Higher TP53BP2 expression is associated with HBsAg loss in peginterferon-α-treated patients with chronic hepatitis B.

BACKGROUND & AIMS: HBsAg loss is only observed in a small proportion of patients with chronic hepatitis B (CHB) who undergo interferon treatment. Investigating the host factors crucial for functional cure of CHB can aid in identifying individuals who would benefit from peginterferon-α (Peg-IFNα) therapy. METHODS: We conducted a genome-wide association study (GWAS) by enrolling 48 patients with CHB who achieved HBsAg loss after Peg-IFNα treatment and 47 patients who didn't. In the validation stage, we included 224 patients, of whom 90 had achieved HBsAg loss, to validate the identified significant single nucleotide polymorphisms. To verify the functional involvement of the candidate genes identified, we performed a series of in vitro and in vivo experiments. RESULTS: GWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in patients with CHB after Peg-IFNα treatment (p = 4.85 × 10-8, odds ratio = 14.47). This association was also observed in two independent validation cohorts. Expression quantitative trait locus analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (p = 2.90 × 10-6). RNA-sequencing of liver biopsies from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 levels were significantly higher in the HBsAg loss group compared to the HBsAg persistence group (p = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated gene levels and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling. CONCLUSION: The rs7519753 C allele is associated with elevated hepatic TP53BP2 expression and an increased probability of serum HBsAg loss post-Peg-IFNα treatment in patients with CHB. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression. IMPACT AND IMPLICATIONS: Chronic hepatitis B (CHB) remains a global public health issue. Although current antiviral therapies are more effective in halting disease progression, only a few patients achieve functional cure for hepatitis B with HBsAg loss, highlighting the urgent need for a cure for CHB. This study revealed that the rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in patients with CHB undergoing Peg-IFNα treatment. This finding not only provides a promising predictor for HBsAg loss but identifies a potential therapeutic target for Peg-IFNα treatment. We believe our results are of great interest to a wide range of stakeholders based on their potential clinical implications.

Peg-IFNα combined with hepatitis B vaccination contributes to HBsAg seroconversion and improved immune function.

PURPOSE: The purpose of this study was to investigate immunological variations between a group that received the hepatitis B vaccine and a non-vaccine group. We focused on a cohort that achieved HBsAg seroclearance after Peg-IFNα treatment of CHB. METHODS: We enrolled twenty-eight individuals who achieved HBsAg seroclearance after Peg-IFNα treatment. They were divided into two groups: a vaccine group (n = 14) and a non-vaccine group (n = 14). We assessed lymphocyte subpopulations, B cell- and T cell-surface costimulatory/inhibitory factors, cytokines and immunoglobulin levels were detected at different time points to explore immune-function differences between both groups. RESULTS: The seroconversion rate in the vaccine group at 24 weeks post-vaccination was 100%, which was significantly higher (p = 0.006) than that of the non-vaccine group (50%). Additionally, more individuals in the vaccine group exhibited anti-HBs levels exceeding 100 IUs/L and 300 IUs/L compared to the non-vaccine group (p < 0.05). The vaccine group demonstrated significantly increase total B cells and class-switched B cells at 24 weeks and plasma cells, CD80+B cells, Tfh cells, and ICOS+Tfh cell at 12 weeks, compared with baseline levels (p < 0.05). Conversely, Bregs (CD24+CD27+ and CD24+CD38high) decreased significantly at 24 weeks (p < 0.05). None of the above changes were statistically significance in the non-vaccine group (p > 0.05). Total IgG increased significantly in the vaccine group, and IL-2, IL-5, and IL-6 concentrations increased significantly at week 24 (p < 0.05). Differences in various types of cytokines and immunoglobulins in the plasma of the non-vaccine group were not significant (p > 0.05). Anti-HBs titers positively correlated with Th1/Th2 cells at 24 weeks (r = 0.448 and 0.458, respectively, p = 0.022 and 0.019, respectively), and negatively with CD24+CD38highBreg cells (r = -0.402, p = 0.042). CONCLUSIONS: After achieving HBsAg seroclearance through Peg-IFNα treatment for CHB, administering the hepatitis B vaccine significantly increased anti-HBs-seroconversion rates and antibody levels. We also observed significant immunological differences between the vaccine and non-vaccine groups. Specifically, the vaccine group exhibited significant increases in B cells, plasma cells, and Tfh cells, while Breg levels was significantly lower. These immunological changes are likely conducive to the production of anti-HBs antibodies. However, in the non-vaccine group, the observed changes were not significantlly significant.

Tandem Nitrate-to-Ammonia Conversion on Atomically Precise Silver Nanocluster/MXene Electrocatalyst.

