Impact of in vitro fertilization-embryo transfer on mother-to-infant transmission in women with chronic HBV infection.

BACKGROUND AND AIMS: In vitro fertilization-embryo transfer (IVF-ET) may increase the risk of mother-to-child transmission (MTCT) of hepatitis B virus (HBV). The purpose of this study was to investigate the impact and safety of IVF-ET on MTCT in women with chronic HBV infection (CHB). METHODS: The data of 298 women who got pregnant by IVF-ET and their 375 children were collected retrospectively. Mothers were divided into the CHB group (n = 224) and the control group (HBsAg negative, n = 74). After birth, newborns were routinely vaccinated with the hepatitis B vaccine, and infants in the CHB group were injected with hepatitis B immunoglobulin within 2 h after birth. Demographic information, clinical data and laboratory test results were collected. The primary outcome measures were the MTCT rate of HBV, and the secondary outcome measures were the safety of the mother and infant. RESULTS: There was no case of HBV MTCT in all 282 newborns born in the CHB group and 93 neonates born in the control group. Of the two groups, the birth weight (3056.74 ± 601.65 vs. 2926.24 ± 704.86, P = .083), length (49.22 ± 1.97 vs. 48.74 ± 3.09, P = .167), 5-min Apgar score (9.97 ± 0.21 vs. 9.90 ± 0.51, P = .212), days of pregnancy (265.70 ± 12.73 vs. 262.02 ± 17.50, P = .064) and neonatal malformation rate (0.71% vs. 0, P = 1.000) were similar. Two cases of neonatal malformation occurred in the CHB group. The incidences of pregnancy and childbirth complications were similar between the two groups. CONCLUSION: IVF-ET does not increase the risk of MTCT in women with chronic HBV infection, and it is safe for mothers and infants.

Emerging nanobiotechnology for precise theranostics of hepatocellular carcinoma.

Primary liver cancer has become the second most fatal cancer in the world, and its five-year survival rate is only 10%. Most patients are in the middle and advanced stages at the time of diagnosis, losing the opportunity for radical treatment. Liver cancer is not sensitive to chemotherapy or radiotherapy. At present, conventional molecularly targeted drugs for liver cancer show some problems, such as short residence time, poor drug enrichment, and drug resistance. Therefore, developing new diagnosis and treatment methods to effectively improve the diagnosis, treatment, and long-term prognosis of liver cancer is urgent. As an emerging discipline, nanobiotechnology, based on safe, stable, and efficient nanomaterials, constructs highly targeted nanocarriers according to the unique characteristics of tumors and further derives a variety of efficient diagnosis and treatment methods based on this transport system, providing a new method for the accurate diagnosis and treatment of liver cancer. This paper aims to summarize the latest progress in this field according to existing research and the latest clinical diagnosis and treatment guidelines in hepatocellular carcinoma (HCC), as well as clarify the role, application limitations, and prospects of research on nanomaterials and the development and application of nanotechnology in the diagnosis and treatment of HCC.

Efficacy and Safety of Glycyrrhizic Acid in Treatment of Autoimmune Hepatitis.

To compare the long-term efficacy and safety of glycyrrhizic acid preparation and hormone treatment in patients with autoimmune hepatitis, we enrolled 377 patients in a study that lasted from January 2009 to January 2020. After performing propensity score matching, we included 58 patients in the hormone group and 58 in the glycyrrhizic acid preparation group in statistical analysis. We then compared the ratio of sustained biochemical responses at 48 weeks after treatment. Adverse events, including some incidence of decompensated liver cirrhosis and liver cancer, were evaluated. The results showed that a total of 61.8% of treated patients achieved complete biochemical remission. The cumulative biochemical remission rate in the hormone group and glycyrrhizic acid preparation group showed no significant difference (62.3% vs. 60.7%, [Formula: see text], [Formula: see text]). At the end of follow-up, the total bile acid in the hormone group was significantly higher than that in the glycyrrhizic acid preparation group (8.9[Formula: see text][Formula: see text]mol/L vs. 5.6[Formula: see text][Formula: see text]mol/L, [Formula: see text], [Formula: see text]). The incidence of adverse reactions in the hormone group was significantly higher than that in the glycyrrhizic acid preparation group (31.03% vs. 15.52%, [Formula: see text], [Formula: see text]). In conclusion, compared with the hormone treatment, glycyrrhizic acid preparation might be a safe and effective treatment for autoimmune hepatitis.

Effects of antiviral therapy and drug withdrawal on postpartum hepatitis in pregnant women with chronic HBV infection.

