Acute hepatitis E infection could induce severe outcomes among chronic hepatitis B (CHB) patients. Between 2016 and 2017, an open-label study was conducted to evaluate the immunogenicity and safety of hepatitis E vaccine (HepE) in CHB patients, using healthy adults as parallel controls in China. Eligible participants who were aged ≥30 y were enrolled in the study. The CHB group included participants who had ever developed symptoms of hepatitis because of CHB but was currently at a clinically stable stage, which was defined as ALT ≤ 1.5 times of upper limit of the normal range (ULN) in this study. The control group included healthy adults who had hepatitis B surface antigen (HBsAg) negative. HepE was administered for 0, 1, 6 months for all participants. At 1 month after the third-dose vaccination (month 7), the seroconversion rates of anti-HEV IgG were >97% in both groups. The geometric mean concentration (GMC) of anti-HEV IgG in the CHB group was non-inferior to the healthy adult group (0.69 WU/mL, 95% CI 0.55-0.85). The proportion of the participants with adverse events ≥ grade 3 was similar in both groups (p = .99), and no vaccine-associated severe adverse events were identified. Changes in the liver function indicators were not of clinical significance. The HepE was highly immunogenic and well tolerated among clinically stable CHB patients and healthy adults.

The severity of liver fibrosis (LF) in chronic hepatitis B (CHB) affects the outcome and treatment. We probed plasma miR-30a expression in CHB patients and its value in assessing LF severity.

This retrospective study included 160 CHB patients and another 98 controls. Levels of lipid parameters, liver function parameters, hemoglobin, and alpha-fetoprotein were quantified by ELISA and chemiluminescence immunoassay. White blood cell, platelet, and red blood cell counts were determined using an automatic hematology analyzer. Fibrosis index based on four factors (FIB-4) was calculated. miR-30a level was determined, followed by the analysis of correlations of miR-30a expression with LF classification or with FIB-4 in CHB patients. The diagnostic value of plasma miR-30a for mild-to-moderate and severe LF in CHB patients was analyzed by receiver operating characteristic (ROC) curve.

Plasma miR-30a was poorly expressed in CHB patients and decreased dependently with LF aggravation. miR-30a was negatively interrelated with LF classification and FIB-4. Plasma miR-30a had high diagnostic value for mild-to-moderate LF in CHB patients [area under the ROC curve (AUC) = 0.775, cutoff value = 0.71, 95% confidence interval (CI) = 0.685-0.849]. Plasma miR-30a had high diagnostic value for severe LF in CHB patients (AUC = 0.873, cutoff value = 0.49, 95% CI = 0.804-0.924).

Plasma miR-30a was weakly expressed in CHB patients. miR-30a expression was negatively correlated with LF severity in CHB patients. miR-30a had high diagnostic value for mild-to-moderate and severe LF in CHB patients. miR-30a might serve as a promising target for LF treatment.

Despite the effectiveness of hepatitis B virus (HBV) antiviral treatment therapy in reducing the risk of liver-related complications, such as cirrhosis and hepatocellular carcinoma among chronically infected patients, medication non-adherence continues to hamper the successful management of the infection. The extent of HBV treatment adherence, associated facilitators, and barriers in South Sudan is not established. This study aimed to explore the predictors of medication non-adherence among HBV patients attending a public health facility in, South Sudan.

We conducted a facility-based cross-sectional study of 392 convenience-selected patients using a pretested interviewer-administered questionnaire premised on the information-motivation-behavioral skills (IMB) adherence model between December 2023 and March 2024. The relationship between medication non-adherence and antecedent variables was ascertained by logistic regression analysis.

The sample was predominantly male (64.3%), and the mean age was 31.06 (30.19-31.93) years, with 28.1% reporting no formal education. The patients demonstrated inadequate HBV information (4.33±1.93), low motivation (8.20±2.69), and inadequate behavioral skills toward medication adherence (8.45±2.99), as measured on their respective rating scales. Further, more than two-thirds of the patients (70.2%) were HBV medication non-adherent. Younger age (AOR = 4.74, 95% CI = 2.13-10.56), being currently unmarried (AOR = 3.25, 95% CI = 1.76-6.01), unemployment (AOR = 4.19, 95% CI = 1.84-9.56), and increased behavioral skills (AOR = 1.12, 95% CI = 1.84-9.56) significantly influenced medication non-adherence. Lower education (AOR = 0.21, 95% CI = 0.10-0.46) and information adequacy (AOR = 0.63, 95% CI = 0.53-0.75) were associated with lower odds of non-adherence.

The study highlights key factors influencing the concerning rate of medication non-adherence among HBV patients in South Sudan. While these identified factors may explain the lingering burden of HBV-related complications, targeted interventions addressing demographic, socioeconomic barriers, and HBV-specific education are essential to enhance adherence and improve health outcomes.

No universal consensus exists as to what the upper limit of normal for alanine aminotransferase (ALT) should be. The purpose of this review is to provide insight on the wide variation in the upper limit of normal for ALT, and to highlight key elements resulting in these differences. We also wish to point to potential solutions for standardizing the upper limit of normal.

There are considerable differences in the values for what constitutes a 'normal' ALT serum concentration set by laboratories, and reference values may vary two-fold between different institutions (from 30 to 60 U/l). Key reasons for this include using markedly different reference populations to establish the bounds of normal, and differences in analyzers and assays used to quantify ALT levels. A number of studies have attempted to re-evaluate the upper limit of normal and propose new cut-offs that would allow better detection of liver disease.

