ABSTRACT
BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96. METHODS: In this multicentre randomized controlled clinical trial, 180 non-cirrhotic HBeAg-negative chronic hepatitis B patients on continuous NUC therapy for ≥ 2.5 years with HBV DNA levels < 60 IU/mL were randomized to discontinue NUC (n=90) or receive 48 weeks of PegIFN-α-2a treatment (n=90) and followed up till 96 weeks. The primary endpoint was the virological relapse rate until week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, P < 0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, P = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, P = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, P = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and achieves higher HBsAg loss rates than NUC treatment cessation alone in HBeAg-negative chronic hepatitis B patients. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimised scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96 in HBeAg-negative chronic hepatitis B patients. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, P < 0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, P= 0.03) than the NUC cessation group until week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.
ABSTRACT
B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4+ T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4+ T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA-/- ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.
Subject(s)
Acute-On-Chronic Liver Failure , Hepatitis B, Chronic , Animals , Humans , Mice , Acute-On-Chronic Liver Failure/complications , CD4-Positive T-Lymphocytes , Cytokines/metabolism , Hepatitis B, Chronic/complications , Phosphatidylinositol 3-Kinases , Receptors, Immunologic/metabolism , T-Cell ExhaustionABSTRACT
INTRODUCTION: The SARS-CoV-2 Omicron variant has decreased virulence and pathogenicity, yet the number of Omicron infections worldwide is unprecedentedly high, with rather high mortality and severe disease rate. Chronic kidney disease (CKD) patients are particularly vulnerable to the SARS-CoV-2 Omicron variant and have unique clinical outcomes. METHODS: We retrospectively collected data from 2140 hospitalized patients with SARS-CoV-2 Omicron variant infection from March 29, 2022, to May 17, 2022. Demographic characteristics, ancillary examination results, and clinical treatments were described. Occurrence of critical COVID-19 or death and time of positive-to-negative conversion was defined as primary outcomes. The presence of COVID-19 pneumonia and the usage of respiratory or circulatory support was defined as secondary outcomes. Univariate or multivariate logistic regression analyses were performed to identify risk factors for primary outcomes. RESULTS: 15.74% of CKD patients infected with the SARS-CoV-2 Omicron variant ended up with critical COVID-19 or death. Pre-existing CKD was a risk factor for critical COVID-19 or death and prolonged time of positive-to-negative conversion of SARS-CoV-2. Nirmatrelvir-ritonavir facilitated viral clearance among COVID-19 patients with non-severe CKD. CONCLUSION: We found patients with CKD and COVID-19 due to Omicron experienced worse clinical outcomes and prolonged time of positive-to-negative conversion of SARS-CoV-2 compared to patients without CKD, which helps rationalize limited medical resources and offers guidance for appropriate clinical treatments.
Subject(s)
COVID-19 , Renal Insufficiency, Chronic , Humans , SARS-CoV-2 , Retrospective Studies , Risk Factors , Hospitals , Renal Insufficiency, Chronic/complicationsABSTRACT
During March 2022 to January 2023, two Omicron waves hit Shanghai and caused a massive number of reinfections. To better understand the incidence and clinical characteristics of SARS-CoV-2 reinfection in Shanghai, China, we conducted a multicenter cohort study. COVID-19 patients first infected with BA.2 (March 1, 2022-May 23, 2022) who were quarantined in Huashan Hospital, Renji Hospital, and Shanghai Jing'an Central Hospital were followed up for reinfection from June 1, 2022 to January 31, 2023. Of 897 primary infections, 148 (16.5%) experienced reinfection. Incidence rate of reinfection was 0.66 cases per 1000 person-days. Female gender (adjusted odds ratio [aOR]= 2.19, 95% confidence interval [CI]: 1.29-3.83) was a risk factor for reinfection. The four most common symptoms of reinfections during the circulation of BA.5 sublineages were cough (62.59%), sore throat (54.42%), fatigue (48.98%), and fever (42.57%). Having received a booster vaccination was not associated with reduced severity of reinfection in comparison with not having received booster vaccination. After matched 1:1 by age and sex, we found that reinfections with BA.5 sublineages had significantly lower occurrence and severity of fever, fatigue, sore throat, and cough, as compared to primary infections with BA.5 sublineages. SARS-CoV-2 Omicron reinfections were less severe than Omicron primary infections during the circulation of the same subvariant. Protection offered by both vaccination and previous infection was poor against SARS-CoV-2 reinfection.
