The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.

To identify factors influencing HBsAg seroclearance rates after stopping nucleos(t)ide analogue (NA) therapy in patients with chronic hepatitis B (CHB).

We conducted a comprehensive literature search in databases from inception to July 2024. Subgroup analyses and meta-regression were performed to determine factors associated with HBsAg seroclearance, including ethnicity, HBV genotype, NA therapy duration, end-of-treatment (EOT) qHBsAg levels, HBeAg status, cirrhosis status, and follow-up duration.

The meta-analysis included 62 studies (n = 9867) with a pooled HBsAg seroclearance rate of 10% (95%CI: 8%-12%, I2 = 92%) after NA cessation. HBeAg-negative patients showed significantly higher rates than HBeAg-positive patients (11% vs. 5%, p = 0.030). Subgroup analysis revealed higher seroclearance with follow-up of >5 years (18%, p = 0.004), showing significantly higher rates were observed in studies with longer follow-up periods. Caucasians showed a higher rate (12%) than Asians (9%, p = 0.067). Studies adhering to AASLD, EASL, or APASL stopping rules showed no significant differences in rates. Patients with EOT qHBsAg ≤2.0 log IU/mL had higher rates (23%) than those with >2.0 log IU/mL (11%). Re-treated patients had lower seroclearance (6%) compared to those not re-treated (17%, p = 0.178). Meta-regression identified ethnicity, HBeAg status, and follow-up duration as significant contributors to heterogeneity. Egger's test showed no evidence of publication bias (p = 0.1928).

Our meta-analysis highlights the role of ethnicity, EOT qHBsAg levels, HBeAg-status, and follow-up duration in determining HBsAg seroclearance rates. These findings stress the need for personalized NA discontinuation strategies and further research on HBV genotypes and biomarkers to improve treatment outcomes and predict seroclearance more accurately.

Functional cure strategies based on interferon therapy for chronic hepatitis B (CHB) are gaining increasing attention among clinicians. However, studies investigating the duration of response after achieving HBsAg clearance with interferon treatment are limited. This study aims to explore the patterns of sustained response following HBsAg clearance in patients treated with pegylated interferon alpha-2b (PegIFNα-2b) through long-term follow-up, providing guidance for clinical practice.

We collected data from CHB patients who achieved HBsAg clearance and were treated with either PegIFNα-2b monotherapy or in combination with nucleos(t)ide analogs (NAs) at Tianjin Third Central Hospital from January 2018 to May 2024. Regular follow-up assessments were conducted to observe the dynamic changes in HBsAg, HBV DNA, and liver function during the follow-up period. We recorded the time to HBsAg reversion (defined as HBsAg ≥ 0.05 IU/mL), analyzed the patterns of HBsAg reversion, and investigated the optimal time points for evaluating sustained HBsAg clearance.

A total of 173 patients with CHB or compensated hepatitis B cirrhosis were included. The mean age was 41.5 ± 9.0 years, with 16.19% of patients having compensated cirrhosis. The median follow-up duration was 89.3 weeks (range: 18.6 to 289.1 weeks). HBsAg reversion occurred in 26 patients, yielding a reversion rate of 15.03% (26/173). Among these 26 patients, 50% (13/26) experienced reversion within 24 weeks, and 80.77% within 48 weeks; thereafter, the number of reversions gradually decreased. At 48 weeks post-treatment cessation, the HBsAg sustained response rate was 95.45%, stabilizing at 100% after 120 weeks. Among patients with regular follow-ups, virtually none experienced reversion beyond 72 weeks. At the time of HBsAg reversion, all 26 patients exhibited normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels, with a median HBsAg level of 0.70 IU/mL (range: 0.05 to 8.13 IU/mL), and only one patient showing low-level positive HBV DNA (117 IU/mL). No adverse events, including liver failure, decompensation, or hepatocellular carcinoma, occurred during the follow-up period.

Patients with chronic hepatitis B treated with PegIFNα-2b demonstrated favorable long-term persistence of HBsAg clearance. However, there remains a risk of HBsAg reversion after treatment cessation, predominantly within the first 48 weeks. HBsAg sustained response (HSR) at 48 weeks post-treatment is a critical follow-up time point for CHB patients post-HBsAg clearance, with HSR at 72 weeks potentially representing an ideal follow-up timeframe, while HSR at 120 weeks may serve as a marker for extended follow-up.

International guidelines suggest cessation of nucleos(t)ide analogues (NA) independent of HBsAg loss in HBeAg-negative patients after 2-3 years of viral suppression. Detectable HBV-RNA levels at the time of NA cessation were linked to a better prediction of relapse after NA withdrawal in small cohorts of HBeAg-negative patients. This study proves the impact of HBV-RNA levels in the prediction of relapse in a large cohort of HBeAg-negative patients, mainly infected with genotype B or C. Serum levels of HBV-RNA, HBsAg, anti-HBc and HBcrAg were determined before NA withdrawal in 154 HBeAg-negative patients, participating either in a therapeutic vaccination trial (NCT02249988) or in an observational register trial (NCT03643172). Importantly, vaccination showed no impact on relapse. Endpoints of the study were virological relapse (HBV-DNA > 2000 IU/mL) or biochemical relapse (attendant ALT levels ≥ 2 × ULN) 24 weeks after NA cessation. Virological relapse occurred in 54.5% of patients (N = 84/154), including eight patients (10%) developing an ALT flare. Baseline HBV-RNA level did not differ significantly between relapsers and off-treatment responders (p = 0.92). No significant difference occurred in proportions of detectable HBV-RNA levels between off-treatment responders (N = 27/70; 38.6%) and relapsers (N = 31/84; 36.9%) (p = 0.99). Combining predefined HBsAg cut-offs (100 IU/mL, p = 0.0013), anti-HBc cut-offs (325 IU/mL, p = 0.0117) or HBcrAg cut-offs (2 log U/mL, p = 0.66) with undetectable HBV-RNA (HBsAg, p = 0.0057; anti-HBc, p = 0.085; HBcrAg, p = 0.60) did not improve relapse prediction. The value of HBV-RNA levels at timepoint of NA cessation for the prediction of relapse is limited in HBeAg-negative patients. Trial Registration: ABX 203-002: NCT02249988; Terminator 2: NCT03643172.

