Evolution in the indications for anti-viral therapy in chronic hepatitis B / 临床肝胆病杂志

In order to reduce the disease burden of chronic hepatitis B (CHB) and improve the treatment rate of CHB, the indications for anti-viral therapy have been gradually expanded and simplified in guidelines for the prevention and treatment of CHB released by Chinese Medical Association from 2005 to 2022. This article elaborates on the evolution in the indications for anti-viral therapy in CHB from the five aspects of converging indications of HBeAg-positive and HBeAg-negative CHB, reduction in the treatment threshold of HBV DNA, reduction in the treatment threshold of serum alanine aminotransferase, emphasis on the risk factors for disease progression, and gradual loosening of the requirements for virological indicators in patients with liver cirrhosis.

Hepatocellular carcinoma prediction model performance decreases with long-term antiviral therapy in chronic hepatitis B patients

Background/Aims@#Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT). @*Methods@#Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict threeyear HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test. @*Results@#The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65–0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61–0.68; untreated models: 0.51–0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis. @*Conclusions@#The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.

Clinical trial protocols of new drugs for nonalcoholic steatohepatitis: A systematic review / 临床肝胆病杂志

Objective To describe the characteristics and registration status of clinical trials of new drugs for nonalcoholic steatohepatitis (NASH), and to provide a reference for the design and implementation of clinical trials of new drugs for NASH. Methods The U.S. Clinical Trials Database, China Clinical Trial Registry, and Center for Drug Evaluation, National Medical Products Administration, were searched for clinical trials of new drug registration and interventional studies with NASH as the indication published up to August 6, 2021, using NASH in English and Chinese characters as the keywords, and liver cirrhosis was excluded. Two researchers independently searched and screened the articles to extract relevant information. Results A total of 196 clinical trials of new drug registration or interventional studies for NASH were included, among which there were 174 trials registered abroad and 22 trials registered in China, and the number of registrations tended to increase year by year. The numbers of phase Ⅰ, phase Ⅰ/Ⅱ(including Ⅰb/Ⅱa), phase Ⅱ, phase Ⅱ/Ⅲ, and phase Ⅲ clinical trials were 45(23.0%), 8(4.1%), 112(57.1%), 4(2.0%), and 19(9.7%), respectively. The main drug types included farnesoid X receptors, fibroblast growth factors, peroxisome proliferator-activated receptor agonists, and glucagon-like peptide-1, with numbers of 16(8.16%), 14(7.14%), 11(5.61%), and 13(6.63%), respectively. The clinical trials of innovative drugs for NASH initiated by the sponsors in European and American regions accounted for the highest proportion, and there was a gradual increase in the number of clinical trials of innovative drugs in China in recent years, with a similar distribution of single-center and multicenter clinical trials. As for the trials with NASH patients as subjects, the numbers of trials with pathology, imaging, and clinical diagnosis as the main inclusion criteria were 125, 66, and 42, respectively. Phase Ⅰ clinical trials used safety, tolerability, and pharmacokinetic parameters as the main assessment indices, while phase Ⅱ and phase Ⅲ clinical trials often used safety and efficacy as the main assessment indices. The number of clinical trials for the registration of innovative drugs for NASH was relatively low but kept increasing in China, and there were fewer clinical trials of innovative traditional Chinese medicine drugs compared with innovative chemical drugs. Conclusion There is a significant increase in the registration of international clinical trials of innovative drugs for NASH, and most of these trials are in the early phases, with large differences in inclusion criteria and assessment indices, a lack of unified evaluation indices, and relatively few trials with new designs. There are fewer clinical trials of innovative drugs for NASH in China than in European and American countries, and the number of such trials is gradually increasing in China.

Evaluation of clinical endpoints in new drug research and development for nonalcoholic steatohepatitis / 临床肝胆病杂志

Nonalcoholic steatohepatitis (NASH) has gradually become a common cause of liver cirrhosis, hepatocellular carcinoma, and liver-related deaths, and currently no effective therapeutic drugs have been approved for the treatment of NASH. Therefore, there is an urgent need for effective new drugs to improve clinical endpoints and reduce disease burden. The development and progression of NASH are closely associated with metabolism and have strong heterogeneity, and it takes a long time to observe its clinical outcome. These characteristics bring challenges to the research and development of new drugs for NASH. In the process of drug research and development, the selection of treatment endpoints is crucial to the evaluation of drug efficacy, and the basic principle of endpoint selection is whether it can reflect clinical outcome and predict clinical benefit. This article summarizes and discusses the selection of treatment endpoints at different stages of the research and development of new drugs for NASH.