Subject(s)
COVID-19 , Pharyngitis , Female , Humans , China/epidemiology , Cohort Studies , Cough , COVID-19/epidemiology , Fatigue , Fever , Incidence , Pain , Reinfection/epidemiology , SARS-CoV-2 , MaleABSTRACT
Objectives: The rapidly evolving organ failure and high short-run mortality of acute-on-chronic liver failure (ACLF) are inseparable from the role of systemic inflammatory response. S100A8 and S100A9 are associated with the excessive cytokine storm and play a decisive part within the process of inflammation. We aimed to clarify the role of them in predicting prognosis of hepatitis B virus-related ACLF (HBV-ACLF). Methods: S100A8 and S100A9 levels were analyzed in plasma of 187 transplant-free HBV-ACLF patients, 28 healthy controls and 40 chronic hepatitis B (CHB) patients. S100A8 and S100A9 mRNAs were checked in liver samples from 32 HBV-ACLF patients with liver transplantation, 19 patients undergoing surgery for hepatic hemangioma and 10 CHB patients with needle biopsy. Results: The plasma levels of the S100A8 and S100A9 were higher in HBV-ACLF patients than in CHB patients (S100A8 : P < 0.001 and S100A9 : P < 0.001) and healthy controls (S100A8 : P < 0.001 and S100A9 : P < 0.001), and similar results were obtained for mRNA expression. Moreover, both proteins were related to ACLF grade, different types of organ failure, and infection, and they correlated with other prognostic scoring systems. S100A8 and S100A9 can dependently predict 28/90-day mortality (28-day: S100A8: hazard ratio (HR): 1.027; 95% confidence interval (CI): 1.007-1.048; P=0.026, S100A9 : HR: 1.009; 95% CI: 1.001-1.017; P=0.007, 90-day: S100A8 : HR: 1.023; 95% CI: 1.011-1.035; P=0.004, S100A9 : HR: 1.008; 95% CI: 1.004-1.012; and P < 0.001). Among all of the scoring systems, the combined scoring model (S100A8 and S100A9 jointly with the Chronic Liver Failure-Consortium Organ Failure score (CLIF-C OFs)) displayed the highest area under the receiver operating curve (0.923 (95% CI, 0.887-0.961)) in the prediction of 90-day mortality. Conclusions: S100A8 and S100A9 are promising biomarkers for the analysis of risk stratification and prognosis in ACLF patients. In addition, combining them with the CLIF-C OFs may better predict the prognosis of ACLF.
Subject(s)
Acute-On-Chronic Liver Failure , Hepatitis B, Chronic , Humans , Acute-On-Chronic Liver Failure/virology , Biomarkers , Hepatitis B virus/genetics , Hepatitis B, Chronic/complications , Organ Dysfunction Scores , Prognosis , Retrospective Studies , ROC CurveABSTRACT
A proportion of chronic hepatitis B virus (HBV) carriers with normal alanine transaminase (ALT) present with significant liver histological changes (SLHC). To construct a noninvasive nomogram model to identify SLHC in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. The training cohort consisted of 732 chronic HBV carriers who were stratified into four sets according to different ULNs for ALT: chronic HBV carriers I, II, III, and IV. The external validation cohort comprised 277 chronic HBV carriers. Logistic regression and least absolute shrinkage and selection operator analyses were applied to develop a nomogram model to predict SLHC. A nomogram model-HBGP (based on hepatitis B surface antigen, gamma-glutamyl transpeptidase, and platelet count) demonstrated good performance in diagnosing SLHC with area under the curve (AUCs) of 0.866 (95% confidence interval [CI]: 0.839-0.892) and 0.885 (95% CI: 0.845-0.925) in the training and validation cohorts, respectively. Furthermore, HBGP displayed high diagnostic values for SLHC with AUCs of 0.866 (95% CI: 0.839-0.892), 0.868 (95% CI: 0.838-0.898), 0.865 (95% CI: 0.828-0.901), and 0.853 (95% CI: 0.798-0.908) in chronic HBV carriers I, II, III, and IV, respectively. Additionally, HBGP showed greater ability in predicting SLHC compared with the existing predictors. HBGP has shown high predictive performance for SLHC, and thus may lead to an informed decision on the initiation of antiviral treatment.