Oral antiviral therapy to hepatitis B virus (HBV) with nucleos(t)ide analogues (NUCs) is effective in suppressing the viral load leading to improved clinical outcomes. However, functional cure of HBV, indicated by hepatitis B surface antigen (HBsAg) clearance from the serum, is rare. Although safety and adherence may represent minor issues in long-term treatment with the available NUCs, more efficacious treatments with finite treatment duration for patients with chronic hepatitis B (CHB) are currently undergoing active clinical investigation. Available data suggest that HBsAg loss can be achieved in 10% to 20% of patients after NUC discontinuation, at the cost of about 50% to 80% virological relapse and 40% to 55% retreatment with NUC. With this, NUC treatment in patients with cirrhosis should not be stopped to avoid detrimental risk of hepatic decompensation and death. Viral and immune biomarkers, which may be potentially useful in stratifying the patients at risk of relapse after stopping NUC therapy, are under investigation. In the era of personalized medicine aided by artificial intelligence tools, tight monitoring of viral kinetics and algorithmic modeling appear a promising strategy to assist in individualized decision and conclude the optimal timing of the NUC treatment discontinuation.

Given advances in antiretroviral therapy (ART), some people with HIV are transitioned to non-tenofovir-containing ART; the implications for people with HIV-hepatitis B virus (HBV) are unknown. We characterized HBV-related outcomes in people with HIV-HBV coinfection while not taking tenofovir-containing ART.

We analyzed participants from the French HIV-HBV Cohort Study in three treatment groups: (1) continuous tenofovir; (2) discontinued tenofovir; (3) never initiated tenofovir. We examined virological and clinical characteristics during follow-up. We assessed determinants of HBV DNA >2000 IU/mL and alanine aminotransferase (ALT) >2x upper limit of normal separately while participants were off tenofovir using univariable logistic regression with generalized estimating equations.

Among 192 participants, 161 (83.9 %) were on continuous tenofovir, 22 (11.5 %) discontinued tenofovir, and 9 (4.7 %) never initiated tenofovir during a median follow-up of 14.5 years (IQR = 10.5-14.8). The median proportion of within-participant visits with undetectable HBV DNA was 96.0 % (IQR = 75.0-100) in the continuous group, 100 % (IQR = 84.0-100) in the discontinued tenofovir group (while off tenofovir), and 100 % (IQR = 95.2-100) in the never initiated tenofovir group. Determinants of HBV DNA >2000 IU/mL while people were off tenofovir were detectable HIV RNA (p = 0.041), lower CD4+ T-cell count (p = 0.027), HBeAg positive serology (p = 0.004) and positive hepatitis D serology (p = 0.001). ALT elevation was associated with positive hepatitis C antibody serology (p = 0.012).

This proof-of-concept study shows that selected people with HIV-HBV coinfection may not lose virologic control of HBV when off tenofovir. HBV virologic activity while off tenofovir may be more closely associated with uncontrolled HIV infection and positive HBeAg serology.

Recommendations for stopping nucleoside analogue (NA) therapy in hepatitis B e antigen-negative chronic hepatitis B (CHB) are unclear. End-of-treatment quantitative hepatitis B serum antigen (EOTqHBsAg) thresholds <100 IU/mL or <1000 IU/mL have been proposed as stopping criteria, which we assessed by meta-analysis and meta-regression.

We searched PubMed, EMBASE, and conference abstracts for studies of hepatitis B e antigen-negative CHB NA discontinuation. Extracted studies were analyzed for risk of bias, pooled risk of hepatitis B serum antigen (HBsAg) loss, virological relapse (VR), and biochemical relapse (BR). Significant heterogeneity (I2) was addressed by subgroup analysis and random-effects meta-regression with known important covariates, including EOTqHBsAg thresholds, ethnicity, duration of therapy, and follow-up.

We found 24 articles (3732 subjects); 16 had low and 8 had moderate risk of bias. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <100 IU/mL were 41.8%, 33.4%, and 17.3%, respectively, vs 4.6%, 72.1%, and 34.6%, respectively, for EOTqHBsAg ≥100 IU/mL. The pooled risks of HBsAg loss, VR, and BR for stopping therapy at EOTqHBsAg <1000 IU/mL were 22.0%, 52.7%, and 15.9%, respectively, vs 3.4%, 63.8%, and 26.4%, respectively, for EOTqHBsAg ≥1000 IU/mL. Multivariable analysis for HBsAg loss showed that ethnicity, follow-up duration, and EOTqHBsAg <100 IU/mL and ≥100 IU/mL explained 85% of the variance in heterogeneity; Asians with EOTqHBsAg <100 IU/mL had 28.2%, while non-Asians with EOTqHBsAg <1000 IU/mL had 38.4% HBsAg loss. Multivariable analysis showed EOTqHBsAg <100 IU/mL and ≥100 IU/mL and other covariates only explained 43% and 63% of the variance in heterogeneity for VR and BR, respectively, suggesting that other factors are also important for relapse.

While EOTqHBsAg thresholds, ethnicity, and follow-up duration strongly predict HBsAg loss, this is not true for VR and BR, hence stopping NA therapy should be considered cautiously.

Pregenomic hepatitis B virus RNA (HBV pgRNA) is a potential biomarker in the management of HBV infected patients. However, prior to the use in routine clinical practice potential confounders of test results need to be identified. This study investigates the stability of HBV pgRNA under various storage conditions. HBV-RNA level of 26 HBV patients were determined using the Roche cobas® 6800/8800 investigational HBV-RNA assay. Plasma and serum were stored for 6,48,169 h at 4,25 and 42 °C, respectively. Additionally, 10 serum and plasma samples underwent 4 or 11 cycles of freezing (-80 °C) and thawing (25 °C). A significant decline in mean pgRNA concentration compared to baseline was observed after storage for 48 h at 25 °C as well as after 6 h of storage at 42 °C. Accordingly, sub-analyses of predefined pgRNA baseline concentrations (≤ 10 cp/mL, > 10-100 cp/ml, > 100 cp/mL) revealed significant changes in pgRNA level after storage at 25 and 42 °C. No effect of freezing and thawing on pgRNA level was observed. A qualitative detection of HBV pgRNA is feasible in samples with > 100 cp/mL up to 48 h under storage temperatures of 4-42 °C. For most stable quantitative HBV pgRNA values storage at 4 °C should be preferred.

