Sustained HBsAg Research Articles

Incidence and Predictors of HBsAg Loss in Paediatric Patients With Chronic Hepatitis B Undergoing Antiviral Treatment.

Achieving HBsAg loss is a critical clinical milestone in the management of chronic hepatitis B (CHB) towards the eradication of hepatitis B. However, there are limited researches on the incidence and determinants of HBsAg loss in paediatric CHB patients undergoing antiviral treatment. Therefore, we aimed to analyse the incidence and potential determinants of HBsAg loss in children who suffered from CHB and received antiviral treatment. This retrospective cohort study was performed on paediatric patients with progressive CHB who initiated either monotherapy or combination therapy using interferon/peg-interferon and entecavir. We utilised Cox regression models to evaluate the relationships between HBsAg loss and various determining factors. In total of 306 subjects with an average age of 4.99 years (range 1-15) were identified in this study, of whom 200 (65.4%) were male. After a median follow-up of 26 months, HBsAg loss occurred in 135 participants. The accumulated rate of HBsAg loss was 67.8% at the end of the follow-up evaluation. Multivariate Cox regression analysis revealed that older age (HR = 0.84, 95% CI: 0.79-0.90), female sex (HR = 1.61, 95% CI: 1.13-2.30), baseline HBsAg levels (HR = 0.72, 95% CI: 0.62-0.84), HBsAb positivity (HR = 1.77, 95% CI: 1.20-2.59) and serum bilirubin levels (HR = 0.96, 95% CI: 0.92-0.99) were statistically significant predictors of HBsAg loss. The incidence of HBsAg loss continues to increase in paediatric patients with CHB after antiviral treatment. Age, sex, baseline HBsAg and bilirubin levels and HBsAb positivity are found to be associated with sustained HBsAg loss.

VIR-2218 (elebsiran) plus pegylated interferon-alfa-2a in participants with chronic hepatitis B virus infection: a phase 2 study

