HBeAg-negative Chronic Hepatitis B Patients Research Articles

Finite nucleos(t)ide-analogue therapy for functional cure in HBeAg-negative chronic hepatitis B: recent development in the paradigm shift.

Long-term nucleos(t)ide analogue (Nuc) therapy in chronic hepatitis B (CHB) may lead to hepatitis B virus (HBV) suppression, alanine aminotransferase (ALT) normalization, improvement of histological lesions, and prevention of liver disease progression, but rarely achieve HBsAg loss, the hallmark of functional cure. HBeAg-negative CHB patients have often been recommended to continue Nuc therapy until HBsAg loss, which usually means indefinitely. However, long-term/life-long Nuc therapy is associated with increasing costs and concerns of adverse outcomes subsequent to poor adherence and/or self-cessation/loss-to-follow-up. Hence, 2012 Asian-Pacific guidelines recommended that HBeAg-negative CHB patients can stop Nuc therapy after ≥12 months of HBV DNA undetectability. Subsequent Asian and few European studies have found the strategy of finite Nuc therapy to be feasible and reasonably safe. In 2016-2017, stopping Nuc was also included as a conditional strategy for HBeAg-negative CHB patients in the American and European guidelines. Furthermore, progressively increasing HBsAg loss rates with prolongation of off-Nuc follow-up were documented, being higher in Caucasians and more apparent beyond years 4-5 in Asian patients. Recently, a large study in patients with HBV cirrhosis showed not only higher 10-year HBsAg loss rate (15.3 vs. 1.6%) but also ~50% lower 10-year hepatocellular carcinoma incidence (16.5 vs. 29.5%) and 60% lower liver-related mortality/transplantation rate (6.1 vs. 15.1%) after Nuc cessation, as compared with well-matched patients continuing Nuc therapy. Since novel drug development aiming for functional cure has not been satisfactory, the strategy of finite Nuc therapy in HBeAg-negative CHB seems to be the best realistic option for functional cure today.

Association of hepatitis B core antibody level and hepatitis B surface antigen clearance in HBeAg-negative patients with chronic hepatitis B

ABSTRACT Predicting hepatitis B surface antigen (HBsAg) clearance is important for chronic hepatitis B (CHB) patients receiving pegylated interferon-alfa (Peg-IFN) therapy. We aimed to determine the predictive value of serum hepatitis B core antibody (anti-HBc) for HBsAg clearance. A total of 189 HBeAg-negative CHB patients who received Peg-IFN based therapy were retrospectively included and classified into two groups: nucleos(t)ide analogues (NAs) add-on Peg-IFN group (add-on group, n = 94) and Peg-IFN combined with NAs or Peg-IFN monotherapy group (combination or monotherapy group, n = 95). After 48 weeks of treatment, 27.5% (52/189) and 15.9% (30/189) of patients achieved HBsAg clearance and seroconversion, respectively. Patients in the combination or monotherapy group tended to achieve relatively higher HBsAg clearance (31.6% vs. 23.4%, p = 0.208) and seroconversion (21.1% vs. 10.6%, p = 0.050) rates than those in the add-on group. In combination or monotherapy group, anti-HBc levels at week 12 were lower in patients with HBsAg clearance (9.0 S/CO vs. 9.9 S/CO, p < 0.001) and seroconversion (8.8 S/CO vs. 9.8 S/CO, p < 0.001) than those without. Anti-HBc level at week 12 was an independent predictor of HBsAg clearance and seroconversion. Patients with lower anti-HBc levels at week 12 showed a more significant decline in HBsAg levels during treatment. Combination of anti-HBc at week 12 and baseline HBsAg could identify over 70% of patients who achieved HBsAg clearance after 48 weeks of treatment. In addition to HBsAg, anti-HBc level could be used as a promising marker for selecting HBeAg-negative CHB patients who are more likely to respond to Peg-IFN-based therapy.

Serum sPD-1 and sPD-L1 as predictive biomarkers for HBsAg clearance in HBeAg-negative CHB patients undergoing IFN-based therapy.

