Current research insights into the role of CTLA-4 in hepatitis B virus (HBV) infection.

Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma.

Development of a machine learning-based model to predict hepatic inflammation in chronic hepatitis B patients with concurrent hepatic steatosis: a cohort study.

Background: With increasingly prevalent coexistence of chronic hepatitis B (CHB) and hepatic steatosis (HS), simple, non-invasive diagnostic methods to accurately assess the severity of hepatic inflammation are needed. We aimed to build a machine learning (ML) based model to detect hepatic inflammation in patients with CHB and concurrent HS. Methods: We conducted a multicenter, retrospective cohort study in China. Treatment-naive CHB patients with biopsy-proven HS between April 2004 and September 2022 were included. The optimal features for model development were selected by SHapley Additive explanations, and an ML algorithm with the best accuracy to diagnose moderate to severe hepatic inflammation (Scheuer's system ≥ G3) was determined and assessed by decision curve analysis (DCA) and calibration curve. This study is registered with ClinicalTrials.gov (NCT05766449). Findings: From a pool of 1,787 treatment-naive patients with CHB and HS across eleven hospitals, 689 patients from nine of these hospitals were chosen for the development of the diagnostic model. The remaining two hospitals contributed to two independent external validation cohorts, comprising 509 patients in validation cohort 1 and 589 in validation cohort 2. Eleven features regarding inflammation, hepatic and metabolic functions were identified. The gradient boosting classifier (GBC) model showed the best performance in predicting moderate to severe hepatic inflammation, with an area under the receiver operating characteristic curve (AUROC) of 0.86 (95% CI 0.83-0.88) in the training cohort, and 0.89 (95% CI 0.86-0.92), 0.76 (95% CI 0.73-0.80) in the first and second external validation cohorts, respectively. A publicly accessible web tool was generated for the model. Interpretation: Using simple parameters, the GBC model predicted hepatic inflammation in CHB patients with concurrent HS. It holds promise for guiding clinical management and improving patient outcomes. Funding: This research was supported by the National Natural Science Foundation of China (No. 82170609, 81970545), Natural Science Foundation of Shandong Province (Major Project) (No. ZR2020KH006), Natural Science Foundation of Jiangsu Province (No.BK20231118), Tianjin Key Medical Discipline (Specialty), Construction Project, TJYXZDXK-059B, Tianjin Health Science and Technology Project key discipline special, TJWJ2022XK034, and Research project of Chinese traditional medicine and Chinese traditional medicine combined with Western medicine of Tianjin municipal health and Family Planning Commission (2021022).

Impact of fatty liver on long-term outcomes in chronic hepatitis B: a systematic review and matched analysis of individual patient data meta-analysis.

BACKGROUND/AIMS: Chronic hepatitis B (CHB) and fatty liver (FL) often co-exist, but natural history data of this dual condition (CHB-FL) are sparse. Via a systematic review, conventional meta-analysis (MA) and individual patient-level data MA (IPDMA), we compared liver-related outcomes and mortality between CHB-FL and CHB-no FL patients. METHODS: We searched 4 databases from inception to December 2021 and pooled study-level estimates using a random- effects model for conventional MA. For IPDMA, we evaluated outcomes after balancing the two study groups with inverse probability treatment weighting (IPTW) on age, sex, cirrhosis, diabetes, ALT, HBeAg, HBV DNA, and antiviral treatment. RESULTS: We screened 2,157 articles and included 19 eligible studies (17,955 patients: 11,908 CHB-no FL; 6,047 CHB-FL) in conventional MA, which found severe heterogeneity (I2=88-95%) and no significant differences in HCC, cirrhosis, mortality, or HBsAg seroclearance incidence (P=0.27-0.93). IPDMA included 13,262 patients: 8,625 CHB-no FL and 4,637 CHB-FL patients who differed in several characteristics. The IPTW cohort included 6,955 CHB-no FL and 3,346 CHB-FL well-matched patients. CHB-FL patients (vs. CHB-no FL) had significantly lower HCC, cirrhosis, mortality and higher HBsAg seroclearance incidence (all p≤0.002), with consistent results in subgroups. CHB-FL diagnosed by liver biopsy had a higher 10-year cumulative HCC incidence than CHB-FL diagnosed with non-invasive methods (63.6% vs. 4.3%, p<0.0001). CONCLUSION: IPDMA data with well-matched CHB patient groups showed that FL (vs. no FL) was associated with significantly lower HCC, cirrhosis, and mortality risk and higher HBsAg seroclearance probability.

