Among patients with hepatitis B virus (HBV)-infected compensated cirrhosis and low-level viremia, there are limited data for comparative outcomes between those treated with oral nucleos(t)ide analogs versus those not. We conducted a large, multi-ethnic, multi-center study to examine the impact of antiviral treatment (AVT) on long-term hepatocellular carcinoma (HCC) risk for compensated cirrhosis and low-level viremia.

Patients with compensated cirrhosis and low-level viremia (serum HBV-DNA 20-2000 IU/mL) at baseline or before AVT were screened for eligibility from 19 hospitals in South Korea, Singapore, and Japan. The primary outcome was HCC development, compared between those receiving AVT versus those untreated throughout follow-up.

Among 848 patients (mean age 55.7 years and 66.9% male), AVT (n = 233) was associated with significantly lower annual HCC incidence compared to non-AVT (n = 615); 1.72/100 versus 2.99/100 person-years (PY), respectively (p = 0.033). Multivariable Cox-regression analyses determined that AVT was associated with significantly lower HCC risk, compared to non-AVT (adjusted HR [HR] 0.514, 95% confidence interval [CI] 0.271-0.976; p = 0.042). In a landmark analysis, HCC incidence was similar between two groups until 18 months, but after this landmark, the treated group had the significantly lower HCC risk compared to untreated group (p = 0.012). Furthermore, propensity score-matching analysis consistently showed that AVT was associated with significantly lower HCC risk, compared to non-AVT; the annual HCC incidence of 1.45/100 PYs versus 2.73/100 PY, respectively (p = 0.043).

Patients with compensated cirrhosis and low-level viremia may benefit from long-term AVT, highlighting appropriate amendment of reimbursement guidelines.

Hepatitis B virus (HBV) RNA is an important serum biomarker of hepatic covalently closed circular DNA (cccDNA) transcriptional activity; however, its clinical characteristics remain unclear. This study evaluated the clinical utility of HBV RNA levels in patients with chronic hepatitis B (CHB).

We studied 87 CHB patients with serum HBV DNA levels ≥ 5.0 log IU/mL who initiated entecavir (ETV) treatment between 2000 and 2018. Serum HBV RNA levels were measured at three-time points: before ETV treatment, at 12 weeks, and at 48 weeks after starting ETV treatment. Clinical markers associated with the antiviral effects of ETV treatment were analyzed.

Serum HBV RNA levels decreased in both HBeAg-positive and -negative patients during the observation period. In HBeAg-positive patients, multivariable analysis showed that lower HBV RNA levels at 48 weeks of ETV treatment were independently associated with HBeAg seroconversion. Additionally, lower baseline HBV RNA levels significantly predicted virologic response in those patients. In contrast, among HBeAg-negative patients, lower HBV core-related antigen (HBcrAg) levels and the FIB-4 index were independently associated with virologic response. In HBeAg-positive patients, those with higher baseline HBV RNA levels showed a more significant reduction in hepatitis B surface antigen levels.

Serum HBV RNA levels predicted HBeAg seroconversion and early HBV DNA reduction in HBeAg-positive patients, while HBcrAg was significantly associated with virologic response in HBeAg-negative patients. These findings highlight the different predictive roles of HBV RNA and HBcrAg based on HBeAg status, which may provide individualized treatment strategies.

The correlation between intrahepatic covalently closed circular DNA (cccDNA) levels and serum hepatitis B virus (HBV) markers in patients with resolved HBV infection (hepatitis B surface antigen [HBsAg]-negative and antibody to hepatitis B core antigen [anti-HBc]-positive) is unclear. We therefore examined the utility of anti-HBc titers as a surrogate marker of intrahepatic cccDNA levels in patients with resolved HBV infections.

Among 1005 patients who underwent hepatectomy between 2010 and 2018, a retrospective review was performed in 114 patients (76 with resolved HBV infection and 38 HBsAg-positive) with frozen specimens of the background liver. Clinical, biochemical, and virological data, including intrahepatic cccDNA levels, were retrospectively evaluated. Intrahepatic cccDNA levels were measured using droplet digital polymerase chain reaction.

Intrahepatic cccDNA levels positively correlated with serum HBsAg levels (r = 0.609, p < 0.001) and anti-HBc titers (r = 0.542, p < 0.001). An intrahepatic cccDNA level of 22.2 copies/μg was the optimal cut-off for HBsAg positivity, with a sensitivity of 86.8% and specificity of 89.5%. Of the 76 cases with resolved HBV infection, 8 had high levels of intrahepatic cccDNA (≥22.2 copies/μg). Multivariate analyses showed that anti-HBc ≥ 11.0 sample/cut-off (S/CO) was an independent risk factor for high intrahepatic cccDNA levels (odds ratio, 12.6; 95% confidence interval, 2.4-66.156; P = 0.003).

Anti-HBc titers were positively correlated with intrahepatic cccDNA levels. Even in patients with resolved HBV infection, anti-HBc ≥ 11.0 S/CO was considered to indicate high intrahepatic cccDNA levels, comparable to those in HBsAg-positive cases. In this group, careful monitoring is required during immunosuppressive therapy to prevent HBV reactivation.

