Hepatitis B Surface Antigen Seroconversion Research Articles

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review.

Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as the clinical endpoint. The purpose of the present meta-analysis was to evaluate pegylated interferon alpha (PEG-IFNα) with or without lamivudine (LAM) or adefovir (ADV) combination treatment in HBsAg seroclearance or seroconversion with CHB. Randomized controlled trials of adults with CHB prior to May 30th 2015, with 48-52 weeks of PEG-IFNα and LAM or ADV combination therapy or monotherapy, were included. Review Manager Software 5.2.0 was used for meta-analysis. No statistical difference was noticed in HBsAg seroclearance (9.9% vs 7.1%, OR = 1.47, 95% CI 0.75, 2.90; p = 0.26) or observed in HBsAg seroconversion (4.2% vs 3.7%, OR = 1.17, 95% CI 0.57, 2.37; p = 0.67) between PEG-IFNα + LAM and PEG-IFNα + placebo for 24-26 weeks follow-up after treatment on hepatitis B e antigen (HBeAg)-positive CHB. Statistical difference was not showed in HBsAg disappearance (10.5% vs 6.4%, OR = 1.68, 95% CI 0.75, 3.76; p = 0.21) but was demonstrated in HBsAg seroconversion (6.3% vs 0%, OR = 7.22, 95% CI 1.23, 42.40; p = 0.03) between PEG-IFNα + ADV and PEG-IFNα for 48-52 weeks treatment on HBeAg-positive CHB By systematical evaluation, there were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM for 48-52 weeks treatment on HBeAg-positive CHB. There were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM during 24 weeks to 3 years follow-up after treatment on HBeAg-negative CHB by systematical evaluation. The combination between PEG-IFNα and LAM or ADV was not superior to monotherapy of PEG-IFNα in terms of HBsAg seroclearance or seroconversion.

Telbivudine vs tenofovir in hepatitis B e antigen-negative chronic hepatitis B patients: OPTIMA roadmap study.

AIMTo make efficacy and safety comparison of telbivudine-raodmap and tenofovir-roadmap in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients.METHODSThis was the first prospective, randomised, two-arm, open-label, non-inferiority study in HBeAg-negative CHB patients that compared telbivudine and tenofovir administered as per roadmap concept. Patients were treated up to 24 wk and, depending on virologic response, continued the same therapy or received add-on therapy up to 104 wk. Eligible patients received an additional 52 wk of treatment in the extension period (i.e., up to 156 wk). Patients who developed virologic breakthrough (VB) while on monotherapy also received add-on therapy. The primary efficacy endpoint was the rate of patients achieving hepatitis B virus (HBV) DNA < 300 copies/mL at week 52. Secondary efficacy endpoints included the rates of HBV DNA < 300 and < 169 copies/mL, HBV DNA change from baseline, alanine aminotransferase normalisation, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, VB, and emergence of resistance at various timepoints throughout the study. Safety and estimated glomerular filtration rate (eGFR) were also analysed.RESULTSA total of 241 patients were randomised. Non-inferiority of telbivudine arm to tenofovir arm was demonstrated at week 52 (± 7 d window), with over 91% of patients in each treatment arm achieving HBV DNA level < 300 copies/mL. Both arms were similar in terms of key secondary efficacy variables at weeks 104 and 156. The percentage of patients achieving HBV DNA < 300 copies/mL remained high and was similar in the telbivudine and tenofovir arms at both weeks 104 and 156. Over 82% of patients in both arms achieved alanine aminotransferase normalisation at week 52, and this percentage remained high at weeks 104 and 156. Telbivudine treatment progressively reduced serum HBsAg levels from baseline while no change was reported in quantitative HBsAg during therapy with tenofovir. Both treaments showed acceptable safety profiles. The telbivudine arm showed eGFR improvement unlike the tenofovir arm.CONCLUSIONEfficacy was shown for both telbivudine-roadmap and tenofovir-roadmap regimens in HBeAg-negative CHB patients over 156 wk. Telbivudine arm was associated with renal improvement.

Hepatitis B surface antigen clearance in inactive hepatitis B surface antigen carriers treated with peginterferon alfa-2a.