The upper limit of normal for ALT continues to vary from one laboratory to another. Despite ongoing efforts, there is still an unmet demand to standardize ALT reference ranges, which is critical for clinical practice. More rigorous inclusion criteria for reference population studies and harmonization in analyzer differences is required to standardize ALT reference ranges universally.

Perinatal transmission of hepatitis B virus (HBV) remains a significant public health issue. To complement vaccination, tenofovir disoproxil fumarate (TDF) prophylaxis is recommended for HBV-infected pregnant women. We aimed to identify a cost-effective strategy for using TDF to prevent perinatal HBV transmission in Ethiopia.

A decision tree combined with a Markov model was used to determine the cost-effectiveness of different strategies for preventing perinatal transmission of HBV in a cohort of 10,000 hepatitis B surface antigen (HBsAg)-positive pregnant women. The existing vaccination strategy (Strategy 1) was compared with three alternative strategies that added TDF prophylaxis to the existing strategy. Strategy 2 (TDF prophylaxis following HBV viral load testing), Strategy 3 (TDF prophylaxis following hepatitis B envelope antigen (HBeAg) testing), and Strategy 4 (TDF prophylaxis for all HBsAg-positive). Costs were measured from the healthcare sector perspective. Effects were measured as HBV infection averted and disability adjusted life years (DALYs) averted. Model input parameters were obtained from the literature review and local data. Cost-effectiveness was determined by the incremental cost-effectiveness ratio (ICER), with thresholds set at 0.34, 1, and 3 times the GDP per capita of Ethiopia. A sensitivity analysis was conducted to test the robustness of the results.

Among the alternatives, Strategy 4 is the most cost-effective strategy, with an ICER of 220.3 US$ per DALY averted. Strategy 4 would prevent 267 perinatal HBV infections and averted 1048 DALYs per 10,000 HBsAg-positive pregnant women. These results were robust to a range of parameters and showed a 97% probability of being cost-effective at one times the GDP per capita of Ethiopia. The next optimal strategy is Strategy 2, compared with the next best alternative, with an ICER of 1175.52 US$ per DALY averted. Strategy 3 was dominated by the available strategies.

Providing TDF prophylaxis for all HBsAg-positive pregnant women starting at 28 weeks of pregnancy has the potential to be a cost-effective strategy in Ethiopia. Introduction of TDF prophylaxis for all HBsAg-positive pregnant women is highly recommended, along with efforts to improve vaccination coverage.

International guidelines suggest cessation of nucleos(t)ide analogues (NA) independent of HBsAg loss in HBeAg-negative patients after 2-3 years of viral suppression. Detectable HBV-RNA levels at the time of NA cessation were linked to a better prediction of relapse after NA withdrawal in small cohorts of HBeAg-negative patients. This study proves the impact of HBV-RNA levels in the prediction of relapse in a large cohort of HBeAg-negative patients, mainly infected with genotype B or C. Serum levels of HBV-RNA, HBsAg, anti-HBc and HBcrAg were determined before NA withdrawal in 154 HBeAg-negative patients, participating either in a therapeutic vaccination trial (NCT02249988) or in an observational register trial (NCT03643172). Importantly, vaccination showed no impact on relapse. Endpoints of the study were virological relapse (HBV-DNA > 2000 IU/mL) or biochemical relapse (attendant ALT levels ≥ 2 × ULN) 24 weeks after NA cessation. Virological relapse occurred in 54.5% of patients (N = 84/154), including eight patients (10%) developing an ALT flare. Baseline HBV-RNA level did not differ significantly between relapsers and off-treatment responders (p = 0.92). No significant difference occurred in proportions of detectable HBV-RNA levels between off-treatment responders (N = 27/70; 38.6%) and relapsers (N = 31/84; 36.9%) (p = 0.99). Combining predefined HBsAg cut-offs (100 IU/mL, p = 0.0013), anti-HBc cut-offs (325 IU/mL, p = 0.0117) or HBcrAg cut-offs (2 log U/mL, p = 0.66) with undetectable HBV-RNA (HBsAg, p = 0.0057; anti-HBc, p = 0.085; HBcrAg, p = 0.60) did not improve relapse prediction. The value of HBV-RNA levels at timepoint of NA cessation for the prediction of relapse is limited in HBeAg-negative patients. Trial Registration: ABX 203-002: NCT02249988; Terminator 2: NCT03643172.

Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.

Aplastic anemia occurs with an incidence of 2-5: 1 million people worldwide. However, the frequency of newly diagnosed cases of bone marrow aplasia is greater, and some of these patients present to emergency departments initially. Description of Case: We present the case of a middle-aged man with pancytopenia. In this case, aplastic anemia associated with hepatitis B and syphilis was only the initial diagnosis. An indolent hematologic malignancy-hairy cell leukemia-was diagnosed as the real cause of the bone marrow failure in a clinic of hematology. Conclusions: This clinical case allows us to make a conclusion, albeit not definitively, about the contribution of hepatitis B and syphilis to the clinical manifestation of hairy cell leukemia. A detailed and consistent diagnostic plan is also required in patients presenting with pancytopenia. Failure to diagnose a hepatitis B infection in a patient with malignant hematologic disease would lead to fatal therapeutic errors.