There are several meta-analyses about the comparison of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) for preventing hepatocellular carcinoma in patients with chronic HBV infection published in recent years. However, the conclusions vary considerably. This umbrella review aims to consolidate evidence from various systematic reviews to evaluate differences in hepatocellular carcinoma prevention between two drugs. Systematic searches were conducted using PubMed, Embase, and Web of Science to identify original meta-analyses. Finally, twelve studies were included for quantitative analyses. We found that TDF treatment was associated with a significantly lower risk of HCC than ETV (hazard ratio, 0.80; 95% CI 0.75-0.86, p < 0.05). The lower risk of HCC in patients given TDF compared with ETV persisted in subgroup analyses performed with propensity score-matched cohorts, cirrhosis cohorts, nucleos(t)ide naïve cohorts and Asian cohorts. In the cohorts of non-Asia and patients without cirrhosis, there was no difference exhibited between these two drugs. Subsequent analyses showed TDF treatment was also associated with a lower incidence of death or transplantation than patients receiving ETV. Overall, the preventive effect of these two drugs on HCC has been studied in several published meta-analyses, but few were graded as high-quality evidence, meanwhile, most of which had high overlap. Thus, future researchers should include updated cohorts or conduct prospective RCTs to further explore this issue.

Progress towards achieving global elimination of hepatitis B virus (HBV) by 2030 remains unsatisfactory. Prevention of mother to child transmission is crucial but current Clinical Practice Guidelines (CPGs) gave diverse recommendations, creating confusion and leading to significant challenges in the practical implementation across various regions owing to global inequity. We reviewed 47 CPGs on the management of hepatitis B during pregnancy against twelve important clinical questions. Of 47 guidelines, 80.9% (38/47) supported the universal approach to HBV screening. To select women for antiviral prophylaxis, 78.7% (37/47) recommended the use of HBV DNA levels, while 31.9% (15/47) recommended the use of HBeAg. Of 37 guidelines recommending HBV DNA levels, 94.6% (35/37) recommended a viral load threshold of >200,000 IU/mL to initiate antiviral prophylaxis. Of 16 guidelines addressing the mode of delivery, 87.5% (14/16) encouraged vaginal birth. Of 30 guidelines addressing breastfeeding, 60% (18/30) recommended breastfeeding. However, controversies were found in the optimal timing of HBV disease evaluation during pregnancy and the ideal timing to stop antiviral prophylaxis after delivery. Of 36 guidelines addressing the timing to initiate antiviral prophylaxis, 25% (9/36) advised starting prophylaxis between 24 and 28 weeks, while 75% (27/36) suggested other timings or provided vague descriptions. Of 38 guidelines addressing birth-dose vaccination, 42% (16/38) emphasized the importance of "vaccination as soon as possible after birth." These deficiencies and discrepancies among CPGs could significantly impede global HBV elimination.

A 75-year-old Japanese woman experienced persistent fatigue and progressive jaundice for 6 weeks, and was subsequently diagnosed with acute liver failure. She had not received any immunosuppressive therapies and/or antineoplastic chemotherapy. Blood tests revealed elevated levels of HBsAg, HBV-DNA, and anti-HBc IgG, while anti-HBc IgM was negative. She had undergone hepatitis virus testing 48 weeks earlier, during which HBsAg was negative, indicating that HBV reactivation occurred in a patient with a previously resolved infection, without any drug therapies as triggers, ultimately leading to acute liver failure. Despite receiving multidisciplinary intensive treatment, her condition worsened, resulting in death. Full-length genomic analysis of the HBV strain, performed using nanopore sequencing technology, identified an I126S substitution in HBsAg, known as a vaccine escape mutation, along with a quasispecies consisting primarily of two HBV clone variants: one full-length and the other with a deletion in the nt2,448-nt488 region (sp1 spliced variant). These genetic factors may have contributed to the spontaneous HBV reactivation.

As new evidence emerges, treatment strategies toward the functional cure of chronic hepatitis B are evolving. In 2019, a panel of national hepatologists published a Consensus Statement on the functional cure of chronic hepatitis B. Currently, an international group of hepatologists has been assembled to evaluate research since the publication of the original consensus, and to collaboratively develop the updated statements. The 2.0 Consensus was aimed to update the original consensus with the latest available studies, and provide a comprehensive overview of the current relevant scientific literatures regarding functional cure of hepatitis B, with a particular focus on issues that are not yet fully clarified. These cover the definition of functional cure of hepatitis B, its mechanisms and barriers, the effective strategies and treatment roadmap to achieve this endpoint, in particular new surrogate biomarkers used to measure efficacy or to predict response, and the appropriate approach to pursuing a functional cure in special populations, the development of emerging antivirals and immunomodulators with potential for curing hepatitis B. The statements are primarily intended to offer international guidance for clinicians in their practice to enhance the functional cure rate of chronic hepatitis B.

Prenatal and intrapartum invasive tests are possible mechanisms of mother to child transmission (MTCT) of hepatitis B virus (HBV). The viral activity can affect the MTCT risk after invasive tests, but the evidence is scarce. This scoping review discussed the effects of prenatal or intrapartum invasive tests on the risk of HBV MTCT. The risk of MTCT after amniocentesis was low among hepatitis B infected pregnant individuals with negative hepatitis B e antigen (HBeAg) statuses or HBV DNA < 7 log10 IU/mL, and comparable to those that did not undergo prenatal invasive tests. Amniocentesis could increase the risk of MTCT among women with seropositive HBeAg statuses or HBV DNA ≥ 7 log10 IU/mL, but there were no MTCT among these women who received antiviral treatment. Data on CVS, cordocentesis and intrapartum invasive tests were insufficient to conclude their effects on MTCT. We also reviewed 50 international clinical practice guidelines. Most of them did not have recommendations on the management of hepatitis B infected pregnant individuals requiring prenatal or intrapartum invasive tests and significant discrepancies existed among the remaining guidelines. A workflow and two pragmatic approaches were discussed to assist clinical management. Furthermore, we would like to encourage future research to provide comprehensive data on the factors influencing the MTCT rate (such as maternal HBV DNA viral load and HBeAg status, availability and timing of neonatal birth dose immunizations, transplacental or transamniotic invasive tests, complications of the invasive tests and the use of antiviral prophylaxis).