To examine the association between interferon (IFN) therapy and loss of hepatitis B surface antigen (HBsAg) in inactive HBsAg carriers. This was a retrospective cohort study in inactive HBsAg carriers, who were treatment-naive, with a serum HBsAg level < 100 IU/mL and an undetectable hepatitis B virus (HBV) DNA level (< 100 IU/mL). All the 20 treated patients received subcutaneous PEG-IFN alfa-2a 180 μg/wk for 72 wk and were then followed for 24 wk. There were 40 untreated controls matched with 96 wk of observation. Serum HBsAg, HBV DNA, and alanine aminotransferases were monitored every 3 mo in the treatment group and every 3-6 mo in the control group. Thirteen (65.0%) of 20 treated patients achieved HBsAg loss, 12 of whom achieved HBsAg seroconversion. Mean HBsAg level in treated patients decreased to 6.69 ± 13.04 IU/mL after 24 wk of treatment from a baseline level of 26.22 ± 33.00 IU/mL. Serum HBV DNA level remained undetectable (< 100 IU/mL) in all treated patients during the study. HBsAg level of the control group decreased from 25.72 ± 25.58 IU/mL at baseline to 17.11 ± 21.62 IU/mL at week 96 (P = 0.108). In the control group, no patient experienced HBsAg loss/seroconversion, and two (5.0%) developed HBV reactivation. IFN treatment results in HBsAg loss and seroconversion in a considerable proportion of inactive HBsAg carriers with low HBsAg concentrations.

Risk factors and outcomes of hepatitis B virus reactivation in hepatitis B surface antigen negative patients with hematological malignancies.

Current guidelines recommend all patients scheduled to receive chemotherapy should be screened for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis B virus core antigen (anti-HBc) status. However, still, more research is needed to identify the risk factors for hepatitis B virus (HBV) reactivation. We retrospectively investigated the incidence, risk factors and outcome of HBV reactivation in HBsAg negative patients with hematological malignancies. Seven hundred and thirty-eight HBsAg negative patients with hematological malignancies were included in the study. HBV reactivation was defined as reverse seroconversion of HBsAg (HBsAg reappearance). Risk factors, cumulative incidence and overall survival of HBV reactivation were analyzed. Reactivation occurred in 23 of the 738 (3.1%) enrolled patients. As expected, the reactivation rate of the anti-HBc positive group was significantly higher than that of the anti-HBc negative group (5.4% vs 0.8%). Multivariate analysis indicated that loss of antibody to the hepatitis B surface antigen (anti-HBs) was an independent risk factor. Patients with acute lymphoblastic leukemia and multiple myeloma showed significantly higher reactivation rate than those with other diseases. The cumulative incidence of HBV reactivation after starting chemotherapy in the anti-HBc positive subgroup was 0.3% at 1year, 1.7% at 2years and 10.5% at 3years. Close monitoring of HBV markers, including anti-HBs, should be performed for longer than 24months. Further study is needed to establish a strategy to prevent HBV reactivation after chemotherapy in HBsAg negative patients with hematological malignancies.

Ten-year follow-up of hepatitis B relapse after cessation of lamivudine or telbivudine treatment in chronic hepatitis B patients

The high rate of relapse after cessation of nucleos(t)ide analogues (NUCs) treatment in chronic hepatitis B (CHB) patients leads us to reassess the feasibility for off-therapy, but long-term follow-up data are scarce. We assessed the feasibility for off-therapy by a long-term observation of relapse in response to lamivudine (LAM) and telbivudine (LdT). Eighty-six NUC-naive CHB patients, treated with LAM (n = 46) or LdT (n = 40) who reached the guidelines recommended for off-therapy, were followed for up to 10 years. Hepatitis B virus (HBV), viral serology and biochemistries were periodically determined. COX model was used to predict the risk of relapse. A total of 52.3% of patients experienced relapse within a median of 115 months (range, 61–122 months). A total of 93.3% of relapses occurred within 48 months. Relapse rates in hepatitis B e antigen (HBeAg)-positive (n = 56) and HBeAg-negative (n = 30) patients were 39.3% and 76.7%, respectively (p < 0.01). HBeAg-positive patients who achieved an early viral response (EVR), defined as undetectable HBV DNA within 6 months, had a lower relapse rate compared to non-EVR patients (21.4% vs. 59.2%, p < 0.01). EVR patients who had both lower HBV DNA (<106 copies/mL) at baseline and lower hepatitis B surface antigen (HBsAg) at end of treatment had a relapse rate of 10.7%. The high relapse rates in CHB patients over this 10-year follow-up make LAM or LdT off therapy infeasible in most of the cases, except in the case of HBsAg loss and/or seroconversion. HBeAg-positive patients with EVR, lower HBV DNA and HBsAg had lower relapse rates and could be good candidates for off-therapy. Long-term monitoring, especially during the first 4 years, is critical for patients off-therapy.

