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Objective@#To investigate the correlation between the frequency and function of early plasmacytoid dendritic cells (pDC) and the treatment response in patients with HBeAg-positive chronic hepatitis B receiving entecavir (ETV).@*Methods@#Patients with HBeAg-positive chronic hepatitis B were enrolled. Antiviral therapy with ETV, serum serological markerso hepatitis B virs (HBV) infection and liver function (HBV DNA load, HBsAg/anti-HBs, HBeAg and anti-HBe levels, and ALT levels) were monitored every three months before and during treatment; the efficacy of ETV was assessed by changes in the level of HBV DNA. Peripheral venous blood was collected before treatment, at 12 weeks and 24 weeks, respectively. Flow cytometry was used to detect the frequency of peripheral blood pDC and the surface co-stimulatory molecule CD86. The baseline and early treatment (12 weeks and 24 weeks) pDC frequency and functional changes were analyzed.@*Results@#Of the 100 patients with chronic hepatitis B, 45 patients received ETV treatment and 48 weeks of follow-up. Within 48 weeks of ETV treatment, HBsAg levels decreased by 0.53±0.78 log IU/mL; HBeAg decreased by 816.61S/CO, and HBeAg seroconversion occurred in 4 cases; HBV DNA content decreased by 6.04±1.12 log IU/mL, in 33 cases (73%) the HBV DNA became undetectable, in 43 cases ALT kept normal continuously for more than 3 months. In the early stage of ETV treatment, pDC% increased significantly, CD86+ pDC%, CD86MFI and CD86ABC showed no significant changes. In ETV-treated HBV DNA responders, pDC% increased significantly, CD86+ pDC%, CD86MFI and CD86ABC showed no significant changes; HBV DNA non-responders had a significant increase in pDC%, but CD86+ pDC% decreased significantly, and CD86MFI and CD86ABC showed no significant changes. The decrease in HBsAg and HBeAg levels in ETV treated patients was not significantly associated with early pDC%, CD86+ pDC%, CD86MFI and CD86ABC changes.@*Conclusions@#ETV treatment can directly inhibit the replication of HBV DNA, but does not enhance the function of immune cells.
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Objective@#To study the factors associated with efficacy of nucleos(t)ide analogues with sequential interferon in HBeAg positive chronic hepatitis B (CHB) patients.@*Method@#HBeAg positive CHB patients treated with nucleoside analogue (NA) treatment received PEG-IFN α-2a 180 μg subcutaneously once weekly.NA was continually used with PEG-IFNα-2a during the first 12 weeks. HBsAg/HBeAg level and HBV DNA load were observed in the sequential pre-treatment (baseline) period, 12 th, 24 th, 36 th, 48 th and 72 nd weeks of sequential therapy in all patients.@*Result@#Of the 56 HBeAg-positive CHB patients, 5 (23.1%) achieved HBsAg loss/seroconversion, the baseline HBsAg level in HBsAg loss/seroconversion group was lower than that of the patients in the group that did not achieve HBsAg loss/seroconversion (2.750 lg IU/ml vs. 3.699 lg IU/ml, t=0.955, P=0.000); the difference was statistically significant in HBsAg decreased at the 12 th, 24 th, 36 th, 48 th week in the course of sequential therapy (0.913 vs 0.149, 2.847 vs 0.189, 4.378 vs 0.248, 4.587 vs 0.274 lg IU/ml) (t=-2.950, P=0.040; t=-8.732, P=0.009; t=-8.483, P=0.001; t=-8.214, P=0.003); 11(19.6%) achieved HBeAg loss/ seroconversion, the HBeAg baseline level in HBeAg loss/seroconversion group was lower than the patients in the group that not achieved HBeAg loss/seroconversion (1.217 lgS/CO vs 1.884 lgS/CO, t=2.061, P=0.044); the difference was statistically significant in HBsAg, HBeAg decreased at 24 th, 36 th, 48 th week in the course of sequential therapy between the two groups (1.330 vs 0.205, 2.084 vs 0.258, 1.972 vs 0.284, lg IU/ml; 1.168 vs 0.455, 1.363 vs 0.461, 1.177 vs 0.447, lg S/CO) (t=2.238, P=0.049; t=2.619, P=0.025; t=2.278, P=0.048); (t=2.273, P=0.043; t=3.415, P=0.001; t=2.271, P=0.049).@*Conclusions@#To HBeAg-positive CHB, lower baseline HBsAg, HBeAg level and HBsAg, HBeAg decreased earlier were could predict easier achievement of HBs(e)Ag loss/seroconversion.
