[Ten-year changes in clinical characteristics and antiviral treatment patterns of chronic hepatitis B in China: a CR-HepB-based real-world study].

Objective: To understand ten-year changes in clinical characteristics and antiviral treatment patterns of chronic hepatitis B in China. Methods: Patients with chronic HBV infection:demographic, virologic, hematologic, blood biochemistry, and antiviral treatment data were extracted from the China Registry of Hepatitis B (CR-HepB) database between 2012 and 2022 for descriptive statistics and change trend analysis. Multiple group comparisons were conducted using the Kruskal Wallis H test, while counting data was compared between groups using χ (2) test. Results: A total of 180 012 patients with chronic HBV infection were included, with a median age of 40 years old, and a male proportion accounting for 60.2%. The HBeAg positive rate was 43.3%. Over time, the median age of new patients each year increased from 39 to 47 years, while the HBeAg positive rate decreased from 51.3% to 32.8%. The initial diagnosis of patients was mainly CHB (71.4%), followed by hepatitis B cirrhosis (11.8%), inactive HBsAg carrier status (10.6%), and chronic HBV carrier status (6.2%). Among the newly registered patients every year from 2012 to 2022, the proportion of hepatitis B cirrhosis remained stable, but after 2019, the proportion of CHB increased and the proportion of other diagnoses decreased. The proportion of patients with cirrhosis increased with age in different age groups, with 3.5%, 19.3%, and 30.4% in the < 40, 40-69, and≥70 age groups, respectively. The proportion of women in patients with cirrhosis also increased with age, from 16.1% in those < 30 years old to 44.3% in those≥80 years old. From 2012 to 2022, the proportion of patients receiving first-line nucleos(t)ide analog antiviral treatment increased year by year, from 51.0% in 2012-2013 to 99.8% in 2022. Conclusion: The CR-HepB registration data reflect the changes in clinical characteristics and antiviral treatment patterns in patients with chronic HBV infection in China over the past ten years and can thus provide a reference to promote hepatitis B diagnosis and treatment practice, as well as scientific research.

[Interpretation of the essential updates in guidelines for the prevention and treatment of chronic hepatitis B (Version 2022)].

Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association update the guidelines for the prevention and treatment of chronic hepatitis B (version 2022) in 2022. The latest guidelines recommend more extensive screening and more active antiviral treating for hepatitis B virus infection. This article interprets the essential updates in the guidelines to help deepen understanding and better guide the clinical practice.

[Treat-all: challenges of partial response and low-level viremia].

The recently updated "Guidelines for the Prevention and Treatment of Chronic Hepatitis B" in China have brought about significant changes. The new treatment indications almost mandate the implementation of a Treat-all strategy for the chronically HBV-infected population in China. While simultaneous negativity for hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA has long been an accepted criterion for treatment discontinuation, there has been controversies over the initiation of treatment criteria starting with HBsAg and HBV DNA positivity. Despite the inconsistent treatment criteria, the academic community has started supporting treat-all strategies in recent years due to the decreasing cost of treatment, prolonged management duration, and growing evidence of poor outcomes in untreated populations. Therefore, this update to the Chinese HBV guidelines represents a new direction that suggests "The greatest truths are the simplest." However, in the process of rolling out the Treat-all strategy, we must remain cautious of possible issues arising from the new strategy. Among them, the problem of partial response or low-level viremia following treatment may become more prominent due to the inclusion of a significant number of patients with normal or low levels of alanine transaminase. As existing evidence suggests that low-level viremia increases the risk of HCC in patients, it is essential to monitor and explore optimal therapeutic options for these patients.

[Multi-omics research contributes to early screening, diagnosis and treatment of liver cancer].

In 2016, the World Health Organization set an ambitious goal of reducing viral hepatitis-related deaths by 65% by 2030. The key to this goal is to reduce viral hepatitis-related HCC deaths. Liver cancer is the fourth most common malignant tumor and the second leading cause of cancer death in China. The onset of HCC is insidious, and most patients are already in the middle and late stage when diagnosed. Despite the great progress on management of HCC, the therapeutic effect and prognosis of HCC are still unsatisfactory. Therefore, multi-dimensional and comprehensive analysis of the mechanism of liver cancer, improving the early screening, diagnosis and treatment rate of liver cancer are the key points of reducing the harm of liver cancer in China. In recent years, multi-omics studies have been widely applied in the field of liver cancer, providing a basis for the pathogenesis of liver cancer, early detection and diagnosis, development of individual treatment strategies and prognosis assessment. This issue will focus on the application of genomics, proteomics, metabolomics and imaging omics in early screening, diagnosis and treatment of liver cancer.

