Hepatitis B core-related antigen serum levels may be a predictor of acute flare of chronic hepatitis B among pregnant women in the immune-tolerant phase of chronic HBV infection after short-course antiviral therapy.

BACKGROUND: Studies have shown acute flares of chronic hepatitis B (CHB) might be related to immunologic changes that occur during pregnancy. However, the indicators for predicting acute flares of CHB among pregnant women still need further study. We aimed to distinguish the relevance between serum levels of HBcrAg and acute flares of CHB in pregnant women in the immune-tolerant phase of chronic HBV infection after short-course antiviral therapy. METHODS: A total of 172 chronic HBV-infected pregnant women who were judged to be in the immune-tolerant phase were recruited in our research. All patients received short-course antiviral therapy with TDF. The biochemical, serological, and virological parameters were measured using standard laboratory procedures. The serum levels of HBcrAg were tested by ELISA. RESULTS: Fifty-two (30.2%) out of 172 patients had acute flares of CHB. At postpartum week 12 (TDF cessation), serum HBcrAg (OR, 4.52; 95% CI, 2.58-7.92) and HBsAg (OR, 2.52; 95% CI, 1.13-5.65) were associated with acute flares of CHB. The serum HBcrAg levels were beneficial for confirmation of patients with acute flares of CHB, with an area under the ROC curve of 0.84 (95% CI, 0.78-0.91). CONCLUSIONS: For pregnant women with chronic HBV infection in the immune-tolerant phase, serum HBcrAg and HBsAg levels at postpartum week 12 were associated with acute flares of CHB after short-course antiviral therapy with TDF. The serum HBcrAg level can correctly identify acute flares of CHB and may be a predictor of the need for continuing antiviral therapy after 12 weeks postpartum.

Effects of hepatitis B virus infection and strategies for preventing mother-to-child transmission on maternal and fetal T-cell immunity.

One of the most common routes of chronic hepatitis B virus (HBV) infection is mother-to-child transmission (MTCT). Approximately 6.4 million children under the age of five have chronic HBV infections worldwide. HBV DNA high level, HBeAg positivity, placental barrier failure, and immaturity of the fetal immune are the possible causes of chronic HBV infection. The passive-active immune program for children, which consists of the hepatitis B vaccine and hepatitis B immunoglobulin, and antiviral therapy for pregnant women who have a high HBV DNA load (greater than 2 × 105 IU/ml), are currently two of the most important ways to prevent the transmission of HBV from mother to child. Unfortunately, some infants still have chronic HBV infections. Some studies have also found that some supplementation during pregnancy can increase cytokine levels and then affect the level of HBsAb in infants. For example, IL-4 can mediate the beneficial effect on infants' HBsAb levels when maternal folic acid supplementation. In addition, new research has indicated that HBV infection in the mother may also be linked to unfavorable outcomes such as gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, and premature rupture of membranes. The changes in the immune environment during pregnancy and the hepatotropic nature of HBV may be the main reasons for the adverse maternal outcomes. It is interesting to note that after delivery, the women who had a chronic HBV infection may spontaneously achieve HBeAg seroconversion and HBsAg seroclearance. The maternal and fetal T-cell immunity in HBV infection is important because adaptive immune responses, especially virus-specific CD8 T-cell responses, are largely responsible for viral clearance and disease pathogenesis during HBV infection. Meanwhile, HBV humoral and T-cell responses are important for the durability of protection after fetal vaccination. This article reviews the literature on immunological characteristics of chronic HBV-infected patients during pregnancy and postpartum, blocking mother-to-child transmissions and related immune mechanisms, hoping to provide new insights for the prevention of HBV MTCT and antiviral intervention during pregnancy and postpartum.

Changes of natural killer cells' phenotype in patients with chronic hepatitis B in intermittent interferon therapy.

Background: To investigate the changes of natural killer (NK) cell phenotype in the interferon alpha (IFN-α) treatment of chronic hepatitis B (CHB) and its relationship with clinical indicators. Methods: The CHB patients who did not receive any antiviral treatment were set as initial treatment group and used pegylated interferon alpha (PEG-IFN α). Peripheral blood samples were collected at baseline, 4 weeks, and 12-24 weeks. For IFN-treated patients who entered the plateau were set as plateau group, and PEG-IFN α was discontinued and resumed after an interval of 12-24 weeks. Besides, we also enrolled some patients who had received oral drug for more than 6 months as oral drug group without follow up. Peripheral blood was collected during the plateau period, which was set as baseline, and after 12-24 weeks of intermittent treatment, and after 12-24 weeks of additional treatment with PEG-IFN α. The aim of the collection was to detect hepatitis B virus (HBV) virology, serology and biochemical indicators, and the NK cell related phenotype was detected by flow cytometry. Results: In the plateau group, subgroup of CD69+CD56dim was higher with statistical significance when comparing with the initial treatment group and oral drug group [10.49 (5.27, 19.07) vs 5.03 (3.67, 8.58), Z = -3.11, P = 0.002; 10.49 (5.27, 19.07) vs 4.04 (1.90, 7.26), Z = -5.30, P < 0.001)]. CD57+CD56dim was significantly lower than that in initial treatment group and oral drug group respectively [68.42±10.37 vs 55.85±12.87, t = 5.84, P < 0.001; 76.38±9.49 vs 55.85±12.87, t = -9.65, P < 0.001]. The CD56brightCD16- subgroup in the plateau group was higher with statistical significance compared with initial treatment group and oral drug group respectively [11.64 (6.05, 19.61) vs 3.58 (1.94, 5.60), Z = -6.35, P < 0.001; 11.64 (6.05, 19.61) vs 2.37 (1.70, 4.30), Z = -7.74, P < 0.001)]. CD57+CD56dim in the plateau group had a significant higher percentage than that at baseline after IFN discontinuation for 12-24 weeks (55.85±12.87 vs 65.95±12.94, t = -2.78, P = 0.011). Conclusion: During the long-term treatment of IFN, the killer subgroup of NK cells is continuously depleted, leading to the differentiation of the regulatory subgroup into the killer subgroup. In the killing subgroup, although the number is continuously depleted, the activity of the subgroup is continuously increased. In the plateau phase, after stopping IFN for a period of time, the number of NK cell subsets would gradually recover, but was still lower than that in the initial treatment group.