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Objective@#We aimed to evaluate changes towards liver fibrosis during entecavir(ETV)treatment by non-invasive fibrosis markers in chronic hepatitis B (CHB) patients who need antiviral therapy.@*Methods@#Totally 303 HBeAg negative treatment-naive CHB patients were enrolled and liver biopsy was performed before starting antiviral therapy in this study. Totally 196 patients who need antiviral therapy were treated with ETV for at least 3 years. A clinical and virological evaluation was performed at baseline and again after 1, 2 and 3 years during ETV treatment. AST-to-platelet ratio index (APRI) was used to assess dynamic changes of liver fibrosis in HBeAg negative CHB patients after 1, 2, 3 years of ETV treatment.@*Results@#All enrolled patients experienced liver biopsy at baseline. According to Metavir fibrosis stages, F1, F2, F3 and F4 patients were 107, 125, 54 and 17, respectively. The APRI score enabled the correct identification of patients with severe fibrosis (METAVIR F3-F4). The APRI values significantly decreased in F2 and F3 patients after 1 year ETV therapy (P<0.01). But for F4 patients, APRI values decreased significantly at year 3 (P<0.05).@*Conclusions@#APRI values decreased significantly during ETV treatment in HBeAg-negative CHB patients indicating that these noninvasive fibrosis tests might be useful for monitoring improvement of liver fibrosis and assessing treatment efficacy during long-term ETV treatment.
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Objective@#To explore the association between the efficacy of peg-IFN and the complexity of TP and RT regions of hepatitis B virus (HBV) in chronic hepatitis B.@*Methods@#Patients with HBeAg positive, HBV DNA positive chronic hepatitis B were given peg-interferon 180 μg once a week for subcutaneous injection, and baseline information was collected from baseline and after 12 weeks’ treatment. The baseline HBV DNA TP and RT fragments were amplified, database, high-throughput sequencing, and the average genetic distance calculation.@*Results@#Data of 108 patients were analyzed by logistic regression. RT area fragment Markov distance and TP area fragment Shannon quotient for HBV DNA response were calculated. ALT level is good for HBeAg response. HBsAg level is bad for HBsAg response.@*Conclusions@#The complexity of the baseline TP and RT regions may be associated with the efficacy of peg-interferon therapy for CHB.
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Objective@#To study the factors associated with efficacy of nucleos(t)ide analogues with sequential interferon in HBeAg negative chronic hepatitis B (CHB) patients.@*Methods@#HBeAg negative CHB patients with NA treatment received PEG-IFNα 2a 180 μg subcutaneously once weekly. NA was continually used with PEG-IFN 2a during the first 12 weeks. HBsAg level and HBV DNA load were observed in the sequential pre-treatment (baseline), 12th, 24th, 36th, 48th, 72nd and 96th weeks of sequential therapy in all patients.@*Results@#Of the 26 HBeAg negative CHB patients, 6 (23.1%) achieved HBsAg loss/seroconversion. The comparison between HBsAg loss/ seroconversion group and the group not achieved HBsAg loss/ seroconversion showed that the baseline HBsAg level in HBsAg loss/seroconversion group was 2.210 log10IU/ml, was lower than (t=-4.252, P=0.000) HBsAg-positive patients (3.385 log10IU/ml) in the groupp that not achieved HBsAg loss/seroconversion, the difference was statistically significant in HBsAg decreased at 72nd, 96th week in the course of sequential therapy (3.511 vs. 0.723log10IU/ml, 4.291 vs. 0.737 log10IU/ml) (t=6.712, P=0.000, t=13.319; P=0.000, 0.00); the difference was not statistically significant in age, gender and NA therapy time between the two groups; 12 (46.2%) of patients achieved sustained virologic response (SVR), the baseline of HBsAg level was 2.575 log10IU/ml, was less than (t=-4.319, P=0.000) the patients who did not achieve SVR (3.576 log10IU/ml), the difference was statistically significant in HBsAg decrease of each time in the course of sequential therapy between the two groups (0.612 vs. 0.088, 1.192 vs. 0.107, 1.566 vs. 0.167, 1.817 vs. 0.176, 2.424 vs. 0.193, 2.188 vs. 0.014, log10IU/ml) (t=3.109, 4.717, 4.500, 4.544, 5.560, 4.265, P=0.008, 0.010, 0.001, 0.001, 0.000, 0.003), the difference was not statistically significant in gender and NA therapy time, the difference was statistically significant in age (30.8 vs. 39.9 years) ( t=-2.219, P=0.038). Of 9 CHB patients whose baseline HBV DNA were positive, 5 patients (55.6%) had HBV DNA loss after sequential treatment, the patients whose HBV DNA loss with HBsAg decreased at 12th week in the course of sequential therapy, but there was no influence in the HBsAg decrease/loss after 12th week, the difference was not statistically significant in age, gender, NA therapy time, HBsAg and HBsAg decrease in the course of sequential therapy between HBV DNA-negative and HBV DNA-positive groups.@*Conclusions@#To HBeAg-negative CHB, patients with low baseline HBsAg (2 log10 IU/ml level) and significantly lower HBsAg decrease early were more likely to receive SVR. Among them, prolonged interferon therapy is easier to achieve HBsAg loss/seroconversion.
