Genome‐free hepatitis B virion levels in patient sera as a potential marker to monitor response to antiviral therapy

Complete virions of hepatitis B virus (HBV) contain a DNA genome that is enclosed in a capsid composed of the HBV core antigen (HBcAg), which is in turn surrounded by a lipid envelope studded with viral surface antigens (HBsAg). In addition, HBV‐infected cells release subviral particles composed of HBsAg only (HBsAg ‘spheres’ and ‘filaments’) or HBsAg enveloping HBcAg but devoid of viral DNA (‘empty virions’). The hepatitis B e antigen (HBeAg), a soluble antigen related to HBcAg, is also secreted in some HBV‐infected patients. The goals of this study were to explore the levels of empty virions in HBV‐infected patients before and during therapy with the nucleotide analog tenofovir disoproxil fumarate (TDF) that inhibits HBV DNA synthesis and the relationships of empty virions to complete virions, HBsAg and HBeAg. HBV DNA, HBcAg and HBsAg levels were determined in serum samples from 21 patients chronically infected with HBV and enrolled in clinical TDF studies. Serum levels of empty virions were found to exceed levels of DNA‐containing virions, often by ≥100‐fold. Levels of both empty and complete virions varied and were related to the HBeAg status. When HBV DNA replication was suppressed by TDF, empty virion levels remained unchanged in most but were decreased (to the limit of detection) in some patients who also experienced significant decrease or loss of serum HBsAg. In conclusion, empty virions are present in the serum of chronic hepatitis B patients at high levels and may be useful in monitoring response to antiviral therapy.     

Baseline and kinetics of serum hepatitis B virus RNA predict response to pegylated interferon‐based therapy in patients with hepatitis B e antigen‐negative chronic hepatitis B

Serum hepatitis B virus (HBV) RNA has emerged as a novel biomarker of treatment response. This study aimed to investigate the role of this marker in predicting long‐term outcome of patients with hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (CHB) receiving pegylated interferon (PEG‐IFN)‐based therapy. Serial serum samples from 91 patients with HBeAg‐negative CHB previously treated with PEG‐IFN alone or combined with entecavir in a randomized trial were retrospectively analysed. HBV RNA quantification was examined by droplet digital PCR. At the end of 3 years post‐treatment follow‐up, maintained virological response (MVR, HBV DNA < 2000 IU/mL), and hepatitis B surface antigen (HBsAg) clearance were achieved in 37.4% (34/91) and 7.7% (7/91), respectively. Baseline serum HBV RNA concentrations correlated with HBV DNA and covalently closed circular DNA but did not correlate with HBsAg levels. Multiple regression analysis showed that pre‐treatment HBV RNA and HBsAg were independently associated with MVR and HBsAg clearance. Baseline HBV RNA (cut‐off 2.0 log₁₀ copies/mL) had a positive predictive value (PPV) and a negative predictive value in predicting MVR of 80.8% and 80.0%, respectively. At the same cut‐off value, PPV and NPV for predicting HBsAg clearance were 30.8% and 95.4%, respectively. At week 12 during therapy, HBV RNA level ≥ 2 log₁₀ copies/mL displayed high NPVs of achieving MVR and HBsAg clearance (95% and 100%, respectively). In conclusion, the measurement of HBV RNA prior to PEG‐IFN‐based therapy could identify patients with high probability of MVR. In addition, HBV RNA kinetics may serve as a promising “stopping rule” in patients infected with HBV genotypes B or C.     

The change of the quantitative HBsAg level during the natural course of chronic hepatitis B