OBJECTIVE: To investigate the effect of antiviral therapy and drug withdrawal on the incidence of hepatitis B after delivery in pregnant women with chronic hepatitis B virus (CHB) infection who received tenofovir disoproxil fumarate (TDF) treatment. METHODS: Eligible CHB pregnant women were enrolled, and received TDF at 32 weeks gestation. The drug was stopped immediately or at 6 weeks after delivery. The HBV biomarkers and clinical biochemical parameters were monitored during gestation and 24 weeks after delivery. RESULTS: There were 264 women completed the observation, including 96 untreated subjects in control group. Among 168 treated subjects, 131 cases stopped drug immediately after delivery and 37 cases delayed the drug withdrawal at 6 weeks after delivery. The incidence of postpartum hepatitis in control, immediate drug withdrawal, and delayed drug withdrawal were 28.1% (27/96), 23.7% (31/131), and 24.3% (9/37), showing no significant difference (χ2 = 0.607, p = 0.738). No factor was found to be associated with the occurrence of postpartum hepatitis. It's noteworthy that 96.3% of postpartum hepatitis in control group and 92.3% of postpartum hepatitis in immediate drug withdrawal group occurred within 12 weeks after delivery. While in delayed drug withdrawal group, the rate of postpartum hepatitis occurred within 12 weeks after delivery was 77.7%. CONCLUSION: Withdrawing antiviral drug immediately or at 6 weeks after delivery did not affect the incidence of postpartum hepatitis in CHB women, but delaying drug withdrawal might delay the onset of postpartum hepatitis. CLINICAL TRIAL REGISTRATION NUMBER: NCT03214302.

Nomogram for evaluating obvious liver inflammation in treatment-naïve HBeAg positive chronic hepatitis B virus infection patients with normal ALT.

The purpose of this study was to develop an effective and non-invasive nomogram for evaluating liver obvious inflammation in untreated HBeAg positive patients with chronic hepatitis B virus (HBV) infection. A nomogram was established on a model cohort of 292 treatment-naïve HBeAg positive patients with normal alanine aminotransferase (ALT ≤40 U/L) at Beijing Ditan Hospital from January 2008 to March 2018. Then the nomogram was prospectively validated in a cohort of 88 patients from July 2019 to May 2021. Calibration curves and Concordance index were used to evaluate the accuracy of prediction and identification performance of the model. In untreated HBeAg positive chronic hepatitis B virus infection patients with normal ALT, the formula for predicting liver inflammation was Logit (P) =-0.91-0.41×log10 (qHBeAg)+0.11×AST-0.01×PLT. The nomogram had C-index of 0.751 (95% CI, 0.688-0.815), indicating a good consistency between prediction and real observation on the model cohort. The validation cohort confirmed its good performance. In this study, liver inflammation nomograms based on HBeAg, AST, and PLT were established and verified in treatment-naïve HBeAg positive chronic HBV patients with normal ALT.

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.

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.

Combination and Intermittent Therapy Based on Pegylated Interferon Alfa-2a for Chronic Hepatitis B with Nucleoside (Nucleotide) Analog-Experienced Resulting in Hepatitis B Surface Antigen Clearance: A Case Report.

Interferon (IFN) and nucleoside (nucleotide) analogs (NAs) are two effective antiviral drugs for chronic hepatitis B (CHB). More and more evidence shows that the combination of the two drugs can better inhibit viral replication and even achieve clinical cure. IFN intermittent therapy is also considered to be an important measure to resolve IFN fatigue when hepatitis B surface antigen (HBsAg) decline appears stagnated during IFN-based antiviral therapy. A 36-year-old male NA-experienced patient with hepatitis B e antigen (HBeAg)-positive CHB was admitted to our hospital. After a poor response to tenofovir disoproxil fumarate (TDF) monotherapy for 1 year, the patient was treated with pegylated interferon alfa-2a combination therapy and finally achieved HBsAg clearance. During the treatment and follow-up, HBsAg, HBeAg, hepatitis B virus (HBV) DNA, and serum alanine aminotransferase, etc. were monitored every 3 months. Between weeks 58 and 71 of combination therapy, IFN was discontinued because of a slow decline in HBsAg, and TDF alone was used for maintenance therapy. Complete virological response, HBeAg and HBsAg seroconversion were observed at weeks 44, 96, and 122, respectively. After 24 weeks of consolidation therapy, HBsAg, HBeAg, and HBV DNA were consistently negative, and hepatitis B surface antibody was 729.30 mIU/mL at week 146 of the combination therapy, then we stopped drugs. Following up after 28 weeks of cessation therapy, the patient still remained clinically cured.

