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This study aimed to evaluate whether the onset of the plateau phase of slow hepatitis B surface antigen decline in patients with chronic hepatitis B treated with intermittent interferon therapy is related to the frequency of dendritic cell subsets and expression of the costimulatory molecules CD40, CD80, CD83, and CD86. This was a cross-sectional study in which patients were divided into a natural history group (namely NH group), a long-term oral nucleoside analogs treatment group (namely NA group), and a plateau-arriving group (namely P group). The percentage of plasmacytoid dendritic cell and myeloid dendritic cell subsets in peripheral blood lymphocytes and monocytes and the mean fluorescence intensity of their surface costimulatory molecules were detected using a flow cytometer. In total, 143 patients were enrolled (NH group, n = 49; NA group, n = 47; P group, n = 47). The results demonstrated that CD141/CD1c double negative myeloid dendritic cell (DNmDC)/lymphocytes and monocytes (%) in P group (0.041 [0.024, 0.069]) was significantly lower than that in NH group (0.270 [0.135, 0.407]) and NA group (0.273 [0.150, 0.443]), and CD86 mean fluorescence intensity of DNmDCs in P group (1832.0 [1484.0, 2793.0]) was significantly lower than that in NH group (4316.0 [2958.0, 5169.0]) and NA group (3299.0 [2534.0, 4371.0]), Adjusted P all < 0.001. Reduced DNmDCs and impaired maturation may be associated with the onset of the plateau phase during intermittent interferon therapy in patients with chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Background & Aims: Nucleotides with add‐on interferon treatment (NUC‐IFN) provide significantly higher rates of hepatitis B surface antigen (HBsAg) loss in patients with chronic hepatitis B (CHB). This study aimed to investigate the sustainability of HBsAg loss and the prevention of clinical relapse. Methods: Patients with CHB who achieved HBsAg loss and HBV DNA levels <20 IU/ml after IFN or NUC‐IFN therapy were enrolled and followed up for 96 weeks. The primary outcome was HBsAg negativity without viremia at week 96. Secondary outcomes included virological or clinical relapse and predictors of relapse. Results: 420 patients were included in intention‐to‐treat analysis with 290 and 130 in the IFN and NUC‐IFN groups respectively. At week 96, the intention‐to‐treat analysis revealed similar outcomes between groups, including HBsAg seroreversion (24.83% vs. 23.08%, P =.70), viremia (16.90% vs 13.08%, P =.32) and clinical relapse (11.38% vs 10.00%, P =.68); the per‐protocol analyses also showed HBsAg seroreversion, viremia and clinical relapse in IFN group (15.50%, 6.59% and 0.39%) did not differ from those in NUC‐IFN group (15.25%, 4.24% and 0.85%, P >.05). These outcomes were similar between patients who received entecavir and those who received telbivudine/lamivudine/adefovir before the combination therapy. In NUC‐IFN‐treated patients, fibrosis regression was observed at week 96. Baseline HBsAb negativity was independent predictors of HBsAg sero‐reversion and recurrence of viremia in IFN treated group. Conclusion: NUC‐IFN and IFN therapies are equally effective in achieving sustained functional cure and fibrosis regression. (ClinicalTrials.gov, Number NCT02336399). [ABSTRACT FROM AUTHOR]

