Hepatitis B E Antigen Loss Research Articles

Determinants of HBeAg loss during follow-up of a multiethnic pediatric cohort.

Hepatitis B e antigen (HBeAg) loss is a key event in the natural history of chronic hepatitis B virus infection. The rate and determinants of HBeAg loss depend upon cohort characteristics at baseline. Few studies have examined the age-dependent rate, and none have examined the effect of patient sex and ethnicity on the age-dependant rate. The study of age-dependent rates requires the identification and long-term follow-up of a pediatric cohort. We have studied the age-dependent rate of HBeAg loss, and the rate of HBeAg loss measured from baseline, in a multi-ethnic cohort of 454 pediatric patients. During observation, HBeAg loss was observed in 121/303 (39.9%) HBeAg-positive patients. The rate of HBeAg loss was greater in the second versus the first and third decades of life. The age-related rate of HBeAg loss was clearly affected by patient sex and ethnicity, with earlier loss observed for males and for White versus both South Asian and Chinese ethnicities. When measured from baseline, Chinese patients had a slower rate of HBeAg loss in comparison with White patients. In multivariate analysis of HBeAg loss during prolonged follow-up, male sex, older age, and White ethnicity were associated with HBeAg loss, but antiviral treatment was not.

Age of hepatitis B e antigen loss in Aboriginal, Torres Strait Islander and non-Indigenous residents of tropical Australia; implications for clinical care.

This study determined the hepatitis B e antigen (HBeAg) status of people living with chronic hepatitis B (CHB) in Far North Queensland (FNQ), Australia and their age of HBeAg loss. It was hoped that this would provide data to explain the stark difference in the incidence of hepatocellular carcinoma (HCC) between Aboriginal and Torres Strait Islander individuals living with CHB in FNQ, a finding that has been hypothesised to relate to differences in hepatitis B virus genotype. We identified every FNQ resident with CHB, determined their country of birth, their HBeAg status, the age they lost HBeAg and whether they identified as an Aboriginal, a Torres Strait Islander or a non-Indigenous individual. We then ascertained whether these demographic and virological variables were correlated. Of 1,474 individuals living with CHB in FNQ, 278 (19%) were Aboriginal, 507 (34%) were Torres Strait Islanders and 689 (47%) were non-Indigenous. Aboriginal individuals were less likely to be HBeAg positive (26/278, 9%) than Torres Strait Islander (91/507, 18%) and non-Indigenous (126/689, 18%) individuals, p < 0.0001. Aboriginal individuals lost HBeAg at an earlier age (median (interquartile range): 30 (23-39) years) than Torres Strait Islander (38 (29-49) years) and non-Indigenous (36 (29-47) years) individuals, p < 0.0001. Aboriginal individuals with CHB in FNQ are more likely to be HBeAg negative than Torres Strait Islander and non-Indigenous individuals and lose HBeAg at a younger age. This provides a biological basis for local clinicians' observation that Aboriginal individuals with CHB in FNQ are at a lower risk of HCC and data to support the principle of genotype-based care in the region.

Impaired HBsAg release and antiproliferative/antioxidant cell regulation by HBeAg-negative patient isolates reflects an evolutionary process.

The hepatitis B e antigen (HBeAg)-negative infection Phase 3 is characterized by no or minimal signs of hepatic inflammation and the absence of hepatic fibrosis. However, underlying molecular mechanisms leading to this benign phenotype are poorly understood. Genotype A, B and D HBeAg-negative patient isolates with precore mutation G1896A from Phase 3 were analysed in comparison with respective HBeAg-positive rescue mutant and HBeAg-positive wild-type reference genomes regarding differences in viral replication, morphogenesis, infectivity and impact on NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE)-dependent gene expression and cellular kinome. In comparison with reference genomes, the patient isolates are characterized by a lower intra- and extracellular hepatitis B surface antigen (HBsAg)-amount, and HBsAg-retention in the endoplasmic reticulum. Rescue of HBeAg expression increased HBsAg-amount but not its release. Expression of the isolated genomes is associated with a higher Nrf2/ARE-dependent gene expression as compared to reference genomes independent of HBeAg expression. Kinome analyses revealed a decreased activity of receptors involved in regulation of proliferative pathways for all patient isolates compared to the reference genomes. No specific conserved mutations could be found between all genomes from Phase 3. HBeAg-negative genomes from Phase 3 exhibit distinct molecular characteristics leading to lower HBsAg synthesis and release, enhanced oxidative stress protection and decreased activity of key kinases, triggering an antiproliferative stage, which might contribute to the lower probability of hepatocellular carcinoma. The observed differences cannot be associated with loss of HBeAg or specific mutations common to all analysed isolates, indicating the phenotype of Phase 3 derived genomes to be the result of a multifactorial process likely reflecting a conserved natural selection process.