Comparison of patients with hepatitis B virus-associated hepatocellular carcinoma: Data from two hospitals from Turkey and China.

Aims: There are many studies on the incidence of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), but very little is known about the HCC features in different populations. The study aimed to compare characteristics in two cohorts of patients with HBV-associated hepatocellular carcinoma, from Turkey and China. Methods: Data on patients with HBV-associated HCC diagnosed by imaging or liver biopsy were retrospectively collected from Shandong Provincial Hospital (n = 578) and Inonu University Hospital (n = 359) between January 2002 and December 2020, and the liver function and HCC characteristics were compared. Continuous variables were compared using Student's t-test or Mann-Whitney U test and categorical variables were compared using the χ2 test or Fisher's exact test. Results: The patients in the Turkish cohort had significantly worse Child-Pugh scores (Child-Pugh A: 38.3% vs. 87.9%; Child-Pugh B: 40.3% vs. 11.1%; Child-Pugh A: 24.1% vs. 1.0%; p < 0.001) and significantly higher levels of aspartate aminotransferase (66.5 vs. 36.0; p < 0.001), alanine aminotransferase (47.5 vs. 33.0; p < 0.001), total bilirubin (20.8 vs. 17.9; p < 0.001), and lower albumin levels (32.0 vs. 40.0; p < 0.001) than patients in Chinese cohort. The tumor characteristics showed the Barcelona Clinic Liver Cancer (BCLC) score (BCLC 1: 5.1% vs. 71.8%; BCLC 2: 48.7% vs. 24.4%; BCLC 3: 24.4% vs. 3.8%; BCLC 4: 21.8% vs. 0; all p < 0.001), maximum tumor diameter (5.0 vs. 3.5; p < 0.001), alpha-fetoprotein values (27.7 vs. 13.2; p < 0.001), and percentage of patients with portal vein tumor thrombus (33% vs. 6.1%; p < 0.001) were all significantly worse in the Turkish cohort compared with Chinese cohort. Conclusions: HBV-associated HCC from the Turkish cohort had worse liver function and more aggressive clinical characteristics than patients from the Chinese cohort.

ADAR1 Inhibits HBV DNA Replication via Regulating miR-122-5p in Palmitic Acid Treated HepG2.2.15 Cells.

Background and Aims: Changes in living standards and diet structure, non-alcoholic fatty liver disease (NAFLD) is prevalent globally, including in Asia, where chronic hepatitis B (CHB) is endemic. As such, cooccurrence of NAFLD with CHB is common in Asia. However, the pathogenesis underlying the onset of fatty liver in CHB prognosis has not been fully elucidated. Therefore, we aimed to investigate the effects and mechanisms of lipotoxicity on hepatitis B virus (HBV) DNA replication. Methods: The expression of adenosine deaminase acting on RNA-1 (ADAR1) and miR-122 was evaluated in liver tissues from patients with CHB concurrent NAFLD. Palmitic acid-treated HepG2.2.15 cells were used as the cell model. The effect of lipotoxicity on HBV DNA replication was evaluated in vitro by transfecting the ADAR1 overexpression or knockdown lentiviral vector into HepG2.2.15 cells, respectively. qRT-PCR, western blotting and immunofluorescence were performed to determine ADAR1 expression. Results: The expression of ADAR1 in the liver tissues of CHB patients with concurrent NAFLD was significantly down-regulated compared with that in CHB patients. Enforced expression of ADAR1 inhibited the HBV DNA replication, whereas ADAR1 knockdown resulted in increased HBV DNA expression in palmitic acid - treated HepG2.2.15 cells. Additionally, ADAR1 inhibited the HBV DNA replication by upregulating miR-122, which is most abundant in the liver and mainly inhibits HBV DNA replication. Conclusions: ADAR1 may act as a suppressor of HBV replication in palmitic acid -treated HepG2.2.15 cells by increasing miR-122 levels. Thus, ADAR1 may serve as a potential biomarker and therapeutic target for CHB with concurrent NAFLD.