For chronic hepatitis B (CHB) patients, there is still a need to improve hepatitis B surface antigen (HBsAg) clearance rates. This study aimed to assess the predictive effectiveness of soluble programmed cell death-1 (sPD-1) and soluble programmed cell death ligand-1 (sPD-L1) for HBsAg clearance in HBeAg-negative CHB patients undergoing peginterferon (Peg-IFN)-based antiviral treatment. This study encompassed 280 patients undergoing treatment with Peg-IFNα. Serum levels of sPD-1 and sPD-L1 were measured using ELISA kits at baseline, as well as at 12, 24 and 48 weeks. The primary endpoint of the study was the determination of HBsAg clearance at 48 weeks. Logistic regression analysis was employed to identify predictors of HBsAg clearance. The clearance group demonstrated significantly lower serum sPD-L1 levels compared to the non-clearance group. While both groups exhibited an increase in sPD-1 levels, only the clearance group showed a rise in sPD-L1 levels. Multivariate analysis identified sPD-L1 increase at 24 weeks, and HBsAg decline at 24 weeks as predictors for HBsAg clearance at 48 weeks. The combined use of these indicators showed a predictive performance for HBsAg clearance with an AUROC of 0.907 (95% CI: 0.861-0.953, p < 0.001). The study revealed an inverse relationship between the trends of sPD-1/sPD-L1 and HBsAg clearance during combined IFN and NAs treatment. Moreover, the magnitude of HBsAg reduction and sPD-L1 increase emerged as significant predictors for HBsAg clearance.

Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA

ABSTRACT Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of “partial cure” in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.

Characterization of BCP/PreC/C region quasispecies in treatment-naive patients with different phases of HBV infection using next-generation sequencing

BackgroundTo analysis of quasispecies (QS) changes and high-frequency mutations in the BCP/PreC/C region of patients at different phases of hepatitis B virus (HBV) infection and provides novel biomarkers for the diagnosis of chronic hepatitis B (CHB) patients. MethodsWith the application of next-generation sequencing technology, we were able to sequence the HBV BCP/PreC/C regions in 40 patients, each at different phases of the HBV infection. The heterogeneity of QS and the frequency of mutations were calculated using MEGA 7 software. ResultsOur results show that the complexity and diversity of the BCP/PreC/C QS in HBeAg-positive CHB patients are significantly higher than those in HBeAg-positive chronic infection patients, while HBeAg-negative chronic infection patients had significantly higher QS complexity and diversity than HBeAg-negative CHB patients. In addition, HBeAg-negative patients showed reduced complexity but increased diversity compared with HBeAg-positive patients. Receiver operating characteristic curves showed that G1764A, C2102T, dN and complexity of QS could be used as potential biomarkers for diagnosing HBeAg-positive CHB, while the A2189C, dS and complexity of QS could be used as potential biomarkers for diagnosing HBeAg-negative chronic hepatitis. Finally, our study also found that G1896A and A2159G may be hotspot mutations affecting HBeAg seroconversion. ConclusionOur research elucidates the evolution of HBV by analyzing QS heterogeneity and mutation patterns, offering novel serum biomarkers for enhancing clinical diagnosis and disease prognosis. This comprehensive approach sheds light on the intricate dynamics of HBV progression and paves the way for more precise medical interventions.

Higher end-of-treatment HBsAg levels is associated with later onset but not severe relapse in HBeAg-negative chronic hepatitis B patients stopping antivirals.

Quantitative hepatitis B surface antigen (qHBsAg) level at end-of-treatment (EOT) predict clinical relapse (CR) after nucleos(t)ide analogues (Nuc) in chronic hepatitis B(CHB) patients. It is unclear if higher EOT qHBsAg leads to earlier onset or more severe off-Nuc CR. This large cohort study investigates the association between EOT qHBsAg and CR onset/severity. This study enrolled HBeAg-negative CHB patients who had achieved undetectable HBV DNA for over 1 year after receiving Nuc therapy before discontinuation. The EOT qHBsAg level was categorised into three groups: <100, 100-999, ≥1000 IU/mL. The study assessed the predictability of qHBsAg levels for CR, and analysed and compared the incidence, time to onset and severity of CR among these three groups. Patients with higher EOT qHBsAg showed a higher incidence of CR (≥1000, 100-999, <100 IU/mL: 73%, 65%, and 38%, p < 0.01) but a later onset of CR (median time to CR: 35, 33 and 27 weeks, p < 0.01). The predictabilities of EOT qHBsAg for CR were greater in patients aged <50-year-old or with genotype C than in those aged ≥50-year-old or with genotype B. There's no correlation between EOT qHBsAg level and ALT folds at CR (Pearson correlation coefficient: r = -0.03, p = 0.35). EOT qHBsAg was neither a predictor for severe hepatitis flare nor a predictor for hepatic decompensation. Predictability using EOT qHBsAg levels for CR differed in subgroups of age and genotypes. Higher EOT qHBsAg levels correlate with higher incidence but later onset of CR. No correlation between EOT qHBsAg and relapse severity was observed.

