Recurrent hyperkalemia in patients with chronic kidney disease and hepatitis C treated with direct antiviral agents.

BACKGROUND: Sofosbuvir is the keystone of direct antiviral agents for the chronic hepatitis C (CHC). The safety of sofosbuvir in patients with stage 4-5 chronic kidney disease (CKD) needs further observation in real world. CASE PRESENTATION: Thirty-three patients with stage 5 CKD and hepatitis C virus (HCV) infection from 2 hemodialysis centers accepted sofosbuvir based treatment as we reported previously. Serum potassium concentrations were tested every 4 weeks or on demand. Ten of 33 patients showed recurrence of hyperkalemia. We summarized the characteristics of hyperkalemia occurrence in these 10 patients. Overall, 24 episodes of hyperkalemia were observed in these 10 patients, 21 were under treatment and 3 were after treatment. Patients with or without hyperkalemia before sofosbuvir treatment didn't show significantly differences in the median frequencies of hyperkalemia episodes during the observation period (3.5 vs. 2, p = 0.264). CONCLUSIONS: Patients with stage 5 CKD and HCV infection treated with sofosbuvir based regimens, even halved sofosbuvir, should be taken caution and closely monitoring serum potassium and renal function is necessary.

SVR Rates of HCV-infected population under PEG-IFN-α/R treatment in Northwest China.

BACKGROUND: Chronic HCV Patients taking PEG-IFN-α/R from different ethnic groups have different probabilities of reaching a sustained viral response (SVR). There are many influence factors, such as HCV genotype, IL-28B single-nucleotide polymorphisms (SNP), Fibrosis 4 index (FIB-4), and aspartate aminotransferase-to-platelet ratio index (APRI) score. But the baseline factors in relation to treatment outcome was still not much clear. METHODS: We evaluated data from 231 chronic HCV patients with or without liver fibrosis and their antiviral efficacy after treatment with pegylated interferon plus ribavirin (PEG-IFN-α/R) for 24-48 weeks. IL-28B SNP and HCV genotypes were analyzed with genome sequencing using pyrosequencing. RESULTS: Sustained viral response (SVR) rates of patients with HCV 1b and 2a genotypes were 52.25% (58/111) and 75.28% (67/89) (P < 0.01). SVR rates of patients with IL-28B rs8099917 TT, rs12979860 CC and rs12980275 AA were 92.41% (25/27), 92.86% (26/28) and 88.89% (24/27) separately. We found that SVR rates in HCV 1b and 2a patients were only 31.0 and 39.4% if their FIB-4 > 3.25. In addition, when their APRI > 2, only 30.3% of HCV 1b patients and 50.2% of HCV 2a patients could obtain SVR. CONCLUSIONS: There were high proportion of HCV genotype 1b and 2a in Northwest China. In both HCV 1b and 2a genotypes, patients with protective-genotype of IL-28B were more likely to obtain SVR. However, those with significant fibrosis or cirrhosis were less likely, no matter their genotype. Combined factors of HCV genotype, IL-28B genotype, FIB-4 and ARPI may indicate high prediction and clinical value regarding treatment with PEG-IFN-α/R and prognostic evaluation of chronic hepatitis C patients.

Role and regulation of autophagy and apoptosis by nitric oxide in hepatic stellate cells during acute liver failure.

