Food Insecurity in Hispanic Populations Is Associated with an Increased Risk of Hepatic Steatosis: A Nationally Representative Study.

Introduction: The Hispanic population in the US faces a higher risk of nonalcoholic fatty liver disease (NAFLD). Multiple factors influence this risk, including genetics, environmental factors, and socioeconomic statuses. Inadequate access to nutritious foods, or food insecurity, is prevalent among Hispanic individuals and poses a metabolic risk for both the onset and development of NAFLD. Materials and Methods: We utilized the National Health and Nutrition Examination Survey (NHANES) 2017-2020 pre-pandemic data to analyze the association between Hispanic ethnicity, hepatic steatosis, fibrosis, and food insecurity. Vibration-controlled transient elastography (VCTE) was employed to assess liver stiffness (LSM) and controlled attenuation parameter (CAP) scores to determine fibrosis and steatosis, respectively. Linear and ordinal logistic regression models were applied to their continuous, log-transformed, and categorical forms, adjusting for demographics, metabolic comorbidities, and socioeconomic factors. Models were subsequently stratified based on food security statuses. Results: A total of 7396 Hispanic participants were included in the study. Under multivariable analysis, Hispanic individuals had higher CAP scores (Beta-coefficient: 10.2 dB/m, 95% CI: 6.1-14.4 dB/m, p = 0.001)) vs. non-Hispanic individuals, without statistically significant differences in fibrosis. Food-insecure participants exhibited higher CAP scores than their food-secure counterparts. After stratification, a stronger association between Hispanic ethnicity and CAP scores was evident in the food-insecure group (Beta-coefficient: 11.8 dB/m, 95% CI: 4.4-19.3 dB/m, p = 0.003). Discussion: This study demonstrates the heightened risk of hepatic steatosis among individuals with Hispanic ancestry in the US. The risk is exacerbated by food insecurity, particularly for Hispanic individuals. The contribution is linked to the dietary habits in this population that lead to metabolic risk factors associated with hepatic steatosis. Considering the rising prevalence of NAFLD and food insecurity, interventions focusing on nutritional support and healthcare access among this population could mitigate these burdens.

Impact of the Early COVID-19 Pandemic on Incidence and Outcomes of Hepatocellular Carcinoma in the United States.

OBJECTIVES: Access to hepatocellular carcinoma (HCC) surveillance and treatments were disrupted during the COVID-19 pandemic. We aimed to characterize the impact of the pandemic on HCC incidence and mortality rates, treatment and outcomes in the U.S. METHODS: Two nationwide databases, the United States Cancer Statistics and the National Vital Statistics System, were used to investigate HCC incidence and mortality between 2001-2020. Trends in age-adjusted incidence (aIR) and mortality (aMR) rates were assessed using joinpoint analysis. The 2020 aIR and aMR were projected based on the pre-pandemic data and compared to actual values to assess the extent of underdiagnosis. We assessed differences in HCC characteristics, treatment and overall survival (OS) between 2020 and 2018-2019. RESULTS: The aIR of HCC in 2020 was significantly reduced compared to 2019 (5.22 vs 6.03/100K PY), representing a 12.2% decrease compared to the predicted aIR in 2020 (5.94/100K PY). The greatest extent of underdiagnosis was observed in Black (-14.87%) and Hispanic (-14.51%) individuals and those with localized HCC (-15.12%). Individuals staged as regional or distant HCC were also less likely to receive treatment in 2020. However, there was no significant difference in short-term OS in 2020 compared to 2018-2019, with HCC mortality rates remaining stable (aMR: 2.76 vs 2.73/100K PY in 2020 vs 2019). CONCLUSIONS: The COVID-19 pandemic resulted in underdiagnosis of HCC, particularly early-stage disease and racial ethnic minorities, and underuse of HCC-directed treatment. Longer follow-up is needed to determine the impact of the COVID-19 pandemic on HCC-related mortality.

Development and validation of a biomarker index for HCC treatment response.