Current guidelines to prevent hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection are based on risk assessments that include age, sex, and virological and biochemical parameters. The study aim was to investigate the impact of predictive markers on long-term outcomes. The clinical outcomes of 100 patients with chronic hepatitis B were investigated 30 years after a baseline assessment that included liver biopsy. A favourable outcome-HBsAg loss or HBeAg-negative infection (ENI; previously termed 'inactive carrier')-was observed in 74% of all patients, whereas 7% developed HCC. HBsAg loss was observed in 75% of patients with genotype A, compared with 42%, 33% and 0% with genotypes D, B and C, respectively (p < 0.0001). HCC developed in 3 patients (33%) with genotype C as compared with 3 (17%), 1 (2%) and 0 patients with genotypes B, D and A, respectively (p < 0.0001). In multiple logistic regression analysis, both HBsAg loss and HCC were associated with HBV genotype and baseline HBV DNA level, and HCC also with histological score. The results suggest that genotyping and histological assessment may improve outcome prediction and help decisions about HCC screening, particularly in populations with HBV-infected individuals of mixed geographic origin.

To investigate the predictive value of serum hepatitis B virus (HBV) RNA on HBeAg seroconversion in treated chronic hepatitis B (CHB) patients.

Sixty-four HBeAg-positive CHB patients were selected. They were divided into HBeAg seroconversion group including 11 cases and HBeAg non-seroconversion group including 53 cases. HBV RNA levels and other laboratory results were measured at baseline and week 12, 24, 48, 72 during treatment in both groups. The predictive value of HBV RNA level for the seroconversion of HBeAg in patients treated for hepatitis B was analyzed.

Significant differences existed in serum HBV DNA and HBV RNA levels between the two groups at baseline while there was no significant difference in HBsAg. The correlation between HBV RNA and HBV DNA was significantly high (r = 0.707, P < 0.05), while the correlation between HBV DNA and HBsAg (r = 0.474, P < 0.05) or HBV RNA and HBsAg was poor (r = 0.372, P < 0.05). Patients with younger age and higher HBV RNA levels at baseline and week 24 were less likely to have HBeAg seroconversion. HBV RNA was better than HBV DNA and HBsAg in predicting HBeAg seroconversion whether at baseline or week 12 and week 24. The area under the curve of HBV RNA level at 24th week was the highest, which was 0.942, and the cutoff value was 4.145 log10 copies/ml.

HBV RNA level may be a suitable serum marker to predict whether HBeAg seroconversion can occur. CHB patients with serum HBV RNA level lower than 4.145 log10 copies/ml at week 24 were more likely to achieve HBeAg seroconversion.

Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (

METHODS

In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. The primary outcome was the proportion of participants with HBsAg <0.05 IU/ml and HBV DNA

RESULTS

The intent-to-treat population included 108 participants (Arm 1, n = 55; Arm 2, n = 53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3,000 IU/ml. Indirect comparison with the phase IIb study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events and treatment-related adverse events in both treatment windows were similar between treatment arms.

CONCLUSIONS

Sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA therapy. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse.

IMPACT AND IMPLICATIONS

This phase IIb study investigated whether sequential therapy with bepirovirsen followed by Peg-IFN could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with chronic HBV. These data show that sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective; in patients with a bepirovirsen response, sequential treatment with Peg-IFN may help to reduce off-treatment relapses in participants on stable NA. Participants had a similar response during bepirovirsen treatment as seen in B-Clear, with increased response rates in participants with lower baseline HBsAg; all responders to the sequential regimen had baseline HBsAg <3000 IU/mL. As the first study of antisense oligonucleotide-mediated RNA silencing followed by interferon immunomodulation in patients with chronic HBV infection, this study is an important proof-of-concept for sequential therapy, shedding light on the therapeutic potential of utilising immunomodulators following suppression of HBV antigens.

CLINICAL TRIAL NUMBER

NCT04676724.

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Key Words

• Hepatitis B
• antisense oligonucleotide
• bepirovirsen
• pegylated interferon-α-2a
• sequential therapy

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MESH Headings

• Humans
• Hepatitis B, Chronic/drug therapy
• Polyethylene Glycols/administration & dosage
• Polyethylene Glycols/therapeutic use
• Male
• Female
• Antiviral Agents/therapeutic use
• Antiviral Agents/administration & dosage
• Adult
• Middle Aged
• Interferon-alpha/administration & dosage
• Interferon-alpha/therapeutic use
• Recombinant Proteins/administration & dosage
• Recombinant Proteins/therapeutic use
• Recurrence
• Drug Therapy, Combination/methods
• Hepatitis B Surface Antigens/blood
• DNA, Viral/blood
• Hepatitis B virus/genetics
• Hepatitis B virus/drug effects
• Hepatitis B virus/immunology
• Treatment Outcome

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Affiliation(s)