Histological prediction of clinical endpoints of liver cirrhosis / 临床肝胆病杂志

Patients with liver cirrhosis have different clinical manifestations and prognoses, and it is necessary to accurately predict the clinical endpoints of liver cirrhosis. Liver pathology can directly display the change in liver structure and thus plays an important role in predicting clinical endpoints. This article summarizes the application of histological staging systems and parameters in predicting clinical endpoints and describes the significance of histological features after etiological treatment in predicting clinical prognosis.

Clinical application of PIR classification in the evaluation of liver fibrosis regression / 临床肝胆病杂志

Liver biopsy has been regarded as the gold standard for the assessment of liver fibrosis regression. In 2017, Liver Research Center, Beijing Friendship Hospital, proposed a new classification called PIR classification for the evaluation of liver fibrosis regression in patients with chronic hepatitis B after antiviral therapy, which was also called “Beijing classification”. This classification is new breakthrough based on conventional staging and grading systems, quantitative assessment methods for liver fibrosis, and the concept of liver biopsy. This article discusses the prospects and shortcomings of PIR classification.

The era of the reversal of liver fibrosis and cirrhosis: Current status and challenges / 临床肝胆病杂志

An increasing number of clinical studies have shown that effective etiological therapy might achieve the reversal of liver fibrosis/early cirrhosis. An accurate assessment of fibrosis reversal is of great importance for treatment decision-making and prognosis prediction. At present, the “gold standard” for the histological evaluation of liver fibrosis/cirrhosis reversal remains to be perfected, and there is still a controversy over the noninvasive assessment of fibrosis reversal. Long-term cohort studies are needed to observe whether it can improve clinical hard endpoint, and the clinical effect of new anti-fibrotic drugs needs to be further confirmed.

Relations between gross motor competence and physical fitness in 3-5 years old children / 中国学校卫生

Objective@#The cross-sectional study examined associations between gross motor competence and physical fitness in 3-5 years old children.@*Methods@#A convenient sampling method was used to select 201 children aged 3-5 years, to assess gross motor competence, each child accomplished the Test of Gross Motor Development-3(TGMD-3). The level of physical fitness was measured by National Physical Fitness Test, comprising eight different tasks including height, weight, flexibility(sit-and-reach test), balance (walking on a balance beam), explosive force(Standing long jump), strength(Tennis ball throwing), agility(10-shuttle-run test), strength and coordination(Continuous foot jump).@*Results@#With the increase of age, the scores of locomotor skills，object control skills, gross motor competence, height, weight, walking on a balance beam, continuous foot jump, tennis ball throwing and standing long jump were better(P<0.01). Significant differences were not found in the gross motor competence, locomotor skills, 10-shuttle-run test, continuous foot jump, standing long jump and walking on a balance beam(P>0.05). In the object control skills and tennis ball throwing, the boys showed a greater performance(P<0.01). In the sit-and-reach test, girls showed a greater performance(P<0.01). The results revealed a significant relationship between gross motor competence and the following items: 10-shuttle-run test, continuous foot jump, standing long jump, walking on a balance beam, tennis ball throwing(P<0.05). There were no associations among gross motor competence, BMI(r=0.02), sit-and-reach test(r=0.07). There were no associations between gross motor competence and physical fitness in 3-5 years old(r=-0.13-0.21), except for 5 years old children’s object control skills and continuous foot jump(r=0.42). Sex, age, height , BMI (R2=0.05,F=2.62, P>0.05) as well as gross motor competence(△R2=0.04, F=2.00, P>0.05) did not predict physical fitness.@*Conclusion@#The results indicated a relationship between motor competence and physical fitness in 3-5 years old. In order to increase the level of physical fitness, the educators should pay attention to the development of children’s gross motor.

