Objective:b> To dynamically observe the clinical efficacy of entecavir and the changes of PD-1⁺CXCR5⁺CD4⁺T lymphocytes and sPD-1 levels in peripheral blood of HBeAg-positive chronic hepatitis B virus carriers treated with entecavir, and further explore its clinical significance. Methods:b> There were 31 cases of chronic hepatitis B virus carriers in the treatment group (A), 32 cases of chronic hepatitis B virus carriers in the treatment group (B), and 15 cases of chronic hepatitis B virus carriers in the non-treatment group (C).Three groups peripheral blood samples and clinical data at 0, 24 and 48 weeks were collected and compared. PD-1⁺CXCR5⁺CD4⁺T lymphocytes were detected by flow cytometry, and the level of sPD-1 was detected by enzyme-linked immunosorbent assay. ANOVA and Spearman correlation analysis were performed on the measurement data among the three groups. Results:b> At week 0, the serum levels of HBsAg, HBeAg and HBV DNA were significantly higher in groups A and C than group B. PD-1⁺CXCR5⁺CD4⁺T lymphocytes in peripheral blood were significantly higher in group B (4.70%±1.58%) than group A (3.25%±1.01%) and group C (2.77%±0.67%) (F=16.65, P<0.05). There was no significant difference between group A and group C (P>0.05). Peripheral blood sPD-1 in group B [(1 866.62±1 472.70) pg/ml] was significantly higher than group A [(824.86±538.66) pg/ml] and group C [(618.19±602.62) pg/ml] (F=10.95, P<0.05). There was no significant difference between group A and group C (P>0.05). At 48 weeks, the serum HBsAg did not decrease significantly in groups A and C than baseline (P>0.05), but were significantly higher than group B (P<0.05). Serum HBeAg levels were decreased significantly in groups A and B than baseline (P<0.05). <0.05), but group A was significantly higher than group B (P<0.05), and there was no significant difference between group A and group C (P>0.05). Serum HBV DNA level was significantly lower in groups A and B than group C (P<0.05), and there was no significant difference between group A and group B (P>0.05). Peripheral blood PD-1⁺CXCR5⁺CD4⁺T lymphocytes were significantly lower in Group A (1.56%±0.73%) and group B (1.32%±0.43%) than group C (2.64%±0.85%) (P<0.05). Peripheral blood sPD-1 were significantly lower in group A [(289.05±215.86) pg/ml] and group B [(236.01±173.92) pg/ml] than group C [(650.34±598.46) pg/ml] (P<0.05). There was no significant difference between group A and group B. Correlation analysis results: In group A at 48 weeks, the decreased level of PD-1⁺CXCR5⁺CD4⁺T lymphocyte ratio had no correlation with the decreased level of HBsAg and HBV DNA, but was positively correlated with the decreased level of HBeAg (r=0.376, P<0.05). The decreased level of sPD-1 had no correlation with the changes of HBsAg, but was positively correlated with the decreased levels of HBeAg and HBV DNA (r=0.598 and 0.384, P<0.05). In group B at 48 weeks, the decreased levels of PD-1⁺CXCR5⁺CD4⁺T lymphocytes and sPD-1 were positively correlated with the decreased levels of HBsAg, HBeAg, and HBV DNA (P<0.05). Conclusion:b> Hepatitis B virus replication and expressions in HBeAg-positive chronic hepatitis B virus carriers were significantly inhibited after 48 weeks of antiviral treatment, which is related not only to entecavir treatment, but also to the immunological mechanism involved in sPD-1. Moreover, the inhibition of HBeAg expression is associated with a decrease in the number and/or activity of PD-1⁺CXCR5⁺CD4⁺T lymphocytes.
Antiviral Agents/therapeutic use* ; DNA, Viral ; Guanine/analogs & derivatives* ; Hepatitis B Surface Antigens ; Hepatitis B e Antigens ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic ; Humans ; Programmed Cell Death 1 Receptor ; Receptors, CXCR5/analysis* ; T-Lymphocytes