Subject(s)
Hepatitis B, Chronic , Humans , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/pathology , Nomograms , Hepatitis B virus/genetics , Liver Cirrhosis/diagnosis , Alanine Transaminase , DNA, Viral , Hepatitis B e AntigensABSTRACT
Background and Aims: To determine whether liver stiffness measurement (LSM) indicates liver inflammation in chronic hepatitis B (CHB) with different upper limits of normal (ULNs) for alanine aminotransferase (ALT). Methods: We grouped 439 CHB patients using different ULNs for ALT: cohort I, ≤40 U/L (439 subjects); cohort II, ≤35/25 U/L (males/females; 330 subjects); and cohort III, ≤30/19 U/L (males/females; 231 subjects). Furthermore, 84 and 96 CHB patients with normal ALT (≤40 U/L) formed the external and prospective validation groups, respectively. We evaluated the correlation between LSM and biopsy-confirmed liver inflammation, and determined diagnostic accuracy using area under the curve (AUC). A noninvasive LSM-based model was developed using multivariate logistic regression. Results: Fibrosis-adjusted LSM values significantly increased with increasing inflammation. The AUCs of LSM in cohorts I, II, and III were 0.799, 0.796, and 0.814, respectively, for significant inflammation (A≥2) and 0.779, 0.767, and 0.770, respectively, for severe inflammation (A=3). Cutoff LSM values in all cohorts for A≥2 and A=3 were 6.3 and 7.5 kPa, respectively. Internal, external, and prospective validations showed high diagnostic accuracy of LSM for A≥2 and A=3, and no significant differences in AUCs among the four groups. LSM and globulin independently predicted A≥2. The AUC of an LSM-globulin model for A≥2 exceeded those of globulin, ALT, and AST, but was similar to that of LSM. Conclusions: LSM predicted liver inflammation and guided the indication of antiviral therapy for CHB in patients with normal ALT.
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Purpose: The study aims to evaluate the effectiveness of a tenofovir alafenamide fumarate (TAF) and pegylated interferon alfa (PegIFN-α) regimen compared to a tenofovir disoproxil fumarate (TDF) and PegIFN-α therapy in patients with chronic hepatitis B (CHB). Patients and Methods: Patients who were treated with PegIFN-α in combination with TAF or TDF were retrospectively enrolled. The primary outcome measured was the HBsAg loss rate. The rates of virological response, serological response for HBeAg, and normalization of alanine aminotransferase (ALT) were also calculated. The cumulative incidences of response rates were compared between the two groups using Kaplan-Meier analysis. Results: A total of 114 patients were retrospectively enrolled in the study, with 33 receiving TAF plus PegIFN-α treatment and 81 receiving TDF plus PegIFN-α treatment. The HBsAg loss rate for the TAF plus PegIFN-α group was 15.2% at 24 weeks and 21.2% at 48 weeks, while the TDF plus PegIFN-α group had rates of 7.4% at 24 weeks and 12.3% at 48 weeks (P=0.204 at 24 weeks, P=0.228 at 48 weeks). In subgroup analysis of HBeAg positive patients, the TAF group had a higher HBsAg loss rate of 25% at week 48, compared to 3.8% in the TDF group (P=0.033). According to Kaplan-Meier analysis, the TAF plus PegIFN-α group achieved virological response more quickly than the TDF plus PegIFN-α group (p=0.013). There was no statistical difference in HBeAg serological rate or ALT normalization rate. Conclusion: There was no significant difference in the HBsAg loss between the two groups. However, subgroup analysis revealed that TAF plus PegIFN-α treatment had a higher HBsAg loss rate than TDF plus PegIFN-α treatment in HBeAg-positive patients. Additionally, TAF plus PegIFN-α treatment demonstrated better virological suppression for CHB patients. Therefore, TAF plus PegIFN-α treatment regimen is recommended for CHB patients who aim to achieve functional cure.