Pathway of Cell Death and Its Role in Virus Infection.

The global pandemic of SARS-CoV-2 in the past 2 years has aroused great attention to infectious diseases, and emerging virus outbreaks have brought huge challenges to the global health system. Viruses are specific pathogens that completely rely on host cells for their own survival and disease transmission. At present, a growing number of studies have proved that inducing the death of virus-infected cells can prevent the spread of virus and promote disease recovery. Therefore, many ways to induce the death of infected cells are considered to be beneficial to host immunity. Cell death is a basic biological phenomenon. Programmed cell death (PCD), as an important part of the host's innate immune response, provides effective protection against virus transmission. Pyroptosis, apoptosis, and necroptosis are the most commonly studied pathways of PCD. Recent studies have found that three pathways of cell death can be activated during virus infection. More and more studies have shown the existence of extensive connections between PCDs, and this complex relationship is defined as PANoptosis, an inflammatory PCD pathway regulated by the PANoptosome complex, whose characteristics cannot be explained by any of the three PCD pathways. During viral infection, PANoptosis can promote inflammatory response by inducing the production of inflammatory cytokines and cell death to exert an antiviral mechanism. This article reviews the various effects of cell death pathways during viral infection and provides new ideas for clinical antiviral therapy and related immunotherapy.

Consolidation treatment needed for sustained HBsAg-negative response induced by interferon-alpha in HBeAg positive chronic hepatitis B patients.

Hepatitis B surface antigen (HBsAg) clearance is considered as functional cure in patients with chronic hepatitis B (CHB). This study aimed to assess the durability of HBsAg clearance achieved by interferon-based therapies in patients with CHB who were originally positive for hepatitis B envelope antigen (HBeAg). In this prospective study, HBeAg-positive CHB patients with confirmed HBsAg loss under interferon-based therapies were enrolled within 12 weeks from end of treatment and followed up for 48 weeks. Virological markers, biochemical indicators, and liver imaging examinations were observed every 3-6 months. Sustained functional cure was analysed as primary outcome. Factor associated with sustained HBsAg loss or reversion was also investigated. The rate of HBsAg loss sustainability was 91.8% (212/231). Patients receiving consolidation treatment for 12-24 weeks or ≥ 24 weeks had higher rates of sustained HBsAg negativity than those receiving consolidation treatment for < 12 weeks (98.3% and 91.2% vs. 86.7%, P â€‹= â€‹0.068), and the former groups had significantly higher anti-HBs levels than the later (P â€‹< â€‹0.05). The cumulative incidence of HBsAg reversion and HBV DNA reversion was 8.2% and 3.9%, respectively. Consolidation treatment of ≥ 12 weeks [odd ratio (OR) 3.318, 95% confidence interval (CI) 1.077-10.224, P â€‹= â€‹0.037) was a predictor of sustained functional cure, and HBeAg-positivity at cessation of treatment (OR 12.271, 95% CI 1.076-139.919, P â€‹= â€‹0.043) was a predictor of HBsAg reversion. Interferon-alpha induced functional cure was durable and a consolidation treatment of ≥ 12-24 weeks was needed after HBsAg loss in HBeAg-positive CHB patients.

An optimized mode of interferon intermittent therapy help improve HBsAg disappearance in chronic hepatitis B patients.

Background: To investigate the effect of intermittent interferon therapy mode on the disappearance of hepatitis B surface antigen (HBsAg) in chronic hepatitis B (CHB) patients. Methods: This is a retrospective cohort study in CHB patients who were suspended from pegylated interferon α (PEG-IFNα) therapy due to a plateau in HBsAg decline during the initial treatment period, and resumed interferon therapy after an interval of 3-6 months. Patients received entecavir or tenofovir during the interval period. Hepatitis B virus (HBV) virological and serological indexes, clinical biochemical indexes, and blood routine tests were performed at the baseline and every 3 months during follow-up of initial interferon treatment. A functional cure was analyzed as a primary outcome. Results: A total of 304 patients treated with intermittent PEG-IFNα were included in the statistical analysis, including 215 men and 89 women, aged 37.97 ± 8.53 years, and 73 hepatitis B e antigen (HBeAg)-negative and 231 HBeAg positive patients. In total 59 patients (19.41%) achieved HBsAg disappearance through the initial, intermittent, and retreatment of PEG-IFNα treatment, of whom 43 patients (14.14%) achieved HBsAg seroconversion. Early HBsAg response to initial treatment was significantly associated with HBsAg response at 12 and 24 weeks of retreatment. After the intermission period, the incidence of HBsAg disappearance in patients with early HBsAg response in the retreatment period was 43.87%. The baseline HBsAg and 12-week HBsAg response in the retreatment period had higher predictive value than the initial treatment HBsAg response. Conclusion: The initial, intermittent, and retreatment mode of interferon can help to improve the HBsAg disappearance rate in CHB patients. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT04028856].

