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Chronic HBV infection can generally be divided into four stages according to the natural course of disease. Clinically, the determination of different natural stages of chronic HBV infection is crucial for patients to start antiviral therapy and to avoid missing the antiviral opportunity and progressing to cirrhosis. In particular, it is a challenge for clinicians to distinguish the immune control stage from the reactive stage. As a novel marker of HBV, the quantitative detection of HBV core-associated antigen (HBcrAg) is of value for the identification of the HBV infection stages. This article reviews the research progress of HBcrAg in the identification of different stages of chronic HBV infection.
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Background:Peripheral blood mononuclear cells containing an aggregate of immune competent cells,such as T lymphocytes, B cells and natural killer cells, play an important role in control or persistence of the hepatitis B virus(HBV) infection. Similarly, the expression of hepatitis B viral antigens on the surface of infected hepatocytes can invoke a cytotoxic T–cell response.Objective:To investigate the dynamic changes in hepatitis B surface antigen (HBsAg) and peripheral lymphocyte subsets of healthy donors and chronic hepatitis B patients. Methodology:Serum HBsAg was quantified by enzyme-linked immunosorbent assayaccording to the manufacturer’s guidelines. Peripheral blood lymphocyte cell phenotyping was carried out by flow cytometry for all chronic hepatitis B patients and healthy blood donors Results:The results of this study showed a significant correlation between HBsAg level and percentage of T and NK cells (r=0.366; P=0.01, r=-0.462; P=0.01,respectively). On the other hand, significance variation in peripheral blood lymphocyte percentage of T lymphocyte subsets in patients were found to be directly proportional to T cell subsets CD4+and CD8+ (P=0.001)compared with healthy blood donor controls. Conclusion:In conclusion this study highlighted the role of the HBsAg level in supressing the immune cells of the innate and adaptive immune system. Understanding the interactions between HBsAg and peripheral blood cells serves as a basis for development of HBV therapeutic vaccines and a prognostic biomarker in persistent HBV infection
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Objective@#To observe the changes of liver function, virology and serology and the safety of drug withdrawal in pregnant women who are chronic hepatitis B virus (HBV) carriers.@*Methods@#A prospective clinical cohort was established to enroll pregnant women who are chronic HBV carriers and they were divided into the nucleoside/nucleotide analogs (NAs) intervention group and the non-NAs intervention group according to patients' wishes. Liver function, HBV DNA and HBV serological markers were detected at gestation, postpartum 6 weeks, 12 weeks, 24 weeks, 36 weeks and 48 weeks.@*Results@#351 patients were enrolled, 320 in the NAs intervention group and 31 in the non-NAs intervention group. The proportion of postpartum hepatitis flares in both groups was higher than that in pregnancy (39.4% vs 12.5%, P < 0.001; 38.7% vs 3.2%, P = 0.001). Six weeks postpartum was the peak period of hepatitis flares, and 96.0% (121/126) of the hepatitis flares occurred within 24 weeks postpartum. At 6 weeks postpartum, there were 6 cases of alanine aminotransferase (ALT) ≥ 10 times upper limit of normal (ULN) in the NAs intervention group. The rate of the hepatitis flare after drug withdrawal was 16.7% (34/203).@*Conclusion@#Regardless of the presence or absence of NAs intervention, pregnant women who are chronic HBV carriers have a certain proportion of hepatitis flares during pregnancy and postpartum, and the hepatitis flare even have a tendency to be severe. Therefore, drug withdrawal after delivery is not always safe, which requires close observation and classification. At 6 weeks postpartum, the incidence of hepatitis flares was high, and those who meet the treatment indications can get better therapeutic effects if given appropriate treatment. The vast majority (96%) of postpartum hepatitis flares occur within 24 weeks, so it is recommended to follow up to at least 24 weeks postpartum after discontinuation.