Prevention of hepatitis B virus (HBV) reactivation is a very important issue, but there is still no clear strategy. This study aimd to develop and evaluate an in-hospital collaboration flow to prevent HBV reactivation, guided by the Japanese Society of Hepatology (JSH) guidelines.

We have strengthened and implemented a screening system and for HBV reactivation from February 2022 to January 2023. We assessed the administration of nucleic acid analogs (NAs) in hepatitis B surface antigen (HBsAg) or HBV DNA-positive cases, the detection rate of HBs or hepatitis B core (HBc) antibodies in HBsAg or HBV DNA-negative cases, and the follow-up status of HBV DNA testing. A total of 1,195 patients were included, with exclusions based on the judgement of no need for testing by the attending physician.

Among 1,172 tested patients, 1.88% (n=22) were HBsAg or HBV DNA-positive, all of whom received NA therapy. Among 1,150 HBsAg or HBV DNA-negative cases, 9.91% (n=114) were HBs or HBc antibody-positive, with 82.5% (n=94) undergoing HBV DNA testing. Over the years, the HBV DNA measurement rates increased significantly to 82.5% in 2022.

The implemented screening regimen resulted in high and improving testing rates over time. Most HBsAg or HBV DNA-positive cases were treated with tenofovir alafenamide (TAF), highlighting its potential benefits in terms of safety and adherence. Continued validation and adaptation of the screening system are necessary to further prevent HBV reactivation.

Achieving HBsAg seroclearance is a key goal in treating chronic hepatitis B virus (HBV) infection but remains difficult with nucleos(t)ide analogues (NAs). Tenofovir alafenamide fumarate (TAF), a recommended NA for managing chronic HBV infection (CHB), has uncertain effects on HBsAg levels and potential adverse events when used long-term after switching from entecavir (ETV). We retrospectively evaluated 77 CHB patients, including 47 who switched from ETV to TAF with a median follow-up of 40 months post-switch and a median of 60 months of HBsAg monitoring pre-switch. No significant change in HBsAg levels was observed in the overall cohort post-switch, consistent with the ETV continuation group. However, a significant decrease in HBsAg was noted in patients with HBsAg < 100 IU/mL at the time of switching. HBsAg loss occurred in three patients who switched to TAF. No adverse effects were observed, and TAF was well tolerated. The most significant factor associated with achieving HBsAg < 100 IU/mL was the Fib-4 index, a marker of liver fibrosis, at the time of switching. Switching from ETV to TAF is an effective strategy in CHB management, with hepatic inflammation potentially playing an essential role in achieving HBsAg decrease. Patients with increased Fib-4 index were significantly more likely to show decreased HBsAg. This finding suggests patients with mild to moderate fibrosis may respond better to TAF in terms of HBsAg reduction.

We aimed to compare the usefulness of the ultra-high-sensitivity hepatitis B surface antigen (iTACT-HBsAg), high-sensitivity hepatitis B core-related antigen (iTACT-HBcrAg), and anti-HBs assays in determination of cessation of nucleot(s)ide analogue (NA) treatment to prevent against hepatitis B virus (HBV) reactivation.

Twenty-two patients who developed HBV reactivation under immunosuppressive therapy or chemotherapy and had been administered NA and subsequently discontinued were enrolled. The stored serum samples taken at NA cessation were applied to iTACT-HBsAg (lower limit of detection; 0.0005 IU/mL), iTACT-HBcrAg (lower limit of detection; 2.1 log U/mL), and anti-HBs assays. Detection of serum HBV DNA level ≥1.3 log IU/mL after NA cessation was defined as virological relapse (VR).

Two patients were excluded due to re-introduction of NA despite a negligible level of HBV DNA (<1.3 log IU/mL). Of the remaining 20 patients, 11 (55 %) had HBcrAg <2.1 log U/mL at the cessation of NA, and 7 of the 11 patients (64 %) had no VR thereafter. On the other hand, 15 patients (75 %) had HBsAg <0.0005 IU/mL at the cessation of NA, and 13 of the 15 patients (87 %) subsequently lacked VR. Further, 12 patients (60 %) had anti-HBs ≥10 mIU/mL at the cessation of NA, and 10 of the 12 patients (83 %) had no VR thereafter. The iTACT-HBsAg assay had the highest positive predictive value and the best overall diagnostic performance for predicting non-VR after cessation of NA.

The iTACT-HBsAg assay was useful to determine the cessation of NA treatment to prevent against HBV reactivation.

We report a case of fulminant hepatitis in a hepatitis B surface antigen (HBsAg)-positive patient with aggressive adult T-cell leukemia-lymphoma who received monotherapy with an anti-CCR4 monoclonal antibody, mogamulizumab, with decreased hepatitis B virus (HBV)- DNA levels by entecavir prophylaxis. Although HBV reactivation-related hepatitis was considered in the differential diagnosis, the patient did not meet the conventional criteria for HBV reactivation and was finally diagnosed with drug-induced hepatitis. Considering that the immunoenhancing effects of mogamulizumab can lead to HBV reactivation-related hepatitis in HBsAg-positive patients, we should differentiate drug-induced hepatitis from HBV reactivation, especially in patients receiving immunomodulatory drugs, if HBV-DNA levels are reduced by antiviral prophylaxis.