A Better Antiviral Efficacy Found in Nucleos(t)ide Analog (NA) Combinations with Interferon Therapy than NA Monotherapy for HBeAg Positive Chronic Hepatitis B: A Meta-Analysis.

Background: The clinical efficacy of nucleos(t)ide analogues (NAs) combined with interferon (IFN) therapy vs. NAs monotherapy for chronic hepatitis B (CHB) remains inconclusive. The aim of this meta-analysis was to determine whether the NAs plus IFN regimen offers synergistic efficacy that justifies the cost and burden of such a combination therapy in CHB patients. Methods: Related publications covering the period of 1966 to July 2014 were identified through searching MEDLINE, EMBASE, Cochrane library, Chinese Biomedical Literature Database, WANFANG, and CNKI database. A total of 17 studies were enrolled, including 6 in English and 11 in Chinese. Then, we established a final list of studies for the meta-analysis by systematically grading the quality and eligibility of the identified individual studies. We used hepatitis B antigen (HBeAg) loss, HBV-DNA undetectable rate, HBeAg seroconversion, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, and histological score at the end of treatment for efficacy evaluation. A quantitative meta-analysis (Review Manager, Version 5.1.0) was performed to assess the differences between NAs and IFN combination therapy and NAs monotherapy. Results: Our analysis demonstrated that HBeAg loss (RR = 1.73, 95% CI = 1.32–2.26, p < 0.001), HBV-DNA undetectable rate (RR = 1.58, 95% CI = 1.22–2.04, p < 0.001), HBeAg seroconversion (RR = 1.68, 95% CI = 1.36–2.07, p < 0.001), and HBsAg loss (RR = 2.51, 95% CI = 1.32–4.75, p < 0.001) in the combination therapy group were significantly higher than those in the monotherapy group. However, there were no significant differences in HBsAg seroconversion (RR = 4.25, 95% CI = 0.62–29.13, p = 0.14), sustained virological response rates, and biochemical response rates observed between the two groups. The results showed that the combination therapy group had more improved HBV histology than the NAs monotherapy group (RR = 1.14, 95% CI = 0.93–1.39, p = 0.22). Conclusions: NAs and IFN or Peg-IFN combination therapy had a better efficacy in terms of HBeAg loss, HBV-DNA undetectable rate, HBeAg seroconversion, and HBsAg loss, compared to the NA monotherapy group at the end of treatment; however, there was no significant difference in HBsAg seroconversion between the two regimens.

Seroclearance of Hbsag in Chronic Hepatitis B Virus Patients on Lamivudine Therapy: A 10 Year Experience.

Introduction:The aim of this study was to determine hepatitis B surface antigen (HBsAg) seroclearance rate among patients treated with lamivudine at a specialized tertiary care referral hospital in Tehran, Iran.Methods:All patients on lamivudine (biovudin®) therapy at a dose of 100 mg/day, who showed seroclearnace between March 2001 and September 2011 were recruited. The main evaluation parameters were duration of HBsAg seroclearance and duration of HBsAg seroconversion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated using standard methods. HBsAg seroclearance was defined as two consecutive negative serums HBsAg at least 6 months apart, whereas HBsAg seroconversion was defined as the disappearance of serum HBsAg and the presence of anti-HBs for >6 months.Results:A total of 203 chronic HBV patients treated with lamivudine at a dose of 100 mg/day were included in the study. HBsAg seroclearance and seroconversion were observed in 11 patients after the initiation of the lamivudine therapy. Overall, in lamivudine responder patients, the mean time to HBsAg seroclearance was 26.90±10.93 months (range: 12-48 months). Furthermore, the responders showed seroconversion after a mean time of 26.90±11.08 months from the initiation of lamivudine therapy. When comparing the characteristics of those who have responded to lamivudine and those who have not responded, baseline HBV-DNA levels was significantly lower in responder than non responder patients (p<0.001). Meantime, there was no difference in age, sex, baseline ALT, AST and liver biopsy score between lamivudine responder and lamivudine non-responder patients.Conclusion:Despite introduction of tenofovir and entecavir as first line treatment for chronic HBV infection, lamivudine remains to be a low cost, safe and effective drug for HBsAg seroclearnace.