Functional molecular expression of nature killer cells correlated to HBsAg clearance in HBeAg-positive chronic hepatitis B patients during PEG-IFN α-2a therapy.

Objective: To explore whether the frequencies and functional molecules expression of Natural Killer cells (NK cells) are related to hepatitis B surface antigen (HBsAg) disappearance in hepatitis B e envelope antigen (HBeAg)-positive patients with chronic hepatitis B (CHB) throughout peginterferon alpha-2a (PEG-IFN α-2a) treatment. Methods: In this prospective research, HBeAg-positive patients with CHB received PEG-IFN α-2a treatment, completing 4-year follow-up. After PEG-IFN α-2a treatment, undetectable HBV DNA, HBsAg loss, and HBeAg disappearance were defined as functional cure. Proportions of NK, CD56dim, CD56bright, NKp46+, NKp46dim, NKp46high, and interferon alpha receptor 2 (IFNAR2)+ NK cells, and the mean fluorescence intensity (MFI) of NK cell surface receptors IFNAR2 and NKp46 were detected. Results: 66 patients were enrolled into the study in which 17 patients obtained functional cure. At baseline, hepatitis B virus desoxyribose nucleic acid (HBV DNA) titer in patients with functional cure was remarkably lower than that in Non-functional cure group. Compared with baseline, HBV DNA levels, HBsAg levels, and HBeAg levels significantly declined at week 12 and 24 of therapy in patients with functional cure. At baseline, the negative correlation between CD56bright NK% and HBV DNA and the negative correlation between CD56dim NK% and HBV DNA was showed; CD56bright NK% and IFNAR2 MFI in patients with functional cure were remarkably higher than those in patients without functional cure. After therapy, CD56bright NK% and NKp46high NK% in patients with functional cure were higher than those in patients without functional cure. In Functional cure group, after 24 weeks of treatment NK%, CD56bright NK%, IFNAR2 MFI weakly increased, and NKp46high NK% and NKp46 MFI significantly increased, meanwhile, CD56dim NK% and NKp46dim NK% decreased. Only NKp46 MFI increased after therapy in patients without functional cure. Conclusion: The lower HBV DNA load and the higher CD56bright NK% before therapy, and the higher the post-treatment CD56bright NK%, IFNAR2 MFI, NKp46high NK%, the easier to achieve functional cure.

Sustained viral response and relapse after discontinuation of oral antiviral drugs in HBeAg-positive patients with chronic hepatitis B infection.

Objective: To investigate the sustained virological response and relapse in chronic hepatitis B (CHB) patients with hepatitis B e antigen (HBeAg) positive after stopping oral antiviral drugs, and to monitor the disease progression and the incidence of adverse events such as liver cirrhosis and hepatocellular carcinoma. Methods: This is a prospective observational study. Patients who continued nucleos(t)ide analogue (NA) treatment after achieving HBeAg seroconversion for more than 3 years were enrolled. After signing the informed consent form, patients stopped NA treatment and received follow-up. During the follow-up, the antiviral treatment information of the patients was collected, and the follow-up observation was carried out every 3 months since the enrollment. We monitored the virological indexes, liver and kidney function, serology and liver imaging during follow-up. The purpose of this study was to explore the sustained virological response rate, HBV DNA recurrence rate, clinical relapse rate and the related factors after drug withdrawal. Results: A total of 82 patients were enrolled, including 42 males (51.22%) and 40 females (48.78%), with a median age of 34.00 (31.00, 37.25) years. All enrolled patients were followed up for 1 year. At the end of the follow-up, 36.59% (30/82) of patients had sustained virological response, 63.41% (52/82) of patients had HBV DNA reactivation, 17.07% (14/82) of patients had clinical relapse, and 10.98% (9/82) of patients had HBeAg reversion. During the follow-up, there were no adverse events such as liver cirrhosis and hepatocellular carcinoma. The median level of hepatitis B surface antigen (HBsAg) in patients with sustained virological response was lower than that in patients with HBV DNA reactivation (2.92 vs.3.18 log10IU/ml, Z=-1.492/P=0.136), and the median level of baseline HBsAg in patients with HBV DNA reactivation was lower than that in patients with clinical relapse (3.01 vs.3.45 log10IU/mL, Z=-1.795/P=0.073), but the difference was not significant. There was no significant statistical difference between patients with sustained virological response and HBV DNA reactivation of the median total treatment time [69.50 (56.25, 86.00) vs.62.50 (44.00, 88.50) months, Z=-0.689/P=0.491], and the consolidation treatment time [41.50 (36.75, 54.75) vs.40.50 (36.00, 53.75) months, Z=-0.419/P=0.675]. Conclusion: The sustained virological response rate of HBeAg positive CHB patients after stopping oral antiviral treatment is lower, and it is more common in patients with lower HBsAg levels. Patients still need to be closely monitored after stopping NA therapy.