Differential HBV replicative markers and covalently closed circular DNA transcription in immune-active chronic hepatitis B with and without HBeAg.

Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg. This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed. Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients. HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB.

Clinical Efficacy and Safety of Long-Term Treatment of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate for Chronic Hepatitis B in Vietnam.

Hepatitis B virus (HBV) infection is a contagious condition posing a major public health risk in various nations, including Vietnam. In 2019, the Ministry of Health introduced tenofovir alafenamide (TAF) to treat patients with chronic HBV infection and reduce the long-term toxicity of tenofovir disoproxil fumarate (TDF). This study aimed to assess the effectiveness and safety of these 2 medications in individuals with hepatitis B e antigen (HBeAg)-positive chronic HBV. This retrospective cohort study included data collected from the medical records of patients with chronic HBV who visited the Liver Clinic at University Medical Center Ho Chi Minh City between 2018 and 2020. After 2 years of treatment, the proportion of HBeAg loss in the TAF group was twice that of the TDF group (22.4% vs 11.2%), indicating a statistically significant difference in the probability of HBeAg loss (adjusted hazard ratio = 2.22; 95% confidence interval [CI] 1.43-3.42; P < 0.01). In addition, there was a statistically significant difference in the rate and ability of antiviral response between patients treated with TAF and TDF (65% vs 54.5%, respectively; adjusted hazard ratio = 1.34; 95% CI 1.08-1.69; P < 0.01). A total of 93.9% of patients achieved the goal of restoring alanine aminotransferase to normal, a higher percentage compared with the 81.2% in the TDF group, and the likelihood of achieving normal alanine aminotransferase levels with TAF was greater compared with those on TDF (adjusted hazard ratio = 1.67; 95% CI 1.38-2.01; P < 0.01). Moreover, there was a statistically significant difference in the variation in renal function between the TAF and TDF groups. Serum creatinine levels in the TAF group increased less than those in the TDF group by 0.03 mg/dL every 6 months (95% CI -0.04 to -0.01, P < 0.01), and the estimated glomerular filtration rate in the TAF group was higher than that in the TDF group every 6 months by 2.78 mL/min/1.73 m 2 (95% CI 0.98-4.57, P < 0.01). However, there was no statistically significant difference in the likelihood of HBeAg seroconversion between patients with chronic hepatitis B treated with TAF or TDF (adjusted hazard ratio = 1.79; 95% CI 0.91-3.53; P = 0.09), nor in the risk of adverse events between the 2 groups (adjusted odds ratio = 1.34; 95% CI 0.88-2.05; P = 0.17). In addition, although the HBsAg concentration in the TAF group was lower than in the TDF group by an average of 0.05 log 10 IU/mL every 6 months (95% CI -0.15 to 0.05), this difference also did not reach statistical significance ( P = 0.35). TAF has been demonstrated to achieve some therapeutic efficacy goals and reduce nephrotoxicity better than TDF. However, no differences were found in seroconversion or adverse events between the patient groups.

Efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B exhibiting suboptimal response to entecavir.