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Objective@#To explore the persistent viral response rate (SVR) in patients with refractory chronic hepatitis C after interferon (IFN) (peginterferon 360 μg qw) and ribavirin (PR) therapy failure. The SVR of patients with refractory chronic hepatitis C was improved by PR combined with direct antiviral agents (DAA) and proper extension of the course of therapy was applied.@*Methods@#Seventeen cases of refractory chronic hepatitis C after IFN(peginterferon 360 μg qw) and ribavirin therapy failure were given PR combined with DAA treatment. The side effects were observed and corresponding adjustments were made on drug dosage, and SVR was recorded.@*Results@#The 17 cases completed the whole course of treatment with PR combined with DAA for 24 weeks. All the 17 patients obtained rapid viralogical response (RVR) and SVR. After treatment, the SVR rate was 100% in patients including those with virologic relapse, retreated or previously non-responsive patients with refractory chronic hepatitis C. The adverse reaction of PR combined with DAA 24 weeks was generally mild.@*Conclusions@#The use of PR combined with DAA re-treatment in patients with refractory chronic hepatitis C can achieve SVR and shorten the treatment time. PR combined with DAA re-therapy is one of effective treatments to improve the rate of sustained viral response in patients with refractory chronic hepatitis C.
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Objective@#To investigate the differences in frequency and function of natural killer cells (NK) between chronic hepatitis B (CHB) and acute hepatitis B (AHB).@*Methods@#Patients with AHB and those with CHB in immune active (IA) phase were enrolled. The frequencies of NK, CD56dimNK, CD56brightNK and the expression of functional molecules IFNAR2 and NKp46 on the surface of NK cells were detected respectively among patients with CHB in IA phase, patients with AHB, and those recovered from AHB. At the same time, their correlations with ALT, HBV DNA and HBV markers were analyzed.@*Results@#Between IA and AHB, the frequencies of NK cells and NKp46dim NK cells in AHB cases were significantly lower than those in IA cases, but the frequency of NKp46high NK cells in AHB was higher than that in IA. For patients who recovered from AHB, the frequency of NK cells and NKp46dim NK cells increased; the varied ranges of frequencies of CD56dimNK, IFNAR2+ NK and NKp46+ NK cells were on the rise, while the frequency of NKp46high NK cells decreased after the recovery from AHB, and the varied ranges of CD56brightNK and IFNAR2MFI, NKp46MFI decreased. In AHB, HBVDNA loads were positively correlated with ALT levels. Before and after the recovery of AHB: ΔHBV DNA and ΔALT, Δ NK/LY (%) were positively correlated; ΔALT and ΔNKp46highNK/NK(%), ΔNKp46MFI, ΔIFNAR2MFI were positively correlated.@*Conclusions@#In CHB immune active phase, the activity of peripheral blood NK cells was too weak to remove the virus, but NK cells play an important role in eliminating the viruses and mediating liver tissue inflammation in AHB.
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Objective@#To observe the changes of peripheral blood image of chronic hepatitis C (CHC) patients treated with pegylated interferon (Peg-IFN) and ribavirin, and explore the relationship between the changes and serum virological respose (SVR).@*Methods@#Patients with CHC treated with Peg-IFN α-2 a and ribavirin in the Second Division of Liver Disease in Beijing Ditan Hospital were monitored for peripheral blood cells routine examination and Liver function, kidney function, thyroid function at baseline and week 2, 4, 8, 12, 24, 36, 48, and week 12, 24, 48 after the end of treatment for chronic hepatitis C, and HCV RNA.@*Results@#The decrease of peripheral blood cell counts began to appear at week 2 of treatment. For CHC patients without cirrhosis, white blood cells, lymphocyte, hemoglobin and platelets at week 2, while minimum values were seen at week 36, and the neutrophils reached the minimum value to at week 24. Significant recovery of the peripheral blood changes was seen at the end of treatment (48 weeks), and reached pre-treatment levels at week 48 after the end of treatment. For CHC patients with cirrhosis, white blood cells, lymphocytes, hemoglobin and platelets significantly decreased at week 2, while neutrophils reached a minimum value at 2 weeks. And hemoglobin and platelets reached a minimum value at 24 weeks, and the white blood cells reached the minimum value at weeks 24-36 besides lymphocyte reached the minimum value at week 36. Significant recovery was seen at the end of treatment (48 weeks), and the blood cell counts reached pre-treatment levels at 48 weeks after the end of treatment. For patients with CHC, hemoglobin decreased by more than 27.47% at week 4, which means that the patient would have a predictive significance for SVR, as well as the of PLT reduction by more than 36.96% at week 8.@*Conclusions@#During the treatment with Peg-interferon and ribavirin, the variation of blood picture has some predicting effect, which predicts the result of antiviral treatment.