ABSTRACT
Hepatitis B virus (HBV) DNA is much higher during HBeAg-positive chronic HBV infection (EP-CBI) than during HBeAg-negative chronic HBV infection (EN-CBI), although the necroinflammation in liver is minimal and the adaptive immune response is similar in both phases. We previously reported that mRNA levels of EVA1A were higher in EN-CBI patients. In this study, we aimed to investigate whether EVA1A inhibits HBV gene expression and examine the underlying mechanisms. The available cell models for HBV replication and model HBV mice were used to investigate how EVA1A regulates HBV replication and the antiviral activity based on gene therapy. The signaling pathway was determined through RNA sequencing analysis. The results demonstrated that EVA1A can inhibit HBV gene expression in vitro and in vivo. In particular, EVA1A overexpression resulted in accelerated HBV RNA degradation and activation of the PI3K-Akt-mTOR pathway, two processes that directly and indirectly inhibiting HBV gene expression. EVA1A is a promising candidate for treating chronic hepatitis B (CHB). In conclusion, EVA1A is a new host restriction factor that regulates the HBV life cycle via a nonimmune process.
Subject(s)
Hepatitis B virus , Hepatitis B, Chronic , Mice , Animals , Hepatitis B virus/genetics , Hepatitis B e Antigens/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Virus ReplicationABSTRACT
BACKGROUND AND AIMS: Persistent inflammatory response and immune activation are the core mechanisms underlying acute-on-chronic liver failure (ACLF). Previous studies have shown that deficiency of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA) exacerbates the progression of inflammatory diseases. We aimed to clarify the role of VISTA in the pathogenesis of ACLF. METHODS: Blood and liver samples were collected from healthy subjects, stable cirrhosis, and ACLF patients to characterize VISTA expression and function. An ACLF mouse model was used to ascertain potential benefits of anti-VISTA monoclonal antibody (mAb) treatment. RESULTS: VISTA expression was significantly reduced in the naïve and central memory CD4+ T cells from patients with ACLF. The expression of VISTA on CD4+ T cells was associated with disease severity and prognosis. VISTA downregulation contributed to the activation and proliferation of CD4+ T cells and enhanced the differentiation of T helper 17 cells (Th17) and secretion of inflammatory cytokines through the activated Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathway. Moreover, agonistic anti-VISTA mAb treatment inhibited the activation and cytokine production of CD4+ T cells and reduced mortality and liver inflammation of the ACLF mice. CONCLUSIONS: The decreased expression of VISTA may facilitate development of Th17 cells and promote the progression of inflammation in ACLF patients. These findings are helpful for elucidating the pathogenesis of ACLF and for the identification of new drug targets.
