Factors associated with persistent positive in HBV DNA level in patients with chronic Hepatitis B receiving entecavir treatment.

Introduction: The clinical significance of persistent positive in Hepatitis B Virus (HBV) DNA level in patients receiving antiviral therapy is not well known. We investigated factors associated with persistent viremia (PV) in patients with chronic hepatitis B (CHB) given 78-week entecavir. Methods: A total of 394 treatment-naïve CHB patients who had undergone liver biopsy at baseline and week 78 of treatment were analyzed in this prospective multicentre study. We identified patients with PV (above the lower limit of quantification, 20 IU/ml) after 78 weeks of entecavir therapy. Stepwise, forward, multivariate regression analyses of specified baseline parameters were apllied to identify factors associated with PV. Futhermore, we assessed the incidence of hepatocellular carcinoma (HCC) in all patients using models of the risk of HCC development. Results: Of the 394 patients, 90 (22.8%) still with PV after 78-week antiviral treatment. Factors associated significantly with PV (vs complete virological response, CVR) were HBV DNA level ≥8 log10 IU/mL (OR, 3.727; 95% CI, 1.851-7.505; P < 0.001), Anti-HBc level < 3 log10 IU/mL (OR, 2.384; 95% CI, 1.223-4.645; P=0.011), and HBeAg seropositivity (OR, 2.871; 95% CI, 1.563-5.272; P < 0.001). Patients with PV were less likely to have fibrosis progression and HCC development than those with the CVR. Of the 11 HBeAg-positive patients with HBV DNA level ≥8 log10 IU/mL and Anti-HBc level < 3 log10 IU/mL at baseline, 9 (81.8%) had persistent positivity in HBV DNA level and 0 had fibrosis progression at week 78 of treatment. Discussion: In conclusion, HBV DNA level ≥8 log10 IU/mL, Anti-HBc level < 3 log10 IU/mL and HBeAg seropositivity at baseline contribute to PV in patients with CHB receiving 78-week antiviral treatment. In addition, the rate of fibrosis progression and the risk of HCC development in patients with PV were kept low. The complete protocol for the clinical trial has been registered at clinicaltrials.gov (NCT01962155 and NCT03568578).

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Significant histological changes and satisfying antiviral efficacy in chronic hepatitis B virus infection patients with normal alanine aminotransferase. Antiviral therapy decision in chronic HBV patients with normal ALT.

BACKGROUND AND AIMS: A proportion of chronic hepatitis B virus (HBV) infection patients with normal alanine aminotransferase (ALT) should start antiviral therapy based on liver biopsy. We aim to evaluate the proportion of such patients, find noninvasive methods for identifying and then evaluate antiviral efficacy. METHODS: 253 chronic HBV infection patients with normal ALT were analyzed at baseline and 57 patients with histological indication for antiviral therapy (Histology activity index ≥5 and/or Ishak fibrosis score ≥3) and 140 patients with elevated ALT received entecavir therapy and were followed-up to 78 weeks with a second liver biopsy in this multi-center study. RESULTS: 127 (50.2%) of 253 patients with normal ALT fulfilled histological indication for antiviral therapy. Aspartate aminotransferase (P=0.049), anti-hepatitis B virus core antibody (P=0.001) and liver stiffness measurement (P=0.000) were independent variables for identifying histological indication for antiviral therapy. A noninvasive model (AAF) performed best among independent variables and other noninvasive models with area under the operating characteristic curve of 0.887. Antiviral efficacy showed that 38 (66.7%) of 57 patients had undetectable HBV DNA. 12 (41.4%) of 29 patients who were hepatitis B e antigen (HBeAg)-positive at baseline achieved HBeAg loss and 3 (10.3%) achieved HBeAg seroconversion. 25 (43.9%) of 57 patients achieved histological response. Moreover, 57 patients with normal ALT had a similar antiviral therapy efficacy with 140 patients with elevated ALT (P>0.1) except proportion of inflammation improvement and histological response (P=0.005, P=0.049). CONCLUSIONS: Half of chronic HBV patients with normal ALT should start antiviral therapy based on liver biopsy. A noninvasive model could be used as a reliable tool for antiviral therapy decision. Patients with normal or elevated ALT had a similar antiviral efficacy.

Multicenter prospective study to validate a new transient elastography device for staging liver fibrosis in patients with chronic hepatitis B.