Chronic hepatitis B virus (HBV) remains a global concern, with current treatments achieving low rates of HBsAg seroclearance. VIR-2218 (elebsiran), a small interfering RNA agent against HBV transcripts, reduces HBsAg concentrations. We aimed to evaluate the safety and antiviral activity of VIR-2218 with and without pegylated interferon-alpha-2a treatment in participants with chronic HBV. This open-label, phase 2 study was conducted at 23 sites in six countries (New Zealand, Australia, Hong Kong, Thailand, South Korea, and Malaysia). Adults (aged 18-65 years) with chronic HBV infection without cirrhosis and with HBsAg more than 50 IU/mL and HBV DNA less than 90 IU/mL who were on continued nucleoside or nucleotide reverse transcriptase inhibitor (NRTI) therapy for 2 months or longer were eligible. Participants were enrolled into one of six cohorts to receive VIR-2218 200 mg subcutaneously every 4 weeks, with or without 180 μg subcutaneous pegylated interferon-alfa-2a once per week. Cohort 1 received six doses of VIR-2218 (total 20 weeks); cohort 2 received six doses of VIR-2218 starting at day 1, plus 12 doses of pegylated interferon-alfa-2a starting at week 12 (total 24 weeks); cohort 3 received six doses of VIR-2218 and 24 doses of pegylated interferon-alfa-2a (total 24 weeks); cohort 4 received six doses of VIR-2218 and up to 48 doses of pegylated interferon-alfa-2a (total 48 weeks); cohort 5 received up to 13 doses of VIR-2218 and up to 44 doses of pegylated interferon-alfa-2a (total 48 weeks); and cohort 6 received three doses of VIR-2218 and 12 doses of pegylated interferon-alfa-2a (total 12 weeks). The primary endpoints were the incidence of adverse events and clinical assessments (including results of laboratory tests). Secondary endpoints were the mean maximum reduction of serum HBsAg at any timepoint; the proportion of participants with serum HBsAg seroclearance at any timepoint and for more than 6 months after the end of treatment; and the proportion of participants with anti-HBs seroconversion at any timepoint. For patients who were HBeAg-positive, we also assessed the proportion with HBeAg seroclearance or anti-HBe seroconversion at any timepoint. This study is registered with ClinicalTrials.gov, NCT03672188, and is ongoing. Between July 2, 2020, and Nov 2, 2021, 124 individuals were screened for eligibility, 84 of whom were enrolled (15 in cohort 1, 15 in cohort 2, 18 in cohort 3, 18 in cohort 4, 13 in cohort 5, and five in cohort 6). Participants were predominantly HBeAg-negative, Asian, and male (66 [79%] participants were male and 18 [21%] were female). Most treatment emergent adverse events were grades 1-2. Three (20%) participants in cohort 1, four (27%) in cohort 2, eight (44%) in cohort 3, seven (39%) in cohort 4, six (46%) in cohort 5, and two (40%) in cohort 6 reported treatment-emergent adverse events related to VIR-2218. 12 (80%) participants in cohort 2, 12 (67%) in cohort 3, 14 (78%) in cohort 4, 13 (100%) in cohort 5, and three (60%) in cohort 6 reported treatment-emergent adverse events related to pegylated interferon-alfa-2a. Two (13%) participants in cohort 1 had elevations in alanine aminotransferase, compared with 13 (87%) participants in cohort 2, 15 (83%) in cohort 3, 17 (94%) in cohort 4, 11 (85%) in cohort 5, and three (60%) in cohort 6. The mean maximum change from baseline at any timepoint in HBsAg concentration was -2·0 log10 IU/mL (95% CI -2·1 to -1·8) in cohort 1, -2·2 log10 IU/mL (-2·5 to -1·8) in cohort 2, -2·5 log10 IU/mL (-2·8 to -2·1) in cohort 3, -2·4 log10 IU/mL (-3·1 to -1·8) in cohort 4, -3·0 log10 IU/mL (-3·7 to -2·3) in cohort 5, and -1·7 log10 IU/mL (-2·1 to -1·4) in cohort 6. 11 participants (one in cohort 2, one in cohort 3, five in cohort 4, and four in cohort 5) receiving VIR-2218 plus pegylated interferon-alfa-2a had HBsAg seroclearance at any timepoint. Of these, ten (91%; one in cohort 2, five in cohort 4, and four in cohort 5) had anti-HBs seropositivity. Six participants (one in cohort 2, three in cohort 4, and two in cohort 5) had sustained HBsAg seroclearance through to 24 weeks after the end of treatment. No participants receiving VIR-2218 monotherapy (cohort 1) or VIR-2218 plus pegylated interferon-alfa-2a 12-week regimen (cohort 6) had HBsAg seroclearance. 12 (42%) of 26 participants (one of four in cohort 1, two of six in cohort 2, four of seven in cohort 3, four of six in cohort 4, and one of three in cohort 5) who were HBeAg positive at baseline had HBeAg seroclearance or anti-HBe seroconversion. The results of this phase 2 study support further development of VIR-2218 as a potential therapy for patients with chronic HBV infection. Additional clinical trials of VIR-2218 with and without pegylated interferon-alfa-2a in combination with an HBsAg-targeting monoclonal antibody are ongoing. Vir Biotechnology.

Early application of IFNγ mediated the persistence of HBV in an HBV mouse model

The antiviral activity of interferon gamma (IFNγ) against hepatitis B virus (HBV) was demonstrated both in vivo and in vitro in a previous study. IFNγ can suppress HBV replication by accelerating the decay of replication-competent nucleocapsids of HBV. However, in this study, we found that the direct application of the mouse IFNγ (mIFNγ) expression plasmid to the liver of an HBV hydrodynamic injection (HI) mouse model led to the persistence of HBV, as indicated by sustained HBsAg and HBeAg levels in the serum as well as an increased percentage of the HBsAg positive mice, whereas the level of HBV DNA in the serum and the expression of HBcAg in the liver were inhibited at the early stage after HI. Meanwhile, we found that the productions of both HBcAb and HBsAb were suppressed after the application of mIFNγ. In addition, we found that HBV could be effectively inhibited in mice immunized with HBsAg expression plasmid before the application of mIFNγ. Furthermore, mIFNγ showed antiviral effect and promoted the production of HBsAb when the mice subjected to the core-null HBV plasmid. These results indicate that the application of mIFNγ in the HBV HI mouse model, the mice showed defective HBcAg-specific immunity that impeded the production of HBcAb and HBsAb, finally allowing the persistence of the virus. Moreover, IFNγ-induced negative immune regulatory factors also play an important role in virus persistence.

A novel, small anti-HBV compound reduces HBsAg and HBV-DNA by destabilizing HBV-RNA.

