Incidence Of Hepatocellular Carcinoma Research Articles

Incidence rates of hepatocellular carcinoma based on risk stratification in steatotic liver disease for precision medicine: A real-world longitudinal nationwide study.

Detailed subgroup incidence rates for steatotic liver disease (SLD)-related hepatocellular carcinoma (HCC) are critical to inform practice and public health interventions but remain sparse. We aimed to fill in this gap. In a retrospective cohort study of adults with SLD from the United States (US) Merative Marketscan Research Databases (1/2007 to 12/2021), we estimated HCC incidence stratified by sex, age, cirrhosis, diabetes mellitus (DM), and a combination of all these 4 factors. We excluded patients with significant alcohol use and chronic viral hepatitis. We analyzed data from 741,816 patients with SLD (mean age 51.5 ± 12.8 years, 46% male, 14.7% cirrhosis). During a 2,410,166 person-years (PY) follow-up, 1,740 patients developed HCC. The overall HCC incidence yielded 0.72 per 1,000 PY (95% confidence interval [CI, 0.68, 0.75]). The incidence was higher in males (0.95, 95% CI [0.89, 1.01]) compared to females (0.52, 95% CI [0.48, 0.56]) (p < 0.001). For those with cirrhosis, the incidence was significantly higher at 4.29 (95% CI [4.06, 4.51]) compared to those without cirrhosis (0.14, 95% CI [0.13, 0.16]) (p < 0.001). Additionally, the incidence was higher in patients with DM (1.19, 95% CI [1.12, 1.26]) compared to those without DM (0.41, 95% CI [0.38, 0.44]) (p < 0.001). Chronic kidney disease (CKD) was also associated with a higher HCC incidence of 2.20 (95% CI [2.00, 2.41]) compared to those without CKD (0.58, 95% CI [0.55, 0.62]) (p < 0.001). Similarly, individuals with cardiovascular disease (CVD) had a higher HCC incidence of 1.89 (95% CI [1.75, 2.03]) compared to those without CVD (0.51, 95% CI [0.48, 0.54]) (p < 0.001). Finally, the incidence of HCC was significantly higher in patients with non-liver cancer (3.90, 95% CI [3.67, 4.12]) compared to those without other cancers (0.29, 95% CI [0.26, 0.31]) (p < 0.001). On further stratification, HCC incidence incrementally rose by 10-year age intervals, male sex, cirrhosis, and DM, reaching 19.06 (95% CI [16.10, 22.01]) and 8.44 (95% CI [6.78, 10.10]) in males and females, respectively, but only 0.04 for non-diabetic, noncirrhotic aged <40 years patients in both sexes. The main limitation of this methodology is the potential misclassification of the International Classification of Diseases (ICD) codes inherent in claims database studies. This nationwide study provided robust granular estimates for SLD-related HCC incidence stratified by several key risk factors. In addition to cirrhosis, future surveillance strategies, prevention, public health initiatives, and future research models should also take into account the impact of sex, age, and DM.

Hepatocellular Carcinoma in Acute Hepatic Porphyria: A Meta-Analysis of Observational Studies.

Hepatocellular carcinoma (HCC) is a long-term complication of acute hepatic porphyria (AHP) inclusive of acute intermittent porphyria [AIP], variegate porphyria [VP], or hereditary coproporphyria [HCP]. Data on HCC risk in AHP patients are limited and heterogeneous. We performed this meta-analysis with aims to (a) determine incidence of HCC in AHP and specific subtypes of AHP and (b) examine high-risk groups for HCC. Data from studies reporting HCC development in AHP patients were pooled and reported per 100 person years with 95% confidence intervals (CI). 12 observational (5 prospective) studies (11 Europe and 1 US) on 2735 patients (mean age 54.8 yrs., 62% females) with AHP (80% AIP) were analyzed. 115 HCC cases were observed with HCC incidence per 100 person years of 0.3 (0.2-0.5) in AHP, 0.4 (0.2-0.6) in AIP, 0.3 (0-0.4) in VP, and 0.2 (0.1-0.6) in HCP. The risk was 0.4 (0.2-0.6) in females, 0.3 (0.1-0.5) in males, 0.9 (0.1-1.7) in symptomatic, and 0.5 (0-1.6) in asymptomatic patients. Analyses were heterogeneous with publication bias. AHP patients with HCC were older females with a higher prevalence of cirrhosis, alcohol use, and viral hepatitis. The annual incidence of HCC in AHP patients is 0.3%, with higher risk in AIP, older females, symptomatic patients, and those with other risk factors of liver disease. Future studies pooling individual patient data and overcoming limitations of the current meta-analysis are needed as a basis for deriving a effective screening and surveillance approach for HCC in patients with AHP.