Maria Buti Liver Unit, Hospital Vall d'Hebrón, Barcelona and CIBER-EHD del Instituto Carlos III, Barcelona, Spain.
Jeong Heo Department of Internal Medicine, College of Medicine, Pusan National University, Busan, Republic of Korea; Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea.
Yasuhito Tanaka Department of Gastroenterology and Hepatology, Kumamoto University Hospital, Kumamoto, Japan
Pietro Andreone Medicina Interna a indirizzo Metabolico-Nutrizionale, Ospedale Clinicizzato di Baggiovara, AOU di Modena, Modena, Italy; Dipartimento SMECHIMAI, Università di Modena e Reggio Emilia, Modena, Italy
Masanori Atsukawa Nippon Medical School Hospital, Tokyo, Japan
Joaquín Cabezas Gastroenterology and Hepatology Department, University Hospital Marques de Valdecilla, Santander, Spain; Clinical and Translational Research in Digestive Diseases, Valdecilla Research Institute (IDIVAL), Santander, Spain
Eric Chak UC Davis, Sacramento, California, USA
Carla S Coffin Department of Medicine, Cumming School of Medicine, University of Calgary, Alberta, Calgary, Canada
Kei Fujiwara Nagoya City University Hospital, Aichi, Japan
Natalya Gankina Krasnojarsk Regional Center of AIDS prevention, Krasnojarsk, Russian Federation
Stuart C Gordon Henry Ford Health and Wayne State University School of Medicine, Detroit, MI, USA
Ewa Janczewska Department of Basic Medical Sciences, Faculty of Public Health in Bytom, Medical University of Silesia, Myslowice, Poland
Atsumasa Komori National Hospital Organization, NHO Nagasaki Medical Center, Nagasaki, Japan
Pietro Lampertico Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Stuart McPherson Hepatology and Newcastle NIHR Biomedical Research Centre, The Newcastle Upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle-upon-Tyne, UK
Vyacheslav Morozov Hepatologist Medical Company, Samara, Russian Federation
Robert Plesniak University of Rzeszow Centrum Medyczne w Lancucie Sp. z o.o., Lancut, Poland
Sébastien Poulin Clinique Médecine Urbaine du Quartier Latin, Montréal, Québec, Canada
Pablo Ryan Hospital Infanta Leonor and CIBERINFEC, del Instituto Carlos III., Madrid, Spain
Olga Sagalova South Ural State Medical University, Chelyabinsk, Russian Federation
Guoping Sheng Department of Infectious Disease, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University, Shulan International Medical College, Hangzhou, Zhejiang, China
Natalya Voloshina Medical Centre Healthy Family, Novosibirsk, Russian Federation
Qing Xie Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Hyung Joon Yim Korea University Ansan Hospital, Ansan, Republic of Korea
Susan Dixon GSK, London, UK
Melanie Paff GSK, Collegeville, PA, USA
Leigh Felton GSK, London, UK
Maximilian Lee GSK, Collegeville, PA, USA
Thomas Greene GSK, Collegeville, PA, USA
Jessica Lim GSK, Collegeville, PA, USA
Divya Lakshminarayanan GSK, Collegeville, PA, USA
Grant McGonagle GSK, London, UK
Helene Plein GSK, London, UK
Amir S Youssef GSK, Collegeville, PA, USA
Rob Elston GSK, Stevenage, UK
Stuart Kendrick GSK, Stevenage, UK
Dickens Theodore GSK, Durham, NC, USA

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The risk of hepatocellular carcinoma (HCC) and hepatic decompensation persists after hepatitis B surface antigen (HBsAg) seroclearance. This study aimed to develop and validate a machine learning model to predict the risk of liver-related outcomes (LROs) following HBsAg seroclearance.

A total of 4,787 consecutive patients who achieved HBsAg seroclearance between 2000 and 2022 were enrolled from six centers in South Korea and a territory-wide database in Hong Kong, comprising the training (n = 944), internal validation (n = 1,102), and external validation (n = 2,741) cohorts. Three machine learning-based models were developed and compared in each cohort. The primary outcome was the development of any LRO, including HCC, decompensation, and liver-related death.

During a median follow-up of 55.2 (IQR 30.1-92.3) months, 123 LROs were confirmed (1.1%/person-year) in the Korean cohort. The model with the best predictive performance in the training cohort was selected as the final model (designated as PLAN-B-CURE), which was constructed using a gradient boosting algorithm and seven variables (age, sex, diabetes, alcohol consumption, cirrhosis, albumin, and platelet count). Compared to previous HCC prediction models, PLAN-B-CURE showed significantly superior accuracy in the training cohort (c-index: 0.82 vs. 0.63-0.70, all p <0.001; area under the receiver-operating characteristic curve: 0.86 vs. 0.62-0.72, all p <0.01; area under the precision-recall curve: 0.53 vs. 0.13-0.29, all p <0.01). PLAN-B-CURE showed a reliable calibration function (Hosmer-Lemeshow test p >0.05) and these results were reproduced in the internal and external validation cohorts.

This novel machine learning model consisting of seven variables provides reliable risk prediction of LROs after HBsAg seroclearance that can be used for personalized surveillance.

Using large-scale multinational data, we developed a machine learning model to predict the risk of liver-related outcomes (i.e., hepatocellular carcinoma, decompensation, and liver-related death) after the functional cure of chronic hepatitis B (CHB). The new model named PLAN-B-CURE was constructed using seven variables (age, sex, alcohol consumption, diabetes, cirrhosis, serum albumin, and platelet count) and a gradient boosting machine algorithm, and it demonstrated significantly better predictive accuracy than previous models in both the training and validation cohorts. The inclusion of diabetes and significant alcohol intake as model inputs suggests the importance of metabolic risk factor management after the functional cure of CHB. Using seven readily available clinical factors, PLAN-B-CURE, the first machine learning-based model for risk prediction after the functional cure of CHB, may serve as a basis for individualized risk stratification.

Recent evidence has indicated that the O-glycosylated PreS2 domain of the middle HBsAg is a distinguishing characteristic that allows the identification of HBsAg of HBV Dane particles and SVPs. This study's objective was to assess the changes in serum O-glycosylated HBsAg levels in CHB patients undergoing ETV or Peg-IFNα treatment.

Our retrospective study enrolled 86 patients with genotype C CHB. We determined the O-glycosylated HBsAg, HBsAg, HBeAg, HBV DNA, and HBV RNA at baseline and during ETV or Peg-IFNα treatment. The correlations between O-glycosylated HBsAg and conventional HBV marker levels were also examined. Furthermore, we performed a ROC analysis to evaluate the predictive value of individual biomarkers for virological response.

