Rajender Reddy, K

INTRODUCTION: Nosocomial infections (NIs) in cirrhosis are associated with high mortality but could be preventable. Logistic regression (LR) models have failed to identify high-risk patients. We aimed to develop machine learning (ML) models to predict NI. METHODS: The CLEARED consortium consists of prospectively enrolled cirrhosis inpatients from >120 centers. Using day-of-admission clinical data, 3 ML approaches (random forest [RF], extreme gradient boosting, and neural networks [NNs]) were used to predict NI. Data were split 80:20 for training and testing stratified by the outcome. Models were compared using area under the receiver operating characteristic curve (AUC). RESULTS: In total, 8,263 patients (55.90 ± 13.34 years; 64.1% men) from 127 centers in 37 countries were included. NI developed in 869 (10.5%), a median of 6 (4–11) days of postadmission. Major NIs were respiratory (29.6%) and urinary tract infection (15.7%), and spontaneous bacterial peritonitis (13.5%). NIs occurred more frequently in patients from low/low-middle income countries and those with severe liver disease, alcohol etiology, and admission infections. NIs were associated with inpatient mortality (31.9% vs 8.1%, P < 0.001) and liver transplantation (4.8% vs 1.9%, P < 0.001). Although the RF model (AUC 0.69) showed good calibration (Brier score 0.09), outperforming extreme gradient boosting, neural network, and LR models (AUC 0.66 for all; LR comparison P = 0.043), no model achieved AUC ≥0.80 for clinical utility. At 10% predicted probability threshold, the RF model demonstrated only 75.4% sensitivity, 52.9% specificity, and 15.9% positive predictive value (PPV). DISCUSSION: NIs cannot be accurately predicted from day-of-admission data using ML models, even in a large, prospective, global cirrhosis cohort. Every hospitalized patient with cirrhosis should receive protocolized infection control measures.

Refractory ascites often requires therapeutic paracentesis, which is associated with potential risks and diminished quality of life. Terlipressin is a vasopressin analog that is indicated for i.v. bolus injection for hepatorenal syndrome, with the potential to reduce large-volume ascites and its complications. Continuous infusion of terlipressin is associated with fewer adverse effects than bolus dosing. The efficacy and safety of continuous infusion of a novel liquid formulation of terlipressin acetate (BIV201) were evaluated in this open-label phase 2 study. Patients with cirrhosis and refractory ascites were randomly assigned (2:1) to receive two 28-day cycles of continuous infusion BIV201 plus standard of care (SOC) separated by a ≤56-day washout (n=10), or SOC alone (n=5). Data analysis was limited by the small sample size and confounded by a potential interaction with gabapentinoids in the BIV201+SOC group. Nonetheless, there were differences in favor of BIV201+SOC versus SOC in the coprimary efficacy endpoints and several quality of life assessments. The beneficial effects of BIV201 on liver complications (mean: 90% CI; BIV201-completers=2.87: 1.51; 5.46 vs. SOC=2.38: 1.20; 4.73) and the change in cumulative ascites (mean: 90% CI; BIV201-completers=−10.76: −26.51; 5.00 vs. SOC=−4.99: −21.95; 11.97) were more pronounced versus SOC in the 5 BIV201+SOC patients who completed both treatment cycles. There were also greater improvements in exploratory quality of life assessments and the percent change in therapeutic paracenteses with BIV201+SOC (−27.94±41.80) versus SOC (−16.67±45.64). Despite the high rate of hyponatremia in the BIV201+SOC group (4/10 patients), the safety profile suggested that continuous BIV201 infusion was well tolerated. These findings support further development of BIV201 in confirmatory trials.

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin (p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo (p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.