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Objective To analyze the sequence of Pre-S gene in asymptomatic chronic HBV carriers (ASCs) with low-level HBsAg.Methods The serum samples were collected from 654 ASCs in the First Affiliated Hospital of Zhejiang University School of Medicine , Hangzhou Sixth People’s Hospital and the 903th Hospital of PLA.According to the level of HBsAg , ASCs were divided into low-level HBsAg group (≤10 IU／mL ) and high-level HBsAg group (＞10 IU／mL ).The pre-S／S gene amplification and sequencing were performed in 138 ASCs with low-level HBsAg and 100 age-matched ASCs with high-level HBsAg.A phylogenetic tree was constructed to determine the genotype , based on the successful sequencing results of Pre-S gene in the high level HBsAg group , the Pre-S gene reference sequences of the main ASCs genotypes in Eastern China were established.The sequence of Pre-S gene in low-level HBsAg group was analyzed and compared with the reference sequences.SPSS 12.01 statistical software was used to analyze the data.Results Sixty-three cases of Pre-S／S were successfully sequenced in 138 ASCs of low-level HBsAg group, including 52 cases of B genotype and 11 cases of C genotype.Among the 100 cases of high-level HBsAg group, 94 cases of Pre-S／S were successfully sequenced , including 48 cases of B genotype and 46 cases of C genotype.The sequence analysis indicated that in the B genotype , 81 amino acid mutation sites were found in the Pre-S protein of the low-level HBsAg group, including 4 significant mutations: F56I／V, T76A／N／P in the Pre-S1 region, P15L／S／T and Y21T／F／H／N in the Pre-S2 region; while 47 amino acid mutation sites were found in Pre-S protein of high-level HBsAg group, including 3 significant mutations :L34F, V49A and P59S／L in Pre-S1 region.The total number of amino acid mutation sites in the low-level HBsAg group of B genotype was higher than that of the high-level HBsAg group (χ2 ＝14.008, P＜0.05). In the C genotype, 19 amino acid mutation sites were found in the Pre-S protein of the low-level HBsAg group, including 3 significant mutations : W66V／G and A79V in the Pre-S1 region,V32A in the Pre-S2 region; while 39 amino acid mutation sites were found in Pre-S protein of the high-level HBsAg group, including 2 significant mutations: A79V in Pre-S1 region and T49I in Pre-S2 region.The total number of amino acid mutation sites of Pre-S protein in the C genotype was significantly different between the two groups (χ2 ＝7.571, P＜0.05).Conclusion Significant mutations in Pre-S gene may be associated with the persistent expression of low-level HBsAg in ASCs.
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Objective To analyze the change of intrahepatic regulatory T cells (Treg )/helper thymphorytes (Th)17 balance in patients with different phases of chronic hepatitis B virus (HBV ) infection ,and to explore the role of Treg/Th17 balance in maintaining immune tolerance and inducing immune clearance ,and its influence on disease progression .Methods Sixty-eight patients with chronic HBV infection who underwent liver biopsy in Tianjin Second People′s Hospital were included .The 68 patients included 20 cases in immune tolerant (IT) phase ,36 cases in immune clearance (IC) phase and 12 cases in inactive phase .Eight healthy liver transplant donors were collected as healthy controls .The intrahepatic Treg/Th17 levels were detected by immuno-histochemical method . The changes of Treg/Th17 balance in patients with different phases of chronic HBV infection ,and the relationship between Treg/Th17 balance and the decreases of hepatitis B surface antigen (HBsAg ) , hepatitis B antigen (HBeAg) and HBV DNA levels in the peripheral blood were analyzed in patients with IC phase at two weeks of admission .Results The intrahepatic Treg and Th17 levels in IC phase group were the highest , then and they were higher in inactive phase group were higher than those in IT phase group ,And they were the lowest in control group .The Treg level in IC phase group increased significantly compared with the other three groups (all P< 0 .01) ,and there were no significant differences among the other three groups (all P> 0 .05) .The Th17 level between IT phase group and inactive phase group was not significantly different (P> 0 .05) ,while the differences were not significant in other groups (all P>0 .05) .Treg/Th17 ratio of IT phase group was the highest ,then the ratio of control group was higher than that of inactive phase group ,and IC phase group was the lowest ratio .The differences between IC phase group ,control group and IT phase group were significant (all P< 0 .05) ,and the difference between inactive phase group and IT phase group was also significant (all P<0 .05);and there was no significant difference among other groups (all P>0 .05) .The decreases of HBsAg ,HBeAg and HBV DNA levels in the peripheral blood at two weeks admission were negatively correlated with the intrahepatic Treg cell level in patients in IC phase of chronic HBV infection ( r= -0 .941 ,-0 .869 ,and -0 .883 ,respectively ,both P<0 .01) .The Treg ,Th17 levels and their ratio in IC phase group with different degree of inflammation and fibrosis had significant differences :G4 group > G3 group > G2 group ,S3 group > S2 group > S1 group (all P<0 .05) .Conclusions There is no change of the Treg/Th17 balance in IT phase ,and Treg has no influence on maintaining immune tolerance in chronic HBV infection .T he imbalance of Treg/Th17 is observed in IC phase .Th17 may actively participate in the immune-mediated liver injury and the development of hepatic fibrosis in CHB patients .Treg may inhibit inflammation and reduce liver injury via the negative feedback regulation mechanism ,and may impede the eradication of HBV simultaneously .