Cytokine profiles and CD8+ T cells in the occurrence of acute and chronic hepatitis B.

Objective: We explore the expression of functional molecules on CD8+ T lymphocytes, cytokines concentration, and their correlation to occurrence of hepatitis B and hepatitis B virus (HBV) desoxyribose nucleic acid (DNA), hepatitis B surface antigen (HBsAg), hepatitis B envelope antigen (HBeAg), and alanine aminotransferase (ALT) in patients infected with HBV. Methods: This is a single center study. 32 patients with acute hepatitis B (AHB), 30 patients with immune tolerant (IT) phase chronic HBV infected, and 50 patients with chronic hepatitis B (CHB) were enrolled. The activation molecules (CD69) and the apoptosis-inducing molecules (CD178) on surface of CD8+ T lymphocytes were tested by the flow cytometry. Fms-like tyrosine kinase 3 ligand (Flt-3L), interleukin 17A (IL-17A), interferon γ (IFN-γ), and Interferon α2 (IFN-α2) were quantitated by Luminex assay. We use linear regression analysis to analyze their correlations to ALT, HBV DNA, HBsAg, and HBeAg. Results: The frequency of CD69+CD8+ T lymphocytes in CHB and AHB groups were increased significantly compared with IT group (4.19[3.01, 6.18]% and 4.45[2.93, 6.71]% vs. 3.02[2.17, 3.44]%; H=26.207, P=0.001; H=28.585, P=0.002), and the mean fluorescence intensity (MFI) of CD69 in AHB group was significantly higher than IT and CHB groups (27.35[24.88, 32.25] vs. 20.45[19.05, 27.75] and 23.40[16.78, 28.13]; H=25.832, P=0.005 and H=22.056, P=0.008). In IT group, HBsAg levels and HBV DNA loads were negatively correlated with CD69MFI (ß=-0.025, t=-2.613, P=0.014; ß=-0.021, t=-2.286, P=0.030), meanwhile, HBeAg was negatively related to the frequency of CD69+CD8+ T lymphocytes (ß=-61.306, t=-2.116, P=0.043). In AHB group, IFN-α2 was positively related to the frequency of CD8+ T lymphocytes (ß=6.798, t=2.629, P=0.016); however, in CHB group, IFN-α2 was negatively associated with frequency of CD8+ T lymphocytes (ß=-14.534, t=-2.085, P=0.043). In CHB group, HBeAg was positively associated with frequency of CD69+CD8+ T lymphocytes (ß=43.912, t=2.027, P=0.048). In AHB group, ALT was positively related to CD69MFI (ß=35.042, t=2.896, P=0.007), but HBsAg was negatively related to CD178MFI (ß=-0.137, t=-3.273, P=0.003). Conclusions: The activation of CD8+ T lymphocytes was associated with the occurrence of AHB and CHB. However, due to the insufficient expression of functional molecules of CD8+ T lymphocytes and the depletion of CD8+ T lymphocytes, CHB patients were difficult to recover from HBV infection.

The relation of the frequency and functional molecules expression on plasmacytoid dendritic cells to postpartum hepatitis in women with HBeAg-positive chronic hepatitis B virus infection.

Objective: To explore the correlation between postpartum hepatitis and changes of plasmacytoid dendritic cells' (pDC) function and frequency in hepatitis B e antigen (HBeAg)-positive pregnant women with chronic hepatitis B virus (HBV) infection. Methods: Pregnant women with chronic HBV infection receiving antiviral treatment (treated group) or not receiving antiviral treatment (untreated group) were enrolled and demographic information was collected before delivery. Clinical biochemical, virological serology, pDC frequency and functional molecular expression were tested before delivery and at 6, 12, 24 weeks after delivery. Results: 90 eligible pregnant women were enrolled, 36 in the untreated group and 54 in the treated group. 36 patients developed postpartum hepatitis, including 17 (17/36, 47.2%) in the untreated group and 19 (19/54, 35.2%) in the treated group (χ2 = 1.304 p=0.253), and 22 cases of hepatitis occurred at 6 weeks postpartum, 12 at 12 weeks postpartum, and 2 at 24 weeks postpartum. The alanine transaminase (ALT) levels at any time postpartum were significantly higher than that of the antepartum, especially at 6 weeks and 12 weeks postpartum. However, the frequencies of pDCs, CD83+ pDCs and CD86+ pDCs antepartum had no significant difference from any time postpartum. The frequencies of CD83+ pDCs, CD86+ pDCs in the treated group antepartum were significantly higher than those in the untreated group [12.70 (9.46, 15.08) vs. 10.20 (7.96, 11.85), p=0.007; 22.05 (19.28, 33.03) vs. 18.05 (14.33, 22.95), p=0.011], and the same at 12 weeks postpartum [12.80 (10.50, 15.50) vs. 9.38 (7.73, 12.60), p=0.017; 22.50 (16.80, 31.20) vs. 16.50 (12.65, 20.80), p=0.001]. The frequency of CD86+ pDCs in the treated group was significantly higher than that in the untreated group at 24 weeks postpartum [22.10 (16.70, 30.00) vs. 17.10 (13.70, 20.05), p=0.006]. Conclusions: Postpartum hepatitis in HBV infected women mainly occurs at 6-12 weeks postpartum. Antiviral treatment during pregnancy can significantly increase the frequencies of CD83+ pDCs and CD86+ pDCs in pregnant women with chronic HBV infection.