Subject(s)
Acute-On-Chronic Liver Failure , Animals , Mice , Th17 Cells/metabolism , Inflammation/metabolism , Cytokines , Cell DifferentiationABSTRACT
Background: Hepatitis B surface antigen (HBsAg) loss, namely, the functional cure, can be achieved through the pegylated interferon (PEG-IFN)-based therapy. However, it is an unignorable fact that a small proportion of patients who achieved functional cure develop HBsAg reversion (HRV) and the related factors are not well described. Methods: A total of 112 patients who achieved PEG-IFN-induced HBsAg loss were recruited. HBV biomarkers and biochemical parameters were examined dynamically. HBV RNA levels were assessed in the cross-sectional analysis. The primary endpoint was HRV, defined as the reappearance of HBsAg after PEG-IFN discontinuation. Results: HRV occurred in 17 patients during the follow-up period. Univariable analysis indicated that hepatitis B e antigen (HBeAg) status, different levels of hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) at the end of PEG-IFN treatment (EOT) were significantly associated with the incidence of HRV through using the log-rank test. Additionally, time-dependent receiver operating characteristic (ROC) analysis showed that the anti-HBs was superior to anti-HBc in predictive power for the incidence of HRV during the follow-up period. Multivariable Cox proportional hazard analysis found that anti-HBs ≥1.3 log10IU/L (hazard ratio (HR), 0.148; 95% confidence interval (CI), 0.044-0.502) and HBeAg negativity (HR, 0.183; 95% CI, 0.052-0.639) at EOT were independently associated with lower incidence of HRV. Cross-sectional analysis indicated that the HBV RNA levels were significantly correlated with the HBsAg levels in patients with HRV (r=0.86, p=0.003). Conclusions: EOT HBeAg negativity and anti-HBs ≥1.3 log10IU/L identify the low risk of HRV after PEG-IFN discontinuation.
Subject(s)
Hepatitis B Surface Antigens , Hepatitis B, Chronic , Humans , Hepatitis B e Antigens/therapeutic use , Interferon-alpha/therapeutic use , Antiviral Agents/therapeutic use , Cross-Sectional Studies , Hepatitis B, Chronic/drug therapy , Treatment Outcome , Polyethylene Glycols/therapeutic use , Hepatitis B Antibodies/therapeutic use , DNA, Viral , Recombinant Proteins/therapeutic use , Hepatitis B virus/geneticsABSTRACT
Prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has received much attention since it is associated with mortality and is hypothesized as the cause of long COVID-19 and the emergence of a new variant of concerns. However, a prediction model for the accurate prediction of prolonged infection is still lacking. A total of 2938 confirmed patients with COVID-19 diagnosed by positive reverse transcriptase-polymerase chain reaction tests were recruited retrospectively. This study cohort was divided into a training set (70% of study patients; n = 2058) and a validation set (30% of study patients; n = 880). Univariate and multivariate logistic regression analyses were utilized to identify predictors for prolonged infection. Model 1 included only preadmission variables, whereas Model 2 also included after-admission variables. Nomograms based on variables of Model 1 and Model 2 were built for clinical use. The efficiency of nomograms was evaluated by using the area under the curve, calibration curves, and concordance indexes (C-index). Independent predictors of prolonged infection included in Model 1 were: age ≥75 years, chronic kidney disease, chronic lung disease, partially or fully vaccinated, and booster. Additional independent predictors in Model 2 were: treated with nirmatrelvir/ritonavir more than 5 days after diagnosis and glucocorticoid. The inclusion of after-admission variables in the model slightly improved the discriminatory power (C-index in the training cohort: 0.721 for Model 1 and 0.737 for Model 2; in the validation cohort: 0.699 for Model 1 and 0.719 for Model 2). In our study, we developed and validated predictive models based on readily available variables of preadmission and after-admission for predicting prolonged SARS-CoV-2 infection of patients with COVID-19.
