Biomarcadores convencionales y emergentes en hepatitis B / Conventional and emerging biomarkers in hepatitis B

A nivel mundial, 300 millones de personas están infectadas por el virus de la hepatitis B (VHB). A pesar de que existe una vacuna que previene la infección y se dispone de tratamiento antiviral que suprime la replicación del virus, no hay cura aún. El principal problema que evita la recuperación total del paciente, incluso para aquel que recibe tratamiento, es la persistencia de dos formas del genoma viral en los hepatocitos: el ADN circular covalentemente cerrado (ADNccc), el cual se encuentra en forma de episoma y tiene la capacidad de replicarse, y las secuencias lineales subge-nómicas que se integran en el genoma humano, con potencial oncogénico. Hasta el momento se dispone de unos pocos biomarcadores para monitorear o predecir la progresión de la enfermedad y la respuesta al tratamiento. Estos biomarcadores se detectan durante la infección, y son la base para la monitorización de la enfermedad y hacer un diagnóstico de la fase clínica de la infección. Recientemente han surgido nuevos biomarcadores como el antígeno relacionado con el core del virus de la hepatitis B (HBcrAg) y la detección del ARN del VHB, que parecen correlacionarse con los niveles transcripcionales del ADNccc, además, durante el tratamiento parecen ayudar a predecir la respuesta y podrían identificar aquellos a quienes se les puede suspender la terapia sin riesgo de recaída. En esta revisión, se describe la utilidad de los principales biomarcadores convencionales en hepatitis B, y se abordan los dos biomarcadores emergentes más estudiados que prometen evaluar el curso de la infección, al igual que determinar la progresión de la enfermedad y la respuesta al tratamiento.

Globally, 300 million people are infected with hepatitis B virus (HBV). Although there is a vaccine that prevents infection and antiviral treatment that suppresses the replication of the virus, there is still no cure. The main problem that prevents the total recovery of the patient, even for those who recei-ve treatment, is the persistence of two forms of the viral genome in hepatocytes: covalently close circular DNA (cccDNA), which is in the form of an episome that has the ability to replicate, and linear subgenomic sequences that are integrated into the human genome, with oncogenic potential. Few biomarkers are currently available to monitor or predict disease progression and response to treatment. These biomarkers are detected during infection and are the basis for monitoring the di-sease and making a diagnosis of the clinical phase of the infection. New biomarkers have recently emerged, such as hepatitis B core-related antigen (HBcrAg) and HBV RNA detection, which seem to correlate with cccDNA transcriptional levels while during treatment seem to help predict response, and could identify those for whom therapy can be discontinued without risk of relapse. In this review, the usefulness of the main conventional biomarkers in hepatitis B is described, and the two most studied emerging biomarkers are mentioned, which promise to evaluate the course of the infection, as well as to determine disease progression and treatment response.

Analysis of influencing factors of serum HBeAg loss in patients with chronic hepatitis B / 中国热带医学

@#Abstract: Objective To explore the influencing factors of serum HBeAg loss in patients with chronic hepatitis B (CHB) and and provide evidence for effective treatment of CHB. Methods A follow-up cohort of HBeAg-positive CHB patients was established in the the Infectious Diseases Outpatient Clinic of hospital. Regular follow-up and laboratory test indicators were collected to analyze the changes of serum HBeAg in HBeAg-positive CHB patients during the follow-up period. The subjects were divided into the case group (serum HBeAg loss) and the control group (serum HBeAg not loss) according to whether serum HBeAg loss occurred. The baseline data characteristics of the two groups were analyzed and compared, and the influencing factors of serum HBeAg loss were analyzed by Cox univariate and multivariate regression. Results A total of 634 HBeAg-positive CHB patients were enrolled, with a total follow-up of 2 570.01 person-years. Among them, 237 cases of serum HBeAg loss occurred, with the mean follow-up time of 40.92 months, and the rate of HBeAg loss was 9.22/100 person-years. There were significant differences in HBV family history, antiviral therapy, baseline WBC, PLT, ALT, AST, T˗Bil, GGT, AFP, quantitative HBsAg and quantitative HBeAg between serum HBeAg loss group and serum HBeAg not loss group (P<0.05). Cox regression analysis showed that family history of HBV (HR 0.68, 95％CI:0.50-0.92, P=0.012), ALT (HR2.06, 95％CI:1.52-2.79, P<0.001), quantitative HBsAg (HR 0.68, 95％CI:0.48-0.95, P=0.024), quantitative HBeAg (HR 0.48, 95％CI:0.31-0.74, P=0.001) were independent influencing factors for HBeAg loss in HBeAg-positive CHB patients. Conclusions HBeAg-positive CHB patients without family history of HBV, initial ALT≥80 U/L, quantitative HBsAg<1 000 IU/ml, quantitative HBeAg<1 000 C.O.I are more likely to have serum HBeAg loss.