Risk factors for relapse after discontinuation of tenofovir or entecavir in hepatitis B e antigen-negative patients.

This study aimed to define the relapse frequency and risk determinants in chronic hepatitis B (CHB) patients who discontinued nucleoside analog (NA) treatment, were HBeAg-negative, and had achieved both a virological and biochemical response. This retrospective cohort study reviewed patients with HBeAg-negative CHB who received antiviral therapy for at least 65 months between January 1, 2013, and December 31, 2020. These patients discontinued treatment after demonstrating a biochemical and virological response and were evaluated at 6, 12, and 24 months post-treatment discontinuation. Sixty-seven patients with CHB who received NA therapy for at least 65 months, discontinued treatment, and had undetectable HBV DNA and normal ALT values were evaluated. After cessation of NA therapy, a relapse was observed in 38 patients (56.7%). The relapse rate was 71.0% in patients treated with tenofovir disoproxil fumarate (TDF) as the last NA type and 37.9% in patients treated with entecavir (ETV) (p=0.017). The cutoff value for the best estimate of age for predicting relapse was 42 years. The relapse rate was 69.2% in patients aged ≥42 years and 39.2% in patients aged <42 years (p=0.007). The relapse rate was 51.3% in patients with a pre-treatment fibrosis score of 2, 56.0% in those with a fibrosis score of 3, and 100% in those with a fibrosis score of 4 (p=0.089). Among HBeAg-negative CHB patients who achieved a virological and biochemical response to long-term antiviral therapy, those aged 42 years and older, those with high fibrosis scores before treatment, and those who used TDF before treatment cessation should be closely monitored for relapse, especially in the first 12 months after stopping NA treatment.

Metabolic Dysfunction-Associated Steatotic Liver Disease Facilitates Hepatitis B Surface Antigen Seroclearance and Seroconversion

BACKGROUND AND AIMSHepatitis B surface antigen (HBsAg) seroclearance is the goal of functional cure for hepatitis B virus (HBV) infection. However, the impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on this favorable outcome remains unclear. METHODSPatients with chronic hepatitis B (CHB) were consecutively recruited. MASLD was defined by the newly proposed disease criteria. Cumulative incidences and associated factors of HBsAg seroclearance/seroconversion were compared between the MASLD and non-MASLD groups. RESULTSFrom 2006 to 2021, 4,084 treatment-naïve HBeAg-negative CHB patients were included. At baseline, CHB patients with concurrent MASLD (n=887) had significantly lower levels of HBsAg and HBV DNA than the non-MASLD group (n=3197). During a median follow-up of 5.0 years, MASLD was associated with a higher likelihood of HBsAg seroclearance (adjusted hazard ratio [aHR]: 1.43, 95% confidence interval [CI]: 1.10-1.85, p = 0.007), and the accumulation of individual metabolic dysfunctions additively facilitated HBsAg seroclearance. In addition, a higher rate of HBsAg seroconversion was observed in patients with MASLD versus those without MASLD (aHR: 1.37, 95% CI: 1.00-1.86, p = 0.049). In sensitivity analysis, patients with intermittent MASLD had an intermediate probability of HBsAg seroclearance. After balancing clinical and virological profiles by inverse probability of treatment weighting (IPTW), MASLD was still associated with a higher HBsAg seroclearance rate (IPTW-adjusted HR 1.41, 95% CI 1.09-1.84, p = 0.010). CONCLUSIONSIn untreated HBeAg-negative CHB patients, concurrent MASLD is associated with higher rates of HBsAg seroclearance and seroconversion. Metabolic dysfunctions have additive effects on the functional cure of CHB.

Antiviral Therapy Favors a Lower Risk of Liver Cirrhosis in HBeAg-negative Chronic Hepatitis B with Normal Alanine Transaminase and HBV DNA Positivity.