BACKGROUND: Serum AFP-L3%, AFP, and DCP are useful biomarkers for HCC detection, but their utility in assessing treatment response remains unknown. We aim to evaluate the accuracy of a biomarker model in the detection of posttreatment viable tumors. METHODS: For model derivation, recipients with HCC undergoing liver transplant from 2018 to 2022 who had biomarkers collected within 3 months before transplant were included. We developed a generalized linear model for detecting posttreatment viable tumors with the 3 biomarkers as covariates, which we termed the "LAD Score." An independent cohort of 117 patients with HCC was used for external validation. RESULTS: Among 205 recipients of transplant, 70.2% had evidence of viable tumor on explant. The median LAD score was higher among patients with viable versus nonviable tumors (1.06 vs. 0.465, p < 0.001). The LAD score had a sensitivity of 55.6% and a specificity of 85.1% at the cutoff of 0.927, which was more accurate than imaging for detecting posttreatment viable tumors (AUROC 0.736 vs. 0.643, respectively; p = 0.045). The superior performance of the LAD score over imaging is primarily driven by its greater accuracy in detecting tumors <2 cm in diameter (AUROC of the LAD score 0.721 vs. imaging 0.595, p = 0.02). In the validation data set, the LAD score had an AUROC of 0.832 (95% CI: 0.753, 0.911) with a sensitivity of 72.5% and a specificity of 89.4% at the cutoff of 0.927. CONCLUSIONS: Our findings suggest the utility of LAD score in treatment response assessment after locoregional therapy for HCC, particularly in detecting small tumors. A larger prospective study is in progress to validate its accuracy and evaluate its performance in recurrence monitoring.

Correction to: Amanita Mushroom Toxin Poisoning in Los Angeles County.

[This corrects the article DOI: 10.14309/crj.0000000000001246.].

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

Amanita Mushroom Toxin Poisoning in Los Angeles County.

Mushroom (amatoxin) poisoning from ingestion is a rare but life-threatening medical emergency characterized by gastrointestinal symptoms before progression to multisystem organ failure in severe cases. Many therapies of amatoxin intoxication have been described, including supportive care, medical therapies, detoxification strategies, and liver transplant. The evidence supporting these therapies remains limited due to the rarity of amatoxin poisoning and challenge of a timely diagnosis. We report a case of amatoxin poisoning in Los Angeles causing severe liver injury without acute liver failure treated successfully using medical therapies, gallbladder drainage, and plasma exchange.

Beyond the Checkpoint: Severe Axitinib-induced Liver Injury.

Understanding the potential adverse effects associated with oncological treatments is crucial in the clinical care of patients with cancer. We describe the first case report delineating severe acute liver injury secondary to axitinib. This is a case of metastatic renal cell carcinoma treated with axitinib and pembrolizumab, complicated by a severe axitinib-induced liver injury, characterized by significant elevations of hepatocellular and cholestatic liver enzymes during initial treatment and rechallenge of axitinib. Remarkably, the liver chemistries normalized upon discontinuation of the medication.

Traditional Chinese Medicine, Cordyceps, Related to Hepatoportal Sclerosis.

We describe a case of hepatoportal sclerosis (HPS) identified in an 81-year-old woman taking a traditional Chinese herbal supplementation, Cordyceps. The patient presented with splenomegaly and weight loss. After an extensive evaluation, liver biopsy confirmed loss of the small portal veins with characteristics of obstruction at the level of the small and large portal veins, suggestive of HPS. After a comprehensive history and exclusion of other etiological factors, patient's HPS was attributed to Cordyceps use. Ultimately, the patient's features of HPS improved with the cessation of Cordyceps.

ChatGPT's ability to comprehend and answer cirrhosis related questions in Arabic.

BACKGROUND AND STUDY AIMS: Cirrhosis is a chronic progressive disease which requires complex care. Its incidence is rising in the Arab countries making it the 7th leading cause of death in the Arab League in 2010. ChatGPT is a large language model with a growing body of literature demonstrating its ability to answer clinical questions. We examined ChatGPT's accuracy in responding to cirrhosis related questions in Arabic and compared its performance to English. MATERIALS AND METHODS: ChatGPTs responses to 91 questions in Arabic and English were graded by a transplant hepatologist fluent in both languages. Accuracy of responses was assessed using the scale: 1. Comprehensive, 2. Correct but inadequate, 3. Mixed with correct and incorrect/outdated data, and 4. Completely incorrect.Accuracy of Arabic compared to English responses was assessed using the scale: 1. Arabic response is more accurate, 2. Similar accuracy, 3. Arabic response is less accurate. RESULTS: The model provided 22 (24.2%) comprehensive, 44 (48.4%) correct but inadequate, 13 (14.3%) mixed with correct and incorrect/outdated data and 12 (13.2%) completely incorrect Arabic responses. When comparing the accuracy of Arabic and English responses, 9 (9.9%) of the Arabic responses were graded as more accurate, 52 (57.1%) similar in accuracy and 30 (33.0%) as less accurate compared to English. CONCLUSION: ChatGPT has the potential to serve as an adjunct source of information for Arabic speaking patients with cirrhosis. The model provided correct responses in Arabic to 72.5% of questions, although its performance in Arabic was less accurate than in English. The model produced completely incorrect responses to 13.2% of questions, reinforcing its potential role as an adjunct and not replacement of care by licensed healthcare professionals. Future studies to refine this technology are needed to help Arabic speaking patients with cirrhosis across the globe understand their disease and improve their outcomes.

