Faculty Bibliography

BACKGROUND:Treatment options are limited for patients with primary biliary cholangitis (PBC) and cirrhosis. Seladelpar, a first-in-class delpar (selective PPAR-δ agonist), had generally similar efficacy and safety among patients with versus without compensated cirrhosis in the phase 3 RESPONSE study. Here we provide additional data on seladelpar in patients with compensated cirrhosis from the phase 3 program. METHODS:In RESPONSE, patients with PBC and an inadequate response or intolerance to UDCA were randomized 2:1 to seladelpar 10 mg or placebo for 1 year. Upon completion, patients rolled over into the open-label (seladelpar 10 mg) phase 3 ASSURE study, which also enrolled patients from earlier seladelpar legacy PBC studies. Here, we assessed the composite endpoint [alkaline phosphatase (ALP) <1.67×upper limit of normal (ULN), ALP decrease ≥15%, and total bilirubin ≤ULN], other laboratory changes, and safety in all patients with cirrhosis from RESPONSE and an interim analysis of the ongoing ASSURE study through January 2024. RESULTS:Twenty-seven patients with compensated cirrhosis enrolled in RESPONSE (18 seladelpar, 9 placebo). At month 12, 38.9% and 22.2% of patients in the seladelpar and placebo groups, respectively, met the composite endpoint; mean percent change from baseline in ALP was -37.1% and -10.1%, respectively. Upon rollover to ASSURE (13 seladelpar, 6 placebo), ALP declines were maintained for up to 18 months. An additional 35 patients with compensated cirrhosis in ASSURE from legacy studies had similar reductions in ALP with up to 2 years of treatment. Bilirubin remained overall stable. No treatment-related serious adverse events occurred. Variceal bleeding and/or ascites developed in 3 patients after ≥9 months. CONCLUSIONS:Seladelpar decreased markers of cholestasis and was overall safe and well-tolerated in patients with PBC and compensated cirrhosis.

BACKGROUND AND AIMS/OBJECTIVE:Although pregnant people are a WHO priority population for hepatitis C (HCV) elimination, there is limited guidance on HCV treatment in pregnancy. Emerging data suggests direct acting antiviral (DAA) therapy is safe and effective. We performed a multinational survey among gastro-hepatologists (GI-Hep), infectious disease (ID) specialists, obstetricians-gynaecologists (ob-gyns), and general practitioners (GP) to evaluate current perspectives on HCV treatment in pregnancy. METHODS:A 39-item survey was designed by experts at The Global Liver Council, the American College of Obstetricians and Gynaecologists, and the Coalition for Global Hepatitis Elimination and distributed electronically. Survey responses were compared across medical specialties and regions. RESULTS:A total of 651 participants from all WHO regions representing 58 countries completed the survey: GI-Hep: 46%, GP-ID: 36%, ob-gyns: 18%. Only 25% would consider treating HCV during pregnancy, with significant differences by specialty. Main reasons for not considering DAAs in pregnancy were insufficient safety data (27%) and no clear guidelines for HCV treatment (32%). The highest acceptance of DAA use in pregnancy was in North America (45% vs. < 20% in other regions (p < 0.01)). Predictors of a greater willingness to treat HCV in pregnancy were having ≥ 10% of practice population with injection drug use (aOR: 2.31; 95% CI: 1.49-3.60; p = 0.0002). GI-Hep specialty was associated with a lower willingness (aOR: 0.47; 95% CI: 0.28-0.78; p = 0.004). CONCLUSIONS:Despite relatively high levels of HCV knowledge, few participants have experience with HCV treatment in pregnancy or would consider such treatment. Further availability of safety evidence and the inclusion of specific recommendations in guidelines could increase uptake of DAAs for pregnant individuals.