Background: There is insufficient information about HBsAg levels and their correlation with serum hepatitis B virus (HBV) DNA in chronic hepatitis B (CHB). Aims: We aimed to describe HBsAg levels during various phases of CHB and to investigate the correlation with serum HBV DNA levels. Methods: A total of 645 treatment‐naïve Korean CHB patients were included in this retrospective cross‐sectional study. They were categorized into immune tolerance (IT, n=56), HBeAg‐positive hepatitis (EPH, n=150), inactive carrier (IC, n=274) and HBeAg‐negative hepatitis (ENH, n=165). The baseline HBsAg and HBV DNA levels were measured. Results: The mean HBsAg titres (log IU/ml) differed (P<0.001): IT 4.29, EPH 3.64, IC 2.05 and ENH 3.23. In 645 patients, HBsAg and HBV DNA showed a significant correlation (r=0.693, P<0.001), and this was also observed in the IT, EPH and IC groups (r=0.664, r=0.541, r=0.505, respectively, all P<0.001), but not in the ENH group (r=0.093, P=0.321). Age had a negative correlation with HBsAg (r=?0.451, P<0.001). The cirrhotic patients had a significantly lower HBsAg level than the non‐cirrhotic patients (2.41 ± 1.36 vs. 3.02 ± 1.21 log IU/ml, P<0.001). Conclusions: The HBsAg level varied significantly in different phases of CHB and was correlated with HBV DNA during the IT, EPH and IC phases. These findings can provide additional information to understand the natural course and pathogenesis of CHB.     

Comparison between quantitative hepatitis B surface antigen,hepatitis B e‐antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon‐α‐2b therapy in hepatitis B e‐antigen‐positive chronic hepatitis B

Aim: The aim of this study was to compare the clinical applicability of quantitative serum hepatitis B surface antigen (HBsAg), hepatitis B e‐antigen (HBeAg) and hepatitis B virus (HBV) DNA for predicting virological response (VR) to pegylated interferon (PEG‐IFN) therapy. Methods: Thirty HBeAg‐positive chronic hepatitis B patients who received PEG‐IFN‐α‐2b for 48 weeks were enrolled. Quantitative HBsAg, HBeAg and HBV DNA were measured before, during and after the therapy. Paired liver biopsies were performed before and after treatment for covalently closed circular (ccc)DNA and intrahepatic HBV DNA analysis. Results: VR at 48 weeks post‐treatment, defined as HBeAg seroconversion and HBV DNA less than 10 000 copies/mL was achieved in 10 (33.3%) patients. Responders had significantly lower baseline HBsAg, HBeAg, cccDNA and intrahepatic HBV DNA levels than non‐responders. Baseline and reduced levels of log₁₀ HBsAg and log₁₀ HBeAg correlated well with those of log₁₀ cccDNA and log₁₀ total intrahepatic HBV DNA. Responders showed consistent decrease in serum HBsAg, HBeAg and HBV DNA levels during therapy. HBeAg level of 2.0 log₁₀ sample to cut‐off ratio at week 24 on therapy provided the best prediction of sustained virological response, with sensitivity and negative predictive values of 85% and 92%, respectively. One patient (3.3%) who cleared HBsAg at follow up exhibited a more rapid decline in serum HBsAg during therapy than those who developed VR without HBsAg clearance. Conclusion: Quantitative measurement of serum HBeAg during therapy may be superior to serum HBsAg and HBV DNA as a prediction of HBeAg seroconversion. Kinetics of HBsAg levels on therapy may help predict HBsAg clearance after treatment.     

Hepatitis B surface antigen monitoring and management of chronic hepatitis B

Serum hepatitis B surface antigen (HBsAg) levels reflect intrahepatic hepatitis B virus (HBV) covalently closed circular DNA and may be a valuable addition to HBV DNA in the management of patients with chronic hepatitis B (CHB). Among HBeAg-negative CHB patients with low HBV DNA levels, HBsAg quantification may help distinguish those with active CHB from true inactive carriers with a very favourable prognosis, thus limiting the need for long-term intensive monitoring of ALT and HBV DNA levels. In patients treated with peginterferon (PEG-IFN), achievement of a decline in HBsAg during therapy appears to be an important marker for treatment outcome, and several groups have proposed stopping rules based on HBsAg thresholds. A recently described stopping rule incorporating a combination of HBsAg and HBV DNA levels can accurately identify HBeAg-negative patients, especially those with HBV genotype D, not responding to PEG-IFN. Current applications of HBsAg levels in the monitoring of patients treated with nucleo(s)tide analogues are still being evaluated. First data from these studies show that HBsAg decline, and thus subsequent clearance, is confined to those with an active immune response to HBV, such as HBeAg-positive patients with elevated ALT, or those who achieve HBeAg clearance.     