To investigate the association between immune-cell-related cytokines and the development of chronic hepatitis B (CHB), patients with chronic hepatitis B virus (HBV) infection in the immunotolerant (IT) phase (n = 30) or hepatitis B envelope antigen (HBeAg)-positive CHB (n = 250) were enrolled in this study. Serological indicators and plasma cytokine levels were measured at the time of enrollment. The results showed that there were significant differences in the median age of the patients (27 vs. 31 years), alanine aminotransferase levels (ALT, 29.85 vs. 234.70 U/L), alanine aminotransferase levels (AST, 23.40 vs. 114.90 U/L), HBsAg levels (4.79 vs. 3.88 log10 IU/ml), HBeAg levels (1606.36 vs. 862.47 S/CO), and the HBV DNA load (8.17 vs. 6.71 log10 IU/ml) between the IT and CHB groups (all P < 0.01). The median values of Fms-like tyrosine kinase 3 ligand (FLT3-L), interferon-gamma (IFN-γ), interleukin- 17A (IL-17A), and transforming growth factor beta (TGF-β1) were significantly higher in the IT group than in the CHB group (FLT3-L, 41.62 vs. 27.47 pg/ml; IFN-γ, 42.48 vs. 33.18 pg/ml; IL-17A, 15.66 vs. 8.90 pg/ml; TGF-β1, 4921.50 vs. 2234 pg/ml; all P < 0.01). The median IFN-α2, TGF-β3 and IL-10 levels in the IT group were significantly lower than those in the CHB group (IFN-α2, 15.24 vs. 35.78 pg/ml, P = 0.000; TGF-β3, 131.69 vs. 162.61 pg/ml, P = 0.025; IL-10, 5.02 vs. 7.9 pg/ml, P = 0.012). Multivariate logistic regression analysis indicated that TGF-β 1 (OR = 0.999, 95% CI 0.999-1.000, P < 0.001) and TGF-β2 levels (OR = 1.008, 95%CI 1.004-1.012, P < 0.001) were modestly but significantly associated with the incidence of CHB. The results suggest that TGF-β level might be an independent factor related to the occurrence of CHB. [ABSTRACT FROM AUTHOR]

To investigate the changes in the cytokine profiles of chronic hepatitis B (CHB) patients undergoing antiviral treatment. Hepatitis B e antigen (HBeAg)-positive patients were treated with Pegylated interferon (PEG-IFN) and entecavir (ETV). Clinical biochemistry and cytokines were detected at baseline and every 3 months. In all, 200 patients completed 48 weeks of treatment, 100 in the PEG-IFN group and 100 in the ETV group. During 3–6 months of treatment, compared with baseline, the PEG-IFN group showed a significant decrease in interferon-gamma (IFN-γ), interleukin-17A (IL-17A), interleukin-6(IL-6), interleukin-10(IL-10), and transforming growth factor beta (TGF-β) (P < 0.001) and a significant increase in interferon-alpha 2(IFN-α2) (P < 0.001). In the ETV group, IL-10 and TGF-β1 decreased significantly (P < 0.001). After 3 months, the levels of IFN-α2, IL-17A, and tumor necrosis factor-alpha(TNF-α) in the PEG-IFN group were significantly higher than those in the ETV group (P < 0.01). The levels of IL-6 and TGF-β3 were significantly lower than those in the ETV group (P < 0.01). After 6 months, the levels of IFN-α2, IFN-γ, and TNF-α in the PEG-IFN group were significantly higher than those in the ETV group (P < 0.01), while the levels of IL-6 and TGF-β3 were significantly lower than those in the ETV group (P < 0.01). Compared with ETV, PEG-IFN had higher HBeAg and HBsAg disappearance rates. During antiviral therapy, a change in the cytokine profile occurred; in the aspect of immune control and functional cure, PEG-IFN was significantly better than ETV. [ABSTRACT FROM AUTHOR]