Subject(s)
COVID-19 , Humans , Aged , Nomograms , SARS-CoV-2 , Retrospective Studies , Post-Acute COVID-19 SyndromeABSTRACT
BACKGROUND: Low-level viremia is usually defined as a detectable but lower than 2000 IU/mL hepatitis B virus DNA level after 12 months or longer duration of antiviral therapy in chronic hepatitis B patients. In this study, we aimed to clarify the factors associated with lowlevel viremia in patients during long-term monotherapy with tenofovir disoproxil fumarate or entecavir. METHODS: Chronic hepatitis B patients having received entecavir or tenofovir disoproxil fumarate treatment for 12 months or more were enrolled from October 2019 to October 2021 at a tertiary hospital in Shanghai, China. In accordance with their hepatitis B virus DNA levels, chronic hepatitis B patients were grouped into 3 categories, hepatitis B virus DNA > 2000 IU/mL, low-level viremia, and complete virological response (hepatitis B virus DNA < 10 IU/mL). Compared with complete virological response patients, factors related to lowlevel viremia were evaluated. RESULTS: This study enrolled a total of 160 chronic hepatitis B patients, whose duration of treatment ranged from 12 to 144 months. In total, 107 patients achieved complete virological response, 51 showed low-level viremia, and 2 showed hepatitis B virus DNA > 2000 IU/mL. After multivariate logistic regression analysis, hepatitis e antigen-positivity (odds ratio = 6.479, 95% CI: 2.480-16.922, P = .000), entecavir treatment (odds ratio = 4.742, 95% CI: 1.855-12.118, P = .001), and duration of therapy (odds ratio = 0.168, 95% CI: 0.072-0.388, P = .000) were independently associated with low-level viremia. CONCLUSION: Having received long-term antiviral treatment, low-level viremia still occurred in 31.9% of patients. Longer duration of therapy was a protective factor, and HBeAg-positivity and entecavir treatment were risk factors for low-level viremia.
Subject(s)
Hepatitis B, Chronic , Humans , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/complications , Prevalence , Viremia/drug therapy , Viremia/epidemiology , Treatment Outcome , China/epidemiology , Tenofovir/therapeutic use , Antiviral Agents/therapeutic use , Hepatitis B e Antigens/therapeutic use , Hepatitis B virus/genetics , DNA, ViralABSTRACT
MicroRNA-124 (miR-124) is related to liver injury due to chronic hepatitis B (CHB) and hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). However, the mechanism whereby miR-124 regulates liver inflammation remains unknown. In this study, we show that serum miR-124 serves as a compensatory predictive factor for organ failure and the 28-day prognosis of patients with HBV-ACLF. Moreover, within a mouse model of concanavalin A-induced acute liver injury, miR-124 is highly expressed in Kupffer cells. Overexpression of miR-124 significantly decreases interleukin-6 (IL-6) secretion, and relieves pathological liver necrosis to a great extent. Mechanistically, miR-124 directly targets the 3'-untranslated region of signal transducer and activator of transcription 3 (STAT3) and inhibits IL-6/STAT3 signaling, which reduces pro-inflammatory Kupffer cell polarization. Collectively, our findings suggest that miR-124 can potentially serve as a predictive biomarker for HBV-ACLF prognosis and may represent a promising therapeutic target for relieving severe liver injury resulting from cytokine storms.
Subject(s)
Hepatitis B, Chronic , MicroRNAs , Animals , Mice , Kupffer Cells/metabolism , Kupffer Cells/pathology , Interleukin-6/metabolism , STAT3 Transcription Factor/metabolism , Liver/pathology , Hepatitis B virus/metabolismABSTRACT
BACKGROUND AND AIMS: Myeloid-derived suppressor cells (MDSCs) and CD4+ regulatory T cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity. However, the relationship between antiviral effect and the frequencies of those immune suppressive cells after pegylated interferon α-2a (PegIFNα-2a) therapy is not clearly understood. This study aimed to investigate the contribution of monocytic MDSCs (mMDSCs) and CD4+ Tregs to functional cure (HBsAg seroclearance) after PegIFNα-2a therapy and evaluate the effect of PegIFNα-2a therapy on these cells. METHODS: Flow cytometry analysis was performed along with longitudinal immune monitoring of 97 hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) patients receiving PegIFNα-2a weekly for 48 weeks. RESULTS: The frequencies of mMDSCs and CD4+ Tregs increased in all HBV patients, and they were higher in the HBsAg persistence group than in the HBsAg seroclearance group. A significant decline in the frequency of mMDSCs was found in patients who realized functional cure after PegIFNα-2a treatment. In contrast, the frequency of CD4+ Tregs in both the HBsAg seroclearance and persistence groups significantly increased. Multivariate analyses indicated that the baseline serum HBsAg levels (p < .001) and mMDSCs frequency (p = .027) were independently associated with the HBsAg clearance, and the combined marker (HBsAg plus mMDSCs) displayed the highest specificity (93.1%) than any other markers in predicting HBsAg seroclearance. CONCLUSIONS: These results suggest that a poor response to PegIFNα-2a treatment in CHB patients may be related to the frequencies of immune suppressive cells, while the therapeutic targeting of these cells might be effective in boosting anti-HBV immunity.