Screening and application of aptamers as fluorescent biosensors for selective and sensitive detection of hepatocellular carcinoma and in vivo targeted delivery studies.

The incidence of primary hepatocellular carcinoma (HCC) has recently ranked fifth in the world, and the incidence rate is increasing year by year worldwide. Therefore, early diagnosis is the highest priority in the treatment of HCC. In this paper, four anti-HCC aptamers were obtained using magnetic bead SELEX technology. Among them, Apt-1 had the smallest Kd value(5.9nM) and the highest affinity. Flow cytometry results showed that the FITC-aptamers only specifically recognized HCC serum. Circular dichronism (CD) spectral characterization showed a positive peak near 275nm and a negative peak near 250nm for all aptamers, elucidating that the secondary structure formed by the candidate aptamers was a stem-loop B-DNA structure. In addition, molecular docking simulations showed that the binding of the HCC target to the candidate aptamer sequences was mainly dominated by hydrogen bonding. The results of the aptamer sensing performance analysis showed that under the optimized assay conditions, a linear relationship (ranging from 1nM to 1µM) was achieved, with a limit of detection (LOD) down to 0.75nM and a LOQ of 2.32nM. This was further validated in clinical samples, with a positive detection rate of more than 90%. Furthermore, aptamer-mediated in vivo delivery of luciferase mRNA showed that Apt-1-luciferase mRNA could be targeted to the liver and hepatic luciferase expression was significantly increased. These results demonstrate that the aptamer paves the way for clinical application, evidencing significant potential to offer reference information for early diagnosis.

Hepatocellular Cancer Surveillance in Patients with Advanced Chronic Liver Disease.

Patients with advanced chronic liver disease (ACLD) are at high risk of developing hepatocellular carcinoma (HCC). Therefore, biannual surveillance is recommended. This large-scale multicenter study aimed to stratify the risk of HCC development in ACLD. From 3016 patients with ACLD screened in 17 European and Chinese centers, 2340 patients with liver stiffness measurement (LSM) determined using different techniques (two-dimensional shear-wave elastography [2D-SWE], transient elastography, and point shear-wave elastography) and with different disease severities were included. Cox regression was used to explore risk factors for HCC. We used these data to create an algorithm, named PLEASE, but referred to in this manuscript as "the algorithm"; the algorithm was validated in internal and two external cohorts across elastography techniques. HCC developed in 127 (5.4%) patients during follow-up. LSM by 2D-SWE (hazard ratio: 2.28) was found to be associated with developing HCC, alongside age, sex, etiology, and platelet count (C-index: 0.8428). We thus established the algorithm with applicable cutoffs, assigning a maximum of six points: platelet count less than 150×109/l, LSM greater than or equal to 15 kPa, age greater than or equal to 50 years, male sex, controlled/uncontrolled viral hepatitis, or presence of steatotic liver diseases. Within 2 years, with a median follow-up of 13.7 months, patients in the high-risk group (≥4 points) had an HCC incidence of 15.6% (95% confidence interval [CI], 12.1% to 18.7%) compared with the low-risk group, at 1.7% (95% CI, 0.9% to 2.5%). Our algorithm stratified patients into two groups: those at higher risk of developing HCC and those at lower risk. Our data provide equipoise to test the prospective utility of the algorithm with respect to clinical decisions about screening patients with ACLD for incident HCC. (Funded by the German Research Foundation and others; ClinicalTrials.gov number, NCT03389152.).

Racial Disparities in Liver Transplant for Hepatitis C-Associated Hepatocellular Carcinoma.

