Ming-Hui Li

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a.

AIM To examine the association between interferon (IFN) therapy and loss of hepatitis B surface antigen (HBsAg) in inactive HBsAg carriers. METHODS This was a retrospective cohort study in inactive HBsAg carriers, who were treatment-naive, with a serum HBsAg level < 100 IU/mL and an undetectable hepatitis B virus (HBV) DNA level (< 100 IU/mL). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBsAg, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. RESULTS Thirteen (65.0%) of 20 treated patients achieved HBsAg loss, 12 of whom achieved HBsAg seroconversion. Mean HBsAg level in treated patients decreased to 6.69 ± 13.04 IU/mL after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/mL. Serum HBV DNA level remained undetectable (< 100 IU/mL) in all treated patients during the study. HBsAg level of the control group decreased from 25.72 ± 25.58 IU/mL at baseline to 17.11 ± 21.62 IU/mL at week 96 (P = 0.108). In the control group, no patient experienced HBsAg loss/seroconversion, and two (5.0%) developed HBV reactivation. CONCLUSION IFN treatment results in HBsAg loss and seroconversion in a considerable proportion of inactive HBsAg carriers with low HBsAg concentrations.

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

Background: 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) &agr;-2a. Methods: 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 &agr;-2a180 &mgr;g/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 &agr;-2a treatment. Biochemical markers and peripheral blood neutrophil and platelet counts were tested every 1–3 months. Results: 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. Conclusions: 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.

Negative Correlation of Serum Hepatitis B Surface Antigen and Hepatitis B e Antigen Levels with the Severity of Liver Inflammation in Treatment-naïve Patients with Chronic Hepatitis B Virus Infection

Background: Estimating the grades of liver inflammation is critical in the determination of antiviral therapy in patients chronically infected with hepatitis B virus (HBV). The aim of this study was to investigate the correlation of serum levels of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) with the liver inflammation grades in treatment-naïve patients with chronic HBV infection. Methods: We retrospectively enrolled 584 treatment-naïve HBeAg-positive patients who underwent liver biopsy in Ditan Hospital from January 2008 to January 2016. Based on the severity of liver inflammation, the patients were divided into minimal, mild, and moderate groups. SPSS software was used for statistical analysis of all relevant data. Results: The liver histological examinations showed that 324, 194, and 66 patients had minimal, mild, and moderate liver inflammation, respectively. The median age of the three groups was 30, 33, and 38 years, respectively (&khgr;2 = 26.00, P < 0.001). The median HBsAg levels in minimal, mild, and moderate inflammation groups were 4.40, 4.16, and 3.67 log U/ml, respectively, and the median HBeAg levels in the three groups were 3.12, 2.99, and 1.86 log sample/cutoff, respectively; both antigens tended to decrease as the grade of inflammation increased (&khgr;2 = 99.68 and &khgr;2 = 99.23, respectively; both P < 0.001). The cutoff values of receiver operating characteristic curve in the age, HBsAg and HBeAg levels were 36 years, 4.31 log U/ml, and 2.86 log S/CO, respectively, l to distinguish minimal grade and other grades of treatment-naïve HBeAg-positive patients with chronic HBV infection. Conclusions: Serum HBsAg and HBeAg quantitation might gradually decrease with aggravated liver inflammation and the corresponding cutoff values might help us to distinguish minimal grades and other grades and detect those who do not need antiviral therapy in treatment-naïve HBeAg-positive patients with chronic HBV infection.

The characteristics and predictors of postpartum hepatitis flares in women with chronic hepatitis B