[Application of liquid biopsy in early screening and recurrence prediction of hepatocellular carcinoma].

The incidence and mortality of HCC in China account for approximately 50% of all cases worldwide. Low early diagnosis rate and high postoperative recurrence rate are two major causes for poor 5-year survival rate of HCC patients in China. At present, multiple problems such as low performance and compliance of screening technology and lack of effective markers for predicting postoperative recurrence, remain to be resolved. Due to the simplicity and accuracy, new molecular markers, such as liquid biopsy, are expected to serve as supplementary tools to traditional screening and early warning approaches, thereby realizing early detection and accurate treatment of HCC. In this article, research progress upon the clinical application of liquid biopsy in early screening and prediction of postoperative recurrence of HCC was reviewed, and prospects the future research.

[Clinical application of serum Golgi protein 73 in patients with chronic liver diseases].

Golgi protein 73 (GP73) is a transmembrane protein on the Golgi apparatus and can be cut and released into the blood. In recent years, an increasing number of clinical studies have shown that the elevated serum GP73 level is closely related to liver diseases. And thus GP73 is expected to be used as a new serum marker for assessing progress of chronic liver diseases. Herein, the clinical application of serum GP73 in chronic hepatitis, liver fibrosis, liver cirrhosis and hepatocellular carcinoma with different etiologies was reviewed based on available literatures; and a research outlook in this field is made.

[Establishing an integrated hospital-community pyramid for screening and achieving hepatocellular carcinoma early diagnosis and treatment].

The comprehensive management of hepatocellular carcinoma (HCC) is a complete, dynamic and personalized process. Therefore, how to scientifically determine the HCC high-risk/extremely high-risk populations and develop a stratified monitoring plan is the key link to early detection, diagnosis and improvement of overall survival. In addition, accurately identifying high-risk/extremely high-risk groups based on the HCC risk prediction model, and applying it to establish an integrated hospital-community pyramid for HCC screening through the implementation of interdisciplinary scientific management and treatment may ultimately reduce HCC-related mortality rate.

[Clinical efficacy and safety analysis of camrelizumab combined with apatinib as a second-line therapy for unresectable hepatocellular carcinoma: a multicenter retrospective study].

Objective: To analyze the clinical efficacy and safety of camrelizumab combined with apatinib as a second-line therapy for unresectable hepatocellular carcinoma (HCC). Methods: Ninety-four cases with mid-and advanced-stage HCC who received camrelizumab combined with apatinib as second-line treatment were enrolled. Routine blood test, blood biochemical indexes, tumor stage, tumor imaging characteristics, previous treatment strategies and other clinical data before treatment were documented. Imaging examination follow-up results and adverse reactions during treatment were followed up until the end of follow-up or loss of follow-up or death. Kaplan-Meier method was used to analyze the clinical efficacy. Results: As of the last follow-up, 94 cases with mid-and advanced-stage HCC had received camrelizumab combined with apatinib as second-line treatment. Among them, 15 cases were lost to follow-up, 31 cases died, and 48 cases survived. The overall remission rate was 31.9%. The overall disease control rate was 71.3%. The median time to disease-free progression was 6.6 months. The median time to disease progression was not yet available. The 1-year cumulative survival rate was 62.3%. Grade 3 and above adverse reactions mainly included were thrombocytopenia (7.4%), abdominal pain (4.3%), active hepatitis (4.3%), leukopenia (4.3%), diarrhea (3.2%), hand-foot syndrome (3.2%). All adverse reactions were effectively controlled. Conclusion: Camrelizumab combined with apatinib can effectively prolong the survival period of patients with mid-and advanced-stage HCC, and it is well tolerated.