In the United States, hepatitis C virus-associated hepatocellular carcinoma incidence and mortality are highest among minorities. Socioeconomic constraints play a major role in inequitable treatment. We evaluated the association between race/ethnicity and outcomes in a population that overcame treatment barriers. We report a retrospective cohort study of 666 patients across 20 institutions in the United States Hepatocellular Carcinoma Liver Transplantation Consortium from 2015 to 2019 with hepatitis C virus-associated hepatocellular carcinoma who completed direct-acting antiviral therapy and underwent liver transplantation. Patients were excluded if they had a prior liver transplantation, hepatocellular carcinoma recurrence, no prior liver-directed therapy, or if race/ethnicity data were unavailable. Patients were stratified by race/ethnicity. Primary outcomes were recurrence-free survival and overall survival, and secondary outcome was major postoperative complication. Race/ethnicity was not associated with differences in 5-year recurrence-free survival (White 90%, Black 88%, Hispanic 92%, Other 87%; p = 0.85), overall survival (White 85%, Black 84%, Hispanic 84%, Other 93%; p = 0.70), or major postoperative complication. Race/ethnicity was not associated with worse oncologic or postoperative outcomes among those who completed direct-acting antiviral therapy and underwent liver transplantation, suggesting that overcoming socioeconomic constraints equalizes outcomes across racial/ethnic groups. Eliminating barriers that prohibit care access among minorities must be a priority.

Impact of GLP-1RA on the Risk of Adverse Liver Outcomes Among Patients With Alcohol-Associated Liver Disease and Type 2 Diabetes.

We sought to characterise the impact of GLP-1RA on adverse liver outcomes (ALO) among patients with alcohol-associated liver disease (ALD) and Type 2 diabetes mellitus (T2DM). Patients with T2DM newly diagnosed with ALD between 2013 and 2020 were identified using IBM MarketScan database and were categorised by GLP-1RA exposure. Overlap propensity score weighting (OPSW) followed by Poisson regression models was used to analyse adjusted risk of ALO, a composite endpoint defined by first occurrence of hepatic decompensation (HD), portal hypertension (PH), hepatocellular carcinoma (HCC) or liver transplantation (LT) relative to GLP-1RA. Among 14 730 patients, most individuals were male (n = 9752, 66.2%) with median age of 57 (IQR 52-61) years; 2.2% (n = 317) of patients had GLP-1RA exposure. Overall, 32.0% (n = 4717) of patients experienced HD, 15.9% (n = 2345) had PH, 3.8% (n = 563) developed HCC, while 2.5% (n = 374) underwent transplantation. Non-GLP-1RA patients had higher incidence of HD (32.2% vs. 22.4%) and HCC (3.9% vs. 0.3%) versus patients taking GLP-1RA (both p < 0.001); in contrast, there was no difference in incidence of PH (14.5% vs. 16.0%) and LT (1.3% vs. 2.6%) (both p > 0.05). After OPSW, overall incidence of ALO was lower in GLP-1RA cohort (GLP-1RA: 12.0%, 95%CI 9.0-16.0 vs. non-GLP-1RA: 21.0%, 95%CI 20.0-22.0) with an absolute incidence risk reduction of 9.0% (95%CI 3.0%-15.0%) associated with GLP-1RA. GLP-1RA was most strongly associated with lower likelihood of HD with reduced adjusted incidence rate of 0.56 (95%CI 0.36-0.86) relative to non-GLP-1RA individuals. GLP-1RA may have a hepatoprotective impact among patients with ALD and T2DM.

Thrombospondin 2 as a Predictive Biomarker for HCC inHepatitis C Patients: A Longitudinal Study Following DAA Therapy.