An accurate assessment of the general condition of patients with hepatocellular carcinoma (HCC) is essential. We evaluated the impact of grip strength (GS) and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) on the clinical outcomes of patients with unresectable HCC (u-HCC) treated with atezolizumab plus bevacizumab.

This observational cohort study analyzed 89 patients with u-HCC treated with atezolizumab plus bevacizumab between October, 2020 and October, 2023. A Cox proportional hazards model and Kaplan-Meier curve were used to identify the prognostic factors associated with survival outcomes.

There were 33 patients who had low GS and 16 had an ECOG-PS ≥1. The frequency of patients with low GS increased as the ECOG-PS score increased. The overall survival of the normal GS group was significantly higher than that of the low GS group (p < 0.01). There was no significant difference in progression-free survival between the normal GS group and low-GS group (p = 0.28). Among the patients in the ECOG-PS 0 groups, the overall survival in the normal GS group was significantly higher than that in the low GS group (p < 0.01). A multivariate analysis revealed that modified albumin-bilirubin 2b (HR 2.24; 95% confidence interval [CI] 1.06-4.73), α-fetoprotein ≥100 ng/mL (HR 2.35; 95% CI 1.20-4.58), and low GS (HR 2.87; 95% CI 1.31-6.27) were independently associated with a poor overall survival.

The present study demonstrated that GS is a sensitive marker for detecting a subclinical decline in the general condition and is therefore a potential predictor of the outcome of u-HCC patients treated with atezolizumab plus bevacizumab.

Whether patients with compensated cirrhosis and low-level viremia (LLV) of hepatitis B should receive antiviral therapy (AVT) is still controversial, and published results are inconsistent.

To investigate the link between LLV in compensated cirrhosis and prognosis concerning hepatocellular carcinoma (HCC), decompensation, and liver-related events.

The PubMed, EMBASE, and Cochrane Library databases were searched up to March 5, 2023. Outcomes of interest were assessed by pooled hazard ratios (HRs). The study was registered with PROSPERO (CRD42023405345).

Six cohort studies representing 3155 patients were included. Compared with patients with undetectable HBV DNA, patients with LLV was associated with increased risk of HCC (HR: 2.06, 95%CI: 1.36-3.13; Q-statistic-P = 0.07, I 2 = 51%) regardless of receiving AVT or not (AVT group: HR: 3.14; 95%CI: 1.73-5.69; Q-statistic-P = 0.60, I 2 = 0%; un-AVT group: HR: 1.73, 95%CI: 1.09-2.76; Q-statistic-P = 0.11, I 2 = 50%). The pooled results showed no statistical association between LLV and decompensation of cirrhosis (HR: 2.06, 95%CI: 0.89-4.76; Q-statistic-P = 0.04, I 2 = 69%), and liver-related events (HR: 1.84, 95%CI: 0.92-3.67; Q-statistic-P = 0.03, I 2 = 72%), respectively. Grading of Recommendations Assessment, Development and Evaluation assessment indicated moderate certainty for HCC, very low certainty for decompensation of cirrhosis and liver-related clinical events.

LLV in compensated cirrhotic patients is associated with increased risk of HCC, higher tendency for hepatic decompensation and liver-related events. Closer screening of HCC should be conducted in this population.

Cross-sectional analyses using liver tissue from chronic hepatitis B patients make it difficult to exclude the influence of host immune responses. In this study, we performed next-generation sequencing using the livers of hepatitis B virus (HBV)-infected uPA/SCID mice with humanized livers before and after antiviral therapy (AVT) with entecavir and pegylated interferon, and then performed a comparative transcriptome analysis of gene expression alteration. After HBV infection, the expression of genes involved in multiple pathways was significantly altered in the HBV-infected livers. After AVT, the levels of 37 out of 89 genes downregulated by HBV infection were restored, and 54 of 157 genes upregulated by HBV infection were suppressed. Interestingly, genes associated with hypoxia and KRAS signaling were included among the 54 genes upregulated by HBV infection and downregulated by AVT. Several genes associated with cell growth or carcinogenesis via hypoxia and KRAS signaling were significantly downregulated by AVT, with a potential application for the suppression of hepato-carcinogenesis.

Hepatitis B surface antigen (HBsAg) seroclearance is considered to be one of the best surrogate endpoints of functional cure for hepatitis B virus (HBV) infection. However, evidence regarding the relationship between achieving HBsAg seroclearance or a low baseline HBsAg level, and long-term clinical outcomes in Japanese patients with chronic HBV infection remains to be confirmed in a real-world setting.

A retrospective observational cohort study was performed with an electronic medical record database, including data from 230 hospitals across Japan. Chronic HBV infection was defined as two consecutive, positive HBsAg laboratory measurements for HBV infection. The date of the second positive was used as a baseline to identify subsequent HBsAg seroclearance and liver disease progression.

In the database, 2523 patients with chronic HBV infection were identified as the chronic hepatitis B (CHB) cohort. Among the CHB cohort with an average observational period of 5.19 ± 3.87 years, 202 patients (8%) achieved HBsAg seroclearance after baseline. They had a lower risk of developing hepatocellular carcinoma (HCC) (adjusted hazard ratio [aHR] 0.206, p < 0.01) and cirrhosis (aHR 0.361, p < 0.01). When the CHB cohort was stratified into two groups based on baseline HBsAg levels (<100 IU/mL and ≥100 IU/mL), patients with a lower baseline level of HBsAg (<100 IU/mL) had a lower risk of developing liver disease (HCC aHR 0.600, p < 0.01; cirrhosis aHR 0.618, p < 0.05).