INTRODUCTION AND OBJECTIVES/OBJECTIVE:Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease but remains widely under-recognized in primary care. The 2023 shift from "nonalcoholic fatty liver disease" to MASLD emphasized metabolic dysfunction as a driver of disease but introduced new communication and educational challenges for primary care providers (PCPs). We aimed to assess PCPs' awareness, risk assessment, and management practices related to MASLD in the four most populous U.S. cities. MATERIALS AND METHODS/METHODS:A cross-sectional online survey was conducted from 5 to 13 September 2024 among 800 primary care providers (PCPs; n = 200 per city) in New York City, Los Angeles, Chicago, and Houston. Participants included physicians, physician assistants, nurse practitioners, and other primary care professionals. The survey assessed awareness of "MASLD" and "fatty liver disease", risk assessment practices for high-risk groups, patient discussions, management strategies, and the use of patient-reported outcomes (PROs). Descriptive statistics characterized sample responses, and logistic regression models identified correlates of awareness. RESULTS:Overall, 54.7% of PCPs reported awareness of MASLD and 86.6% were aware of fatty liver disease. Awareness of MASLD was highest among physicians (81.3%) and hospital-based practitioners (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.02-4.02) and lowest among nurse practitioners (OR = 0.21, 95% CI 0.09-0.49). Awareness of fatty liver disease increased with provider age (OR = 1.04, 95% CI 1.00-1.08). Lifestyle modification was the most recommended management approach (41.3-65.5%), while referral rates to specialists and PRO use varied substantially across cities, and 48.5% were aware of the FIB-4 Index. CONCLUSIONS:Only half of PCPs recognized the term MASLD, highlighting gaps in awareness and clinical practice following the mid-2023 terminology change. Targeted educational initiatives and standardized implementation of MASLD guidelines in primary care are needed to improve timely detection and management of this highly prevalent condition.

Hepatitis D virus (HDV) screening rates in the United States are low. We evaluated the impact of double reflex-based HDV testing on HDV-related morbidity and mortality in the United States. A Screen and Treat model simulated the HDV screening cascade (decision tree) and assessed the natural history of HDV (Markov model) over a 5-year time horizon from a United States third-party payer perspective, for patients positive for HBV. The number of patients diagnosed with HDV and liver-related outcomes were compared under double reflex screening (100% patients screened for HDV antibodies and HDV RNA) and current practice (11% patients screened for HDV antibodies and 25% anti-HDV-positive patients for HDV RNA). Implementation of HDV double reflex testing predicted a 3655% increase in patients diagnosed versus current practice (n = 7231 vs. n = 193, respectively). The number of predicted occurrences of all liver-related outcomes over 5 years is lower with double reflex testing versus current practice (difference in numbers of events: -7% for compensated cirrhosis, -40% for decompensated cirrhosis, -23% for hepatocellular carcinoma, -34% for liver transplantation, and -32% for liver-related deaths). Results of scenario analyses with varying HBV prevalence, treatment received, or treatment rates were similar. Simulation of double reflex testing predicted earlier detection of HDV patients, increased numbers of patients diagnosed and treated, and reduced rates of disease progression, liver-related complications and deaths. These findings highlight the need for implementing strategies to improve HDV screening and linkage to care and treatment in the United States. Trial Registration: ClinicalTrials.gov identifier: NCT03852719.

BACKGROUND & AIMS/OBJECTIVE:Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease. Elafibranor, a dual peroxisome proliferator-activated receptor-α/δ agonist, was investigated in the phase II ELMWOOD trial (NCT05627362). METHODS:This 12-week, double-blind trial enrolled adults with PSC and alkaline phosphatase (ALP) ≥1.5× the upper limit of normal. The primary endpoint was elafibranor safety vs. placebo. Additional endpoints included relative mean change from baseline in ALP and enhanced liver fibrosis (ELF) score. RESULTS:A total of 68 participants (male: 54.4%; mean age: 46.3 years; inflammatory bowel disease: 55.9%) were randomized to elafibranor 80 mg (n = 22), elafibranor 120 mg (n = 23), or placebo (n = 23). At baseline, 70.6% were on ursodeoxycholic acid, 48.5% had ELF scores >9.8, and the mean ALP level was 369.5 U/L. At Week 12, rates of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation in participants on elafibranor 80 mg, 120 mg, and placebo were 68.2%, 78.3%, and 69.6%, and 4.5%, 4.3%, and 8.7%, respectively. Serious TEAEs occurred only in participants on placebo (4.3%). Participants on elafibranor 80 mg and 120 mg had reductions in ALP vs. placebo (least squares mean treatment difference [95% CI]: -35.3% [-49.2, -21.4] and -54.7% [-68.3, -41.0], respectively). ALP normalization occurred only in participants on elafibranor 80 mg (9.1%) and 120 mg (17.4%). The LS mean treatment differences (95% CI) in change from baseline in ELF scores in participants on elafibranor 80 mg and 120 mg vs. placebo were -0.19 (-0.52, +0.15) and -0.28 (-0.62, +0.06), respectively. CONCLUSIONS:Elafibranor was well tolerated in people with PSC and associated with greater biochemical improvements over 12 weeks compared with placebo. A greater magnitude of response was observed with elafibranor 120 mg compared with 80 mg. IMPACT AND IMPLICATIONS/UNASSIGNED:For people with primary sclerosing cholangitis (PSC), there is a need for a well-tolerated and effective treatment that will enhance quality of life, prevent disease progression, and improve long-term outcomes. Here, we present results from the double-blind period of the phase II ELMWOOD trial in PSC, wherein elafibranor, a peroxisome proliferator-activated receptor-α/δ agonist, demonstrated a favorable safety profile, provided greater biochemical improvements over 12 weeks compared with placebo, and appeared to stabilize markers of fibrosis and improve pruritus. These findings support larger and longer term investigations of elafibranor to explore its therapeutic potential as a treatment for people with PSC.