Electrocatalytic reduction of nitrate (NO3 RR) to synthesize ammonia (NH3 ) provides a competitive manner for carbon neutrality and decentralized NH3 synthesis. Atomically precise nanoclusters, as an advantageous platform for investigating the NO3 RR mechanisms and actual active sites, remain largely underexplored due to the poor stability. Herein, we report a (NH4 )9 [Ag9 (mba)9 ] nanoclusters (Ag9 NCs) loaded on Ti3 C2 MXene (Ag9 /MXene) for highly efficient NO3 RR performance towards ambient NH3 synthesis with improved stability in neutral medium. The composite structure of MXene and Ag9 NCs enables a tandem catalysis process for nitrate reduction, significantly increasing the selectivity and FE of NH3 . Besides, compared with individual Ag9 NCs, Ag9 /MXene has better stability with the current density performed no decay after 108 hours of reaction. This work provides a strategy for improving the catalytic activity and stability of atomically precise metal NCs, expanding the mechanism research and application of metal NCs.

Serum HBV RNA is associated with liver fibrosis regression in HBeAg-positive chronic hepatitis B patients treated with nucleos(t)ide analogues.

Noninvasive methods for assessing hepatic fibrosis are clinically necessary. This study aims to explore HBV markers correlated with liver fibrosis and capable of diagnosing significant fibrosis and predicting fibrosis regression. Seventy-four HBeAg-positive chronic hepatitis B (CHB) patients were enrolled and started on entecavir or adefovir therapy. Serum HBV RNA, HBV DNA, HBsAg and hepatitis B core-related antigen (HBcrAg) levels were measured at baseline and during treatment. Liver fibrosis was assessed at baseline and month 60 by liver biopsy. Fibrosis regression was defined as Ishak fibrosis score decreased ≥1-point. At baseline, HBsAg, HBcrAg and HBV RNA levels had a stronger correlation with Ishak fibrosis score (r = -.441, p = .002; r = -.469, p = .001; r = -.398, p = .001) than APRI and FIB-4 (r = .321 p = .006; r = .371, p = .001). HBsAg >4 log10 IU/ml plus HBcrAg >7 log10 IU/ml or HBsAg >4 log10 IU/ml plus HBV RNA >5 log10 copies/ml exhibited the same excellent diagnostic ability for significant fibrosis with the AUROC of 0.857. After 60 months of antiviral treatment, 66.7% of patients who suffered significant fibrosis at baseline achieved fibrosis regression, and an HBV RNA decline from baseline to month 6 greater than 0.63 log10 copies/ml could predict the fibrosis regression at month 60. In conclusion, serum HBsAg, HBcrAg and HBV RNA are potential markers for predicting significant liver fibrosis. HBV RNA measurement would be particularly useful for monitoring hepatic fibrosis changes in HBeAg-positive CHB patients.

Prediction of biochemical nonresolution in patients with chronic drug-induced liver injury: A large multicenter study.

BACKGROUND AND AIMS: To clarify high-risk factors and develop a nomogram model to predict biochemical resolution or biochemical nonresolution (BNR) in patients with chronic DILI. APPROACH AND RESULTS: Retrospectively, 3655 of 5326 patients with chronic DILI were enrolled from nine participating hospitals, of whom 2866 underwent liver biopsy. All of these patients were followed up for over 1 year and their clinical characteristics were retrieved from electronic medical records. The endpoint was BNR, defined as alanine aminotransferase or aspartate aminotransferase >1.5× upper limit of normal or alkaline phosphatase >1.1× ULN, at 12 months from chronic DILI diagnosis. The noninvasive high-risk factors for BNR identified by multivariable logistic regression were used to establish a nomogram, which was validated in an independent external cohort. Finally, 19.3% (707 of 3655) patients presented with BNR. Histologically, with the increase in liver inflammation grades and fibrosis stages, the proportion of BNR significantly increased. The risk of BNR was increased by 21.3-fold in patients with significant inflammation compared to none or mild inflammation (p < 0.001). Biochemically, aspartate aminotransferase and total bilirubin, platelets, prothrombin time, sex, and age were associated with BNR and incorporated to construct a nomogram model (BNR-6) with a concordance index of 0.824 (95% CI, 0.798-0.849), which was highly consistent with liver histology. These results were successfully validated both in the internal cohort and external cohort. CONCLUSIONS: Significant liver inflammation is a robust predictor associated with biochemical nonresolution. The established BNR-6 model provides an easy-to-use approach to assess the outcome of chronic DILI.

Lower end of treatment HBsAg and HBcrAg were associated with HBsAg loss after nucleos(t)ide analog cessation.