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Objective@#To investigate the differences in function of plasmacytoid dendritic cells (pDC) and CD4+ T helper cells (CD4+ Th cells) between acute hepatitis B (AHB) and chronic hepatitis B (CHB).@*Methods@#In this study, patients with AHB and those with CHB in immune active (IA) phase were enrolled. The frequencies of pDC, CD86+ pDC, CD4+ T cells and their subsets, surface functional molecules were detected respectively among patients with chronic HBV infection in IA phase, patients with AHB, those recovered from AHB. Meanwhile, their correlations with ALT, HBV DNA and HBV markers were analyzed.@*Results@#The ALT level in AHB was significantly higher than that in IA, and inflammation was more obvious in AHB. Between IA and AHB, CD86+ pDC frequency and the mean fluorescence intensity of functional molecule CD86 (CD86MFI) were higher in IA than those in AHB, but the frequency of CD4+ T cells in AHB was higher than that in IA. For patients who got over AHB, the frequency of CD86+ pDC increased; Th1 were on the rise, while the frequencies of CD4+ T and Th2 decreased after the recovery of AHB, and Th2 / Th1 ratio decreased..In AHB, HBVDNA loads were positively correlated with ALT levels and Th2 frequencies.@*Conclusions@#In CHB immune active phase, CD86+ pDC with stimulating function played an important role, but the cellular immune response of CD4+ T cells decreased. In AHB inflammatory stage, CD4+ T cells played a strong cellular immune response, which result ed in viral clearance. Th2 cells regulation of CD4+ T cells played a dominant role, which was involved in the inflammatory response, and the cytotoxic role of Th1 cells during the recovery period was dominant, playing a strong cellular immune response, then the virus were completely eliminated.
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Objective@#To observe the changes of peripheral blood picture of CHB with Peg-IFN, and explored the relationship between the changes and decline of HBV DNA, clearance of HBsAg.@*Methods@#Patients with CHB treated with Peg-IFN α-2 a in the Second Division of Liver Disease in Beijing Ditan Hospital were monitored for blood routine examination and Liver function, kidney function, thyroid function of baseline and weeks 2, 4, 8, 12, 24, 36, 48, and weeks 12, 24, and 48 after the end of treatment for chronic hepatitis B, and HBV DNA, HBsAg.@*Results@#The decrease of peripheral blood cells began to occur at week 2 of treatment. For CHB with HBeAg negative patients, white blood cells, lymphocyte, neutrophils, hemoglobin and platelets significantly decreased at 2 weeks, while a minimum value occurred at 48 weeks. The recovery was obvious at the end of treatment (48 weeks), and reached pre-treatment levels at 48 weeks after the end of treatment. For CHB with HBeAg positive patients, white blood cells, neutrophils, hemoglobin and platelets significantly decreased at 2 weeks, while a minimum value was found at 36-48 weeks. The recovery was obvious at the end of treatment (48 weeks), and reached pre-treatment levels at 48weeks after the end of treatment. For patients with CHB, hemoglobin declined by more than13.64% at 36th week, which means that the patient would have a predictive significance for decrease of HBV DNA, and drops of more than 0.33% at 2nd week means that the patient would have a predictive significance for clearance of HBsAg.@*Conclusions@#During the treatment with interferon, the variation regularity of blood picture for predicting result have a certain effect, which may help predict and monitor the change of blood picture in clinical work.