Entecavir (ETV) is a potent and safe antiviral agent for patients with chronic hepatitis B (CHB); however, some patients may exhibit suboptimal response or resistance to ETV. Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved pharmacokinetics and reduced renal and bone toxicity compared with tenofovir disoproxil fumarate. To evaluate the efficacy and safety of switching from ETV to TAF in patients with CHB exhibiting suboptimal response to ETV. A total of 60 patients with CHB who had been treated with ETV for at least 12 mo and had persistent or recurrent viremia [Hepatitis B virus (HBV) DNA ≥ 20 IU/mL] or partial virologic response (HBV DNA < 20 IU/mL, but detectable) were enrolled in the study. The patients were randomly assigned to either continue ETV (0.5 mg) daily or switch to TAF (25 mg) daily for 48 wk. The primary endpoint was the proportion of patients who achieved a virologic response (HBV DNA level < 20 IU/mL) at week 48. Secondary endpoints included changes in serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and anti-HBe levels, and renal and bone safety parameters. At week 48, the proportion of patients who achieved a virologic response was significantly higher in the TAF group than in the ETV group (93.3% vs 66.7%, P = 0.012). The mean reduction in HBV DNA from baseline was also significantly greater in the TAF group than in the ETV group (-3.8 vs -2.4 Log10 IU/mL, P < 0.001). The rates of ALT normalization, HBeAg loss, HBeAg seroconversion, and HBsAg loss were not found to significantly differ between the two groups. None of the patients developed genotypic resistance to ETV or TAF. Both drugs were well tolerated, with no serious adverse events or discontinuations caused by adverse events. No significant changes were observed in the estimated glomerular filtration rate, serum creatinine level, or urine protein-to-creatinine ratio in either group. The TAF group had a significantly lower decrease in bone mineral density at the lumbar spine and hip than the ETV group (-0.8% vs -2.1%, P = 0.004; -0.6% vs -1.8%, P = 0.007, respectively). Switching from ETV to TAF is effective and safe for patients with CHB exhibiting a suboptimal response to ETV and may prevent further viral resistance and reduce renal and bone toxicity.

Tenofovir disoproxil fumarate therapy in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis

Tenofovir disoproxil fumarate (TDF) is the first-line therapy for chronic hepatitis B. This interim analysis presents the efficacy and safety data for TDF at Week 144 in patients with chronic hepatitis B and advanced fibrosis or compensated cirrhosis from China. Patients were assessed for incidence of newly diagnosed hepatocellular carcinoma (HCC) and disease progression, liver stiffness measurement (LSM), virological suppression (serum hepatitis B virus DNA <20 IU/mL), alanine aminotransferase normalization, hepatitis B e antigen (HBeAg) loss and seroconversion, histological liver fibrosis score, and safety at Week 144. Overall, 197 patients were enrolled. At Week 144, the incidence of newly diagnosed HCC was observed in 2.1% patients, and the incidence of disease progression was observed in 3.6% patients. The mean (standard deviation) change in LSM from baseline was −5.1 (5.85) kPa. Serum hepatitis B virus DNA <20 IU/mL was observed in 94.1% patients, alanine aminotransferase normalization in 33.5% patients, HBeAg loss in 35.6% patients, and HBeAg seroconversion in 14.4% patients. Among patients with stage F3 or F4 fibrosis at baseline by LSM, 38.3% patients regressed to stage F0/1, and 22.0% of patients regressed to stage F2 at Week 144. Overall, 67.7% patients experienced ≥1 adverse events, 13.8% patients experienced TDF-related adverse events, and 16.4% patients experienced serious (none were TDF-related). At Week 144 of TDF treatment, low incidence of HCC and disease progression were reported. Virological suppression was observed in 94.1% patients, which was associated with fibrosis regression. No new safety events were identified. • Tenofovir disoproxil fumarate (TDF) lowered hepatocellular carcinoma incidence. • TDF resulted in reduced disease progression after 144 weeks of treatment. • Virological suppression occurred in 94.1% of patients after 144 week TDF treatment.

Clearance of Hepatitis B e Antigen in Untreated Chronic Hepatitis B Virus Infection: A Systematic Review and Meta-analysis.