Prospective Randomized Open-label Trial Protocol Investigating the Addition of Pegylated Interferon-alpha to an Ongoing Nucleos(t)ide Treatment Regimen of HBeAg Negative Chronic Hepatitis B Patients (PADD-ON)

Background: Hepatitis B surface antigen (HBsAg) clearance marks the prime event of HBV elimination in chronic hepatitis B and is associated with better overall outcome. Despite reliable viral suppression under standard treatment with nucleos(t)ide analogues (NUCs) the goal of HBsAg clearance is rarely achieved. Also synchronous combination of NUCs with pegylated interferon-α-2a (peg-IFNα) has not been superior compared to peg-IFNα monotherapy in prospective randomized trials. However, sequential addition of peg-IFNα to an ongoing NUC regimen has provided higher HBsAg clearance rates in uncontrolled pilot studies. Methods/Design: In this protocol we investigate the sequential addition of open-label peg-IFNα for 48 weeks to an ongoing NUC regimen following patients written informed consent. Included are patients with HBeAg negative chronic hepatitis B and a suppressed HBV DNA (<20 IU/mL) for a minimum of 12 months under NUCs prior to trial enrollment. Patients are randomized (2:1 ratio) to peg-IFNα add-on/ NUC treatment or a control group receiving continuous NUCs only. Patients are followed regularly during the trial intervention including a per protocol follow-up for 24 weeks after end of treatment. The primary endpoint is the objective response after 48 weeks of combination therapy, defined by a confirmed reduction of HBsAg by ≥ 1log10 IU/mL compared to baseline. Secondary endpoints are the HBsAg seroconversion rate, safety and tolerability of the IFN add-on therapy regimen. The trial was approved by the local ethic committees of all participating study sites. Trial registration: The trial was registered on the 10th of June 2011 at EudraCT (ID number 2011-002812-10).

Understanding early serum hepatitis D virus and hepatitis B surface antigen kinetics during pegylated interferon-alpha therapy via mathematical modeling.

There is little information on the early kinetics of hepatitis delta virus (HDV) and hepatitis B surface antigen (HBsAg) during interferon-α therapy. Here a mathematical model was developed and fitted to frequent HDV and HBsAg kinetic data from 10 patients during the first 28 weeks of pegylated-interferon-α2a (peg-IFN) therapy. Three patients achieved a complete virological response (CVR), defined as undetectable HDV 6 months after treatment stopped with loss of HBsAg and anti-HBsAg seroconversion. After initiation of therapy, a median delay of 9 days (interquartile range [IQR]: 5-15) was observed with no significant changes in HDV level. Thereafter, HDV declined in a biphasic manner, where a rapid first phase lasting for 25 days (IQR: 23-58) was followed by a slower or plateau second phase. The model predicts that the main effect of peg-IFN is to reduce HDV production/release with a median effectiveness of 96% (IQR: 93-99.8). Median serum HDV half-life (t1/2 ) was estimated as 2.9 days (IQR: 1.5-5.3) corresponding to a pretreatment production and clearance of about 10(10) (IQR: 10(9.7) -10(10.7) ) virions/day. None of the patients with flat second phase in HDV achieved CVR. HBsAg kinetics of decline paralleled the second phase of HDV decline consistent with HBsAg-productive-infected cells being the main source of production of HDV, with a median t1/2 of 135 days (IQR: 20-460). The interferon lambda-3 polymorphism (rs12979860) was not associated with kinetic parameters. Modeling results provide insights into HDV-host dynamics, the relationship between serum HBsAg levels and HBsAg-infected cells, IFN's mode of action, and its effectiveness. The observation that a flat second phase in HDV and HBsAg kinetics was associated with failure to achieve CVR provides the basis to develop early stopping rules during peg-IFN treatment in HDV-infected patients.

Alteration of the glycan profile of serum glycoproteins during the seroconversion process in hepatitis B virus-infected patients treated with antiviral therapy and its clinical significance