Direct evidence on the outcomes of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal alanine transaminase after long-term antiviral treatment is lacking. HBeAg-negative patients with normal ALT and positive HBV DNA (≥20 IU/mL) were retrospectively enrolled. The endpoints included virological response (HBV DNA<100 IU/mL), changes in aspartate aminotransferase to platelet ratio index (APRI) and fibrosis-4 index (FIB-4), and the incidence of liver nodules, cirrhosis, and hepatocellular carcinoma (HCC). This cohort (n=194) was divided into three subgroups, untreated (n=67), treatment-continued (n=87), and treatment-discontinued patients (n=40), with a median follow-up of 54 months. The treatment-continued group achieved 100% (95% CI: 94.7-100) virological response, and significantly reduced APRI and FIB-4 scores (both p<0.001). The risk of liver nodules and cirrhosis in that group was reduced by 76% (HR: 0.24, 95% CI: 0.11-0.54, p<0.001) and 89% (HR: 0.11, 95% CI: 0.14-0.91, p=0.041) vs. the untreated group and by 77% (HR: 0.23, 95% CI: 0.10-0.49, p<0.001) and 95% (HR: 0.05, 95% CI: 0.01-0.44, p=0.006) vs. the treatment-discontinued group. For patients with HBV DNA≥2,000 IU/mL, adherence to treatment lowered the risks of liver cirrhosis by 92% (95% CI: 0.01-0.67) and 93% (95% CI: 0.01-0.53) vs. the untreated and treatment-discontinued patients, respectively. No patient adhering to treatment developed HCC, but one in each of the remaining groups did. Continuous nucleos(t)ide analog (NA) treatment has a satisfactory effectiveness and helps to lower the risk of liver cirrhosis in HBeAg-negative CHB patients with normal alanine transaminase, especially in those with HBV DNA≥2,000 IU/mL.

Evaluation and Determination of Quantitative Hepatitis B Surface Antigen Diagnostic Performance in Chronic Hepatitis B Virus-Infected Patients.

Background Hepatitis B virus DNA (HBV-DNA) assessment is recommended for diagnosing and monitoring chronic hepatitis B (CHB) patients. Quantitative hepatitis B surface antigen (qHBsAg) estimation adjunct to HBV-DNA is vital for assessing HBV chronicity and therapeutic prognosis. This study aimed to estimate the qHBsAg and compare its diagnostic performance with that of the HBV-DNA levels in CHB patients from Bangladesh. Methodology A total of 148 CHB patients were enrolled in this study. qHBsAg and hepatitis B e-antigen (HBeAg) were estimated using chemiluminescent and enzyme immunoassays, respectively, and HBV-DNA was quantified using real-time polymerase chain reaction. The parameters and diagnostic performances were analyzed by receiver operating characteristic (ROC) curve analysis. Results The overall levels (mean ± SD) of qHBsAg, HBV-DNA, and alanine aminotransferase (ALT) among the total population (n = 148) were 3.45 ± 0.80 log10 IU/mL, 4.40 ± 2.44 log10 IU/mL, and 86.17 ± 39.06 IU/L, respectively. Significant differences were observed in the levels of both qHBsAg (p = 0.004) and HBV-DNA (p < 0.0001) in cases with HBeAg positivity. qHBsAg levels showed a weak positive correlation with the levels of HBV-DNA and ALT in HBeAg-positive CHB patients, but no such relationship was observed in HBeAg-negative CHB patients. ROC curve analysis showed that the area under the curve for the qHBsAg level to distinguish high HBV-DNA levels (>5 log10 IU/mL) was 0.653 (p = 0.002), which indicated an acceptable diagnostic performance. The best cut-off of qHBsAg for predicting high HBV-DNA levels was 3.469 log10 IU/mL. Conclusions Our results indicated that qHBsAg might be a useful marker for monitoring HBV-DNA in CHB patients throughout treatment and follow-up.

Immune drivers of HBsAg loss in HBeAg-negative CHB patients after stopping nucleotide analog and administration of Peg-IFN.