We aimed to explore the risk factors associated with virological and clinical relapse, as well as their impact on overall mortality, in hepatitis B virus (HBV)-infected patients receiving nucleos(t)ide analogues (NUCs) therapy prior to chemotherapy initiation.

From 2010 to 2020, we conducted a prospective cohort study involving patients with HBV infection undergoing cytotoxic chemotherapy. We utilized the Kaplan-Meier method and Cox proportional hazard regression models to assess risk factors.

We observed that TDF or TAF (HR: 2.16, 95% CI 1.06-4.41; p = .034), anthracycline (HR: 1.73, 95% CI 1.10-2.73; p = .018), baseline HBV DNA (HR: 1.55, 95% CI 1.33-1.81; p < .001) and end-of-treatment HBsAg titre >100 IU/mL (HR: 7.81, 95% CI 1.94-31.51; p = .004) were associated with increased risk of virological relapse. Additionally, TDF or TAF (HR: 4.91, 95% CI 1.45-16.64; p = .011), baseline HBV DNA (HR: 1.48, 95% CI 1.10-1.99; p = .009) and end-of-treatment HBsAg titre >100 IU/mL (HR: 6.09, 95% CI .95-38.87; p = .056) were associated with increased risk of clinical relapse. Furthermore, we found that virological relapse (HR: 3.32, 95% CI 1.33-8.32; p = .010) and clinical relapse (HR: 3.59, 95% CI 1.47-8.80; p = .005) significantly correlated with all-cause mortality in HBV patients receiving cytotoxic chemotherapy with prophylactic NUCs therapy.

The risk of virological and clinical relapse was linked to baseline HBV DNA, end-of-treatment HBsAg levels and TDF or TAF for prophylaxis; additionally, experiencing relapse heightens the risk of all-cause mortality. Further research is warranted to explore potential strategies for preventing virological and clinical relapse in high-risk patients.

Complete viral suppression with nucleos(t)ide analogs (NAs) has led to a profound reduction in hepatocellular carcinoma and mortality among patients with chronic hepatitis B. Finite therapy yields higher rates of functional cure; however, initial hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) elevations are almost certain after treatment interruption. We aimed to analyze off-treatment outcomes beyond 12 months after NA cessation.

Patients with well-suppressed chronic hepatitis B who were hepatitis B e antigen-negative at NA cessation and remained off treatment without hepatitis B surface antigen (HBsAg) loss at 12 months were included (n = 945). HBV DNA and ALT fluctuations were allowed within the first 12 months. We used Kaplan-Meier methods to analyze outcomes beyond 12 months. Sustained remission was defined as HBV DNA <2,000 IU/mL and ALT <2× upper limit of normal (ULN) and an ALT flare as ALT ≥5× ULN.

Cumulative probability of sustained remission was 29.7%, virological relapse was 65.2% with a mean peak HBV DNA of 5.0 ± 1.5 log 10 IU/mL, an ALT flare was 15.6% with a median peak ALT × ULN of 8.3 (5.7-11.3), HBsAg loss was 9.9% and retreatment was 34.9% at 48 months after NA cessation. A single occurrence of virological relapse or an ALT flare within the first 12 months off-treatment were associated with significantly lower rates of sustained remission beyond 12 months.

Despite allowing for HBV DNA and ALT fluctuations within the first 12 months off-treatment, most patients without HBsAg loss did not maintain a sustained response thereafter. The best candidates for NA withdrawal are patients with low HBsAg levels at NA cessation, and those without profound or recurrent virological and biochemical relapses in the first off-treatment year.

Current recommendations for refractory status epilepticus (SE) unresponsive to benzodiazepines suggest a loading dose of levetiracetam (LEV) of 60 mg/kg to a maximum of 4500 mg. LEV therapeutic drug monitoring can help guide therapy and is garnering increasing attention. The objective of this study is to simulate the probability of target attainment (PTA) of fixed dose and weight-based loading doses of LEV with respect to established therapeutic target concentrations. Meta-regression of the current literature was performed to evaluate the relationship between intravenous LEV loading dose and seizure cessation in refractory SE patients. A previously published pharmacokinetic model was used to simulate the PTA capacity of competing single intravenous dosing schemes (fixed vs weight-based dosing) to achieve maximum (Cpeak) and 12-h (C12h) plasma concentrations that exceed 12 mg/L. The meta-regression indicated that dosage was not a statistically significant modulator of seizure control at dosages between 20 and 60 mg/kg. Stochastic simulations showed all dosing schemes achieved plasma Cpeak >12 mg/L, but C12h levels were <12 mg/L in subjects over 60 kg with a fixed dose ≤2000 mg or in subjects <60 kg with a weight-based dose <30 mg/kg. Dosages of 40 and 60 mg/kg provided ≥90% PTAs across all weights. Using a weight-based loading dose of 40 mg/kg, up to a suggested maximum of 4500 mg, improves the likelihood of achieving a sustained therapeutic drug concentration after the initial LEV dose, whereas fixed <3000 mg may not achieve the desired concentration before maintenance dosing.

The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.

Few studies have reported hepatitis B surface antigen (HBsAg) kinetics after nucleos(t)ide analog (NA) discontinuation in patients with noncirrhotic chronic hepatitis B (CHB). The study specifically investigated long-term HBsAg kinetics after NA discontinuation.

Between January 2014 to January 2024, this study prospectively enrolled 106 outpatients with noncirrhotic CHB who met the discontinuation criteria after NA consolidation treatment. Demographic, clinical, and laboratory data were collected and analyzed after NA discontinuation.

Ninety-six patients who finished 5 years of follow-up were included. HBsAg remained undetectable in 29 patients with end of treatment (EOT) HBsAg negativity. Among 67 patients with EOT HBsAg positivity, HBsAg seroclearance occurred in 12 (17.9%) patients with an estimated annual incidence of HBsAg seroclearance of 3.6%. Patients with EOT HBsAg levels of ≤1000 IU/mL had a higher HBsAg seroclearance rate than those with EOT HBsAg levels of >1000 IU/mL (33.3% vs. 5.4%). The proportion of patients with HBsAg ≤1000 IU/mL increased during follow-up. Logistic regression analysis indicated that the EOT HBsAg level was an independent factor for HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL. The optimal EOT HBsAg cutoff for both HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL was 359 IU/mL.

