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In this second installment of “Expert Picks” from The Liver Meeting 2022, Ashwani K. Singal, MD, MS, a professor of medicine at the University of South Dakota Sanford School of Medicine and the chief of clinical research at Avera Health’s liver disease program, in Sioux Falls, S.D., discusses six more of his favorite abstracts.


Abstract 7. Effect of the MMaT-3 policy on post-transplant outcomes (Shaikh et al)

In 2019, the United Network for Organ Sharing (UNOS) implemented a policy to reduce liver transplant disparities that have historically favored patients with hepatocellular carcinoma (HCC). UNOS named the policy MMaT-3 for its algorithm—median MELD (Model for End-Stage Liver Disease) score at transplant minus 3 points—which capped HCC patient exception scores to after a six-month wait.

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In this study, investigators measured the policy’s effect on posttransplant outcomes. They analyzed the UNOS registry to compare posttransplant outcomes in HCC patients who received a liver transplant before (Aug. 15, 2017, to Nov. 15, 2018) and after (June 1, 2019, to Aug. 30, 2020) implementation of the MMaT-3 policy. Follow-up continued until Dec. 31, 2021, and primary outcomes were patient survival and HCC recurrence rates, defined as death due to HCC, reported recurrence by a center or poorly differentiated pathology on explant.

Compared with transplant recipients in the pre–MMaT-3 era (n=1,899), those after MMaT-3 implementation (n=1,491) had 35% higher mortality, with a hazard ratio (HR) of 1.35 (95% CI, 1.02-1.78) after adjusting for age, sex and race/ethnicity. The MMaT-3 era group also had a 70% higher HCC recurrence risk (odds ratio [OR], 1.70; 95% CI, 1.33-2.17). Of note, poorly differentiated HCC at explant increased by about threefold, with a standardized HR of 2.92 (95% CI, 1.58-5.4) after the MMaT-3 policy was implemented. The investigators concluded that further studies are needed to examine mechanisms and determinants of worse patient survival and HCC recurrence post-policy.

Dr. Singal: As patients with HCC were considered to be unusually advantaged for receiving a liver transplant compared with non-HCC patients, the MMaT-3 policy was introduced. But the posttransplant outcomes for HCC patients have worsened since MMaT-3 was implemented. I think lowering the exception score by 3 points and then lowering the cap for the exception score resulted in longer waiting times on the transplant list before patients received grafts. Whether or not the required minimum wait time of six months before listing the patient could have resulted in these findings is unclear. Six months of waiting would be expected to improve outcomes, since it gives physicians time to understand HCC’s behavior and select better patients for the list. If studies validate these findings, does it mean that we should go back to the liver transplant allocation policy we used before 2019? More data and studies are needed to examine and answer this question.

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Abstract 12. Early versus standard initiation of terlipressin for HRS-AKI in ACLF - a randomized controlled trial (ETERLI study) (Singh et al)

Acute-on-chronic liver failure (ACLF) is a unique clinical syndrome in patients with cirrhosis and chronic liver disease presenting with failure of multiple organs and having the potential for very high short-term mortality. Kidney failure with acute kidney injury (AKI) due to hepatorenal syndrome (HRS) is very common in these patients. It also progresses faster and is a major reason for mortality. Researchers from New Delhi investigated whether early use of IV terlipressin (Terlivaz, Mallinckrodt) could improve outcomes in patients with HRS-AKI and ACLF.

The investigators randomly assigned ACLF patients with stage 2 or 3 AKI, who had failed 40 g of albumin resuscitation over a period of 12 hours, to receive either terlipressin early at 2 mg/24 hours plus albumin (n=35) or albumin for 48 hours before initiation of terlipressin at the same dosage (n=35). The primary end point was AKI reversal by day 7. Secondary end points were need for dialysis, treatment-related adverse events and mortality at 28 and 90 days.

