BACKGROUND & AIMS:While patients with grade 3 acute-on-chronic liver failure (ACLF-3), have high mortality, there is a subset requiring maximal life support. We report post liver transplant (LT) outcomes and identify factors associated with futility in extreme ACLF-3 (eACLF-3) recipients, all requiring intubation, vasopressors, and dialysis at LT. METHODS:We identified adult eACLF-3 LT recipients between January 2010 and December 2021. Pre-LT characteristics were compared among eACLF-3 recipients with and without the futile outcome (one-year or in-hospital mortality), predictors of futility were identified, and a logistic regression model was evaluated using 5-fold cross validation. Findings were validated using the Multi-Organ Dysfunction and Evaluation for Liver Transplantation (MODEL) Consortium. RESULTS:Of 1,608 adult LT recipients at our center, 177 (11%) were eACLF-3. Thirty-five (20%) eACLF-3 recipients experienced futility. Predictors of futility were previous upper abdominal surgery (OR=4.6, P=0.002), sepsis within 14 days prior to LT (OR= 5.9, P= 0.013), intubation due to pneumonia or acute respiratory distress syndrome (OR= 3.5, P= 0.010), worsening PaO2:FiO2 ratio (OR= 3.9, P=0.008), and pre-LT base deficit (OR=1.27, P=0.007). Futility was predicted with an AUROC of 0.74 (SD 0.15). When compared to the MODEL Consortium, our cohort had improved three-, six-, and twelve-month survivals of 89%, 85%, and 80%, compared to 83%, 79%, and 70% (p=0.048); however overall 5-year survival was similar (63% vs 59%, p=0.14). CONCLUSIONS:We report the largest single-center experience of LT for eACLF-3 patients, demonstrating acceptable survival despite high acuity, validated in the MODEL Consortium dataset. Prospective validation of the predictive model and identified risk factors is necessary, and may aid in appropriate selection of ACLF-3 patients requiring maximal life support prior to LT. IMPACT AND IMPLICATIONS:There has been persistent interest in the liver transplant community regarding transplant for acute-on-chronic liver failure grade 3 (ACLF-3) recipients. In this work, we report on a large single-center experience transplanting ACLF-3 recipients, specifically investigating an extreme subset of these patients who were all mechanically ventilated, receiving vasopressors, and receiving hemodialysis at time of transplant. We characterized their outcomes, identifying clear risk factors associated with futility in this hyper-acute subgroup and demonstrating that with appropriate selection, even patients in this extreme subgroup can experience acceptable five-year post-transplant survival. While we could not externally validate our model due to data availability, the obtained external patient cohort of extreme ACLF-3 patients broadly validates our findings. We feel that these results represent an important contribution to the liver transplant community given concerns about transplanting this hyper-acute subpopulation. These results may help guide physicians in selecting appropriate candidates for transplant.

BACKGROUND:Larsucosterol is a DNA methyltransferase inhibitor in development for alcohol-associated hepatitis (AH), a disease for which there is no approved therapy. METHODS:In this phase 2b trial, patients with severe AH were randomly assigned 1:1:1 to receive 30 mg or 90 mg of larsucosterol or placebo; a second dose was administered after 72 hours if the patient remained hospitalized. All patients received supportive care as determined by investigators. Patients in the placebo group, if prescribed, received 32 mg of methylprednisolone, while patients in the larsucosterol groups received matching placebo capsules. The primary end point was 90-day mortality or liver transplant (LT) rate. The key secondary end point was 90-day mortality. We prespecified the reporting of U.S. results separately. RESULTS:Among 307 enrolled patients, 301 received at least one treatment dose. The difference in 90-day mortality or LT between the 30-mg or 90-mg larsucosterol and placebo groups did not reach statistical significance. Ninety-day mortality in the placebo and the 30-mg and 90-mg groups was 25 out of 103, 15 out of 102, and 17 out of 102, respectively. Among U.S. patients (76% of all enrolled patients), there were 21 deaths and 4 LTs among 77 patients in the placebo group, 8 deaths and 5 LTs among 73 patients in the 30-mg larsucosterol group, and 10 deaths and 8 LTs among 77 patients in the 90-mg larsucosterol group. In patients who were treated within less than 10 days of hospitalization (75%), mortality in the placebo group was 20 out of 79 (U.S. patients 17/57), mortality in the 30-mg larsucosterol group was 7 out of 74 (U.S. patients 4/57), and mortality in the 90-mg larsucosterol group was 13 out of 77 (U.S. patients 9/66). Most adverse events arising during treatment were attributable to hepatic disease, and there was no imbalance in adverse events that could not be ascribed to liver disease. CONCLUSIONS:The trial did not meet the primary end point of showing a beneficial effect of larsucosterol on 90-day mortality or LT in patients with severe AH. Equipoise has been established for a further trial of larsucosterol on AH survival. (The trial was funded by the DURECT Corporation; its ClinicalTrials.gov number is NCT04563026.).

