BACKGROUND AND AIMS: The aim of this systematic literature review (SLR) was to examine outcomes and associated predictors following nucleos(t)ide analog (NA) treatment cessation in adult patients with chronic hepatitis B virus infection. METHODS: The SLR was conducted according PRISMA methodology. All included studies were quality assessed using appropriate scales or checklists. RESULTS: The SLR identified 145 studies. Cumulative rates of clinical relapse (40 studies), virological relapse (53 studies), biochemical relapse (10 studies) and retreatment events (14 studies) post NA cessation varied widely across studies (clinical relapse: 40%-65%, virological relapse: 75%-94%, biochemical relapse: 63%-73%, retreatment rates: 30%-78% at 24 and 144 weeks, respectively). Significant predictors with adequate evidence clinical relapse included older age, male gender, and higher hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA at baseline and end of treatment. HBsAg loss was reported 25 studies, with overall median HBsAg loss rates ranging from 2% at 24 weeks (5 studies) to 11% at 192 weeks (2 studies) post NA cessation. There was adequate evidence for lower HBsAg level at baseline and end of treatment as a significant and consistent predictor of HBsAg loss. CONCLUSION: There considerable heterogeneity among studies of NA cessation. Data are currently incomplete to provide strong recommendations for NA cessation or to identify patients who may benefit most from this approach in clinical practice. Further studies are required to provide clearer guidelines, and tools to assess and monitor patients who may benefit from NA treatment cessation.

Background In B-Clear (NCT04449029), some participants with chronic hepatitis B virus infection on and not on nucleos(t)ide analogue (NA) therapy (On-NA and Not-on-NA) achieved a response at end of bepirovirsen treatment, sustained for 24 weeks’ follow-up. We present preliminary data from B-Sure (NCT04954859) examining durability of response for B-Clear complete responders.

Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.

Chronic hepatitis B (CHB) infection affects approximately 90 million people in China, where there are profoundly unmet clinical and public health needs. This study evaluated patient demographics, disease progression, and treatment management using national administrative claims data. This retrospective, observational study used anonymized data from the China Health Insurance Research Association claims database (January 1-December 31, 2016); data that could not be validated, or from duplicate entries, were excluded. Patients were identified using the International Classification of Diseases, 10th Revision diagnostic code for CHB (B18.0 and B18.1), using keyword searches for "CHB or HBV" and free-text descriptions of CHB treatments including nucleos(t)ide analogues. Primary objectives included evaluation of: demographics and clinical characteristics of patients with CHB, overall and by presence or absence of cirrhosis and hospital tier; proportion of patients prescribed CHB treatment; and healthcare costs and utilization overall and by presence or absence of cirrhosis and hospital tier. Most identified patients with CHB were male, aged 25 to 65 years, resided in East China, and had employee health insurance. Cirrhosis was common (16.20%) and associated with male preponderance, older age, hepatitis C virus coinfection, and higher hospital care demands and costs. The most frequently visited hospitals were Tier III; patients visiting Tier III generally required more hospital care compared with those visiting Tier I/II hospitals. Only two-thirds of patients were prescribed antiviral therapy for CHB (most commonly nucleos(t)ide analogues). Results from this study highlight a substantial need to improve access to appropriate CHB treatment in China.