Effect of ALT level on liver stiffness measurement in patients with hepatitis B cirrhosis / 临床肝胆病杂志

ObjectiveTo investigate the effect of alanine aminotransferase (ALT) level on liver stiffness measurement (LSM) in patients with hepatitis B cirrhosis. MethodsThe patients who were diagnosed with hepatitis B cirrhosis by liver biopsy in Beijing Friendship Hospital from January 2012 to May 2015 and did not receive antiviral therapy were enrolled. Their demographic characteristics, routine blood test results, biochemical parameters, hepatitis B virus (HBV) DNA level, alpha-fetoprotein level, LSM, abdominal ultrasound findings, and liver biopsy data were collected. LSM was compared between hepatitis B cirrhosis patients with different ALT levels. The one-way analysis of variance or rank sum test was used for comparison of continuous data between groups, and the chi-square test was used for comparison of categorical data. Pearson correlation analysis and partial correlation analysis were performed. ResultsA total of 104 patients were recruited and divided into three groups according to their ALT levels (≤2×upper limit of normal ［ULN］, 2-5×ULN, and ≥5×ULN). There were no significant differences between the three groups in sex ratio, body mass index, HBeAg status, HBV DNA level, albumin level, and platelet count (all P＞0.05). The median values of LSM for the three groups were 15.4 kPa, 18.8 kPa, and 29.9 kPa, respectively, suggesting that LSM increased as the ALT level increased, and there was a significant difference in LSM between the three groups (χ2=10.07, P＜0.05). After adjusting for age, which was significantly different between the three groups, LSM was still found to be positively correlated with ALT level (r=0.220, 95% confidence interval: 0.101-0.468, P＜0.05). ConclusionIn patients with hepatitis B cirrhosis, LSM increased with the increasing ALT level, and the positive correlation remains after adjusting for age.

Qualitative pathological assessment of liver fibrosis regression after antiviral therapy in patients with chronic hepatitis B / 中华肝脏病杂志

Objective@#To investigate the methods for qualitative pathological assessment of dynamic changes in liver fibrosis/cirrhosis after antiviral therapy in patients with chronic hepatitis B (CHB), since antiviral therapy can partially reverse liver fibrosis and cirrhosis caused by hepatitis B and semi-quantitative, rather than qualitative, pathological assessment is often used for the research on liver fibrosis regression.@*Methods@#Previously untreated CHB patients with liver fibrosis and cirrhosis were enrolled, and liver biopsy was performed before treatment and at 78 weeks after the antiviral therapy based on entecavir. The follow-up assessment was performed once every half a year. Based on the proportion of different types of fibrous septum, we put forward the new qualitative criteria called P-I-R classification (predominantly progressive, predominantly regressive, and indeterminate) for evaluating dynamic changes in liver fibrosis. This classification or Ishak fibrosis stage was used to evaluate the change in liver fibrosis after treatment and Ishak liver inflammation score was used to evaluate the change in liver inflammation after treatment.@*Results@#A total of 112 CHB patients who underwent liver biopsy before and after treatment were enrolled, and among these patients, 71 with an Ishak stage of ≥3 and qualified results of live biopsy were included in the final analysis. Based on the P-I-R classification, 58% (41/71) were classified as predominantly progressive, 29% (21/71) were classified as indeterminate, and 13% (9/71) were classified as predominantly regressive; there were no significant differences between the three groups in alanine aminotransferase, aspartate aminotransferase, albumin, HBeAg positive rate, HBV DNA, and liver stiffness (P < 0.05). After treatment, the proportion of predominantly progressive, indeterminate, or predominantly regressive patients changed to 11% (8/71), 11% (8/71), and 78% (55/71), respectively. Among the 35 patients who had no change in Ishak stage after treatment, 72% (25/35) were classified as predominantly regressive and had certain reductions in the Laennec score, percentage of collagen area, and liver stiffness.@*Conclusion@#This new P-I-R classification can be used to assess the dynamic changes in liver fibrosis after antiviral therapy in CHB patients.

New advances in the diagnosis of liver fibrosis / 中华肝脏病杂志

Various chronic liver diseases may progress to liver fibrosis or liver cirrhosis. Assessment of the degree of liver fibrosis helps with clinical decision-making, prognosis prediction, and evaluation of therapeutic effect, and therefore, accurate diagnosis and evaluation of the degree of liver fibrosis is a research hotspot at present. The advances in the diagnosis of liver fibrosis in recent years include the publication of international consensuses and guidelines, evaluation of the outcome of liver fibrosis after antiviral therapy, development of the diagnosis of liver fibrosis in patients with non-viral hepatitis, and constant update of noninvasive diagnostic techniques.

Advances in staging and treatment of hepatitis B cirrhosis / 临床肝胆病杂志

Liver cirrhosis is an important stage of the progression of chronic hepatitis B, and it is of great significance to clarify the severity of liver cirrhosis in evaluating prognosis. At present, the clinical staging based on the complications of liver cirrhosis is widely used, but pathological staging still needs to be refined. In the aspect of treatment, liver disease associations updated the guidelines for the diagnosis and treatment of chronic hepatitis B in 2015, and the antiviral therapy for hepatitis B cirrhosis has become more active. As for the prognosis, effective antiviral treatment realizes the reversion of early cirrhosis and reduces the incidence of liver-related complications, but the mechanism of reversion awaits further investigation.