At baseline, the serum O-glycosylated HBsAg levels were significantly correlated with the HBsAg (r = 0.754), HBV DNA (r = 0.498), HBeAg (r = 0.404), and HBV RNA (r = 0.399) in HBeAg positive patients. O-glycosylated HBsAg decreased after antiviral therapy. Both O-glycosylated HBsAg and HBsAg were significantly correlated with serum HBV DNA as well as HBV RNA at baseline, while only O-glycosylated HBsAg still correlated with HBV RNA (r = 0.397) in DNA-undetectable patients after ETV therapy. O-glycosylated HBsAg was significantly correlated with HBV RNA (r = 0.846) in DNA-undetectable patients after Peg-IFNα therapy compared to that of HBsAg (r = 0.800).

Serum O-glycosylated HBsAg level decreased during anti-viral therapy and correlated well with conventional HBV markers in HBeAg positive genotype C patients, suggesting that it could be a potential monitoring biomarker in HBV DNA-suppressed patients.

The presence of significant liver inflammation is an important indication for antiviral therapy in immune-tolerant (IT)phase with chronic hepatitis B(CHB) patients. This study aims to establish a non-invasive model to assess significant liver inflammation in the IT-phase of CHB patients. This multicenter retrospective study included a total of 535 IT-phase CHB patients who underwent liver biopsy, and were randomly divided into a training and a validation set. In the training cohort, the relevant indices were initially screened using univariate analysis. Then the least absolute shrinkage and selection operator and multivariable logistic regression were used to identify the significant independent risk factors and establish a predictive model. A diagnostic nomogram was constructed. Calibration curves, decision curve analysis, and receiver operating characteristic curves were utilized to evaluate the performance of the nomogram. In this study, 37.0% of the patients exhibited significant liver inflammation. Baseline characteristics revealed a median age of 35.0 years, with males accounting for 51.7% of the cohort. Age, Aspartate aminotransferase (AST), Prothrombin (PT), Albumin (ALB) and Hepatitis B virus DNA (HBV DNA) were identified as independent predictors of significant liver inflammation in the immune-tolerant phase, and a nomogram was constructed based on these indicators. The predictive model demonstrated good calibration and discrimination in both the training set and the validation set (aera under the curve (AUC) of 0.741 and 0.740, respectively). The nomogram can accurately identify significant liver inflammation in immune-tolerant phase CHB patients and facilitate the early initiation of antiviral therapy, thereby reducing the need for clinical liver biopsies.

Patients with chronic hepatitis B infection (CHB) have an increased risk for death from liver cirrhosis and hepatocellular carcinoma (HCC). In the United States, only an estimated 37% of adults with chronic hepatitis B diagnosis without cirrhosis receive monitoring with at least an annual alanine transaminase (ALT) and hepatitis B deoxyribonucleic acid (DNA), and an estimated 59% receive antiviral treatment when they develop active hepatitis or cirrhosis. A Markov model was used to calculate the costs, health impact and cost-effectiveness of increased monitoring of adults with HBeAg negative inactive or HBeAg positive immune tolerant CHB who have no cirrhosis or significant fibrosis and are not recommended by the current American Association for the Study of Liver Diseases (AASLD) clinical practice guidelines to receive antiviral treatment, and to assess whether the addition of HCC surveillance would be cost-effective. For every 100,000 adults with CHB who were initially not recommended for treatment, if the monitoring rate increased from the current 37% to 90% and treatment rate increased from 59% to 80%, 4,600 cases of cirrhosis, 2,450 cases of HCC and 4,700 HBV-related deaths would be averted with a gain of 45,000 QALYs and a savings of $180 million in lifetime health care costs. At a willingness to pay threshold of $100,000/QALY, the addition of HCC surveillance with the standard recommended biannual liver ultrasound and alfa fetoprotein levels is likely cost-effective if the HCC risk ≥ 0.55%/year. Regular monitoring of persons with inactive or immune tolerant CHB who are initially not recommended to receive antiviral treatment in the United States is cost-saving. The addition of HCC surveillance with biannual US and AFP would be cost-effective for individuals with HCC incidence ≥ 0.55%/year.

Information on circulating HBV (sub-)genotype, variants, and hepatitis D virus (HDV) coinfection, which vary by geographical area, is crucial for the efficient control and management of HBV. We investigated the genomic characteristics of HBV (with a prevalence of 8.1%) and the prevalence of HDV in Nigeria. We utilised 777 HBV-positive samples and epidemiological data from the two-stage sampled population-based, nationally representative Nigeria HIV/AIDS Indicator and Impact Survey conducted in 2018. We assessed 732 HBV DNA-extracted samples with detectable viral loads (VLs) for (sub-)genotypes and variants by whole-genome pre-amplification, nested PCR of the s-and pol-gene, and BigDye Terminator sequencing. We conducted HDV serology. In total, 19 out of the 36 + 1 states in Nigeria had a high prevalence of HBV (≥8%), with the highest prevalence (10.4%) in the north-central geopolitical zone. Up to 33.2% (95% CI 30.0-36.6) of the participants had detectable VLs of ≥300 copies/mL. The predominant circulating HBV genotype was E with 98.4% (95% CI 97.1-99.1), followed by A with 1.6% (95% CI 0.9-2.9). Drug-resistant associated variants and immune escape variants were detected in 9.3% and 0.4%, respectively. The seroprevalence of HDV was 7.34% (95% CI 5.5-9.2). Nigeria has subtype E as the major genotype with many variants.