Patients with EOT HBsAg negativity experienced no relapse and maintained HBsAg seroclearance during 5 years of follow-up after NA discontinuation. A higher HBsAg seroclearance rate can be obtained in patients with EOT HBsAg levels of ≤1000 IU/mL during 5 years of follow-up after NA discontinuation. Close monitoring and proper NA retreatment are recommended to guarantee the safety of NA discontinuation.

Clinicaltrials.gov number NCT02883647.

The immune system plays a central role in controlling acute hepatitis B infection and in patients resolving chronic hepatitis B (CHB). Given that 221 million (75%) of CHB patients reside in low- and middle-income countries, the development of a vaccine with therapeutic properties represents a rational and cost-effective approach more than a romantic endeavor. This review systematically analyzes the key variables related to the safety, efficacy, and effectiveness of CHB treatments. HeberNasvac experience is revisited for addressing the challenges and potentialities of therapeutic vaccines, as well as the current roadblocks in research and development, registration, and large-scale implementation.

Aguilar JC, Akbar SMF, Al-Mahtab M, et al. HeberNasvac: Development and Application in the Context of Chronic Hepatitis B. Euroasian J Hepato-Gastroenterol 2024;14(2):221-237.

Chronic hepatitis B (CHB) remains a major threat to global public health, affecting 296 million people worldwide. Although there is no curative treatment for CHB today, the virus can be effectively controlled with current antiviral treatment strategies. Since HBsAg loss can rarely (1%) be achieved with current nucleos(t)ide analogues (NA) options, lifelong treatment is usually required in HBeAg-negative patients. In recent years, guidelines have stated that long-term NA treatments can be discontinued for HBeAg-negative patients without achieving HBsAg loss. There is no general consensus on how discontinuation of NA can be included in the treatment approach. This review aimed to evaluate the current literature regarding the discontinuation of NA treatment in HBeAg-negative patients. Patients with HBeAg-negative CHB who have a higher chance of response after discontinuation of NA therapy can be defined as non-cirrhotic patients who have low HBsAg, HBcrAg, and HBV RNA levels at the discontinuation of treatment and accept close follow-up. The management of relapses that develop after NA discontinuation in patients is also unclear. The agent used in NA treatment itself may also affect the pattern of relapse development. Relapse after NA treatment occurs significantly slower and less frequently with entecavir compared to other regimens, including tenofovir dipivoxil. Prospective studies are needed in order to maintain the chance of HBsAg clearance in case of exacerbation and to treat acute exacerbations that can be fatal in a timely manner. Algorithms to be developed for use after discontinuation of NA treatment will help the clinician manage the patient safely.

The uncertain treatment duration for nucleos(t)ide analogues (NA) used in the treatment of chronic hepatitis B (CHB) is an important problem for both patients and physicians. The aim of this study was to evaluate the determinants of virologic relapse (VR) and the optimum time of treatment discontinuation in the follow-up of CHB patients who voluntarily discontinued treatment after virological suppression was achieved under NA use.

Data from 138 patients from 11 centers were included in this registry-based study. Factors associated with VR were investigated using multivariate Cox regression analysis.

Ninety-nine (71.7%) of the patients were HBeAg (Hepatitis B e antigen) negative. During the 24-month follow-up period after treatment discontinuation, VR occurred in 58.7% (n = 81) of all patients and 57.6% (n = 57) of HBeAg-negative patients. The duration of NA treatment was significantly shorter (cutoff 60 months) in HBeAg-negative patients who later developed VR. In addition, the duration of virologic remission achieved under NA treatment was significantly shorter (cutoff 52 months) in those who later developed VR. In the Cox multivariate regression model of HBeAg-negative patients, having less than 60 months of NA treatment (HR = 2.568; CI:1.280-5.148; P  = 0.008) and the levels of alanine aminotransferase being equal to or higher than twice the upper level of normal at the beginning of treatment (HR = 3.753; CI:1.551-9.081; P  = 0.003) were found to be statistically significant and independently associated with VR.

The findings of this study may provide clinical guidance in terms of determining the most appropriate discontinuation time for NA.

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.

The clinical routine test of HBV-specific T cell reactivity is still limited due to the high polymorphisms of human leukocyte antigens (HLA) in patient cohort and the lack of universal detection kit, thus the clinical implication remains disputed.

A broad-spectrum peptide library, which consists of 103 functionally validated CD8+ T-cell epitopes spanning overall HBsAg, HBeAg, HBx and HBpol proteins and fits to the HLA polymorphisms of Chinese and Northeast Asian populations, was grouped into eight peptide pools and was used to establish an ELISpot assay for enumerating the reactive HBV-specific T cells in PBMCs. Totally 294 HBV-infected patients including 203 ones with chronic hepatitis B (CHB), 13 ones in acute resolved stage (R), 52 ones with liver cirrhosis (LC) and 26 ones with hepatocellular carcinoma (HCC) were detected, and 33 CHB patients were longitudinally monitored for 3 times with an interval of 3-5 months.

The numbers of reactive HBV-specific T cells were significantly correlated with ALT level, HBsAg level, and disease stage (R, CHB, LC and HCC), and R patients displayed the strongest HBV-specific T cell reactivity while CHB patients showed the weakest one. For 203 CHB patients, the numbers of reactive HBV-specific T cells presented a significantly declined trend when the serum viral DNA load, HBsAg, HBeAg or ALT level gradually increased, but only a very low negative correlation coefficient was defined (r = - 0.21, - 0.21, - 0.27, - 0.079, respectively). Different Nucleotide Analogs (NUCs) did not bring difference on HBV-specific T cell reactivity in the same duration of treatment. NUCs/pegIFN-α combination led to much more reactive HBV-specific T cells than NUCs monotherapy. The dynamic numbers of reactive HBV-specific T cells were obviously increasing in most CHB patients undergoing routine treatment, and the longitudinal trend possess a high predictive power for the hepatitis progression 6 or 12 months later.

The presented method could be developed into an efficient reference method for the clinical evaluation of cellular immunity. The CHB patients presenting low reactivity of HBV-specific T cells have a worse prognosis for hepatitis progression and should be treated using pegIFN-α to improve host T-cell immunity.

