OBJECTIVE: To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients. METHODS: A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented. RESULTS: The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns. CONCLUSION Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).
Adenine ; analogs & derivatives ; therapeutic use ; Adult ; Antiviral Agents ; therapeutic use ; Double-Blind Method ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Hepatitis B e Antigens ; immunology ; Hepatitis B, Chronic ; drug therapy ; immunology ; Humans ; Male ; Medicine, Chinese Traditional ; Organophosphonates ; therapeutic use ; Young Adult

OBJECTIVE: To evaluate the therapeutic effects of entecavir (ETV) and interferon- (IFN-) treatments for 48 weeks for chronic hepatitis B (CHB) in patients with different baseline alanine aminotransferase (ALT) levels. METHODS: We retrospectively analyzed the data of 369 CHB patients receiving ETV and IFN- treatments for 48 weeks. We compared the virological response rates, HBsAg clearance, and HBsAg reduction between the patients receiving ETV and IFN- treatments with different baseline ALT levels[≤ 5×upper limits of normal (ULN) level (subgroup 1), 5-10×ULN (subgroup 2), and > 10× ULN (subgroup 3)]. RESULTS: In patients receiving ETV treatment, the virological response rate was 83.3% in subgroup 1, 91.4% in subgroup 2, and 95.5% in subgroup 3, as compared with 19.7%, 40%, and 42.9% in the 3 subgroups with IFN- treatment, respectively, showing significantly differences both among different subgroups with the same treatment and between the same subgroup with different treatments ( < 0.05). HBeAg clearance rates in the 3 subgroups were 8.3%, 16.7% and 35.5% in patients with ETV treatment and were 1.8%, 41.9%, and 38.1% in patients with IFN- treatment, respectively, showing significant differences among the 3 subgroups with the same treatment ( < 0.05); in the same subgroups with different treatments, the rates differed significantly only between subgroups 2 ( < 0.05). In ETV group, the rate of HBsAg reduction to below 200 IU/ml was 2.5% in subgroup 1 and 13.8% in subgroup 2, showing no significant difference between the two subgroups; in IFN- group, the rates were also similar between subgroups 1 and 2 (30.6% 33.3%, > 0.05); but the rates differed significantly between the same subgroups with different treatments ( < 0.05). CONCLUSIONS In all the subgroups with different baseline ALT levels, ETV treatment for 48 weeks results in significantly higher virological response rates than IFN- treatment in patients with CHB. In patients with a baseline ALT of 5-10 ×ULN, IFN- can result in a higher HBeAg clearance rate than ETV. In patients with comparable baseline ALT level, IFN- more effectively reduces HBsAg level than ETV. The patients with a relatively high baseline ALT level (> 5 × ULN) show better responses to both ETV and IFN- treatment than those with ALT level below 5×ULN. We thus recommend IFN- for patients with a baseline ALT of 5-10×ULN and ETV for patients with a baseline ALT either below 5 × ULN or beyond 10×ULN.
Alanine Transaminase ; blood ; Antiviral Agents ; therapeutic use ; DNA, Viral ; Guanine ; analogs & derivatives ; therapeutic use ; Hepatitis B Surface Antigens ; blood ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; immunology ; Hepatitis B, Chronic ; drug therapy ; enzymology ; immunology ; virology ; Humans ; Interferon-alpha ; therapeutic use ; Retrospective Studies ; Time Factors ; Treatment Outcome ; Viral Load ; drug effects

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

<b>OBJECTIVEb>To explore the effect of Telbivudine (LDT) Tablet combined with Jianpi Bushen Recipe (JBR) on serum hepatitis B virus (HBV) specific cytotoxic T lymphocyte (CTL) and HBeAg seroconversion in chronic hepatitis B (CHB) patients.

<b>METHODSb>Totally 90 HBeAg-positive and human leukocyte antigen (HLA)-A2 positive CHB patients were randomly assigned to the treatment group and the control group, 45 cases in each group. Patients in the treatment group took LDT Tablet (600 mg, once per day) combined with JBR granule (twice per day), while those in the control group took LDT Tablet alone. The therapeutic course for all was one year. HBV DNA negative conversion rate, HBeAg seroconversion rate, and level of HBV specific CTL were compared after 1 year treatment; liver function, drug resistance mutations, and adverse reactions were also compared between the two groups.