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.
Adult ; Alanine Transaminase ; blood ; Antigens, Surface ; Case-Control Studies ; Cytokines ; blood ; DNA, Viral ; Female ; Hepatitis B ; Hepatitis B Surface Antigens ; analysis ; Hepatitis B e Antigens ; Hepatitis B virus ; Hepatitis B, Chronic ; blood ; immunology ; Humans ; Male ; Young Adult

BACKGROUND/AIMS: Clinical characteristics of patients with chronic hepatitis B (CHB) who developed genotypic resistance to entecavir (ETV) were compared to those without resistance. METHODS: Two hundred fifty eight CHB patients who underwent ETV treatment in our institution from July 2007 to May 2013 were included. RESULTS: Eight (3.1%) patients developed genotypic resistance to ETV during the follow-up period. The patterns of genotypic resistance to ETV were as follows: L180M + M204V + S202G (n=3); M204I + V173M (n=1); I169V + V173M (n=1); L180M + M204V + V173L (n=1); L180M + M204V + V173L + M250V (n=1); M204I + V214A + P237H (n=1). The cumulative occurrence rates of genotypic resistance to ETV were not significantly different between CHB patients with prior nucleos(t)tide analogues (NA) exposure (NA experienced, n=56) and NA naïve patients (n=202, P=0.823 by log rank comparison). Older age, higher baseline log10hepatitis B virus-deoxynucleic acid (log10HBV-DNA), higher log10HBV-DNA at 3, 6, 12 and 24 months after baseline, and complete virologic response (CVR, undetectable serum HBV-DNA by polymerase chain reaction 6 months after ETV treatment) were significant contributors to the development of genotypic resistance to ETV. Multivariate analyses showed higher log10HBV-DNA 6 months after baseline and absence of CVR were independent and significant contributors to the development of ETV resistance. CONCLUSIONS: Clinical characteristics of patients who developed ETV resistance were higher log10HBV-DNA 6 months after baseline and absence of CVR during the ETV treatment.
Follow-Up Studies ; Hepatitis B e Antigens ; Hepatitis B, Chronic* ; Hepatitis, Chronic* ; Humans ; Multivariate Analysis ; Polymerase Chain Reaction

BACKGROUND/AIMS: Entecavir is a potent nucleoside analogue with high efficacy and barrier for resistance. We aimed to investigate the long-term efficacy and viral resistance rate of entecavir and explore the factors associated with virologic response, including quantitative hepatitis B surface antigen (qHBsAg) levels. METHODS: One thousand and nine treatment-naïve chronic hepatitis B (CHB) patients were evaluated for cumulative rates of virologic response, biochemical response, and entecavir mutations. The role of baseline qHBsAg for virologic response was assessed in 271 patients with qHBsAg prior to entecavir treatment. RESULTS: The median duration of entecavir treatment was 26.5 months. The cumulative rate of virologic response at years 1, 3, and 5 were 79.0%, 95.6%, and 99.4%, respectively. The cumulative rate of entecavir resistance was 1.0% and 2.1% in years 3 and 5. Multivariate analysis identified baseline hepatitis B e antigen (HBeAg) negative status (p < 0.001) and lower hepatitis B virus (HBV) DNA (p < 0.001) as predictors of virologic response. Lower qHBsAg was an independent predictor of virologic response in patients with baseline qHBsAg. There were no serious adverse events during treatment. CONCLUSIONS: Long-term entecavir treatment of nucleos(t)ide-naïve CHB patients was associated with an excellent virologic response and a low rate of entecavir-resistant mutations at 5 years. Baseline HBV DNA load, qHBsAg levels, and HBeAg status were predictors of virologic response during entecavir treatment.
DNA ; Hepatitis B e Antigens ; Hepatitis B Surface Antigens* ; Hepatitis B virus* ; Hepatitis B* ; Hepatitis B, Chronic ; Hepatitis* ; Humans ; Multivariate Analysis