Current guidelines suggest that nucleos(t)ide analogues (NA) can be discontinued before HBsAg loss in a selected group of chronic hepatitis B (CHB) patients. We aimed to study the safety and off-treatment response after NA cessation.

This is a prospective, multicentre, cohort study in which eligible patients discontinued NA therapy. Adult patients, with a CHB mono-infection, HBeAg-negative, without a (history of) liver cirrhosis, who had achieved long-term viral suppression were eligible. Follow-up visits were planned at week 2-4-8-12-24-36-48-72-96. Re-treatment criteria included severe hepatitis (ALT >10x ULN), signs of imminent liver failure (bilirubin >1.5x ULN or INR >1.5), or at the physician's own discretion.

In total, 33 patients were enrolled. Patients were predominantly Caucasian (45.5%) and had genotype A/B/C/D/unknown in 3/4/6/10/10 (9.1/12.1/18.2/30.3/30.3%). At week 48, 15 patients (45.5%) achieved a sustained response (HBV DNA <2,000 IU/mL). At week 96, 13 patients (39.4%) achieved a sustained response, 4 (12.1%) achieved HBsAg loss, and 12 (36.4%) were re-treated. Severe hepatitis was the main reason for re-treatment (n=7, 21.2%). One patient with severe hepatitis developed jaundice, without signs of hepatic decompensation. Re-treatment was successful in all patients.

NA therapy can be ceased in a highly selected group of CHB patients if close follow-up can be guaranteed. Treatment cessation may increase the chance of HBsAg loss in selected patients, which is counterbalanced by a significant risk of severe hepatitis.

A rebalance between energy supply and demand in HBV-specific-CD8+ activated progenitor (AP) cells could restore the functionality of proliferative progeny (PP) in e-antigen(Ag)-negative chronic hepatitis B (CHBe(-)). We observed that quiescent progenitor (QP [TCF1+/FSClow]) HBVcore-specific-CD8+ cells displayed a memory-like phenotype. Following Ag-encounter, the generated AP [TCF1+/FSChigh] subset maintained the PD1+/CD127+ phenotype and gave rise to proliferative progeny (PP [ TCF1-/FSChigh]). In AP cells, IL-15 compared to IL2 decreased the initial mTORC1 boost, but maintained its activation longer linked to a catabolic profile that correlated with enhanced PP effector abilities. In nucleos(t)ide analogue (NUC)-treated CHBe(-), AP subset showed an anabolic phenotype associated with a dysfunctional PP pool. In CHBe(-) cases with low probability of HBVcore-specific-CD8+ cell on-NUC-treatment restoration, according to a clinical predictive model, IL-15/anti-PD-L1 treatment re-established their reactivity. Therefore, IL-15 could improve AP pool energy balance by decreasing intensity but extending T cell activation and by inducing a more catabolic metabolism.

Hepatitis B virus (HBV) infection has been declared an ongoing health threat, especially infections among children. We compared and updated the disease burden of HBV infection and the effectiveness of vaccination among children younger than 5 years to offer indications for hepatitis B prevention across the world. The country-level data on the prevalence of hepatitis B surface antigen (HBsAg), the coverages of hepatitis B vaccine birth-dose (HepB-BD), three-dose series (HepB3), income level, population density/size, and human development index were collected from open access databases including WHO, UNICEF, and World Bank. Comparison of the prevalence of HBsAg under 5 years old between 2015 and 2019 based on vaccination coverages was conducted by the gamma generalized linear mixed model. Globally, more than 6.3 million HBV infections were estimated in children under 5 years in 2019, compared to 10.1 million in 2015 within the 179 countries involved. The pooled average prevalence of HBsAg among children younger than 5 years decreased from 1.4% (95% confidence interval [CI]: 1.1-1.8) to 0.9% (95% CI: 0.7-1.2). The rate difference or rate ratio was -0.5% (95% CI: -0.6% to -0.3%) or 0.51(95% CI: 0.44-0.58), respectively. Countries from the African region or with lower income/population density/human development indexes bore the most significant disease burden of hepatitis B. Higher coverages of hepatitis B vaccine birth-dose or primary series correlated with significant HBsAg prevalence decreases and much-decreased ratio, independently. Hepatitis B prevention among children under 5 years has significantly been achieved while remaining the most life-threatening disease burden, unequally distributed worldwide. The hepatitis B vaccination should be prioritized for all newborns, especially in those resource-constrained countries or regions.

A complete investigation of the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss is limited. We retrospectively recruited 242 HBeAg-positive patients with HBeAg loss after a median duration of 37.2 months with tenofovir (TDF, n = 77) or entecavir (ETV, n = 165) treatment. There were 77 (31.8%) patients with sustained virological remission (SVR), 85 (35.1%) with HBeAg-reversion virological relapse, 80 (33.1%) with HBeAg-negative virological relapse after treatment cessation, and 23 (9.5%) with HBsAg loss. Clinical data at baseline, on-treatment and during off-treatment follow-up were analyzed. The 3-year cumulative incidences of overall, HBeAg-reversion and HBeAg-negative virological relapse were 70.2%, 54%, and 53.5%, respectively. The common factors associated with HBeAg-reversion and HBeAg-negative virological relapse were tenofovir treatment (hazard ratio [HR] = 5.411, p < 0.001; HR = 2.066, p = 0.006, respectively) and HBsAg at end of treatment (EOT) (HR = 1.461, p = 0.001; HR = 1.303, p = 0.019, respectively). The 5-year cumulative incidence of HBsAg loss in SVR patients was 13.7% and EOT HBsAg was the only associated factor (HR = 0.524, p = 0.024). Compared to that of ETV-treated patients, TDF-treated patients had a significantly higher 3-year cumulative incidence of virological relapse (87.3% vs. 62.8%, p < 0.001), earlier HBeAg-reversion virological relapse (2.9 vs. 7.8 months, p < 0.001), a higher rate of HBeAg-reversion virological relapse (53.2% vs. 26.7%) and a lower SVR rate (15.6% vs. 39.4%) (p < 0.001). In summary, the clinical outcomes after treatment cessation in HBeAg-positive patients with HBeAg loss were composed of HBeAg-reversion virological relapse, HBeAg-negative virological relapse and SVR. TDF was significantly associated with off-treatment virological relapse. EOT HBsAg plays an important role in HBsAg loss among SVR patients and posttreatment virological relapse.