To use a lectin microarray to study the alteration of glycan affinity profiles of serum glycoproteins during the hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) seroconversion in patients with chronic hepatitis B (CHB) following treatment with antiviral therapy,and to explore its biological significance. CHB patients were divided into the following four groups:untreated HBeAg-positive,HBeAg seroconversion after anti-HBV therapy,HBsAg loss after anti-HBV therapy,and healthy individuals (controls).Serum samples were collected from each participant,depleted of high abundance proteins and analyzed by a lectin microarray containing 50 lectins.The lectin-affinity glycan profiles of serum proteins were partially verified by lectin blotting.Between-group differences were analyzed by one-way analysis of variance,and pairwise comparisons were carried out with the Student-Newman-Keuls (SNK) method. The results from the lectin microarray and lectin blotting assay showed significantly reduced affinity for 16 lectins in the untreated HBeAg-positive group compared to the control group (P less than 0.05);in addition,the specific glycan profiles of the untreated HBeAg-positive group included decreased terminal and core fructose,GalNAc alpha-Thr/Ser (T,Tn-antigen),GalNac alpha,terminal beta1-4,and beta-D galactose,bisecting and/or GlcNAc,mannose and Sia.However,the HBeAg seroconversion after anti-HBV therapy group showed enhanced binding of PSA,MPL and the above-mentioned 16 lectins (P less than 0.05),suggesting that the reduced serum glycoprotein glycan structures returned to normal or slightly higher than healthy levels after the therapy-induced seroconversion.Comparison of the group with HBsAg loss after anti-HBV therapy to the group with HBeAg seroconversion after anti-HBV therapy showed the binding ability of ten lectins (AAL,ACL,HAL,HPL,RCA-I,LEL,STL,PHA-E,NML and PCL) were weakened to near control levels and six lectins (VAL,LCA,GNL,PSA,MPL and JAC) were significantly strengthened (all P less than 0.05). These findings implied that the glycan containing terminal fructose, GalNacalpha, terminal beta1-4 galactose,and bisecting GlcNAc glycan structures dropped to near control levels, while the terminal beta-D-galactose residues and core fructose structure increased significantly. The glycan structures of serum glycoproteins are closely related to HBeAg and HBsAg seroconversion in CHB patients.It is possible that a special lectin binding glycan involving the terminal beta-D-galactose residues and core fructose may act as sugar markers associated with the disappearance of serum HBsAg during anti-HBV therapy for CHB.

Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Māori: results from a 28-year follow-up study

BackgroundChronic hepatitis B infection is endemic in New Zealand and has high prevalence in New Zealand Māori. Previous longitudinal studies in populations with predominantly vertically acquired chronic hepatitis B have...

Interferon for Chinese patients with chronic hepatitis B e antigen-positive diseases-the controversy arises again?

In 2014, seven drugs were registered for the treatment of chronic hepatitis B (CHB) infection. Two were immunomodulatory agents, conventional interferon(IFN)-a and pegylated IFN-a2a, and five were direct antiviral nucleos(t)ide analogs (NUCs), lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. Due to the high resistance barrier of entecavir and tenofovir as compared to the other NUCs, only these two drugs are now in practical use in most parts of the world [1]. For chronic hepatitis B e antigen (HBeAg)-positive patients, HBeAg seroconversion, defined as the loss of HBeAg with the appearance of anti-HBe, is often associated with clinical remission and a transition to inactive liver disease. Accompanying HBeAg seroconversion, there is a reduction in liver fibrosis and a lower incidence of cirrhosis and hepatocellular carcinoma. HBeAg seroconversion, whether spontaneous or treatment induced, is also associated with a higher probability of hepatitis B surface antigen (HBsAg) loss and seroconversion, which is considered to be a more permanent clinical remission of liver disease. Thus, the achievement as well as maintenance of HBeAg seroconversion, in association with low serum hepatitis B virus (HBV) DNA levels (\3–4 log IU/ml), is an important goal in the management of patients with HBeAg-positive CHB [2]. Based on evidence demonstrating HBeAg seroconversion is an important hallmark event of a durable clinical remission of liver disease, most hepatology society treatment guidelines have adopted HBeAg seroconversion with sustained suppression of HBV DNA as an end point for treatment in patients with HBeAgpositive CHB who do not have cirrhosis or decompensated liver disease [1]. Previously, the conflicting data related to the importance of HBeAg seroconversion were largely related to the existence of a group of HBeAg seroconverters with a high HBV DNA viral load. In fact, this merely represented a transition from chronic HBeAgpositive disease to chronic HBeAg-negative disease, with little impact on the natural history of CHB. This important point was emphasized by a recent study in Taiwan, which included 2,946 chronic CHB Chinese patients. It was shown that high serum HBV DNA levels at the seroclearance of HBeAg could explain the nonsignificant association between HBeAg seroclearance and HCC risk [3]. Among the various forms of treatment, 1-year treatment with pegylated IFN-a2a yielded the highest rate of HBeAg seroconversion (around 40 %); among them, one-tenth further benefited from HBsAg seroconversion. On the other hand, treatment with NUCs achieved a much lower rate of HBeAg seroconversion; hence, more prolonged therapy is required when one has started treating CHB patients with NUCs. Hence, one of the key questions is related to the durability of HBeAg seroconversion with the various forms of therapy. This will affect the physician’s decision when choosing a therapy for our chronic HBeAg-positive patients between nucleos(t)ide analogs (NUCs) or pegylated IFN. Clinically, this has always led to a painful choice between either life-long medication with NUCs with a high genetic barrier (entecavir or tenofovir disoproxil fumarate) or lasting remission with a relatively short duration but sometimes side effect-prone therapy with 48 weeks of pegylated IFN. Previously, two large-scale clinical studies in Chinese subjects demonstrated that treatment with G. K. K. Lau (&) Humanity and Health GI and Liver Centre, Hong Kong, Hong Kong SAR e-mail: gkklau@netvigator.com

