Association of Cytokines with Alanine Aminotransferase, Hepatitis B Virus Surface Antigen and Hepatitis B Envelope Antigen Levels in Chronic Hepatitis B / 中华医学杂志(英文版)

Background@#Cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to investigate the changes of cytokines concentration and its correlation to alanine aminotransferase (ALT), HBV deoxyribonucleic acid (HBV-DNA), hepatitis B envelope antigen (HBeAg), and HBV surface antigen (HBsAg) in the development of chronic hepatitis B (CHB).@*Methods@#Thirteen healthy individuals (HI), 30 chronic HBV-infected patients in immune tolerant (IT) phase, and 55 CHB patients were enrolled between August 2015 and May 2017. The peripheral blood samples were collected from all individuals. The levels of interferon (IFN)-α2, interleukin (IL)-10, transforming growth factor (TGF)-β1, HBV-DNA, HBsAg, and HBeAg and liver function were measured. The quantitative determinations of cytokines levels, including IFN-α2, IL-10, and TGF-β1 were performed using Luminex multiplex technology. The correlation of cytokines to ALT, HBV-DNA, HBsAg, and HBeAg was analyzed by linear regression analysis.@*Results@#IFN-α2 levels were similar between HI and IT groups (15.35 [5.70, 67.65] pg/ml vs. 15.24 [4.07, 30.73] pg/ml, Z = -0.610, P = 0.542), while it elevated significantly in CHB group (35.29 [15.94, 70.15] pg/ml vs. 15.24 [4.07, 30.73] pg/ml; Z = -2.522, P = 0.012). Compared with HI group (3.73 [2.98, 11.92] pg/ml), IL-10 concentrations in IT group (5.02 [2.98, 10.11] pg/ml), and CHB group (7.48 [3.10, 18.00] pg/ml) slightly increased (χ = 2.015, P = 0.365), and there was no significant difference between IT and CHB group (Z = -1.419, P = 0.156). The TGF-β1 levels among HI (3.59 ± 0.20 pg/ml), IT (3.62 ± 0.55 pg/ml), and CHB groups (3.64 ± 0.30 pg/ml) were similar (χ = 2.739, P = 0.254). In all chronic HBV-infected patients (including patients in IT and CHB groups), the elevation of IFN-α2 level was significantly associated with ALT level (β= 0.389, t = 2.423, P = 0.018), and was also negatively correlated to HBV-DNA load (β = -0.358, t = -2.308, P = 0.024), HBsAg (β = -0.359, t = -2.288, P = 0.025), and HBeAg contents (β = -0.355, t = -2.258, P = 0.027). However, when both ALT level and cytokines were included as independent variable, HBV-DNA load, HBsAg, and HBeAg contents were only correlated to ALT level (β = -0.459, t = -4.225, P = 0.000; β = -0.616, t = -6.334, P = 0.000; and β = -0.290, t = -2.433, P = 0.018; respectively).@*Conclusions@#IFN-α2 elevation was associated with ALT level in patients with chronic HBV infection. However, in CHB patients, only ALT level was correlated to HBV-DNA, HBsAg and HBeAg contents.