Nucleos(t)ide analogues (NA) are widely used to treat hepatitis B virus (HBV) infection, but they cannot eradicate the virus and treatment duration can be lifelong if the endpoint is set at seroclearance of the hepatitis B surface antigen (HBsAg). As an alternative strategy, finite NA therapy without the prerequisite of HBsAg seroclearance has been proposed to allow treatment cessation in patients with sustained undetectable HBV viremia for two to three years. However, reactivation of viral replication almost always follows NA withdrawal. Whereas HBV reactivation might facilitate HBsAg seroclearance in some, it could lead to serious acute flare-ups in a certain proportion of patients. Occurrence and consequences of NA withdrawal flares are complicated with various factors involving the virus, host, and treatment. Accurate risk prediction for severe flares following NA cessation is essential to ensure patient safety. The risks of life-threatening flares in patients who discontinued NA according to the stopping rules of current guidelines or local reimbursement policies have recently been quantitatively estimated in large-scale studies, which also provided empirical evidence to help identify vulnerable patients at risk of devastating outcomes. Moreover, risk predictors were further explored and validated to hopefully aid in patient selection and management. In this narrative review with a focus on patient safety, we summarize and discuss current literature on the incidence of severe flares following NA cessation, risk stratification for candidate selection, rules of posttreatment monitoring, and indications for treatment resumption. We also share our thoughts on the limitations of existing knowledge and suggestions for future research.

Despite improvements in the management of chronic hepatitis B (CHB), risk of cirrhosis and hepatocellular carcinoma remains. While hepatitis B surface antigen loss is the optimal end point, safe discontinuation of nucleos(t)ide analog (NA) therapy is controversial because of the possibility of severe or fatal reactivation flares.

This is a multicenter cohort study of virally suppressed, end-of-therapy (EOT) hepatitis B e antigen (HBeAg)-negative CHB patients who stopped NA therapy (n = 1,557). Survival analysis techniques were used to analyze off-therapy rates of hepatic decompensation and differences by patient characteristics. We also examined a subgroup of noncirrhotic patients with consolidation therapy of ≥12 months before cessation (n = 1,289). Hepatic decompensation was considered related to therapy cessation if diagnosed off therapy or within 6 months of starting retreatment.

Among the total cohort (11.8% diagnosed with cirrhosis, 84.2% start-of-therapy HBeAg-negative), 20 developed hepatic decompensation after NA cessation; 10 events were among the subgroup. The cumulative incidence of hepatic decompensation at 60 months off therapy among the total cohort and subgroup was 1.8% and 1.1%, respectively. The hepatic decompensation rate was higher among patients with cirrhosis (hazard ratio [HR] 5.08, P < 0.001) and start-of-therapy HBeAg-positive patients (HR 5.23, P < 0.001). This association between start-of-therapy HBeAg status and hepatic decompensation remained significant even among the subgroup (HR 10.5, P < 0.001).

Patients with cirrhosis and start-of-therapy HBeAg-positive patients should be carefully assessed before stopping NAs to prevent hepatic decompensation. Frequent monitoring of viral and host kinetics after cessation is crucial to determine patient outcome.

The majority of chronic viral hepatitis cases are induced via infection with the hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). These patients are at increased risk for progressive liver disease leading to cirrhosis as well as hepatocellular carcinoma (HCC). HBV infection is well controlled by the currently available nucleosides as well as nucleotides, and the development of cirrhosis can be prevented. Additionally, it has been shown that HBV-induced liver fibrosis can regress during successful antiviral treatment; however, a "functional cure", i.e., loss of HBsAg, is a rare event when these drugs are used. Therefore, novel therapeutic strategies are aiming at the selective suppression of HBsAg levels in combination with immunostimulation. The development of directly acting antivirals (DAAs) has revolutionized HCV therapy, as almost all patients can be cured via this treatment. Additionally, DAA therapy has few, if any, side effects, and is generally well tolerated by patients. HDV remains the most challenging type of chronic viral hepatitis. Although novel therapeutic options have recently been approved, response rates are still less favorable compared to HBV and HCV. This review discusses current and future options for the treatment of chronic HBV, HCV, and HDV infection.

Nucleos(t)ide analogues (NAs) are effective in suppressing the replication of the hepatitis B virus. However, NAs cannot effectively induce hepatitis B surface antigen (HBsAg) seroclearance, which represents the optimal treatment endpoint in chronic hepatitis B (CHB). Hence, most CHB patients are advised for indefinite NA therapy, but recent data has supported the concept of finite NA therapy before HBsAg seroclearance.

This article covered the latest evidence on stopping NAs in CHB, with a focused analysis on international guidelines. Articles were retrieved by a literature search on PubMed with the keywords 'chronic hepatitis B,' 'antiviral therapy,' 'nucleos(t)ide analogue,' 'cessation,' 'stopping', and 'finite.' Studies up till 1 December 2022 were included.

Finite NA therapy in CHB has the potential in enhancing HBsAg seroclearance, however it also carries rare but potentially severe risks. NA cessation before HBsAg seroclearance is only suitable for a highly selected group of patients, whereas the majority of CHB patients should be treated indefinitely or until HBsAg seroclearance. Current guidelines have provided recommendations on stopping NAs, but further research is required to optimize the monitoring and retreatment protocol after stopping NAs.

Nucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach.

In this multicenter, randomized-controlled trial, 166 HBeAg-negative patients with chronic hepatitis B on continuous long-term NUC treatment, with HBV DNA <172 IU/ml (1,000 copies/ml) for ≥4 years, were randomized to either stop (Arm A) or continue NUC treatment (Arm B) for a 96-week observation period. In total, 158 patients were available for final analysis, 79 per arm. The primary endpoint was sustained HBsAg loss up to week 96.

Our study met its primary objective by demonstrating HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in Arm A and in no patient in Arm B (p = 0.006). Among patients with baseline HBsAg levels <1,000 IU/ml, seven (28%) achieved HBsAg loss. In Arm A, re-therapy was initiated in 11 (13.9%) patients, whereas 32 (40.5%) patients achieved sustained remission. A decrease of HBsAg >1 log IU/ml was observed in 16 patients (20.3%) in Arm A and in one patient (1.3%) in Arm B. No serious adverse events related to treatment cessation occurred.