A K-nearest Neighbor Model to Predict Early Recurrence of Hepatocellular Carcinoma After Resection.

Background and Aims: Patients with hepatocellular carcinoma (HCC) surgically resected are at risk of recurrence; however, the risk factors of recurrence remain poorly understood. This study intended to establish a novel machine learning model based on clinical data for predicting early recurrence of HCC after resection. Methods: A total of 220 HCC patients who underwent resection were enrolled. Classification machine learning models were developed to predict HCC recurrence. The standard deviation, recall, and precision of the model were used to assess the model's accuracy and identify efficiency of the model. Results: Recurrent HCC developed in 89 (40.45%) patients at a median time of 14 months from primary resection. In principal component analysis, tumor size, tumor grade differentiation, portal vein tumor thrombus, alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II (PIVKA-II), aspartate aminotransferase, platelet count, white blood cell count, and HBsAg were positive prognostic factors of HCC recurrence and were included in the preoperative model. After comparing different machine learning methods, including logistic regression, decision tree, naïve Bayes, deep neural networks, and k-nearest neighbor (K-NN), we choose the K-NN model as the optimal prediction model. The accuracy, recall, precision of the K-NN model were 70.6%, 51.9%, 70.1%, respectively. The standard deviation was 0.020. Conclusions: The K-NN classification algorithm model performed better than the other classification models. Estimation of the recurrence rate of early HCC can help to allocate treatment, eventually achieving safe oncological outcomes.

Increased Risk of Liver-Related Outcomes in Chronic Hepatitis B Patients with Metabolic Syndrome: A Systematic Review and Meta-Analysis.

INTRODUCTION: Chronic hepatitis B (CHB) patients with metabolic syndrome (MetS) may present increased risk of liver-related outcomes (LROs), but prior studies were limited by small sample size and/or conflicting results. Using a systematic review and meta-analytic approach, we aimed to determine the association between MetS and LROs in CHB. METHODS: Two researchers independently screened studies from the PubMed, Embase, Web of Science, and Cochrane Library databases from inception to January 21, 2020, and extracted the data. Estimates were pooled using a random-effects model. RESULTS: We screened 2,228 articles and included 10 eligible studies (18,360 CHB patients, 2,557 with MetS). MetS was significantly associated with LROs overall (odds ratio = 2.45, 95% confidence interval = 1.39-4.32) but not the individual LRO components but subgroup analyses were limited by small study numbers. DISCUSSION/CONCLUSION: MetS is associated with almost 3-folds higher risk of LROs in CHB and should be considered in management decisions. However, additional studies are needed.