Baseline lymphocyte and cholinesterase levels may be the predictors of chronic herbal drug-induced liver injury.

Objective: To investigate the factors influencing the chronicity of drug-induced liver injury (DILI) caused by Chinese herbal medicine. Methods: Patients with DILI diagnosed by using the RUCAM score were enrolled retrospectively. The subjects were patients with DILI induced by taking Chinese herbal medicine and were followed up for 48 weeks. These patients were divided into a cure group and a chronic group. The biochemical indicators were monitored at baseline and every 3 months. Logistic regression was used to analyze the risk factors of DILI chronicity. The ROC (receiver operator characteristic) curve was used to analyze the diagnostic efficiency of each factor. Results: A total of 420 patients with DILI were enrolled; 122 of them were caused by Chinese herbal medicine, 70.5% (86/122) of them were female, chronic group 31.2% (39/122), and cure group 68.0% (83/122); cholinesterase (ChE) in the chronic group was lower than that in the cure group (5467.10 ± 2010.40 U/L vs. 6248.52 ± 1901.78 U/L, p = 0.04, t = 2.078). There was no significant difference in the age between cured patients and chronic patients (p = 0.156, Z = -1.417). There was no significant difference between the prognosis of different genders (p = 0.521, Z = -0.639). The logistic regression analysis showed that baseline lymphocyte (OR = 0.429, 95%CI = 0.205-0.898, p = 0.025) and cholinesterase (OR = 0.088, 95%CI = 0.008-0.994, p = 0.049) were independent risk factors of drug-induced chronicity. Conclusion: Baseline lymphocyte and cholinesterase may be the predictive factors for the chronicity of Chinese herbal medicine-induced liver injury.

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.

Effect of Antiviral Therapy During Pregnancy on Natural Killer Cells in Pregnant Women With Chronic HBV Infection.

Objective: To study the effect of antiviral therapy during pregnancy on the frequency of natural killer (NK) cells in peripheral blood of women with HBV DNA positive chronic hepatitis B (CHB). Method: In total 124 female subjects were divided into four groups: 11 healthy non-pregnant women (Normal group), 26 non-pregnant women in immune tolerance period of chronic hepatitis B virus (HBV) infection (CHB group), 41 pregnant CHB women without antiviral treatment during pregnancy (Untreated group), and 46 pregnant CHB women receiving antiviral treatment during pregnancy (Treated group). The frequency of NK cells in peripheral blood were detected by flow cytometry. Result: The frequency of NK cells in healthy women [15.30 (12.80, 18.40)] was higher than that in women with HBV infection, but there was no significant statistical difference (p=0.436). The frequency of NK cells in CHB group [10.60 (6.00, 18.30)] was higher than those in pregnant CHB women [Untreated: 6.90 (4.89, 10.04), P=0.001; Treated: 9.42 (6.55, 14.10), P=0.047]. The frequency of NK cells in treated group was significantly higher than that in untreated group (P = 0.019). The frequencies of NK cells, CD56bright NK cells and NKp46dim NK cells at 12 and 24 weeks postpartum in the untreated group were increased significantly than those before delivery. In treated group, the frequencies of NK cells, CD56bright NK cells, NKp46+ NK cells and NKp46dim NK cells were significantly increased at 6 and 12 weeks than those before delivery. The frequencies of NK cells and CD56bright NK cells postpartum were increased significantly in treated group than those in untreated group. The frequencies of CD56dim NK cells decreased significantly after delivery in treated than those in untreated patients. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) significantly increased after delivery than those before delivery. The results showed that the postpartum ALT level was weak positive correlated with NKp46high frequency (r=0.199) and was weak negative correlated with NKp46dim frequency (r= -0.199). Conclusion: Antiviral treatment during pregnancy could significantly increase the frequency of NK cells postpartum. Postpartum hepatitis may be related to the immune injury caused by change of NK cell frequency and HBV infection.

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 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.

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.