These results confirm the clinical significance of HBsAg seroclearance and low HBsAg level at baseline with respect to long-term outcomes of patients with CHB in the Japanese population.

Data on the economic burden of chronic hepatitis B infection in Japan are lacking. This study investigated healthcare resource utilization and costs of chronic hepatitis B infection and liver complications in Japan.

This non-interventional study used the Medical Data Vision database. For the first analysis, a population with prevalent chronic hepatitis B infection and absence of liver complications was identified and further stratified by nucleos(t)ide analog treatment history. In the second analysis, patients with prevalent chronic hepatitis B infection and incident liver complications were identified. Patients were followed for 1 year in the first analysis and 2 years in the second analysis. Numbers of all-cause outpatient, inpatient, emergency hospitalizations, medication use, and associated costs per person-year were described across patients without/with nucleos(t)ide analog treatment and in those without/with liver complications.

For patients with chronic hepatitis B infection, 75,967 had no liver complications while 17,678 patients had liver complications. All-cause outpatient visits were the largest contributor to healthcare resource utilization and costs, for patients without and with liver complications, and were numerically higher for patients on nucleos(t)ide analog than not. Patients with liver complications had numerically higher all-cause healthcare resource utilization and total costs than patients without complications.

Japan has a high economic burden of chronic hepatitis B infection, particularly in patients with liver complications. Optimizing treatment to prevent complications may reduce this burden.

Data on the economic burden of chronic hepatitis B infection in Japan are lacking. This study investigated healthcare resource utilization and costs of chronic hepatitis B infection and liver complications in Japan.

This non-interventional study used the Medical Data Vision database. For the first analysis, a population with prevalent chronic hepatitis B infection and absence of liver complications was identified and further stratified by nucleos(t)ide analog treatment history. In the second analysis, patients with prevalent chronic hepatitis B infection and incident liver complications were identified. Patients were followed for 1 year in the first analysis and 2 years in the second analysis. Numbers of all-cause outpatient, inpatient, emergency hospitalizations, medication use, and associated costs per person-year were described across patients without/with nucleos(t)ide analog treatment and in those without/with liver complications.

For patients with chronic hepatitis B infection, 75,967 had no liver complications while 17,678 patients had liver complications. All-cause outpatient visits were the largest contributor to healthcare resource utilization and costs, for patients without and with liver complications, and were numerically higher for patients on nucleos(t)ide analog than not. Patients with liver complications had numerically higher all-cause healthcare resource utilization and total costs than patients without complications.

Japan has a high economic burden of chronic hepatitis B infection, particularly in patients with liver complications. Optimizing treatment to prevent complications may reduce this burden.

Several studies have reported that chronic hepatitis B (CHB) patients with low hepatitis B surface antigen (HBsAg) levels (100 or 10 IU/mL) at the cessation of nucleot(s)ide analogs (NA) have a favorable prognosis. In this retrospective study, we evaluated the duration of NA treatment and the factors associated with achieving these low HBsAg levels. We also examined the relationship between HBsAg and hepatitis B core-related antigen (HBcrAg) levels at the time of NA discontinuation and subsequent clinical outcomes.

This study included 153 CHB patients who initiated NA therapy at our hospital, received treatment, and were followed up for over 1 year.

The cumulative incidence rates of achieving low HBsAg levels at 5 and 10 years post-NA administration were as follows: 19.0% and 29.2% for HBsAg <100 IU/mL, 13.8% and 17.6% for HBsAg <10 IU/mL, and 9.5% and 13.5% for HBsAg <0.05 IU/mL, respectively. Hepatitis B virus genotypes other than genotype C (hazard ratio [HR] 3.47; p < 0.001) and an HBsAg level <1000 IU/mL at the start of NA therapy (HR 2.49; p = 0.008) were significantly associated with achieving HBsAg levels <100 IU/mL. Among 27 patients who discontinued NA therapy, 5 patients with HBsAg levels <100 IU/mL and HBcrAg levels <3 log U/mL at the time of discontinuation did not experience virological relapse.

The cumulative rates of achieving HBsAg levels <100 IU/mL were relatively high. Discontinuation of NA may be considered based on HBsAg and HBcrAg levels during the course of NA therapy.

Patients with chronic hepatitis B virus (HBV) infection experiencing viral breakthrough (BTH) or partial response (PR) during lamivudine (LAM) or entecavir hydrate (ETV) administration often took ETV plus tenofovir alafenamide fumarate (TAF) due to the emergence of a drug-resistance mutation. However, in patients lacking drug-resistance mutation against TAF, sufficient antiviral effects may be achievable with TAF monotherapy. We assessed the drug-resistance profile through nucleotide sequences of HBV pregenome RNA, and subsequently changed to TAF monotherapy from ETV plus TAF.

This prospective study included 25 patients with serum HBV-DNA below 20 IU/mL under ETV plus TAF administration. Pregenome RNA nucleotide sequences of HBV in the sera were analyzed using direct sequencing and deep sequencing. ETV was discontinued in patients without rtA194T and rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutations in direct sequencing.

LAM-PR, LAM-BTH, ETV-PR, and ETV-BTH were observed in 1, 16, 7, and 1 patient(s), respectively. Pregenome RNA nucleotide sequences were analyzable in 20 patients. Among the 12 patients classified as LAM-BTH, six patients showed rtL180M + rtM204V/I in direct sequencing, and one patient showed minor clones containing rtL180M + rtM204V + A194T in deep sequencing at a frequency of 0.3%. In the six patients classified as ETV-PR, one patient harbored rtM204I. No clones showing rtS106C + rtH126Y + rtD134E + rtL269I quadruple mutation were detected in deep sequencing. Subsequently, ETV was discontinued, and serum HBV-DNA remained undetectable up to 48 weeks in all patients.