The stoppage of nucleoside analog (NA) can lead to immune flare and loss of HBsAg in a proportion of HBeAg-negative chronic hepatitis B (CHB) patients. HBsAg loss could be improved by instituting Peg-Interferon therapy in those who show an immune flare after the stoppage of NA. We investigated the immune drivers of HBsAg loss in NA-treated HBeAg-negative CHB patients after stopping NAs and administration of Peg-IFN-α2b therapy. Fifty-five NA-treated eAg-ve, HBV DNA not detected CHB patients were subjected to stopping NA therapy. Twenty-two (40%) patients relapsed (REL-CHBV) within 6 months (HBV DNA ≥2000IU/mL, ALT ≥2XULN) and were started on Peg-IFN-α2b (1.5mcg/kg) for 48 weeks (PEG-CHBV). Cytokine levels, immune responses, and T-cell functionality were assessed. Only 22 (40%) of 55 patients clinically relapsed, of which 6 (27%) cleared HBsAg. None of the 33 (60%) nonrelapsers cleared HBsAg. REL-CHBV patients had significantly increased IL-6 (p=0.035), IFN-γ (p=0.049), Th1/17 (p=0.005), CD4 effector memory (EM) (p=0.01), Tfh1/17 (p=0.005), and mature B cells (p=0.04) compared with CHBV. Six months after Peg-IFN therapy, immune resetting with a significant increase in CXCL10 (p=0.042), CD8 (p=0.01), CD19 (p=0.001), and mature B cells (p=0.001) was observed. HBV-specific T-cell functionality showed increased Tfh-secreting IFN-γ (p=0.001), IL-21 (p=0.001), and TNF-α (p=0.005) in relapsers and IFN-γ-secreting CD4 T cell (p=0.03) in PEG-CHBV. Stopping NA therapy induces flare in about 40% of HBeAg-negative patients. Peg-IFN therapy given to such patients causes immune restoration with HBsAg loss in one fourth of them.

Significant histological disease of patients with chronic hepatitis B virus infection in the grey zone.

Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg-positive, normal ALT and HBV DNA ≤106 IU/ml (GZ-A); HBeAg-positive, elevated ALT and HBV DNA ≤2× 104 IU/ml (GZ-B); HBeAg-negative, normal ALT and HBV DNA ≥2× 103 IU/ml (GZ-C) and HBeAg-negative, elevated ALT and HBV DNA ≤2× 103 IU/ml (GZ-D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg-positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg-negative GZ patients (91.1% vs. 68.5%, p= 0.002). GZ-D (42.6%) was the dominant category, followed by GZ-C (38.8%), GZ-A (10.3%) and GZ-B (8.3%). The highest proportion of significant histological disease was observed patients in GZ-B (100.0%), followed by GZ-A (84.0%), GZ-D (69.9%) and GZ-C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg-negative GZ. Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg-positive and HBeAg-negative GZ CHB patients with high PT.

Some HBeAg-negative chronic hepatitis B patients treated with nucleos(t)ide analogue can achieve HBsAg loss after drug withdrawal: stop-to-cure may be coming

Nucleoside/Nucleotide analogues (NAs) are widely used for the antiviral treatment of chronic hepatitis B (CHB), however, it is difficult to achieve serum hepatitis B surface antigen (HBsAg) loss with NAs therapy. In recent years, several prospective trails have reported that HBsAg loss (functional cure or clinical cure) also occurs in a small number of hepatitis B e antigen (HBeAg) negative CHB patients who discontinued long-term treatment with NAs. Accordingly, the "stop-to-cure" strategy is proposed. Although the mechanism has not been fully elucidated, the known factors related to serum HBsAg loss with NAs withdrawal include HBV genotype, duration of NAs treatment, serum HBsAg and HBV RNA levels at end-of-treatment, and ethnic differences. In the review, we discuss the best time to stop NAs therapy, the potential markers for predicting relapse after cessation of NAs and the possible mechanism of "stop-to-cure" in HBeAg-negative CHB patients, and propose some suggestions on the time of retreatment.

Expanding antiviral therapy indications for HBeAg-negative chronic hepatitis B patients with normal ALT and positive HBV DNA.

With the improved efficacy and accessibility of antiviral agents as well as the concerns about disease progression, there is a hot discussion on whether HBeAg-negative chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) and positive HBV DNA should be treated. According to the international guidelines on the stages of the natural history of HBV infection, HBeAg-negative CHB patients with normal ALT and positive HBV DNA can be divided into two groups: one is the well-known "inactive carrier phase", which is defined as serum HBV DNA<2000 IU/ml and no significant liver inflammation; and the other is the "indeterminate phase", which is defined as serum HBV DNA≥2000 IU/mL regardless of the pathological changes in liver tissue, or HBV DNA<2000 IU/mL but accompanied by significant pathological changes in the liver. In this minireview, we will expound the disease characteristics, disease progression, and clinical management status of these two groups. Based on the analysis, we propose that HBeAg-negative patients with normal ALT but detectable serum HBV DNA should be treated, regardless of their age, family history of hepatocellular carcinoma (HCC) or the severity of liver necroinflammation. Expanding the indications of antiviral therapy will help improve the survival and quality of life of patients by preventing disease progression, and consequently reduce the risk of HCC development.