Currently, standard treatments for chronic hepatitis B such as nucleos(t)ide analogs (NAs), effectively reduce hepatitis B virus (HBV) loads but rarely result in a functional cure (defined as sustained HBsAg loss). We report the discovery of a novel, 4-pyridone compound, SAG-524, a potent and orally bioavailable small molecule inhibitor of HBV replication. The antiviral characteristics and selectivity of SAG-524 and its derivative compound against HBV were evaluated in HBV-infection assays and HBV-infected chimeric urokinase-type plasminogen activator/severe combined immunodeficiency mice with humanized livers (PXB mice), alone or in combination with entecavir. Toxicity studies were conducted in mice and monkeys. SAG-524 reduced HBV-DNA (IC50 = 0.92nM) and HBsAg (IC50 = 1.4nM) in the supernatant of the HepG2.2.15 cells. SAG-524 selectively destabilized HBV-RNA via PAPD5, but not GAPDH or albumin mRNA, by shortening the poly(A) tail. PAPD5 may also be involved in HBV regulation via ELAVL1. In a study of HBV-infected PXB mice, SAG-524 produced potent reductions of serum HBsAg and HBcrAg, and the minimum effective dose was estimated to be 6mg/kg/day. The combination therapy with entecavir greatly reduced HBsAg and cccDNA in the liver due to reduction of human hepatocytes with good tolerability. Administration of SAG-524 to monkeys, up to 1000mg/kg/day for two weeks, led to no significant toxicity, as determined by blood tests and pathological images. We have identified SAG-524 as novel and orally bioavailable HBV-RNA destabilizers which can reduce HBsAg and HBV-DNA levels, and possibly contribute a functional cure.

Sustained Liver HBsAg Loss and Clonal T- and B-Cell Expansion upon Therapeutic DNA Vaccination Require Low HBsAg Levels.

Suppression of HBV DNA, inhibition of HBV surface (HBsAg) production and therapeutic vaccination to reverse HBV-specific T-cell exhaustion in chronic HBV patients are likely required to achieve a functional cure. In the AAV-HBV mouse model, therapeutic vaccination can be effective in clearing HBV when HBsAg levels are low. Using a single-cell approach, we investigated the liver immune environment with different levels of HBsAg and sustained HBsAg loss through treatment with a GalNAc-HBV-siRNA followed by therapeutic vaccination. AAV-HBV-transduced C57BL/6 mice were treated with GalNAc-HBV-siRNA to lower HBsAg levels and then vaccinated using a DNA vaccine. We used single-cell RNA and V(D)J sequencing to understand liver immune microenvironment changes. GalNAc-HBV-siRNA, followed by therapeutic vaccination, achieved sustained HBsAg loss in all mice. This was accompanied by CD4 follicular helper T-cell induction, polyclonal activation of CD8 T cells and clonal expansion of plasma cells that were responsible for antibody production. This study provides novel insights into liver immune changes at the single-cell level, highlighting the correlation between induced reduction of HBsAg levels and clonal expansion of CD4, CD8 T cells and plasma cells in the liver upon HBV siRNA and subsequent therapeutic vaccination.

Sustained response and HBsAg loss after nucleo(s)tide analogue discontinuation in chronic hepatitis B patients: the prospective SNAP study

Background & Aim(s)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. MethodsThis 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. ResultsIn 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. ConclusionNA 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.

Guidance on treatment endpoints and study design for clinical trials aiming to achieve cure in chronic hepatitis B and D: Report from the 2022 AASLD-EASL HBV-HDV Treatment Endpoints Conference.

Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level < 100IU/mL and HBV DNA < LLOQ 24 weeks off-treatment. Clinical trials should initially focus on patients with HBeAg positive or negative CHB, who are treatment-naive or virally suppressed on nucleos(t)ide analogs. Hepatitis flares may occur during curative therapy and should be promptly investigated and outcomes reported. HBsAg loss would be the preferred endpoint for chronic hepatitis D, but HDV RNA < LLOQ 24 weeks off-treatment is a suitable alternate primary endpoint of phase II/III trials assessing finite strategies. For trials assessing maintenance therapy, the primary endpoint should be HDV RNA < LLOQ assessed at on-treatment week 48. An alternate endpoint would be ≥2 log reduction in HDV RNA combined with normalization of alanine aminotransferase level. Suitable candidates for phase II/III trials would be treatment-naiive or experienced patients with quantifiable HDV RNA. Novel biomarkers (hepatitis B core-related antigen [HBcrAg] and HBV RNA) remain exploratory, while nucleos(t)ide analogs and pegylated interferon still have a role in combination with novel agents. Importantly, patient input is encouraged early on in drug development under the FDA/EMA patient-focused drug development programs.

