[Predictive Value of Baseline Serum Marker Levels for the Effect of Interferon Therapy in Patients With Chronic Hepatitis B]. / æ ¢æ€§ä¹™åž‹è‚ç‚Žæ‚£è€ çš„è¡€æ¸ æ ‡å¿—ç‰©åŸºçº¿æ°´å¹³å¯¹å¹²æ‰°ç´ æ²»ç–—æ•ˆæžœçš„é¢„æµ‹ä»·å€¼.

Objective: To study the changes in the serum markers in chronic hepatitis B patients who have had previous treatment with long-acting interferon therapy of nucleoside and those who have not and to assess the value of the serum markers for clinical prognosis evaluation. Methods: The clinical data of 411 cases of chronic hepatitis B were collected. All cases were given the additional treatment of long-acting interferon between October 2019 to April 2022. The cases were divided into two groups, a previously treated group consisting of patients who had been treated with nucleoside and nucleotide analogues (NAs) for more than 6 months after they became infected with hepatitis B virus (HBV) for over 6 months and an initial treatment group, or treatment naïve group, consisting of patients who had HBV infection for over 6 months and received no treatment or patients who have stopped NAs therapy for more than 6 months. The serum marker levels of the previously treated group and the initial treatment group, i.e., the previously treatment-naïve patients, were compared, and the receiver operating characteristics (ROC) curve was used to evaluate the value of the baseline levels of hepatitis B surface antigen (HBsAg) and HBV pregenomic RNA (pgRNA) for predicting the rate of cured cases in the two groups. Results: There was no significant difference in the rate of cured cases between the previously treated group and the initial treatment group. The baseline HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg) levels of the cured cases in both groups were significantly lower than those in the uncured cases (P<0.0001). After 48 weeks of treatment, the serum HBsAb levels (mIU/mL) of the cured cases in both the previously treated and initial treatment groups were significantly higher than those of the uncured cases in the two groups (previously treated group: 78.97±22.57 vs. 0.99±0.38, P<0.0001; initial treatment group: 235.50±175.00 vs. 1.32±0.88, P<0.0001). The serum HBsAb levels (mIU/mL) of the cured cases in the initial treatment groups were significantly higher than that of cured cases in the previously treated group (235.50±175.00 vs. 78.97±22.57, P<0.0001). Within 0 to 60 weeks of treatment, HBV pgRNA levels of cured cases in both groups were significantly lower than those of the the uncured cases in both groups (P<0.0001). Multivariate logistic regression and ROC curve analysis showed that baseline serum HBsAg was the influencing factor and predictor of interferon efficacy in both the previously treated cases and the initial treatment cases, with the area under the curve (AUC) being 0.80 (95% confidence interval [CI]: 0.7423-0.8615, P<0.0001) and 0.74 (95% CI: 0.6283-0.8604, P=0.0079), respectively, and the optimal cut-off values being 244.60 IU/mL and 934.40 IU/mL, respectively. However, the baseline serum HBV pgRNA level of under 1340.00 copies/mL in the initial treatment cases led to better sensitivity and better specificity in efficacy prediction, with the AUC of the baseline HBV pgRNA being 0.9649 (95% CI: 0.9042-1.0000, P<0.0001). Conclusion: Among the previously treated cases and the initial treatment cases, patients who achieve clinical cure have lower levels of HBV DNA, HBsAg, and HBeAg at baseline, lower level of HBV pgRNA over the course of their treatment, and higher level of HBsAb at week 48. Baseline HBsAg levels can be used to effectively predict the clinical cure outcomes in previously treated cases and initial treatment cases. Baseline HBV pgRNA levels also exhibit a high predictive value for treatment outcomes in initial treatment cases.

Corrigendum: Novel molecular therapeutics targeting signaling pathway to control hepatitis B viral infection.

[This corrects the article DOI: 10.3389/fcimb.2022.847539.].

[Analyze the clinical characteristics of mild and severe SARS-CoV-2 infected patients based on the local Omicron variant epidemic].