Immunotherapy and Transarterial Radioembolization Combination Treatment for Advanced Hepatocellular Carcinoma.

INTRODUCTION: The efficacy and safety of combined immunotherapy and transarterial radioembolization (TARE) were suggested in preclinical and early-phase trials, but these were limited by small sample sizes. We sought to compare the efficacy of combined therapy and immunotherapy alone in patients with advanced hepatocellular carcinoma (HCC). METHODS: The National Cancer Database was used to identify patients with advanced HCC diagnosed between January 1, 2017, and December 31, 2019. We included patients who received combined therapy or immunotherapy alone as first-line treatment. Multivariable logistic regression was conducted to determine predictors of combined therapy. Kaplan-Meier and Cox regression approaches were used to identify predictors of overall survival and to compare hazards of mortality between the patients who received combined therapy and immunotherapy alone. RESULTS: Of 1,664 eligible patients with advanced-stage HCC, 142 received combined TARE/immunotherapy and 1,522 received immunotherapy alone. Receipt of combination therapy was associated with care at an academic center and inversely associated with racial/ethnic minority status (Hispanic and Black individuals). The median overall survival was significantly higher in the combination group than in the immunotherapy alone group (19.8 vs 9.5 months). In multivariable analysis, combined therapy was independently associated with reduced mortality (adjusted hazard ratio 0.50, 95% confidence interval: 0.36-0.68, P < 0.001). Results were consistent across subgroups and in sensitivity analyses using propensity score matching and inverse probability of treatment weighting. DISCUSSION: The combination of TARE and immunotherapy was associated with improved survival compared with immunotherapy alone in patients with advanced-stage HCC. Our findings underly the importance of large clinical trials evaluating combination therapy in these patients.

Assessing the performance of ChatGPT in answering questions regarding cirrhosis and hepatocellular carcinoma.

BACKGROUND/AIMS: Patients with cirrhosis and hepatocellular carcinoma (HCC) require extensive and personalized care to improve outcomes. ChatGPT (Generative Pre-trained Transformer), a large language model, holds the potential to provide professional yet patient-friendly support. We aimed to examine the accuracy and reproducibility of ChatGPT in answering questions regarding knowledge, management, and emotional support for cirrhosis and HCC. METHODS: ChatGPT's responses to 164 questions were independently graded by two transplant hepatologists and resolved by a third reviewer. The performance of ChatGPT was also assessed using two published questionnaires and 26 questions formulated from the quality measures of cirrhosis management. Finally, its emotional support capacity was tested. RESULTS: We showed that ChatGPT regurgitated extensive knowledge of cirrhosis (79.1% correct) and HCC (74.0% correct), but only small proportions (47.3% in cirrhosis, 41.1% in HCC) were labeled as comprehensive. The performance was better in basic knowledge, lifestyle, and treatment than in the domains of diagnosis and preventive medicine. For the quality measures, the model answered 76.9% of questions correctly but failed to specify decision-making cut-offs and treatment durations. ChatGPT lacked knowledge of regional guidelines variations, such as HCC screening criteria. However, it provided practical and multifaceted advice to patients and caregivers regarding the next steps and adjusting to a new diagnosis. CONCLUSION: We analyzed the areas of robustness and limitations of ChatGPT's responses on the management of cirrhosis and HCC and relevant emotional support. ChatGPT may have a role as an adjunct informational tool for patients and physicians to improve outcomes.

Racial and Ethnic Disparities in Years of Potential Life Loss Among Patients With Cirrhosis During the COVID-19 Pandemic in the United States.