SAT-148 - Low HBV DNA and HBsAg levels at 24 weeks off-treatment predict sustained response and HBsAg loss in patients who discontinued antiviral therapy

SAT-148 - Low HBV DNA and HBsAg levels at 24 weeks off-treatment predict sustained response and HBsAg loss in patients who discontinued antiviral therapy

FRI-217 - RBD1016-a novel anti-HBV GalNAc-siRNA drug resulted in sustained HBsAg reduction and seroconversion in mice models

FRI-217 - RBD1016-a novel anti-HBV GalNAc-siRNA drug resulted in sustained HBsAg reduction and seroconversion in mice models

Class A capsid assembly modulator RG7907 clears HBV-infected hepatocytes through core-dependent hepatocyte death and proliferation.

Effective therapies leading to a functional cure for chronic hepatitis B are still lacking. Class A capsid assembly modulators (CAM-As) are an attractive modality to address this unmet medical need. CAM-As induce aggregation of the HBV core protein (HBc) and lead to sustained HBsAg reductions in a chronic hepatitis B mouse model. Here, we investigate the underlying mechanism of action for CAM-A compound RG7907. RG7907 induced extensive HBc aggregation in vitro , in hepatoma cells, and in primary hepatocytes. In the adeno-associated virus (AAV)-HBV mouse model, the RG7907 treatment led to a pronounced reduction in serum HBsAg and HBeAg, concomitant with clearance of HBsAg, HBc, and AAV-HBV episome from the liver. Transient increases in alanine transaminase, hepatocyte apoptosis, and proliferation markers were observed. These processes were confirmed by RNA sequencing, which also uncovered a role for interferon alpha and gamma signaling, including the interferon-stimulated gene 15 (ISG15) pathway. Finally, the in vitro observation of CAM-A-induced HBc-dependent cell death through apoptosis established the link of HBc aggregation to in vivo loss of infected hepatocytes. Our study unravels a previously unknown mechanism of action for CAM-As such as RG7907 in which HBc aggregation induces cell death, resulting in hepatocyte proliferation and loss of covalently closed circular DNA or its equivalent, possibly assisted by an induced innate immune response. This represents a promising approach to attain a functional cure for chronic hepatitis B.

Use of HBV RNA and to predict change in serological status and disease activity in CHB.

Predicting changes in disease activity and serological endpoints is necessary for the management of patients with chronic hepatitis B (CHB). We examined whether HBV RNA and hepatitis B core-related antigen (HBcrAg), two specialized virological markers proposed to reflect the activity of covalently closed circular DNA, may improve the ability to predict not sustained inactive carrier phase, spontaneous alanine aminotransferase (ALT) flare, HBeAg loss, and HBsAg loss. Among eligible participants enrolled in the North American Hepatitis B Research Network Adult Cohort Study, we evaluated demographic, clinical, and virologic characteristics, including HBV RNA and HBcrAg, to predict not sustained inactive carrier phase, ALT flare, HBeAg loss, and HBsAg loss through a series of Cox proportional hazard or logistic regression models, controlling for antiviral therapy use. Among the study population, 54/103 participants experienced not sustained inactive carrier phase, 41/1006 had a spontaneous ALT flare, 83/250 lost HBeAg, and 54/1127 lost HBsAg. HBV RNA or HBcrAg were predictive of all 4 events. However, their addition to models of the readily available host (age, sex, race/ethnicity), clinical (ALT, use of antiviral therapy), and viral factors (HBV DNA), which had acceptable-excellent accuracy (e.g., AUC = 0.72 for ALT flare, 0.92 for HBeAg loss, and 0.91 for HBsAg loss), provided only small improvements in predictive ability. Given the high predictive ability of readily available markers, HBcrAg and HBV RNA have a limited role in improving the prediction of key serologic and clinical events in patients with CHB.

What will it take to cure hepatitis B?

