation (73% vs. 24%) and being post-transplant (49% vs. 10%), all P < 0.05. All patients with eGFR≤45 were treated with SOF 400 mg/day (including those on haemodialysis) and had median starting ribavirin (RBV) dose of 800 mg (IQR: 400-1200). Sustained virologic response (SVR) frequencies were similar across eGFR groups, ranging from 82-83%. Patients with eGFR ≤45 more frequently experienced anaemia, worsening renal function and serious AEs (all P < 0.05), and these associations persisted when limiting analysis to RBV-free regimens. Patients with baseline eGFR≤30 and eGFR 31-45 had similar frequencies of efficacy and safety outcomes. CONCLUSIONS: Sustained viral clearance was achieved in 83% of patients with renal impairment (eGFR ≤45 ml/min/1.73 m(2) ) treated with SOF-containing regimens. However, these patients had higher rates of anaemia, worsening renal dysfunction and serious adverse events regardless of use of RBV. Patient with renal impairment require close monitoring and should be treated by providers extensively experienced with SOF-containing regimens.

Non-alcoholic fatty liver disease following liver transplantation: a clinical review.

Non-alcoholic steatohepatitis (NASH) is rapidly becoming the leading indication for liver transplantation (LT) in the United States. While post-transplantation outcomes are similar to other indications for transplant, recent evidence has suggested that reduction in risk factors for post-transplant metabolic syndrome may impose a significant survival benefit in this patient population. Cardiovascular mortality is the leading cause of death following transplantation for NASH. While pre-transplant pharmacologic and surgical approaches have been utilized to reduce cardiovascular risk factors following transplantation, the effectiveness of these treatment approaches in the post-transplant setting is poorly defined. Studies are urgently needed in the treatment of this rapidly growing population.