This multicentre study investigated the dynamics of thrombospondin 2 (TSP2) levels during direct-acting antiviral (DAA) therapy in hepatitis C virus (HCV) infected patients and evaluated TSP2's potential as a predictive marker for hepatocellular carcinoma (HCC). All 134 participants achieved sustained virological response at 12 weeks (SVR12) with DAA therapy, and serum TSP2 levels significantly decreased from before and after treatment (p < 0.001). During the median follow-up period of 6.0 years, HCC after DAA therapy was observed in 16 patients (11.9%). Patients with serum TSP2 High (≥ 32 ng/mL) at SVR12 had a significantly higher cumulative occurrence of HCC than did those without (26.5% vs. 7.0%, p = 0.0033). A multivariate Cox proportional hazards model identified male gender (HR 4.84, p = 0.005), HCC history (HR 4.61, p = 0.017) and TSP2 High (HR 3.93, p = 0.009) as significant independent predictors of HCC occurrence after DAA therapy. The model had a high concordance index of 0.878. Additionally, combining TSP2 High and FIB-4 High (≥ 3.538) at SVR12 yielded high specificity and negative predictive value (0.941 and 0.917, respectively) for predicting HCC. Kaplan-Meier analysis showed a higher HCC incidence in the TSP2 High + FIB-4 High group (log-rank p < 0.0001). In conclusion, TSP2 may be a promising biomarker for personalised HCC surveillance in DAA-treated hepatitis C patients.

DAA treatment for HCV reduce risk of hepatocellular carcinoma: a 10-years follow-up study based on Chinese patients with hepatitis C

The long-term benefits of direct-acting antiviral (DAA) therapy after achieving sustained virological response (SVR) remain uncertain in the Chinese population. This study evaluates the incidence of hepatocellular carcinoma (HCC), hepatic decompensation, and all-cause mortality among Chinese hepatitis C patients treated with DAAs. We included patients diagnosed since 2011 and followed them until November 1, 2022. The primary outcomes were HCC, hepatic decompensation, and mortality. Multivariable proportional hazards model was used to assess the impact of SVR and cirrhosis status. The cohort consisted of 1272 patients with SVR (92.1%) and 109 without SVR (7.9%), with a median follow-up of 61 months. The incidence of HCC was significantly lower in the SVR group (5.1 per 1000 person-years) compared to the no-SVR group (15.0 per 1000 person-years). Achieving SVR was associated with a significantly reduced risk of HCC (adjusted hazard ratio: 0.32; 95% CI 0.16–0.67). Cirrhosis was linked to an increased risk of developing HCC and hepatic decompensation. These findings highlight the importance of early DAA treatment, particularly for patients with cirrhosis.

Characteristics and prognosis of hepatocellular carcinoma patients after direct-acting antiviral hepatitis C virus therapy in a single medical center in Egypt

Objective: Hepatocellular carcinoma (HCC) incidence has increased dramatically over the previous two decades and is anticipated to rise further in some countries, notably the United States, by 2030. HCC is most widespread in Asia and Africa, where hepatitis B and C are ubiquitous and lead to the development of chronic liver disease and, finally, HCC. In this study, we examined changes in the characteristics and prognosis of HCC patients, as well as the risk of developing HCC after direct-acting antiviral (DAA) medication.Methods: The study enrolled all individuals who attended the Clinical Oncology and Nuclear Medicine Department, Suez Canal University Hospital, Ismailia, Egypt, with a proven diagnosis of HCC in the period between January 2020 and December 2021. HCC is diagnosed based on radiographic appearance (arterial enhancement phase and delayed washout phase) or compatible histology.Results: This retrospective cohort included 254 HCC patients, separated into three groups. Kaplan-Meier curves with log-rank analysis revealed that hepatitis C virus (HCV) treatment therapy considerably reduced the time to HCC development following hepatitis diagnosis (p &lt; .001). HCV therapy had a substantial impact on progression-free survival and overall survival in HCC patients (p &lt; .001).Conclusions: The emergence of DAA medication has greatly altered the management of HCV patients in the context of HCC. DAAs have been shown to be both safe and beneficial in these individuals, particularly in terms of lowering the risk of hepatic decompensation. DAAs have been reported to enhance overall survival in patients with cirrhotic HCV-related HCC, most likely due to decreased hepatic decompensation.

Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and Delays Tumor Growth in a Preclinical Model.

The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.