Cytokine Profiles and Virological Marker Monitoring during 48 Weeks Peginterferon Alfa Treatment for HBeAg-Positive Chronic Hepatitis B / 生物医学与环境科学（英文）

Objective@#This study aimed to investigate whether cytokine profiles and virological markers might add value in monitoring the effects of peginterferon (PEG-IFN) therapy for hepatitis B e-antigen (HBeAg) positive chronic hepatitis B (CHB).@*Methods@#HBeAg positive patients with CHB were treated with PEG-IFN for 48 weeks. Clinical biochemical, and HBV serological indexes, as well as cytokines, were detected at baseline and every 12 weeks.@*Results@#A total of 116 patients with CHB were enrolled in this study; 100 patients completed the 48-week treatment and follow-up, of whom 38 achieved serum HBeAg disappearance, 25 achieved HBeAg seroconversion, 37 showed HBsAg decreases ≥ 1 log 10 IU/mL, 9 showed HBsAg disappearance, and 8 became HBsAb positive. The cytokine levels at baseline and during treatment were similar between the HBeAg disappearance group and non-disappearance group. The disappearance of HBeAg was independently associated with HBeAg levels at weeks 12 and 24, and with the HBeAg decline at week 24 ( P < 0.05). The HBsAg response was independently associated with HBsAg, the HBsAg decline, HBeAg, the HBeAg decline at week 12, and HBsAg at week 24 ( P< 0.05).@*Conclusion@#There was no significant correlation between the response to interferon (IFN) and cytokines during PEG-IFN treatment. The changes in virological markers predicted the response to IFN after 48 weeks.

Adefovir Dipivoxil plus Chinese Medicine in HBeAg-Positive Chronic Hepatitis B Patients: A Randomized Controlled 48-Week Trial / 中国结合医学杂志

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).

Prevalence of Hepatitis B and C Virus Infection among Students of a Private Tertiary Institution in South-Western Nigeria

Background: Hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is a major health problem and account for a substantial proportion of liver diseases worldwide. Aim:The aim of this study was to determine the prevalence rate of Hepatitis B and C virus infection among undergraduate students of Babcock University. Methodology: The blood samples of 200 participants (96 males and 104 females) were randomly collected and screened using rapid serological methods. HBV markers were determined using a HBV 5 in 1 Panel cassette (Innovita Biological Technology Co., Ltd., China); while antibody to HCVOriginal Research Article was detected using anti-HCV test strip (Blue Cross Bio-Medical Co., Ltd., China). The demographic and clinical information of the participants were collected using structured questionnaires. Results: Out of the 200 participants screened, 3 (1.5%) were positive for HBsAg, 10 (5.0%) were positive for HBsAb, 3 (1.5%) were positive for HBcAb, 2 (1.0%) were positive for HBeAb and none (0%) was positive for HBeAg. 2 (2.1%) of the 96 males screened were positive for HBsAg, while only one (1%) out of the 104 females screened was positive for HBsAg. There was no significant difference (P>0.05) between the number of male and female students positive for HBsAg. On the basis of age distribution, data show that 3 (2.7%) out of the 110 students that were 16-20 years old were positive for HBsAg, while students in the other age groups were negative for HBsAg. Risk factors associated with infection include: tattooing, history of blood transfusion and shared sharp objects. Interestingly, zero prevalence rate (0%) of HCV mono-infection, as well as HBV/HCV co-infection was recorded in this current study. Conclusion: The outcome of this study showed that a low prevalence rate of HBV mono-infection exists among undergraduate students of Babcock University, therefore the on-going public health campaign programme against Hepatitis B and C should be sustained

Studies of Efficacy of tenofoviralafenamide in the treatment of chronic hepatitis B infection / Монголын Анагаах Ухаан