In people with hepatitis B virus (HBV) infection, persistence of hepatitis B e antigen (HBeAg) is associated with clinical progression and need for treatment. HBeAg loss represents partial immune control and is a critical event in the natural history of chronic HBV. We conducted a systematic review and meta-analysis of cohort studies that report HBeAg loss among people with untreated chronic HBV. We evaluated HBeAg loss using a random-effects model and conducted subanalysis on region. We screened 10 560 publications, performed 196 full-text analyses, and included 26 studies for meta-analysis. The pooled rate of HBeAg loss was 6.46/100 person-years (PYs) (95% confidence interval, 5.17-8.08). Meta-regression showed that older age of participants and studies in Europe were associated with higher rate of HBeAg loss. Rates per 100 PYs were 7.43 (95% confidence interval, 6.30-8.75; 1 study) in Africa, 3.24 (2.61--4.02; 1 study) in the Eastern Mediterranean, 13.67 (11.21-16.66; 4 studies) in Europe, 7.34 (4.61--11.70; 5 studies) in North America, and 5.53 (4.05--7.55; 15 studies) in the Western Pacific. Spontaneous HBeAg loss occurs at a rate of 6.46/100 PYs. Variations by region and age group may reflect epidemiological, immunological, or HBV genotype-related differences.

Earlier and Higher Rate of Hepatitis B Virus Relapse After Discontinuing Tenofovir Versus Entecavir in Hepatitis B e Antigen–Positive Patients

This study investigated the incidence and predictors of hepatitis B virus (HBV) relapse in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who discontinued entecavir (ETV) or tenofovir disoproxil fumarate (TDF). A total of 205 and 111 HBeAg-positive patients without cirrhosis who had stopped ETV or TDF treatment, respectively, for at least 6 months were recruited. In the entire cohort, patients with HBeAg seroconversion during treatment, and propensity score-matched patients, those who discontinued TDF had significantly higher rates of virological and clinical relapse than patients who discontinued ETV therapy. Multivariate analysis identified that TDF was independently associated with virological and clinical relapse in the entire cohort and subgroup analysis. Patients with HBeAg loss without anti-HBe antibody formation during treatment had significantly higher rates of off-therapy HBV relapse and HBeAg seroreversion than patients with HBeAg seroconversion during treatment. The hepatitis B core-related antigen (HBcrAg) level at end of treatment (EOT) was independently associated with HBV relapse and HBeAg seroreversion in all patients and patients with HBeAg seroconversion during treatment. TDF therapy, HBeAg loss without seroconversion during treatment, and higher HBcrAg levels at EOT are significant predictors of HBV relapse in HBeAg-positive patients who discontinued ETV or TDF.

A baseline model including quantitative anti-HBc to predict response of peginterferon in HBeAg-positive chronic hepatitis B patients.

Few models to predict antiviral response of peginterferon were used in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B patients and the prediction efficacy was unsatisfied. Quantitative antibody to hepatitis B core antigen (anti-HBc) is a new predictor of treatment response. We aimed to develop a new model to identify HBeAg-positive Chinese patients who were more likely to respond to peginterferon. Data from 140 peginterferon recipients with HBeAg-positive were applied with generalized additive models and multiple logistic regression analysis to develop a baseline scoring system to predict serological response (SR: HBeAg loss and HBeAg seroconversion 24weeks post-treatment) and combined response (CR: SR plus serum HBV DNA levels <2000 IU/mL 24 weeks post-treatment). Anti-HBc levels, alanine aminotransferase ratio, and HBeAg were retained in the final model. The new model scored from 0 to 3. Among patients with scores of 0, 1, or ≥2, SR was achieved in 6.45% (2/31), 13.21% (7/51), and 55.36% (31/56), respectively, and CR in 3.23% (1/31), 9.43% (5/53), and 25.00% (14/56), respectively. Our model has a higher AUROC for SR comparing to Chan's (Z = 2.77 > 1.96, p < 0.05) and Lampertico's (Z = 2.06 > 1.96, p < 0.05) model. The negative predictive value for SR and CR were both 100% in patients with score 0 and hepatitis B surface antigen ≥20,000 IU/mL at week 12. Patients with higher scores at baseline were more likely to respond to peginterferon. This new model may predict the treatment response.