BACKGROUND & AIMS: We previously found that hepatic stellate cell activation induced by autophagy maintains the liver architecture to prevent collapse during acute liver failure. Nitric oxide has shown to induce hepatic stellate cell apoptosis. Whether and how nitric oxide is involved in acute liver failure and autophagy remains unclear. METHODS: Acute liver failure patients were recruited to investigate the correlation between plasma nitric oxide levels and clinical features. Liver tissues were collected from chronic hepatitis patients by biopsy and from acute liver failure patients who had undergone liver transplantation. The expression of nitric oxide synthases and hepatic stellate cell activation (alpha-SMA), and autophagic activity (LC3) were investigated by immunohistochemistry. Autophagy and apoptosis were investigated by immunoblot analysis, confocal microscopy, and flow cytometry in hepatic stellate cells treated with nitric oxide donors. RESULTS: Plasma nitric oxide level was significantly increased in patients with acute liver failure compared to those with cirrhosis (53.60±19.74 µM vs 19.40±9.03 µM, Z=-7.384, P<.001) and positively correlated with MELD-Na score (r=.539, P<.001), implicating nitric oxide in acute liver failure. At least some Nitric oxide was produced by overexpression of inducible nitric oxide synthases and endothelial nitric oxide synthases, but not neuronal nitric oxide synthases in the liver tissue. In vivo observation revealed that autophagy was inhibited in hepatic stellate cells based on decreased LC3 immunostaining, and in vitro experiments demonstrated that Nitric oxide can inhibit autophagy. Moreover, nitric oxide promoted hepatic stellate cell apoptosis, which was rescued by an autophagy inducer. CONCLUSIONS: Increased nitric oxide synthases/ nitric oxide promotes apoptosis through autophagy inhibition in hepatic stellate cells during acute liver failure, providing a novel strategy for the treatment of patients with acute liver failure.

Role of A20 in interferon-α-mediated functional restoration of myeloid dendritic cells in patients with chronic hepatitis C.

Hepatitis C virus (HCV) infection is a global health problem characterized by a high rate of chronic infection, which may in part be due to a defect in myeloid dendritic cells (mDCs). This defect appears to be remedied by treatment with interferon-α (IFN-α) -based antiviral therapies; however, the molecular mechanisms underlying mDC dysfunction in HCV infection and restoration by IFN-α treatment are unclear. The ubiquitin-editing protein A20 plays a crucial role in controlling the maturation, cytokine production and immunostimulatory function of mDCs. We propose that the expression of A20 correlates with the function of mDCs during HCV infection and IFN-α therapy. In this study, we observed that A20 expression in mDCs isolated from chronically HCV-infected subjects was significantly higher than healthy subjects or subjects achieving sustained virological responses (SVR) following antiviral treatment. Notably, A20 expression in mDCs from HCV patients during IFN-α treatment was significantly lower than for untreated patients, SVR patients, or healthy subjects. Besides, A20 expression in mDCs stimulated by polyI:C differed between HCV patients and healthy subjects, and this difference could be abrogated by the treatment with IFN-α in vitro. Additionally, A20 expression by polyI:C-activated mDCs, with or without IFN-α treatment, negatively correlated with the expression of HLA-DR, CD86 and CCR7, and the secretion of interleukin-12 (IL-12), but positively associated with the production of IL-10. Importantly, silencing A20 expression using small interfering RNAs increased the production of IL-12 in mDCs of chronically HCV-infected individuals. These findings suggest that A20 plays a crucial role in negative regulation of innate immune responses during chronic viral infection.

Hantaan virus infection induces CXCL10 expression through TLR3, RIG-I, and MDA-5 pathways correlated with the disease severity.

Hantaan virus (HTNV) is a major agent causing hemorrhagic fever with renal syndrome (HFRS). Although the pathogenesis of HFRS is unclear, some reports have suggested that the abundant production of proinflammatory cytokines and uncontrolled inflammatory responses may contribute to the development of HFRS. CXCL10 is one of these cytokines and is found to be involved in the pathogenesis of many virus infectious diseases. However, the role of CXCL10 in the pathogenesis of HFRS and the molecular regulation mechanism of CXCL10 in HTNV infection remain unknown. In this study, we report that CXCL10 expresses highly in the HFRS patients' sera and the elevated CXCL10 is positively correlated with the severity of HFRS. We find that HTNV, a single-strand RNA virus, can act as a double-strand RNA to activate the TLR3, RIG-I, and MDA-5 signaling pathways. Through the downstream transcription factors of these pathways, NF-κB and IRF7, which bind directly to the CXCL10's promoter, the expression of CXCL10 is increased. Our results may help to better understand the role of CXCL10 in the development of HFRS and may provide some novel insights into the immune response of HTNV infection.

Hantaan virus RNA load in patients having hemorrhagic fever with renal syndrome: correlation with disease severity.