BACKGROUND/AIMS: The optimal timing for discontinuing oral antiviral therapy in patients with HBeAg-positive chronic hepatitis B (CHB) is unclear. The aim of our study was to investigate sustained remission after stopping antiviral therapy in patients with HBeAg-positive CHB. METHODS: We analyzed the medical records of 58 patients who were HBeAg-positive and had discontinued antiviral therapy. Antiviral therapy was discontinued after HBeAg seroconversion and HBV DNA negativity for 6-12 months with consolidation therapy. Virologic relapse was defined as an increase in serum HBV DNA >2,000 IU/mL. RESULTS: No difference was observed between the virologic non-relapse and virologic relapse groups in baseline HBV DNA level (p=0.441) or duration of seroconversion (p=0.070). Time-to-undetectable HBV DNA during treatment was shorter in the virologic non-relapse group (29 patients) compared to the relapse group (29 patients) (4.9+/-2.6 vs. 13.2+/-12.7 months; p<0.01). Cumulative relapse rates were 12.7 in month 3, 32.7 in month 6, 47.3 in month 12, and 52.7% in month 18. We determined by multivariate analysis that the consolidation period (> or =18 months, p=0.020) and early virologic response (HBV DNA <20 IU/mL) at six months during antiviral therapy (p=0.017) were significant predictors for sustained remission. CONCLUSIONS: A consolidation period of at least 18 months and early virological response at six months during antiviral therapy were associated with sustained remission in patients with HBeAg-positive CHB after treatment.
Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/analysis ; Female ; Hepatitis B e Antigens/*blood ; Hepatitis B virus/genetics/isolation & purification ; Hepatitis B, Chronic/*drug therapy ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Proportional Hazards Models ; Recurrence ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Withholding Treatment

<b>OBJECTIVEb>To investigate the risk factors for mother-to-child transmission of hepatitis B virus (HBV) and the efficacy of hepatitis B immunoprophylaxis in children at high risk of hepatitis B.

<b>METHODSb>A questionnaire survey was performed on 539 HBsAg-positive mothers and their 551 children (aged from 6 months to 5 years) at high risk of hepatitis B. Serum markers of hepatitis B in the children at high risk of hepatitis B were measured. Univariate logistic regression analysis was used to investigate the risk factors for mother-to-child transmission of HBV.

<b>RESULTSb>The rate of hepatitis B vaccination in the children at high risk of hepatitis B was 100%, and 96.6% received injections of hepatitis B vaccine and hepatitis B immunoglobulin (HBIG). The HBsAg positive rate showed no significant differences between different age groups. The HBsAb positive rate gradually decreased with the increasing age (P<0.01). The children born to HBsAg- and HBeAg-positive mothers had a significantly higher hepatitis B infection rate than those born to HBsAg-positive mothers (15.1% vs 0.2%; P<0.01). The high-risk children who received hepatitis B vaccination alone had a significantly higher hepatitis B infection rate than those who received both hepatitis B vaccine and HBIG injections (28.6% vs 2.8%; P<0.01).

<b>CONCLUSIONSb>The HBsAb positive rate gradually decreases with the increasing age in children at high risk of hepatitis B. Maternal HBsAg and HBeAg positivity and the absence of HBIG combined with hepatitis B vaccine injections for children at high risk of hepatitis B are the risk factors for mother-to-child transmission of HBV.

Child, Preschool ; Female ; Hepatitis B ; etiology ; prevention & control ; Hepatitis B Surface Antigens ; analysis ; Hepatitis B Vaccines ; immunology ; Hepatitis B e Antigens ; analysis ; Humans ; Immunoglobulins ; immunology ; Infant ; Infectious Disease Transmission, Vertical ; prevention & control ; Male ; Risk Factors