Cessation of NUC treatment was associated with a significantly higher rate of HBsAg loss than continued NUC treatment, which was largely restricted to patients with end of treatment HBsAg levels <1,000 IU/ml.

As HBeAg-negative patients with chronic hepatitis B on nucleos(t)ide analogues (NUCs) rarely achieve functional cure, treatment is almost always lifelong. The STOP-NUC trial was conducted to investigate whether discontinuing long-term NUC treatment can increase the cure rate. We found that some patients achieved functional cure after stopping NUCs, which was especially pronounced in patients with HBsAg levels <1,000 at the end of NUC treatment, and that many did not need to resume therapy. The results of the Stop-NUC trial provide evidence for the concept of stopping NUC treatment as a therapeutic option that can induce functional cure.

Cellular senescence is a cellular state with a broad spectrum of age-related physiological conditions that can be affected by various infectious diseases and treatments. Therapy of hepatitis B virus (HBV) infection with nucleos(t)ide analogs [NA(s)] is well established and benefits many HBV-infected patients, but requires long-term, perhaps lifelong, medication. In addition to the effects of HBV infection, the effects of NA administration on hepatocellular senescence are still unclear. This study investigated how HBV infection and NA treatment influence cellular senescence in human hepatocytes and humanized-liver chimeric mice chronically infected with live HBV. HBV infection upregulates or downregulates multiple cellular markers including senescence-associated β-galactosidase (SA-β-Gal) activity and cell cycle regulatory proteins (e.g., p21CIP1) expression level in hepatocellular nuclei and humanized-mice liver. A novel highly potent anti-HBV NA, E-CFCP, per se did not have significant disturbance on markers evaluated. Besides, E-CFCP treatment restored HBV-infected cells to their physiological phenotypes that are comparable to the HBV-uninfected cells. The results reported here demonstrate that, regardless of the mechanism(s), chronic HBV infection perturbates multiple senescence-associated markers in human hepatocytes and humanized-mice liver, but E-CFCP can restore this phenomenon.

Hepatitis B virus (HBV) infection is a major public health problem, with an estimated 296 million people chronically infected and 820 000 deaths worldwide in 2019. Diagnosis of HBV infection requires serological testing for HBsAg and for acute infection additional testing for IgM hepatitis B core antibody (IgM anti-HBc, for the window period when neither HBsAg nor anti-HBs is detected). Assessment of HBV replication status to guide treatment decisions involves testing for HBV DNA, whereas assessment of liver disease activity and staging is mainly based on aminotransferases, platelet count, and elastography. Universal infant immunisation, including birth dose vaccination is the most effective means to prevent chronic HBV infection. Two vaccines with improved immunogenicity have recently been approved for adults in the USA and EU, with availability expected to expand. Current therapies, pegylated interferon, and nucleos(t)ide analogues can prevent development of cirrhosis and hepatocellular carcinoma, but do not eradicate the virus and rarely clear HBsAg. Treatment is recommended for patients with cirrhosis or with high HBV DNA levels and active or advanced liver disease. New antiviral and immunomodulatory therapies aiming to achieve functional cure (ie, clearance of HBsAg) are in clinical development. Improved vaccination coverage, increased screening, diagnosis and linkage to care, development of curative therapies, and removal of stigma are important in achieving WHO's goal of eliminating HBV infection by 2030.

Worldwide, an estimated 296 million people are living with chronic hepatitis B virus (HBV) infection, with a significant risk of morbidity and mortality. Current therapy with pegylated interferon (Peg-IFN) and indefinite or finite therapy with nucleoside/nucleotide analogues (Nucs) are effective in HBV suppression, hepatitis resolution, and prevention of disease progression. However, few achieve hepatitis B surface antigen (HBsAg) loss (functional cure), and relapse often occurs after the end of therapy (EOT) because these agents have no direct effect on durable template: covalently closed circular DNA (cccDNA) and integrated HBV DNA. Hepatitis B surface antigen loss rate increases slightly by adding or switching to Peg-IFN in Nuc-treated patients and this loss rate greatly increases up to 39% in 5 years with finite Nuc therapy with currently available Nuc(s). For this, great effort has been made to develop novel direct-acting antivirals (DAAs) and immunomodulators. Among the DAAs, entry inhibitors and capsid assembly modulators have little effect on reducing HBsAg levels; small interfering RNA, antisense oligonucleotides, and nucleic acid polymers in combination with Peg-IFN and Nuc may reduce HBsAg levels significantly, even a rate of HBsAg loss sustained for > 24 weeks after EOT up to 40%. Novel immunomodulators, including T-cell receptor agonists, check-point inhibitors, therapeutic vaccines, and monoclonal antibodies may restore HBV-specific T-cell response but not sustained HBsAg loss. The safety issues and the durability of HBsAg loss warrant further investigation. Combining agents of different classes has the potential to enhance HBsAg loss. Compounds directly targeting cccDNA would be more effective but are still in the early stage of development. More effort is required to achieve this goal.

Antiviral treatments against hepatitis B virus (HBV) suppress viral replication but do not eradicate the virus, and need therefore to be taken lifelong to avoid relapse. Mathematical models can be useful to support the development of curative anti-HBV agents; however, they mostly focus on short-term HBV DNA data and neglect the complex host-pathogen interaction. This work aimed to characterize the effect of treatment with lamivudine and/or pegylated interferon (Peg-IFN) in 1,300 patients (hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative) treated for 1 year. A mathematical model was developed incorporating two populations of infected cells, namely I 1 , with a high transcriptional activity, that progressively evolve into I 2 , at a rate δ tr , representing cells with integrated HBV DNA that have a lower transcriptional activity. Parameters of the model were estimated in patients treated with lamivudine or Peg-IFN alone (N = 894), and the model was then validated in patients treated with lamivudine plus Peg-IFN (N = 436) to predict the virological response after a year of combination treatment. Lamivudine had a larger effect in blocking viral production than Peg-IFN (99.4-99.9% vs. 91.8-95.1%); however, Peg-IFN had a significant immunomodulatory effect, leading to an enhancement of the loss rates of I 1 (×1.7 in HBeAg-positive patients), I 2 (> ×7 irrespective of HBeAg status), and δ tr (×4.6 and ×2.0 in HBeAg-positive and HBeAg-negative patients, respectively). Using this model, we were able to describe the synergy of the different effects occurring during treatment with combination and predicted an effect of 99.99% on blocking viral production. This framework can therefore support the optimization of combination therapy with new anti-HBV agents.