Plasmacytoid Dendritic Cell Function and Cytokine Network Profiles in Patients with Acute or Chronic Hepatitis B Virus Infection / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Plasmacytoid dendritic cells (pDCs) and cytokines play an important role in occurrence and recovery of hepatitis B virus (HBV) infection. The aim of this study was to explore the frequency and function of pDC and serum cytokine network profiles in patients with acute or chronic HBV infection.</p><p><b>METHODS</b>The healthy individuals (HI group), hepatitis B envelope antigen (HBeAg)-positive chronic HBV patients in immune tolerance (IT) phase (IT group), HBeAg-positive chronic HBV patients (CHB group), and acute HBV patients (AHB group) were enrolled in this study. The frequency of cluster of differentiation antigen 86 (CD86) + pDC and the counts of CD86 molecular expressed on surface of pDC were tested by flow cytometer. The quantitative determinations of cytokines, including Fms-like tyrosine kinase 3 ligand (Flt-3L), interferon (IFN)-α2, IFN-γ, interleukin (IL)-17A, IL-6, IL-10, transforming growth factor (TGF)-β1 and TGF-β2, were performed using Luminex multiplex technology.</p><p><b>RESULTS</b>In this study, there were 13 patients in HI group, 30 in IT group, 50 in CHB group, and 32 in AHB group. Compared with HI group, HBV infected group (including all patients in IT, CHB and AHB groups) had significantly higher counts of CD86 molecular expressed on the surface of pDC (4596.5 ± 896.5 vs. 7097.7 ± 3124.6; P < 0.001). The counts of CD86 molecular expressed on the surface of pDC in CHB group (7739.2 ± 4125.4) was significantly higher than that of IT group (6393.4 ± 1653.6, P = 0.043). Compared with IT group, the profile of cytokines of Flt-3L, IFN-γ, and IL-17A was decreased, IFN-α2 was significantly increased (P = 0.012) in CHB group. The contents of IL-10, TGF-β1, and TGF-β2 in AHB group were significantly increased compared with IT and CHB groups (all P < 0.05).</p><p><b>CONCLUSIONS</b>This study demonstrated that the function of pDC was unaffected in HBV infection. The enhanced function of pDC and IFN-α2 might involve triggering the immune response from IT to hepatitis active phase in HBV infection. Acute patients mainly presented as down-regulation of the immune response by enhanced IL-10 and TGF-β.</p>

Ratios of T-helper 2 Cells to T-helper 1 Cells and Cytokine Levels in Patients with Hepatitis B / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Hepatitis B is an immune response-mediated disease. The aim of this study was to explore the differences of ratios of T-helper (Th) 2 cells to Th1 cells and cytokine levels in acute hepatitis B (AHB) patients and chronic hepatitis B virus (HBV)-infected patients in immune-tolerance and immune-active phases.</p><p><b>METHODS</b>Thirty chronic HBV-infected patients in the immune-tolerant phase (IT group) and 50 chronic hepatitis B patients in the immune-active (clearance) phase (IC group), 32 AHB patients (AHB group), and 13 healthy individuals (HI group) were enrolled in the study. Th cell proportions in peripheral blood, cytokine levels in plasma, and serum levels of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen were detected.</p><p><b>RESULTS</b>The Th1 cell percentage and Th2/Th1 ratio in the HBV infection group (including IT, IC, and AHB groups) were significantly different from those in HI group (24.10% ± 8.66% and 1.72 ± 0.61 vs. 15.16% ± 4.34% and 2.40 ± 0.74, respectively; all P < 0.001). However, there were no differences in the Th1 cell percentages and Th2/Th1 ratios among the IT, IC, and AHB groups. In HBV infection group, the median levels of Flt3 ligand (Flt3L), interferon (IFN)-γ, and interleukin (IL)-17A were significantly lower than those in HI group (29.26 pg/ml, 33.72 pg/ml, and 12.27 pg/ml vs. 108.54 pg/ml, 66.48 pg/ml, and 35.96 pg/ml, respectively; all P < 0.05). IFN-α2, IL-10, and transforming growth factor (TGF)-β2 median levels in hepatitis group (including patients in AHB and IC groups) were significantly higher than those in IT group (40.14 pg/ml, 13.58 pg/ml, and 557.41 pg/ml vs. 16.74 pg/ml, 6.80 pg/ml, and 419.01 pg/ml, respectively; all P < 0.05), while patients in hepatitis group had significant lower Flt3L level than IT patients (30.77 vs. 59.96 pg/ml, P = 0.021). Compared with IC group, patients in AHB group had significant higher median levels of IL-10, TGF-β1, and TGF-β2 (22.77 pg/ml, 10,447.00 pg/ml, and 782.28 pg/ml vs. 8.66 pg/ml, 3755.50 pg/ml, and 482.87 pg/ml, respectively; all P < 0.05).</p><p><b>CONCLUSIONS</b>Compared with chronic HBV-infected patients in immune-tolerance phase, chronic HBV-infected patients in immune-active phase and AHB patients had similar Th2/Th1 ratios, significantly higher levels of IFN-α2, IL-10, and TGF-β. AHB patients had significantly higher IL-10 and TGF-β levels than chronic HBV-infected patients in immune-active phase.</p>