The primary outcome was achieved in 68.6% patients in the early group, and 31.4% in the standard group (P=0.03). In addition, the early terlipressin group experienced significant improvements in ACLF grade, mean arterial pressure and urine output. Mortality was higher in the standard group than in those who received terlipressin early, both at 28 days (65.7% vs. 40%; P=0.031) and 90 days (69.6% vs. 57.2%; P=0.14). Although several patients (n=9) had adverse effects related to the medication, none were life-threatening. Hepatic encephalopathy at presentation, baseline MELD score and admission blood urea independently predicted 28-day mortality.

The investigators concluded that initiating terlipressin early during the course of HRS-AKI in ACLF patients is associated with improved response to treatment and improved outcomes.

Dr. Singal: This is a very provocative and important study, as it challenges the criteria for diagnosis of HRS. Traditionally, patients were diagnosed after they experienced no response to volume replacement over 24 to 48 hours, and intrarenal or postrenal causes of AKI were excluded. This study suggests that an earlier determination of HRS-AKI and initiation of the specific vasoconstrictor treatment with terlipressin is associated with improved outcomes.

These findings aren’t necessarily surprising since the major factor determining response to terlipressin, or any vasoconstrictor therapy, is the baseline serum creatinine at treatment initiation. It would be interesting to analyze serum creatinine and MELD score in the two groups at start of terlipressin treatment. It also would be interesting to see whether similar findings are observed in cirrhosis patients without ACLF. Pending validation in other larger studies, these study findings would change the current practice of treating patients with HRS-AKI.


Abstract 27. Comparable outcomes between immune-tolerant and active phases in non-cirrhotic chronic hepatitis B: a meta-analysis (Lee et al)

Treating chronic hepatitis B viral infection during the immune-tolerant phase remains controversial. In this meta-analysis, researchers from South Korea pooled data from studies comparing the untreated immune-tolerant (IT) phase versus the treated immune-active (IA) phase in hepatitis B e antigen–positive patients without cirrhosis.

Outcomes included the incidence rate of HCC and mortality. The pooled five- and 10-year incidence rates of HCC were similar between the IT and IA cohorts in 13 studies including 11,903 patients (median age, 40 years; 59.6% men), with a median follow-up period of 62.4 months (five year: IT, 1.1% [95% CI, 0.4%-2.8%] vs. IA, 1.1% [95% CI, 0.5%-2.3%] and 10 year: 2.7% [95% CI, 1.0%-7.3%] vs. 3.6% [95% CI, 2.4%-5.5%]; all P>0.05). The pooled five-year mortality rate was also similar between the IT and IA cohorts (1.9% [95% CI, 1.1%-3.4%] vs. 1.0% [95% CI, 0.3%-2.9%]; P=0.285). The pooled five-year incidence rate of phase change in the IT cohort was 36.1% (95% CI, 29.5%-43.2%).

The investigators concluded that study findings support the timely use of antiviral treatments during the active disease course but not in chronic hepatitis B patients in the IT phase. However, as there was a phase change from IT to IA in 36%, it is recommended to closely monitor patients with chronic hepatitis B in the IT phase.

Dr. Singal: As it’s unclear how patients with chronic hepatitis B should be treated during the IT phase, these study findings are very relevant. Particularly valuable are the data that conclude that IT patients need close monitoring, while treatment should be reserved for situations when there is immune activation and evidence of liver injury. I think these data will make physicians confident in recommending close follow-up and no antiviral treatment of chronic hepatitis B patients in routine clinical practice, as long as the patient is in the IT phase.


Abstract 100. A 52-week phase 3 clinical trial of resmetirom in 180 patients with well-compensated NASH cirrhosis (Harrison et al)

Nonalcoholic steatohepatitis is a very common liver disease worldwide, with a prevalence of about 5% to 6% in the United States. Other than controlling metabolic syndrome—the major risk factor—there are no effective therapies for this disease. Dr. Harrison et al report results from 180 patients in the MAESTRO-NAFLD-1 trial (ClinicalTrials.gov Identifier: NCT04197479), a 52-week, phase 3, randomized, double-blind, placebo-controlled clinical trial in 1,200 NASH patients with metabolic syndrome and cirrhosis on a liver biopsy.