Background & Aims: Twenty-eight-day mortality ranges from 30-90% in patients with acute-on-chronic liver failure grades 2/3 (severe ACLF). Though liver transplantation (LT) has demonstrated a survival benefit, the scarcity of donor organs and uncertainty regarding post-LT mortality among patients with severe ACLF may cause hesitancy. We developed and externally validated a model to predict 1-year post-LT mortality in severe ACLF, called the Sundaram ACLF-LT-Mortality (SALT-M) score, and estimated the median length of stay (LoS) after LT (ACLF-LT-LoS).Methods: In 15 LT centers in the US, we retrospectively identified a cohort of patients with severe ACLF transplanted between 2014-2019, followed up to Jan'2022. Candidate predictors included demographics, clinical and laboratory values, and organ failures. We selected predictors in the final model using clinical criteria and externally validated them in two French cohorts. We provided measures of overall performance, discrimination, and calibration. We used multivariable median regression to estimate LoS after adjusting for clinically relevant factors.Results: We included 735 patients, of whom 521 (70.8%) had severe ACLF (120 ACLF-3, external cohort). The median age was 55 years, and 104 with severe ACLF (19.9%) died within 1-year post-LT. Our final model included age >50 years, use of 1/=2 ino-tropes, presence of respiratory failure, diabetes mellitus, and BMI (continuous). The c-statistic was 0.72 (derivation) and 0.80 (validation), indicating adequate discrimination and calibration based on the observed/expected probability plots. Age, respiratory failure, BMI, and presence of infection independently predicted median LoS. Conclusions: The SALT-M score predicts mortality within 1-year after LT in patients with ACLF. The ACLF-LT-LoS score pre-dicted median post-LT stay. Future studies using these scores could assist in determining transplant benefits.

INTRODUCTION: This study is to evaluate the safety and pharmacokinetics (PK) of larsucosterol (DUR-928 or 25HC3S) in subjects with alcohol-associated hepatitis (AH), a devastating acute illness without US Food and Drug Administration–approved therapies. METHODS: This phase 2a, multicenter, open-label, dose escalation study evaluated the safety, PK, and efficacy signals of larsucosterol in 19 clinically diagnosed subjects with AH. Based on the model for end-stage liver disease (MELD) score, 7 subjects were considered to have moderate AH and 12 to have severe AH. All subjects received 1 or 2 intravenous infusions (72 hours apart) of larsucosterol at a dose of 30, 90, or 150 mg and were followed up for 28 days. Efficacy signals from a subgroup of subjects with severe AH were compared with those from 2 matched arms of those with severe AH treated with standard of care (SOC), including corticosteroids, from a contemporaneous study. RESULTS: All 19 larsucosterol-treated subjects survived the 28-day study. Fourteen (74%) of all subjects including 8 (67%) of the subjects with severe AH were discharged ≤72 hours after receiving a single infusion. There were no drug-related serious adverse events nor early terminations due to the treatment. PK profiles were not affected by disease severity. Biochemical parameters improved in most subjects. Serum bilirubin levels declined notably from baseline to day 7 and day 28, and MELD scores were reduced at day 28. The efficacy signals compared favorably with those from 2 matched groups treated with SOC. Lille scores at day 7 were <0.45 in 16 of the 18 (89%) subjects with day 7 samples. Lille scores from 8 subjects with severe AH who received 30 or 90 mg larsucosterol (doses used in phase 2b trial) were statistically significantly lower ( P < 0.01) than those from subjects with severe AH treated with SOC from the contemporaneous study. DISCUSSION: Larsucosterol was well tolerated at all 3 doses in subjects with AH without safety concerns. Data from this pilot study showed promising efficacy signals in subjects with AH. Larsucosterol is being evaluated in a phase 2b multicenter, randomized, double-blinded, placebo-controlled (AHFIRM) trial.