To investigate the role of viral load in the pathogenesis of hemorrhagic fever with renal syndrome, the Hantaan virus RNA load in plasma from 101 patients was quantified, and the relationships between viral load and disease course, severity, and level of specific humoral immunity were analyzed. The viral load, detectable in 79 patients, ranged from 3.43 to 7.33 log10 copies/mL of plasma. In the early stage of disease, patients in severe/critical group were found to have higher viral loads than those in the mild/moderate group (5.90 vs 5.03 log10 copies/mL; P = .001), suggesting an association between Hantaan virus load and disease severity.

Clinical and virological features of asymptomatic and mild symptomatic patients with SARS-CoV-2 Omicron infection at Shanghai Fangcang shelter hospital.

OBJECTIVE: The objective of this study is to evaluate and compare clinical and virological characteristics of asymptomatic and mild symptomatic patients of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.2.2 variant infection and identify risk factors associated with the prolonged viral negative conversion duration. METHODS: We conducted a retrospective observational study in a Shanghai (China) Fangcang shelter hospital from April 9 to May 17, 2022. The patient-related demographic or clinical data were retrospectively recorded. Comparisons of demographic and clinical characteristics between asymptomatic and mild-symptomatic patients were performed. Cox regression was performed to identify the risk factors of prolonged viral negative conversion duration. RESULTS: A total of 551 patients confirmed with SARS-CoV-2 Omicron variant infection were enrolled in the study. Of these, 297 patients (53.9%) were asymptomatic and 254 patients (46.1%) had mild symptoms. When comparing the clinical and virological characteristics between the asymptomatic and mild symptomatic groups, several clinical parameters, including age, gender, time to viral clearance from the first positive swab, chronic comorbidities, and vaccination dose did not show statistically significant differences. In mild symptomatic patients, the median viral negative conversion duration (NCD) was 7 days (interquartile range [IQR]: 5-9), which was comparable to the median of 7 days (IQR: 5-10) in asymptomatic patients (p = .943). Multivariate Cox analysis revealed that patients age ≥ 60 years had a significantly higher hazard ratio (HR) for prolonged viral NCD (HR: 1.313; 95% confidence interval: 1.014-1.701, p = .039). CONCLUSION: Asymptomatic and symptomatic patients with non-severe SARS-CoV-2 Omicron BA.2.2 variant infection have similar clinical features and virological courses. Old age was an independent risk factor for prolonged SARS-CoV-2 conversion time.

Dysregulation of the ß3 integrin-VEGFR2 complex in Hantaan virus-directed hyperpermeability upon treatment with VEGF.

Hantaviruses infect human endothelial cells (ECs) and are known to cause vascular-permeability-based diseases, including hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The αvß3 integrins, which are highly expressed on the surface of ECs, serve as hantavirus receptors. Specifically, the ß3 integrin and vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) form a functional complex and interact with each other. Signaling through this complex causes cytoskeletal reorganization, which is one of the most important mechanisms underlying hyperpermeability. In this study, we show that VEGF dramatically enhances Hantaan virus (HTNV)-directed permeability and increases the reorganization of the cytoskeleton and the disruption of junctional organizations in an EC monolayer at 3 days postinfection. HTNV infection reduced the effect of VEGF on adhesion, migration, and the upregulation of ß3 expression, but the infection alone upregulated the expression of ß3 and VEGFR2. These results indicate that in addition to its role in blocking ß3 integrin activation as reported previously, HTNV blocks the function of the complex of VEGFR2 and ß3 integrin, and the dysfunction of the complex may contribute to cytoskeletal reorganization in an HTNV-directed hyperpermeability response to VEGF.

Sustained high level of serum VEGF at convalescent stage contributes to the renal recovery after HTNV infection in patients with hemorrhagic fever with renal syndrome.