OBJECTIVE: To analyze the epidemic characteristics and clinical key indicators of the patients infected with SARS-CoV-2 of the local Omicron variant epidemic, to understand the clinical characteristics of mild and severe patients, and to provide a scientific basis for the effective treatment and prevention of severe disease. METHODS: From January 2020 to March 2022, the clinical and laboratory data of COVID-19 patients admitted to the Fifth People's Hospital of Wuxi were retrospective analyzed, including virus gene subtypes, demographic information, clinical classification, main clinical symptoms, and key indicators of clinical testing, and the changes of clinical characteristics of the patients infected with SARS-CoV-2. RESULTS: A total of 150 patients with SARS-CoV-2 infection were admitted, 78, 52 and 20 in 2020, 2021 and 2022, including 10, 1 and 1 severe patient, and the main infected virus strains were L, Delta, and Omicron variants. The relapse rate of patients infected with the Omicron variant was as high as 15.0% (3/20), the incidence of diarrhea decreased to 10.0% (2/20), the incidence of severe disease decreased to 5.0% (1/20), and the number of hospitalization days of mild patients increased compared with 2020 (days: 20.43±1.78 vs. 15.84±1.12); respiratory symptoms were reduced, and the proportion of pulmonary lesions decreased to 10.5%; the virus titer of severely ill patients with SARS-CoV-2 Omicron variant infection (day 3) was higher than that of L-type strain (Ct value: 23.92±1.16 vs. 28.19±1.54). The acute plasma cytokines interleukin (IL-6, IL-10) and tumor necrosis factor-α (TNF-α) were significantly lower in patients with severe Omicron variant new coronavirus infection than those with mild disease [IL-6 (ng/L): 3.92±0.24 vs. 6.02±0.41, IL-10 (ng/L): 0.58±0.01 vs. 4.43±0.32, TNF-α (ng/L): 1.73±0.02 vs. 6.91±1.25, all P < 0.05], while γ-interferon (IFN-γ) and IL-17A were significantly higher than patients with mild disease [IFN-γ (ng/L): 23.07±0.17 vs. 13.52±2.34, IL-17A (ng/L): 35.58±0.08 vs. 26.39±1.37, both P < 0.05]. Compared with previous epidemics (2020 and 2021), the proportion of CD4/CD8 ratio, lymphocyte count, eosinophil and serum creatinine decreased in patients with mild Omicron infection in 2022 (36.8% vs. 22.1%, 9.8%; 36.8% vs. 23.5%, 7.8%; 42.1% vs. 41.2%, 15.7%; 42.1% vs. 19.1%, 9.8%), the proportion of patients with elevated monocyte count and procalcitonin was large (42.1% vs. 50.0%, 23.5%; 21.1% vs. 5.9%, 0). CONCLUSIONS: The incidences of severe disease in patients with SARS-CoV-2 Omicron variant infection was significantly lower than that of previous epidemics, and the occurrence of severe diseases was still related to the underlying diseases.

[Etiology and related clinical indicators of liver failure: an analysis of 3-year case data of Wuxi designated hospital for treatment of liver failure].

OBJECTIVE: To analyze the characteristics of etiology and clinical indicators of hepatitis B virus (HBV) and non-HBV liver failure, and to evaluate their potential roles in reflecting disease outcomes. METHODS: The clinical data of 369 patients with liver failure admitted to the intensive care unit (ICU) of the Fifth People's Hospital of Wuxi which was the designated hospital for treatment of liver failure from January 2018 to December 2020 were retrospectively analyzed. The classification and comparison of etiology of non-HBV and HBV liver failure patients were performed according to the Guidelines on the Diagnosis and Treatment of Liver Failure (2018 edition). The indicators of liver failure related etiologies, including gender, age, anticoagulant enzyme III (AT III), total bilirubin (TBil), length of ICU stay, hepatic encephalopathy, underlying disease (liver cirrhosis and liver cancer, etc.) and usage of artificial liver were analyzed. According to the 6-month follow-up results after discharge, the differences in the etiological indicators of died and survival patients and the outcome of patients with different types of liver failure were analyzed. RESULTS: A total of 369 patients were enrolled, including 134 (36.3%) with liver failure not caused by HBV and 235 (63.7%) with liver failure caused by HBV. The male with HBV-related liver failure was 4.34 times higher than female (cases: 191 vs. 44), which was higher than non-HBV-related liver failure (1.03 times, cases: 68 vs. 66). The 6-month follow-up showed that the proportion of male with HBV-related liver failure who died and survived was significantly higher than that of female (78.76% vs. 21.24% in died patients, 92.86% vs. 7.14% in survival patients, both P < 0.01). The age of died patients in the non-HBV-related liver failure group was significantly higher than that of the survival patients (years: 58.53±0.15 vs. 54.38±3.01, P < 0.05), and the AT III level was significantly lower than that of the survival patients [(32.20±6.43)% vs. (38.63±2.74)%, P < 0.05]. The length of ICU stay of the died HBV-related liver failure group was significantly shorter than that of the survival patients (days: 23.77±11.74 vs. 35.51±2.85, P < 0.01). The 6-month mortality after discharge of HBV-related liver failure combined with liver cancer was significantly higher than that of non-HBV-related liver failure (12.34% vs. 2.24%, P < 0.01), but there was no significant difference in 6-month mortality after discharge of patients receiving artificial liver and those with hepatic encephalopathy and cirrhosis between different types of liver failure groups. CONCLUSIONS: HBV is the main cause of liver failure. Patients with HBV-related liver failure were younger and had a longer hospitalization period, which was conducive to the recovery of the disease. HBV-related liver failure accompanied with liver cancer is the main factors of death. The AT III has the potential value to reflect the disease outcome.