Dynamic changes of cytokine profiles and virological markers during 48 weeks of entecavir treatment for HBeAg-positive chronic hepatitis B.

Objective: The aims of this study were to investigate the kinetic changes of serum, virological, and immunological markers during entecavir (ETV) antiviral therapy and to explore whether these indicators can predict the antiviral efficacy of ETV in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. Methods: HBeAg-positive CHB patients were enrolled and treated with ETV 0.5 mg/day. Clinical biochemical, virological, and serological tests were performed at baseline and every 12 weeks during the 48-week treatment. Plasma levels of cytokines (Flt-3L, IFN-α2, IFN-γ, IL-10, IL-17A, IL-6, TGF-ß1, TGF-ß2, TGF-ß3, and TNF-α) were measured at baseline and at 12 and 24 weeks after treatment. Analysis of the trends of these clinical indicators in ETV antiviral therapy was performed. Results: A total of 105 HBeAg-positive CHB patients were enrolled, and 100 of them completed 48 weeks of ETV treatment and follow-up. After 48 weeks of treatment, hepatitis B s antigen (HBsAg) decline ≥ 1 log10 was found in seven patients, but no patient achieved HBsAg disappearance. serological HBeAg disappeared in 13 patients, and serological HBeAg transformed in 3 patients. The baseline HBsAg and HBeAg levels, HBV DNA load, IL-10, and TGF-ß1 levels in the complete virological response group were lower than those in the incomplete virological response group, while the ALT level in the complete virological response group was higher than that in the incomplete virological response group. Both univariate analysis and multivariate analysis showed that baseline biochemical indexes, virological indexes, and cytokine levels had no correlation with the complete virological response at 48 weeks. In multivariate analysis, low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment (HBeAg OR = 1.003, 95% CI 1.001-1.006, p = 0.007; HBV DNA OR = 0.184, 95% CI 0.046-0.739, p = 0.017; IL-10 OR = 0.040, 95% CI 0.972-0.999, p = 0.040). Conclusion: Cytokine levels changed dynamically during ETV antiviral therapy. Low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment.

Expression of Functional Molecule on Plasmacytoid Dendritic Cells Is Associated With HBsAg Loss in HBeAg-Positive Patients During PEG-IFN α-2a Treatment.

Objective: The ideal endpoint of antiviral therapy in chronic hepatitis B (CHB) patients is to clear hepatitis B surface antigen (HBsAg). This study aimed to evaluate whether the expression of functional molecules on plasmacytoid dendritic cells (pDCs) is associated with HBsAg loss in HBeAg-positive patients during peginterferon alpha-2a (PEG IFN α-2a) therapy. Methods: A single-center prospective cohort study was performed in HBeAg-positive CHB patients who were treated with PEG-IFN α-2a and followed up for 4 years. HBsAg clearance, HBeAg loss and undetectable HBV DNA achieved by PEG-IFN α-2a therapy was considered as functional cure. The frequencies of pDC and CD86+ pDC in peripheral blood, and the mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDC were measured at starting therapy, after 12 and 24 weeks of therapy. Results: Of 63 patients enrolled, 17 patients achieved HBsAg loss. The baseline HBV DNA load in Non-functional-cure group was significantly higher than that in Functional cure group, and the CD86+ pDC% was significantly lower in patients without functional cure. HBV DNA load (OR=0.146, P = 0.002) and CD86+ pDC% (OR=1.183, P = 0.025) were independent factors associated with functional cure confirmed by binary logistic regression analysis. In the Functional cure group, HBsAg, HBeAg, and HBV DNA loads decreased remarkably after 12 weeks and 24 weeks of treatment compared to baseline. In Non-functional-cure group, CD86+ pDC% and CD86MFI increased significantly from baseline after 12 weeks of treatment. In the Functional cure group, compared with baseline, pDC% increased significantly at 24 weeks, while CD86MFI increased significantly after 24 weeks of treatment. Conclusion: The lower the baseline HBV DNA load and the more the baseline CD86+ pDC%, the easier it is for patients to obtain functional cure.

Severe coagulopathy caused by cefminox sodium in a liver cirrhosis patient: a case report.

Cefminox sodium is an antimicrobial agent with broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria. Cefminox sodium has high security in clinical practice for its few adverse effects such as coagulation dysfunction, which is rare in clinical treatment. Even in patients suffering from chronic liver disease with coagulation dysfunction, it rarely leads to further deterioration of coagulation function. Therefore, patients with chronic liver disease develop severe coagulation dysfunction during the application of cefminox sodium, which is often mistaken for worsening of liver disease other than considered to be the side effect of the drug. Therefore, we report a 55-year-old female patient with liver cirrhosis and hepatocellular carcinoma treated with cefminox sodium intravenously twice for peritonitis. During the treatments, severe coagulopathy occurred, and the coagulation function quickly recovered after drug withdrawal. The diagnosis and treatment of this patient provides us with ideas for dealing with similar problems in clinical practice in the future.

Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection.

It is considered that chronic hepatitis B patients have obtained functional cure if they get hepatitis B surface antigen (HBsAg) seroclearance after treatment. Serum HBsAg is produced by cccDNA that is extremely difficult to clear and dslDNA that is integrated with host chromosome. High HBsAg serum level leads to failure of host immune system, which makes it unable to produce effective antiviral response required for HBsAg seroclerance. Therefore, it is very difficult to achieve functional cure, and fewer than 1% of chronic hepatitis B patients are cured with antiviral treatment annually. Some chronic hepatitis B patients are coinfected with other chronic viral infections, such as HIV, HCV and HDV, which makes more difficult to cure. However, it is found that the probability of obtaining HBsAg seroclearance in patients with coinfection is higher than that in patients with HBV monoinfection, especially in patients with HBV/HIV coinfection who have an up to 36% of HBsAg 5-year-seroclerance rate. The mechanism of this interesting phenomenon is related to the functional reconstruction of immune system after antiretroviral therapy (ART). The quantity increase and function recovery of HBV specific T cells and B cells, and the higher level of cytokines and chemokines such as IP-10, GM-CSF, promote HBsAg seroclearance. This review summarizes recent studies on the immune factors that have influence on HBsAg seroconversion in the chronic hepatitis B patients with viral coinfection, which might provide new insights for the development of therapeutic approaches to partially restore the specific immune response to HBV and other viruses.

Dynamic Changes of Cytokine Profiles and Virological Markers Associated With HBsAg Loss During Peginterferon Alpha-2a Treatment in HBeAg-Positive Chronic Hepatitis B Patients.

Objective: To explore dynamic changes of cytokines and virological markers associated with hepatitis B surface antigen (HBsAg) loss during peginterferon alpha-2a (PEG-IFN α-2a) treatment in hepatitis B e antigen (HBeAg) positive chronic hepatitis B (CHB) patients. Methods: It was a single-center prospective cohort study. HBeAg-positive CHB patients were prospectively and consecutively enrolled. Cytokines were detected at baseline, week 12 and 24 of PEG-IFN treatment. HBsAg disappearance rate was the primary evaluation index at 48 weeks of PEG-IFN treatment. Results: Among 100 patients who completed the 48-week PEG-IFN α-2a treatment, 38 patients achieved serum HBeAg disappearance, 25 patients achieved HBeAg seroconversion, 9 patients achieved functional cure, 37 patients had HBsAg decline of ≥1 log IU/ml, and 8 patients produced hepatitis B surface antibody (HBsAb). Albumin (ALB), fms-like tyrosine kinase 3 ligand (FLT3-L) and interferon-alpha2 (IFN-α2) in the clinical cure group were significantly lower than those in the non-clinical-cure group at baseline. After 12 weeks of treatment, HBsAg in the clinical cure group was significantly lower than that in the non-clinical-cure group (median 1.14 vs. 3.45 log10IU/ml, Z=-4.355, P < 0.001). The decrease of HBsAg and hepatitis B virus desoxyribose nucleic acid (HBV DNA) in the clinical cure group was significantly higher than that in non-clinical-cure group (median: HBsAg 1.96 vs. 0.33 log10IU/ml, Z=-4.703, P< 0.001; HBV DNA 4.49 vs.3.13 log10IU/ml, Z=-3.053, P=0.002). The increase of IFN-α2 in the cure group was significantly higher than that in the non-clinical-cure group (497.89 vs. 344.74, Z=-2.126, P=0.034). After 24 weeks of treatment, HBsAg, HBeAg, Flt3-L, and IL-10 in the clinical cure group were significantly lower than those in the non-clinical-cure group (median: HBsAg 0.70 vs. 3.15 log10IU/ml, Z=-4.535, P< 0.001; HBeAg 1.48 vs. 13.72 S/CO, Z = 2.512, P = 0.012; Flt3-l 0.00 vs 2.24 pg/ml, Z = 3.137, P=0.002; IL-10 0.70 vs. 2.71 pg/ml, Z=-4.067, P < 0.001). HBsAg decreased significantly in the clinical cure group compared with non-clinical-cure group (median 3.27 vs. 0.45, Z=-4.463, P < 0.001). Conclusion: Dynamic changes of cytokines and virology markers during early PEG IFN α-2a treatment were associated with HBsAg loss in HBeAg-positive CHB patients.

Hepatitis B core-related antigen serum levels are associated with significant liver fibrosis in treatment-naive chronic HBV infection patients.