The primary aim was to study the safety and biomarker effects of 80 to 100 mg of resmetirom (Madrigal), a selective thyroid hormone receptor beta agonist. At baseline, the 180 patients receiving open-label resmetirom (64% women; mean age, 63 years) had a mean MELD score of 8.2 (SD, 1.7). To be eligible, patients had at least three metabolic risk factors and NASH cirrhosis diagnosed by liver biopsy or according to accepted criteria. Mean liver stiffness was 5.7 kPa (SD, 2.1) and 24.6 kPa (SD, 14.9) assessed by magnetic resonance elastography (MRE) and FibroScan (Echosens), respectively. The mean steatosis was 318 (SD, 59) on controlled attenuation parameter (CAP) and 8.1% (SD, 5%) on MRI–proton density fat fraction (MRI-PDFF).

The study was split into two cohorts: 105 patients (cohort 1) completed 52 weeks, and the trial is ongoing in another 75 patients (cohort 2). Study end points were relative reduction of MRI-PDFF at week 16, low-density lipoprotein cholesterol (LDL-C) at week 24, apolipoprotein B (apo-B) and triglycerides, and fibrosis based on noninvasive assessment.

At week 52, cohort 1 showed a decrease in steatosis by 38% on MRI-PDFF and by 38 points on CAP (P<0.001 for both). The researchers also found that fibrosis decreased by 10.2 kPa on FibroScan (by 25% in 40%) and by 0.73 kPa on MRE (P=0.03). The effects were associated with a decrease in liver enzymes, and liver volume decreased by 16% at week 16 and by 9% at week 52 (P<0.001) Other benefits of resmetirom, regardless of cirrhosis stage, were 20% reductions in LDL-C, triglycerides and apo-B. Overall, resmetirom was safe and well tolerated, with no decompensation events during the 52 weeks of treatment. The researchers concluded resmetirom effectively improves steatosis, fibrosis and metabolic syndrome parameters in patients with NASH and cirrhosis.

Dr. Singal: Cirrhosis occurs in 15% to 20% of NASH patients. Over time, patients with cirrhosis can develop decompensation and complications, and NASH is the second most common indication for liver transplant in the United States, after alcohol-associated liver disease. This study is relevant, as it is focused on patients with cirrhosis and shows an improvement in fibrosis, suggesting a potential reversibility of the disease. In addition, resmetirom not only showed hepatic safety but, in contrast to some of the previous drugs in the landscape of NASH pharmacotherapy clinical trials, also improved metabolic syndrome markers, which is critical because NASH is a metabolic disease. If the anticipated data from this phase 3 trial in 1,200 patients confirm these findings, resmetirom might play an important and critical role in the management of patients with NASH.


Abstract 3013. Granulocyte colony stimulating factor (G-CSF) in decompensated cirrhosis, acute alcoholic hepatitis, and acute-on-chronic liver failure: a comprehensive meta-analysis of randomized controlled trials (RCTs) (Di Martino et al)

Based on the beneficial effects of granulocyte colony-stimulating factor (G-CSF) on hepatic regeneration and immune restoration, several randomized controlled trials of this drug have been performed in patients with decompensated cirrhosis, ACLF and alcoholic hepatitis (AH). However, the data on survival benefits have remained controversial. Di Martino et al performed this comprehensive meta-analysis of 19 randomized controlled trials investigating G-CSF in a total of 1,291 patients with three conditions: decompensated cirrhosis (n=569), ACLF (n=487) or AH (n=186). Study outcomes were survival (28 days, 90 days, six months and one year) and occurrence of sepsis, and were adjusted by study weight in the pooled data.