BACKGROUND: Since hepatitis B surface antigen (HBsAg) loss is rarely achieved with nucleos(t)ide analog (NA) treatment, most patients require life-long NA treatment. Previous studies have shown that some patients remain virologically responsive even after NA cessation. However, there is still controversy surrounding whether NA discontinuation increases the HBsAg loss rate. Therefore, this study aimed to assess the cumulative rate of HBsAg loss and identify the predictors of HBsAg loss after NA discontinuation. METHODS: This multicenter prospective study included HBV e antigen (HBeAg)-positive patients without cirrhosis from 12 hospitals in China who met the inclusion criteria. The enrolled patients stopped NA and were followed up with clinical and laboratory assessments every 3 months for 24 months after NA cessation or until clinical relapse (CR) occurred. RESULTS: Overall, 158 patients were classified into two groups. Group A included patients with HBsAg positivity at NA cessation (n = 139), and Group B included patients with HBsAg negativity at NA cessation (n = 19). In Group A, the 12-month and 24-month cumulative rates of HBsAg loss were4.3%and 9.4%, respectively. End of treatment (EOT) HBsAg (hazard ratio (HR) = 0.152, P < 0.001) and EOT hepatitis B core-related antigen (HBcrAg) (HR = 0.257, P = 0.001) were associated with HBsAg loss. The areas under the receiver operating characteristic curves for EOT HBsAg and HBcrAg levels were 0.952 (P < 0.001) and 0.765 (P < 0.001), respectively. Patients with EOT HBsAg ≤ 135 IU/mL (59.2% vs. 1.3%, P < 0.001) or HBcrAg ≤ 3.6 logU/mL (17% vs. 5.4%, P = 0.027) had a higher 24-month cumulative HBsAg loss rate. In Group B, none of the patients experienced virological relapse after NA cessation. Only 1 (5.3%) patient had HBsAg reversion. CONCLUSIONS: EOT HBsAg ≤ 135 IU/mL or HBcrAg ≤ 3.6 logU/mL can be used to identify patients with a higher likelihood of HBsAg loss after NA cessation. Patients with HBsAg negativity after NA cessation have favorable clinical outcomes, and HBsAg loss was durable in most cases.

IP10 and Anti-HBc can Predict Virological Relapse and HBsAg Loss in Chronic Hepatitis B Patients after Nucleos(t)ide Analog Discontinuation.

INTRODUCTION: To assess predictive ability of serum interferon-inducible protein 10 (IP10) and hepatitis B core antibody (anti-HBc) levels for virological relapse (VR) and hepatitis B surface antigen (HBsAg) loss after nucleos(t)ide analog (NA) discontinuation. METHODS: In this multicenter prospective study, overall 139 patients were followed up for 24 months after NA discontinuation. RESULTS: End of treatment (EOT) IP10 and anti-HBc were 29.2 (5.1-66.4) pg/mL and 193.6 (136.9-221.4) IU/mL. EOT IP10 and anti-HBc were independent predictors for VR and HBsAg loss in Cox regression analysis. Cumulative rates of VR in patients with EOT IP10 > 26.99 pg/mL was 31.9% (vs. 70.1%, hazard ratio [HR] 2.998, p < 0.001). Cumulative incidences of VR in patients with EOT anti-HBc ≤141.35 IU/mL was 49.1% (vs. 60.6%, HR 2.99, p < 0.001). Cumulative probabilities of VR was 16.7% in patients with EOT IP10 > 26.99 pg/mL plus anti-HBc ≤141.35 IU/mL (vs. 73.6%, HR 6.464, p < 0.001). Cumulative probabilities of HBsAg loss in patients with EOT IP10 > 93.5 pg/mL was 46.2% (vs. 4.7%, HR 10.94, p < 0.001). Cumulative probabilities of HBsAg loss in patients with EOT anti-HBc ≤78.42 IU/mL were 47.1% (vs. 5%, HR 12.27, p < 0.001). Patients with EOT IP10 > 93.5 pg/mL plus anti-HBc ≤78.42 IU/mL had the highest 24-month cumulative HBsAg loss rate (53.8% vs. 4%, HR 16.83, p < 0.001). CONCLUSION: High EOT IP10 and low EOT anti-HBc levels were related to both lower risk of VR and higher probability of HBsAg loss.

Analysis of clinical characteristics of thyroid disorders in patients with chronic hepatitis B treated with pegylated-interferon alpha.

