In this first part of a two-part series of Expert Picks from The Liver Meeting 2024, Ashwani Singal, MD, MS, a professor of medicine at the University of Louisville School of Medicine and transplant hepatologist at Jewish Hospital at Trager Transplant Center, in Kentucky, discusses abstracts on managing variceal bleeding, hepatocellular carcinoma and more.
Abstract 0005. Preemptive TIPS: the new standard for gastric variceal bleeding in patients with cirrhosis? Results of a large multicenter randomized controlled trial (Cervoni et al)
A multicenter team of researchers in France compared the efficacy of preemptive transjugular intrahepatic portosystemic shunt (TIPS) with that of variceal glue obturation (GO) to prevent rebleeding in patients with acute gastric variceal bleeding.
Patients who had an acute gastric variceal bleeding episode and were stabilized after treatment with GO were randomized to receive either preemptive TIPS (within 72 hours of initial endoscopy) or continued GO (on demand) plus nonselective beta-blockers. Patients with gastroesophageal varices type 1 were excluded.
After being stabilized, 47 patients were randomized to preemptive TIPS and 54 to continued GO plus beta-blockers. The majority (80%) were male, and the median age of the participants was 59 years. Alcohol-associated cirrhosis was the most common etiology among participants (90%); 84% had Child-Pugh scores of B or C, and the median Model for End-Stage Liver Disease (MELD) score was 14.
Patients randomized to TIPS had lower rates of rebleeding (10.6% vs. 44.4%; P<0.001) and required fewer blood units (2 vs. 3; P=0.05) than those randomized to GO plus beta-blockers.
Survival was comparable in the TIPS and GO arms at one year (84% vs. 77%), but 19 patients in the GO arm received rescue treatment with TIPS during follow-up. The rate of one-year survival free of rebleeding was 75% (95% CI, 60%-86%) in the TIPS arm and 37% (95% CI, 24%-50%) in the GO arm.
When looking at a sensitivity analysis of TIPS as a time-dependent variable, regardless of randomization, the investigators found that TIPS was associated with a lower hazard for mortality (adjusted hazard ratio [aHR], 0.41; 95% CI, 0.17-1.02).
The groups were comparable in terms of hepatic encephalopathy, further decompensation and hospital length of stay.
Dr. Singal: We know that glue is not the definitive treatment for gastric varices. This is the first study on the use of preemptive TIPS for gastric variceal bleeding, and the results confirm that preemptive TIPS after glue stabilization is the right thing to do in patients with gastric varices. This study is especially useful for GI fellows to give them more confidence in deciding on TIPS as a potential definitive treatment option for gastric variceal bleeding after initial stabilization.
Abstract 0014. Impact of pre-transplant immune checkpoint inhibitors on downstaging of outcomes: a prospective intention-to-treat analysis from a multi-center US study (Tabrizian et al)
Investigators at liver transplant centers across the United States conducted a prospective study to assess downstaging and survival in hepatocellular carcinoma (HCC) patients treated with pre-transplant immune checkpoint inhibitors (ICIs).
Between 2015 and 2024, the investigators enrolled and categorized patients with HCC based on whether they met the following criteria: United Network for Organ Sharing (UNOS) downstaging criteria (n=201), “all comer” criteria (patients with any number of tumors of any size and diameter, with a six-month wait before liver transplantation) (n=122), and ICI treatment criteria (patients who had “exhausted locoregional therapy options or with more aggressive tumor biology”) (n=64). Patients were excluded from analyses if they had complete response to their first locoregional therapy or were treated with immunotherapy alone.
Patients in the three groups were similar in terms of age (median, approximately 64 years), sex (approximately 80% male), underlying liver disease, Child-Pugh class (approximately 75% class A) and MELD score at diagnosis (8-9 years).
Among patients in the ICI group, 78% achieved successful downstaging (residual tumors within Milan criteria) in a median of 7.2 months. This time to downstaging was longer than that seen in the UNOS downstaging (three months) and all-comers (4.7 months) groups. The probability of downstaging by year 3 also was lower in the ICI group (78.3%) than in the UNOS downstaging (92.4%) and all-comers (88.1%) groups.
The probability of liver transplantation by year 3 was lower in the ICI group (29.5%) than in the UNOS downstaging (46.8%) and all-comers (50.9%) groups. However, the probability of dropout by year 3 was similar across the three groups (approximately 45%).
In the intention-to-treat analysis, three-year survival was 71.7% in the ICI group, 68.8% in the UNOS downstaging group and 61.7% in the all-comers group (P=0.313). Child-Pugh class B or C, as opposed to A, was predictive of worse survival (HR, 1.56; 95% CI, 1.04-2.36). Factors associated with better survival included having a partial response to initial locoregional therapy, as opposed to stable disease (HR, 0.48; 95% CI, 0.28-0.81), and being eligible to receive three (HR, 0.47; 95% CI, 0.24-0.89) or four (HR, 0.34; 95% CI, 0.19-0.62) locoregional therapies, rather than just one.
In patients who were transplanted, post-transplant survival at three years was 93.8% in the ICI group, compared with 83.6% in the UNOS downstaging group and 81.9% in the all-comers group (P=0.795). In addition, those in the ICI group had a higher likelihood of complete tumor necrosis in the explant (31.6% vs. 19.5% in UNOS downstage and 0% in all-comers).