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Background: Research has shown that hepatitis B virus (HBV) genotypes are closely linked to the clinical manifestations, treatment, and prognosis of the disease. Objective: To study the association between genotype and drug-resistant HBV mutations in 620 Chinese patients with chronic HBV infection. Methods: HBV DNA levels were determined using real-time quantitative PCR in plasma samples. Microarrays were performed for the simultaneous detection of HBV genotypes (HBV/B, C, and D) and drug-resistance-related hotspot mutations. A portion of the samples analyzed using microarrays was selected randomly and the data were confirmed using direct DNA sequencing. Results: Most samples were genotype C (471/620; 76.0%), followed by genotype B (149/620; 24.0%). Among the 620 patient samples, 17 (2.7%) had nucleotide analogs (NA) resistance-related mutations. Of these, nine and eight patients carried lamivudine (LAM)-/telbivudine (LdT)-resistance mutations (rtL180M, rtM204I/V) and adefovir (ADV)-resistance mutations (rtA181T/V, rtN236T), respectively. No patients had both lamivudine (LAM)- and either ade-fovir (ADV) or entecavir (ETV) resistance mutations. Additionally, out of the 620 patient samples, 64.0% (397/620) were also detected with the precore stop-codon mutation (G1896A) by microarray assay. Conclusion: The results of the current study revealed that the prevalence of nucleotide analogs (NA)-resistance in Chinese hospitalized HBV-positive patients was so low that intensive nucleotide analogs (NA)-resistance testing before nucleotide analog (NA) treatment might not be required. In addition, the present study suggests that chronic HBV patients with genotype C were infected with fitter viruses and had an increased prevalence of nucleotide analogs (NA)-resistance mutations compared to genotype B virus. .
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Adult , Female , Humans , Male , Antiviral Agents/administration & dosage , Drug Resistance, Viral/genetics , Hepatitis B virus/genetics , Hepatitis B, Chronic/virology , Mutation , Asian People , Adenine/administration & dosage , Adenine/analogs & derivatives , DNA, Viral/genetics , Genotype , Guanine/administration & dosage , Guanine/analogs & derivatives , Hepatitis B virus/drug effects , Hepatitis B, Chronic/drug therapy , Lamivudine/administration & dosage , Microarray Analysis , Organophosphonates/administration & dosage , Prognosis , Sequence Analysis, DNA , Thymidine/administration & dosage , Thymidine/analogs & derivativesABSTRACT
Objective To investigate the influence factors of chronic hepatitis B virus(HBV) infection complicated with chronic liver failure.Methods One hundred and eighty-six chronic HBV infection patients with chronic liver failure were selected as our subjects,who were hospitalized in the Affiliated Hospital of Hebei United University from Jul.2008 to Dec.2013 and they served as case group.Meanwhile,186 patients with chronic HBV infection were selected and served as control group,who were hospitalized during the same period.A self-mad questionnaire was used to collect the information.The influence factors related to HBV infection complicated with acute on chronic liver failure were recorded.Results Multivariate conditional Logistic regression analysis showed that 8 variables were risk factors in terms of chronic HBV infection complicated with acute on chronic liver failure and they were virus overlap infection (OR =6.523,95％ CI:2.034 -10.030),drug application (OR =9.012,95％ CI:3.018-13.241),alcohol (OR =7.2520,95％ CI:1.985 -11.247),bacterial infection(OR =4.378,95％ CI:2.032-5.648),surgical operation (OR =8.514,95％ CI:2.114-17.253),emotional stress and fatigue (OR =2.217,95％ CI:1.729-5.648),genetic (OR =11.124,95％ CI:2.168-13.429),high PCR-HBVDNA quantity (OR =1.628,95％ CI:1.504-3.282).And one protective factorwas the usage of antiviral drug(OR=0.163,95％CI:0.085-0.417).Conclusion The risk factors include virus over infection,application of hepatotoxic drugs,disease before drinking,bacterial infection,surgical operation,emotional stress and fatigue,the genetic parents and high PCR-HBVDNA quantification;and antiviral drugs application is the protective factor in terms of Chronic HBV infection complicated with acute-on-chronic liver failure.