Pradefovir Treatment in Patients With Chronic Hepatitis B: Week 24 Results From a Multicenter, Double-Blind, Randomized, Noninferiority, Phase 2 Trial

BackgroundPradefovir is a liver-targeted prodrug of adefovir, a nucleoside/nucleotide analogue with antiviral activity against hepatitis B virus (HBV) DNA polymerase. This phase 2 study compared the efficacy and safety of oral pradefovir (30, 45, 60, or 75 mg) versus tenofovir disoproxil fumarate (TDF; 300 mg) and aimed to identify the most appropriate dose of pradefovir for the forthcoming phase 3 study.MethodsTreatment-naive and experienced (not on treatment >6 months) patients with chronic hepatitis B were eligible.ResultsA total of 240 participants were randomized and treated in the study (48 per group). Approximately 80% were hepatitis B e antigen (HBeAg) positive, and 10% had liver cirrhosis. The reductions from baseline in HBV DNA levels achieved at week 24 were 5.40, 5.34, 5.33, and 5.40 log10 IU/mL, with pradefovir doses of 30-, 45-, 60-, and 75-mg, respectively, compared with 5.12 log10 IU/mL with TDF. However, HBeAg loss was attained by more participants who received 45-, 60-, or 75-mg pradefovir than by those receiving TDF (12%, 6%, and 9% vs 3%). The TDF group exhibited a more significant increase in serum creatinine than the pradefovir 30- and 45-mg groups, and serum phosphate levels were comparable among all groups. Most adverse events (AEs) were mild (grade 1). No treatment-related severe AEs were reported. Overall, AEs and laboratory abnormalities were comparable to those in the TDF group.ConclusionsPradefovir and TDF exhibited comparable reductions in HBV DNA levels. All treatments were safe and well tolerated.Clinical Trials registrationNCT00230503 and China Drug Trials CTR2018042

Long-term benefits of interferon-α therapy in children with HBeAg-positive immune-active chronic hepatitis B.

The long-term benefits of interferon-α (IFN-α) treatment in children with chronic hepatitis B (CHB) remain unclear. We conducted a retrospective and real-world study to evaluate the safety and long-term clearance rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) in CHB children who received IFN-α monotherapy for 72weeks and were with 13-year follow-up visit. Participants treated with IFN-α (n=316) were more likely to become HBeAg negatve (39.87% vs. 27.37%; p<.05) and HBsAg negative (11.08% vs. 3.16%; p<.05) by the end of the treatment period than untreated participants (n=95). Treated participants also had higher cumulative rates of HBeAg loss (74.13% vs. 59.27%; p<.05) and HBsAg loss (46.95 vs. 33.11%; p< 0.05) than untreated participants in parallel by the end of 13-year follow-up. In particular, the cumulative rate of HBsAg loss was higher in treated children aged 1-7years than in those aged 8-17years (71.40% vs. 39.0%; p<.01). Children who were HBeAg-negative at the end of IFN-α treatment or who had serum alanine aminotransferase levels of≥80IU/L at baseline were likely to have higher cumulative HBsAg loss rates. Accordingly, HBeAg loss at 72weeks was positively associated with the cumulative HBsAg loss rate in untreated children. There were no serious adverse events of IFN-α therapy for the treated patients throughout the study period. Overall, IFN-α therapy was effective in obtaining higher long-term cumulative rates of HBeAg and HBsAg loss in children with HBeAg-positive immune-active CHB, especially among those aged 1-7years.

Hepatitis B e antigen loss in adults and children with chronic hepatitis B living in North America: A prospective cohort study.