Introduction: We aimed to characterize postpartum disease flares among treatment‐naive mothers with chronic hepatitis B (CHB). CHB mothers were enrolled and compared with non‐infected mothers in terms of postpartum alanine aminotransferase (ALT) abnormalities. Methods: Demographic, virological, and biochemical parameters were collected up to postpartum week 16, with flares and exacerbations defined as ALT levels 5–10 and >10 times the upper limit of normal, respectively. Outcome assessments included ALT flares or exacerbation and their predictive parameters. Results: Among 4236 patients enrolled, 869 and 3367 had no infection (group A) and had CHB (group B), respectively. Infected mothers were further stratified into two subgroups by the presence (B1, n = 1928) or absence (B2, n = 1439) of detectable serum levels of hepatitis B virus (HBV) DNA (lowest level of quantitation, 100 IU/mL). A significantly higher frequency of abnormal ALT levels was observed in group B vs. group A (28.27 vs. 20.37%, p < 0.001). ALT events mainly occurred in group B1 (flares, 115/1928, 5.96%; exacerbations, 57/1928, 2.96%). The ALT levels had a bimodal pattern, with peaks at postpartum weeks 3–4 and 9–12. On multivariate analysis, elevated ALT levels and detectable levels of HBV DNA at delivery were independent risk factors for postpartum disease flares. Further subgroup analysis in group B1 demonstrated that a cut‐off HBV DNA level of 5 log10 IU/mL at delivery predicted ALT events (positive predictive value, 14.4%; negative predictive value, 98.2%). Conclusions:: Postpartum ALT level elevation is common in CHB patients. ALT flares or exacerbations are mainly observed in mothers with elevated ALT or HBV DNA levels ≥5 log10 IU/mL at delivery.

Quantitation of Plasmacytoid Dendritic Cells in Chronic Hepatitis B Patients with HBeAg Positivity During PEG-IFN and Entecavir Therapy

Plasmacytoid dendritic cells (pDCs) are crucial for control of chronic hepatitis B (CHB) virus infection. In this study, we evaluated the frequencies of pDCs and expression of functional molecules on pDCs in patients treated with PEG-IFN-α-2a or entecavir (ETV) and investigated changes during treatment. The mean fluorescence intensity of CD86 (CD86MFI) on the surface of pDCs and frequencies of pDCs and CD86+ pDCs in peripheral blood were measured. Compared with baseline, CD86+ pDC% and CD86MFI increased obviously after PEG-IFN-α-2a treatment for 12 and 24 weeks. For patients treated with ETV, only pDC% increased observably after treatment weeks 12 and 24 (P < 0.001) compared with baseline. Hepatitis B surface antigen (HBsAg) decline was significantly associated with elevated CD86+ pDC% (r = 0.348, P = 0.015) during PEG-IFN-α-2a treatment. In the HBsAg response group, CD86+ pDC% and CD86MFI (P < 0.001) increased observably after PEG-IFN-α-2a therapy, whereas only CD86MFI had a statistically significant difference after therapy compared with baseline (12 weeks versus 0 weeks, P = 0.022; 24 weeks versus 0 weeks, P = 0.015) in the HBsAg nonresponse group. CD86+ pDC% between the 2 groups had statistically significant differences at baseline (P = 0.001) and at the treatment time points of 12 and 24 weeks (P < 0.001), respectively. For patients receiving ETV therapy, pDC% increased observably, but CD86+ pDC% decreased significantly (P < 0.001) in the HBV DNA nonresponse group during early treatment with ETV. In CHB patients, HBsAg response in PEG-IFN-α-2a therapy correlated with the increase of CD86+ pDC% and HBV DNA nonresponse in ETV treatment correlated with the decrease of CD86+ pDC%.

Plasmacytoid Dendritic Cell Function and Cytokine Network Profiles in Patients with Acute or Chronic Hepatitis B Virus Infection

Background: 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. Methods: 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)-&agr;2, IFN-&ggr;, interleukin (IL)-17A, IL-6, IL-10, transforming growth factor (TGF)-&bgr;1 and TGF-&bgr;2, were performed using Luminex multiplex technology. Results: 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-&ggr;, and IL-17A was decreased, IFN-&agr;2 was significantly increased (P = 0.012) in CHB group. The contents of IL-10, TGF-&bgr;1, and TGF-&bgr;2 in AHB group were significantly increased compared with IT and CHB groups (all P < 0.05). Conclusions: This study demonstrated that the function of pDC was unaffected in HBV infection. The enhanced function of pDC and IFN-&agr;2 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-&bgr;.