Key Points Hepatorenal syndrome type 1 (HRS-1) is an often fatal, but potentially reversible, kidney failure in patients with decompensated cirrhosis. Treatment with terlipressin in patients with HRS-1 is associated with a reduction in the need for RRT. Background Hepatorenal syndrome type 1 (HRS-1)—also known as hepatorenal syndrome-AKI (HRS-AKI)—is a rapidly progressing and usually fatal, but potentially reversible, kidney failure occurring in patients with decompensated cirrhosis. A large proportion of patients with HRS-1 require renal replacement therapy (RRT). Terlipressin demonstrated efficacy in reversing HRS and improving renal function in patients with HRS-1 in three phase III, randomized, clinical trials (RCTs; i.e. , OT-0401, REVERSE, and CONFIRM). However, these RCTs were not designed to evaluate the effect of terlipressin on the requirement of RRT. In this study, the effect of terlipressin on RRT requirements in the pooled phase III patient population was assessed. Methods For this retrospective analysis, data from patients who participated in the OT-0401, REVERSE, and CONFIRM studies were integrated in the largest-to-date randomized database ( N =608). Results The need for RRT was significantly decreased in patients in the terlipressin group versus the placebo group by day 30 (28.1% versus 35.9%, respectively; P = 0.040) and day 60 (30.1% versus 37.9%, respectively; P = 0.045) in the pooled population and also postliver transplantation (LT) at day 60 (20.5% versus 40.3%, respectively; P = 0.008) and day 90 (25.3% versus 43.1%, respectively; P = 0.018). More patients were alive and RRT-free by day 90 in the overall population (36.9% versus 28.5%; P = 0.030) and among patients who received an LT (60.0% versus 39.7%; P = 0.010). Random assignment to receive terlipressin was an independent positive predictor of avoidance of RRT ( P = 0.042); while higher baseline serum creatinine (sCr) level and Child-Pugh scores were negatively associated with RRT avoidance ( P < 0.001 and P = 0.040, respectively). Conclusions Terlipressin decreased the requirement of RRT compared with placebo among patients with HRS-1, including those receiving LT. A lower sCr level at the beginning of therapy was associated with avoidance of RRT.

Liver transplantation (LT) is a life‐saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long‐term outcomes after LT for ALF. We combined prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT. Cohort analysis of detailed pretransplantation data for patients listed for LT for ALF in the ALFSG Registry between January 1998 and October 2018 matched with transplantation‐related data from the SRTR. Primary outcomes were 1‐ and 3‐year post‐LT patient survival. Secondary outcome was receipt of LT; independent associations with successful receipt of LT were determined using multivariable logistic regression. Of 624 patients with ALF listed for LT, 398 (64%) underwent LT, 100 (16%) died without LT, and 126 (20%) recovered spontaneously. Among LT recipients, etiologies included seronegative/indeterminate (22%), drug‐induced liver injury (18%), acetaminophen overdose (APAP; 16%), and viral hepatitis (15%). The 1‐ and 3‐year post‐LT patient survival rates were 91% and 90%, respectively. Comparing those dying on the waiting list versus with those who received LT, the former had more severe multiorgan failure, reflected by increased vasopressor use (65% vs. 22%), mechanical ventilation (84% vs. 57%), and renal replacement therapy (57% vs. 30%; p < 0.0001 for all). After adjusting for relevant covariates, age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00–1.04), APAP etiology (aOR 2.72, 95% CI 1.42–5.23), requirement for vasopressors (aOR 4.19, 95% CI 2.44–7.20), Grade III/IV hepatic encephalopathy (aOR 2.47, 95% CI 1.29–4.72), and Model for End‐Stage Liver Disease (MELD) scores (aOR 1.05, 95% CI 1.02–1.09; p < 0.05 for all) were independently associated with death without receipt of LT. Post‐LT outcomes for ALF are excellent in this cohort of very ill patients. The development of multiorgan failure while on the transplantation list and APAP ALF etiology were associated with a lower likelihood of successful receipt of LT.