Prediction of hepatocellular carcinoma and liver-related events in anti-HDV positive individuals

Chronic hepatitis D (CHD) is the most severe form of chronic viral hepatitis, with a high risk of developing hepatocellular carcinoma (HCC) and liver-related mortality. Risk stratification is needed to guide HCC surveillance strategies and to prioritize treatment with antiviral agents. We conducted a multicenter retrospective cohort of anti-HDV positive individuals managed at sites in the Netherlands and the United Kingdom. We studied the 5-year cumulative incidences of HCC and liver-related events (first of HCC, liver transplantation and liver-related mortality), in the overall cohort and among relevant subgroups. We analyzed 269 anti-HDV positive individuals with a median follow-up of 4.3 years in which 47 first events occurred. The 5-year cumulative incidences of HCC and liver-related events were 3.8% and 15.6% in the overall cohort. The 5-year cumulative incidence of HCC and liver-related events for individuals without cirrhosis was 0% and 0.9% compared to 12% and 41.3% for individuals with cirrhosis (p<0.001). The 5-year cumulative incidence of HCC and liver-related events was 0% and 2.1% among individuals with low PAGE-B scores, compared to 3.2% and 21.1% with intermediate and 25.4% and 45.5% with high risk scores (p<0.001). We found comparable results for the FIB-4 score. Findings were consistent regardless of cirrhosis or detectable HDV RNA (p<0.001). Anti-HDV positive individuals are at high risk of adverse liver-related outcomes. The incidences of HCC was negligible among individuals without cirrhosis and among individuals with low baseline PAGE-B and/or FIB-4 scores. Therefore, these score can be used to guide HCC surveillance strategies and potentially also for treatment prioritization.

Hepatitis D virus infection markedly increases the risk of hepatocellular carcinoma in patients with viral B cirrhosis

The specific causative role of HDV infection in the development of hepatocellular carcinoma (HCC) remains debated and was not specifically demonstrated in cirrhotic patients. Here we compared HCC incidence in HBV-HDV co-infected and HBV mono-infected cirrhotic patients. A total of 142 HBV-HDV and 271 HBV-infected cirrhotic patients from the French ANRSCO12 CirVir and DeltaVir cohorts, with histologically proven cirrhosis and no history of decompensation, were included in the study. HBV-HDV patients were younger than HBV patients (37.2 vs. 53.8 years), they were more often immigrants from sub-Saharan Africa, and displayed less co-morbidities and more altered liver tests. After adjustment for age, cumulative incidences of HCC in co-infected and mono-infected patients at 1, 3 and 5 years were 5.2%, 11.8% and 20.2% vs. 1.1%, 2.5% and 4.4%, respectively (P< .001). In multivariate analysis, HDV infection was an independent factor associated with the development of HCC (HR 2.94, 95% CI 1.19-7.25; P= .019). Other independent factors were age (HR 1.08, 1.05-1.11; P< .001), overweight (HR 0.45, 0.22-0.93; P= .031), smoking (HR 2.26, 1.23-4.16; P= .009), increased GGT (HR 2.73, 1.24-6.00; P= .013), total bilirubin >17 μmol/L (HR 2.68, 1.33-5.42; P= .006) and platelet count <150.000/mm3 (HR 3.11, 1.51-6.41; P= .002). HDV co-infection was not an independent factor of liver decompensation, transplantation or death. The incidence of HCC appears significantly higher in HBV-HDV than in HBV-infected cirrhotic patients. HDV infection emerges as an independent risk factor for HCC, indicating that in cirrhotic patients, HDV plays a causative role for HCC independently of HBV.

Hepatitis Delta Virus Testing, Prevalence, and Liver-Related Outcomes Among U.S. Veterans with Chronic Hepatitis B