BACKGROUND:Hepatitis delta virus (HDV) requires hepatitis B virus (HBV) surface antigen to enter hepatocytes. Although HBV/HDV coinfection is the most severe form of viral hepatitis, disease progression and liver-related data are limited. AIMS/OBJECTIVE:To evaluate the characteristics of studies reporting HDV outcomes and the incidence of liver-related events among individuals with HDV. METHODS:We searched online databases from 1 January 2000 to 14 December 2022 and congress proceedings from 2021 to 2022. Randomised controlled trials (RCTs), non-randomised interventional studies and observational studies reporting incidence of cirrhosis, hepatic decompensation, hepatocellular carcinoma (HCC), liver transplant (LT) and liver-related death in ≥ 20 adults with active HDV infection were included. Study/participant characteristics, cumulative incidence and incidence rates were extracted. RESULTS:Data were extracted from 32 unique studies in 47 publications. While most (n = 19; 59%) studies included < 100 individuals, five included ≥ 200. Most were retrospective cohort (n = 19; 59%), and the remainder were prospective cohort (n = 5), non-randomised interventional (n = 3), RCT (n = 3) or registry/database studies (n = 2). Outcomes reported by the largest numbers of studies were hepatic decompensation (n = 21) and HCC (n = 20); the least reported was cirrhosis (n = 9). Heterogeneity existed in participant populations, with variability in baseline markers of liver disease severity. Consequently, a wide range of cumulative incidence values was observed (cirrhosis, 0%-63%; hepatic decompensation, 0%-52%; HCC, 0%-19%; LT, 2%-43%; liver-related death, 0%-19%; composite endpoint, 3%-74%). CONCLUSIONS:The number of studies describing the incidence of liver-related outcomes among people with HDV remains limited. Quantifying incidence of liver-related events can improve our understanding of disease progression and inform potential treatment strategies. TRIAL REGISTRATION/BACKGROUND:PROSPERO registration ID: CRD42023386845.

BACKGROUND:Chronic hepatitis B virus (HBV) infection is a common but underdiagnosed and undertreated health condition and is the leading cause of hepatocellular carcinoma (HCC) worldwide. HBV (rated a Grade 1 carcinogen by the International Agency for Research on Cancer) drives the transformation of hepatocytes in multiple ways by inducing viral DNA integrations, genetic dysregulation, chromosomal translocations, chronic inflammation, and oncogenic pathways facilitated by some HBV proteins. Importantly, these mechanisms are active throughout all phases of HBV infection. Nevertheless, most clinical guidelines for antiviral therapy recommend treatment based on a complex combination of HBV DNA levels, transaminasemia, liver histology, and demographic factors, rather than prompt treatment for all people with infection. AIMS/OBJECTIVE:To determine if current frameworks for antiviral treatment address the impacts of chronic HBV infection particularly preventing cancer development. MATERIALS AND METHODS/METHODS:We reviewed the recent data demonstrating pro-oncogenic factors acting throughout a chronic HBV infection can be inhibited by antiviral therapy. RESULTS:We extensively reviewed Hepatitis B virology data and correlating clinical outcome data. From thi, we suggest that new findings support simplifying and expanding treatment initiation to reduce the incidence ofnew infections, progressive liver disease, and risk of hepatocellular carcinoma. We also consider lessons learned from other blood-borne pathogens, including the benefits of antiviral treatment in preventing transmission, reducing stigma, and reframing treatment as cancer prevention. CONCLUSION/CONCLUSIONS:Incorporating these practice changes into treatment is likely to reduce the overall burden of chronic HBV infections and HCC. Through this, we may better achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat and minimise its impact on people's lives.