Patients receiving ETV plus TAF due to partial response or BTH during initial LAM or ETV administration were able to safely transition to TAF monotherapy based on nucleotide sequences of HBV pregenome RNA in the sera.

Accurate biomarkers to predict outcomes following discontinuation of nucleos(t)ide analogue (NA) therapy are needed. We evaluated serum hepatitis B core-related antigen (HBcrAg) level as a biomarker for predicting outcomes after NA discontinuation.

Patients with HBeAg-negative chronic hepatitis B (CHB) without cirrhosis were enrolled in a prospective trial evaluating clinical outcomes until 96 weeks after NA discontinuation. End of treatment (EOT) and off-treatment levels of serum HBcrAg, HBsAg, HBV RNA and HBV DNA were used to predict key clinical outcomes including hepatitis flare (ALT ≥5 × ULN and HBV DNA > 2000 IU/mL). The SCALE-B score was calculated for the purposes of model validation.

HBcrAg was tested amongst 65 participants. The median age was 54 years, 54% were male and 83% were Asian. HBcrAg was detectable in 86% patients. HBcrAg level ≥4 log U/mL at EOT was predictive of hepatitis flare [8/10 (80%) vs. 17/55 (31%), p = .001]. The presence of either HBcrAg ≥4 log U/mL or detectable HBV RNA at EOT predicted for both biochemical relapse and hepatitis flare. The SCALE-B model at EOT predicted for virological relapse, biochemical relapse, hepatitis flare and HBsAg loss in this cohort. An increase in the serum HBcrAg level off-treatment was also associated with hepatitis flare. No participant with EOT HBcrAg level ≥4 log U/mL achieved HBsAg loss.

High levels of serum HBcrAg predict for hepatitis flare after stopping NA therapy and low likelihood of HBsAg loss at week 96. People with high levels of serum HBcrAg are not suitable candidates for NA discontinuation.

Background and Objectives: The measurement of hepatitis B surface antigen (HBsAg) is essential for managing chronic hepatitis B virus infection (CHB). HBsAg consists of three different surface envelope proteins: large, middle, and small HB surface proteins. However, in clinical practice, it is not common to evaluate each of these HB surface proteins separately. Materials and Methods: In this study, we investigated preS1 expression using seven monoclonal antibodies (mAbs) in 68 CHB patients, as well as examining their antigenicity. Results: Although the seven mAbs had been derived from genotype (Gt) C, they could recognize preS1 with Gts A to D. The epitopes were concentrated within the aa33-47 region of preS1, and their antigenicity was significantly reduced by an aa45F substitution. We found that preS1 expression remained consistent regardless of HBsAg levels and different Gts in CHB patients, in contrast to what was observed in SHBs. Conclusions: These results suggest that the antigenic epitope is preserved among different Gts and that the expression pattern of preS1 is altered during CHB, highlighting its vital role in the HBV infection cycle. Our present results suggest preS1 is a promising therapeutic target in CHB.

The study aims to determine the prognostic impact of obesity, sarcopenic obesity, and dynapenic obesity in patients with chronic liver disease.

This retrospective observational study enrolled patients with chronic hepatitis (n = 746) and liver cirrhosis (n = 434) without hepatocellular carcinoma at entry. The patients were evaluated for sarcopenia and obesity between April 2016 and April 2022. Obesity was defined as a body mass index of ≥ 25 kg/m2. Sarcopenic obesity was defined as low skeletal muscle mass (pre-sarcopenia) with obesity and dynapenic obesity was defined as low muscle strength (dynapenia) with obesity. The effects of obesity on survival were evaluated retrospectively.

The mean observation period was 2.5 years. Obesity, sarcopenic obesity, and dynapenic obesity were found in 271 (45.5%), 17 (2.9%), and 21 (3.5%) men, and 261 (44.7%), 59 (10.1%), and 53 (9.1%) women, respectively. A multivariate Cox proportional hazards model revealed that Child-Pugh class, dynapenia (hazard ratio [HR] 3.89), elderly (≥ 65 years old) (HR 2.11), and obesity (HR 0.58) were independently associated with overall survival (OS). However, neither sarcopenic nor dynapenic obesity were associated with OS. In patients with cirrhosis, the OS of the obese group was significantly higher than that of the non-obese group. The effect of obesity on OS was significant in elderly patients, but not in younger patients.

Sarcopenic and dynapenic obesity seem unrelated to the prognosis of patients with chronic liver disease. Obesity has a positive effect on the prognosis of elderly patients with cirrhosis.

Although patients with HBV have a risk of reactivation after immunosuppressive therapy (IST), the status of their risk management is unclear in Japan. This study aims to describe the proportion of patients who received preventive management of HBV reactivation during ISTs in patients with chronic HBV infection of HBsAg or resolved HBV infection.

A retrospective cohort study was conducted using the JMDC Japanese claims database from April 2011 to June 2021. Patients with HBV infections of HbsAg who received ISTs or patients who had resolved HBV infections who received ISTs were identified from the database and evaluated for appropriate management to prevent HBV reactivation.