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

BACKGROUND & AIMS: GLIMMER assessed dose-response, efficacy, and safety of linerixibat, an ileal bile acid trans-porter inhibitor in development for cholestatic pruritus associated with primary biliary chol-angitis (PBC). METHODS: GLIMMER was a Phase 2b, multicenter, randomized, parallel-group study in adults with PBC and moderate-to-severe pruritus (& DDAG;4 on 0-10 numerical rating scale [NRS]). After 4 weeks of single-blind placebo, patients with NRS & DDAG;3 were randomized (3:1) to double-blind linerixibat/placebo for 12 weeks (to week 16), followed by single-blind placebo (to week 20). The primary objective was to investigate dose-related changes in mean worst daily itch (MWDI) score. RESULTS: One hundred forty-seven patients received placebo (n = 36) or linerixibat (once daily: 20 mg, n = 16; 90 mg, n = 23; 180 mg, n = 27; twice daily: 40 mg, n = 23; 90 mg, n = 22). Linerixibat groups exhibited Z2-point mean reductions in MWDI from baseline at week 16; however, differences from placebo were not significant. Post hoc analysis of change from baseline in monthly itch score over the treatment period (Phase 3 endpoint) showed significant differences between placebo and linerixibat 180 mg once daily (P = .0424), 40 mg twice daily (P = .0105), and 90 mg twice daily (P = .0370). A significant relationship between total daily dose and response was observed post hoc in the per protocol population (P = .0542). Consistent with mechanism of action, diarrhea was the most frequent adverse event, and incidence increased with dose. CONCLUSIONS: Linerixibat effect on itch was not significantly different versus placebo in the primary intent-to treat analysis but was associated with a significant dose-dependent reduction in itch in the per protocol population. A well-tolerated dose was identified for Phase 3 investigation for cholestatic pruritus in PBC. ClinicalTrials.gov ID: NCT02966834.

Bepirovirsen (GSK3228836) is an antisense oligonucleotide that induced rapid and prolonged hepatitis B surface antigen (HBsAg) reduction with a favorable safety profile following 4 weeks of treatment in participants with chronic hepatitis B virus (HBV) infection. The objective of the phase 2b study B-Clear is to access the efficacy and safety of bepirovirsen in participants with chronic HBV infection. B-Clear is a phase 2b, multicenter, randomized, partial-blind (sponsor/participant-blinded, investigator-unblinded) study in participants with chronic HBV infection receiving stable nucleos(t)ide analogue (On-NA) or not currently receiving NA therapy (Not-on-NA). Eligibility criteria included HBsAg > 100 IU/mL, HBV DNA < 90 IU/mL (On-NA) or > 2000 IU/mL (Not-on-NA), and alanine aminotransferase ≤ 2 × upper limit of normal (ULN; On-NA) or < 3 × ULN (Not-on-NA). Participants were randomized 3:3:3:1 to one of four treatment arms, with treatment administered weekly as subcutaneous injections with or without loading doses (LD) on days 4 and 11: bepirovirsen 300 mg (with 300 mg LD) for 24 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then bepirovirsen 150 mg for 12 weeks; bepirovirsen 300 mg (with 300 mg LD) for 12 weeks then placebo for 12 weeks; placebo for 12 weeks (with placebo LD) then bepirovirsen 300 mg without LD for 12 weeks. The primary endpoint of the study was HBsAg < lower limit of detection and HBV DNA < lower limit of quantification for 24 weeks after the end of bepirovirsen treatment in the absence of rescue medication. The study enrolled 457 participants (On-NA, n = 227; Not-on-NA, n = 230) and the last patient visit occurred in March 2022. The novel design of the B-Clear study will allow assessment of HBsAg and HBV DNA seroclearance post bepirovirsen treatment discontinuation in the presence and absence of background NA therapy. ClinicalTrials.gov (NCT04449029; GSK study 209668).