To investigate the role of vascular endothelial growth factor (VEGF) in the increased permeability of vascular endothelial cells after Hantaan virus (HTNV) infection in humans, the concentration of VEGF in serum from HTNV infected patients was quantified with sandwich ELISA. Generally, the level of serum VEGF in patients was elevated to 607.0 (542.2-671.9) pg/mL, which was dramatically higher compared with healthy controls (P < 0.001). There was a rapid increase of the serum VEGF level in all patients from the fever onset to oliguric stage, at which the serum creatinine reached the peak level of the disease, indicating that VEGF may be involved in the pathogenesis of renal hyper-permeability. Moreover, the serum VEGF level at convalescent stage was positively correlated with the degree of the disease severity. The sustained high level of serum VEGF at convalescence was observed in critical HFRS patients, suggesting that VEGF would probably contribute to the renal recovery after the virus clearance. Taken together, our results suggested that the VEGF would be involved in the pathogenesis of renal dysfunction at the oliguric stage after HTNV infection, but may function as a recovery factor during the convalescence to help the body self-repair of the renal injury.

The genetic polymorphisms of HLA are strongly correlated with the disease severity after Hantaan virus infection in the Chinese Han population.

The polymorphism of human leukocyte antigen (HLA), which is a genetic factor that influences the progression of hemorrhagic fever with renal syndrome (HFRS) after Hantaan virus (HTNV) infection, was incompletely understood. In this case-control study, 76 HFRS patients and 370 healthy controls of the Chinese Han population were typed for the HLA-A, -B, and -DRB1 loci. The general variation at the HLA-DRB1 locus was associated with the onset of HFRS (P < 0.05). The increasing frequencies of HLA-DRB1∗09 and HLA-B*46-DRB1*09 in HFRS patients were observed as reproducing a previous study. Moreover, the HLA-B*51-DRB1*09 was susceptible to HFRS (P = 0.037; OR = 3.62; 95% CI: 1.00-13.18). The increasing frequencies of HLA-B*46, HLA-B*46-DRB1*09, and HLA-B*51-DRB1*09 were observed almost in severe/critical HFRS patients. The mean level of maximum serum creatinine was higher in HLA-B∗46-DRB1*09 (P = 0.011), HLA-B*51-DRB1*09 (P = 0.041), or HLA-B*46 (P = 0.011) positive patients than that in the negative patients. These findings suggest that the allele HLA-B*46 and haplotypes HLA-B*46-DRB1*09 and HLA-B*51-DRB1*09 in patients could contribute to a more severe degree of HFRS and more serious kidney injury, which improve our understanding of the HLA polymorphism for a different outcome of HTNV infection.

Cystatin C, a novel urinary biomarker for sensitive detection of acute kidney injury during haemorrhagic fever with renal syndrome.

To explore the value of cystatin C for evaluating acute kidney injury (AKI) in haemorrhagic fever with renal syndrome (HFRS), the concentrations of cystatin C in serum and urine samples from HFRS patients were determined. The serum and urinary cystatin C concentrations significantly increased in HFRS patients compared with normal controls (p < 0.001). In the acute phase of HFRS, urinary cystatin C increased to higher levels than serum creatinine, especially in severe or critical cases in the oliguric stage. Furthermore, higher levels of urinary cystatin C in the acute phase positively correlated with increased severity of the subsequent kidney injury. In conclusion, urinary cystatin C is a more sensitive clinical marker for AKI in HFRS, which may enable us to initiate treatment measures as early as possible.

Contributions of PD-1/PD-L1 pathway to interactions of myeloid DCs with T cells in atherosclerosis.

Although inflammatory cells contribute to immunopathogenesis of atherosclerosis, underlying molecular mechanisms remain largely undefined. Recently, it has been demonstrated in mouse model that Programmed death-1 (PD-1)/PD-1 ligand (PD-L) pathway plays a critical role in proatherogenic immune responses. Here we examined the expression of PD-1 and PD-L1 on peripheral blood mononuclear cells by flow cytometry in 76 patients with coronary artery disease (CAD), and 25 healthy volunteers. The expression of PD-1 and PD-L1 is significantly down-regulated on T cells and myeloid dendritic cells (mDCs) in CAD patients than in healthy individuals, respectively. More importantly, we found that decreased PD-L1 expression on mDCs is related with the increased T cell immune responses in CAD patients. In addition, stimulation of PD-L1 expression in vitro could attenuate the stimulatory ability on allogeneic T cell proliferation and its cytokine production, including IFN-gamma and IL-2, and also influence the production of IL-10 and IL-12 by mDCs. Taken together, we can draw a conclusion that PD-1/PD-L1 pathway plays a key role in the regulation of proatherogenic T cell immunity by intervening antigen presenting cell (APC)-dependent T cell activation, which associates with pro-inflammatory or anti-inflammatory cytokine production, and further studies need gain insight into that this pathway represents a strategy of immunotherapy for atherosclerosis.