In total, 6242 eligible patients were identified. The proportions of patients with appropriate HBV reactivation management, stratified by the HBV reactivation risk level of IST, was 43.1% (276/641) for high-risk, 40.2% (223/555) for intermediate-risk and 14.9% (741/4965) for low-risk patients. When the evaluation period for the outcome calculation was shortened from 360 to 180 days, the proportion for high risk increased to 52.7%. The odds ratios of large hospitals for receiving appropriate management were 2.16 (95% CI 1.12-4.44) in the high-risk, 4.63 (95% CI 2.34-10.25) in the intermediate-risk and 3.60 (95% CI 3.07-4.24) in the low-risk patients.

HBV reactivation management was tailored according to the reactivation risk associated with IST. However, adherence to HBV reactivation management guidelines was sub-optimal, even among high-risk patients. This is especially the case for ensuring smaller-sized medical institutions, highlighting the need for further educational activities.

A recombinant monoclonal antibody against the hepatitis B surface antigen glycan isomer (HBsAgGi) was newly developed using the O-glycosylated PreS2 peptide in M-HBsAg of hepatitis B virus (HBV) genotype C. However, the association between HBsAgGi and the development of hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy remains unknown.

A total of 112 HBV genotype C-infected patients who were treated with NA were included in this study. We assessed the association between HBV markers, including HBsAgGi and other conventional markers, and the development of HCC during NA therapy.

Ten patients developed HCC during the follow-up period. Of the HBV markers, HBsAg (≤3.53 log IU/mL; p = 0.047), HBsAgGi/HBsAg ratio (≥1.10; p = 0.035), and HBV DNA (≤6.3 log copies/mL; p = 0.012) at baseline and HBsAg (≤3.19 log IU/mL; p = 0.033) and HBsAgGi/HBsAg ratio (≥1.09; p = 0.003) at 48 weeks after NA therapy were significantly associated with the development of HCC according to the log rank test. In contrast, no significant association was observed between HBsAgGi and the development of HCC. Multivariate analysis revealed that a platelet count at baseline ≤88 × 103/mm3 (p = 0.026; hazard ratio [HR], 10.577) and an HBsAgGi/HBsAg ratio at 48 weeks after NA therapy ≥1.09 (p = 0.040; HR, 10.099) were independently and significantly associated with the development of HCC.

Our findings suggest that a combination of on-treatment HBsAgGi and HBsAg predicts the development of HCC during NA therapy.

Hepatitis B virus reactivation (HBVr) can occur in solid organ transplant (SOT) recipients with previously inactive hepatitis B virus (HBV) infection. Previous studies have reported that HBVr is generally less than 10% in nonliver SOT recipients with past HBV infection.

We conducted a retrospective study from January 2018 to August 2023 at Mayo Clinic sites in Arizona, Florida, and Minnesota. We examined the antiviral prophylaxis strategy used and the characteristics of HBVr in hepatitis B core antibody-positive (HBcAb +) nonliver SOT adult recipients. Past HBV infection was defined as HBcAb + / hepatitis B surface antigen (HBsAg) -. Chronic HBV infection was defined as HBcAb + / HBsAg +.

A total of 180 nonliver SOT recipients were identified during the study period. Indefinite antiviral prophylaxis was utilized in 77 recipients, and none developed HBVr after transplantation. In 103 recipients without antiviral prophylaxis, the incidence of HBVr was 12% (12/97) and 33% (2/6) in those with past HBV infection and chronic HBV infection. The incidence of HBVr in patients with past HBV infection is 16% (8/50), 15% (3/20), and 5% (1/22) in kidney, heart, and lungs, respectively. HBVr was more frequent in those who received alemtuzumab. Among 14 recipients with HBVr, none had HBV-associated liver failure or death.

Our study observed a higher rate of HBVr (12%) in nonliver SOT recipients with past HBV infection compared to the previous studies. Further studies are needed to identify predictors of HBVr in nonliver SOT recipients and optimize antiviral prophylaxis guidance.

A 71-year-old woman was treated with osimertinib for stage IV adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Treatment led to improvements in the primary tumor, multiple lung metastases, and multiple bone metastases. However, nine months later, she presented with marked liver dysfunction and jaundice. Chest and abdominal computed tomography did not show abnormal findings in the liver parenchyma or biliary system. However, blood tests were positive for hepatitis B surface antigen and hepatitis B virus DNA, suggesting hepatitis B virus reactivation. The patient died of liver failure despite treatment with steroids and antiviral drugs.

Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed.

Magnetic resonance elastography (MRE) is used for the evaluation of liver fibrosis; however, it remains unclear whether MRE-based liver stiffness is associated with hepatocellular carcinoma (HCC) development, particularly in patients with chronic hepatitis B.

A total of 504 patients with chronic hepatitis B receiving MRE were enrolled. The primary endpoint was the association between MRE-based liver stiffness and HCC.

In a cross-sectional analysis at the time of MRE measurement, the median (interquartile range) liver stiffness values in patients with presence or history of HCC and those without HCC were 3.68 (2.89-4.96) and 2.60 (2.22-3.45) kPa, respectively, and liver stiffness was significantly higher in patients with presence or history of HCC than in those without HCC (P < 0.001). In a longitudinal analysis of patients without HCC, the 1-, 3-, and 5-year cumulative incidence of HCC in patients with liver stiffness ≥3.6 kPa and those with liver stiffness <3.6 kPa were 3.8%, 7.0%, and 22.9%, and 0%, 0.9%, and 1.5%, respectively (P < 0.001). In the multivariable analysis, MRE-based liver stiffness (per 1 kPa) or liver stiffness ≥3.6 kPa was an independent factor for HCC development with an adjusted hazard ratio (aHR) of 1.61 (95% confidence interval [CI], 1.3-2.0) or aHR of 8.22 (95% CI, 2.1-31).