Background and Aims:Functional cure, which requires sustained hepatitis B surface antigen (HBsAg) loss after treatment cessation, is currently the optimal treatment endpoint for chronic hepatitis B virus infection. We performed a systematic literature review (SLR) and meta-analyses to assess the association between HBsAg loss and long-term clinical outcomes. Methods:We performed a SLR of scientific literature published in Medline and Embase reporting the incidence of cirrhosis, hepatic decompensation (HD), hepatocellular carcinoma (HCC), liver-related mortality (LRM), and all-cause mortality (ACM) in relation to HBsAg status. Bayesian hierarchical commensurate prior meta-analyses synthesized evidence on the association between HBsAg loss and each outcome. Results:Thirty-eight studies, comprising 50,354 patients with 350,734 patient-years of follow-up, were included in the meta-analyses, reporting on cirrhosis (n = 12), HD (n = 12), HCC (n = 36), LRM (n = 12), and ACM (n = 16). Pooled incidence rate ratios (IRRs; vs HBsAg persistence) and respective credible intervals (Crls) were 0.28 (0.060-1.070) for cirrhosis, 0.13 (0.013-0.38) for HD, 0.27 (0.11-0.53) for HCC, 0.17 (0.028-0.61) for LRM, and 0.64 (0.24-1.17) for ACM. Single-predictor-adjusted IRRs remained consistent with those from the primary analyses for all outcomes except cirrhosis and LRM. Outcome incidence rates were modified by selected study, patient and infection characteristics, but trended in the same direction of reduced risk after loss. Conclusion:Overall, HBsAg loss was associated with a reduced risk of most clinically relevant outcomes. While the magnitude of the effect differed across subgroups, the direction of the association remained similar. Our results validate the need to develop new strategies to achieve HBsAg loss.

Chronic hepatitis B virus (HBV) infection is associated with significant global morbidity and mortality. Low treatment rates are observed in patients living with HBV; the reasons for this are unclear. This study sought to describe patients’ demographic, clinical and biochemical characteristics across three continents and their associated treatment need. This retrospective cross-sectional post hoc analysis of real-world data used four large electronic databases from the United States, United Kingdom and China (specifically Hong Kong and Fuzhou). Patients were identified by first evidence of chronic HBV infection in a given year (their index date) and characterized. An algorithm was designed and applied, wherein patients were categorized as treated, untreated but indicated for treatment and untreated and not indicated for treatment based on treatment status and demographic, clinical, biochemical and virological characteristics (age; evidence of fibrosis/cirrhosis; alanine aminotransferase [ALT] levels, HCV/HIV coinfection and HBV virology markers). In total, 12,614 US patients, 503 UK patients, 34,135 patients from Hong Kong and 21,614 from Fuzhou were included. Adults (99.4

Background In the B-Clear study, bepirovirsen 300 mg for 24 weeks achieved hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA

Figure: Liver inflammation and fibrosis in chronic hepatitis B with different phases of natural history and grey zones.

humanized liver mouse, 14 days of GLS4 (5 μM) and HEC121120 (2 μM) treatment resulted in suppression of HBV DNA, HBsAg and HBeAg while entecavir (ETV) had no effect on either viral antigen.To compare with similar compounds in AAV-HBV mouse model, treatment with ETV (0.1 mg/kg, QD, p.o.) and JNJ-632 (200 mg/kg, QD, s.c.) resulted in potent reduction of serum HBV DNA but no significant impact on serum HBsAg and HBeAg level.In contrast, both GLS4/RTV (25/20 mg/kg, BID, p.o.) and HEC121120 (12.5 mg/kg or 50 mg/kg, BID, p.o.) potently suppressed HBsAg and HBeAg in addition to HBV DNA.At the end of treatment, HBV DNA declined 3.6, 1.7, 3.5, 4.2, 5.5 log10 for ETV, JNJ-632, GLS4/RTV, HEC121120 (12.5 mg/kg dose) and HEC121120 (50 mg/kg dose), respectively.The mean decline for HBsAg was 1.0, 0.9, 1.4 log10 and the mean decline of HBeAg was 0.6, 0.8, 1.2 log10 for GLS4/RTV, HEC121120 low dose and HEC121120 high dose.There was no significant rebound of viral antigens in GLS4/RTV and HEC121120 treated animals during the 4week follow-up period.Furthermore, liver IHC showed HBcAg positive hepatocytes were significantly reduced in HEC121120 treated groups compared to control.Similar to GLS4, HEC121120 caused a dose dependent, self-limiting ALTelevations but at an earlier time and with increased magnitude in higher dose group of HEC121120.Concomitantly, the decrease of HBsAg correlated well with the timing and magnitude of ALT, indicative of ALT flare as a therapeutic effect.