Effect of Menarche Onset on the Clinical Course in Females with Chronic Hepatitis B Virus Infection

To investigate the impact of menarche on the natural course of chronic hepatitis B virus (HBV) infection in women. Young women who are positive for hepatitis B e antigen (HBeAg; n = 101) chronically infected with genotypes B and C HBV were recruited at a mean age of 4.57 ± 3.08 years, and a mean follow-up duration of 23.98 ± 3.77 years. Clinical data, including age at menarche, HBV genotypes, serum HBV viral loads, hepatitis B surface antigen (HBsAg) titers, and serial liver functional profiles were analyzed. Women with earlier onset of menarche had earlier spontaneous HBeAg seroconversion than others (hazard ratio, 2.0; P = .02) adjusting for HBV genotype and peak alanine aminotransferase levels before HBeAg seroconversion. The annual decrease in HBsAg titer from 15 to 20 years of age also was greater in the early menarche group compared with the late menarche group (0.11 ± 0.11 vs 0.05 ± 0.11 log10 IU/mL, P = .04). The baseline HBV viral load was also borderline low in female subjects with earlier menarche as compared with others (P = .06). Earlier menarche onset was associated with higher spontaneous HBeAg seroconversion, HBsAg seroclearance, and HBsAg seroconversion rate before 15 years of age in females with chronic HBV infection. Earlier puberty-onset, indicated by menarche-onset, was associated with earlier spontaneous HBeAg seroconversion and greater rate of HBV clearance before 15 years of age in female subjects with chronic HBV infection.

Artificial neural network accurately predicts hepatitis B surface antigen seroclearance.

Background & AimsHepatitis B surface antigen (HBsAg) seroclearance and seroconversion are regarded as favorable outcomes of chronic hepatitis B (CHB). This study aimed to develop artificial neural networks (ANNs) that could accurately predict HBsAg seroclearance or seroconversion on the basis of available serum variables.MethodsData from 203 untreated, HBeAg-negative CHB patients with spontaneous HBsAg seroclearance (63 with HBsAg seroconversion), and 203 age- and sex-matched HBeAg-negative controls were analyzed. ANNs and logistic regression models (LRMs) were built and tested according to HBsAg seroclearance and seroconversion. Predictive accuracy was assessed with area under the receiver operating characteristic curve (AUROC).ResultsSerum quantitative HBsAg (qHBsAg) and HBV DNA levels, qHBsAg and HBV DNA reduction were related to HBsAg seroclearance (P<0.001) and were used for ANN/LRM-HBsAg seroclearance building, whereas, qHBsAg reduction was not associated with ANN-HBsAg seroconversion (P = 0.197) and LRM-HBsAg seroconversion was solely based on qHBsAg (P = 0.01). For HBsAg seroclearance, AUROCs of ANN were 0.96, 0.93 and 0.95 for the training, testing and genotype B subgroups respectively. They were significantly higher than those of LRM, qHBsAg and HBV DNA (all P<0.05). Although the performance of ANN-HBsAg seroconversion (AUROC 0.757) was inferior to that for HBsAg seroclearance, it tended to be better than those of LRM, qHBsAg and HBV DNA.ConclusionsANN identifies spontaneous HBsAg seroclearance in HBeAg-negative CHB patients with better accuracy, on the basis of easily available serum data. More useful predictors for HBsAg seroconversion are still needed to be explored in the future.

The effects of different dosage levels of hepatitis B vaccine as booster on anti-HBs-negative children 5–15 y after primary immunization; China, 2009–2010