The current treatment of chronic HBV infection, pegylated interferon-α (pegIFNα) and nucleos(t)ide analog (NA), can suppress HBV replication, reverse liver inflammation and fibrosis and reduce the risks of cirrhosis, HCC, and HBV-related deaths, but relapse is common when the treatment is stopped before HBsAg loss. There have been major efforts to develop a cure for HBV, defined as sustained HBsAg loss after a finite course of therapy. This requires the suppression of HBV replication and viral protein production and the restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. Immune modulatory therapies to stimulate adaptive or innate immunity and/or to remove immune blockade are being tested. NAs are included in most and pegIFNα in some regimens. Despite the combination of 2 or more therapies, HBsAg loss remains rare in part because HbsAg can be derived not only from the covalently closed circular DNA but also from the integrated HBV DNA. Achievement of a functional HBV cure will require therapies to eliminate or silence covalently closed circular DNA and integrated HBV DNA. In addition, assays to differentiate the source of circulating HBsAg and to determine HBV immune recovery, as well as standardization and improvement of assays for HBV RNA and hepatitis B core-related antigen, surrogate markers for covalently closed circular DNA transcription, are needed to accurately assess response and to target treatments according to patient/disease characteristics. Platform trials will allow the comparison of multiple combinations and channel patients with different characteristics to the treatment that is most likely to succeed. Safety is paramount, given the excellent safety profile of NA therapy.

A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B

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 week96. 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 <1,000at 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.

S1189 Safety and Efficacy of Oral TLR8 Agonist, Selgantolimod, in Viremic Adult Patients With Chronic Hepatitis B

Introduction: Selgantolimod (GS-9688, SLGN) is an oral, Toll-like receptor 8 agonist in clinical development for the treatment of chronic hepatitis B (CHB). Here we present the results through week 48 on the safety and efficacy of 24 weeks of SLGN treatment in viremic CHB patients. Methods: In this multicenter, double-blind, phase 2 study, viremic CHB patients were randomized (2:2:1) to SLGN 3 mg, 1.5 mg, and placebo (PBO) once a week for 24 weeks in combination with tenofovir alafenamide. Safety assessments included monitoring of treatment emergent adverse events (TEAE) and laboratory abnor-malities. The primary efficacy end point was the proportion of patients with ≥1 log10IU/ml decline in HBsAg levels from baseline at week 24. Exploratory end points include changes in pharmacodynamic (PD) markers (e.g. IL-12p40 and IL-1RA) and changes in peripheral T- cell, myeloid and NK-cell subsets. Results: 67 patients (39 HBeAg-positive) were randomized. Baseline characteristics were similar across groups: majority were Asian (98.5%), male (58%) with a median (IQR) age of 47 (35–54) years, HBsAg level of 4.1 (3.5–4.7) log10IU/ml, and HBV DNA level of 7.5 (5.4–8.3) log10IU/ml. No patients achieved the primary end point of ≥1 log10IU/ml decline in HBsAg levels at week 24; however, 3 (6%) patients in the SLGN-treated achieved HBsAg decline ≥0.5 log10IU/ml compared to none in the placebo group. At week 48, 4 (7.4%) patients in the SLGN-treated group (including the 3 subjects at week 24) while none in the placebo group achieved HBsAg decline ≥0.5 log10IU/ml. Most frequent (≥10% SLGN-treated) TEAE (SLGN v PBO) were: nausea (26% v 0%), headache (15% v 15%), vomiting (17% v 0%), fatigue (15% v 0), and dizziness (11% v 0%). Grade ≥3 TEAE were observed in 0 (SLGN) v 7.7% (PBO) subjects; 1 subject (SLGN 3 mg) discontinued study due to TEAE of vomiting and abdominal pain. Most patients treated with SLGN showed decline of immune cell subsets in the circulation 4 h after dosing, concurrent with increases of circulating IL-12p40 and IL-1RA. Cell populations that decreased in the circulation included effector and memory T cell subsets. These parameters reverted to baseline values at 24 h post-dosing. Conclusion: Oral SLGN up to 3 mg once weekly for 24 weeks is safe and well-tolerated. SLGN can induce sustained HBsAg declines of ≥0.5 log10IU/ml in some patients out to Week 48. Further evaluation of SLGN in combination with immunomodulatory and antiviral agents is planned.

Quantitative HBsAg an unreliable marker for diagnosis and disease progression in genotype F chronic HBeAg-negative infections.