@#Worldwide, an estimated two billion people have evidence of HBV infection, and approximately 240 million have CHB. In April 2017, EASL added a drug newly approved for treatment of CHB, tenofoviralafenamide (TAF) to their list of recommended first-line therapies. Treatment with these therapies can achieve sustained suppression of HBV DNA replication, decreases in inflammation, and histological activity that decrease the risk of cirrhosis and hepatocellular carcinoma in both cirrhotic and noncirrhotic patients and, ultimately, of CHB-associated mortality [1, 2]. However, recent advances in understanding the HBV life cycle have enabled multiple, novel therapeutic targets to be identified and new therapies of direct-acting antiviral (DAAs) and host-targeting agents (HTAs) are indevelopment.</br> In most clinical trials, TAF was non-inferior to TDF in achieving HBV DNA levels below 29 IU/ml.No amino-acid substitutions associated with viral breakthrough were detected by deep sequencing, and no resistance to TAF.With clear evidence from major studies showing that TAF is safe, tolerable, and non-inferior to TDF, its recommendation as a first-line therapy is appropriate.</br> Long-term safety is an important consideration in the therapeutic management of patients with CHB because treatment is often life-long.</br> The efficacy of TAF in patients with resistance mutations associated with older nucleos(t)ide analogues is unclear. Although no evidence of TAF or TDF resistance was detected in the phase III studies through 96 weeks of treatment, very small numbers of patients had baseline mutations indicating resistance to lamivudine, adefovir or entecavir and efficacy data specifically for this group is not available.

Efficacy of tenofovir alafenamide in the treatment of chronic hepatitis B infection / Монголын Анагаах Ухаан

Introduction@#Worldwide, an estimated two billion people have evidence of HBV infection, and approximately 240 million have CHB. In this study, a representative group of Mongolian adults was tested for hepatitis B virus (HBV) in 2017. The prevalence estimates of HBV the general Mongolian adult population were found to be 11.1%, respectively.</br> In April 2017, EASL added a drug newly approved for treatment of CHB, tenofovir alafenamide (TAF) to their list of recommended first-line therapies. The requirement for long-term therapy in chronic HBV highlights the importance of these efficacy and safety trends, however their true clinical relevance is yet to be established and further studies with long-term follow up and real-world clinical data are needed.@*Goal@#Evaluate for result of tenofovir alafenamide in the treatment of chronic hepatitis B infection.@*Materials and Methods@#The clinical trials have evaluated TAF in HBeAg-positive and HBeAg-negative chronic HBV patients. The trials have similar designs and are randomized, double blind, non-inferiority studies. The primary efficacy endpoint was the proportion of patients with HBV DNA<29 IU/ml at week 24 and 48. Other prespecified efficacy endpoints were the proportion of patients with HBsAg seroncoversion to anti-HBs at week 24 and 48. Key secondary safety end- points at week 24 and 48 included the percentage change in T-score, and Z-score bone mineral density (BMD), percentage change in BMD and change from baseline serum creatinine.@*Results@#The primary efficacy endpoint, an HBV DNA level <29 IU/ml at week 24, was achieved by 120 (59.1%) of 203 patients receiving TAF, which was non-inferior to the 63 (55.2%) of 114 patients receiving TDF who had an HBV DNA<29 IU/ml. After 24 weeks of treatment, patients receiving TAF had significantly smaller reductions in bone mineral density (BMD) compared with patients receiving TDF.@*Conclusion@#The development of TAF, specifically designed to deliver potent antiviral activity but with an improved safety profile compared with TDF, is therefore timely.

The results of Short-term of Tenofovir alafenamide treatment in patients with chronic hepatitis B virus infection / Монголын Анагаах Ухаан

Introduction@#Worldwide, an estimated two billion people have evidence of HBV infection, and approximately 240 million have CHB. In this study, a representative group of Mongolian adults was tested for hepatitis B virus (HBV) in 2017. The latest data shows that 11,1% of Mongolian adult population are infected with HBV.@*Goal@#Evaluate the efficacy and safety of tenofovir alafenamide treatment in patients with chronic hepatitis B.@*Materials and Methods@#The clinical trials have evaluated TAF in HBeAg-positive and HBeAg-negative chronic HBV patients. The trials have similar design and randomized, single blind, non-inferiority studies. The primary efficacy endpoint was the proportion of patients with HBV-DNA<29IU/ml at weeks 24 and 48. Other prespecified efficacy endpoints were the proportion of patients with HBsAg seroconversion to antiHBs at weeks 24 and 48. Study protocol approved at Ethical review Committee of “Ach” Medical University in January 2019 (#19/01/06).@*Results@#The primary efficacy endpoint, an HBV-DNA<29IU/ml at weeks 48 and was achieved by 251 (79.9%) of 314 patients receiving TAF, which was non-inferior to the 113(74.8%) of 151 patients receiving TDF who had an HBV-DNA<29IU/ml. After 48 weeks of treatment, patients receiving TAF hed significantly smaller reductions in bone mineral density(BMD) compared with patients receiving TDF. At weeks 48, median changes in eGFR were signifi-cantly smaller in the TAF recipients compared with the TDF recipients.@*Conclusion@#TAF treatment has the same efficacy as TDF treatment. However, TAF treatment demonstrates more safety profile compared with TDF treatment. Patients receiving TAF had a significantly smaller median decrease in eGFR, by Cockcroft-Gault equation, than patients receiving TDF.