This study evaluated the long-term efficacy and safety of the widely used drugs entecavir (ETV) and tenofovir alafenamide (TAF), as well as the incidence of HCC.A nonrandomized, prospective, observational analysis included 77 patients with chronic hepatitis B who were assigned to continue ETV or switch TAF. After 240 weeks, the mean changes in serum hepatitis B surface antigen (- 0.365 ± 0.069 log IU/mL vs. 0.301 ± 0.039 log IU/mL, p = 0.39) and hepatitis B core-related antigen (- 0.215 ± 0.092 log IU/mL vs. - 0.195 ± 0.056 log IU/mL) were not significantly different between the ETV and TAF groups. There were also no differences between the two groups in estimated glomerular filtration rate (- 5.407 ± 1.660 vs. - 2.666 ± 1.52, p = 0.240), urinary β2-microglobulin β/creatinine (ETV: 2.330 ± 0.374 at baseline and 2.335 ± 0.257 at 240 weeks; TAF: 2.720 ± 0.073 and 2.123 ± 0.310, p = 0.996 and 0.455, respectively) or urinary N-acetyl-β-D-glucosaminidase/creatinine (ETV: 0.040 ± 0.005 at baseline and 0.044 ± 0.004 at 240 weeks; TAF: 0.049 ± 0.005 and 0.053 ± 0.005, p = 0.642 and 0.684, respectively). Finally, no significant difference was found in the incidence of HCC between the ETV and TAF groups (log-rank test, p = 0.08). In conclusion, the long-term observation of this study demonstrated that ETV and TAF have comparable efficacy and safety.Clinical trial registration: UMIN000026465.

Chronic hepatitis B remains a substantial global health challenge, impacting approximately 254 million people worldwide. A cure for this condition is yet to be discovered. Early identification and effective treatments coupled with vigilant monitoring can help alleviate associated morbidity and mortality due to potential complications such as liver cirrhosis and hepatocellular carcinoma.

Background. Chronic hepatitis B (CHB) is a lifelong disease requiring long-term or indefinite therapy, resulting in substantial economic burden. Thus, careful consideration must be used in the selection of therapies. Aim. This analysis assessed the cost-effectiveness of tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) from the perspective of the Taiwan National Health Insurance Administration Healthcare payer for the management of CHB over a lifetime horizon. Methods. An individual patient simulation model assessed the impact of treatment on CHB infection for liver- and safety-related outcomes. Patients could achieve spontaneous or treatment-induced responses, experience a reactivation of the disease, develop long-term liver complications, or experience treatment-related renal or bone complications. Patient population profiles were based on clinical trial and real-world data. Data on clinical parameters (safety, mortality, resistance risk, and flare), health utilities, and costs were sourced from the published literature. Results. TAF was associated with fewer liver disease events and fewer cases of bone and renal complications per 100 person-years. TAF also had higher eAg and sAg seroconversion compared with TDF and ETV. As compared with both treatments, TAF was both more effective and more costly, resulting in incremental cost-effectiveness ratios of USD 3,348 and USD 3,940 per quality-adjusted life-year gained versus TDF and ETV, respectively. Conclusion. TAF leads to better health outcomes at acceptable incremental costs compared with the most commonly used therapies in the management of CHB, thus making it a cost-effective option for the treatment of CHB in Taiwan.

The cost-effectiveness of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was assessed in patients with chronic hepatitis B in Taiwan.TAF was associated with fewer liver disease events, fewer cases of bone and renal complications, and higher eAG and sAG seroconversion compared with TDF and ETV; TAF was found to be cost-effective compared with both treatments.

Hepatitis B virus (HBV) X protein (HBx) is a key factor for regulating viral transcription and replication. We recently characterized homeobox protein MSX-1 (MSX1) as a host restriction factor that inhibits HBV gene expression and genome replication by directly binding to HBV enhancer II/core promoter (EnII/Cp) and suppressing its promoter and enhancer activities. Notably, HBx expression was observed to be repressed more drastically by MSX1 compared to other viral antigens. In this work, we report that in addition to transcriptional repression, MSX1 also post-transcriptionally downregulates HBx protein stability. Mechanistically, MSX1 induces ubiquitin-independent proteasomal degradation of HBx, which is mediated through HBx C-terminal domain. Furthermore, this effect on HBx degradation correlates with MSX1-induced upregulation of DNAJA4 and CRYAB expression. Similar to MSX1, both DNAJA4 and CRYAB promote HBx degradation and repress HBV gene expression and genome replication. In chronic hepatitis B (CHB) patients, immune active phase (IA) is associated with higher intrahepatic expression of MSX1, DNAJA4 and CRYAB, and lower serum HBV markers compared to immune tolerant (IT) phase. Finally, HBV infection is significantly suppressed by MSX1 overexpression in both NTCP-overexpressing cell and humanized liver mouse models. These results demonstrate additional and novel mechanisms of MSX1-mediated repression of HBV, and establish MSX1 as a multi-functional HBV restriction factor with therapeutic potential.

Xalnesiran, a small interfering RNA molecule that targets a conserved region of the hepatitis B virus (HBV) genome and silences multiple HBV transcripts, may have efficacy, with or without an immunomodulator, in patients with chronic HBV infection.

We conducted a phase 2, multicenter, randomized, controlled, adaptive, open-label platform trial that included the evaluation of 48 weeks of treatment with xalnesiran at a dose of 100 mg (group 1), xalnesiran at a dose of 200 mg (group 2), xalnesiran at a dose of 200 mg plus 150 mg of ruzotolimod (group 3), xalnesiran at a dose of 200 mg plus 180 μg of pegylated interferon alfa-2a (group 4), or a nucleoside or nucleotide analogue (NA) alone (group 5) in participants with chronic HBV infection who had virologic suppression with NA therapy. The primary efficacy end point was hepatitis B surface antigen (HBsAg) loss (HBsAg level, <0.05 IU per milliliter) at 24 weeks after the end of treatment. Safety was also assessed.