Effectiveness of antiviral treatment in HBeAg-negative chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase: a retrospective study

BackgroundThere are inadequate data and no histological evidence regarding the effects of antiviral treatment for hepatitis B e-antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal or mildly elevated alanine aminotransferase (ALT). This study investigated the effects of antiviral treatment on these patients.MethodsWe retrospectively analysed the outcomes of antiviral treatment for HBeAg-negative CHB patients with normal or mildly elevated ALT who were treated with nucleoside/nucleotide analogues (NAs) for up to 96 weeks.ResultsA total of 128 patients were enrolled; 74 patients had normal ALT and 54 patients had mildly elevated ALT. The total cumulative rates of viral suppression were 64.06%, 81.97%, and 96.39%, at weeks 24, 48, and 96, respectively. The cumulative rates of viral suppression for the normal and mildly elevated ALT groups were 67.85% and 58.97%, 86.39% and 76.31%, and 93.13% and 97.04% at weeks 24, 48, and 96, respectively. The serum HBV DNA levels at week 12 and hepatitis B surface antigen (HBsAg) levels at week 24 were significant predictors of the 96-week virological response. Of the 128 patients, 54 with normal ALT and 33 with mildly elevated ALT underwent FibroScan at baseline. Significant fibrosis (F ≥ 2) was found in 44.4% (n = 24) and 51.5% (n = 17) of the patients in the normal ALT group and mildly elevated ALT group, respectively. Compared with the values at baseline, liver stiffness values significantly decreased at week 48 (8.12 kPa vs. 6.57 kPa; p < 0.001) and week 96 (8.87 kPa vs. 6.43 kPa; p < 0.001), respectively.ConclusionsHBeAg-negative CHB patients with normal ALT could benefit from antiviral therapy with NAs, similar to patients with mildly elevated ALT. Antiviral treatment is strongly recommended for HBeAg-negative CHB patients with normal ALT. Additionally, significant liver fibrosis is not rare in HBeAg-negative CHB patients with ALT less than two-times the upper limit of normal, and FibroScan should be performed regularly for these patients.

Correlation between Results of Semi-Quantitative and Quantitative Tests for Hepatitis B Virus Surface Antigen among Patients Achieving Viral Suppression with Antiviral Treatment.

Background: Hepatitis B virus (HBV) infection remains a threat to global public health. Serum hepatitis B surface antigen (HBsAg) has been used in screening for HBV infection. Quantitative HBsAg assays are useful for monitoring the natural history of HBV infection and its response to therapy. The aim of this study was to determine the relationship between quantitative (qHBsAg; IU/mL) and semi-quantitative (sqHBsAg; signal-to-cutoff ratio [S/Co]) HBsAg titers in patients with chronic hepatitis B (CHB). Methods: We retrospectively included 284 samples with HBV DNA < 20 IU/mL from patients who had simultaneous qHBsAg (using electrochemiluminescence assay) and sqHBsAg tests. Patients were grouped according to their serum HBV-envelope antigen (HBeAg) status (HBeAg-negative, n = 239 and HBeAg-positive, n = 45). The Spearman test was used to analyze the correlation between the quantitative and semi-quantitative assays. Results: There was a significant linear correlation between sqHBsAg and qHBsAg in the HBeAg-negative patients (qHBsAg [IU/mL] = 0.0094 × sqHBsAg [S/Co]1.323; adjusted R2 = 0.8445; p < 0.001). There was a substantial hook effect in the assays from the HBeAg-positive patients, so we performed a stratified analysis according to qHBsAg <1000 IU/mL or ≥1000 IU/mL and found a significant positive linear correlation between sqHBsAg S/Co and qHBsAg (qHBsAg [IU/mL] = 0.072 × sqHBsAg [S/Co]1.331; adjusted R2 = 0.7878; p < 0.001) in HBeAg-positive patients with qHBsAg titers of <1000 IU/mL and a significant negative correlation in HBeAg-positive patients with qHBsAg titers of ≥1000 IU/mL (qHBsAg [IU/mL] = 8.987 × 1014 × sqHBsAg [S/Co]−3.175; adjusted R2 = 0.6350; p < 0.001). Conclusions: There was a highly linear, positive correlation between qHBsAg and sqHBsAg in HBeAg-negative CHB patients. The hook effect led to a negative correlation in HBeAg-positive CHB patients with qHBsAg titers ≥1000 IU/mL.