Post-transplant HCC recurrence was seen in 15% of patients in the ICI group in a median time of 23.8 months (IQR, 6.8-40.7 months), in 10.2% of patients in the UNOS downstaging group in a median time of 14 months (IQR, 11-20.9 months) and in 8.7% of patients in the all-comers group in a median of 5.1 months (3.8-7.9 months).
In terms of the safety of the ICIs, no patients experienced grade 4 or 5 adverse events while on the transplant waiting list, and three patients (15%) experienced rejection.
Dr. Singal: This nicely performed study clearly shows benefit of immunotherapy in patients with HCC outside of Milan criteria and when locoregional therapy is ineffective in downstaging these tumors to make them eligible for liver transplantation. The excellent overall and tumor-free survival at three years post-transplantation are reassuring for the transplant community and providers if they were to consider immunotherapy for downstaging of HCC in scenarios when locoregional treatments like chemoembolization or radioembolization are ineffective to achieve the same goal.
Abstract 0021. Association of hepatitis delta virus infection and hepatocellular carcinoma, hepatic decompensation, all-cause and liver-related death in a U.S. national cohort (John et al)
Investigators conducted a retrospective analysis of hepatitis delta virus (HDV) outcomes, including HCC, hepatic decompensation and mortality, in a cohort of patients treated by the Veterans Health Administration.
Patients with hepatitis B virus (HBV) who were tested for HDV from 2000 to 2022 were included in analyses. Among 4,817 patients tested, 3.3% (n=158) were positive for HDV. HDV-positive and HDV-negative patients were comparable in terms of age (54.8 vs. 56.9 years) and proportion with HIV coinfection (13.9% vs. 13.4%), but HDV-positive patients more commonly were male (98.7% vs. 94.9%), had a non-alcohol substance use disorder (76.0% vs. 56.7%) and had a history of being HCV RNA-positive (26.0% vs. 12.0%). In addition, HDV-positive patients had higher baseline alanine aminotransferase levels, platelet counts and Fibrosis-4 Index scores, and more commonly had cirrhosis and a liver transplant.
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Compared with HDV-negative patients, those who were HDV-positive had a higher incidence of HCC (16.5% vs. 3.9%), hepatic decompensation (13.9% vs. 5.6%), all-cause mortality (48.7% vs. 31.0%), liver-related mortality (16.5% vs. 7.7%) and the composite end point of liver-related outcomes (31% vs. 11.3%). This same trend was seen at five and 10 years from baseline.
In their multivariable Cox proportional hazards model, the investigators found that HDV-positive patients had 2.63 times the hazard of experiencing the composite liver outcomes (95% CI, 1.94-3.56) and 1.52 times the hazard of experiencing all-cause mortality (95% CI, 1.20-1.93) compared with HDV-negative patients. Similarly, HCC (aHR, 3.61; 95% CI, 2.35-5.54), hepatic decompensation (aHR, 2.36; 95% CI, 1.50-3.70) and liver-related mortality (aHR, 1.89; 95% CI, 1.25-2.86) were more likely in HDV-positive patients.
Dr. Singal: HDV is an incomplete virus and requires HBV for its replication. HDV can be acquired concomitantly with HBV (coinfection) or subsequently (superinfection). The findings of this study showing worse acute outcomes of decompensation and mortality and chronic outcomes of disease progression and HCC suggest that clinicians should consider screening for HDV in HBV-positive patients, especially when the index of suspicion is high. The study raises awareness about screening for HDV, and this is especially relevant now that HDV is treatable with specific antiviral drugs.
Abstract 4096. Role of high versus standard dose of terlipressin in reversing HRS-AKI: pooled analysis from phase 3 clinical trials (Sharma et al)
Pooling results from three phase 3 studies (OT-0401, REVERSE and CONFIRM), a multicenter team of researchers evaluated the efficacy and safety of standard- and escalated-dose terlipressin (Terlivaz, Mallinckrodt) compared with placebo for the management of hepatorenal syndrome–acute kidney injury (HRS-AKI).
Initial dosing of terlipressin, a vasopressin receptor agonist, is 1 mg every six hours, with escalation to 2 mg every six hours recommended on day 4 in patients who have a 30% reduction from baseline in serum creatinine.
Among 349 patients who received terlipressin, 72.8% had the standard dose, while 27.2% had dose escalation (at least one dose =2 mg).
In their intention-to-treat analysis, the investigators found that 31.2% of standard-dose patients and 40% of escalated-dose patients achieved HRS reversal (at least one serum creatinine level of =1.5 mg/dL up to 24 hours after last dose) (P=0.12). A greater proportion of standard-dose terlipressin patients than their placebo comparators achieved HRS reversal (31.2% vs. 13.4%; P<0.001), as was the case for the escalated-dose patients and their comparators (40.0% vs. 23.3%; P=0.016).
Serious adverse events were seen in 66.1% of patients who received standard-dose terlipressin, 62.1% of patients who received escalated-dose terlipressin and 59.8% of patients who received placebo.
Dr. Singal: This analysis of pooled data from three randomized trials of terlipressin in patients with HRS showed that although one-fourth of these patients needed escalation of the terlipressin dose, the proportion of patients reversing HRS was 40%, versus 23% of patients receiving placebo. Furthermore, the side effect profile including serious adverse effects of respiratory failure was similar for standard- and high-dose terlipressin. These data are encouraging to clinicians considering dose escalation when serum creatinine does not decrease by 30% or more within the first three to four days (partial HRS reversal).
—Compiled and written by Natasha Albaneze, MPH
This article is from the April 2025 print issue.