Quantitative hepatitis B surface antigen (qHBsAg) has been proposed as a biomarker to distinguish HBeAg-negative chronic infections (ENI) from HBeAg-negative chronic hepatitis (ENH), identify patients prone to achieving sustained HBsAg loss, and predict the risk of liver disease progression. There is evidence that qHBsAg varies among genotypes, however there is a paucity of data on genotype F. The aim of this study was to investigate the performance of qHBsAg in the diagnosis and evolution of genotype F chronic HBeAg-negative infections. HBV-DNA and HBsAg levels from 153 patients with ENI were correlated with the genotype. Liver disease progression was assessed by abdominal ultrasound and a transient elastography. The qHBsAg levels were significantly different among genotypes (p <0.001), being GTF: 4.0±1.1, GTA: 3.9±0.6 and GTD: 2.4±0.9 Log10 IU/ml. Only 10.7 and 11.5% of GTA and GTF showed qHBsAg <3.0 Log10 IU/ml. Regardless of HBV genotype, HBsAg clearance was observed in 17 cases, of which 12 showed qHBsAg <100 IU/ml before clearance. Despite of a large number of patients having qHBsAg >3.0 log10 IU/ml, no cases of advanced liver disease were observed at the end of follow-up. This study provides new insights into the impact of HBV genotypes, in particular GTF, on serum HBsAg levels, emphasizing the need to implement a genotype-specific cut-off to achieve diagnostic certainty in the identification of ENI and the risk of liver disease progression. Regardless of HBV genotype, qHBsAg has been shown to be a powerful and reliable biomarker for predicting HBsAg loss.

Incidence and prediction of HBsAg seroclearance in a prospective multi-ethnic HBeAg-negative chronic hepatitis B cohort.

Achieving HBsAg loss is an important landmark in the natural history of chronic hepatitis B (CHB). A more personalized approach to prediction of HBsAg loss is relevant in counseling patients. This study sought to develop and validate a prediction model for HBsAg loss based on quantitative HBsAg levels (qHBsAg) and other baseline characteristics. The Hepatitis B Research Network (HBRN) is a prospective cohort including 1240 untreated HBeAg-negative patients (1150 adults, 90 children) with median follow-up of 5.5 years. Incidence rates of HBsAg loss and hepatitis B surface antibody (anti-HBs) acquisition were determined, and a predictor score of HBsAg loss using readily available variables was developed and externally validated. Crude incidence rates of HBsAg loss and anti-HBs acquisition were 1.6 and 1.1 per 100 person-years (PY); 67 achieved sustained HBsAg loss for an incidence rate of 1.2 per 100 PY. Increased HBsAg loss was significantly associated with older age, non-Asian race, HBV phenotype (inactive CHB vs. others), HBV genotype A, lower HBV-DNA levels, and lower and greater change in qHBsAg. The HBRN-SQuARe (sex,∆quantHBsAg, age, race) score predicted HBsAg loss over time with area under the receiver operating characteristic curve (AUROC) (95% CIs) at 1 and 3 years of 0.99 (95% CI: 0.987-1.00) and 0.95 (95% CI 0.91-1.00), respectively. In validation in another cohort of 1253HBeAg-negative patients with median follow-up of 3.1 years, HBRN SQuARe predicted HBsAg loss at 1 and 3 years with AUROC values of 0.99 (0.98-1.00) and 0.88 (0.77-0.99), respectively. HBsAg loss in predominantly untreated patients with HBeAg-negative CHB can be accurately predicted over a 3-year horizon using a simple validated score (HBRN SQuARe). This prognostication tool can be used to support patient care and counseling.

Mean HBsAg decline at week 24 of PEG-IFN-based treatment predicts subsequent rate of HBsAg clearance - suggesting a valuable endpoint for early development HBV trials.

Earlier identification of potentially efficacious treatments in early development trials requires on-treatment response markers. We hypothesized that mean week 12 or 24 HBsAg decline could be a useful marker for subsequent off-treatment sustained HBsAg clearance at the treatment arm level in HBV trials. We used individual patient data from the studies HBV 9901 (peginterferon [PEG-IFN] versus PEG-IFN+lamivudine for HBeAg-positive CHB), PARC (PEG-IFN±ribavirin for HBeAg-negative CHB) and published data from 0149 (PEG-IFN±tenofovir for HBeAg-positive and HBeAg-negative CHB) and LIRA-B (PEG-IFN for HBeAg-positive CHB) to define the relationship between mean week HBsAg decline and HBsAg loss at 6months post-treatment. A within-study comparison of HBsAg decline at weeks 12 and 24 between patients with or without HBsAg clearance was used to make projections beyond the observed HBsAg data. Across trials, a more pronounced mean HBsAg decline at week 24 was associated with higher rates of subsequent HBsAg loss. Mean HBsAg decline data at week 24 for patients with or without HBsAg clearance from HBV 9901 (4.3 vs 0.5), PARC (4.8 vs 0.3) and 0149 (PEG-IFN+TDF arm; 4.6 vs 0.6) were used to extrapolate this relationship beyond observed rates of HBsAg. An additional mean 1 log10 decline at week 24 versus a comparator arm is expected to translate into a 20%-30% increase in subsequent HBsAg loss during off-treatment follow-up. Observations were similar for week 12 data, but the relationship was less strong. Mean week 24 HBsAg decline predicts subsequent HBsAg loss and could be a valuable and useful early endpoint in HBV-treatment trials.