OBJECTIVES: To validate the operational and diagnostic performances of a new device for transient elastography (TE), FibroTouch, for liver fibrosis in patients with chronic hepatitis B (CHB). METHODS: In this prospective multicenter study, adult patients with CHB and valid liver pathological results were recruited to validate the operational and diagnostic performance of a TE device by FibroTouch for staging liver fibrosis. RESULTS: In total, 517 patients with histologically proven CHB were enrolled. All had achieved at least 10 successful liver stiffness measurements (LSM), resulting in a success rate of 99.1% and reliable evaluations of 95.2%. Altogether 412 patients were included to analyze the diagnostic performance of FibroTouch. The area under the receiver operating characteristic curve for the LSM was 0.846 (95% confidence interval [CI] 0.808-0.880) for fibrosis stage ≥ F1, 0.850 (95% CI 0.811-0.883) for ≥ F2, 0.908 (95% CI 0.876-0.934) for ≥ F3 and 0.874 (95% CI 0.836-0.903) for F4. The diagnostic accuracy of LSM was superior to that of gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aminotransferase-to-platelet ratio index (APRI), or fibrosis index based on 4 factors (FIB-4) index in staging fibrosis F2-F4 (P = 0.007 to < 0.0001). Optimal LSM cut-off values for diagnosing fibrosis stage ≥ F1, ≥ F2, ≥ F3, and F4 were 5.5 kPa, 7.85 kPa, 10.0 kPa, and 12.7 kPa, respectively. CONCLUSION: FibroTouch has a high success rate and good reliability in staging liver fibrosis in patients with CHB.

Unsatisfying antiviral therapeutic effect in patients with mother-to-child transmissed chronic hepatitis B virus infection: a prospective multi-center clinical study.

BACKGROUND: Few data are available regarding the progression of liver disease and therapeutic efficacy in chronic hepatitis B virus (HBV) carriers infected by mother-to-child transmission (MTCT). This study aimed to investigate these two aspects by comparing the adult chronic HBV carriers in MTCT group with those in horizontal transmission group. METHODS: The 683 adult chronic HBV patients qualified for liver biopsy including 191 with MTCT and 492 with horizontal transmission entered the multi-center prospective study from October 2013 to May 2016. Biopsy results from 217 patients at baseline and 78 weeks post antiviral therapy were collected. RESULTS: Patients infected by MTCT were more likely to have e antigen positive (68.6% vs. 58.2%, χ = -2.491, P = 0.012) than those with horizontal transmission. However, in patients with MTCT, levels of alkaline phosphatase (ALP) (P = 0.031), Fibroscan (P = 0.013), N-terminal propeptide of Type III procollagen (PIIINP) (P = 0.014), and Laminin (LN) (P = 0.006) were high, in contrast to the patients with horizontal transmission for whom the levels of albumin (ALB) (P = 0.041), matrix metalloproteinase-3 (MMP-3) (P = 0.001) were high. The 47.2% of patients with MTCT and 36.8% of those with horizontal transmission had significant liver fibrosis (P = 0.013). Following antiviral therapy for 78 weeks, 21.2% and 38.0% patients with MTCT and horizontal transmission acquired hepatitis B e antigen (HBeAg) clearance, respectively (P = 0.043), and the virological response rates were 54.7% and 74.1% in the MTCT and horizontal groups, respectively (P = 0.005). MTCT was a risk factor for HBeAg clearance and virological response. CONCLUSION: Adult patients with MTCT were more prone to severe liver diseases, and the therapeutic efficacy was relatively poor, which underlined the importance of earlier, long-term treatment and interrupting perinatal transmission. TRIAL REGISTRATION: NCT01962155; https://clinicaltrials.gov.

Selected Cytokines Serve as Potential Biomarkers for Predicting Liver Inflammation and Fibrosis in Chronic Hepatitis B Patients With Normal to Mildly Elevated Aminotransferases.

Previous studies of small cohorts have implicated several circulating cytokines with progression of chronic hepatitis B (CHB). However, to date there have been no reliable biomarkers for assessing histological liver damage in CHB patients with normal or mildly elevated alanine aminotransferase (ALT). The aim of the present study was to investigate the association between circulating cytokines and histological liver damage in a large cohort. Also, this study was designed to assess the utility of circulating cytokines in diagnosing liver inflammation and fibrosis in CHB patients with ALT less than 2 times the upper limit of normal range (ULN). A total of 227 CHB patients were prospectively enrolled. All patients underwent liver biopsy and staging by Ishak system. Patients with at least moderate inflammation showed significantly higher levels of CXCL-11, CXCL-10, and interleukin (IL)-2 receptor (R) than patients with less than moderate inflammation (P < 0.001). Patients with significant fibrosis had higher levels of IL-8 (P = 0.027), transforming growth factor alpha (TGF-α) (P = 0.011), IL-2R (P = 0.002), and CXCL-11 (P = 0.032) than the group without significant fibrosis. In addition, 31.8% and 29.1% of 151 patients with ALT < 2 × ULN had at least moderate inflammation and significant fibrosis, respectively. Multivariate analysis demonstrated that CXCL-11 was independently associated with at least moderate inflammation, and TGF-α and IL-2R independently correlated with significant fibrosis in patients with ALT < 2 × ULN. Based on certain cytokines and clinical parameters, an inflammation-index and fib-index were developed, which showed areas under the receiver operating characteristics curve (AUROC) of 0.75 (95% CI 0.66-0.84) for at least moderate inflammation and 0.82 (95% CI 0.75-0.90) for significant fibrosis, correspondingly. Compared to existing scores, fib-index was significantly superior to aspartate aminotransferase (AST) to platelet ratio index (APRI) and FIB-4 score for significant fibrosis. In conclusion, CXCL-11 was independently associated with at least moderate inflammation, whereas IL-2R and TGF-α were independent indicators of significant fibrosis in both, total CHB patients and patients with normal or mildly elevated ALT. An IL-2R and TGF-α based score (fib-index) was superior to APRI and FIB-4 for the diagnosis of significant fibrosis in patients with normal or mildly elevated ALT.