Multiple regression analysis of the risk factors to predict different recurrent stroke types after initial ischemic stroke / 中华神经科杂志

Objective To respectively analyze the patterns and possible predictors of recurrent strokes among patients with initial ischemic stroke.Methods Three hundred and sixty-one patients with recurrent strokes (acute ischemic stroke or intracerebral hemorrhage) after initial ischemic strokes were collected from Jan 2004 to Dec 2009.The data about conventional risk factors such as smoking,heavy alcohol drinking,hypertension,diabetes,hyperlipidemia,heart diseases,head trauma,migraine,family history of cardiovascular disease,and the use of preventive medications were collected and analyzed among patients with different types of recurrent strokes.Results Patients (n =361) were divided into ischemic stroke group (n =321) and hemorrhagic stroke group (n =40) according to the recurrent stroke type.The ischemic stroke group was further divided into the anterior circulation stroke subgroup (n =234),the posterior circulation stroke subgroup (n =75) and watershed cerebral infarction or multiple infarction subgroup (n =12).Multivariate logistic regression analysis revealed that older age at initial stroke onset (OR =1.036,95 ％ CI 1.006-1.067,P =0.02) and hyperlipidemia (OR =2.253,95 ％ CI 1.092-4.647,P =0.028) were both the independent risk factors for the recurrent ischemic stroke.Comparing the subgroups,multivariate logistic regression analysis showed that atrial fibrillation (OR =4.217,95％ CI 1.489-11.942,P =0.007) was the independent risk factor for the recurrent ischemic stroke in the posterior circulation territory.Conclusion Aging and hyperlipidemia are possible predictors of recurrent ischemic stroke after the initial ischemic stroke which would be useful for individualized secondary prevention of stroke.

An analysis of risk factors for ischemic stroke of different age and gender / 中华内科杂志

Objective To compare distribution difference in risk factors of patients with first-ever ischemic stroke (IS) of different age and gender.Methods A total of 1027 patients admitted to the neurological department in Shanghai Renji Hospital with first-ever IS were recruited and divided into young adult group ( ＜ 50 years old),middle-aged group (50-80 years old),and very old group ( ＞ 80 years old)according to their ages.Risk factor analysis included history of smoking,high alcohol consumption,hypertension (HT),diabetes mellitus (DM),heart diseases,atrial fibrillation (AF) and family history of cardiovascular diseases.Results Female patients were globally older than male patients (71.1 vs 65.7,P ＜ 0.001 ) at the first attack of IS and having higher prevalence of DM (26.8％ vs 19.2％,P =0.004 ),heart diseases (28.8％ vs 19.2％,P＜0.001) and AF (7.6％ vs 3.9％,P=0.009).However,female patients were less likely to drink heavily ( 1.0％ vs 31.6％,P ＜0.001 ) or smoke (4.4％ vs 59.9％,P ＜0.001 ) than the male patients.The rates of smoking and heavy drinking in young adult group were higher than that in other two groups.Patients in very old group had higher prevalence of heart diseases and AF but lower proportion of positive family cardiovascular diseases history than patients in other two groups.HT and DM were equally frequent among three groups.In young adult group,female patients were more likely to have heart diseases and family history of heart diseases (P =0.015 and P =0.048).In middle-old group,HT,DM,heart disease and AF were more common in women than in men (P =0.021,P =0.004,P =0.001 and P =0.039).Conclusion There are differences in risk factor distribution in patients with first-ever IS of different age and gender.Therefore,screening and health education should be performed in allusion to different risk factors.

Endovascular Treatment of Carotid Stenosis / 国际脑血管病杂志

Carotid endarterectomy (CEA) is the accepted standard therapy for prevention of stroke in patients with high-grade symptomatic and asymptomatic carotid stenoses. In recent years, the endovascular treatment of carotid artery stenosis has been widely used in clinical practice, including balloon angioplasty and stenting. Both single-center and multicenter studies worldwide have demonstrated good therapeutic efficacy, especially in patients with high risk of CEA. The efficacy of carotid angioplasty and stenting with an emboli-protection device are much better. A growing body of evidence has indicated that endovascular treatment may become another important approach after CEA in the treatment of carotid atherosclerotic stenosis.