BACKGROUND: Thyroid disorders (TD) is a common complication of pegylated-interferon alpha (Peg-IFNα) therapy. Few studies have investigated the relationship between TD and the efficacy of interferon therapy for chronic hepatitis B (CHB). Therefore, we analyzed the clinical characteristics of TD in patients with CHB treated with Peg-IFNα, and evaluated the correlation between TD and Peg-IFNα treatment efficacy. METHODS: In this retrospective study, the clinical data of 146 patients with CHB receiving Peg-IFNα therapy were collected and analyzed. RESULTS: During the course of Peg-IFNα therapy, positive conversion of thyroid autoantibodies and TD occurred in 7.3% (85/1158) and 8.8% (105/1187) patients, respectively, and was diagnosed more often in women. The most common thyroid disorder was hyperthyroidism (53.3%), followed by subclinical hypothyroidism (34.3%). We found that thyroid function returned to normal in 78.7% of patients with CHB, and thyroid antibody levels returned to the negative range in approximately 50% of patients after interferon treatment cessation. Only 25% of patients with clinical TD required treatment. Compared with patients with hypothyroidism/subclinical hypothyroidism, patients with hyperthyroidism/subclinical hyperthyroidism showed greater reduction and seroclearance of hepatitis B surface antigen (HBsAg) levels. CONCLUSIONS: TD are not an absolute contraindication for interferon therapy; however, patients should be monitored closely during interferon therapy. In pursuit of functional cure, a balance between efficacy and safety must be achieved.

Meta-Analysis of the Risk for Abnormal Liver Function in Pregnancy with High HBV DNA After Antiviral Therapy Withdrawal.

Objective: We aimed to explore the relationship between the withdrawal of antiviral therapy after delivery and the risk for abnormal liver function (ALF) after delivery in pregnant women with high hepatitis B virus (HBV) DNA load by meta-analysis, in order to provide the corresponding theoretical basis for further guiding the clinical use of antiviral drugs in such pregnant women. Methods: We searched multiple databases for controlled studies that enrolled pregnant women with chronic HBV infection treated with antiviral therapy from January 1, 2010 to November 1, 2020. Study selection and data extraction were performed by pairs of independent reviewers. The main index was the percentage of ALF higher than the upper limit of normal at 0 to 12 and 12 to 24 weeks after delivery. Meta-analysis was used to compare the risk for ALF after stopping antiviral drugs at different time points following delivery, and subgroup analysis was conducted according to the types of drugs used. Results: We included 10 studies that enrolled 1080 pregnant women. There were 749 pregnant women in the treatment group and 331 pregnant women in the control group (who were not treated with antiviral therapy). The risk ratio (RR) for ALF in the 2 groups at 0 to 12 weeks after delivery: RR = 0.88; 95% CI, 0.71-1.09; at 12-24 weeks: RR = 0.46; 95% CI, 0.29-0.73, were compared. According to the different types of medication, subgroup analysis showed that the lamivudine treatment group compared with the control group at 0-12 weeks: RR = 0.67; 95% CI, 0.26-1.75; at 12-24 weeks, RR = 0.27; 95% CI, 0.11-0.67. The telbivudine treatment group was compared with the control group: at 0-12 weeks: RR = 0.77; 95% CI, 0.43-1.39; at 12-24 weeks: RR = 0.62, 95% CI, 0.23-1.64. The tenofovir treatment group was compared with the control group: at 0-12 weeks RR = 1.02; 95% CI, 0.67-1.55; at 12-24 weeks RR = 0.5; 95% CI, 0.25, 0.99. The lamivudine antiviral treatment group was further analyzed according to different treatment withdrawal time points. Compared with the control group, the immediate withdrawal of lamivudine in labor group at 0-12 weeks RR = 0.29; 95% CI, 0.11-0.77; at 12-24 weeks RR = 0.22; 95% CI, 0.05-0.88; the results were significantly different. There was no significant difference between the 4-week group and the 4-12 week group and the control group. Conclusion: In pregnant women with a high HBV DNA load, immediate withdrawal after antiviral treatment in the second or third trimester of pregnancy did not increase the risk for ALF after delivery.

Serum HBV RNA predicts HBeAg clearance and seroconversion in patients with chronic hepatitis B treated with nucleos(t)ide analogues.