[Application of aMAP score to assess the risk of hepatocarciongenesis in population of chronic liver disease in primary hospitals].

Objective: The aMAP score is a hepatocellular carcinoma (HCC) risk prediction model based on an international cooperative cohort, which can be applied to various liver diseases. The aim of this study is to use the aMAP score to stratify the risk of HCC in patients with chronic liver disease (combined or non-combined metabolic diseases) admitted to People's Hospital of Yudu County, Ganzhou City, Jiangxi Province, in order to guide personalized HCC screening. Methods: The demographic information, laboratory test results (platelets, albumin, and total bilirubin) and combined disease information of patients with chronic liver disease who were admitted to People's Hospital of Yudu from January 2016 to December 2020 were collected, and the aMAP score was calculated to stratify HCC risk in this population. Results: A total of 3629 cases with chronic liver disease were included in the analysis, including 3 452 (95.1%) cases with hepatitis B virus (HBV) infection, 177 (4.9%) cases with fatty liver, and 22 (0.6%) cases with HBV infection and fatty liver. There were 2 679 (73.8%) male and the median age was 44 (35, 54). In the overall population, low, medium and high risk of HCC accounted for 52.6%, 29.0%, and 18.4% respectively. In the HBV-infected population, the proportion of high risk of HCC was significantly higher than that of fatty liver (18.9% vs. 9.6%, P = 0.001). The proportion of chronic liver disease patients with combined hypertension or diabetes was significantly higher than that of those with non-combined metabolic diseases (combined hypertension: 32.3% vs. 17.9%, P < 0.001; combined diabetes: 36.5% vs. 18.1%, P < 0.001). Moreover, the proportion of high-risk population with two metabolic diseases was significantly higher than that with one and no metabolic diseases (40.9% vs. 31.8% vs. 17.7%, P < 0.001). Conclusion: The aMAP score can be used as a simple tool for HCC screening and management of chronic liver disease in primary hospitals, and it is helpful to improve the personalized follow-up management system of chronic liver disease population. Chronic liver disease patients with metabolic diseases have a higher risk of HCC, and people with high risk of HCC should be given special priority in follow-up visits, so as to improve the rate of HCC early diagnosis and reduce the mortality rate.

[A 2020 update on the progress of treatment and new drug clinical trials for hepatitis B].

Long term antiviral therapy with nucleos(ti)ide analogues could suppress HBV viral load thereby prevent the progression to cirrhosis and hepatocellular carcinoma. Interferon-based therapy could result in sustained virological response in a fair proportion of patients and even HBsAg loss in a small proportion of them. Novel therapies aiming at functional cure (loss of HBsAg) are under active development. Among the categories of many, HBV core protein inhibitors are safe and could suppress the HBV DNA and HBV RNA, but only with modest effect on the level of HBsAg; silencing of HBV mRNA by siRNA or antisense oligonucleotides could produce meaningful and sustainable declining in HBsAg levels; immune modulators with different mode of action showed modest effect on the reduction of HBsAg, but with noticeable adverse event (especially transaminase flares) related to the mode of action. Novel clinical trial design on the combination or sequential use of innovative molecules will ultimately lead to the functional cure of CHB in the near future.

[New progress in the diagnosis and treatment of hepatocellular carcinoma: a decade of grinding sword].

Globally, hepatocellular carcinoma (HCC) is one of the most highly morbid, fatal, and malignant tumors, with a poor prognosis in advanced stage. In the past decade, new advances have been emerged in the field of HCC therapy, including surgery, ablation, transvascular intervention, external radiotherapy, and systemic therapy. Among them, systemic treatments, particularly targeted and immune checkpoint drugs have made outstanding progress, significantly improving the five-year survival rate of liver cancer patients. In addition, the management of liver cancer patients, especially the screening management and multidisciplinary collaborative diagnosis and treatment of high-risk populations, has significantly increased the early diagnosis rate and improved the overall treatment efficacy. Considering our country's condition and the development of existing treatment, the most effective strategy to reduce HCC mortality in the future is to accurately identify high-risk populations, increase the early diagnosis rate, and formulate personalized treatment strategies.

[Clinical cure of hepatitis B: consensus and controversy].