Predictors of sustained functional cure in hepatitis B envelope antigen‐negative patients achieving hepatitis B surface antigen seroclearance with interferon‐alpha–based therapy

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)‐negative CHB patients. In this prospective study, 176 HBeAg‐negative CHB patients with functional cure were enrolled for 12 weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3 months; liver imaging examinations were performed every 3‐6 months during the 48‐week follow‐up. The sustained functional cure was evaluated. After the 48‐week follow‐up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment ≥ 12 weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment < 12 weeks (76.19% vs 90.00%, P = 0.022 and 23.81% vs 9.23%, P = 0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P = 0.012). Consolidation treatment ≥ 12 weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135‐127.151; P = 0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824‐37.881; P = 0.006) were independent predictors of sustained functional cure. Results suggested that 12 weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure.     

Hepatitis B surface antigen loss and sustained viral suppression in Asian chronic hepatitis B patients: A community‐based real‐world study

Community‐based real‐world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re‐emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti‐HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re‐emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg‐positive and HBeAg‐negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti‐HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on‐treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re‐emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community‐based real‐world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti‐HBs, nearly all patients achieved sustained undetectable virus.     

Long‐term efficacy and safety of peginterferon in the treatment of children with HBeAg‐positive chronic hepatitis B

Achieving ‘clinical cure’ in children with chronic hepatitis B (CHB) with safe and effective antiviral treatment is an unmet medical need. Peginterferon (PegIFN) has higher hepatitis B s antigen (HBsAg) clearance than nucleoside analogs (NUC). Currently, studies on interferon (IFN) in the treatment of Chinese children with CHB are relatively rare. This study aimed to further explore the efficacy of PegIFNα‐2a as an antiviral treatment in Chinese children and analyse the long‐term follow‐up after drug discontinuation. We enrolled 118 patients with CHB (2‐16 years old, 79 cases are males) treated with PegIFNα‐2a by the author in the Third People's Hospital of Kunming City from February 2009 to February 2015. The course of treatment was 52 weeks, with a follow‐up period of 104 weeks. All the patients completed at least 1 dose, of which 104 completed at least 36 weeks of treatment and 104 weeks of follow‐up. During treatment and follow‐up, indicators such as alanine aminotransferase (ALT), hepatitis B virus (HBV) DNA and HBV serological markers were monitored, and the efficacy and safety of PegIFNα‐2a in the treatment of CHB patients were observed. Hepatitis B e antigen (HBeAg) clearance and seroconversion rates were 53.8% and 49%, respectively, when the drug was discontinued; 72.1% and 72.1%, respectively, at the end of the follow‐up; and 98.2% and 98%, respectively, for sustained response. HBsAg clearance and seroconversion rates were 48.1% and 47.1%, respectively, when the drug was discontinued; 53.8% and 52.9%, respectively, at the end of the follow‐up; and 94% and 95.9%, respectively, for sustained response. The HBV DNA suppression rate was 89.4% when the drug was discontinued, 90.4% at the end of the follow‐up and 97.8% for sustained response. Two patients had virological relapse (2.3%) during follow‐up; however, no clinical relapse occurred. Multivariate regression analysis showed that genotype B, weight < 25 kg or between 25 and 45 kg, and reduction of HBsAg by more than 1 log following 24 weeks of treatment were independent predictors of HBsAg clearance at the end of follow‐up. Adverse events that occurred during treatment were similar to those reported in previous clinical studies on PegIFN. The results of this study showed that PegIFN was safe and effective in the treatment of children with CHB, and sustained response could be achieved after treatment. PegIFN treatment of children with CHB helps more achieve ‘clinical cure’.     