MRE-based liver stiffness is associated with HCC risk in patients with chronic hepatitis B and may be used for the early prediction of HCC development and determination of indications for treatment.

Tenofovir alafenamide (TAF), a prodrug of tenofovir, delivers high levels of active drug to hepatocytes and is given in a lower dose than tenofovir disoproxil fumarate (TDF). TAF reduces viral replication in patients with chronic hepatitis B (CHB) similar to TDF and has shown a lower risk of the renal and bone toxicities associated with TDF use. This post-marketing surveillance study examined the safety and effectiveness of TAF in treatment-naïve and -experienced CHB patients who received TAF for 144 weeks at real-world clinical sites in Japan. Safety assessments included the incidence of adverse drug reactions (ADRs), renal and bone events, and changes in selected laboratory parameters. Effectiveness was based on the proportion of patients with HBV DNA levels below the lower limit of quantitation or <29 IU/mL. This analysis included 580 patients; 18.4% of whom were treatment-naïve. The cumulative incidence of ADRs was 0.21 per 100 person-months, and the incidence of serious ADRs was 0.01 (95% CI, 0.00-0.04) per 100 person-months. There were no ADRs of declines in estimated glomerular filtration rates, renal failure or proximal tubulopathy. The most common ADR was hypophosphataemia in seven (1.2%) patients. Two (0.4%) patients each had decreased blood phosphorus, bone mineral density decreased, dizziness and alopecia. Overall, the proportion of virologically suppressed patients increased from 68.8% at baseline to 97.5% at Week 144. These results confirm the real-world safety and effectiveness of TAF in Japanese patients with CHB and are consistent with the findings of other evaluations of the safety and efficacy of TAF in CHB.

Hepatitis B virus reactivation (HBVr) during and after immunosuppressive/immunomodulatory (IS/IM) therapy is associated with significant morbidity and mortality, including hepatic decompensation and acute liver failure. The risk of HBVr with IS/IM has been heterogeneous and often unpredictable. As a result, patients with active or previous HBV infection are often excluded from clinical drug trials of such agents. Thorough screening for HBV infection, antiviral prophylaxis, and careful monitoring for HBVr have proven to be effective in reducing the rate of HBVr and improving its outcome in the context of IS/IM. Therefore, safe enrollment and management of certain HBV-marker-positive patients in clinical trials is possible. There is a great, unmet need for consistent, evidence-based recommendations for best practices pertaining to enrollment, monitoring, and management of HBVr in clinical trial participants receiving IS/IM. The aim of these consensus guidelines is to provide a step-by-step blueprint to safely enroll, monitor and manage the patient with inactive chronic or resolved HBV in IS/IM clinical trials from the time of screening through to the end of post-treatment follow up.

Hepatitis B virus (HBV) infection is a serious global health problem, and chronic HBV infection significantly increases the risk of liver fibrosis, cirrhosis, and even hepatocellular carcinoma in patients. Current first-line therapeutics such as nucleos(t)ide analogues and interferons are unable to completely clear cccDNA, so the vast majority of patients need to take long-term or even lifelong medication. However, long-term virological and biochemical responses can be achieved in some patients after drug withdrawal. Successfully screening these patients with drug withdrawal advantages is difficult. Hepatitis-B-core-related antigen (HBcrAg) is a new HBV serological marker that which can reflect the level and transcription activity of cccDNA in hepatocytes. Therefore, HBcrAg has potential value in guiding patients in drug withdrawal. This review summarizes previous reports on HBcrAg and evaluates the application value of HBcrAg in safe drug discontinuation.

Monitoring of hepatitis B virus (HBV)-DNA and HBV-DNA-guided preemptive therapy using nucleos(t)ide analogs (NAs) are recommended to prevent the development of hepatitis due to HBV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in recipients with resolved HBV infection. However, little is known about the appropriate duration of NA treatment and the effect of NA cessation on the recurrence of HBV reactivation. This study aimed to clarify the consequences of NA cessation in allo-HSCT recipients with resolved HBV infection who experienced HBV reactivation following transplantation. We retrospectively reviewed the clinical records of recipients with resolved HBV infection (hepatitis B surface antigen [HBsAg]-negative, anti-HBc-positive) before allo-HSCT who had been diagnosed with HBV reactivation (HBsAg-positive and/or HBV-DNA detectable) after allo-HSCT between January 2010 and December 2020. A total of 72 patients from 16 institutions were registered (median age, 60 years; age range, 27 to 73 years; 42 males and 30 females). The day of initial HBV reactivation ranged from day 10 to day 3034 after allo-HSCT (median, 513 days). Anti-HBs were lost in >80% of the patients at the time of HBV reactivation. All 72 patients received preemptive NAs, and no fatal HBV reactivation-related hepatitis was observed. HBV-DNA without hepatitis was continuously detected in 5 patients during the follow-up period. Administration of NAs was discontinued in 24 of 72 patients (33%) by physician decision. Second HBV reactivation occurred in 11 of the 24 patients (46%) in whom administration of NAs was discontinued. The duration of NA treatment did not differ significantly between patients with or without second HBV reactivation. The frequency of further HBV reactivation tended to be lower in patients with an anti-HBs titer of >10 mIU/mL at the time of NA cessation. Multiple reactivations of HBV after NA cessation was common in patients with HBV reactivation who underwent allo-HSCT despite the long duration of NAs. Careful monitoring of HBV-DNA is important even after the discontinuation of NAs in the case with HBV reactivation after allo-HSCT, because multiple reactivations could occur. Active immunization by HB vaccine might be effective for suppressing further HBV reactivation after cessation of NAs.