Hepatitis B virus (HBV) infection is a serious global public health issue. At present, clinical cure is the ideal endpoint for hepatitis B treatment. That is to say, after the completion of treatment, the serum hepatitis B virus surface antigen (HBsAg) is negative, with or without the presence of antibody against hepatitis B virus surface antigen (anti-HBs), undetectable HBV DNA, liver biochemical indicators within normal range, and improved liver tissue lesions. However, it is difficult to achieve a satisfactory clinical cure effect based on the existing therapeutic drugs. To this end, scientists have conducted many explorations, whether it is a combination of nucleos(t)ide analogues and pegylated interferon therapy strategies, or timely termination of antiviral drug treatment, or accelerate the research and development of innovative drugs. The road to clinical cure of hepatitis B is obstructive and long, with full of opportunities and controversies, but the lead is about to come. We always believe that through unremitting efforts, the dream of helping chronic hepatitis B patients to obtain clinical cure or even complete cure will eventually come true.

[Clinical considerations in the design of clinical trial for innovative hepatitis B drugs].

The research and development of chronic hepatitis B (CHB) therapeutic drugs has been undergoing rapid development in recent years in order to achieve the World Health Organization's goal of eliminating viral hepatitis as a major public health threat by 2030. The focus of early stage clinical trials (including the first human trial) is the selection of subjects, study design, dose selection, administration method, dose escalation, monitoring, observation and reporting procedures for adverse events/reactions (tolerability evaluation), and criteria for subjects to continue and discontinue administration. Therefore, quantitative pharmacology knowledge is required to analyze the relationship between in vivo drug exposure, efficacy and adverse reactions, and the inclusion of exploratory indicators such as HBV RNA, hepatitis B virus core-related antigen (HBcrAg), etc., to analyze the mechanism and target of innovative drugs and the efficacy of cccDNA in anti-hepatocytes. On the other hand, Phase II-III clinical trials prioritize the optimal dose, efficacy and safety indicators to verify the efficacy and safety of new drugs in a wider range of subjects. This paper refers to the relevant domestic and foreign literature, combined with the author's practical experience in early clinical research, and then briefly introduces the clinical issues that should be paid attention to in the design of clinical trials of CHB innovative drugs.

[Prevalence and risk factors of nonalcoholic fatty liver disease in patients with chronic hepatitis B receiving antiviral therapy].

Objective: To investigate the prevalence and risk factors of non-alcoholic fatty liver disease(NAFLD) in patients with chronic hepatitis B(CHB) receiving antiviral treatment. Methods: The cross-sectional study included 3 477 cases with CHB who received antiviral therapy. The prevalence of NAFLD was investigated, and then the risk factors were screened and analyzed by stepwise regression method in CHB patients with NAFLD as the dependent variable and the related influencing factors as independent variables. Results: The prevalence of NAFLD was 24.1% in CHB patients who received antiviral therapy. After adjusting for age and gender, central obesity (OR: 7.44, 95%CI: 6.06 ~ 9.14), hypertension (OR: 1.74, 95%CI: 1.51 ~ 2.20), and triglyceride (OR: 1.52, 95%CI: 1.18 ~ 1.96) were positively associated with NAFLD, and cirrhosis was negatively associated with NAFLD (OR: 0.42, 95%CI: 0.34 ~ 0.53). Patients with long-term antiviral therapy had increased risk of NAFLD. Conclusion: A significant proportion of CHB patients receiving antiviral therapy have suffered from NAFLD. Therefore, CHB patients receiving long-term antiviral treatment should pay more attention to the prevalence of NAFLD.

[A phase II, single-arm, open-label, multicenter clinical study to evaluate the efficacy and safety of sofosbuvir combined with ribavirin in patients with genotype 2 chronic hepatitis C virus infection].