Elevated interleukin-35 suppresses liver inflammation by regulation of T helper 17 cells in acute hepatitis B virus infection.

Interleukin (IL)-35 is a responsive anti-inflammatory cytokine implicated in different diseases processes. It has been reported that elevated IL-35 contributed to immunosuppression in chronic hepatitis by modulation of T helper 17 (Th17) and regulatory T cells. However, the role of IL-35 in acute hepatitis B (AHB) was still not completely elucidated. Thus, in the present study, we analyzed the expression and regulatory activity of IL-35 to Th17 cells and inflammatory response during acute hepatitis B virus (HBV) infection in both peripheral blood cells isolated from AHB patients and in hydrodynamic induced HBV-infected mouse model. Plasma IL-35 level and circulating HBV peptides-induced Th17 frequency was significantly elevated in AHB patients, and IL-35 expression negatively correlated with liver inflammation. In vitro IL-35 stimulation to CD4+ T cells purified from AHB patients down-regulated HBV peptides-induced Th17-phenotype, which presented as reduced IL-17 and IL-22 production. In vivo IL-35 administration dampened liver inflammation in HBV plasmid injected mice, however, did not affect HBV antigens production. This process was accompanied by suppression of natural killer cells and down-regulation of HBV peptides-induced Th17 cells in the liver, but did not affect total intrahepatic lymphocytes and other cell subsets numbers or chemokines expression in the liver. In conclusion, the current data indicated that IL-35 might be a novel mediator associated with hepatocytes damage and liver inflammation by regulating HBV peptides-induced Th17 cells during acute HBV infection. The potential anti-inflammatory property of IL-35 might be pivotal for developing new therapeutic approaches for hepatitis B.

Computed Tomography-guided Cryoablation for Adrenal Pheochromocytoma: Safety and Clinical Effectiveness.

PURPOSE: To evaluate the safety and clinical effectiveness of computed tomography (CT)-guided cryoablation for adrenal pheochromocytoma (AP). MATERIALS AND METHODS: From July 2015 to October 2018, we observed 8 patients that underwent CT-guided cryoablation for AP. The blood pressure and pulse before treatment did not exceed 150/90 mm Hg and 90 times/min, respectively. Complete ablation rate, clinical success rate, and long-term outcomes were analyzed. RESULTS: A total of 8 patients with 8 APs were treated by CT-guided cryoablation. The mean duration of the procedure was 67.5±4.6 minutes. No patient achieved complete ablation, yet the clinical success rate was 100%. The mean metanephrine decreased from 61.7±11.1 to 2.0±1.1 nmol/L (P<0.001). Hypertensive crisis was found in 5 (67.5%) patients during the procedure. During a mean follow-up of 16.9±13.4 months, no patient experienced tumor progression. CONCLUSION: CT-guided cryoablation is an effective method for patients with AP.

Alcohol consumption analysis among patients with liver disease in China.