HBsAg疫苗冲击树突状细胞联合乙肝免疫球蛋白对慢性乙型肝炎及HBV携带者的疗效

目的:观察HBsAg疫苗冲击的树突状细胞与乙肝免疫球蛋白联合应用对慢性乙型肝炎的疗效．方法:慢乙肝患者66例每月1次注射HBsAg疫苗(106／次)冲击的树突状细胞,乙肝免疫球蛋白200 U／次,6次为1疗程,共2疗程,治疗结束后检查肝功能,HBV DNA定量及乙肝标志．结果:HBeAg阳性慢乙肝27例治疗后有7例显示完全应答,14例显示部分应答．HBeAg阴性的慢乙肝15例中有4例出现完全应答,8例显示部分应答．慢性HBV携带者13例中5例显示完全应答,2例表现为部分应答．11例非活动性 HBsAg携带者中2例出现完全应答．结论:HBsAg疫苗冲击的树突状细胞与乙肝免疫球蛋白联合可试用于慢乙肝的治疗．     

Viral suppression correlates with dendritic cell restoration in chronic hepatitis B patients with autologous cytokine‐induced killer cell transfusion

Background: Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are functionally impaired in patients with chronic hepatitis B (CHB). Adoptive immunotherapy can suppress hepatitis B virus (HBV) replication in CHB patients, but whether it can restore the functionality of mDCs and pDCs remains unknown. Methods: Autologous cytokine‐induced killer (CIK) cells obtained from 14 CHB patients were transfused back to patients, case by case, to observe the effect of CIK‐cell treatment on the frequency and functionality of mDCs and pDCs in CHB patients during a 24‐week follow‐up investigation. Results: Seven virological responders exhibited a sustained decrease in HBV load after CIK‐cell transfusion; another seven non‐virological responders showed only sustained high levels of HBV load during the 24‐week period following CIK‐cell transfusion. The rate of hepatitis B e antigen loss or seroconversion was also higher in virological responders than in non‐virological responders. Importantly, we found that the frequency and cytokine‐producing capacity of mDCs and pDCs increased significantly in virological responders, but not in non‐virological responders. In addition, these patients exhibited a close correlation between restoration DC subsets and a decrease in HBV DNA load, rather than a change in the alanine aminotransferase level. Conclusion: Cytokine‐induced killer‐cell treatment reduced HBV DNA load in some CHB patients; the efficiency at least partially correlates with the restoration of frequency and functionality of mDCs and pDCs.     

Long‐term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide‐naïve chronic hepatitis B patients

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long‐term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide‐naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow‐up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed‐up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.     

Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside‐naïve HBeAg‐positive patients with chronic hepatitis B*

Summary. This retrospective analysis was conducted to describe the characteristics of nucleoside‐naïve hepatitis B e antigen (HBeAg)‐positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg‐positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double‐blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off‐treatment follow‐up. Through a maximum duration of 96 weeks on‐treatment and 24 weeks off‐treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside‐naïve HBeAg‐positive patients treated with entecavir, and that HBsAg loss is associated with sustained off‐treatment suppression of HBV DNA.     

Assessment of chronic hepatitis B: the importance of hepatitis B virus DNA testing

Background: Chronic hepatitis B (CHB) has an estimated prevalence of 90 000 to 160 000 in Australia. Cirrhosis and hepatocellular carcinoma are important complications of CHB and appropriate evaluation of hepatitis B surface antigen (HBsAg)‐positive individuals is vital to identify treatment candidates. Methods: A review of the database of a tertiary hospital was performed and 348 HBsAg‐positive individuals with baseline demographic, virological, serological and biochemical variables were identified and evaluated cross‐sectionally. A small subgroup of hepatitis B e antigen (HBeAg)‐negative patients with normal alanine aminotransferase (ALT) at baseline were identified and followed longitudinally. Results: 175/348 (50%) of patients were in the HBeAg‐negative, chronic hepatitis phase of disease, 22% in the HBeAg‐positive immune clearance and 6% in the immune tolerant phases. HBeAg‐negative patients were older and more likely to be male than HBeAg‐positive patients. The correlation between hepatitis B virus (HBV) DNA and ALT levels was examined. ALT and HBV DNA levels showed no correlation in HBeAg‐positive CHB and only a weak correlation in HBeAg‐negative patients. Furthermore, 35% of HBeAg‐negative patients with detectable HBV DNA had a normal ALT. Conversely 38% of HBeAg‐negative patients with no detectable HBV DNA had an elevated ALT. A persistently normal ALT over 24 months was seen in five of nine HBeAg‐negative patients with normal initial ALT and detectable HBV DNA. Conclusion: Appropriate evaluation of HBeAg‐negative CHB must include HBV DNA because the ALT is not a reliable guide to underlying viral replication.     