This study evaluated the predictive value of serum HBV DNA, HBV RNA, HBcrAg, HBsAg, intrahepatic HBV DNA and cccDNA for HBeAg clearance and seroconversion during long-term treatment with nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). A single centre, prospective cohort of CHB patients was used for this study. Serum HBV RNA levels were retrospectively measured at baseline, 6, 12, 24, 36, 48, 60, 72 and 84 months post-NAs treatment. Serum HBsAg and HBcrAg levels were quantified at baseline, month 6, 60 and 72. Histological samples from liver biopsy at baseline and month 60 were analysed for intrahepatic HBV DNA and cccDNA. Eighty-three HBeAg-positive patients were enrolled with a median follow-up time of 108 months (range 18-138 months). Of them, 53 (63.86%) patients achieved HBeAg clearance, and 37 (44.58%) achieved HBeAg seroconversion. Cox multivariate analysis showed that only baseline HBV RNA was independently associated with HBeAg clearance and seroconversion (<5.45 log10 copies/mL, HR = 5.06, 95% CI: 1.87-13.71, p = .001; HR = 3.38, 95% CI: 1.28-8.91, p = .01). The independent association with HBeAg clearance and seroconversion remained for HBV RNA levels at month 6 (<4.72 log10 copies/mL, HR = 4.16, 95% CI: 1.61-10.72, p = .003; HR = 6.52, 95% CI: 1.85-22.94, p = .003) and month 12 (<4.08 log10 copies/mL, HR = 3.68, 95% CI: 1.96-6.90, p < .001; HR = 2.79, 95% CI: 1.31-5.94, p = .008). The AUCs of baseline HBV RNA for predicting the HBeAg clearance (0.83, 95% CI: 0.70-0.96, 0.83, 95% CI: 0.70-0.96 and 0.82, 95% CI: 0.69-0.95 respectively) and seroconversion (0.89, 95% CI: 0.77-1.00; 0.81, 95% CI: 0.66-0.95 and 0.84, 95% CI: 0.71-0.98 respectively) at month 36, 60 and 84 were higher than those of HBV DNA, HBsAg and HBcrAg. In conclusion, lower serum HBV RNA at baseline, month 6 and 12 post-NAs treatment could predict HBeAg clearance and seroconversion during long-term NAs treatment.

Respiratory failure as the prominent manifestation of entecavir-associated mitochondrial myopathy: a case report.

BACKGROUND: Mitochondrial myopathy caused by the long-term use of nucleos(t)ide analogue in patients with chronic hepatitis B (CHB) is mostly characterized by myasthenia and myalgia. Cases with respiratory failure as the prominent manifestation and multisystem symptoms have not been reported. CASE REPORT: We report a case of mitochondrial myopathy associated with the long-term use of entecavir for CHB. The patient was a 54-year-old male who was treated with entecavir for 9 years. During the treatment, hepatitis B virus (HBV) DNA was negative and liver function was normal. However, generalized fatigue, poor appetite, dysosmia and other discomforts gradually presented starting at the 5th year of treatment, and respiratory failure was the prominent manifestation in the later stage of disease progression. The diagnosis was based on histopathology examination. The dysosmia, hypoxemia and digestive tract symptoms were gradually improved after withdrawal of entecavir. DISCUSSION: Mitochondrial myopathy is a rare side effect of entecavir and can be diagnosed by muscle biopsy. Although the incidence is extremely low, but the severe cases can lead to respiratory failure. We should receive adequate attention in clinical practice.

Bariatric Surgery is Effective and Safe for Obese Patients with Compensated Cirrhosis: A Systematic Review and Meta-Analysis.

BACKGROUND: With the global pandemic of obesity and nonalcoholic fatty liver disease (NAFLD), the incidence of cirrhosis associated with nonalcoholic steatohepatitis (NASH) has greatly increased. This study aimed to evaluate the efficacy and safety of bariatric surgery in obese cirrhotic patients. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for relevant studies. Effectiveness outcomes were weight loss, remission of comorbidities, and improvement in liver function. Safety outcomes were procedural complications and mortality. RESULTS: A total of 15 studies were included in this meta-analysis. Patients with compensated cirrhosis lost weight significantly after surgery, and the percentage of excess weight loss was 60.44 (95% CI, 44.34 to 76.55). Bariatric surgery resulted in remission of NAFLD in 57.9% (95% CI, 27.5% to 88.3%), T2DM in 58.4% (95% CI, 48.4% to 68.4%), hypertension in 53.1% (95% CI, 43% to 63.3%), dyslipidemia in 59.8% (95% CI, 41.1% to 78.5%) of patients with cirrhosis. Bariatric surgery reduced the levels of alanine aminotransferase and aspartate aminotransferase. The incidence of surgical complications in patients with cirrhosis was about 19.2% (95% CI, 11.7% to 26.6%), which was higher than that in patients without cirrhosis (OR 2.67 [95% CI, 1.26 to 5.67]). Patients with cirrhosis had an overall mortality rate of 1.3%, and the mortality rates for compensated cirrhosis and decompensated cirrhosis were 0.9% and 18.2%, respectively. CONCLUSIONS: Bariatric surgery is effective for weight loss, remission of comorbidities, and reversal of liver damage. Although cirrhotic patients have a higher risk of complications and death, bariatric surgery is relatively safe for well-compensated cirrhosis.