240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C.

This study aimed to evaluate the efficacy and safety of entecavir(ETV) versus ETV maleate in Chinese patients with chronic hepatitis B(CHB). This was a randomized, double‐blind, double‐dummy, controlled, multicentre study. Patients were randomly assigned to receive 48 weeks of treatment with 0.5 mg/day ETV (group A) or 0.5 mg/day ETV maleate (group B), then, all patients received treatment with 0.5 mg/day ETV maleate from week 49 onwards. Patients were regularly followed up. Serum hepatitis B virus (HBV) markers were detected. Adverse events (AE) were recorded. The primary endpoint was the decline in HBV DNA in each group at the end of treatment. Secondary endpoints included the rate of HBV DNA below the lower limit of detection (LLOD) (20 I U/ml) at the end of treatment, the rate of hepatitis B e antigen (HBeAg) loss, the rate of HBeAg seroconversion and serum alanine aminotransferase (ALT) normalization. One hundred and thirty‐seven (71 in group A) patients with HBeAg‐positive CHB and 46 (21 in group A) patients with HBeAg‐negative CHB completed the 240‐week treatment and follow‐up. Baseline characteristics were well balanced between the two groups. For the HBeAg‐positive CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.67 log10 IU/ml vs. B: by 6.74 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA (<20 IU/ml) at Week 240 were similar between groups (A:91.55% vs. B:87.88%; p > .05). Both groups achieved similar HBeAg seroconversion rates at week 240 (A:26.98% vs. B:20.97%; p > .05). Both groups achieved similar normalization of ALT (A:87.32% vs. B:83.61%; p > .05) at Week 240 (p > .05). For the HBeAg‐negative CHB patients, the mean HBV DNA level had similarly decreased from baseline in both groups (A: by 6.05 log10 IU/ml vs. B: by 6.10 log10 IU/ml; p > .05) at Week 240. Patients who achieved undetectable levels of serum HBV DNA at Week 240 were similar between groups (A:100% vs. B:100%). Both groups achieved similar normalization rates (A:90.91% vs. B: 95.45%; p > .05) of ALT at Week 240 (p > .05). In conclusion, long‐term ETV maleate treatment was safe and efficient in Chinese CHB predominantly of genotype B or C.

Bushen Jianpi Formula Combined with Entecavir for the Treatment of HBeAg-Negative Chronic Hepatitis B: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background Bushen Jianpi formula (BSJPF, also known as Lingmao formula) is a traditional Chinese medicine for chronic hepatitis B (CHB). The previous study has suggested that the treatment combination of BSJPF and entecavir (ETV) can achieve a significant loss of hepatitis B e antigen (HBeAg) and a significant decrease in serum level of hepatitis B virus (HBV) DNA in HBeAg-positive CHB patients with mildly elevated alanine aminotransferase. Objective This study aimed to evaluate the efficacy and safety of BSJPF combined with ETV for treating HBeAg-negative CHB patients. Methods A total of 640 patients were assigned randomly to the treatment group (receiving BSJPF combined with ETV for 96 weeks) or the control group (receiving a placebo combined with ETV for 96 weeks) in a 1 : 1 ratio. The primary endpoints are the rate of loss of hepatitis B surface antigen (HBsAg). The secondary outcomes included the rate of decrease in the HBsAg concentration to ≥1 lg·IU/mL, the HBV DNA suppression, the decline of the level of covalently closed circular DNA (cccDNA) in the liver, histological improvements, and the rate of ALT normalization. Results The rate of HBsAg loss in the treatment group was significantly higher than that of the control group (5.5% versus 1.8%, P=0.031). There were 11.1% of patients in the treatment group who recorded a reduction in HBsAg ≥1 lg·IU/mL, which is better than 5.9% of patients in the control group (P=0.043). There was no significant difference between the two groups with regard to the rate of HBV DNA clearance, the reduction in intrahepatic cccDNA, and the rate of ALT normalization (P > 0.05). The rate of liver fibrosis improvement in the treatment group was better than that of the control group (35.5% versus 11.8%, P=0.031), but there was no difference in necroinflammatory improvement (P > 0.05). The adverse events (AEs) were similar between the two groups, except for the abnormal kidney function, with 2.2% in the control group and 0.0% in the treatment group (P=0.028). Conclusion The combination of BSJPF and ETV can increase the rate of HBsAg loss and the rate of histological fibrosis improvement without serious adverse events in CHB patients. Trial Registration. This trial is registered with ChiCTR-IOR-16009880 on November 16, 2016—retrospectively registered, http://www.chictr.org.cn/showproj.aspx?proj=16836.