Among 159 participants (30, 30, 34, 30, and 35 in groups 1 through 5, respectively), the primary end-point event occurred in 7% (95% confidence interval [CI], 1 to 22) of those in group 1, in 3% (95% CI, 0 to 17) of those in group 2, in 12% (95% CI, 3 to 28) of those in group 3, in 23% (95% CI, 10 to 42) of those in group 4, and in none (95% CI, 0 to 10) of those in group 5. In groups 1 through 5, respectively, HBsAg seroconversion occurred in 3%, none, 3%, 20%, and none of the participants at 24 weeks after the end of treatment. HBsAg loss with or without seroconversion occurred only in participants with a screening HBsAg level below 1000 IU per milliliter. In groups 1 through 5, respectively, grade 3 or 4 adverse events occurred in 17%, 10%, 18%, 50%, and 6% of the participants, with the most frequent event being an elevated alanine aminotransferase level.

Among participants with chronic HBV infection who had virologic suppression with NA therapy, treatment with xalnesiran plus an immunomodulator resulted in HBsAg loss at 24 weeks after the end of treatment in a substantial percentage of participants. Grade 3 or 4 adverse events were not uncommon. (Funded by F. Hoffmann-La Roche; Piranga ClinicalTrials.gov number, NCT04225715.).

Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause acute or chronic hepatitis, representing a significant global health concern. By 2019, approximately 296 million individuals were chronically infected with HBV, with 1.5 million new cases annually and 820,000 deaths due to HBV-related cirrhosis and liver cancer. Current treatments for chronic hepatitis B include nucleotide analogs (NAs) and interferons (IFNs), particularly IFN-α. NAs, such as entecavir and tenofovir, inhibit viral reverse transcription, while IFN-α exerts antiviral effects by directly suppressing viral replication, modulating viral genome epigenetics, degrading cccDNA, and activating immune responses. Despite its potential, IFN-α shows limited clinical efficacy, partly due to HBV's interference with the IFN signaling pathway. HBV encodes proteins like HBc, Pol, HBsAg, and HBx that disrupt IFN-α function. For example, HBV Pol inhibits STAT1 phosphorylation, HBsAg suppresses STAT3 phosphorylation, and HBx interferes with IFN-α efficacy through multiple mechanisms. Additionally, HBV downregulates key genes in the IFN signaling pathway, further diminishing IFN-α's antiviral effects. Understanding these interactions is crucial for improving IFN-α-based therapies. Future research may focus on overcoming HBV resistance by targeting viral proteins or optimizing IFN-α delivery. In summary, HBV's ability to resist IFN-α limits its therapeutic effectiveness, highlighting the need for new strategies to enhance treatment outcomes.

The persistence of HBV covalently closed circular DNA (cccDNA) and HBV integration into the host genome in infected hepatocytes pose significant challenges to the cure of chronic HBV infection. Although CRISPR/Cas9-mediated genome editing shows promise for targeted clearance of viral genomes, a safe and efficient delivery method is currently lacking. Here, we developed a novel approach by combining light-induced heterodimerization and protein acylation to enhance the loading efficiency of Cas9 protein into extracellular vesicles (EVs). Moreover, vesicular stomatitis virus-glycoprotein (VSV-G) was incorporated onto the EVs membrane, significantly facilitating the endosomal escape of Cas9 protein and increasing its gene editing activity in recipient cells. Our results demonstrated that engineered EVs containing Cas9/gRNA and VSV-G can effectively reduce viral antigens and cccDNA levels in the HBV-replicating and infected cell models. Notably, we also confirmed the antiviral activity and high safety of the engineered EVs in the HBV-replicating mouse model generated by hydrodynamic injection and the HBV transgenic mouse model. In conclusion, engineered EVs could successfully mediate functional CRISPR/Cas9 delivery both in vitro and in vivo, leading to the clearance of episomal cccDNA and integrated viral DNA fragments, and providing a novel therapeutic approach for curing chronic HBV infection.

Liver stiffness measurement is principal for staging liver fibrosis but not included in routine examinations. We investigated whether comparable diagnostic performance can be achieved by mining ultrasound images and developing a novel serum index (NSI).

Texture features were extracted from ultrasound images. Spearman correlation and logistics regression selected independent variables for significant (F ≥ 2) and advanced (F ≥ 3) fibrosis. We compared the diagnostic performance of transient elastography (TE), ultrasound image biomarker, conventional serum indices (aspartate aminotransferase-to-platelet ratio index, fibrosis-4 index, gamma-glutamyl transpeptidase-to-platelet ratio), and NSI in 365 patients with chronic hepatitis B.

Among patients, 52.1% had significant fibrosis and 24.2% had advanced fibrosis. PLT, gamma-glutamyl transferase, prealbumin, and globulin were incorporated into NSI. In the validation group, TE achieved the best performance (area under the curve [AUC]: 0.765 [0.690-0.849] for significant fibrosis; 0.812 [0.745-0.878] for advanced fibrosis), followed by ultrasound image biomarker (AUC: 0.712 [0.629-0.795]; 0.678 [0.595-0.763]) and NSI (AUC: 0.630 [0.534-0.725]; 0.659 [0.572-0.745]), outperforming conventional indices.