[Analyze the application rules and effects of "Four Elements, One Peptide, and Two Transplantations" based on bundle treatment in coronavirus disease 2019].

OBJECTIVE: To explore the application rules and effects of "Four Elements, One Peptide, and Two Transplantations" in the bundle treatment of the patients with coronavirus disease 2019 (COVID-19), so as to provide a scientific evidence for effective treatment and prevention of severe type. METHODS: A retrospective comparative study method was used to analyze the clinical data of COVID-19 patients admitted to Wuxi Fifth People's Hospital from January 2020 to March 2022, including demographic information, underlying diseases, clinical classification, length of hospital stay, treatment cost, clinical symptoms, laboratory tests and other key indicators, and evaluate the application rules and effect of "Four Elements, One Peptide, and Two Transplantations" in the bundle treatment of the patients with COVID-19. RESULTS: The L-type new coronavirus strain was predominant in 2020, the Delta variant in 2021, and the Omicron variant in 2022. The proportion of mild cases was highest in 2022, with the highest proportion of > 65 years old patients developing severe and critical. Among the 150 patients, the proportion of interferon use (100.0%) was the highest in the bundle treatment regimen of "Four Elements, One Peptide, and Two Transplantation". The combined use of vitamin C, interferon and thymopeptide was highest in 2022. More than 75.0% of the age > 65 years old group had underlying diseases, which was also the age group with the highest proportion of "Four Elements, One Peptide, and Two transplantations". Compared with mild cases, the age, length of hospital stay, and hospitalization cost of patients with COVID-19 increased significantly with severity. Mild, ordinary, severe, and critically ill patients all had low lymphocyte counts, with 40.0% of severe patients having the lowest lymphocyte counts within 3 days of admission. The lymphocyte count of critically ill patients was reduced or continuously reduced after admission, and the use of the "Four Elements, One Peptide, and Two transplantations" method to regulate immunity can effectively save the lives of critically ill patients. Of all cases of COVID-19 infection, 51.3% were asymptomatic, followed by respiratory symptoms (48.7%) and lung lesions (38.0%). Patients with renal dysfunction received this bundle therapy was highest, followed abnormal coagulation and abnormal liver function. This bundle therapy promoted a significant increase in CD4+ T lymphocytes and B lymphocytes in various cases. After treatment, as the virus turns negative, the proportion of M1 type macrophages increased, and the proportion of regulatory T cell (Treg cells) that suppress immunity and the infection related C-C chemokine receptor type (CCR10+) Treg cells decreased. Mild adult cases showed a great change and declined rapidly. CONCLUSIONS: Advanced age with underlying diseases is a risk factor for severe disease of COVID-19, the "Four Elements, One Peptide, and Two transplantations" bundle fine treatment of COVID-19 can improve the proportion of lymphocyte composition and organ function, which can control the occurrence and development of severe diseases. In addition to the proportion of CD4+ T cells, the changes of the M1 macrophage, total Treg cell, and CCR10+ Treg cell proportions can be used to determine disease changes of adult patients.

[The predictive value of liver failure-related etiology for clinical outcomes].