Acoustic radiation force impulse elastography, FibroScan®, Forns' index and their combination in the assessment of liver fibrosis in patients with chronic hepatitis B, and the impact of inflammatory activity and steatosis on these diagnostic methods.

The aim of the present study was to investigate the combination of certain serological markers (Forns' index; FI), FibroScan® and acoustic radiation force impulse elastography (ARFI) in the assessment of liver fibrosis in patients with hepatitis B, and to explore the impact of inflammatory activity and steatosis on the accuracy of these diagnostic methods. Eighty­one patients who had been diagnosed with hepatitis B were recruited and the stage of fibrosis was determined by biopsy. The diagnostic accuracy of FI, FibroScan and ARFI, as well as that of the combination of these methods, was evaluated based on the conformity of the results from these tests with those of biopsies. The effect of concomitant inflammation on diagnostic accuracy was also investigated by dividing the patients into two groups based on the grade of inflammation (G<2 and G≥2). The overall univariate correlation between steatosis and the diagnostic value of the three methods was also evaluated. There was a significant association between the stage of fibrosis and the results obtained using ARFI and FibroScan (Kruskal­Wallis; P<0.001 for all patients), and FI (t-test, P<0.001 for all patients). The combination of FI with ARFI/FibroScan increased the predictive accuracy with a fibrosis stage of S≥2 or cirrhosis. There was a significant correlation between the grade of inflammation and the results obtained using ARFI and FibroScan (Kruskal­Wallis, P<0.001 for all patients), and FI (t-test; P<0.001 for all patients). No significant correlation was detected between the measurements obtained using ARFI, FibroScan and FI, and steatosis (r=­0.100, P=0.407; r=0.170, P=0.163; and r=0.154, P=0.216, respectively). ARFI was shown to be as effective in the diagnosis of liver fibrosis as FibroScan or FI, and the combination of ARFI or FibroScan with FI may improve the accuracy of diagnosis. The presence of inflammatory activity, but not that of steatosis, may affect the diagnostic accuracy of these methods.

Randomized, vitamin E-controlled trial of bicyclol plus metformin in non-alcoholic fatty liver disease patients with impaired fasting glucose.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with a high morbidity in patients with impaired fasting glucose (IFG). Bicyclol is a synthetic compound known to protect the liver against oxidation and lipid injuries. OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of metformin and bicyclol in the treatment of NAFLD patients with IFG. METHODS: After lifestyle changes and metformin treatment (500 mg orally three times daily), the 248 patients enrolled with NAFLD and IFG were equally randomized to two 24-week treatment groups: bicyclol 25 mg three times daily or vitamin E (α-tocopherol) 100 mg three times daily (control). Anthropometric measurements, serum biochemistry, liver/spleen computed tomography ratio, and changes in liver histological parameters were compared before and after treatments. RESULTS: A total of 223 patients completed the treatment, and there were significant improvements in body mass index, waist-to-hip ratio, and biochemical parameters in both groups (P < 0.01). Compared with the control group, the improvement in serum alanine aminotransferase levels in the bicyclol group was statistically significant (P < 0.01). Liver histological assessments revealed that steatosis, inflammation, hepatocellular ballooning, and NAFLD activity scores (NAS) were all decreased in both groups after treatment (P < 0.01). However, decreases in inflammation and NAS in the bicyclol group were statistically significant compared with the vitamin E group (P < 0.01). Adverse events in the bicyclol and control groups occurred in 1.79 and 1.80 %, respectively. CONCLUSION: Metformin combined with bicyclol is effective and safe in the treatment of patients with NAFLD and IFG. However, further studies with a larger sample size are needed to confirm the efficacy and safety of the combination.