Hepatitis B e antigen (HBeAg) is a soluble viral protein in plasma of patients with hepatitis B virus infection. HBeAg loss is an important first stage of viral antigen clearance. We determined the rate and predictors of HBeAg loss in a North American cohort with chronic hepatitis B viral infection (CHB). Among children and adults with CHB and without HIV, HCV or HDV co-infection enrolled in the Hepatitis B Research Network prospective cohort studies, 819 were HBeAg positive at their first assessment (treatment naïve or >24weeks since treatment). Of these, 577 (200 children, 377 adults) were followed every 24-48weeks. HBeAg loss was defined as first HBeAg-negative value; sustained HBeAg loss was defined as ≥2 consecutive HBeAg-negative values ≥24weeks apart. During a median follow-up of 1.8years, 164 participants experienced HBeAg loss, a rate of 11.4 (95% CI, 9.8-13.3) per 100 person-years. After adjustment for confounders, HBeAg loss rate was significantly higher in males than females, in older than younger individuals, in Whites or Blacks than Asians, in those with genotype A2 or B versus C, and in those with basal core promoter/pre-core mutations versus wild type. Additionally, during follow-up, an ALT flare and a lower quantitative HBsAg, quantitative HBeAg or HBV DNA level predicted higher rates of HBeAg loss. The majority (88%) with HBeAg loss had sustained HBeAg loss. In conclusion, a number of specific demographic, clinical and viral characteristics impacted rate of HBeAg loss and may prove useful in design and interpretation of future therapeutic studies.

Immunogenicity and Antiviral Response of Therapeutic Hepatitis B Vaccination in a Mouse Model of HBeAg-Negative, Persistent HBV Infection.

During the natural course of chronic hepatitis B virus (HBV) infection, the hepatitis B e antigen (HBeAg) is typically lost, while the direct transmission of HBeAg-negative HBV may result in fulminant hepatitis B. While the induction of HBV-specific immune responses by therapeutic vaccination is a promising, novel treatment option for chronic hepatitis B, it remains unclear whether a loss of HBeAg may influence its efficacy or tolerability. We therefore generated an adeno-associated virus (AAV)-vector that carries a 1.3-fold overlength HBV genome with a typical stop-codon mutation in the pre-core region and initiates the replication of HBeAg(−) HBV in mouse livers. Infection of C57BL/6 mice established persistent HBeAg(−) HBV-replication without any detectable anti-HBV immunity or liver damage. HBV-carrier mice were immunized with TherVacB, a therapeutic hepatitis B vaccine that uses a particulate HBV S and a core protein for prime vaccination, and a modified vaccinia Ankara (MVA) for boost vaccination. The TherVacB immunization of HBeAg(+) and HBeAg(−) HBV carrier mice resulted in the effective induction of HBV-specific antibodies and the loss of HBsAg but only mild liver damage. Intrahepatic, HBV-specific CD8 T cells induced in HBeAg(−) mice expressed more IFNγ but showed similar cytolytic activity. This indicates that the loss of HBeAg improves the performance of therapeutic vaccination by enhancing non-cytolytic effector functions.

Analysis of Hepatitis B Virus Haplotype Diversity Detects Striking Sequence Conservation Across Genotypes and Chronic Disease Phase

We conducted haplotype analysis of complete hepatitis B virus (HBV) genomes following deep sequencing from 368 patients across multiple phases of chronic hepatitis B (CHB) infection from four major genotypes (A-D),analyzing 4,110 haplotypes to identify viral variants associated with treatment outcome and disease progression. Between 18.2% and 41.8% of nucleotides and between 5.9% and 34.3% of amino acids were 100% conserved in all genotypes and phases examined, depending on the region analyzed. Hepatitis B e antigen (HBeAg) loss by week 192 was associated with different haplotype populations at baseline. Haplotype populations differed across the HBV genome and CHB history, this being most pronounced in the precore/core gene. Mean number of haplotypes (frequency) per patient was higher in immune-active, HBeAg-positive chronic hepatitis phase 2 (11.8) and HBeAg-negative chronic hepatitis phase 4 (16.2) compared to subjects in the "immune-tolerant," HBeAg-positive chronic infection phase 1 (4.3, P< 0.0001). Haplotype frequency was lowest in genotype B (6.2, P< 0.0001) compared to the other genotypes (A = 11.8, C = 11.8, D = 13.6). Haplotype genetic diversity increased over the course of CHB history, being lowest in phase 1, increasing in phase 2, and highest in phase 4 in all genotypes except genotype C. HBeAg loss by week 192 of tenofovir therapy was associated with different haplotype populations at baseline. Despite a degree of HBV haplotype diversity and heterogeneity across the phases of CHB natural history, highly conserved sequences in key genes and regulatory regions were identified in multiple HBV genotypes that should be further investigated as targets for antiviral therapies and predictors of treatment response.