Viral hepatitis has long been underrated as a danger to global health. The UN only recently called for worldwide action to tackle viral hepatitis and lessen the disease burden in its "2030 Agenda for Sustainable Development". Hepatitis B virus (HBV), which causes liver cirrhosis and malignancy, is a main cause of death globally. This review analyses innovative HBV therapeutic vaccine candidates for which a patent was filed between January 2010 and March 2022 and presents future improvement techniques for vaccine efficacy. Although there is a preventative vaccine for HBV infection, over 3% of people worldwide have the disease on a long-term basis and can no longer benefit from it. Most people will have chronic HBV infection for the rest of their lives once it has been diagnosed. Moreover, only a small percentage of treated patients experience a functional cure with persistent hepatitis B surface antigen reduction. A significant proportion of deaths are caused by liver cirrhosis and hepatocellular cancer, which are both caused by chronic hepatitis B infection. Hence, there is an urgent need for novel medications due to the inadequacies of the current therapies.

Nasvac (HeberNasvac®) is a novel therapeutic vaccine for chronic hepatitis B (CHB). This product is a formulation of the core (HBcAg) and surface (HBsAg) antigens of the hepatitis B virus (HBV), administered by nasal and subcutaneous routes, in a distinctive schedule of immunizations. In the present review article, we discuss the action mechanisms of HeberNasvac, considering the immunological properties of the product and their antigens. Specifically, we discuss the capacity of HBcAg to activate different pathways of innate immunity and the signal transduction after a multi-TLR agonist effect, and we review the results of recent clinical trials and in vitro studies. Aimed at understanding the clinical results of Nasvac and other therapeutic vaccines under development, we discuss the rationale of administering a therapeutic vaccine through the nasal route and also the current alternatives to combine therapeutic vaccines and antivirals (NUCs). We also disclose potential applications of this product in novel fields of immunotherapy.

Low anti-HBc serum levels at the time of therapy cessation were linked to a higher relapse risk in predominantly HBeAg-positive cohorts. We investigated the association of anti-HBc levels with relapse in HBeAg-negative patients.

Serum levels of anti-HBc, HBsAg and HBcrAg were determined in 136 HBeAg-negative patients, participating in a vaccination trial (ABX-203, NCT02249988), before treatment cessation or vaccination. Importantly, vaccination showed no impact on relapse. The correlation between the biomarkers and their predictive value for relapse (HBV DNA >2000 IU/ml ± ALT >2xULN) was investigated.

After therapy cessation 50% (N = 68) of patients relapsed. Median anti-HBc prior to treatment stop was significantly higher among relapsers compared to off-treatment responders (520 IU/ml vs. 330 IU/mL, p = .0098). The optimal anti-HBc cut-off to predict relapse was 325 IU/ml according to the Youden-Index. About 35% of patients with anti-HBc level < 325 IU/ml versus 60% of those with values ≥325 IU/mL relapsed (p = .0103; sensitivity 50%, specificity 75%). Combining the optimal cut-offs of HBsAg (>3008 IU/mL) or HBcrAg (≥1790 U/ml) with anti-HBc increased the proportion of patients with relapse to 80% (p < .0001) and 74% (p = .0006), respectively.

In contrast to predominantly HBeAg-positive cohorts, in our cohort of HBeAg-negative patients lower anti-HBc levels are associated with a significantly lower relapse risk after nucleos(t)ide analogue cessation. The vast majority of included patients were either genotype B or C and the applicability to other genotypes has to be further evaluated. However, anti-HBc level as an indicator of the host response might be prospectively further explored for prediction models.

To investigate the sustained virological response and relapse in chronic hepatitis B (CHB) patients with hepatitis B e antigen (HBeAg) positive after stopping oral antiviral drugs, and to monitor the disease progression and the incidence of adverse events such as liver cirrhosis and hepatocellular carcinoma.

This is a prospective observational study. Patients who continued nucleos(t)ide analogue (NA) treatment after achieving HBeAg seroconversion for more than 3 years were enrolled. After signing the informed consent form, patients stopped NA treatment and received follow-up. During the follow-up, the antiviral treatment information of the patients was collected, and the follow-up observation was carried out every 3 months since the enrollment. We monitored the virological indexes, liver and kidney function, serology and liver imaging during follow-up. The purpose of this study was to explore the sustained virological response rate, HBV DNA recurrence rate, clinical relapse rate and the related factors after drug withdrawal.

A total of 82 patients were enrolled, including 42 males (51.22%) and 40 females (48.78%), with a median age of 34.00 (31.00, 37.25) years. All enrolled patients were followed up for 1 year. At the end of the follow-up, 36.59% (30/82) of patients had sustained virological response, 63.41% (52/82) of patients had HBV DNA reactivation, 17.07% (14/82) of patients had clinical relapse, and 10.98% (9/82) of patients had HBeAg reversion. During the follow-up, there were no adverse events such as liver cirrhosis and hepatocellular carcinoma. The median level of hepatitis B surface antigen (HBsAg) in patients with sustained virological response was lower than that in patients with HBV DNA reactivation (2.92 vs.3.18 log10IU/ml, Z=-1.492/P=0.136), and the median level of baseline HBsAg in patients with HBV DNA reactivation was lower than that in patients with clinical relapse (3.01 vs.3.45 log10IU/mL, Z=-1.795/P=0.073), but the difference was not significant. There was no significant statistical difference between patients with sustained virological response and HBV DNA reactivation of the median total treatment time [69.50 (56.25, 86.00) vs.62.50 (44.00, 88.50) months, Z=-0.689/P=0.491], and the consolidation treatment time [41.50 (36.75, 54.75) vs.40.50 (36.00, 53.75) months, Z=-0.419/P=0.675].

The sustained virological response rate of HBeAg positive CHB patients after stopping oral antiviral treatment is lower, and it is more common in patients with lower HBsAg levels. Patients still need to be closely monitored after stopping NA therapy.