Subject(s)
Hepatitis B, Chronic , Myeloid-Derived Suppressor Cells , Humans , Hepatitis B Surface Antigens , Antiviral Agents , Hepatitis B e Antigens , Polyethylene Glycols/therapeutic use , Recombinant Proteins/therapeutic use , Hepatitis B virus/genetics , DNA, ViralABSTRACT
CD7 and CD57 are related to the differentiation and functional stages of CD8+ T cells. However, the role of their combined presence in CD8+ T cells in patients with chronic hepatitis B virus (HBV) infection, especially those with end-stage liver disease, remains unclear. Blood samples from healthy volunteers and patients with chronic hepatitis B were analyzed via Luminex assay and ELISA to measure plasma cytokine levels. Further, recombinant IL-22 was used to stimulate peripheral blood mononuclear cells from healthy volunteers, and the frequency of CD3+ CD4- CD7+ CD57- T cells and apoptosis rates were investigated via flow cytometry. Patients with end-stage liver disease, particularly those with acute to chronic liver failure, showed decreased CD3+ CD4- CD7+ CD57- T cell frequency. Furthermore, the prevalence of CD3+ CD4- CD7+ CD57- T cells was negatively correlated with disease severity, prognosis, and complications (ascites). We also observed that IL-22 promoted apoptosis and brought about a decrease in the number of CD3+ CD4- CD7+ CD57- T cells in a dose-dependent manner. CD3+ CD4- CD7+ CD57- T cells displayed a B and T lymphocyte attenuator (BTLA)high CD25high CD127high immunosuppressive phenotype and showed low interferon-γ, tumor necrosis factor-α, granzyme A, and perforin expression levels. The present findings will elucidate the pathogenesis of HBV-related end-stage liver disease and aid the identification of novel drug targets.
Subject(s)
End Stage Liver Disease , Hepatitis B, Chronic , Humans , Hepatitis B virus , Hepatitis B, Chronic/complications , CD8-Positive T-Lymphocytes , Leukocytes, Mononuclear , T-Lymphocyte Subsets , Disease ProgressionABSTRACT
Background: Nucleotide analogues (NTs) monotherapy may have a more significant effect on reducing hepatitis B surface antigen (HBsAg) than nucleoside analogues (NSs) due to their immunomodulatory function. However, this superiority remains unknown when combined with PEGylated interferon α (PegIFNα). Therefore, this study aimed to explore whether NTs have more significant antiviral effects than NSs in combination therapy with PegIFNα. Methods: Chronic hepatitis B (CHB) patients treated with PegIFNα plus nucleos(t)ide analogues (NAs) were retrospectively recruited. Efficacy and the predictors of hepatitis B surface antigen (HBsAg) reduction >1 log10 IU/mL after 48 weeks were analyzed. Results: A total of 95 patients were included and divided into the PegIFNα + NTs group and the PegIFNα + NSs group. Propensity score matching (PSM) was performed. The PegIFNα + NTs group had a greater reduction of HBsAg (-3.52 vs. -2.33 log10 IU/mL, P=0.032) and a higher proportion of patients with HBsAg reduction >1 log10 IU/mL (100.0% vs. 72.2%, P=0.003) even after PSM. However, HBsAg and hepatitis B e-antigen (HBeAg) loss rates, HBeAg seroconversion rates, degree of HBeAg and hepatitis B virus (HBV) DNA decline, HBV DNA undetectable rates, and alanine aminotransferase (ALT) normalization rates showed no significant differences. Subgroup analyses showed the difference in the reduction of HBsAg was particularly evident in HBeAg-positive and the "add-on" subgroups. PegIFNα plus NTs (OR = 36.667, 95% CI = 3.837-350.384) was an independent predictor for HBsAg reduction >1 log10 IU/mL after 48 weeks. Conclusion: This study suggests that PegIFNα plus NTs may lead to more HBsAg reduction, especially in HBeAg-positive and "add-on" patients.