Several hepatitis B virus (HBV) serum markers have been identified as risk factors for liver fibrosis in patients with chronic HBV infection, and several noninvasive fibrosis tests based on serum indexes are now used to identify the severity of liver fibrosis. We aimed to identify the relationship between hepatitis B core-related antigen (HBcrAg) serum levels and liver fibrosis in treatment-naive chronic HBV infection patients. A total of 246 treatment-naive chronic HBV infection patients were enrolled in this study. All of the patients underwent liver biopsies at baseline. Using the METAVIR fibrosis stages, there were 15, 140, 50, 26 and 15 patients in the F0, F1, F2, F3 and F4 stages (METAVIR scoring system), respectively. The biochemical, serological and virological parameters were measured using standard laboratory procedures. The HBcrAg serum levels of the patients were examined via ELISA. HBcrAg serum levels of F2, F3 and F4 stage patients were significantly higher than those of nonsignificant liver fibrosis patients (METAVIR F0-F1), but there were no significant differences among F2, F3 and F4 stage patients. Serum HBcrAg (OR, 2.18; 95% confidence interval [CI], 1.51-3.16), albumin (ALB) (OR, 0.60; 95% CI, 0.41-0.87), prothrombin activity (PTA) (OR, 0.58; 95% CI, 0.40-0.83) and platelet (PLT) counts (OR, 0.38; 95% CI, 0.25-0.57) were associated with significant liver fibrosis (METAVIR F2-F4). The serum HBcrAg value enabled the correct identification of patients with significant fibrosis, with an area under the receiver operating characteristic curve of 0.81 (95% CI, 0.75-0.88). The APRI, FIB-4 index and ALBI score can identify significant liver fibrosis with an area under the ROC curve of 0.74 (95% CI, 0.66-0.81), 0.73 (95% CI, 0.65-0.80) and 0.63 (95% CI, 0.55-0.72), respectively. Compared with these three indexes, the accuracy rate of diagnosis of significant fibrosis based on HBcrAg was higher than that of the FIB-4 index (p = 0.0479) and ALBI score (p = 0.0030). HBcrAg, ALB, PTA serum levels and PLT counts were associated with significant liver fibrosis in treatment-naive chronic HBV infection patients. HBcrAg serum levels enabled the correct identification of patients with significant fibrosis (METAVIR F2-F4), and HBcrAg was more effective than the FIB-4 index and ALBI score.

Study on pathological and clinical characteristics of chronic HBV infected patients with HBsAg positive, HBV DNA negative, HBeAg negative.

Aims: Study of clinical characteristics of hepatitis B virus deoxyribonucleic acid (HBV DNA)-negative, hepatitis B surface antigen (HBsAg)-positive, hepatitis B e antigen (HBeAg)-negative patients based on liver histopathology. Methods: We retrospectively enrolled patients with chronic HBV infection diagnosis at Beijing Ditan Hospital from May 2008 to November 2020. To study the differences between patients with significant hepatic histopathology and those without significant hepatic histopathology. And to study the independent factors of significant hepatic histopathology. Results: 85 HBV DNA-negative and HBeAg-negative patients were 37.90 ± 10.30 years old, 23.50% of patients with grade of inflammation (G) >1, 35.30% of patients with liver fibrosis stage (S) >1, 44.70% patients were diagnosed with significant hepatic histopathology. Compared to the no significant hepatic histopathology group, another group had older age (41.70 ± 10.70 vs 34.80 ± 8.87 years, t=-3.28, P=0.002), higher total bilirubin (TBIL) [14.9(10.3, 22.4) vs 11(8.9, 14.4) µmol/L, z=-2.26, P=0.024], lower cholinesterase (CHE) (t=-2.86, P=0.005, 7388.00 ± 2156.00 vs 8988.00 ± 2823.00 U/L) and lower platelet (PLT) (t=2.75, P=0.007, 157.00 ± 61.40 vs 194.00 ± 61.00 10^9/L). Abnormal ALT patients are more likely to have significant hepatic histopathology (z=5.44, P=0.020, 66.70% vs 337.50%). G had significant correlation with CHE (P=0.008, r=-0.23), alanine aminotransferase (ALT) (P=0.041, r=0.18), aspartate aminotransferase (AST) (P=0.001, r=0.29). S had significant correlation with TBIL (P = 0.008, r = 0.23), age (P < 0.001, r = 0.32), international normalized ratio (INR) (P = 0.04, r = 0.23), CHE (P < 0.001, r = -0.30), PLT (P < 0.001, r = -0.40) and prothrombin time activity (PTA) (P = 0.046, r = -0.22). Multivariate logistic analysis indicated only age (95%CI=1.014~1.130, OR=1.069, P=0.013) was an impact factor for significant hepatic histopathology. The cutoff point of age was 34.30 years. Conclusions: A large proportion of chronic HBV infection patients with HBeAg-negative and HBV DNA-negative still have chronic hepatitis. Age is an independent factor for significant hepatic histopathology.

Postpartum hepatitis and host immunity in pregnant women with chronic HBV infection.