In patients with decompensated cirrhosis, G-CSF was associated with a relative risk reduction in patient mortality of 67% at 90 days (OR, 0.33; 95% CI, 0.18-0.58), 69% at six months (OR, 0.31; 95% CI, 0.15-0.62), and 79% at one year (OR, 0.21; 95% CI, 0.12-0.38) as well as with a 28% reduction in the risk for sepsis (OR, 0.28; 95% CI, 0.16-0.49) (P<0.001 for all). In patients with AH, G-CSF was associated with a relative risk reduction in mortality of 69% at 28 days (OR, 0.31; 95% CI, 0.11-0.83; P=0.021) and 83% at 90 days (OR, 0.17; 95% CI, 0.07-0.41; P<0.001) as well as a 42% reduction in the risk for sepsis (OR, 0.17; 95% CI, 0.08-0.38; P<0.001). However, these positive results in the settings of decompensated cirrhosis and AH were seen only in studies in Asian patients. Results were less consistent in patients with ACLF.

The investigators concluded that G-CSF was beneficial in patients with AH and those with decompensated cirrhosis. However, multicenter studies are needed to examine ACLF patients and confirm the findings in decompensated cirrhosis and AH in studies from countries outside of Asia.

Dr. Singal: G-CSF is a promising drug, but its use remains controversial given that positive results only come from Asian studies. Data from Europe did not show any benefit. It would be interesting to propose multicenter studies across continents with a uniform study design and drug regimen. This might allow researchers to determine what’s driving these discrepancies. The contrasting data could be due to differences in populations or in the populations’ disease severity, as we know that patients from Asia, especially those with AH, have a more severe disease than their European counterparts.


Abstract 4722. Adequate biochemical response to ursodeoxycholic acid in patients with primary biliary cholangitis: is normalization of serum liver tests important? (Corpechot et al)

An adequate response to ursodeoxycholic acid (UDCA) therapy predicts good outcomes for patients with primary biliary cholangitis (PBC). The Paris II criteria define this response as a normal total bilirubin with at most 1.5 times the normal upper limits of alkaline phosphatase (ALP) and aspartate aminotransferase (Am J Gastroenterol 2020;115[7]:1066-1074; J Hepatol 2011;55[6]:1361-1367). However, it remains unclear whether a deep biochemical response—normal ALP and total bilirubin of less than 0.6 times the normal upper limit—adds to the survival benefit.

This retrospective cohort study followed 1,034 PBC patients (91% women; mean age, 61 years; 16% of patients with liver stiffness >10 kPa on FibroScan) between 2004 and 2022 at 24 centers in 13 countries, with a mean follow-up of 4.5 years. Patients received UDCA therapy for at least one year (mean duration of treatment, 7.7 years), and the researchers compared outcomes between patients with only an adequate response and those who showed a deep biochemical response. The primary end point was patient survival without decompensation and/or need for a liver transplant.

A total of 80 patients (7.7%) reached the study end point. Patient survival was higher at both five and 10 years in the deep response group than in the adequate response group (five years, 95.9% vs. 91.2%; 10 years, 85.3% vs. 73%, respectively). After adjusting for age, sex, albumin, bilirubin, liver stiffness and UDCA duration, patient survival was 5.5 months (95% CI, 0.6-10.4 months) longer among those with a deep response (P=0.027). This corresponded to a 4.9% (95% CI, 0.1%-9.9%; P=0.044) increase in life span over 10 years and a 54.2% (95% CI, 31.9%-69.1%; P<0.001) decreased risk for poor outcomes. Of the patients meeting the study end point, normal ALP was associated with improved survival (log-rank P=0.003), with a mean difference in 10-year survival time of 7.0 months (95% CI, 2.7-11.4 months) (P<0.001). The authors concluded that patients with an adequate response but still elevated ALP above the upper limit of normal should be considered for second-line treatment.

Dr. Singal: The results from this retrospective study show better long-term survival and outcomes with complete normalization of ALP in PBC patients treated with UDCA. Clearly, these findings need confirmation with a randomized controlled study or prospective data before we move forward with the recommendation to use second-line treatment in patients who are responders but still have ALP above upper limits of normal.

—Compiled and written by Donavyn Coffey


Dr. Singal is a member of the Gastroenterology & Endoscopy News editorial board.

This article is from the April 2023 print issue.