BACKGROUND/AIMS: The optimal management of patients exhibiting a partial virologic response (PVR) to entecavir (ETV) has not been determined . The aim of this study was to determine the long-term efficacy of prolonged ETV monotherapy in treatment-naive chronic hepatitis B (CHB) patients exhibiting a PVR to ETV therapy. METHODS: This study included 364 treatment-naive CHB patients treated with ETV for > or =48 weeks and who received continuous ETV monotherapy for > or =96 weeks. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA of more than 2 log10 IU/mL from baseline but with detectable HBV DNA by real-time PCR assay at week 48. RESULTS: Fifty-two of the 364 patients (14.3%) showed a PVR. Among them, 41 patients received continuous ETV monotherapy for > or =96 weeks (median duration 144 weeks, range 96-312 weeks), and 40 of these patients (95%) achieved a virologic response (VR, HBV DNA <20 IU/mL) during prolonged ETV monotherapy (median duration 78 weeks, range 60-288 weeks). The cumulative probabilities of a VR at weeks 96, 144, and 192 from treatment initiation were 78.0%, 92.7%, and 95.1%, respectively. The VR rate was 97.2% (35/36) in HBeAg-positive patients and 100% (5/5) in HBeAg-negative patients. In multivariate analysis, HBeAg positivity (odds ratio [OR], 9.231; 95% confidence interval [CI], 1.03-82.91; P=0.047) and a high baseline HBV DNA level (OR, 0.170; 95% CI, 0.08-0.37; P=0.000) were independently associated with a delayed virologic response. No patient developed genotypic resistance to ETV during follow-up. CONCLUSIONS: Long-term ETV monotherapy is effective for achieving a VR in treatment-naive CHB patients exhibiting a PVR to ETV. HBeAg positivity and high baseline HBV DNA level were independently associated with a delayed virologic response.
Adult ; Aged ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Drug Administration Schedule ; Female ; Genotype ; Guanine/*analogs & derivatives/therapeutic use ; Hepatitis B e Antigens/blood ; Hepatitis B virus/genetics ; Hepatitis B, Chronic/*drug therapy/pathology/virology ; Humans ; Liver Cirrhosis/etiology/radiography/ultrasonography ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Multivariate Analysis ; Odds Ratio ; Real-Time Polymerase Chain Reaction ; Retrospective Studies ; Tomography, X-Ray Computed ; Treatment Outcome

<b>BACKGROUNDb>Cirrhosis is a common complication of chronic hepatitis B. It remains unclear if viral and biochemical parameters at baseline affect virological response to entecavir and therefore warrant investigation. In the present study, we aimed to evaluate the efficacy of entecavir therapy by monitoring virological response at the end of the 3 rd month of treatment and try to figure out whether baseline factors could help predict it in a cohort of hepatitis B virus (HBV) compensated cirrhosis patients and to determine the cut-off value of a predicting parameter.

<b>METHODSb>A total of 91 nucleos(t)ide-naïve patients with HBV induced cirrhosis (compensatory stage) were enrolled in a prospective cohort. HBV DNA and alanine aminotransferase (ALT) were tested at baseline and monitored every 3-6 months after starting therapy.

<b>RESULTSb>Of all 91 patients, the median follow-up time was 12 (9-24) months. Overall, 64 patients (70.3%) achieved virological response in the 3 rd month. Univariate analysis showed that the 3 rd month virological response can be predicted by baseline HBV DNA levels (P < 0.001, odds ratio [OR]: 2.13, 95% confidence interval [CI]: 1.44-3.15), ALT value (P = 0.023, OR: 1.01, 95% CI: 1.00-1.01) and hepatitis B e antigen (HBeAg) negativity (P = 0.016, OR: 0.30, 95% CI: 0.11-0.80). Multiple regression analysis showed baseline HBV DNA level was the only parameter related to full virological response. Higher baseline HBV DNA strata indicated a higher probability that HBV DNA remains detectable at the 3 rd month (P = 0.001). Area under receiver operating characteristic curve for determining the 3 rd month virological response by baseline HBV DNA was 77.6% (95% CI: 66.7-85.2%), with a best cut-off value of 5.8 log 10 .

<b>CONCLUSIONSb>Baseline HBV DNA, HBeAg negativity, and ALT were independent factors contributing to virological response at the 3 rd month. Further, multiple regression showed that HBV DNA level was the only parameter predicting full virological response as early as the 3 rd month, in this cirrhosis cohort.