In order to develop immune tolerant to the fetal, maternal immune system will have some modification comparing to the time before pregnancy. Immune tolerance starts and develops at the maternal placental interface. In innate immunity, decidual natural killer (dNK) cells, macrophages and dendritic cells play a key role in immue tolerance. In adaptive immunity, a moderate increase of number and immune inhibition function of regulatory T cells (Treg) are essential for immune tolerance. The trophoblast cells and immune cells expressing indoleamine 2,3-dioxygenase (IDO), the trophoblast cells expressing HLA-G, and Th1/Th2 shifting to Th2 dominant and Th17/Treg shifting to Treg domiant are in favor of maternal fetal immune tolerance. Steroids (estrogen and progesterone) and human chorionic gonadotropin (HCG) also participate in immune tolerance by inducing Treg cells or upregulating immunosuppressive cytokines. Most of the patients with chronic HBV infection are in the "HBV immune tolerance period" before pregnancy, and the liver disease is relatively stable during pregnancy. In chronic HBV infection women, after delivery, the relative immunosuppression in vivo is reversed, and Th1 is dominant in Th1/Th2 and Th17 is dominant in Th17/Treg balance. After delivery, the number of Treg decrease and NK cells increase in quantity and cytotoxicity in peripheral blood. Liver NK cells may cause liver inflammation through a non-antigen specific mechanism. After delivery, the number of CD8+ T cells will increase and HBV specific T cell response recovers from the disfunction in pregnancy. Under the background of postpartum inflammation, the rapid decrease of cortisol after delivery, and especially the enhancement of HBV specific T cell response induced by HBV DNA and cytokines, are the main reasons for postpartum hepatitis. HBeAg positive, especially HBeAg<700 S/CO, and HBV DNA>3-5Log10IU/ml are risk factors for postpartum hepatitis. Antiviral treatment in late pregnancy can reduce the incidence of mother to child transmission (MTCT) in chronic HBV infection women. Chronic HBV infection women have hepatitis both during pregnancy and more often in 12 weeks postpartum. It is generally agreed that postpartum hepatitis is mild symptoms and self-limited. Delaying drug withdrawal to 48 weeks can increase the seroconversion rate of HBeAg in delivery women with elevated alanine aminotransferase (ALT) in pregnancy.

A nomogram based on HBeAg, AST, and age to predict non-minimal liver inflammation in CHB patients with ALT <80 U/L.

Objective: Precise assessment of liver inflammation in untreated hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) infection can determine when to initiate antiviral therapy. The aim of this study was to develop and validate a nomogram model for the prediction of non-minimal liver inflammation based on liver pathological injuries combined with age and alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis B surface antigen (HBsAg), HBeAg, and HBV DNA quantification. Methods: We retrospectively included 735 HBeAg-positive chronic hepatitis B (CHB) patients with ALT < 80 U/L as the primary cohort and prospectively enrolled 196 patients as the validation cohort. Multivariate logistic regression analysis identified independent impact factors. A nomogram to predict significant liver inflammation was developed and validated. Results: Multivariate logistic regression analysis showed that HBeAg, AST, and age were independent risk factors for predicting non-minimal liver inflammation in untreated CHB patients. The final formula for predicting non-minimal liver inflammation was Logit(P) = -1.99 - 0.68 × Log10HBeAg + 0.04 × Age + 0.06 × AST. A nomogram for the prediction of non-minimal liver inflammation was established based on the results from the multivariate analysis. The predicted probability of the model being consistent with the actual probability was validated by the calibration curves, showing the best agreement in both the primary and validation cohorts. The C-index was 0.767 (95%CI = 0.734-0.802) in the primary cohort and 0.749 (95%CI = 0.681-0.817) in the prospective validation cohort. Conclusions: The nomogram based on HBeAg, AST, and age might help predict non-minimal liver inflammation in HBeAg-positive CHB patients with ALT < 80 U/L, which is practical and easy to use for clinicians.

Dynamic changes of the proportion of HLA-DR and CD38 coexpression subsets on T lymphocytes during IFN-based chronic hepatitis B treatment.

Background: To investigate the changes of human leukocyte antigen DR (HLA-DR) and CD38 coexpression subsets on T lymphocytes following interferon (IFN) therapy for those who have chronic hepatitis B (CHB). Methods: A prospective cohort of CHB patients participated in this study. CHB patients without IFN treatment (including naïve and nucleoside [nucleotide] analogs [NAs]-treated patients) were given pegylated interferon alfa (Peg-IFNα) treatment. Peripheral blood samples were taken at baseline, 4 weeks and 12-24 weeks of Peg-IFNα treatment. For the patients who entered the Peg-IFNα plateau phase due to the stagnation of the decrease in HBsAg, and Peg-IFNα was discontinued and Peg-IFNα therapy was resumed after an interval of 12-24 weeks. During the interval, they received first-line NAs treatment. Peripheral blood samples were collected at the baseline of the plateau phase, 12-24 weeks of intermittent treatment, and 12-24 weeks of Peg-IFNα retreatment. The peripheral blood samples were taken to determine virological, serological and biochemical indices of hepatitis B virus (HBV), and T lymphocyte related phenotypes were detected using flow cytometry. Results: In the process of long-term treatment of Peg-IFNα, the percentage of HLA-DR+CD38dim subsets increased significantly at first, then decreased gradually, while the percentage of HLA-DR+CD38hi subsets markedly increased. During long-term Peg-IFNα treatment, there was a considerable negative correlation between HBsAg and the HLA-DR+CD38hi subset percentage. The persistent high proportion of HLA-DR+CD38hi subsets was related to the occurrence of Peg-IFNα plateau phase. After Peg-IFNα intermittent treatment, the percentage of HLA-DR+CD38hi subsets decreased significantly. After Peg-IFNα retreatment, the level of HBsAg began to decrease again. At the same time, the percentage of HLA-DR+CD38hi subsets significantly increased, but it was still lower than that at the baseline level. Conclusions: The spectrum of HLA-DR and CD38 coexpression subsets on T lymphocytes changed during the long-term treatment of IFN. The establishment of the IFN plateau phase was linked to the persistence of a considerable proportion of HLA-DR+CD38hi subsets on T lymphocytes. IFN intermittent treatment could significantly reduce the proportion of HLA-DR+CD38hi subsets, helping regain the antiviral efficacy of IFN during IFN retreatment.