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Objective@#To investigate the change of hepatitis B surface antibody (HBsAb) titer and its long-term protection and infection rates between 1 and 3-year-old children whose mothers were chronic hepatitis B pregnant woman with HBeAg positive and high viral load after successful blocking of mother-to-child transmission.@*Methods@#One-year-old children whose mothers were hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) positive, with HBV DNA≥106IU/ml were enrolled, then were followed up till 3 years old, and tested the five serological markers of hepatitis B and biochemical parameters at the age of one and three years respectively, and analyzed HBsAb titer, positive rate, negative rate and infection rate of 1 to 3-year-old children without enhanced vaccination; meanwhile, data of HBsAb titers at the age of 7 months were collected HBsAb titer, positive rate, and negative rate were analyzed.@*Results@#Totally 264 1-year-old children were enrolled into the study, including 178 children without enhanced vaccination between seven months and 1 year of age, and 114 children without enhanced vaccination between 1 year and 3 years of age. Our result showed that there were no infected children at the age between 1 and 3 years. HBsAb titer decreased from 7 months to 1 year old and dropped from 1 000 IU/L to 509.43 IU/L (P<0.05), and the antibody was still protective. From 1 year to 3 years old, HBsAb titer dropped from 466.72 IU/L to 67.3 IU/L (P< 0.05); at the age of 3 years, 60.52 % children were either weakly positive or negative, but still protective, but significantly less than those who had the reinforced vaccination. As a result , the children without the enhanced vaccination between 1 and 3 years of age were still at high risk.@*Conclusions@#If the antibody was protective at 7 months, children were not easily infected between 1 year and 3 years of age. At the age of 3, the antibody dropped to low or no responsive levels, and the children were still at high risk. It is necessary to take protective measures and supplement the vaccine.
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Currently, there are two kinds of academic degree and professional degree in viral hepatitis postgraduate degrees. This kind of trainingmethod cannot combine clinical thinking and scientific research thinking. The combination of good research thinking and clinical foundation is beneficial to talent cultivation. In the future, the training of viral hepatitis graduate students requires students to have a clinical basis, and also requires students to have rigorous research thinking.
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Objective@#To elucidate the functions of peripheral blood NK cells in chronic hepatitis B patients treated with interferon.@*Methods@#Venous whole blood samples were obtained from patients in the immune clearance (IC) phase treated with peg-interferon-alpha-2a (Peg-IFNα-2a) at baseline (t=0), 12 weeks (t=12) and 24 weeks (t=24). The frequencyies of peripheral blood CD3-CD56+ NK cells, CD56brightNK cells and CD56dimNK cells, the expression level of IFNAR2 and NKp46 on NK cells were detected by flow cytometry. The levels of serum HBV DNA, HBsAg, HBeAg and ALT were detected by Ditan Hospital clinical laboratory.@*Results@#Forty-one patients in the IC phase treated with Peg-IFNα-2a, including 21 poor response (PR) patients and 20 good response (GR) patients, were recruited for this study. Theresult were as follows: The frequency of peripheral blood CD3-CD56+ NK cells was increased at week 24 in GR compared with the baseline(11.74, 5.69%-18.15% vs 13.7, 9.36-20.18%, P>0.05), and it also was increased in PR(8.94, 6.26%-14.15% vs 12.5, 7.64-16.55%, P>0.05). The frequency of peripheral blood CD56brightNK cells was increased at week 24 in GR compared with the baseline(9.49, 6.2%-12.48% vs 12.98, 7.75%-20.93%, P>0.05), and it also was increased in PR(11.45, 8.27%-19.13% vs 17.52, 12.3%-22.42%, P=0.0239). The expression level of NKp46 on NK cells was significantly increased at week 24 in GR compared with the baseline(90.55, 83.8-94.78 vs 93.8, 92.28-96.4, P=0.0263), but it was not increased in PR(95, 90.6-96.15 vs 94.3, 92.1-95.6, P>0.05). The expression level of NKp46high on NK cells was significantly increased at week 24 in GR compared with the baseline(12.4, 8.58-19.08 vs 39.3, 23.15-49.3, P=0.0011), at that range of the increase was significantly higher than PR(14.2, 9.78-17.65 vs 27.58, 19.13-36.56, P=0.006).@*Conclusions@#The frequencies of peripheral blood CD3-CD56+ NK cells and CD56brightNK cells were increased from patients in the IC phase treated with Peg-IFNα-2a. The expression level of NKp46 on NK cells was increased in GR patients treated with Peg-IFNα-2a. The expression level of NKp46high on NK cells was significantly increased, especially in GR patients treated with Peg-IFNα-2a.
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With the rapid development and popularization of problem-based learning (PBL) teaching, its role in clinical medicine teaching is becoming more and more important. PBL teaching in the teaching of viral hepatitis is a new model of the clinical teaching exploration.This kind of teaching takes the student as the main body.The purpose of PBL teaching is to improve students' ability to solve clinical problems.PBL teaching not only stimulated the learning enthusiasm of the students in the teaching of viral hepatitis, but also improved the students' ability of independent thinking and scientific research innovation.