BACKGROUND: Alcohol consumption has been observed to be a contributing factor in liver damage. However, very few studies have tried to decipher the correlation between patients with liver disease and alcohol consumption. Therefore, this study was planned to determine the prevalence of alcohol consumption among patients with liver disease, and to evaluate the risk factors, liver diseases, and chronic medical conditions associated with alcohol drinking. METHODS: A cross-sectional study was conducted among patients with liver disease in 30 provinces, autonomous regions, and municipalities across China. All participants answered the questionnaire, which led to the calculation of Alcohol Use Disorders Inventory Test (AUDIT) score for each patient. Based on this score, low-risk drinkers, hazardous drinkers, and harmful drinkers were defined as having AUDIT score of <8, between 8 and 15, and ≥16, respectively. RESULTS: A total of 1489 participants completed the questionnaire. Based on this information, 900 (60.44%) participants were classified as alcohol drinkers. Among these, 8.66% were ex-drinkers, 22.10% were low-risk drinkers, 17.13% were hazardous drinkers, and 12.56% were harmful drinkers. Further investigation of the association between alcohol consumption and other baseline characteristics of patients with liver disease revealed that usually men <40 years old, participants having higher family annual income, having college degree or higher education, living alone, having higher body mass index (BMI), current smokers, and ex-smokers had significant association with higher risk of alcohol consumption. In addition, among the 18.07% of the participants with cirrhosis, it was observed that risk of cirrhosis increased with higher alcohol consumption. Furthermore, harmful drinkers showed greater odds of hypertension and heart diseases, while hazardous drinkers and harmful drinkers, both had greater odds of hyperlipidemia. CONCLUSIONS: Overall our analyses indicated that among the patients with liver disease in China, there was high rate of alcohol consumption and dependence. Alcohol consumption usually associated with men <40 years old, higher family income, education level, living alone, high BMI, and smoking. Increased alcohol consumption not only increased the risk of cirrhosis, but also enhanced the risk of hypertension, heart diseases, and hyperlipidemia.

[Study on the mechanism of HLA-I-expressing regulation caused by the core region mutation of HBV adr subtype].

OBJECTIVE: To study the influence and mechanism of HBV core region mutation on HLA-I expression. METHODS: Eukaryotic expression vectors of HBV core region mutations L97, G87 and V60 were constructed and transfected into HepG2 cells. Then the expressions of HLA-I were detected by RT-PCR and Western blot. The mRNA of antigen-presentation-associated genes, including LMP2, TAP1 and tapasin, were measured using RT-PCR. RESULTS: Different levels of HBsAg in the supernatants of transfected cells were detected by ELISA. The HBsAg of the mutated groups was markedly higher than that of the wild ones. All the transfected cells expressed HLA-I molecules, especially the L97 group. It was also found that the mRNA of TAP1 gene was up-regulated, while the mRNA of LMP and tapasin genes had no changes. CONCLUSION: The core region mutation of HBV can lower the expression of HBsAg; mutated groups and wild ones both can increase the expression of HLA-I molecules. The up-regulation of TAP1 gene expression might be the cause of these changes.

Interferon-α-Enhanced CD100/Plexin-B1/B2 Interactions Promote Natural Killer Cell Functions in Patients with Chronic Hepatitis C Virus Infection.

BACKGROUND: CD100, also known as Sema4D, is an immune semaphorin constitutively expressed on natural killer (NK) cells and T cells. As an immune activation molecule, CD100 has important immunoregulatory effects on NK functions by enhancing the interactions between NK cells and target cells. The aim of this study was to investigate whether hepatitis C virus (HCV) infection affects CD100 expression, and whether interferon-α treatment enhances NK killing activity to facilitate HCV clearance via CD100. METHODS: Expression of CD100 on NK cells was evaluated by flow cytometry in patients with chronic HCV infection, with or without pegylated interferon-α-based therapy. NK cell cytotoxicity and interferon (IFN)-γ production were measured by flow cytometry upon culturing the NK cells with K562 and Huh7.5 or HCV JFH-1-infected Huh7.5 cells. RESULTS: The frequency of CD100+ NK cells in HCV-infected individuals was slightly suppressed compared to healthy subjects. IFN-α treatment could significantly upregulate CD100 expression, which was confirmed by in vitro studies using peripheral blood mononuclear cells cocultured with HCV-expressing Huh7.5 cells or IFN-α. Importantly, the expression of CD100 on NK cells from HCV patients was inversely associated with the HCV-RNA levels in the early phase of IFN-α therapy, and the IFN-α upregulated CD100 led to an enhanced NK killing activity through ligations with its receptors plexin-B1/B2 on target cells. CONCLUSION: These results implied a novel mechanism by which IFN-α enhanced CD100/Plexin-B1/B2 interaction plays an important role in promoting NK functions in patients with chronic hepatitis C.