Cellular immune responses in hepatitis B virus e antigen negative chronic hepatitis B

The immunopathogenesis of hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) virus (HBV) infection has not been adequately investigated. We studied the cellular immune responses of peripheral lymphocytes using proliferating assays, intracellular cytokine staining (ICS) and ELISPOT interferon-gamma (IFN-gamma) assays after non-specific and specific stimulation with whole HBV proteins and synthetic peptides. Thirty patients with HBeAg negative CHB, eleven HBsAg inactive carriers, nine patients with acute hepatitis B and 22 healthy controls were included in the study. Patients with HBeAg negative CHB demonstrated an increased number of peripheral CD8+ T cells while their peripheral blood mononuclear cells showed increased proliferation after in vitro stimulation with overlapping hepatitis B core derived peptides and an envelope derived epitope (HBs 182-191 aa), similar to those observed in acute hepatitis B. Using ICS, we found an expanded population of IFN-gamma producing T lymphocytes, CD4+ and CD8+, after non-specific stimulation, in HBeAg negative CHB compared to all other groups. HBeAg negative CHB and acute hepatitis B patients had a similarly increased number of core specific T cells measured by the IFN-gamma assays. Inactive HBsAg carriers showed minimal proliferative responses overall while they exhibited an increased number of envelope specific effector T cells (measured by ICS). In conclusion, we showed that overall CD4+ T cell responses from patients with HBeAg negative CHB were comparable to those of acute hepatitis B, while inactive HBsAg carriers despite their limited proliferative capacity the effector activity of their peripheral T cells was maintained.     

Hepatitis B surface antigen levels during natural history of chronic hepatitis B: A Chinese perspective study

AIM: To determine the baseline hepatitis B surface antigen (HBsAg) levels during the different phases of chronic hepatitis B (CHB) patients in China.METHODS: Six hundred and twenty-three hepatitis B virus or un-infected patients not receiving antiviral therapy were analyzed in a cross-sectional study. The CHB patients were classified into five phases: immune-tolerant (IT, n = 108), immune-clearance (IC, n = 161), hepatitis B e antigen negative hepatitis (ENH, n = 149), low-replicative (LR, n = 135), and liver cirrhosis (LC, n = 70). HBsAg was quantified (Abbott ARCHITECT assay) and correlated with hepatitis B virus (HBV) DNA, and serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) in each phase of CHB was also determined.RESULTS: Median HBsAg titers were different in each phase of CHB (P < 0.001): IT (4.85 log₁₀ IU/mL), IC (4.36 log₁₀ IU/mL), ENH (2.95 log₁₀ IU/mL), LR (3.18 log₁₀ IU/mL) and LC (2.69 log₁₀ IU/mL). HBsAg titers were highest in the IT phase and lowest in the LC phase. Serum HBsAg titers showed a strong correlation with HBV viral load in the IC phase (r = 0.683, P < 0.001). No correlation between serum HBsAg level and ALT/AST was observed.CONCLUSION: The mean baseline HBsAg levels differ significantly during the five phases of CHB, providing evidence on the natural history of HBV infection. HBsAg quantification may predict the effects of immune-modulator or oral nucleos(t)ide analogue therapy.     

Hepatitis B surface antigen seroconversion is associated with favourable long-term clinical outcomes during lamivudine treatment in HBeAg-negative chronic hepatitis B patients

The aims of this study were to assess hepatitis B surface antigen (HBsAg) seroconversion and to determine its impact on the natural course of the disease in patients with HBeAg-negative chronic hepatitis B (CHB) during lamivudine (LMV) treatment. A total of 183 consecutive patients with HBeAg-negative CHB who were treated with LMV were included in the study. Data were retrospectively collected from outpatient visit charts. The primary endpoint was HBsAg seroconversion to anti-HBs. The secondary endpoint was to determine the development of cirrhosis. Loss of HBsAg was confirmed in 10 patients and seroconversion to anti-HBs in nine patients during LMV treatment or after its discontinuation. HBsAg seroconversion was achieved on-treatment in four patients after a median treatment duration of 30 months and off-treatment in the remaining five patients in a median 61 months after LMV discontinuation. The cumulative probability of HBsAg seroconversion increased from 0.6% at 1 year and 1.9% at 5 years to 21.5% at 10 years of LMV during and after LMV treatment. HBsAg clearance was preceded by undetectable serum hepatitis B virus (HBV) DNA. The majority of the patients responding to treatment had undetectable HBV DNA levels at 24 weeks of treatment. The cumulative probability of LMV resistance increased from 2.2% at 1 year to 37.3% at 5 years. No baseline parameter predicting either HBsAg seroconversion or the emergence of LMV resistance was identified. None of the patients with HBsAg seroconversion experienced virological breakthrough or disease progression during the follow-up period. These results indicate that HBsAg seroclearance can occur in patients with HBeAg-negative CHB under LMV therapy and predicts better clinical outcome.     