Objective: To evaluate the efficacy and safety of sofosbuvir (Nanjing Zhengda Tianqing Pharmaceutical Co., Ltd.) combined with ribavirin in patients with genotype 2 chronic hepatitis C virus infection. Methods: Treatment-naïve or treatment experienced genotype 2 chronic hepatitis C patients from sixteen research centers of China were screened. All subjects received once-daily dose of sofosbuvir (400 mg) combined with ribavirin (body weight < 75 kg, 1 000 mg/day, 400 mg in the morning and 600 mg in the evening; body weight > 75 kg, 1 200 mg/d, 600 mg in the morning and 600 mg in the evening) for 12 weeks. Patients were followed-up for a period of 12 weeks after discontinuation of treatment. Continuous variables were expressed as mean ± standard deviation. The proportion of subjects with virologic response at different follow-up time points and 95% confidence intervals were estimated by maximum likelihood ratio and Clopper-Pearson interval. Results: 132 cases with genotype 2 chronic hepatitis C virus infection from sixteen research centers of China were included, 12 cases of whom were associated with cirrhosis, and the remaining 120 cases were not associated with cirrhosis. One hundred and thirty-one cases completed the study, and one patient lost to follow-up at week 4 after the end of treatment. The sustained virological response rate was 96.2% (95% confidence interval: 92.37% - 99.16%) after 12 weeks of drug withdrawal. Virological relapse occurred in four cases. Of the 132 subjects enrolled in the study, 119 (90.2%) reported 617 adverse events during treatment, of which 359 (76.5%) were TEAE related to sofosbuvir and/or ribavirin. There were nine TEAEs of grade 3 and above, and six cases (4.5%) of them had six severe adverse events. Only one serious adverse event was associated with sofosbuvir and ribavirin (unstable angina pectoris). There were no adverse events leading to drug discontinuation or death. Conclusion: Sofosbuvir combined with ribavirin has a high SVR rate in the treatment of genotype 2 chronic hepatitis C virus infection, and most of the adverse events occurred were mild with acceptable safety profile.

[Action for shield project promoting zero mother-to-child transmission of hepatitis B virus].

The World Health Organization(WHO)has set the goal to eliminate viral hepatitis as a public health threat by 2030, and the key to achieve this ambitious goal lies on the standardized and precise management of pregnant women and their infants by effectively blocking mother-to-child transmission (MTCT) of hepatitis B virus (HBV). Standardized management includes screening and antiviral intervention during pregnancy, infant immunization, and evaluation of immune effect, breastfeeding and mode of delivery. The results of randomized controlled clinical trials and real-world data have confirmed that the comprehensive prevention strategy based on combined immune prophylaxis of neonates can effectively block MTCT of HBV. It is one of the key links to eliminate viral hepatitis in our country, and to formulate a new strategy in line with the public health needs at home and abroad and thereby promote the implementation and application of standardized management process to improve the public's awareness of the disease.

[Organizing an assembly to eliminate hepatitis B virus through a project zero mother-to-child transmission of hepatitis B virus].

The China Foundation of Hepatitis Prevention and Control (CFHPC) initiated a project named, "getting to zero mother-to-child transmission of Hepatitis B," in July 2015, which aims to further reduce the incidence of mother-to-child transmission through standardized follow-up management of pregnant women and their infants with chronic hepatitis B virus infection by means of mobile medical application. Over the past three years, the project has established a nationwide collaborative network for interruption of mother-to-child transmission of hepatitis B virus, with 123 hospitals as project members. In addition, it has formulated a technical guidance document (Clinical Management Algorithm for Interrupting Mother-to-Child Transmission of HBV), which is designed and developed as a mobile medical application (SHIELD APP), and was released in an international conference on the theme to eliminate viral hepatitis. Following the measures mentioned above, the public's awareness rate of hepatitis B have been raised, and a good social atmosphere has been formed, which has played a positive role in promoting the prevention and control of viral hepatitis in China.

[Promoting thorough action for early screening, diagnosis and treatment of liver cancer].

The World Health Organization has proposed a 65% reduction in viral hepatitis-related mortality by 2030, and the key to achieve this ambitious goal is to reduce mortality from viral hepatitis-related hepatocellular carcinoma (HCC). HCC is the second leading cause of death in patients with malignant tumors in China. Notably, one of the important links to reduce the risk of HCC is based on HCC risk factors and very early warning HCC biomarkers. Therefore, constructing a HCC risk prediction model, accurately identifying high-risk HCC population, developing an individualized HCC screening strategy, may improve the early HCC diagnosis and cure rate in China.