Background and AimsHepatitis delta virus (HDV) infection in patients with chronic hepatitis B (CHB) is associated with worse liver-related outcomes. We aim to comprehensively evaluate HDV testing, diagnosis, and liver-related outcomes among a national cohort of U.S. Veterans with CHB. MethodsU.S. Veterans with CHB from 2010 to 2023 were evaluated to determine trends in HDV testing (anti-HDV antibody, HDV RNA) and proportion positive among those tested. HDV positive patients were 1:2 propensity score matched to CHB patients who were HDV negative to evaluate incidence (per 100,000 person-years) of cirrhosis, hepatic decompensation, or hepatocellular carcinoma using competing risks Nelson-Aalen methods for estimating cumulative hazards. ResultsAmong 27,548 CHB patients identified, 16.1% completed HDV testing, among whom 3.25% (n=144) were positive. After excluding patients with cirrhosis or HCC at baseline, 71 patients with HDV (median follow-up 5.3 years, IQR 2.5-7.6) were propensity score matched to 140 CHB patients without HDV (median follow-up 4.5 years, IQR 2.6-8.1). Compared to CHB patients without HDV, those with concurrent HDV had significantly greater incidence of cirrhosis (4.39 vs. 1.30 per 100,000 person-years, p < 0.01) and hepatic decompensation (2.18 vs. 0.41 per 100,000 person-years, p=0.01). ConclusionAmong a national cohort of U.S. Veterans with CHB, low rates of HDV testing were observed. This is concerning given that patients with concurrent HDV infection had >3 times and >5 times greater risks of cirrhosis and hepatic decompensation, respectively, compared to CHB patients without HDV, highlighting the importance of timely HDV diagnosis and treatment.

S1789 Incidence and Survival Outcomes of Hepatocellular Carcinoma in the United States From 2000 to 2021

S1789 Incidence and Survival Outcomes of Hepatocellular Carcinoma in the United States From 2000 to 2021

Advances in Immune Checkpoint Therapy in Hepatocellular Carcinoma.

The incidence and lethality of hepatocellular carcinoma (HCC) are increasing annually, and traditional treatments have been proven to be ineffective for patients with advanced stages of the disease. In recent years, immune checkpoint therapy has rapidly evolved, demonstrating promising results across a wide range of cancers and offering new hope for cancer treatment. However, the efficacy of immune checkpoint therapy in HCC varies greatly among individuals, with only a small proportion of HCC patients responding positively. A major cause of immune resistance and poor efficacy in HCC patients is immune evasion, which is often due to insufficient infiltration of immune cells. Understanding the mechanisms underlying immune evasion is crucial for enhancing the efficacy of immune therapies. In this review, we aim to summarize the mechanisms of immune evasion observed during immune checkpoint therapy and discuss future directions for this therapeutic approach. Our goal is to provide insights that could help overcome immune evasion, thereby improving the efficacy of immune therapies and extending patient survival time.

Glucose-lowering drugs and liver-related outcomes among individuals with type 2 diabetes: A systematic review of longitudinal population-based studies.

While randomized controlled trials data on the long-term effect of glucose-lowering drugs (GLDs) on liver-related outcomes are lacking, population-based studies have evaluated the associations of GLDs with liver-related outcomes in individuals with type 2 diabetes (T2D). we aimed to conduct a systematic review of population-based studies evaluating the effects of GLDs on liver-related outcomes in people with T2D. PubMed, Web of Science, and Embase databases were systematically searched for population-based studies testing the associations of GLDs with liver-related outcomes in individuals with T2D and no liver disease other than non-alcoholic fatty liver disease (NAFLD) from inception to 23 February 2024. GLDs included SGLT2is, TZDs, insulin, GLP-1 RAs and dipeptidyl peptidase-4 inhibitors (DPP4Is). Ten cohort studies, comprising 1,274,641 participants, met the inclusion criteria. The median follow-up period ranged from 8.9 to 76 months. Of all the GLDs under investigation, SGLT2is were associated with the strongest reduction in NAFLD incidence, cirrhosis, and composite liver-related events compared to other medications. TZDs were associated with a reduced risk of developing NAFLD and cirrhosis but were not significantly associated with a lower incidence of hepatocellular carcinoma. GLP-1 RAs demonstrated a significant association with reduced liver-related mortality. Observational data from population-based studies suggest that GLDs such as SGLT2is are associated with beneficial long-term liver-related outcomes in T2D patients with NAFLD. Additional studies, including randomized controlled trials with long-term follow-up, are needed to confirm these findings. PROSPERO CRD442024536872.