Prediction of response to entecavir therapy in patients with HBeAg-positive chronic hepatitis B based on on-treatment HBsAg, HBeAg and HBV DNA levels

Summary. Quantitative hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) assays are emerging as effective tools of on‐treatment predictors of response to antiviral agents, in addition to monitoring serum HBV DNA levels. However, the dynamic relationship between quantitative HBsAg, as well as HBeAg and HBV DNA, and the predictability of subsequent clinical outcomes during entecavir (ETV) therapy remain unclear. Eighty‐two patients with HBeAg‐positive chronic hepatitis B (CHB) received ETV therapy for ≥3 years. Virologic response (VR) after 3 years of ETV therapy was achieved in 73 (89.0%) patients. Among baseline and on‐treatment factors, on‐treatment HBV DNA levels performed better with respect to the prediction of response than HBsAg and HBeAg levels. Especially, the performance of absolute values of HBV DNA with respect to response was superior to HBV DNA decline from the baseline. The best predictive value was an absolute HBV DNA level of 2.3 log₁₀ IU/mL at month 6 (areas under the curve [AUROC], 0.977; 95% CI, 0.940–1.000; P < 0.001). HBeAg seroconversion after 3 years of therapy was achieved in 26 (31.7%) patients. On‐treatment HBeAg levels performed better with respect to the prediction of seroconversion than HBsAg and HBV DNA levels. The best cut‐off value for the HBeAg level at month 12 for the prediction of seroconversion was 0.62 log₁₀ PEIU/mL. Although the HBsAg level at baseline is often used to predict the antiviral potency of entecavir, on‐treatment HBV DNA and HBeAg levels are more helpful for prediction of subsequent clinical outcomes in HBeAg‐positive CHB patients with entecavir treatment.     

Interferon alpha treatment leads to a high rate of hepatitis B surface antigen seroconversion in Chinese children with chronic hepatitis B

Chronic hepatitis B virus (HBV) infection (CHB) in children remains a public health challenge despite significant success in programme is established to prevent mother‐to‐child transmission. In particular, CHB in Chinese children are mostly acquired through vertical transmission, which differs from the common infection route reported in other countries and regions. This situation has resulted in a high endemic prevalence of CHB in Chinese adults. Thus, successful treatment of children with CHB will prevent the development of advanced liver diseases in late adulthood. However, there is still no consensus on the clinical guideline to treat paediatric CHB. In this study, we evaluated the potential of interferon alpha (IFNa) treatment for Chinese children with CHB. A total of 41 patients with CHB aged 3‐17 years were enrolled in this retrospective study: 21 patients were treated with pegylated (PEG)‐IFNa and 20 patients without treatment served as the control group. The rates of HBV DNA suppression, hepatitis B e antigen (HBeAg) clearance and hepatitis B surface antigen (HBsAg) clearance were significantly higher in the PEG‐IFNa treatment group than in the control group (P < 0.05 at 48 weeks). Unexpectedly, PEG‐IFNa treatment achieved a high rate of HBsAb production, far exceeding the clinical outcome in documented PEG‐IFNa‐treated CHB adults. Further analysis revealed that younger children (3‐6 years old) were more responsive to PEG‐IFNa treatment with respect to achieving a protective level of HBsAb in a short treatment cycle than adolescents (10‐17 years old). Overall, these results indicate that the immune system of children might have a preserved PEG‐IFNa‐mediated mechanism to completely control HBV, which can help to design new strategies to treat CHB patients.