To investigate the characteristics of cytokines in patients with different HBV infection status and their correlation with HBV DNA, HBsAg, and HBeAg levels. Peripheral blood samples were collected from patients with chronic HBV infection in immune tolerance phase (IT), HBeAg‐positive chronic hepatitis B (CHB), and acute hepatitis B (AHB) groups, and levels of cytokines were detected by Luminex technique, and analyzed by FLEXMAP 3D analyzer. The correlation between cytokines and HBV DNA load, HBsAg, HBeAg, and alanine aminotransferase (ALT) level in patients with chronic HBV infection was analyzed. In total 312 subjects (184 males and 128 females) were enrolled in the study. There were significant differences among IT, CHB, and AHB groups in Flt‐3L value (P =.003; H = 12.312), IFN‐γ (P =.001; H = 11.723), IL‐10 (P =.001; H = 18.736), IL‐17A ((P =.001; H = 12.735), and TGF‐β1 (P =.001; Z = 48.571). IFN‐α2 levels in CHB group were significantly higher than those in IT and AHB groups (15.24 vs 35.78 pg/mL, P =.000; Z = 3.727; 13.88 vs 35.78 pg/mL, P =.024; Z = −2.258. In CHB group, the levels of HBsAg and ALT were positively correlated with the levels of IL‐10 (r =.173; P =.006; r = 0.176; P =.006, respectively), while HBeAg level was positively correlated with the IFN‐α2 level (r =.153; P =.016). In AHB group, the HBsAg level was positively correlated with Flt‐3L, IFN‐α2, IL‐10, and IL‐6 (r =.402; P =.023; r =.436; P =.016; r =.524, P =.002; r =.405; P =.022, respectively). HBeAg level was positively correlated with IFN‐γ and IL‐17A levels (r =.400; P =.023; r =.373; P =.036, respectively), and ALT level was positively correlated with IL‐6 levels (r =.367; P =.039). In either AHB or CHB group, HBV DNA load was only related to TGF‐β level (r =.493; P =.004; r = −.218, P = 0.009 respectively). The correlation between Flt‐3L and HBsAg (F = 7.422; P =.007); IL‐17, IL‐6, and HBeAg (F = 5.757; P =.017; F = 6.156; P =.014) were statistically significant. There was significant correlation between TGF‐β2 and HBV DNA (F = 11.795; P =.001), and between ALT and HBsAg, HBV DNA (F = 26.089; P =.000; F = 4.724; P =.031). HBsAg, HBeAg, and HBV DNA were correlated with cytokines and ALT in patients with HBV infection. The level of IFN‐α2 was significantly higher in patients with CHB. HBV DNA load was only correlated with the level of TGF‐β in acute or CHB. Highlights: Recover from acute HBV infection or the onset of hepatitis in patients with chronic HBV infection depend on host immune response. Immune cells and relevant cytokines are closely related to the pathogenesis and chronicity of hepatitis B, as well as efficiency of treatments. This study focused on the relation of serum cytokines levels to the HBV load, HBV antigens levels in patients with chronic hepatitis B and patients with acute hepatitis B. It was demonstrated that levels of HBsAg, HBeAg, and HBV DNA load were correlated with serum concentration of cytokines and ALT levels, also to provide the basis for identifying the treatment opportunity of chronic HBV infection in clinical practice. [ABSTRACT FROM AUTHOR]

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)‐negative CHB patients. In this prospective study, 176 HBeAg‐negative CHB patients with functional cure were enrolled for 12 weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3 months; liver imaging examinations were performed every 3‐6 months during the 48‐week follow‐up. The sustained functional cure was evaluated. After the 48‐week follow‐up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment ≥ 12 weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment < 12 weeks (76.19% vs 90.00%, P = 0.022 and 23.81% vs 9.23%, P = 0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P = 0.012). Consolidation treatment ≥ 12 weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135‐127.151; P = 0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824‐37.881; P = 0.006) were independent predictors of sustained functional cure. Results suggested that 12 weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure. [ABSTRACT FROM AUTHOR]

Liver necroinflammation is the indicator for treating patients with chronic hepatitis B (CHB) infection. However, there is no suitable non‐invasive index for diagnosing liver necroinflammation. This study aimed to create a non‐invasive index to predict liver necroinflammation in patients who lack clear‐cut clinical inflammation parameters. Patients who were hepatitis B e antigen (HBeAg)‐negative and underwent liver histological diagnosis, had a normal or minimally increased alanine aminotransferase (ALT) level were enrolled. Liver necroinflammation was defined as histological active index ≥4. A logistic regression model (LRM) was established based on the parameters independently associated with liver necroinflammation. Of all 550 patients, 36.73% had necroinflammation. In patients with an abnormal ALT level, the rate of necroinflammation was 52.49%. The area under the curve (AUC) of the ALT level for predicting necroinflammation was 0.655 (95% confidence interval [CI], 0.609‐0.702), and that of the HBV DNA level ≥2000 IU/mL combined with an abnormal ALT level was 0.618. By using the LRM, the AUC improved to 0.769 (95% CI, 0.723‐0.815) with a Youden index of 0.519 and diagnostic accuracy of 75.3%. The cutoff value ≥0.7 in the LRM had a specificity of 97.4% and positive predictive value of 85.0% for predicting necroinflammation. By using the cutoff value <0.15 in the LRM, the presence of necroinflammation could be excluded with a negative predictive value of 90.8%. This study indicated that the LRM can be used to effectively diagnose liver necroinflammation in HBeAg‐negative patients with CHB who have normal or minimally elevated ALT levels. [ABSTRACT FROM AUTHOR]

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