Subject(s)
Hepatitis B Surface Antigens , Hepatitis B, Chronic , Humans , Hepatitis B e Antigens , Nucleosides/therapeutic use , Nucleotides/therapeutic use , Retrospective Studies , Propensity Score , Polyethylene Glycols/therapeutic use , Treatment Outcome , Interferon-alpha/therapeutic use , Antiviral Agents/therapeutic use , Hepatitis B virus/genetics , DNA, ViralABSTRACT
HBx plays a significant role in the cccDNA epigenetic modification regulating the hepatitis B virus (HBV) life cycle and in hepatocyte proliferation and carcinogenesis. By using the sleeping-beauty transposon system, we constructed a tetracycline-induced HBx-expressing stable cell line, SBHX21. HBx with a HiBiT tag can be quickly detected utilizing a NanoLuc-based HiBiT detection system. By screening a drug library using SBHX21 cells, we identified estradiol benzoate as a novel anti-HBx agent. Estradiol benzoate also markedly reduced the production of HBeAg, HBsAg, HBV pgRNA, and HBV DNA in a dose-dependent manner, suggesting that estradiol benzoate could be an anti-HBV agent. Docking model results revealed that estradiol benzoate binds to HBx at TRP87 and TRP107. Collectively, our results suggest that estradiol benzoate inhibits the HBx protein and HBV transcription and replication, which may serve as a novel anti-HBV molecular compound for investigating new treatment strategies for HBV infection.
Subject(s)
Hepatitis B virus , Trans-Activators , Estradiol/analogs & derivatives , Hep G2 Cells , Hepatitis B virus/metabolism , Humans , Luciferases , Trans-Activators/genetics , Trans-Activators/metabolism , Viral Regulatory and Accessory Proteins/metabolism , Virus ReplicationABSTRACT
Background and Aims: Aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) are widely used to assess liver fibrosis in chronic hepatitis B virus (HBV) infection. Currently, the definition of normal alanine aminotransferase (ALT) is controversial. We aimed to examine the diagnostic value of APRI and FIB-4 in chronic HBV carriers with different upper limits of normal (ULNs) for ALT. Methods: 581 chronic HBV carriers were divided into the following four groups based on different ULNs for ALT: chronic HBV carriers I, II, III, and IV. Furthermore, 106 chronic HBV carriers formed an external validation group. Predictive values of APRI and FIB-4 were elucidated using the area under the curve (AUC). A liver fibrosis-predictive model-GPSA (named for its measure of gamma glutamyl transpeptidase, platelet count, HBsAg and albumin) was developed using multivariate logistic regression analysis. Results: In chronic HBV carriers I, the AUCs of APRI and FIB-4 were 0.680 and 0.609 for significant fibrosis and 0.678 and 0.661 for cirrhosis, respectively. The AUCs of GPSA for significant fibrosis in the training group, internal group, and external validation group were 0.877, 0.837, and 0.871, respectively. The diagnostic value of GPSA differed among chronic HBV carriers I, II, III, and IV, with AUCs for significant fibrosis being 0.857, 0.853, 0.868, and 0.905 and AUCs for cirrhosis being 0.901, 0.905, 0.886, and 0.913, respectively. GPSA showed a higher diagnostic value than APRI and FIB-4 for predicting significant fibrosis in the four groups. Conclusions: The GPSA model allows for accurate diagnosis of liver fibrosis in chronic HBV carriers with different ULN for ALT.