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Objective To investigate hepatitis B virus surface antign (HBsAg) quantitative value quantitatively in serum of chronic hepatitis B virus (HBV) infection patients with different clinical stages,at the same time,to explore the correlation between HBV DNA,patient's age and HBsAg quantitative values.Methods Collected 774 cases without antiviral treatment of chronic HBV infection from our hospital,according to the clinical features,divided cases into six groups:chronic HBV carrier group (102 cases),inactive HBsAg carrier group (211 cases),hepativis B virus e antigen (HBeAg) positive chronic hepatitis B group (236 cases),HBeAg negative chronic hepatitis B group (114 cases),HBeAg positive hepatitis B cirrhosis group (52 cases),HBeAg negative hepatitis B cirrhosis group (59 cases).Used chemiluminescence immunoassay particles analysis to determine HBsAg quantitative value in serum in patients,used real-time fluorescent quantitative polymerase chain reaction method to determine HBV DNA quantitative value in patients,and then compared differences among groups.Results HBsAg quantitative value from high to low respectively were chronic HBV cartier group,HBeAg positive chronic hepatitis B group,HBeAg negative chronic hepatitis B group,inactive HBsAg carrier group,HBeAg negative hepatitis B cirrhosis group,HBeAg positive hepatitis Bcirrhosis group,the median quantitative value of HBsAg were [7.80 (6.69-8.32),7.11 (5.42-8.27),6.57 (5.66-7.53),6.38 (4.39-7.40),6.22 (4.84-6.91),6.13 (5.48-7.01)] ; positive correlation was found between HBsAg quantitative value and HBV DNA in HBeAg positive chronic hepatitis B group and HBeAg negative chronic hepatitis B group (r =0.714,0.390,P ＜ 0.01); negative correlation was found between HBsAg quantitative value and age in chronic HBV infection(r =-0.416,P ＜ 0.01) ; Monitored HBsAg quantitative value of inactive HBsAg carriers after the age 40 had important clinical value.Conclusions HBsAg quantitative value is different in the various phases of chronic HBV infection.HBV DNA levels and age are related with HBsAg quantitative value.HBsAg quantitative value should be monitored in inactive HBsAg carriers after the age 40.
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Objective To explore the association between TNF-α gene 308 locus polymorphism and the risk of chronic HBV infection in Chinese population.Methods PubMed,Embase,CNKI and SinoMed database were searched for relevant articles published from January 2001 to May 2013.Case-control studies on TNF-α-308 polymorphism with chronic HBV infection in Chinese population were gathered with meta-analysis applied for calculation of pooled OR value (with 95％CI) after data abstraction.Results Eleven case-control studies for the TNF-α-308 polymorphism with a total of 1 872 cases and 1 471 controls were included.Results from the overall meta-analysis indicated that-308A allele had a significant decreased risk of chronic HBV infection (A vs.G:OR=0.579,95％CI:0.422-0.794; GA vs.GG:OR=0.525,95％CI:0.325-0.847; AA vs.GG:OR=0.301,95％CI:0.125-0.720; GA+AA vs.GG:OR=0.490,95％CI:0.309-0.777; AA vs.GA+GG:OR=0.542,95％CI:0.394-0.746).In subgroup analyses by region,a significantly decreased risk seemed associated with-308A allele in population from northern China.When stratified by case type,control type and genotyping methods,there apppeared no significant association between TNF-α-308A allele and chronic HBV infection in the studies when spontaneously recovered one' s were used as controls and PCR used as its methodology.Conclusion TNF-α-308A allele seemed a protective factor for chronic HBV infection in the Chinese population.