Association between serum sphingolipids and necroinflammation of liver tissue pathology in chronic hepatitis B.

Background & Aims: Accurately identifying liver necroinflammation was essential for the timely implementation of antiviral therapy in chronic hepatitis B(CHB) patients. The sphingolipids were involved in various chronic inflammatory processes. This study aimed to evaluate the association between serum sphingolipids and liver necroinflammation in CHB patients. Methods: The study prospectively enrolled patients with a diagnosis of chronic hepatitis B who were subsequently treated with nucleos(t)ide analogs (NAs). Liver biopsy was performed at baseline and 5-year follow-up, and serum sphingolipid levels were measured by ultra-high-performance liquid chromatography tandem mass spectrometry. Results: A total of 70 CHB patients were enrolled with baseline liver necroinflammation of 27(38.6%) G1, 23(32.9%) G2, and 20(28.6%) G ≥ 3, respectively. A total of 126 liver biopsies were performed on the study population over a 5-year period, of which 80 (63.5%) G<2 and 46 (36.5%) G≥2. Serum ALT, ALP, SM d16:0/16:1, SM d16:0/17:1, SM d18:0/17:0 and Cer d18:2/22:0 showed significant differences between two groups (P<0.01). Multivariate analysis showed that serum ALT (OR 1.006, 95% CI: 1.000-1.011), SM d16:0/16:1 (OR 1.552, 95% CI: 1.150-2.093), Cer d18:2/22:0 (OR 0.003, 95% CI: 0.000-0.173) were associated with G ≥ 2. In the subgroup of patients with normal serum ALT, serum Cer d18:2/22:0 was lower in patients with G ≥ 2 than that with G < 2. After 5 years, alleviated inflammation was accompanied by decreased serum SM d16:0/16:1 and increased serum Cer d18:2/22:0 in patients with baseline G ≥ 2. Conclusions: Lower serum Cer d18:2/22:0 could reflect hepatic necroinflammation (G ≥ 2) in CHB patients including those with normal serum ALT, and its elevation predicts the inflammation improvement after NAs treatment.

Serum HBV DNA plus RNA reflecting cccDNA level before and during NAs treatment in HBeAg positive CHB patients.

Background & Aims: Correlations between serum viral markers and intrahepatic cccDNA in patients undergoing long-term nucleos(t)ide analogues (NAs) treatment haven't been fully explored. In this study, we evaluate the correlation between intrahepatic cccDNA and other serum viral markers and intrahepatic HBV DNA in HBeAg positive chronic hepatitis B (CHB) patients during 60-month treatment with NAs. Methods: Fifty-four HBeAg positive CHB patients received long-term NAs treatment were included in this study. Serial serum samples were regularly collected and quantitatively analyzed for HBsAg, HBV DNA, HBV RNA and HBcrAg. Histological samples from liver biopsy at baseline and month 60 were analyzed for intrahepatic HBV DNA and cccDNA. Results: At baseline, serum HBV DNA plus RNA was positively associated with intrahepatic cccDNA in multivariate regression analysis (ß=0.205, P<0.001). In the correlation analysis between cccDNA and serum viral markers, HBV DNA plus RNA had the highest correlation coefficient (r=0.698, P<0.001), followed by serum HBV DNA (r=0.641, P<0.001), HBV RNA (r=0.590, P<0.001), and HBcrAg (r=0.564, P<0.001). At month 60, correlations between these serum viral markers and cccDNA were not observed (P>0.05). Multivariate regression analysis showed that only the decreased HBV DNA plus RNA was positively associated with cccDNA decline (ß=0.172, P =0.006). Changes of HBV DNA plus RNA (r=0.525, P=0.001) was better correlated with cccDNA decline as compared to HBV RNA (r=0.384, P=0.008), HBV DNA (r=0.431, P=0.003), and HBsAg (r=0.342, P=0.029). Conclusions: Serum HBV DNA plus RNA better correlated with intrahepatic cccDNA than other viral makers before and during NAs treatment in HBeAg positive CHB patients.

Association of HSD17B13 rs72613567: TA allelic variant with liver disease: review and meta-analysis.