Clinical characteristics of hepatic flare and efficacy of antiviral therapy in pregnant women with chronic hepatitis B virus infection / 中华肝脏病杂志

Objective@#To analyze the clinical characteristics of hepatic flare and evaluate efficacy of antiviral treatment in pregnant women with chronic HBV infection.@*Methods@#A single-center, open-label, prospective study was conducted, and pregnant women with chronic HBV infection were enrolled. Liver function, HBV serum markers and HBV DNA of pregnant women with chronic HBV infection were reviewed during every 4 to 12 weeks of gestation period. The proportion and clinical characteristics of hepatitis flare during pregnancy were observed. Logistic regression analysis was used to predict hepatic flare in pregnant women with chronic HBV infection. Antiviral therapy with telbivudine (LdT) or tenofovir dipivoxil (TDF) was used to treat hepatic flare during pregnancy. Sequential entecavir (ETV) or TDF was applied after the delivery. Treatment course and drug withdrawal in pregnant women with hepatic flare was the same as those of the general patients with chronic hepatitis B. Liver function, HBV serum markers and HBV DNA were measured in pregnant women with hepatic flare at different time points (4, 12, 24 and 52 weeks). A t-test was used to compare the hepatic flare in pregnant women with and without hepatitis group. HBsAg and HBeAg were used to quantify the receiver operating characteristic (ROC) curve of pregnant women with hepatic flare during pregnancy. Area under the ROC curve was used to calculate the optimal cut-off value corresponding to the maximum sensitivity and specificity of the ROC curve.@*Results@#Of the 220 pregnant women with chronic HBV infection, 55 (25%) had hepatitis flare during pregnancy and received antiviral treatment. Among the 55 women with hepatic flare during gestation, 47 (85.46%) had hepatic flare in the mid-second trimester (12-24 weeks); average peak value of alanine aminotransferase (ALT) was 220.62 U/L, and the average peak value of ALT in 32 cases (58.18%) of pregnant women with hepatic flare was between 2–5 × ULN. HBsAg and HBeAg quantification were significantly lower in pregnant women with hepatic flare during pregnancy than with non-hepatitis (t = -3.745, P < 0.001; t = -2.186, P = 0.030). Multivariate logistic regression analysis showed that pregnant women with HBeAg < 3.065 log10 s/co were 7.576 times more likely to have hepatic flare during pregnancy (95% confidence interval: 3.779-15.190). ALT normalization, undetectable HBV DNA levels, HBeAg loss and HBeAg seroconversion in 55 pregnant women with hepatic flare at 52-week treatment was 100% (55/55), 74.55% (41/55), 47.27% (26/55) and 41.82% (23/55), respectively. HBsAg quantification at 52 weeks was significantly lower than baseline HBsAg quantification (3.32 + 0.37) log10 IU/ml and (3.95 + 0.40) log10 IU/ml; t = 8.465, P < 0.001).@*Conclusion@#Hepatic flare often occurs in the second trimester of pregnancy in pregnant women with chronic HBV infection and baseline HBeAg quantification is an independent predictor of hepatic flare. HBeAg seroconversion rate increased at 52 weeks after antiviral therapy.

Generation of a novel HBeAg transgenic mice using CRISPR/Cas9 technique / 南方医科大学学报

