Faculty Bibliography

BACKGROUND AND AIMS/UNASSIGNED:Accurate detection and treatment of hepatitis D virus (HDV)-infected patients can reduce disease-related morbidity and mortality. This study developed and validated real-world evidence-based algorithms to detect ribonucleic acid (RNA)-positive HDV patients from administrative claims data. METHODS/UNASSIGNED:This retrospective observational study identified hepatitis B virus and HDV patients from laboratory testing data linked to administrative claims (HealthVerity; 2015-2022), with external validation performed using electronic health records (TriNetX; 2005-2023). Both diagnosis-based and machine learning algorithms were evaluated. Performance metrics included area under the receiver-operating characteristic curve (AUROC), area under the precision-recall curve, sensitivity, specificity, positive predictive value, and accuracy. Internal validation results showed that diagnosis code-based algorithms identified HDV RNA-positivity with ≥88% accuracy. RESULTS/UNASSIGNED:The best-performing algorithm-based approach in terms of optimism-adjusted AUROC was a random forest model with the following covariates: age, gender, hepatitis complications, HDV, and hepatitis B virus diagnosis, inpatient/outpatient diagnosis, hepatitis medication, and physician specialty (AUROC 97%). Decision curve analysis showed that the random forest algorithm with covariates excluding physician specialty, both inpatient/outpatient diagnosis, and physician specialty performed best. External validation indicated the random forest algorithm using equivalent covariates but without physician specialty had the best performance (positive predictive value 34%; accuracy 92%). CONCLUSION/UNASSIGNED:Algorithms based on HDV diagnosis were more effective for identifying HDV RNA-positive patients than algorithms using HDV-based variables from claims data. Further research into improving such algorithms is needed. Although fair discrimination may occur without claims data, key metrics were not able to replace traditional testing methods. The proposed models could help identify high-risk patients where certain strategies could be prioritized.

Occult hepatitis B virus (HBV) infection (OBI) is defined as the presence of replication-competent HBV DNA in the liver or blood of individuals who are seronegative for hepatitis B surface antigen. The prevalence of OBI varies hugely according to the local endemicity of chronic HBV infection and risk of HBV exposure, ranging from 0.8% in the general population to >10% in those with hepatitis C virus or HIV infection, and to >40% in individuals with isolated positive antibody to hepatitis B core antigen (anti-HBc). Diagnosing OBI remains challenging due to extremely low and fluctuating levels of HBV DNA in individuals over time. Positive serological markers, such as anti-HBc, only arouse clinician suspicion, with no diagnostic confidence, but can be used to identify people with previous exposure to HBV and for subclassification of OBI, which should be combined with serum HBV DNA testing. The consequences of OBI include transmission of HBV during the transfusion of blood products or solid organ transplantation, reactivation of HBV in patients undergoing immunosuppressive therapy, acceleration of disease progression in those with pre-existing chronic liver diseases, and an increased risk of hepatocellular carcinoma development. In this Review, we describe the core knowledge of OBI - epidemiology, diagnosis, mechanisms and virology, and clinical management - that clinicians should be aware of, and elaborate on challenges and future directions associated with OBI.

Chronic hepatitis B virus (HBV) infection remains a serious global public health concern and a leading cause of liver cirrhosis and hepatocellular carcinoma. Although currently available oral therapies can effectively suppress HBV DNA, there is no approved regimen that has shown to reliably achieve a functional cure. In recent years, various classes of novel therapy for HBV infection have undergone considerable research and advanced to clinical trials, targeting multiple stages of the viral life cycle and systemic immunomodulatory pathways. This article discusses the complex HBV life cycle and highlights emerging therapeutic advances on the horizon for HBV treatment.