Although liver transplantation (LT) yields survival benefit for patients with acute‐on‐chronic liver failure grade 3 (ACLF‐3), knowledge gaps remain regarding risk factors for post‐LT mortality. We retrospectively reviewed data from 10 centers in the United States and Canada for patients transplanted between 2018 and 2019 and who required care in the intensive care unit prior to LT. ACLF was identified using the European Association for the Study of the Liver‐Chronic Liver Failure (EASL‐CLIF) criteria. A total of 318 patients were studied, of whom 106 (33.3%) had no ACLF, 61 (19.1%) had ACLF‐1, 74 (23.2%) had ACLF‐2, and 77 (24.2%) had ACLF‐3 at transplantation. Survival probability 1 year after LT was significantly higher in patients without ACLF (94.3%) compared with patients with ACLF (87.3%; P = 0.02), but similar between ACLF‐1 (88.5%), ACLF‐2 (87.8%), and ACLF‐3 (85.7%; P = 0.26). Recipients with ACLF‐3 and circulatory failure (n = 29) had similar 1‐year post‐LT survival (82.3%) compared with patients with ACLF‐3 without circulatory failure (89.6%; P = 0.32), including those requiring multiple vasopressors. For patients transplanted with ACLF‐3 including respiratory failure (n = 20), there was a trend toward significantly lower post‐LT survival (P = 0.07) among those with respiratory failure (74.1%) compared with those without (91.0%). The presence of portal vein thrombosis (PVT) at LT for patients with ACLF‐3 (n = 15), however, yielded significantly lower survival (91.9% versus 57.1%; P < 0.001). Multivariable logistic regression analysis revealed that PVT was significantly associated with post‐LT mortality within 1 year (odds ratio, 7.3; 95% confidence interval, 1.9‐28.3). No correlation was found between survival after LT and the location or extent of PVT, presence of transjugular intrahepatic portosystemic shunt, or anticoagulation. LT in patients with ACLF‐3 requiring vasopressors yields excellent 1‐year survival. LT should be approached cautiously among candidates with ACLF‐3 and PVT.

METHODS: We retrospectively reviewed data from 10 centers in North America of patients transplanted between 2018 and 2019. ACLF was identified by using the European Association for the Study of the Liver-Chronic Liver Failure criteria.RESULTS: We studied 318 patients of whom 106 patients (33.3%) had no ACLF, 61 (19.1%) had ACLF-1, 74 (23.2%) had ACLF-2, and 77 (24.2%) had ACLF-3 at transplantation. Healthcare resource utilization after LT was greater among recipients with ACLF compared with patients without ACLF regarding median post-LT length of hospital stay (LOS) (P < .001), length of post-LT dialysis (P < .001), discharge to a rehabilitation center (P < .001), and 30-day readmission rates (P [ .042). Multivariable negative binomial regression analysis demonstrated a signifi- cantly longer LOS for patients with ACLF-1 (1.9 days; 95% confidence interval [CI], 0.82-7.51), ACLF-2 (6.7 days; 95% CI, 2.5-24.3), and ACLF-3 (19.3 days; 95% CI, 1.2-39.7), compared with recipients without ACLF. Presence of ACLF-3 at LT was also associated with longer length of dialysis after LT (9.7 days; 95% CI, 4.6-48.8) relative to lower grades. Multivariable logistic regression analysis revealed greater likelihood of discharge to a rehabilitation center among recipients with ACLF-1 (odds ratio [OR], 1.79; 95% CI, 1.09-4.54), ACLF-2 (OR, 2.23; 95% CI, 1.12-5.01), and ACLF-3 (OR, 2.23; 95% CI, 1.40-5.73). Development of bacterial infection after LT also predicted LOS (20.9 days; 95% CI, 6.1-38.5) and 30-day readmissions (OR, 1.39; 95% CI, 1.17-2.25).CONCLUSIONS: Patients with ACLF at LT, particularly ACLF-3, have greater post-transplant healthcare resource utilization.