Association of Cytokines with Alanine Aminotransferase, Hepatitis B Virus Surface Antigen and Hepatitis B Envelope Antigen Levels in Chronic Hepatitis B

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)-&agr;2, interleukin (IL)-10, transforming growth factor (TGF)-&bgr;1, HBV-DNA, HBsAg, and HBeAg and liver function were measured. The quantitative determinations of cytokines levels, including IFN-&agr;2, IL-10, and TGF-&bgr;1 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-&agr;2 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 (&khgr;2= 2.015, P = 0.365), and there was no significant difference between IT and CHB group (Z = −1.419, P = 0.156). The TGF-&bgr;1 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 (&khgr;2= 2.739, P = 0.254). In all chronic HBV-infected patients (including patients in IT and CHB groups), the elevation of IFN-&agr;2 level was significantly associated with ALT level (&bgr;= 0.389, t = 2.423, P = 0.018), and was also negatively correlated to HBV-DNA load (&bgr; = −0.358, t = −2.308, P = 0.024), HBsAg (&bgr; = −0.359, t = −2.288, P = 0.025), and HBeAg contents (&bgr; = −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 (&bgr; = −0.459, t = −4.225, P = 0.000; &bgr; = −0.616, t = −6.334, P = 0.000; and &bgr; = −0.290, t = −2.433, P = 0.018; respectively). Conclusions: IFN-&agr;2 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.

Prospective cohort study on the efficacy and safety of telbivudine used throughout pregnancy in blocking mother-to-child transmission of hepatitis B virus

Women with chronic hepatitis B should maintain nucleotide analogue treatment to prevent disease progression during pregnancy. The aim of this study was to prospectively evaluate the efficacy and safety of telbivudine used throughout pregnancy for preventing hepatitis B virus (HBV) mother‐to‐child transmission (MTCT). From January 2012 to June 2014, women who were receiving telbivudine therapy and became pregnant were enrolled in group A at 28 weeks of gestation. Pregnant women with an HBV DNA level >106 IU/mL were enrolled in either group B (telbivudine started at 28 weeks of gestation) or group C (control group without treatment). MTCT was defined as infants who were positive for serum hepatitis B surface antigen at 7 months after birth. There were 41, 179 and 177 pregnant women (397 infants) enrolled in groups A, B and C, respectively. The HBV DNA load at 28 weeks of gestation and delivery was 1.50 ± 0.62 vs 1.45 ± 0.61, 8.05 ± 0.37 vs 4.24 ± 0.89 and 7.94 ± 0.62 vs 7.86 ± 0.73 log10 IU/mL in groups A, B and C, respectively. The rate of MTCT in group C was 4.60%, which was significantly higher than the rates in groups A and B (0% and 0.6%, respectively) (P = .043). The difference between group A and group B was not significant. The rates of neonatal congenital abnormalities were 2.4%, 0.6% and 2.3% in groups A, B and C, respectively, and there were no significant differences (P = .140). Telbivudine used throughout pregnancy may be safe and effective for mothers and infants, but it may not enhance the efficacy of an HBV MTCT block compared with treatment starting at 28 weeks of gestation (NCT02253485).

Ratios of T-helper 2 Cells to T-helper 1 Cells and Cytokine Levels in Patients with Hepatitis B

Background: 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. Methods: 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. The 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. Results: 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)-&ggr;, 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-&agr;2, IL-10, and transforming growth factor (TGF)-&bgr;2 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-&bgr;1, and TGF-&bgr;2 (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). Conclusions: 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-&agr;2, IL-10, and TGF-&bgr;. AHB patients had significantly higher IL-10 and TGF-&bgr; levels than chronic HBV-infected patients in immune-active phase.

The Predictive Value of On-treatment Virological Response for Sustained Virological Response in Chronic Hepatitis C Patients Receiving a Personalized Treatment Program

Abstract Objective To investigate the effects of individualised treatment with peginterferon alpha-2a (40 kD) plus ribavirin in Chinese patients with CHC. Methods Total of 297 consecutive Chinese patients were enrolled, including 250 naïve cases and 47 cases who were previously treated. Treatment duration was determined according to viral genotypes, prior treatment history and viral responses at week 4, 12 and 24. Results Totally, 235 patients (79.1%) completed treatment and 186 (87.3%) achieved SVR. And 219 out of 289 (75.8%) patients achieved HCV RNA negative at week 4 (RVR) and 259 of 276 (93.8%) at week 12. Among the 164 patients with RVR who completed follow-up, 158 (96.3%) achieved SVR. Patients with RVR had lower baseline viral loads than patients without RVR (P = 0.034). The positive predictive value (PPV) of RVR for SVR was 90.7% (OR 2.10 vs. non-RVR, 95% CI: 0.50 - 8.7). Similar outcomes were observed among patients with HCV undetectable at week 12. Conclusions Complete viral suppression by week 4 is associated with a high rate of treatment success in treatment naïve and experienced patients receiving individualized CHC therapy.