The changes in lgG antibody levels to hepatitis B surface antigen (HBsAg) and in antibody to HBsAg (anti-HBs) seroconversion rates due to different dosages of hepatitis B vaccine (HepB) were compared in 2106 children. Children who had been previously vaccinated as infants with HepB were revaccinated at 5–15 y of age, after which the antibody titers were determined. After the first booster dose, the anti-HBs seroconversion rate (defined as an anti-HBs ≥10 mIU/ml) with 10 μg of HepB (93.6%) was significantly greater than the rate with 5 µg of HepB (90.3%) (P < 0.05); the anti-HBs seroconversion rate in 10–15-y-old boys vaccinated with 10 μg of HepB (90.9%) was significantly greater than the rate with 5 µg of HepB (84.3%) (P < 0.05). The anti-HBs seroconversion rates after the third booster dose with 5 or 10 μg of HepB were greater than those after the first booster dose (99.6% and 99.7%, vs. 90.3% and 93.6%, P < 0.05); as was the corresponding GMTs (658 ± 4 mIU/ml and 2599 ± 3 mIU/ml, vs. 255 ± 11 mIU/ml and 877 ± 11 mIU/ml [P < 0.05]). The immunization effects of booster vaccination with 3 doses of HepB with 5 or 10 µg are effective; a single booster dose with 10 µg of HepB for 10–15-y-old boys and with 5 or 10 µg of HepB for 5–9 y old boys and for 5–15-y-old girls are effective in generating protective antibody against HBV; however, for anti-HBs-negative children after a single dose of booster, 3 doses are needed.

Extended treatment with peginterferon α‐2a in combination with lamivudine or adefovir for 96 weeks yields high rates of HBeAg and HBsAg seroconversion

The study aimed to investigate the efficacy and safety of peginterferon α-2a (PEG IFNα-2a) in combination with lamivudine or adefovir in the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB). In total, 47 patients with HBeAg-positive CHB received either PEG IFNα-2a (135 μg once weekly) plus lamivudine (100 mg daily) or adefovir (10 mg daily). All patients completed 96 weeks of therapy and were followed up for a further 24 weeks. Baseline characteristics and treatment efficacy of the two groups were similar. All patients achieved hepatitis B virus (HBV) DNA <500 copies/mL at 96 weeks, and none had a virological rebound after stopping the therapy. The rate of HBeAg seroconversion was 46.8% at 48 weeks, increased to 74.5% at 96 weeks, and kept at 72.3% at 120 weeks. Hepatitis B surface antigen (HBsAg) seroconversion rate was 6.4% at 48 weeks, increased to 21.3% at 96 weeks, and kept at 27.7% at 120 weeks. Extended treatment with PEG IFNα-2a with lamivudine or adefovir for 96 weeks is a promising strategy to achieve high rates of sustainable HBeAg and HBsAg seroconversion and HBV DNA suppression in patients with HBeAg-positive CHB.

Highly Sensitive Detection of Hepatitis B Virus Surface Antigen by Use of a Semiautomated Immune Complex Transfer Chemiluminescence Enzyme Immunoassay

The performance of hepatitis B surface antigen (HBsAg) screening assays is continuously improved to reduce the risk of transfusion-associated hepatitis B. In this study, a semiautomated immune complex transfer chemiluminescence enzyme immunoassay (ICT-CLEIA) for the detection of HBsAg, which is as sensitive as hepatitis B virus (HBV) DNA PCR, was developed; the ICT-CLEIA assay performance was compared with the performance of the Architect HBsAg QT assay and HBV DNA PCR. The specificities in the initial assay and after retesting were 99.50% (1,988/1,998 samples) and 99.95% (1,997/1,998 samples), respectively. The analytical detection limit was determined to be 0.2 mIU/ml using the 2nd International WHO HBsAg standard, and the cutoff value (0.5 mIU/ml) of the ICT-CLEIA assay was 8.0 standard deviations (SD) above the mean of the HBsAg-negative specimens. The ICT-CLEIA assay could detect HBsAg even in the presence of anti-HBs antibodies and demonstrated a 23.6-day-shorter window period using commercially available HBsAg seroconversion panels than the Architect HBsAg QT assay. Furthermore, the monitoring of the viral kinetics by the ICT-CLEIA assay and the HBV DNA PCR produced very similarly shaped curves during both the HBsAg seroconversion and reverse seroconversion periods. Therefore, the ICT-CLEIA assay may be useful not only for an earlier detection of HBV reactivation but also for the monitoring of hepatitis B patients.