Kinetics of Hepatitis B Surface Antigen Level in Chronic Hepatitis B Patients who Achieved Hepatitis B Surface Antigen Loss during Pegylated Interferon Alpha-2a Treatment / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Hepatitis B surface antigen (HBsAg) loss/seroconversion is considered to be the ideal endpoint of antiviral therapy and the ultimate treatment goal in chronic hepatitis B (CHB). This study aimed to assess the patterns of HBsAg kinetics in CHB patients who achieved HBsAg loss during the treatment of pegylated interferon (PEG-IFN) α-2a.</p><p><b>METHODS</b>A total of 150 patients were enrolled, composing of 83 hepatitis B envelope antigen (HBeAg)-positive and 67 HBeAg-negative patients. Patients were treated with PEG-IFN α-2a180 μg/week until HBsAg loss/seroconversion was achieved, which occurred within 96 weeks. Serum hepatitis B virus deoxyribonucleic acid and serological indicators (HBsAg, anti-HBs, HBeAg, and anti-HBe) were determined before and every 3 months during PEG-IFN α-2a treatment. Biochemical markers and peripheral blood neutrophil and platelet counts were tested every 1-3 months.</p><p><b>RESULTS</b>Baseline HBsAg levels were 2.5 ± 1.3 log IU/ml, and decreased rapidly at 12 and 24 weeks by 48.3% and 88.3%, respectively. The mean time to HBsAg loss was 54.2 ± 30.4 weeks, though most patients needed extended treatment and 30.0% of HBsAg loss occurred during 72-96 weeks. Baseline HBsAg levels were significantly higher in HBeAg-positive patients (2.9 ± 1.1 log IU/ml) compared with HBeAg-negative patients (2.0 ± 1.3 log IU/ml; t = 4.733, P < 0.001), but the HBsAg kinetics were similar. Patients who achieved HBsAg loss within 48 weeks had significantly lower baseline HBsAg levels and had more rapid decline of HBsAg at 12 weeks compared to patients who needed extended treatment to achieve HBsAg loss.</p><p><b>CONCLUSIONS</b>Patients with lower baseline HBsAg levels and more rapid decline during early treatment with PEG-IFN are more likely to achieve HBsAg loss during 96 weeks of treatment, and extended therapy longer than 48 weeks may be required to achieve HBsAg loss.</p>

The Predictive Value of Baseline HBsAg Level and Early Response for HBsAg Loss in Patients with HBeAg-positive Chronic Hepatitis B during Pegylated Interferon Alpha-2a Treatment / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To explore the predictive value of baseline HBsAg level and early response for HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment.</p><p><b>METHODS</b>A total of 121 patients with HBeAg-positive chronic hepatitis B who achieved HBsAg loss were enrolled; all patients were treated with PEG-IFNα-2a 180 μg/week. Serum HBV DNA and serological indicators (HBsAg, anti-HBs, HBeAg, and anti-HBe) were determined before and every 3 months during treatment.</p><p><b>RESULTS</b>The median treatment time for HBsAg loss was 84 weeks (7-273 weeks), and 74.38% (90 cases) of the patients needed extended treatment (> 48 weeks). The correlation between baseline HBsAg levels and the treatment time of HBsAg loss was significant (B = 14.465, t = 2.342, P = 0.021). Baseline HBsAg levels together with the decline range of HBsAg at 24 weeks significantly correlated with the treatment time of HBsAg loss (B = 29.862, t = 4.890, P = 0.000 and B = 27.993, t = 27.993, P = 0.005).</p><p><b>CONCLUSION</b>Baseline HBsAg levels and extended therapy are critical steps toward HBsAg loss. Baseline HBsAg levels together with early response determined the treatment time of HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment.</p>