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This study was aimed to compare the effect of traditional Chinese medicine ( TCM ) treatment method of kidney-tonification, spleen-invigoration and detoxification on T lymphocytes of patients with chronic HBV infec-tion, which were mediated by peripheral blood dendritic cells (DCs). Ten patients with chronic HBV infection and eight healthy controls were included in this study. DCs were differentiated from PBMCs which were isolated from their peripheral blood, incubated and induced. Then, the DCs were interfered by plasma of medicine through the treatment methods of kidney-tonification, spleen-invigoration and detoxification. Models of interaction were estab-lished. Expressions of CD3+, CD4+, CD8+, CD8+CD28+, CD8+PD-1 of DCs and T cells were detected by FACS; and the levels of IFN-γ in supernatants were detected by ELISA. The results showed that the kidney-tonification plasma, spleen-invigoration plasma, detoxification plasma deal with HBcAg in load DCs incubated T lymphocytes. The CD3+ and CD4+ expression rate were increased; the CD8+ and CD8+PD-1 expression were reduced; IFN-γ level was increased; but only the Liuweidihuang Tang group was with significant difference compared to the model group (P < 0.05); the CD8+CD28+ expression rate was increased in the Sijunzi Tang and Liuweidihuang Tang group compared to the model group ( P < 0 . 05 ) . It was concluded that to a certain extent , the treatment method of kidney-tonification, spleen-invigoration and detoxification can restore the function of peripheral blood DCs in chronic HBV infection patients in order to restore its downstream T lymphocyte function. Among these treatment methods, the optimal method is kidney-tonification.
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Objective To explore the psychological stressors of pregnant women with chronic HBV infection.Methods Using phenomenological method of qualitative study,there were 9 pregnant women with chronic HBV infection participated in the study and their mental stress was investigated by deep interview.Results Five main psychological stressors of pregnant women with chronic HBV infection emerged:fear of children being infected; anxious about giving birth in the hospital for infectious diseases; having no idea of selecting the mode of delivery and feeding pattern; worrying about their own health; to feel nervous about playing the role of mothers.Conclusions Healthcare workers should make appropriate health guidance and psychological supports to alleviate the psychological distress combined with features of pregnant women with HBV infection.At the same time,it is necessary to make change of public misunderstanding of hepatitis B,so as to create a fair and friendly social atmosphere for all the hepatitis B patients.
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Objective To establish a standard anti-viral treatment for chronic HBV carriers. Methods With reference to the domestic and abroad literatures, the diagnostic and therapeutic standards were set and prepared to be verified. ResultsThe diagnostic standards included:(①ALT 30 -40 IU/L: add 2 scores. (②Age:30 -39 ,add 1 score; ≥40,add 2 scores. (③Ultrasound examination: obviously abnormal,add 1 score;deteriorated during follow up:add 2 scores. ④Fibrosis markers positive: add 1 score. (⑤History of HCC in vertical relatives:add 1 score. ⑥ Existence of conditions which can induced elevation of ALT such as fatty liver or alcoholic liver or BMI ＞ 23 kg/m2,minus 2 scores. The therapeutic standards included:(①≥5 scores: should be treated;(②3 -4 scores: may be treated or just follow up;(③≤2 scores;follow up and reexamine every 6 months. ConclusionsThe above standards are preliminary suggestions which should be checked and rectified by liver biopsy to achieve a more accurate and more practical standard.