<b>RESULTSb>After 1 year treatment, HBV DNA negative conversion rate and HBeAg seroconversion rate were 88.89% (40/45) and 40.00% (18/45) in the treatment group, higher than those of the control group [68.89% (31/45) and 20.00% (9/45)], with statistical difference (P < 0.05). Level of HBV specific CTL in the treatment group was 0.78% +/- 0.09% after treatment, higher than that of the control group after 1 year treatment (0.54% +/- 0.11%) and that before treatment (0.36% +/- 0.07%), with statistical difference (P < 0.01). Level of HBV specific CTL in 27 patients with HBeAg seroconversion was 0.81% 0.10%, higher than that of 63 patients without HBeAg seroconversion (0.60% +/- 0.09%), with statistical difference (P < 0.01). ALT returned to normal in 44 cases of the treatment group (97.78%), while it was 42 cases (93.33%) of the control group, with no statistical difference between the two groups (P > 0.05). Total bilirubin (TBil) in the two groups all turned to normal. rtM204I variation occurred in 1 case (2.22%) of the treatment group and 2 cases (4.44%) in the control group. No obvious adverse reaction occurred in the two groups.

<b>CONCLUSIONb>LDT Tablet combined with JBR could elevate levels of HBV specific CTL and HBeAg seroconversion in CHB patients.

Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; Hepatitis B, Chronic ; drug therapy ; Humans ; Seroconversion ; T-Lymphocytes, Cytotoxic ; immunology ; Tablets ; Thymidine ; analogs & derivatives ; therapeutic use

<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: Quantification of hepatitis B surface antigen (HBsAg) is an emerging serologic test and may be useful for identifying treatment strategies for chronic hepatitis B (CHB). This study aimed to evaluate HBsAg titers during the natural course of CHB and identify correlations between HBsAg titers and hepatitis B virus (HBV) DNA concentrations across different CHB phases measured using an immunoradiometric assay (IRMA). METHODS: CHB phases were defined on the basis of HBV DNA concentrations, the presence of hepatitis B e antigen/antibody (HBeAg/Ab) and serum alanine aminotransferase levels. Serum HBsAg titers and paired HBV DNA concentrations in the different phases of CHB were compared using 627 serum samples. RESULTS: Mean HBsAg titers were significantly higher in the immunotolerant (IT) phase and immunoreactive (IR) HBeAg-positive phase than in the low-replicative (LR) and HBeAg-negative CHB (ENH) states. The correlation between HBsAg titers and HBV DNA concentrations was modest in the IT (n=36, r=0.804, p<0.001) and IR (n=48, r=0.773, p<0.001) phases, and it was poor in the LR state (n=116, r=0.289, p=0.002); however, no significant correlation was observed in the ENH state (n=67, r=0.146, p=0.237) or in the oral nucleos(t)ide analogue-treated group (n=267). CONCLUSIONS: HBsAg quantification using IRMA might be useful for discriminating different CHB phases and different stages of chronic liver disease.
Adult ; Alanine Transaminase/blood ; Biomarkers/blood ; DNA, Viral/*blood ; Disease Progression ; Female ; Hepatitis B Surface Antigens/*blood ; Hepatitis B e Antigens/blood ; Hepatitis B virus/*genetics/immunology ; Hepatitis B, Chronic/*immunology ; Humans ; *Immunoradiometric Assay ; Male ; Middle Aged ; Seoul ; Viral Load ; Virus Replication