MAFLD is Associated with the Risk of Liver Fibrosis and Inflammatory Activity in HBeAg-Negative CHB Patients.

PurposeChronic hepatitis B (CHB) and metabolic associated fatty liver disease (MAFLD) are both important public health problems. The effect of concomitant MAFLD on patients with CHB is still unclear. This study aimed to explore the influence of MAFLD on liver fibrosis and inflammation in CHB patients with different hepatitis B e antigen (HBeAg) status.Patients and MethodsWe retrospectively collected the clinical data of 399 treatment-naïve CHB patients who underwent liver biopsy. All patients were divided into two groups (HBeAg± group). Logistic regression analysis was used to identify factors associated with liver inflammatory activity and significant fibrosis in patients with CHB. Multivariable logistic regressions were repeated in subgroups stratified by HBeAg status.ResultsIn patients with CHB, MAFLD was independently associated with a risk of moderate-to-severe liver activity and significant fibrosis (P <0.05). In the HBeAg-negative group, patients with MAFLD had significantly higher levels of alanine aminotransferase (ALT) (P <0.05) and more severe liver inflammatory activity and fibrosis (P <0.05) compared to those without MAFLD. MAFLD was independently associated with a risk of moderate-to-severe liver activity (A ≥3: OR 3.97, 95% CI 1.71–9.22, P =0.001) and significant fibrosis (F ≥2: OR 2.02, 95% CI 1.09–3.73, P =0.026). In the HBeAg-positive group, MAFLD was found to be independently associated with moderate-to-severe liver activity (OR 2.44, 95% CI 1.03–5.79, P =0.044) but not fibrosis (P =0.618).ConclusionMAFLD is associated with the risk of liver fibrosis and inflammatory activity in HBeAg-negative CHB patients. Sufficient attention should be paid to the prevention and treatment of MAFLD in patients with CHB, especially in HBeAg-negative patients.

Hepatitis B Core-Related Antigen Stratifies the Risk of Liver Cancer in HBeAg-Negative Patients With Indeterminate Phase.

Many patients with chronic hepatitis B (CHB) are classified as indeterminate patients because they fall outside the defined CHB phases. We aimed to explore hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-negative patients with indeterminate phase and investigated whether the risk could be stratified by serum levels of hepatitis B core-related antigen (HBcrAg). Two retrospective cohorts enrolling HBeAg-negative, treatment-naïve CHB patients without cirrhosis were constructed (N = 2,150 in Taiwanese discovery cohort and N = 1,312 in Japanese validation cohort with a mean follow-up period of 15.88 and 12.07 years, respectively). The primary end point was HCC development. According to the American Association for the Study of Liver Disease guidelines, 990 (46%) HBeAg-negative patients had indeterminate CHB phase at baseline in the Taiwanese cohort. Compared with the patients with inactive CHB and those with immune-active CHB, the indeterminate patients exhibited intermediate but diverse risk of HCC. When HCC risk was stratified by a HBcrAg level of 10,000 U/mL, 10-year HCC cumulative incidence was 0.51% and 5.33% for low HBcrAg and high HBcrAg groups, respectively, with a hazard ratio of 4.47 (95% confidence interval: 2.62-7.63). This cutoff was validated to stratify HCC risk not only in different subgroup analyses but also in an independent Japanese cohort. Finally, the overall HBeAg-negative CHB patients could be simply reclassified into high-risk and low-risk groups by combining ALT, hepatitis B virus DNA, and HBcrAg levels in both cohorts. Serum HBcrAg level of 10,000 U/mL stratifies HCC risk in HBeAg-negative patients with indeterminate phase, which is useful for optimizing their clinical management.