Adolescent ; Adult ; Aged ; Alanine Transaminase ; metabolism ; Antiviral Agents ; therapeutic use ; DNA, Viral ; genetics ; Female ; Guanine ; analogs & derivatives ; therapeutic use ; Hepatitis B e Antigens ; metabolism ; Hepatitis B virus ; genetics ; metabolism ; pathogenicity ; Hepatitis B, Chronic ; drug therapy ; virology ; Humans ; Liver Cirrhosis ; drug therapy ; virology ; Male ; Middle Aged ; Prospective Studies ; Regression Analysis ; Retrospective Studies ; Young Adult

<b>OBJECTIVEb>To evaluate long-term cost-effectiveness of nucleoside analogues and peg-interferon alfa-2a (peg-IFNa2a) for the treatment of chronic hepatitis B (CHB) in hepatitis B e antigen (HBeAg)-negative patients.

<b>METHODSb>A multi-health slate Markov model was developed based on the disease progression pattern to estimate the long-term effect and medical expense of different treatments for HBeAg-negative CHB.Incremental cost-effectiveness analysis was then carried out.

<b>RESULTSb>In comparison with no antiretroviral treatment, all of the antiretroviral treatments were capable of prolonging CHB patients' life years.In particular, entecavir plus adefovir dipivoxil combination therapy showed the best 2 year survival, with expected life-years and quality-adjusted life-years (QALYs) being 19.59 years and 10.12 years, respectively, which were 1.46 years and 1.12 years better than with no antiretroviral treatment. The most cost-effective treatment for HBeAg-negative CHB was lamivudine plus adefovir dipivoxil rescue therapy, as it prolonged survival by 0.95 QALYs with an additional 15459 yuan; the incremental medical cost for gaining 1 QALY was 16273 yuan.

<b>CONCLUSIONb>Among the antiretroviral medicines applied as therapy for HBeAg-negative CHB in China, the most effective treatment is entecavir plus adefovir dipivoxil rescue therapy and the most cost-effective treatment is lamivudine plus adefovir dipivoxil rescue therapy.

Adenine ; analogs & derivatives ; Antiviral Agents ; China ; Cost-Benefit Analysis ; Economics, Pharmaceutical ; Guanine ; analogs & derivatives ; Hepatitis B e Antigens ; Hepatitis B, Chronic ; Humans ; Interferon-alpha ; Lamivudine ; Organophosphonates ; Polyethylene Glycols ; Quality-Adjusted Life Years ; Recombinant Proteins

BACKGROUND/AIMS: Long-term use of nucleos(t)ide analogues (NA) may lead to genotypic and/or phenotypic resistance of the hepatitis B virus (HBV). We investigated the efficacy of tenofovir-based rescue therapy in chronic hepatitis B (CHB) patients with newly developed genotypic resistance to prior NAs or partial virologic response to sequential rescue therapies. METHODS: Fifty-four CHB patients were included retrospectively. The patients were treated with tenofovir alone or combined with lamivudine or entecavir. RESULTS: There were 26 forms of genotypic resistance at enrollment. The median amount of serum HBV-DNA was 18,438 IU/mL and 83% of samples were positive for hepatitis B e antigen (HBeAg). Serum HBV-DNA was undetectable in 50%, 61%, and 76% of the patients at 3, 6, and 12 months, respectively. In multivariate analysis, HBV-DNA < 20,000 IU/mL and negative HBeAg at baseline were independent predictors of negativity for serum HBV-DNA. Interestingly, the rtS202 mutation tended to be associated with an unfavorable response. Other clinical variables and viral resistance genotypes showed non-significant viral response. CONCLUSIONS: Lower serum HBV-DNA, negative HBeAg and lack of rtS202G mutations at baseline may predict a favorable response to tenofovir-based rescue therapies in CHB patients with newly developed genotypic resistance to prior NAs or a partial virologic response to sequential rescue therapies.
Drug Resistance ; Genotype ; Hepatitis B ; Hepatitis B e Antigens ; Hepatitis B virus ; Hepatitis B, Chronic* ; Hepatitis, Chronic* ; Humans ; Lamivudine ; Multivariate Analysis ; Retrospective Studies ; Tenofovir