BACKGROUND/AIMS: The efficacy of tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B (CHB) patients following prior treatment failure with multiple nucleos(t)ide analogues (NAs) is not well defined, especially in Asian populations. In this study we investigated the efficacy and safety of TDF rescue therapy in CHB patients after multiple NA treatment failure. METHODS: The study retrospectively analyzed 52 CHB patients who experienced failure with two or more NAs and who were switched to regimens containing TDF. The efficacy and safety assessments included hepatitis B virus (HBV) DNA undetectability, hepatitis B envelop antigen (HBeAg) seroclearance, alanine transaminase (ALT) normalization and changes in serum creatinine and phosphorus levels. RESULTS: The mean HBV DNA level at baseline was 5.4 +/- 1.76 log10 IU/mL. At a median duration of 34.5 months of TDF treatment, the cumulative probabilities of achieving complete virological response (CVR) were 25.0%, 51.8%, 74.2%, and 96.7% at 6, 12, 24, and 48 months, respectively. HBeAg seroclearance occurred in seven of 48 patients (14.6%). ALT levels were normalized in 27 of 31 patients (87.1%) with elevated ALT at baseline. Lower levels of HBV DNA at baseline were significantly associated with increased CVR rates (p < 0.001). However, CVR rates did not differ between TDF monotherapy or combination therapy with other NAs, and were not affected by mutations associated with resistance to NAs. No significant adverse events were observed. CONCLUSIONS: TDF is an efficient and safe rescue therapy for CHB patients after treatment failure with multiple NAs.
Adenine/adverse effects/*analogs & derivatives/therapeutic use ; Adult ; Aged ; Alanine Transaminase/blood ; Antiviral Agents/adverse effects/*therapeutic use ; Biological Markers/blood ; Creatinine/blood ; DNA, Viral/blood ; Drug Resistance, Viral/genetics ; Drug Substitution ; Female ; Genotype ; Hepatitis B e Antigens/blood ; Hepatitis B virus/*drug effects/genetics/immunology/pathogenicity ; Hepatitis B, Chronic/blood/diagnosis/*drug therapy ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Mutation ; Phosphorous Acids/adverse effects/*therapeutic use ; Phosphorus/blood ; Retrospective Studies ; Time Factors ; Treatment Failure ; Viral Load ; Young Adult

<b>OBJECTIVEb>To explore the effect of compound qizhu granule (CQG) on cellular immunity of chronic hepatitis B (CHB) patients.

<b>METHODSb>Totally 103 CHB patients treated with lamivudin (LAM) for 6 months, who had partial virological response (HBeAg positive) were randomly assigned to two groups, 50 in the treatment group and 53 in the control group. All patients took LAM 100 mg (once a day) plus ADV 10 mg (once a day). Patients in the treatment group additionally took CQG, one dose per day. After one-year treatment hepatitis B virus (HBV) DNA negative rates, HBeAg seroconversion, levels of HBV specific cytotoxic T lymphocyte (CTL), non-specific CTL and natural killing (NK) cells were compared between the two groups.

<b>RESULTSb>After 1-year treatment, HBV DNA negative rate of the treatment group was 88: 0% in 44 cases, slightly higher than that of the control group (41 cases, 77.4%), but with no statistical difference (P >0.05). HBeAg seroconversion of the treatment group was 32.0% in 16 cases, higher than that of the control group (8 cases, 15.1%), with statistical difference (P <0.05). Levels of HBV specific CTL (0.79%±0. 07%), non-specific CTL (19.4%±1.8%) and NK cells (14. 1%± 1.5%) of the treatment group were higher than those of the control group (0.58% ± 0.08%, 17.5% ± 1.7%, and 11.1%±1.5%, respectively; allP <0.01).

<b>CONCLUSIONb>Treating CHB patients with partial virological response by ADV plus CQG could improve specific and non-specific cellular immunity, thereby elevating HBeAg seroconversion rate.

Drugs, Chinese Herbal ; therapeutic use ; Hepatitis B e Antigens ; immunology ; Hepatitis B virus ; genetics ; Hepatitis B, Chronic ; drug therapy ; immunology ; Humans ; Immunity, Cellular ; immunology ; T-Lymphocytes, Cytotoxic ; drug effects