The price tag of a potential cure for chronic hepatitis B infection: A cost threshold analysis for USA, China and Australia.

We aim to capture the economic impact of a potential cure for chronic hepatitis B infection (CHB) in three countries (USA, China and Australia) with different health systems and epidemics to estimate the threshold drug prices below which a CHB cure would be cost-saving and/or highly cost-effective. We simulated patients' hepatitis B progression, under three scenarios: current long-term suppressive antiviral therapy, functional cure defined as sustained undetectable HBsAg and HBV DNA, and partial cure defined as sustained undetectable HBV DNA only after a finite, 48-week treatment. Compared with current long-term antiviral therapy, a 30% effective functional cure among patients with and without cirrhosis in the USA, China and Australia would yield 17.50, 17.32 and 20.42 QALYs per patient, and 20.61, 20.42 and 20.62 QALYs per patient respectively. In financial terms, for CHB patients with and without cirrhosis, this would be cost-saving at a one-time treatment cost under US$11944 and US$6694, respectively, in the USA, US$1744 and US$1001 in China, and US$12063 and US$10983 in Australia. We show that in purely economic terms, a CHB cure will be highly cost-effective even if effective in only 30% of treated patients. The threshold price for cure is largely determined by the current antiviral drug costs, since it will replace a daily antiviral pill that is inexpensive and effective, although not curative. The likely need for combination therapies to achieve cure will also present cost challenges. While cost-effectiveness is important, it cannot be the only consideration, as cure will provide many benefits in addition to reduced liver disease and HCC, including eliminating the need for a long-term daily pill and reducing stigma often associated with chronic viral infection.

Risk of hepatocellular carcinoma after spontaneous and nucleos(t)ide analogue induced hepatitis B surface antigen seroclearance.

e16162 Background: Despite a favorable clinical course, the risk of hepatocellular carcinoma (HCC) still exists in patients achieving HBsAg seroclearance. Therefore, we investigated the incidence of HCC after spontaneous and nucleos(t)ide analogue (NA) induced HBsAg seroclearance in real-life clinical practice. Methods: A cohort study was conducted using data from Gangnam Severance Hospital. We identified all subjects with positive HBsAg between January 1, 2001 and March 21, 2018. NA use, liver biochemistries, serial HBsAg and anti-HBs results were retrieved. The primary endpoint was the incidence of HCC after naturally and NA induced HBsAg seroclearance. Results: Among the 5,609 HBsAg-positive patients, 83 chronic hepatitis B (CHB) patients achieved HBsAg seroclearance during 19 years. The cumulative incidence of HBsAg seroclearance was 0.024% at 2 years to 32.4% at 19 years. Of the 83 patients with HBsAg seroclearance, 52 patients achieved spontaneous HBsAg seroclearance and 31 patients achieved NA-induced HBsAg seroclearance. Of 52 patients with spontaneous HBsAg seroclearance, only one patient (2%) developed HCC 6 months after HBsAg seroclearance. On the other hands, there was no development of HCC in patients with NA-induced HBsAg seroclearance. No significant difference was observed in the cumulative incidence of HCC between two groups ( P=0.443). All patients had sustained HBsAg seroclearance and there was no HBsAg seroreversion. Conclusions: The incidence of HCC was extremely rare after spontaneous and NA induced HBsAg seroclearance in real-life clinical practice. NA-induced HBsAg seroclearance is also as durable as spontaenous HBsAg seroclearance.

SAT459 - HBV RNA decline without concomitant HBsAg decrease is associated with a low probability of sustained response and HBsAg loss

SAT459 - HBV RNA decline without concomitant HBsAg decrease is associated with a low probability of sustained response and HBsAg loss