OBJECTIVE: To assess the predictors of outcomes for different subtypes of liver failure, and the effectiveness of artificial liver support systems in the treatment of liver failure. METHODS: The clinical data of 112 patients with hepatitis B virus (HBV)- and non-HBV-related liver failure admitted to the intensive care unit (ICU) of the Fifth People's Hospital of Wuxi were collected from January to December 2020. The relevant etiologies of acute, subacute, acute-on-chronic, subacute-on-chronic, chronic subtype liver failure were analyzed. The efficacies of artificial liver support systems in the treatment of various subtypes of liver failure were also compared. The correlation of various indicators was analyzed by Spearman correlation analysis, the risk factors affecting the prognosis of patients with liver failure were analyzed by multivariate Logistic regression equation, and receiver operator characteristic curve (ROC curve) of subjects was plotted to evaluate the predictive value of each risk factor for the prognosis of patients with liver failure. RESULTS: Among the 112 liver failure patients, 63 were caused by hepatitis B and 49 were caused by non-hepatitis B. The liver failure caused by hepatitis B was 6 times higher than for men than for women, which was higher than that of non-HBV liver failure group (1.33 times). Antithrombin III (AT III) and total bilirubin (TBil) levels of subacute liver failure were higher than those of pre-liver failure in the HBV liver failure group [AT III: (59.33±14.57)% vs. (35.66±20.72)%, TBil (µmol/L): 399.21±112.94 vs. 206.08±126.96, both P < 0.05]. The levels of AT III in patients with pre-liver failure and chronic liver failure in the non-HBV liver failure group were significantly higher than those with acute liver failure [(58.33±15.28)%, (44.00±19.10)% vs. (31.33±7.57)%, both P < 0.05], patients with acute liver failure had significantly lower level of TBil than pre-liver failure (µmol/L: 107.83±49.73 vs. 286.20±128.92, P < 0.05), the TBil levels in patients with subacute and acute-on-chronic liver failure were also significantly higher than that in pre-liver failure group (µmol/L: 417.27±118.60, 373.00±187.00 vs. 286.20±128.92, both P < 0.05). Patients with subacute liver failure, subacute-on-chronic liver failure and chronic liver failure in the non-HBV failure group were significantly longer than those in acute liver failure (days: 36.00±8.31, 27.52±11.71, 27.72±22.71 vs. 11.00±1.41, all P < 0.05). There was no statistically significant difference in the case fatality rate of using the artificial liver support system between the HBV failure group and the non-HBV failure group (55.6% vs. 50.0%, P < 0.05), the levels of AT III in the two groups of surviving patients were significantly higher than that of the dead [HBV liver failure group: (36.20±6.26)% vs. (27.33±8.87)%, non-HBV liver failure group: (41.06±4.16)% vs. (28.71±12.35)%, both P < 0.01]. Correlation analysis showed that there was a clear positive correlation between AT III and TBil in the dead patients of HBV liver failure group and the survival and death patients of non-HBV liver failure group (r values were 0.069, 0.341, 0.064, and P values were 0.723, 1.196 and 0.761, respectively); there was a significant inverse correlation between AT III and TBil in the HBV liver failure group (r = -0.105, P = 0.745). Multivariate Logistic regression analysis showed that AT III was an independent risk factor affecting the prognosis of patients with non-HBV liver failure [odd ratio (OR) = 1.023, 95% confidence interval (95%CI) was -0.001 to 0.001, P = 0.007]. TBil was an independent risk factor affecting prognosis of patients with HBV liver failure (OR = 1.005, 95%CI was -0.002 to -7.543, P = 0.033). The analysis of ROC curve showed that AT III had a predictive value for the prognosis of patients with non-HBV liver failure, the area under the ROC curve (AUC) = 0.747, the 95%CI was 0.592-0.902, P = 0.009. When the optimal truncation value was 39.5%, its sensitivity and specificity were 83.33% and 56.25%, respectively. CONCLUSIONS: Artificial liver support system treatment of liver failure was difficult to effectively reduce the mortality of patients with end-stage liver failure. In addition to AT III, TBil also could be used as an indicator to assess liver compensatency and predict prognosis in liver failure patients.

Novel Molecular Therapeutics Targeting Signaling Pathway to Control Hepatitis B Viral Infection.

Numerous canonical cellular signaling pathways modulate hepatitis B virus (HBV) replication. HBV genome products are known to play a significant role in regulating these cellular pathways for the liver's viral-related pathology and physiology and have been identified as the main factor in hepatocarcinogenesis. Signaling changes during viral replication ultimately affect cellular persistence, multiplication, migration, genome instability, and genome damage, leading to proliferation, evasion of apoptosis, block of differentiation, and immortality. Recent studies have documented that numerous signaling pathway agonists or inhibitors play an important role in reducing HBV replication in vitro and in vivo, and some have been used in phase I or phase II clinical trials. These optional agents as molecular therapeutics target cellular pathways that could limit the replication and transcription of HBV or inhibit the secretion of the small surface antigen of HBV in a signaling-independent manner. As principle-based available information, a combined strategy including antiviral therapy and immunomodulation will be needed to control HBV infection effectively. In this review, we summarize recent findings on interventions of molecular regulators in viral replication and the interactions of HBV proteins with the components of the various targeting cellular pathways, which may assist in designing novel agents to modulate signaling pathways to prevent HBV replication or carcinogenesis.

CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance.

BACKGROUND: Chemokine (C-C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. METHODS: We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C-C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. RESULTS: From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. CONCLUSIONS: Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.