BACKGROUND: To assess the association of HSD17B13 rs72613567:TA allelic variant with liver disease, we performed the current review and meta-analysis. METHODS: Seven studies were identified by a search of CNKI,CBM,MEDLINE, PubMed, EMBASE, and CENTRAL databases from inception to November 2021. Odds ratios (ORs) with 95% confidence interval (CI) were calculated using random effects model or fixed effects model based on the between-study heterogeneity. The Stata 14.0 software was employed for data analysis. RESULTS: Statistical analysis showed that the HSD17B13 rs72613567:TA allelic variant can decrease the risk of hepatocellular carcinoma(HCC) in nonalcoholic fatty liver disease (NAFLD) patients, alcoholic fatty liver disease (ALD) patients and viral hepatitis patients (TA vs T OR = 0.766, 95% CI = 0.682-0.860, P = 0.000; TATA + TAT vs TT OR = 0.755, 95% CI = 0.645-0.885, P = 0.001) or healthy controls(TA vs T OR = 0.649, 95% CI = 0.431-0.977, P = 0.038). Besides, the HSD17B13 rs72613567:TA allelic variant can also provide protection from nonalcoholic fatty liver disease (NAFLD) not only in entire population (TA vs T OR = 0.669, 95% CI = 0.524-0.856, P = 0.001) but also in healthy people (TA vs T OR = 0.600, 95% CI = 0.464-0.777, P = 0.000). No significant publication bias found in this airticle. CONCLUSION: The present findings suggest HSD17B13 rs72613567:TA allelic variant can reduce the risk of HCC and NAFLD in the entire population studied.

Seraprevir and sofosbuvir for treatment of chronic hepatitis C virus infection: A single-arm, open-label, phase 3 trial.

BACKGROUND AND AIM: This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of seraprevir, an hepatitis C virus (HCV) nonstructural protein 3/4A (NS3/4A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic HCV infection without cirrhosis. METHODS: Treatment-naive or interferon-experienced adult patients without cirrhosis were treated with a universal, combinational regimen of seraprevir 100 mg, twice daily and sofosbuvir 400 mg, once daily, for 12 or 24 weeks. The primary efficacy endpoint was sustained virologic response at week 12 after treatment (SVR12). RESULTS: Overall, 205 patients with genotype 1 HCV infection without cirrhosis were enrolled from 23 sites, 202 of whom completed the full treatment and post-treatment course and 3 discontinued follow-up. In total, 27 patients (13.2%) were interferon experienced. SVR12 was achieved by 201 out of 205 (98.0% [95% CI, 95.1%, 99.5%]) patients, 100.0% of patients with genotype 1a, and 98.0% of genotype 1b. In the other exploratory study, SVR 12 was achieved by 100% patients with genotype 2 (n = 21), genotype 3 (n = 7), and genotype 6 (n = 8). The majority of adverse events were mild to moderate and transient and did not require a specific medical intervention. CONCLUSIONS: The all-oral, ribavirin-free regimen of seraprevir and sofosbuvir is an effective and well-tolerated treatment option for Chinese patients mono-infected with HCV, including those with a history of interferon treatment.

Coblopasvir and sofosbuvir for treatment of chronic hepatitis C virus infection in China: A single-arm, open-label, phase 3 trial.

BACKGROUND & AIM: An affordable, pangenotypic regimen remains as an unmet medical need for chronic hepatitis C patients in China. This single-arm, open-label, multicenter, phase 3 trial evaluated the efficacy and safety of coblopasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, combined with sofosbuvir for treating Chinese patients with chronic hepatitis C virus (HCV) infection. METHODS: Treatment-naïve and interferon-experienced adult patients, including those with advanced fibrosis (F3) or compensated cirrhosis (F4), were treated with a universal, combinational regimen of coblopasvir 60 mg and sofosbuvir 400 mg, once daily, for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (SVR12). RESULTS: Overall, 371 patients (men, 51%; age, 47 ± 11 years; genotype 1a < 1%, 1b 48%, 2a 26%, 3a 6%, 3b 7% and 6 12%) were enrolled from 19 sites. Fifty-one patients (14%) had F3, 39 patients (11%) had F4 and 39 patients (11%) were interferon experienced. The overall SVR12 was 97% (95% CI, [94%, 98%]) for the full analysis set and was equal to or above 90% for all predefined subsets. Ten patients (3%) experienced virological relapse and two patients did not complete follow-up. No adverse events (AEs) occurred at a frequency ≥5%, and the most often reported AEs (≥1%) were neutropenia and fatigue. The majority of AEs were mild to moderate and transient without specific medical intervention. CONCLUSIONS: The universal, pangenotypic combo of coblopasvir plus sofosbuvir is an efficacious and safe treatment for Chinese patients monoinfected with HCV of genotype 1, 2, 3 and 6, including those with compensated cirrhosis. LAY SUMMARY: The regimen of coblopasvir and sofosbuvir is a safe and effective treatment for Chinese patients with genotype 1, 2, 3 and 6 HCV infection, including those with compensated cirrhosis. Therefore, this regimen would be a novel choice of treatment for this patient population.