The Efficacy of Add-on Telbivudine Versus Switching to Pegylated Interferon Alfa-2a in Chronic Hepatitis B Patients With Poor Responses to Adefovir.

BACKGROUND: There are limited options for chronic hepatitis B (CHB) patients who have poor responses to adefovir (ADV). OBJECTIVES: The aim of this study is to evaluate the effects of adding on telbivudine (LdT) or switching to pegylated interferon alfa-2a (PEG-IFN-α2a) as alternative rescue therapies for patients with poor responses to the initial ADV treatments. PATIENTS AND METHODS: Ninety-seven CHB patients with HBV DNA > 2 log10 copies/mL 48 weeks after ADV monotherapy were included in this study. Fifty-nine of these patients were treated with a combination of LdT plus ADV (LdT + ADV) daily, while thirty-eight patients were switched to PEG-IFN-α2a subcutaneous injections weekly for 48 weeks. RESULTS: Both rescue strategies were proven to be safe and the majority of patients tolerated the therapies well. LdT + ADV led to more rapid reductions in viral loads than PEG-IFN-α2a monotherapy, with 2.14 (LdT + ADV) and 0.98 (PEG-IFN-α2a) log10 copies/mL decreases 48 weeks after rescue treatments, respectively (P < 0.00001). The rates corresponding to virological and biochemical responses were also elevated in patients who received the LdT + ADV combination therapy at the end of the observation period (88.1 vs. 68.4% for virological response, P = 0.017; 83.3 vs. 47.2%, P = 0.00045). However, the decline in the hepatitis B surface antigen (HBsAg) was more pronounced in PEG-IFN-α2a treated patients. Moreover, the cumulative rates of serological responses were higher in patients who switched to the PEG-IFN-α2a therapy. CONCLUSIONS: Both add-on LdT and switching to PEG-IFN-α2a were satisfactory and optimal treatments for CHB patients with poor responses to ADV. Both rescue strategies resulted in significant reductions in serum viral load and ALT levels, and were associated with high rate of serological outcomes in our hospital.

Notch Signaling Contributes to Liver Inflammation by Regulation of Interleukin-22-Producing Cells in Hepatitis B Virus Infection.

The mechanism of hepatitis B virus (HBV) induced liver inflammation is not fully elucidated. Notch signaling augmented interleukin (IL)-22 secretion in CD4+ T cells, and Notch-IL-22 axis fine-tuned inflammatory response. We previously demonstrated a proinflammatory role of IL-22 in HBV infection. Thus, in this study, we analyzed the role of Notch in development of IL-22-producing cells in HBV infection by inhibition of Notch signaling using γ-secretase inhibitor DAPT in both hydrodynamic induced HBV-infected mouse model and in peripheral blood cells isolated from patients with HBV infection. mRNA expressions of Notch1 and Notch2 were significantly increased in livers and CD4+ T cells upon HBV infection. Inhibition of Notch signaling in vivo leaded to the reduction in NKp46+ innate lymphoid cells 22 (ILC22) and lymphoid tissue inducer 4 (LTi4) cells in the liver. This process was accompanied by downregulating the expressions of IL-22 and related proinflammatory cytokines and chemokines in the liver, as well as blocking the recruitment of antigen-non-specific inflammatory cells into the liver and subsequent liver injury, but did not affect HBV antigens production and IL-22 secretion in the serum. Furthermore, IL-22 production in HBV non-specific cultured CD4+ T cells, but not HBV-specific CD4+ T cells, was reduced in response to in vitro inhibition of Notch signaling. In conclusion, Notch siganling appears to be an important mediator of the liver inflammation by modulating hepatic ILC22. The potential proinflammatory effect of Notch-mediated ILC22 may be significant for the development of new therapeutic approaches for treatment of hepatitis B.