OBJECTIVE@#To generate a new strain of HBeAg transgenic mice using CRISPR/Cas9 technique.@*METHODS@#Hepatitis B virus (HBV) HBeAg gene was cloned and inserted in the pliver-HBeAg expression frame at the site of Rosa26 gene using CRISPR/Cas9 and homologous recombination techniques to construct the pliver-HBeAg expression vector containing HBeAg gene. The linear DNA fragment containing HBeAg gene was obtained by enzyme digestion. Cas9 mRNA, gRNA and the donor vector were microinjected into fertilized eggs of C57BL/6J mice, which were then transplanted into the uterus of C57BL/6J female surrogate mice to obtain F0 generation mice. The F0 generation mice were identified by long fragment PCR to obtain F0 transgenic mice with HBeAg gene. The positive F0 generation mice were bred with wild-type C57BL/6J mice to produce the F1 mice, which were identified by PCR and sequencing. The positive F1 transgenic mice carrying HBeAg gene were backcrossed until the homozygous offspring transgenic mice were obtained. The genotypes of the offspring mice were identified. The expressions of HBeAg and HBeAb in the heterozygous and homozygous HBeAg transgenic mice were detected by automatic chemiluminescence immunoassay, immune colloidal gold technique and immunohistochemistry method.@*RESULTS@#A total of 56 F0 mice were obtained, and 2 of them carried homologous recombined HBeAg gene. Six positive F1 mice were obtained, from which 22 homozygous and 29 heterozygous F2 generation HBeAg transgenic mice were obtained. High concentration of HBeAg protein was detected in the peripheral blood of all the positive HBeAg transgenic mice without HBeAb expression. HBeAg expression was detected in the hepatocytes of HBeAg transgenic mice.@*CONCLUSIONS@#We obtained a new strain of HBeAg transgenic mice with stable expression of HBeAg in the hepatocytes and immune tolerance to HBeAg using CRISPR/Cas9 technique, which provide a new animal model for studying HBV.

Result Patterns and Characteristics of HBeAg and HBV DNA in Patients with Chronic Hepatitis B

BACKGROUND: Discrepancies in the results between hepatitis B e-antigen (HBeAg) and hepatitis B virus (HBV) DNA levels pose difficulties in the management of chronic hepatitis B (CHB). This study aims to better understand the different phases of CHB and to detect additional meaningful parameters for CHB patients. METHODS: We collected datasets of HBeAg and HBV DNA levels measured during 2016 and the follow-up results for CHB patients for past 3 years. We analyzed the collected data by applying the definitions of CHB clinical phase and compared the results of semi-quantitative and quantitative HBeAg assays. RESULTS: About 55% of 2,291 result pairs from CHB patients showed qualitative agreement between HBeAg and HBV DNA results. HBeAg (−) CHB was reported in 16.49%, while hepatitis B surface antigen (HBsAg) loss occurred in 0.18% among 1,146 patients annually. HBeAg reversion occurred in 2.74% of 839 patients that experienced HBeAg seroconversion. Patients with HBeAg (+) and HBV DNA (−) showed statistically significant differences in the levels and percentage abnormality of alanine aminotransferase (ALT) based on whether HBV DNA was ‘Target not detected’ or ‘Detected,

Clearance of HBsAg in patients with chronic hepatitis B treated by entecavir plus Peg IFNα-2b following initial entecavir monotherapy / 中华临床感染病杂志

Objective To analyze the efficacy of entecavir (ETV) combined with Peg IFNα-2b in chronic hepatitis B ( CHB) patients with low levels HBsAg following initial ETV treatment.Methods Sixty-nine CHB outpatients achieving serum HBsAg ＜2 000 IU/mL and HBV DNA＜100 IU/mL following initial ETV treatment in Pujiang People's Hospital and the First Affiliated Hospital of Zhejiang University School of Medicine from January 2014 to January 2016 were enrolled.Patients were randomly assigned in two groups: 39 patients in combination group received ETV (0.5 mg/d ) and Peg IFNα-2b (1.5 μg· kg－1· week －1, hypodermic injection), and 30 patients in ETV group received ETV (0.5 mg/d) alone.Serum HBsAg quantification, negative conversion rate of HBsAg and HBeAg , and levels of aminotransferase (ALT) were measured at baseline , 12th, 24th, 48th, 72th and 96th week after treatment.Results The levels of HBsAg in the combination group decreased gradually with the prolongation of therapy , which were lower than those in ETV group 24 week after treatment (Z＝－2.566,P＜0.05),and at 48th, 72th and 96th week (Z＝－3.499,－3.825 and －3.864,P＜0.01).Clearance of HBsAg appeared in the combination group at 24th week,the clearance rates were 7.70%(3/39) and 28.20%(11/39) at 24th and 96th week, respectively;while the clearance of HBsAg occurred in ETV group at 96th week, the clearance rate was only 3.30%(1/30).The negative conversion rates of HBsAg in combination group were higher than those in ETV group at 48th,72th and 96th week (P＜0.05 or＜0.01).In the combination group, there were 11 cases of clinical cure , 11 cases of clinical efficacy and 17 cases of clinical effectiveness , while there were 1, 1 and 28 cases in ETV group,respectively.The treatment effect of the combination group was better than that of ETV group(χ2＝18.496,P＜0.01).Serological conversion rates of HBeAg were 30.00%(6/20) and 65.00%(13/20) in combination group at 12th and 96th week, while those were 11.11%(2/18) and 22.22%(4/18) in ETV group at 48th and 96th week.There were significant differences in the HBeAg serological conversion rates at 12th, 24th, 72th and 96th week between two groups (P＜0.05 or ＜0.01). The levels of ALT in combination group increased at 12th and 24th week, which had significant difference compared with ETV group (Z＝－1.236 and －2.658,P＜0.05), and the ALT levels gradually declined 48 week after treatment in combination group and there were no statistical differences between two groups at other time points.The ETV combined with Peg IFNα-2b and low baseline HBeAg levels were associated with the clearance rate of HBsAg (both P＜0.01).Conclusions CHB patients with low HBsAg levels following initial ETV monotherapy can achieve high negative conversion rate of HBeAg and HBsAg with the combination treatment of ETV and Peg IFN α-2b.