A retrospective follow-up study of prolonged nucleos(t)ide analogue and interferon combination therapy in HBeAg-positive chronic hepatitis B patients

To investigate the efficacy of a 96-week course of nucleos(t)ide analogue and interferon (IFN) combination therapy for achieving seroconversion at 24 weeks after completion in patients with chronic hepatitis B (CHB). One-hundred-and-thirty-five CHB patients with positivity for hepatitis B e antigen (HBeAg) were recruited for study between January 2005 and December 2008. All patients were given a 96-week course of nucleos(t)ide analogue (lamivudine or adefovir dipivoxil) alone (monotherapy controls, n = 45) or in combination with IFN or Pegylated-IFN-alpha-2a (Peg-IFNa-2a) (n = 90). At treatment weeks 12, 24, 48, 72, and 96, and at 24 weeks after treatment completion, serum samples were collected from all patients for assessment of biochemical, virological and serological responses to treatment. The biochemical response was indicated by normalization of the alanine aminotransferase (ALT) level. The virologic response was indicated by a reduction in the hepatitis B virus (HBV) DNA level to less than 1000 copies/ml. The serological response was indicated by seroconversion of either HBeAg or hepatitis B surface antigen (HBsAg). Statistical analysis was performed with the Chi-squared test. Among the patients treated with nucleos(t)ide analogue and IFN combination therapy, 41.1% (37/90) achieved HBeAg seroconversion and 18.9% (17/90) achieved HBsAg seroconversion at the end of treatment. However, significantly less of the patients treated with nucleos(t)ide analogue monotherapy achieved HBeAg seroconversion and none achieved HBsAg seroconversion by end of treatment (33.3% and 0%, respectively; x2= 8.08, P less than 0.01 vs. the combination therapy group). Age stratification of the 17 HBsAg-seroconverted patients treated with combination therapy indicated that the HBsAg seroconversion rate was significantly higher in patients less than 30-years-old than those 30 and older (x2= 12.62 and 4.24, respectively, P less than 0.05). At post-treatment week 24, the 17 HBsAg-seroconverted patients treated with combination therapy showed HBsAg titers of less than 250 IU/ml; moreover, 11.8% (2/17) of these patients remained HBeAg-positive and 17.6% (3/17) showed abnormal ALT levels and elevated HBV DNA. Prolonged nucleos(t)ide analogue plus IFN combination therapy can significantly improve the rate of HBsAg seroconversion in HBeAg-positive CHB patients, and this treatment regimen is especially efficacious in patients under the age of 30.

Resolution of chronic hepatitis delta infection after five years of peginterferon–adefovir: Lessons from a case report

There is still some controversy about the treatment of hepatitis delta virus (HDV) infection and the treatment endpoints. A 48-year-old patient was treated with a combination of peginterferon-α and adefovir, and HDV RNA clearance occurred after 3 years of treatment. However, treatment was continued until HBs antigen (Ag) seroconversion, which occurred after 5 years of therapy. One year after the end of the treatment, the patient was still HBs Ag and HDV RNA negative. This case report suggests that combined peginterferon-α and adefovir may be effective in treating HDV infection and, if given over a longer period, may result in hepatitis B surface antigen (HBsAg) seroconversion. It highlights the interest of using HBsAg quantification associated with a sensitive RT-PCR approach for monitoring the treatment of chronic hepatitis delta. HBsAg seroconversion, or at least significant decrease, could be a more relevant endpoint than HDV RNA undetectability for discontinuing HDV treatment and preventing the occurrence of virological relapses.

Outcome of Various Treatments for Posttransplant Hepatitis B Virus Recurrence

Currently, no treatment guidelines are available for posttransplant hepatitis B virus (HBV) recurrence. We retrospectively evaluated the rate of clearance of hepatitis B surface antigen (HBsAg) from serum according to various treatment regimens in two large Korean liver transplantation centers. Between 1996 and 2008, HBV recurred in 59 patients among 933 HBV liver recipients (6.3 %). Patients with HBV recurrence were divided into four groups according to their treatment: group L (lamivudine-based therapy n = 21) and group N [new nucleos(t)ide analogue (NA)-based therapy, n = 38]. Intravenous hepatitis B immunoglobulin (ivHBIG) had been simultaneously administered to 10 patients in group L and 26 patients in group N. The mean posttransplant follow-up duration and time to HBV recurrence were 69 (14-152) months and 37 (3-120) months. Overall, 22 patients (37.3 %) showed seronegative conversion of HBsAg for a median 8 months after treatment (range 1-15 months). The seroclearance rate was significantly higher in group N (n = 20, 52.6 %) than in group L (n = 2, 9.5 %) (p < 0.000). The time to seroconversion did not differ between group L (7 months, range 5-16) and group N (7 months, range 1-15) (p = 0.428). Subgroup analysis showed that the HBsAg seroconversion rate was much higher for patients given combined ivHBIG and new NAs (15/26 patients, 58.0 %) than the others (p = 0.006). Seroclearance of HBsAg could be achieved using new NAs in half of the patients after posttransplant HBV recurrence. Combined ivHBIG may add a synergistic effect to new NAs for clearing HBsAg.