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Objective To explore the effects of intensive health education on psychological stress of outpatients with chronic HBV infection. Methods A convenient sample of 80 patients was selected as the subjects of the study. They were randomly allocated to the control and the intervention group with 40 patients in each group. The intervention group received intensive heath education, which was designed spe-cially by researcher, while the control group just received the routine clinic health education. Demographic Data Recording Form (DDRF) and the Perceived Stress Scale specific to Hepatitis B Patients (PSSH) were used to assess the intervention effect pre-treatment and 3 months after intervention. Results The scores of PSSH were high in two groups before intervention. Compared with the control group, the intensive health education decreased the score of PSSH more significantly in the intervention group. Conclusions The intensive heath education can reduce the psychological stress of the outpatients with chronic HBV infection.
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Objective To analyze of CD4+ CD25high regulatory T cells(Treg)in peripheral blood of chronic HBV patients and its correlation with multiple clinical indicators.Methods Thirty-five hepatitis B virus(HBV)infected patients in this study were divided into four different clinical types:HBsAb+group(n=5),inactive hepatitis group(n=8),chronic hepatitis group(n=12),and immune tolerance group(n=10).The number of CD4+CD25high Treg and related T cells subgroup in CD3/CD4/CD8 was thoroughly examined by flow cytometry in peripheral blood of HBV infected patients and the healthy contrast group(n=12).Serum HBV markers were determined by commercial ELISA kits.Serum HBV DNA was quantified by commercial real-time PCR kit.Statistical differences were studied to investigate the correlations between CD4+CD25high Treg and different clinical types of HBV infection and clinical indicators.Results The absolute counts of CD25high Treg and its frequency in CD4+ T cells were similar between HBV infected patients [(12.35±6.48)/μ,(1.82±0.87)%]and health controls[(8.91±3.11)/μl,(1.35±0.39)%],P＞0.05.The frequency of CD25high Treg in CD4+ T cells from the immune tolerance group was significantly higher than that of the HBsAb+ group,chronic hepatitis group,and the healthy contrast group(P＜0.05).The absolute counts of CD25high Treg from the immune tolerance group were significantly higher than the healthy control group(P＜0.05),and the frequency of CD25high Treg in CD4+ T cells is negatively correlated to the ALT level(r=-0.418,P=0.038),positively correlated to CD4/CD8 ratio(r=0.344,P=0.021),no correlation to the HBV DNA level(r=0.118,P＞0.05).The absolute counts of CD25high Treg were positively correlated to CD4/CD8 ratio(r=0.360,P=0.015),no correlation to ALT level and HBV DNA level(r=-0.211,r=0.060,P＞0.05).Conclusion CD4+ CD25high Treg may play a role in immunopathogenesis of chronic HBV infection.
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Objective To mvesugate the Tate of YMDD mutation accompamed with pre-core(region and core promotor region mutation and the clinical significance.Methods YMDD mutation and pre-core(at 1896 nu- cleotide)region and core promotor region(at 1762.1764 nucleotide)mutation were detected from the 122 patients with chronic hepatitis B virus after receiving lamivudine treatment above 6 months.Results 40 cases were tested for YMDI)mutations in 122 HBV patients with lamivudine treatment,and the positive rate of YMDD mutation was 32.8 %.After YMDD mutation,ALT,AST and HBV DNA of the patients significantly increased(P0.05).Conclusion The patients with YMDD mutation had higher rate of pre-core region(at 1896 nucleotide)and basal core promotor region(at 1762, 1764 nucleotide)mutation than those without YMDD mutation,but there was no correlation between the mutation and the deterioration of disease condition and the bad prognosis.
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No abstract available.
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Humans , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/diagnosis , Serologic TestsABSTRACT
Infection rate of HBV in the high-risk population, such as dentists and the patients undertaking hemodialysis, was not higher than those in general population. The occurrence of the subclinical infection state might be resulted from hypo-responsiveness of humoral and cellular immunity to HBsAg. Of 257 cases of liver biopsy, 44% of them were diagnosed as chronic hepatitis of various categories. No relationship was found between the expression patterns of viral antigens and the inflammatory activity in the liver. The infection state was quite stable. HBeAg/anti-HBe seroconversion was not a turning point from replicative to nonreplicative phase of the virus. The individuals with intrahepatic integrated HBV DNA might be the genome carriers with sero-negative HBsAg. The above results illustrate the characteristics of hyporesponsive HBV infection in hyperendemic area in China.