Comparison of efficacy and safety between entecavir versus adefovir dipivoxil in the treatment of HBeAg positive chronic hepatitis B / 中国综合临床

Objective To compare the efficacy and safety of entecavir versus adefovir dipivoxil in the treatment of HBeAg positive chronic hepatitis B ( CHB) . Methods Ninety?six cases with HBeAg positive CHB were divided into ETV group and ADV group according to different medication. In addition to conventional treatment,ETV group received entecavir 0. 5 mg/d,ADV group received adefovir dipivoxil 10 mg/d. HBV DNA negative conversion rate,alanine aminotransferase ( ALT) recurrence rate and HBeAg negative conversion rate in 24 weeks,48 weeks and 96 weeks were compared as well as the adverse reactions and liver function in 96 weeks. Results HBV DNA negative conversion rates in ETV group were significantly higher than those in ADV group in 24 weeks,48 weeks and 96 weeks (24 weeks:64. 6％(31/48) vs. 41. 7％(20/48);48 weeks:83. 3％(40/48) vs. 52. 1％(25/48);96 weeks:97. 9％(47/48) vs. 62. 5％(30/48),χ2 =5. 06,10. 72,18. 96,P<0. 05) . ALT recurrence rates in ETV group were significantly higher than those in ADV group at 24 weeks,48 weeks ( 24weeks:77. 1％( 37/48 ) vs. 54. 2％( 26/48 );48weeks:85. 4％( 40/48 ) vs. 62. 5％( 30/48 ) ,χ2=5. 59,6. 54,P<0. 05). There was no significant difference in ALT complication rate at 96 week(χ2=0. 71,P>0. 05) . There was no significant difference in HBeAg negative conversion rate between the two groups through treatment(χ2=0. 07, 0. 22, 0. 44, P>0. 05 ) . After 96 weeks, ALT in both groups decreased significantly ( t =13. 56,11. 85,P<0. 05) ,while ALT in ETV group was significantly lower than that in ADV group ( ( 31. 8 ±8. 6) U/L vs. (38. 5±7. 5) U/L,t=4. 07,P<0. 05). AST in both groups decreased significantly(t=41. 27, 33. 68,P<0. 05),while AST in ETV group was significantly lower than that in ADV group ( (30. 3±6. 5) U/L vs.(37.6±7.1)U/L,t=5.25,P<0.05).TBIL in both groups decreased significantly(t=28.92,22.23,P<0. 05),while TBIL in ETV group was significantly lower than that in ADV group ( (13. 5±3. 3) μmol/L vs. (18. 7±3. 9) μmol/L,t=7. 05,P<0. 05). GGT in both groups decreased significantly (t=16. 99,13. 97,P<0.05),while GGT in ETV group was significantly lower than that in ADV group ( (35.6±10.4)U/L vs. (59. 7±12. 5)U/L,t=10. 27,P<0. 05). There was no significant difference in adverse reaction between the two groups (χ2=1. 96,P>0. 05) . Conclusion Entecavir has a higher rate of HBV DNA negative conversion rate, ALT recurrence rate and HBeAg negative conversion rate in the treatment of HBeAg positive CHB. It is an ideal antiviral drug.