Predictors of liver disease outcomes in individuals with hemophilia and HCV infection

AbstractHemophilia is an X-linked congenital bleeding disorder for which factor replacement is life-saving but complicated by the sequelae of chronic hepatitis C virus (HCV) infection acquired decades ago. Although antiviral therapy clears HCV and reduces end-stage liver disease (ESLD), it may not reverse cirrhosis or prevent hepatocellular cancer (HCC). This was a retrospective cohort study of 121 men with hemophilia and HCV infection cared for at the Hemophilia Center of Western Pennsylvania to determine the incidence and predictors of ESLD and HCC. ESLD and HCC predictors were analyzed using Fisher exact test, and HCV-associated outcomes by Kaplan-Meier time-to-event and Cox proportional hazards regression analyses. At a mean 54 years (36-80) duration of HCV, ESLD occurred in 24 (19.8%), 0.365 per 100 person-years (py); and HCC in 7 (5.8%), 0.106 per 100 py. All 46 (38.0%) alive when HCV antiviral therapy became available, received it. Overall, 31 (25.6%) were HIV+. The leading causes of death were ESLD in 11 (32.3%), bleeding in 9 (26.5%), and HCC in 6 (17.6%). Major risk factors for ESLD included platelets <100 × 103/μL (odds ratio [OR], 6.009; P = .012) and HIV infection (OR, 3.883; P = .001). The major predictors of HCC were ESLD (OR, 11.476; P = .003) and platelets <100 000/μL (OR, 6.159; P = .014). No antiviral-treated subject developed ESLD, P = .001. For men with hemophilia, the sequelae of chronic HCV infection were significant. The major risk factors for ESLD were platelets <100 000/μL and HIV infection. Despite antiviral therapy, ESLD is the most significant predictor of HCC, and ESLD is the leading cause of death.

Finite nucleos(t)ide-analogue therapy for functional cure in HBeAg-negative chronic hepatitis B: recent development in the paradigm shift.

Long-term nucleos(t)ide analogue (Nuc) therapy in chronic hepatitis B (CHB) may lead to hepatitis B virus (HBV) suppression, alanine aminotransferase (ALT) normalization, improvement of histological lesions, and prevention of liver disease progression, but rarely achieve HBsAg loss, the hallmark of functional cure. HBeAg-negative CHB patients have often been recommended to continue Nuc therapy until HBsAg loss, which usually means indefinitely. However, long-term/life-long Nuc therapy is associated with increasing costs and concerns of adverse outcomes subsequent to poor adherence and/or self-cessation/loss-to-follow-up. Hence, 2012 Asian-Pacific guidelines recommended that HBeAg-negative CHB patients can stop Nuc therapy after ≥12 months of HBV DNA undetectability. Subsequent Asian and few European studies have found the strategy of finite Nuc therapy to be feasible and reasonably safe. In 2016-2017, stopping Nuc was also included as a conditional strategy for HBeAg-negative CHB patients in the American and European guidelines. Furthermore, progressively increasing HBsAg loss rates with prolongation of off-Nuc follow-up were documented, being higher in Caucasians and more apparent beyond years 4-5 in Asian patients. Recently, a large study in patients with HBV cirrhosis showed not only higher 10-year HBsAg loss rate (15.3 vs. 1.6%) but also ~50% lower 10-year hepatocellular carcinoma incidence (16.5 vs. 29.5%) and 60% lower liver-related mortality/transplantation rate (6.1 vs. 15.1%) after Nuc cessation, as compared with well-matched patients continuing Nuc therapy. Since novel drug development aiming for functional cure has not been satisfactory, the strategy of finite Nuc therapy in HBeAg-negative CHB seems to be the best realistic option for functional cure today.

Impact of occult hepatitis B virus infection and high-fat diet on hepatocellular carcinoma development

In the areas where viral infections are more common, the incidence of hepatocellular carcinoma (HCC) has declined. This is largely attributed to the availability of vaccines against hepatitis B virus (HBV), antiviral treatments, and a change in diet with healthier foods. However, in the Western world, the HCC incidence rate has risen steadily, probably due to an increased prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD), a condition that has increasingly been considered an important risk factor for HCC. Despite this, in 2019, 41% of HCC cases were diagnosed globally and a majority of diagnosed cases from mainland China were related to HBV. Some HCC cases tested negative for hepatitis B surface antigen (HBsAg) but tested positive for HBV-DNA in blood. This is considered an occult HBV infection (OBI). OBI is related to various mutations in the viral genome, which modifies host immunity, subsequently leading to the long-term persistence of cccDNA in the nucleus of infected hepatocytes. Many OBIs are associated with HBV variants carrying mutations in preS/S genomic regions, which occur either spontaneously or as a result of antiviral treatments. OBIs are also frequently reported in HBV-vaccinated individuals. HBV variants post-HBV vaccination carry mutations in the preS area. This review discusses the relationship between preS variant-related OBIs and the development of HCC in the context of a high-fat diet, one of the preventable behavioral risk factors for MAFLD.