BACKGROUND & AIMS/OBJECTIVE:We report 104-week placebo-controlled data and long-term open-label extension (OLE) data from the ongoing ELATIVE® phase III trial (NCT04526665) of elafibranor in primary biliary cholangitis (PBC). METHODS:161 patients were randomized 2:1 to elafibranor 80 mg or placebo. The double-blind period (DBP) consisted of 52-week common (Part 1) and variable (Part 2) periods. Patients completing Part 1 continued into Part 2 until all patients completed Part 1, or for a maximum of 104 weeks. All patients completing Part 1 could enter the OLE and receive elafibranor. RESULTS:At Week 104 in the DBP Part 2, 64.3% (18/28) and 10.7% (3/28) of elafibranor-treated patients achieved biochemical response and alkaline phosphatase (ALP) normalization, versus no placebo-treated patients. In patients with moderate-to-severe fatigue or pruritus at baseline, mean (SE) changes to Week 104 in PROMIS Fatigue Short Form 7a (PFSF 7a) and PBC Worst-Itch Numeric Rating Scale (PBC WI NRS) were -6.3 (2.2) versus -0.4 (1.2) and -4.1 (1.0) versus 0.3 (1.2) with elafibranor versus placebo. 138 patients entered the OLE (continuous elafibranor: n=93; crossover elafibranor: n=45). In continuous patients at Weeks 104 and 156, 58.8% (47/80) and 65.0% (13/20) achieved biochemical response, and 15.0% (12/80) and 25.0% (5/20) achieved ALP normalization. In crossover patients, 51.2% (21/41) and 22.0% (9/41) achieved biochemical response and ALP normalization after 52 weeks. In continuous patients with baseline moderate-to-severe symptoms, mean (SE) changes to Week 130 in PFSF 7a and PBC WI NRS were -4.8 (1.5) and -4.0 (0.7). There were no unexpected safety findings. CONCLUSIONS:Through three years of treatment, elafibranor led to sustained biochemical improvements and was generally well tolerated, with numerical improvements in fatigue and pruritus. TRIAL REGISTRATION/BACKGROUND:NCT04526665 (https://clinicaltrials.gov/study/NCT04526665); first registered 08/26/2020 IMPACT AND IMPLICATIONS: • Given the chronic, progressive nature of primary biliary cholangitis (PBC), the long-term efficacy and tolerability of treatments is important.• Here, we present two-year results from the double-blind period, and long-term data from the ongoing open-label extension of the phase III ELATIVE® trial, wherein elafibranor (a peroxisome proliferator-activated receptor-α/δ agonist) treatment led to sustained biochemical improvements, stable non-invasive tests of fibrosis, and numerical improvements in fatigue and pruritus, through three years.• Elafibranor demonstrated a favorable safety profile up to a maximum treatment exposure of 3.5 years, including in patients crossing over from placebo.• These findings support elafibranor's role as a durable long-term treatment for patients with PBC, and are particularly relevant for clinicians managing patients with inadequate response or intolerance to first-line treatments.

BACKGROUND AIMS/UNASSIGNED:AHB-137 is a novel ASO targeting a conserved region near the 3' end of all HBV mRNA. This first-in-human phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and antiviral efficacy in healthy subjects and chronic hepatitis B (CHB) patients. METHODS:Forty healthy subjects were randomized into four placebo-controlled single ascending dose (100-450 mg, 6:2 AHB-137:placebo) cohorts and one multiple-dose (MD; 300 mg, 6:2) cohort receiving four weekly subcutaneous doses with a Day 4 loading dose (5 doses). Twenty-four virally suppressed, HBeAg-negative CHB patients on stable nucleos(t)ide analogue therapy were enrolled: four in an open-label 300-mg MD cohort (5 doses) and 20 in two placebo-controlled 300-mg MD cohorts (4:1, stratified by baseline HBsAg), receiving an additional loading dose on Day 11 (6 doses). RESULTS:Treatment-related adverse events occurred in 73% of healthy subjects and 71% of CHB patients and were primarily mild or moderate injection-site reactions and headaches. No treatment-related serious adverse events, discontinuations, or deaths were observed. PK profiles showed rapid absorption (Tmax 2.96-5.50 h), dose-proportional exposure, no significant accumulation, long terminal half-life (150-220 h), and minimal renal excretion. In CHB patients, AHB-137 treatment led to a rapid HBsAg decline (mean 0.7-1.0 log10 IU/mL). HBsAg loss (<0.05 IU/mL) for at least one timepoint was observed in three patients, including two with baseline HBsAg <1 IU/mL and one with baseline HBsAg <1.5 IU/mL. CONCLUSIONS:In this Phase 1 study, AHB-137 demonstrated an acceptable safety profile, predictable PK, and rapid and prolonged HBsAg reductions, supporting further evaluation of dosing and treatment duration in CHB.

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.