Management of chronic hepatitis B patients in immunetolerant phase: what latest guidelines recommend

The natural history of chronic hepatitis B (CHB) is complex and may run through different immune phases that may overlap. In particulars, the immune-tolerant phase is the most interesting and not as well understood as we thought. The concept of true immune tolerance have been under challenged from immunology points of view. The major international guidelines have not yet reached a consensus on the definition of the immune-tolerant phase. While positive hepatitis B e antigen (HBeAg), high serum hepatitis B virus (HBV) DNA and normal serum alanine aminotransferase (ALT) levels are the three key features of this phase, some guidelines also put age into consideration. A new nomenclature, Phase 1 or HBeAg-positive chronic HBV infection, is given by the latest European Association for the Study of the Liver (EASL) published in April 2017. While current guidelines advise against starting antiviral treatment for immune-tolerant CHB patients, some new data suggest treating such patients may reduce the risk of liver fibrosis progression and hepatocellular carcinoma.

Clinical characteristics of patients with chronic hepatitis B who developed genotypic resistance to entecavir: Real-life experience

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.

The Predictive Value of Baseline HBsAg Level and Early Response for HBsAg Loss in Patients with HBeAg-positive Chronic Hepatitis B during Pegylated Interferon Alpha-2a Treatment / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To explore the predictive value of baseline HBsAg level and early response for HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment.</p><p><b>METHODS</b>A total of 121 patients with HBeAg-positive chronic hepatitis B who achieved HBsAg loss were enrolled; all patients were treated with PEG-IFNα-2a 180 μg/week. Serum HBV DNA and serological indicators (HBsAg, anti-HBs, HBeAg, and anti-HBe) were determined before and every 3 months during treatment.</p><p><b>RESULTS</b>The median treatment time for HBsAg loss was 84 weeks (7-273 weeks), and 74.38% (90 cases) of the patients needed extended treatment (> 48 weeks). The correlation between baseline HBsAg levels and the treatment time of HBsAg loss was significant (B = 14.465, t = 2.342, P = 0.021). Baseline HBsAg levels together with the decline range of HBsAg at 24 weeks significantly correlated with the treatment time of HBsAg loss (B = 29.862, t = 4.890, P = 0.000 and B = 27.993, t = 27.993, P = 0.005).</p><p><b>CONCLUSION</b>Baseline HBsAg levels and extended therapy are critical steps toward HBsAg loss. Baseline HBsAg levels together with early response determined the treatment time of HBsAg loss in patients with HBeAg-positive chronic hepatitis B during pegylated interferon alpha-2a treatment.</p>

Clinical Observation of Entecavir Combined with Long-acting Interferon in the Treatment of HBeAg Positive Chronic Hepatitis B / 中国药房

OBJECTIVE:To observe therapeutic efficacy and safety of entecavir combined with long-acting interferon in the treatment of HBeAg positive chronic hepatitis B (CHB).METHODS:A total of 140 patients with HBeAg positive CHB selected from our hospital during May 2013-May 2015 were divided into observation group and control group according to random number table,with 70 cases in each group.Both groups received routine liver-protecting treatment;control group was additionally given Peginterferon α-2b injection 80 μg subcutaneously,once a week;observation group was additionally given Entecavir dispersible tablets 0.5 mg,po,qd,on the basis of control group.Both groups received treatment for consecutive 50 weeks.Clinical efficacies,liver function indexes before and after treatment,virological efficacies and the occurrence of ADR of 2 groups were observed.RESULTS:Each 5 cases withdrew from the study in 2 groups,and 130 cases (65 cases in each group) completed the study.Total response rate of observation group was 90.8％,which was significantly higher than 76.9％ of control group,with statistical significance (P＜0.05).Before treatment,there was no statistical significance in the levels of ALT,AST,ALB or TBIL between 2 groups (P＞0.05).After treatment,the levels of ALT,AST and TBIL in 2 groups were decreased significantly,while ALB level was increased significantly,the observation group was significantly better than the control group,with statistical significance (P＜0.05).After 50 weeks of treatment,the negative conversion rate of HBV-DNA,HBeAg serology conversion rate and ALT normalizing rate of observation group were significantly higher than those of control group,and virologic breakthrough rate was significantly lower than control group,with statistical significance (P＜0.05).No severe ADR was found in 2 groups.There was no statistical significance in the incidence of ADR (P＞0.05).CONCLUSIONS:The entecavir combined with long-acting interferon show defmite therapeutic efficacy for HBeAg positive CHB,inhibit the replication of HBV and improve liver function of patients with good safety.