Serum Total Bile Acid is Closely Related to the Significant Liver Injury in Patients with Non-Cholestatic Chronic Hepatitis B Virus Infection: a Cross-Sectional Study.

BACKGROUND: The relationship between non-cholestatic liver disease and total bile acid (TBA) remains obscure. The present study aimed to verify this relationship in patients with non-cholestatic chronic hepatitis B virus (HBV) infection. METHODS: A total of 922 consecutive chronic HBV infected patients with alkaline phosphatase (ALP) ≤ 1.5 upper limit of normal (ULN) and gamma-glutamyl transferase (GGT) ≤ 3 ULN were rigorously included in this cross-sectional study. Liver biopsy was performed in 53 patients and Scheuer scoring system was used to evaluate inflammation grade. G3/G4 or Child-Pugh B/C were considered to be significant liver injury. RESULTS: Compared to Child-Pugh A, TBA, total bilirubin (TBIL), ALP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and AST to ALT ratio (AST/ALT) were significantly higher in Child-Pugh B/C, while TBIL to TBA ratio (TBIL/TBA) was significantly lower (all p < 0.001). In multivariate analysis, TBA and AST/ALT were independently correlated with Child-Pugh B/C [odds ratio (OR) = 1.04, p < 0.001; OR = 1.79, p < 0.001, respectively]. The area under the curve (AUC) of TBA (0.82) was significantly higher than that of AST (0.73, p < 0.001) and ALT (0.63, p < 0.001). Furthermore, in patients with liver biopsy, TBA was also significantly higher in G3/G4 while TBIL/TBA was significantly lower (p < 0.05). After adjusting the factors related to bile excretion, TBIL/TBA was independently associated with G3/G4 (OR = 0.89, p = 0.037). CONCLUSIONS: Serum TBA shows a close relationship with significant liver injury in chronic HBV infected patients without cholestasis. Assessment of TBA, especially in combination with TBIL/TBA, may serve as a non-invasive marker for the diagnosis of non-cholestatic hepatic damage.

Complex ATP7B mutation patterns in Wilson disease and evaluation of a yeast model for functional analysis of variants.

Wilson disease (WD) is a rare autosomal recessive genetic disorder that is associated with various mutations in the ATP7B gene. Although ATP7B variants are frequently identified, the exact mutation patterns remain unknown because of the absence of pedigree studies, and the functional consequences of individual ATP7B variants remain to be clarified. In this study, we recruited 65 clinically diagnosed WD patients from 60 unrelated families. Pedigree analysis showed that besides several ATP7B homozygous variants (8/65, 12.3%), compound heterozygous variants (43/65, 66.2%) were present in the majority of WD patients. There were 20% of the patients had one (12/65, 18.5%) or multiple (1/65, 1.5%) variants in only a single allele, characterized by a high ratio of splicing or frameshift variants. Nine ATP7B variants were cloned into the pAG426GPD yeast expression vector to evaluate their functional consequences, and the results suggested different degrees of functional disruption from mild or uncertain to severe, consistent with the corresponding phenotypes. Our study revealed the complex ATP7B mutation patterns in WD patients and the applicability of a yeast model system to the evaluation of the functional consequences of ATP7B variants, which is essential for WD cases that are difficult to interpret.

Efficacy of antepartum administration of hepatitis B immunoglobulin in preventing mother-to-child transmission of hepatitis B virus.

The aim of this study was to investigate the efficacy of antepartum administration of three doses of hepatitis B immunoglobulin (HBIG) in interrupting mother-to-child transmission (MTCT) of hepatitis B virus (HBV). In this trial, a total of 728 HBeAg-positive pregnant women with chronic HBV infection who had an HBV DNA level higher than 6log10  copies/mL were enrolled. They were divided into three groups based on individual preference. Subjects in group A and group B received 200 IU (unit) HBIG and 400 IU (unit) HBIG intramuscularly once a month at the third, second and first month before delivery, respectively. Subjects in the control group (C) received no special treatment. All the infants received passive-active immunoprophylaxis. The HBsAg-positive rate of all infants at 7-12 months of age was 5.1% (37/728). Specifically, the HBsAg-positive rate of infants was comparable in all three groups (5.3% vs 5.1% vs 5%, P = 0.988). No significant difference was found in anti-HBs levels between the infants aged 7-12 months in the three groups (P = 0.469). HBV DNA levels of the umbilical cord blood in the HBV-infected group were higher than those in the uninfected group (5.2 vs 3.4log10  copies/mL, P < 0.001), and these with family history of HBV infection were also higher (45.9% vs 28.5%, P = 0.034). To conclude, administration of passive-active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti-HBs levels of infants born to HBsAg-positive mothers with HBV DNA higher than 6log10  copies/mL.