PURPOSEHepatocellular carcinoma (HCC) has well-defined environmental risk factors. In addition, epidemiologic studies have suggested hereditary risk factors. The goals of this study were to determine the rate of pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes in patients with HCC, possible enrichment of P/LP variants in particular genes, and potential impact on clinical management.MATERIALS AND METHODSA prospective study at a tertiary medical center enrolled 217 patients with a personal history of HCC. Multigene panel testing was performed for 134 cancer predisposition genes in all patients. The rate of P/LP variants was compared with population rates. A separate retrospective cohort included 219 patients with HCC who underwent testing at a commercial laboratory.RESULTSIn the prospective cohort, P/LP germline variants were identified in 25 of 217 patients with HCC (11.5%). Four patients (1.8%) had P/LP variants in the highly penetrant cancer genes BRCA2 (n = 2), MSH6 (n = 1), and PMS2 (n = 1). In addition, multiple patients had P/LP variants in FANCA (n = 5) and BRIP1 (n = 4), which were significantly enriched in HCC compared with the general population. Detection of P/LP variants led to changes in clinical management in regard to therapy selection, screening recommendations, and cascade testing of relatives. In a separate retrospective analysis of 219 patients with HCC, 30 (13.7%) were positive for P/LP variants including 13 (5.9%) with highly penetrant genes APC (n = 2), BRCA1 (n = 1), BRCA2 (n = 6), MSH2 (n = 2), or TP53 (n = 2).CONCLUSIONP/LP germline variants in cancer predisposition genes were detected in 11%-14% of patients with HCC. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.

Background and Aims Compared to other chronic diseases, patients with chronic liver disease (CLD) have significantly higher inpatient mortality; accurate models to predict inpatient mortality are lacking. Serum lactate (LA) may be elevated in patients with CLD due to both tissue hypoperfusion as well as decreased LA clearance. We hypothesized that a parsimonious model consisting of Model for End‐Stage Liver Disease (MELD) and LA at admission may predict inpatient mortality in patients with CLD. Approach and Results We examined all patients with CLD in two large and diverse health care systems in Texas (North Texas [NTX] and Central Texas [CTX]) between 2010 and 2015. We developed (n = 3,588) and validated (n = 1,804) a model containing MELD and LA measured at the time of hospitalization. We further validated the model in a second cohort of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 726). MELD‐LA was an excellent predictor of inpatient mortality in development (concordance statistic [C‐statistic] = 0.81, 95% confidence interval [CI] 0.79‐0.82) and both validation cohorts (CTX cohort, C‐statistic = 0.85, 95% CI 0.78‐0.87; multicenter cohort C‐statistic = 0.82, 95% CI 0.74‐0.88). MELD‐LA performed especially well in patients with specific cirrhosis diagnoses (C‐statistic = 0.84, 95% CI 0.81‐0.86) or sepsis (C‐statistic = 0.80, 95% CI 0.78‐0.82). For MELD score 25, inpatient mortality rates were 11.2% (LA = 1 mmol/L), 19.4% (LA = 3 mmol/L), 34.3% (LA = 5 mmol/L), and >50% (LA > 8 mmol/L). A linear increase (P < 0.01) was seen in MELD‐LA and increasing number of organ failures. Overall, use of MELD‐LA improved the risk prediction in 23.5% of patients compared to MELD alone. Conclusions MELD‐LA (bswh.md/meldla) is an early and objective predictor of inpatient mortality and may serve as a model for risk assessment and guide therapeutic options.

Acute‐on‐chronic liver failure (ACLF) characterized with ≥2 extrahepatic organ failures in cirrhosis carries a high mortality. Outcomes of patients listed for liver transplantation (LT) after ACLF and after LT are largely unknown. The North American Consortium for the Study of End‐Stage Liver Disease prospectively enrolled 2793 nonelectively hospitalized patients with cirrhosis; 768 were listed for LT. Within 3 months, 265 (35%) received a LT, 395 remained alive without LT, and 108 died/delisted. Compared with nonlisted patients, those listed were younger and more often had ACLF, acute kidney injury, and a higher admission Model for End‐Stage Liver Disease (MELD) score. ACLF was most common in patients who died/delisted, followed by those alive with and without LT respectively, (30%, 22%, and 7%, respectively; P < 0.001). At LT, median MELD was 27.9% and 70% were inpatients; median time from hospitalization to LT was 26 days. Post‐LT survival at 6 months was unchanged between those with and without ACLF (93% each at 6 months). There was no difference in 3‐ and 6‐month mean post‐LT creatinine in those with and without ACLF, despite those with ACLF having a higher mean pre‐LT creatinine and a higher rate of perioperative dialysis (61%). In conclusion, patients with and without ACLF had similar survival after transplant with excellent renal recovery in both groups.