Switching to or Add-on Peginterferon in Patients on Nucleos(t)ide Analogues for Chronic Hepatitis B: The SWAP RCT

The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA. We conducted a randomized controlled trial of CHB patients on NA >12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 μg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg) >1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg <200 IU/mL, qHBsAg <100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT). A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P < .0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P < .001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P < .0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy). ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss.

BACKGROUNDNucleos(t)ide analogs (NAs) cessation in chronic hepatitis B (CHB) patients remains a matter of debate in clinical practice. Current guidelines recommend that patients with hepatitis B e antigen (HBeAg) seroconversion discontinue NAs after relatively long-term consolidation therapy. However, many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg, even if hepatitis B surface antigen (HBsAg) loss occurs. It remains unclear whether NAs can be discontinued in this subset of patients.AIMTo investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss (without hepatitis B e antibody) after cessation of NAs.METHODSWe studied patients who discontinued NAs after achieving HBeAg loss. The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs. The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves; we confirmed the cut-off value of HBsAg according to a previous study. The log-rank test was used to compare cumulative relapse rates among groups. We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates. Propensity score matching analysis (PSM) was used to balance baseline characteristics between the groups.RESULTSWe included 83 patients with HBeAg loss. The mean age of these patients was 32.1 ± 9.5 years, and the majority was male (67.5%). Thirty-eight patients relapsed, and the cumulative relapse rate at months 3, 6, 12, 24, 36, 60, 120, and 180 were 22.9%, 36.1%, 41.0%, 43.5%, 45.0%, 45.0%, 45.0%, and 52.8%, respectively. Twenty-six (68.4%) patients relapsed in the first 3 mo after NAs cessation, and 35 patients (92.1%) relapsed in the first year after NAs cessation. Consolidation period (≥ 24 mo vs < 24 mo) (HR 0.506, P = 0.043) and HBsAg at cessation (≥ 100 IU/mL vs < 100 IU/mL) (HR 14.869, P = 0.008) were significant predictors in multivariate Cox regression. In the PSM cohort, which included 144 patients, there were lower cumulative relapse rates in patients with HBeAg seroconversion (P = 0.036).CONCLUSIONHBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation, especially in patients with HBsAg at cessation < 100 IU/mL. Careful monitoring, especially in the early stages after cessation, may ensure a favorable outcome.

Serum IL-21 levels predict HBeAg decline during rescue therapy in patients with partial response to nucleos(t)ide analogues.

To investigate whether IL-21 levels predict treatment outcomes of salvage therapy among patients with suboptimal response (SOR) to nucleos(t)ide analogues (NAs), serum IL-21 levels were measured in a prospective cohort of hepatitis B e antigen (HBeAg)-positive patients with SOR to antiviral therapy. The patients switched therapy to entecavir (ETV) with or without adefovir (ADV) for 104 weeks. IL-21 levels at treatment week 12 in patients who achieved HBeAg loss with undetectable levels of hepatitis B virus (HBV)-DNA at week 104 were the primary endpoint and the results were compared with those of corresponding patients without such an endpoint. Furthermore, IL-21 levels at treatment week 12 in patients who achieved an HBeAg-level decline at week 104 were assessed as the secondary endpoint. Among 24 enrolled patients with SOR to ADV (n=21), telbivudine (n=2) or ETV (n=1), the median (10-90th percentile) levels of HBeAg, HBV-DNA and ALT at baseline were 2.7 (0.2-3.1) log10 S/CO, 5.2 (3.5-7.5) log10 IU/ml and 0.9 (0.5-3.1) upper limit of normal, respectively. Comparison of the patients with and without HBeAg loss at week 104 indicated that their mean IL-21 levels did not significantly differ at week 12 (63.0±14.4 vs. 55.9±10.5 pg/ml; P=0.26). In the secondary endpoint analyses of patients with and without HBeAg level decline, the elevated levels of IL-21 at the first 12 weeks were significantly higher in the decline group (15.6±8.3 vs. 3.1±13.2 pg/ml; P=0.03). Following adjustment for confounding factors, the elevated levels of IL-21 from baseline to week 12 independently predicted an HBeAg level decline at week 104 (odds ratio=1.137, R2=0.23; P=0.047). In conclusion, the serum IL-21 levels at the first 12 weeks during the salvage therapy independently predicted HBeAg level decline at treatment week 104 in patients with SOR to NAs (ClinicalTrials.gov identifier: NCT01829685; date of registration, April 2013).