G1986A and G1899A in the pre-C region of HBV promote the serological conversion of e antigen / 实用医学杂志

Objective To investigate the correlation of the 1896 and 1899 mutations of hepatitis B virus (HBV)with the conversion of e antigen in serum and the progression of the disease. Methods 238 serum samples from the patients with HBsAg positive for over six months and HBV-DNA copy number > 5.0 × 102 IU/mL were collected,and the sequence analysis was used to analyze the nucleotide sequences of the 1896 and 1899 sites in the pre-C region of HBV. At the same time,the relevant clinical data and the expressions of HBeAg were collected,followed by Spearman correlation analysis and chi square test with SPSS 20.0. Results Both 1896 and 1899 sites in the pre-C region of HBV were mutated,and the base G was A,which was closely related to the expression of e antigen(P<0.05). Both G1896A and G1899A promoted the e antigen serological conversion ,and the e antigen serological conversion of G1899A was higher than that of G1896A. G1899A was associated with HBV related disease progression (correlation coefficient 0.280,P < 0.05),especially with the incurrence of HCC. Conclusions G1896A and G1899A in the pre-C region of HBV can promote the serological conversion of e antigen.

Mutations in C region of hepatitis B virus may contribute to occult hepatitis B virus infection / 实用医学杂志

Objective To investigate the role of mutations in C region that may contribute to occult hepatitis B virus infection.Methods C genes were amplified from two OBI blood donor samples respectively.Plasmids with mutations in C region of hepatitis B virus were constructed by overlapping PCR.HBsAg and HBeAg in Huh7 cells and in the serum of Balb/c mice were detected by CMLA.HBcAg in liver tissue was detected by immunohistochemistry,while HBV-RNA was tested by RT-PCR.Results Mutations in C region significantly reduced the expression level of HBeAg and HBcAg,but had no significant effect on HBsAg and HBV-RNA.Conclusion The mutations in C region affect the expression level of HBeAg and HBcAg,which may play an important role in the occurrence of OBI.

Clinical Observation of Recombinant Human Interferon α2b Combined with Bozhi Glycopeptides and Thymopentin in the Treatment of HBeAg-positive Chronic Hepatitis B / 中国药房

OBJECTIVE:To observe the clinical efficacy and safety of recombinant human interferon α2b (rhIFN α2b) combined with bozhi glycopeptides or thymopentin in the treatment of chronic hepatitis B (CHB).METHODS:Ninety HBeAg-positive CHB patients were selected from our hospital during Jan.2014-Jan.2015 and then randomly divided into group A,B,C,with 30 cases in each group.Group A was given rhINF α2b for injection (Pseudomonas) 5 million IU subcutaneously,qod;group B was additionally given Bozhi glycopeptides injection 4 mL added into 5％ Glucose injection 250 mL,ivgtt,qd,on the basis of group A;group C was additionally given Thymopentin for injection 2 mg added into 5％ Glucose injection 250 mL,ivgtt,qd,on the basis of group A.Three groups were treated for 24 weeks.The rate of ALT recovering to normal,negative rate of HBeAg,transformation rate of HBeAg/anti-HBeAg serum,negative rate of HBV-DNA and the decrease of HBsAg and HBV-DNA were compared among 2 groups after 4,8,12,24 weeks of treatment.The occurrence of ADR was recorded.RESULTS:After 4,8,12 weeks of treatment,there was no statistical significance in the rate of ALT recovering to normal,negative rate of HBeAg,transformation rate of HBeAg and the decrease of HBsAg among 3 groups (P＞0.05).After 4 weeks,negative rate of HBV-DNA in group B,C were significantly higher than group A;the decrease of HBV-DNA in group C were more significant than group A and B,with statistical significance (P＜0.05).After 8,12 weeks of treatment,the negative rate of HBV-DNA and the decrease of HBV-DNA in group B,C were significantly higher than group A,with statistical significance (P＜0.05);but there was no statistical signifi cance between group B and C (P＞0.05).After 24 weeks of treatment,there was no statistical significance in the rate of ALT recovering to normal,transformation rate of HBeAg,the decrease of HBsAg and negative rate of HBsAg among 3 groups (P＞0.05).The negative rate of HBsAg,negative rate of HBV-DNA and the decrease of HBV-DNA in group B,C were significantly higher than group A,with statistical significance (P＜0.05);there was no statistical significance between group B and C (P＞0.05).There was no statistical significance in the incidence of ADR among 3 groups(P＞0.05).CONCLUSIONS:rhIFN α2bcombined with bozhi glycopeptides or thymopentin shows good inhibitory effect on CHB,therapeutic efficacies of them are similar in the rate of ALT recovering to normal,but transformation rate of HBeAg,the decrease of HBsAg and negative rate of HBeAg.