Cyy260, a novel small molecule inhibitor, suppresses non-small cell lung cancer cell growth via JAK2/STAT3 pathway.

Non-small cell lung cancer (NSCLC) is a malignant tumor that accounts for the most new cancer cases and cancer-related deaths worldwide, and the proliferation and metastasis of NSCLC are the main reasons for treatment failure and patient death. Traditional chemotherapeutic drugs have low selectivity, which can kill cancer cells and cause damage to normal cells at the same time. Therefore, it is particularly important to study therapies that target cancer cells and to find low-toxicity, high-efficiency anticancer drugs. Cyy260 is a novel small molecule inhibitor that we synthesized for the first time. Here, we investigated the in vitro and in vivo antitumor activities of Cyy260 and explored the underlying mechanisms in NSCLC. Cyy260 had a concentration- and time-dependent inhibitory effect on NSCLC cells, but it was less toxic to normal cells. Cyy260 regulated apoptosis through intracellular and extracellular apoptotic pathways. In addition, Cyy260 could also induce cell cycle arrest, thereby inhibiting cell proliferation. Further analysis of molecular mechanisms showed that the JAK2/STAT3 signaling pathway was involved in the antitumor effect mediated by Cyy260. Analysis of subcutaneously transplanted tumors in mice showed that Cyy260 suppressed tumor growth in vivo. Our results proved that Cyy260 is a novel inhibitor of the JAK2/STAT3 pathway thus may have potential in therapy of NSCLC and other cancers.

Effects of continuing nursing care under cognitive behavioral intervention on psychological state and living quality in patients with double J catheter after ureterolithiasis surgery.

OBJECTIVE: The effects of continuing nursing care under cognitive behavioral intervention on the psychological state and living quality of patients with double J catheter after ureterolithiasis surgery were analyzed in this research. METHODS: The research subjects in this study were 142 patients who were discharged from our hospital with a double J tube after ureterolithiasis surgeries from June 2019 to June 2020. According to the patient care plan, the subjects were divided into the control group (n=71) and the observation group (n=71) and respectively treated with routine basic nursing measures and continuing nursing care under cognitive-behavior intervention. Subsequently, the psychological state, living quality and the complications that occurred were compared between the two groups. RESULTS: The depression and anxiety scores of the two groups after 4 weeks of intervention, comparing to thoes before intervention, were seen with remarkably decreased significance (P<0.05). The scores of living quality and self-care quality of patients in the observation group were obviously higher than those in the control group (P<0.05). In addition, the incidence of complications in the observation group was critically lower than that in control group (P<0.05). CONCLUSION: Continuous nursing care under cognitive behavioral intervention can substantially improve the psychological state, living quality and self-care ability of patients with double J tube after ureterolithiasis surgery, and reduce the incidence of complications, which is worthy of clinic promotion.

Clinical Outcomes of Reresection in Patients with High-Risk Nonmuscle-Invasive Bladder Cancer Treated with En Bloc Transurethral Resection: A Retrospective Study with a 1-Year Follow-Up.

Purpose: To evaluate the impact of reresection on the clinical outcome in patients with primary high-risk nonmuscle-invasive bladder cancer (NMIBC) who initially received en bloc transurethral resection. Methods: A retrospective analysis of data on eligible high-risk NMIBC with en bloc resection from June 2015 to June 2019 was performed. Patients were divided into two groups based on the presence or absence of reresection after the initial en bloc resection. In the first group (reresection group), patients underwent en bloc reresection within 6 weeks. In the second group (non-reresection group), patients did not undergo en bloc reresection. Pathologic findings in patients with reresection and cystoscopic findings in all patients 3 months after initial resection were recorded. The primary study endpoint was recurrence-free survival (RFS). The secondary outcomes were the residual rate of the tumor after initial en bloc resection, tumor upstaging rate, and progression-free survival. Results: We identified 115 eligible patients, including 51 (44.3%) who underwent reresection within 6 weeks of the initial en bloc resection and 64 (55.7%) who did not undergo en bloc reresection after the initial en bloc resection. The clinicopathologic features were similar in patients with or without reresection. On finding tumor residues after the first en bloc resection, there were three cases (5.9%) in the reresection group compared with two cases (3.1%) in the non-reresection group (p = 0.473). Two patients (3.9%) in the reresection group had tumor progression to muscle-invasive bladder cancer, whereas one patient (1.6%) in the non-reresection group exhibited tumor progression (p = 0.430). The 1-year RFS rate was 94.1% in the reresection group and 90.6% in the non-reresection group (p = 0.269). In multivariate analysis, multifocality and T1 staging were independent prognostic factors for recurrence in patients with high-risk NMIBC who underwent en bloc resection. Conclusion: In patients with high-risk NMIBC not exceeding 4 cm in diameter with no more than four lesions and not in the anterior bladder wall, reresection after en bloc resection seems to have failed to improve the patient's prognosis. We predict that the future trend in the treatment of patients with high-risk NMIBC is from reresection to en bloc resection. However, a randomized controlled clinical study is required to confirm this hypothesis.