Spontaneous loss of chronic HBV infection markers in treatment-naïve children: a systematic review and pooled meta-analyses

ABSTRACT Objectives: Chronicity could be a serious threat to hepatitis B virus (HBV)-infected children. The necessity of antiviral treatment to HBV-infected children has caused much controversy. The authors aimed to conduct a systematic review and meta-analysis of synthesized evidence regarding the spontaneous loss of chronic HBV infection markers in treatment-naïve children for exploring their long-term management. Methods: Observational cohort studies and non-treatment arms of randomized controlled trials were searched that reported the spontaneous loss of chronic HBV infection markers in untreated children (characterized by the presence of HBsAg ≥6-month), via the rates of hepatitis B surface antigen (HBsAg) loss, hepatitis B e antigen (HBeAg) seroconversion, and HBV DNA suppression with random-effects model. Results: Of 7,427 studies screened, 20 were included in meta-analysis. With cumulative 23,153 person-years of follow-up, the pooled annual incidences of HBsAg and HBeAg loss, HBV DNA suppression were 1, 6, 7%, respectively. Rates within HBeAg loss and HBV DNA suppression did differ by the transmission modes and ALT levels, not in HBsAg. Conclusion: Spontaneous HBsAg loss (function cure) occurs infrequently in treatment-naïve children with chronic HBV infection. Design of practically applicable programs aiming at therapeutics of children may be necessary to support the goal of eliminating HBV infection worldwide.

Entecavir combining Chinese herbal medicine for HBeAg-positive chronic hepatitis B patients: a randomized, controlled trial.

Traditional Chinese medicine (TCM) is widely accepted and prescribed in China alongside Nucleoside analogs (NAs). In this double-blind, placebo-controlled, randomized, multi-center trial, we evaluated whether entecavir (ETV) plus TCM formulas Tiao-Gan-Yi-Pi granule (TGYP) and Tiao-Gan-Jian-Pi-Jie-Du granule (TGJPJD) increase the rate of hepatitis B e antigen (HBeAg) loss in Chinese patients. 596 eligible participants were randomly assigned, in a 1:1 ratio, to two study groupsin this 108-week trial: The experiment group was assigned ETV plus the TCM formula. The control group was assigned ETV plus a TCM placebo. We compared the rate of HBeAg loss by the end of week 108 between the two arms as the primary outcome. Secondary outcomes included hepatitis B surface antigen (HBsAg) level, proportion of undetectable HBV-DNA, and liver enzymes (ALT, AST, GGT) at week 108. The combination therapy achieved superior HBeAg loss at 108weeks, without additional adverse events. The rate of HBeAg loss at week 108 was 37.54% (95% CI 31.9-43.2%) in the experiment group and 27.21% (95% CI 22.0-32.4%) in the control group. There was a statistically significant difference between the two arms of 10.33% (95% CI 8.4-12.3%, p = 0.008). The DNA loss rate, serum HBsAg level, and liver enzymes were similar between the groups by the end of 108th week. Combining the Chinese herbal formula with ETV therapy demonstrated superior HBeAg clearance compared with ETV monotherapy. This finding indicates that this combined therapy could produce an improved therapeutic effect and safety profile. ChiCTR-TRC-12002784 (Chinese Clinical Trial Registry).