Texture analysis enhances ultrasound's diagnostic utility, but TE remains superior. When TE is unavailable, ultrasound image analysis and NSI, incorporating prealbumin, can serve as alternative tools for fibrosis staging.

Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression.

We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up.

We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse.

While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.

Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an 'indeterminate phase' or 'grey zone'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.

The construction of a robust healthcare information system is fundamental to enhancing countries' capabilities in the surveillance and control of hepatitis B virus (HBV). Making use of China's rapidly expanding primary healthcare system, this innovative approach using big data and machine learning (ML) could help towards the World Health Organization's (WHO) HBV infection elimination goals of reaching 90% diagnosis and treatment rates by 2030. We aimed to develop and validate HBV detection models using routine clinical data to improve the detection of HBV and support the development of effective interventions to mitigate the impact of this disease in China.

Relevant data records extracted from the Family Medicine Clinic of the University of Hong Kong-Shenzhen Hospital's Hospital Information System were structuralized using state-of-the-art Natural Language Processing techniques. Several ML models have been used to develop HBV risk assessment models. The performance of the ML model was then interpreted using the Shapley value (SHAP) and validated using cohort data randomly divided at a ratio of 2:1 using a five-fold cross-validation framework.

The patterns of physical complaints of patients with and without HBV infection were identified by processing 158,988 clinic attendance records. After removing cases without any clinical parameters from the derivation sample (n = 105,992), 27,392 cases were analysed using six modelling methods. A simplified model for HBV using patients' physical complaints and parameters was developed with good discrimination (AUC = 0.78) and calibration (goodness of fit test p-value >0.05).

Suspected case detection models of HBV, showing potential for clinical deployment, have been developed to improve HBV surveillance in primary care setting in China. (Word count: 264).

Hepatitis B virus (HBV) affects hundreds of millions globally, with many cases stemming from perinatal transmission. Chronic hepatitis B (CHB) in children can progress to cirrhosis and hepatocellular carcinoma (HCC) in adulthood. Treatment options include interferons and nucleos(t)ide reverse transcriptase inhibitors (N[t]RTIs) such as tenofovir alafenamide (TAF).

This review covers the epidemiology of pediatric CHB and current treatments, with a focus on tenofovir-based therapies, particularly tenofovir disoproxil fumarate (TDF) and TAF. TDF has been used for years, but its risks of bone mineral density loss and renal impairment have raised concerns. TAF, with lower systemic exposure, appears to mitigate these risks. Ongoing trials are evaluating TAF's safety in younger children. There are knowledge gaps in long-term safety and the potential for combination therapies.

TAF offers a safer alternative to TDF for children with CHB, showing high antiviral efficacy and fewer side effects. However, more data are needed on its use in younger children and long-term safety. The future of CHB treatment in pediatrics may include combination therapies and personalized approaches, potentially improving outcomes and minimizing risks over a lifetime of treatment. As research progresses, TAF is likely to become a cornerstone in pediatric CHB management.

Hepatitis B virus (HBV) infection remains a major public health problem and, in associated co-infection with hepatitis delta virus (HDV), causes the most severe viral hepatitis and accelerated liver disease progression. As a defective satellite RNA virus, HDV can only propagate in the presence of HBV infection, which makes HBV DNA and HDV RNA the standard biomarkers for monitoring the virological response upon antiviral therapy, in co-infected patients. Although assays have been described to quantify these viral nucleic acids in circulation independently, a method for monitoring both viruses simultaneously is not available, thus hampering characterization of their complex dynamic interactions. Here, we describe the development of a dual fluorescence channel detection system for pan-genotypic, simultaneous quantification of HBV DNA and HDV RNA through a one-step quantitative PCR. The sensitivity for both HBV and HDV is about 10 copies per microliter without significant interference between these two detection targets. This assay provides reliable detection for HBV and HDV basic research in vitro and in human liver chimeric mice. Preclinical validation of this system on serum samples from patients on or off antiviral therapy also illustrates a promising application that is rapid and cost-effective in monitoring HBV and HDV viral loads simultaneously.

The immune microenvironment (IME) plays a crucial role in the progression of hepatocellular carcinoma (HCC). In HCC, the IME is often compromised by hepatitis B virus (HBV) infection, chronic inflammation, and fibrosis. Both antiviral therapy (AVT) and the alleviation of inflammation and fibrosis (AIF) have been shown to improve prognosis. However, the relationship among the IME of HCC, AVT, and AIF remains unclear.

A total of 140 and 110 primary HBV-related HCC patients were enrolled as training and validation sets, respectively, to establish a HCC-immune microenvironment score (H-IME score). Immunohistochemistry was performed to assess the number of granzyme B+ (GrB+) and Foxp3+ cells, as well as the expression of CTLA-4, PD-1, LAG3, TIGIT, TIM3, and VISTA. Another cohort consisting of 114 recurrent HBV-related HCC patients with paired primary and recurrent tissues was used to study the relationship among the IME of HCC, AVT, and AIF.

The H-IME score, including GrB, Foxp3, CTLA-4, PD-1, LAG3, and TIGIT, was established to evaluate the IME. A higher H-IME score indicates stronger immunosuppressive activities. Both AVT and AIF were found to inhibit immunosuppressive activities in the IME. Compared to primary tumors, the H-IME scores of recurrent tumors in the effective AVT group (e-AVT, classified by HBV DNA) with AIF decreased, while the scores increased in the non-AVT group without AIF.

The IME of HCC is closely related to AVT and AIF. e-AVT can enhance anti-tumor activities in the IME by alleviating inflammation and fibrosis.