INTRODUCTION: Our aim was to evaluate the impact of race/ethnicity on cirrhosis-related premature death during the COVID-19 pandemic. METHODS: We obtained cirrhosis-related death data (n = 872,965, January 1, 2012-December 31, 2021) from the US National Vital Statistic System to calculate age-standardized mortality rates and years of potential life lost (YPLL) for premature death aged 25-64 years. RESULTS: Significant racial/ethnic disparity in cirrhosis-related age-standardized mortality rates was noted prepandemic but widened during the pandemic, with the highest excess YPLL for the non-Hispanic American Indian/American Native (2020: 41.0%; 2021: 68.8%) followed by other minority groups (28.7%-45.1%), and the non-Hispanic White the lowest (2020: 20.7%; 2021: 31.6%). COVID-19 constituted >30% of the excess YPLLs for Hispanic and non-Hispanic American Indian/American Native in 2020, compared with 11.1% for non-Hispanic White. DISCUSSION: Ethnic minorities with cirrhosis experienced a disproportionate excess death and YPLLs in 2020-2021.

Machine learning models are superior to noninvasive tests in identifying clinically significant stages of NAFLD and NAFLD-related cirrhosis.

BACKGROUND AND AIMS: We assessed the performance of machine learning (ML) models in identifying clinically significant NAFLD-associated liver fibrosis and cirrhosis. APPROACH AND RESULTS: We implemented ML models including logistic regression (LR), random forest (RF), and artificial neural network to predict histological stages of fibrosis using 17 demographic/clinical features in 1370 patients with NAFLD who underwent liver biopsy, FibroScan, and labs within a 6-month period at multiple U.S. centers. Histological stages of fibrosis (≥F2, ≥F3, and F4) were predicted using ML, FibroScan liver stiffness measurements, and Fibrosis-4 index (FIB-4). NASH with significant fibrosis (NAS ≥ 4 + ≥F2) was assessed using ML, FibroScan-AST (FAST) score, FIB-4, and NAFLD fibrosis score (NFS). We used 80% of the cohort to train and 20% to test the ML models. For ≥F2, ≥F3, F4, and NASH + NAS ≥ 4 + ≥F2, all ML models, especially RF, had primarily higher accuracy and AUC compared with FibroScan, FIB-4, FAST, and NFS. AUC for RF versus FibroScan and FIB-4 for ≥F2, ≥F3, and F4 were (0.86 vs. 0.81, 0.78), (0.89 vs. 0.83, 0.82), and (0.89 vs. 0.86, 0.85), respectively. AUC for RF versus FAST, FIB-4, and NFS for NASH + NAS ≥ 4 + ≥F2 were (0.80 vs. 0.77, 0.66, 0.63). For NASH + NAS ≥ 4 + ≥F2, all ML models had lower/similar percentages within the indeterminate zone compared with FIB-4 and NFS. Overall, ML models performed better in sensitivity, specificity, positive predictive value, and negative predictive value compared with traditional noninvasive tests. CONCLUSIONS: ML models performed better overall than FibroScan, FIB-4, FAST, and NFS. ML could be an effective tool for identifying clinically significant liver fibrosis and cirrhosis in patients with NAFLD.

HCC EV ECG score: An extracellular vesicle-based protein assay for detection of early-stage hepatocellular carcinoma.

BACKGROUND AND AIMS: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC. APPROACH AND RESULTS: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99). CONCLUSION: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes.

Emerging drugs for the treatment of hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) remains a leading cause of liver-related mortality. Cirrhosis of any etiology is the major risk factor although HCC can develop in its absence in patients with hepatitis B and increasingly in those with nonalcoholic fatty liver disease. When detected at an early stage, curative options include surgical resection, liver transplantation, and/or ablative therapies. Unfortunately, most cases of HCC are recognized at an advanced stage when options are limited and noncurative. However, new systemic therapies with tyrosine kinase inhibitors and immunotherapy have expanded therapeutic options in advanced HCC. Advances in systemic therapy have given patients with advanced HCC hope and prolonged their survival. AREAS COVERED: We discuss recent data and ongoing research efforts to improve the treatment of hepatocellular carcinoma with discussion of current and upcoming systemic therapies combining agents of different classes. EXPERT OPINION: Systemic therapy for HCC is in evolution. The inclusion of immunotherapy to systemic therapy has revolutionized the field of HCC treatment. Identification of the appropriate combination and sequence of systemic therapy coupled with discovery of reliable HCC biomarkers will lead to improved survival and individualized HCC therapy.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.