Abstract A024: Exploring liver cancer risk factors by birth cohort: An electronic health record (EHR)-based epidemiologic cohort study

Abstract Background: Most hepatocellular carcinoma (HCC) cases in the U.S. have been attributed to chronic hepatitis B (HBV) and hepatitis C virus (HCV) infections, though burden of alcoholic liver disease and metabolic-dysfunction associated fatty liver disease (MAFLD) is rising. Individuals born between 1945-1965 (“the baby boomers”), comprise 25% of the U.S. population but account for 81% of chronic HCV infections and thus bear a disproportionate burden of HCC compared to younger or older cohorts. We examined the association of HCV and other risk factors to liver cancer incidence within liver cancer birth cohorts. Methods: Adults with at least one visit from 2000-2017 to San Francisco Health Network (SFHN), Sutter Health Northern California, and Kaiser Permanente Hawai’i (KPH) were linked to data on incident HCC from the California (SFHN/Sutter) and Hawai’i (KPH) cancer registries through 2017. The three birth cohorts were defined as 1)1895-1944 (“pre-baby boomer”); 2)1945-1965 (“baby boomer”); 3)1966-1999 (“post-baby boomer”). We used Cox proportional hazards regression with age as the timescale to examine association of each risk factor (i.e., HBV, HCV, metabolic syndrome, MAFLD, alcohol use, smoking history) with incident HCC stratified by sex and birth cohort; models were adjusted for site, baseline year, number of encounters, length of active follow-up, race/ethnicity, and cirrhosis. For next steps, we plan to calculate the population attributable fraction for each of these risk factors. Results: From the pooled cohort of 4,248,553 individuals, 2,916 had incident HCC. 15% were born between 1895-1944; 32% from 1945-1965; and 53% from 1966-1999; 55% were females; 39% identified as non-Hispanic (NH) White; 14% as Asian American; 11% as Hispanic; 5% as NH Black. Across all birth cohorts, males and females with active chronic hepatitis B had higher HCC risk compared to those with inactive status. Males and females in the pre-baby boomer and baby boomer cohorts (but not post baby-boomers) with active chronic hepatitis C had higher HCC risk. Males and females in the pre-baby boomer cohort (Hazard Ratio [HR]=2.58, 95% Confidence Interval [CI] 2.01-3.31); HR=2.85, 95% CI 2.03-4.00, respectively) and females in the baby boomer cohort (HR=1.55, 95% CI 1.03-2.32) with metabolic syndrome had higher HCC risk. Having MAFLD was associated with increased HCC risk among males from all three birth cohorts and females in the pre-baby boomer and baby-boomer cohort. Alcohol use was associated with higher HCC among pre-baby boomer males (HR=1.23, 95% CI 1,04-1.46) and baby boomer females (HR=1.39, 95% CI 1.10-1.76). Conclusion: In this racially, ethnically, and socioeconomically diverse cohort, HBV is a significant risk factor in HCC risk across birth cohorts for both males and females, while HCV is among older birth cohorts. Consistent with recent studies, MAFLD is a growing cause across birth cohorts. Understanding the contribution of these risk factors and for whom they are most relevant can help identify targets for intervention to reduce liver cancer burden. Citation Format: Janet N. Chu, Aly Cortella, Alison J. Canchola, Pushkar Inamdar, Sixiang Nie, Mai Vu, Ma Somsouk, Michele M. Tana, Caroline A. Thompson, Chanda Ho, Hashem B. El-Serag, Mi-Ok Kim, Mark Segal, Yihe G. Daida, Su-Ying Liang, Scarlett L. Gomez, Mindy C. Derouen, Salma Shariff-Marco. Exploring liver cancer risk factors by birth cohort: An electronic health record (EHR)-based epidemiologic cohort study [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A024.