2019 Global NAFLD Prevalence: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The increasing rates of obesity and type 2 diabetes mellitus may lead to increased prevalence of nonalcoholic fatty liver disease (NAFLD). We aimed to determine the current and recent trends on the global and regional prevalence of NAFLD. METHODS: Systematic search from inception to March 26, 2020 was performed without language restrictions. Two authors independently performed screening and data extraction. We performed meta-regression to determine trends in NAFLD prevalence. RESULTS: We identified 17,244 articles from literature search and included 245 eligible studies involving 5,399,254 individuals. The pooled global prevalence of NAFLD was 29.8% (95% confidence interval [CI], 28.6%-31.1%); of these, 82.5% of included articles used ultrasound to diagnose NAFLD, with prevalence of 30.6% (95% CI, 29.2%-32.0%). South America (3 studies, 5716 individuals) and North America (4 studies, 18,236 individuals) had the highest NAFLD prevalence at 35.7% (95% CI, 34.0%-37.5%) and 35.3% (95% CI, 25.4%-45.9%), respectively. From 1991 to 2019, trend analysis showed NAFLD increased from 21.9% to 37.3% (yearly increase of 0.7%, P < .0001), with South America showing the most rapid change of 2.7% per year, followed by Europe at 1.1%. CONCLUSIONS: Despite regional variation, the global prevalence of NAFLD is increasing overall. Policy makers must work toward reversing the current trends by increasing awareness of NAFLD and promoting healthy lifestyle environments.

NASH/Liver Fibrosis Prevalence and Incidence of Nonliver Comorbidities among People with NAFLD and Incidence of NAFLD by Metabolic Comorbidities: Lessons from South Korea.

BACKGROUND: NAFLD incidence, NASH prevalence, NAFLD fibrosis prevalence, incidence of metabolic comorbidities, and mortality data in the NAFLD population remain limited. AIMS: We used a meta-analytic approach to "stage" NAFLD among the Korean population. METHODS: We searched PubMed, Embase, Cochrane Library, and KoreaMed from inception until June 29, 2019, and calculated pooled estimates via the random-effects model. RESULTS: We screened 1,485 studies and analyzed 191 eligible studies: 179 (3,556,579 participants) for NAFLD prevalence and outcome analysis and 32 (1,089,785 participants) for NAFLD incidence analysis. NAFLD prevalence was 31.46% overall and 50-60% in those with metabolic risks. The incidence (per 1,000 person-years) of NAFLD was 42.8 overall and 70-77% in those with metabolic risk. The incidence (per 1,000 person-years) of new-onset T2DM, hypertension, cardiovascular disease, and chronic kidney disease was found to be 16.9, 47.9, 100.6, and 13.9, respectively. From biopsy data, 30.21% of the NAFLD population had moderate-to-severe steatosis (9 studies, 2,461 participants) and 52.27% had NASH (7 studies, 1,168 participants) and 85.41% had fibrosis

Epidemiology of COVID-19: A systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes.

Coronavirus disease 2019 (COVID-19) has become a pandemic, but its reported characteristics and outcomes vary greatly amongst studies. We determined pooled estimates for clinical characteristics and outcomes in COVID-19 patients including subgroups by disease severity (based on World Health Organization Interim Guidance Report or Infectious Disease Society of America/American Thoracic Society criteria) and by country/region. We searched Pubmed, Embase, Scopus, Cochrane, Chinese Medical Journal, and preprint databases from 1 January 2020 to 6 April 2020. Studies of laboratory-confirmed COVID-19 patients with relevant data were included. Two reviewers independently performed study selection and data extraction. From 6007 articles, 212 studies from 11 countries/regions involving 281 461 individuals were analyzed. Overall, mean age was 46.7 years, 51.8% were male, 22.9% had severe disease, and mortality was 5.6%. Underlying immunosuppression, diabetes, and malignancy were most strongly associated with severe COVID-19 (coefficient = 53.9, 23.4, 23.4, respectively, all P < .0007), while older age, male gender, diabetes, and hypertension were also associated with higher mortality (coefficient = 0.05 per year, 5.1, 8.2, 6.99, respectively; P = .006-.0002). Gastrointestinal (nausea, vomiting, abdominal pain) and respiratory symptoms (shortness of breath, chest pain) were associated with severe COVID-19, while pneumonia and end-organ failure were associated with mortality. COVID-19 is associated with a severe disease course in about 23% and mortality in about 6% of infected persons. Individuals with comorbidities and clinical features associated with severity should be monitored closely, and preventive efforts should especially target those with diabetes, malignancy, and immunosuppression.