BACKGROUND/AIMS: The Ministry of Health and Welfare and the Korea Centers for Disease Control and Prevention in South Korea have been organizing hepatitis B virus (HBV) vertical infection prevention projects since July 2002. In this single-institute study, the results of surveys conducted in target mothers who delivered babies in a tertiary hospital were investigated and analyzed. METHODS: Of the 9,281 mothers and their 9,824 neonates born between July 2002 and December 2012, 308 hepatitis B surface antigen (HBsAg)-positive mothers and their 319 neonates were selected for this study, and their records were analyzed retrospectively. RESULTS: A total of 308 mothers were HBsAg-positive, with an HBV prevalence of 3.32% (308/9,281). There were 319 neonates born to these HBsAg-positive mothers, and 252 were confirmed to as either HBsAg-positive or -negative. Four were confirmed as HBsAg-positive, with a 1.59% (4/252) HBV vertical infection rate. All the mothers of neonates who had an HBV vertical infection were hepatitis B e antigen (HBeAg)-positive. Among the HBsAg-positive neonates, three were HBeAg-positive and had an HBV DNA titer of 1.0 x 10(8) copies/mL. CONCLUSIONS: The HBV prevalence of mothers was 3.32% (308/9,281), and their vertical infection rate was 1.59% (4/252). Thus, the South Korean HBV vertical infection prevention projects are effective, and, accordingly, HBV prevalence in South Korea is expected to decrease continuously.
Adult ; Biological Markers/blood ; DNA, Viral/blood ; Female ; Health Surveys ; Hepatitis B/blood/diagnosis/epidemiology/prevention & control/*transmission/virology ; Hepatitis B Surface Antigens/blood ; Hepatitis B e Antigens/blood ; Hepatitis B virus/genetics/immunology ; Humans ; Infant, Newborn ; *Infectious Disease Transmission, Vertical/prevention & control ; *National Health Programs ; Pregnancy ; Prevalence ; Republic of Korea/epidemiology ; Retrospective Studies ; *Tertiary Care Centers ; Viral Load

<b>BACKGROUNDb>Some hepatitis B extracellular antigen (HBeAg)-positive chronic hepatitis B (CHB) patients in their immune active phase can clear the virus spontaneously and enter into an inactive hepatitis B virus (HBV) carrier state, indicating a benign prognosis. In this study, the association between cytokine-inducible SRC homology 2 domain protein (CISH) gene polymorphisms at -292 (rs414171) and the spontaneous clearance of HBV in HBeAg-positive CHB patients in immune the active phase was investigated.

<b>METHODSb>Seventy HBeAg-positive CHB patients in the immune active phase were followed up for 76 weeks without antiviral therapy. The alanine transaminase, aspartate transaminase, HBV DNA, HBeAg and hepatitis B extracellular antibody levels were tested regularly. At week 76, 27 patients were classified into group A (HBV DNA level below 2 104 IU/ml and the value of HBeAg declined below 10% of the baseline at week 76), and 43 patients were classified into group B (HBV DNA level higher than 2×10(4) IU/ml or the value of HBeAg did not decline substantially at week 76). CISH (rs414171) polymorphisms were also tested using the iPLEX system.

<b>RESULTSb>The HBV DNA levels at week 12 were significantly greater in group B compared with group A (group A: (6.87±1.40) log10IU/ml; group B: (7.61±1.38) log10IU/ml, P = 0.034) and the HBeAg values were greater in group B at week 28 compared with group A (P = 0.001). The differences in HBV DNA and HBeAg values increased between the groups over time. Sixteen patients in group A and 11 in group B were genotype AA. Those with genotype AT or TT included 11 in group A and 31 in group B (AA vs. AT and TT, odds ratio 4.10 (95% confidence interval: 1.462-11.491), P = 0.006).

<b>CONCLUSIONb>CISH gene polymorphisms at -292 (rs414171) are associated with HBV clearance in HBeAg-positive CHB patients in the immune active phase, and AA is a favorable genotype for this effect.

Adolescent ; Adult ; Aged ; Female ; Genotype ; Hepatitis B e Antigens ; metabolism ; Hepatitis B virus ; genetics ; immunology ; Hepatitis B, Chronic ; immunology ; Humans ; Male ; Middle Aged ; Polymorphism, Genetic ; genetics ; Suppressor of Cytokine Signaling Proteins ; genetics ; Young Adult