BACKGROUND & AIMS:The impact of hepatitis B surface antigen (HBsAg) reduction from small interfering RNA (siRNA) treatments on hepatitis B virus (HBV)-specific immunity of individuals with chronic hepatitis B (CHB) has not been adequately analyzed in humans. We conducted a phase 2a study treating CHB participants with nine 4-weekly doses of HBV-targeted siRNA elebsiran (BRII-835), either alone (n = 10) or in combination with a virus-like particle-based therapeutic vaccine (BRII-179) containing Pre-S1, Pre-S2, and S antigens, coadministered with (n = 39) or without (n = 41) interferon alfa. METHODS:We analyzed longitudinally for 72 weeks virologic, clinical, and immunologic parameters, including HBsAg, alanine aminotransferase, hepatitis B surface antibody (anti-HBs), the neutralizing activity of representative sera, and frequency and cytokine secretion ability of T cells specific for Pre-S1, Pre-S2, and S both directly ex vivo and after in vitro expansion. RESULTS:Combination therapy with elebsiran and BRII-179 was well tolerated. Although no sustained HBsAg seroclearance or notable difference in mean HBsAg reduction at the group level was observed, we detected marked heterogeneity in immunologic responses among groups. HBsAg reduction mediated by siRNA alone was associated with minimal HBV-specific immune response recovery. In contrast, combination of elebsiran with BRII-179 induced a significant modification of immune responses demonstrated by anti-HBs antibody production and an expansion of interleukin 2-producing helper T cells specific for Pre-S1/Pre-S2 antigens only. Importantly, anti-HBs antibodies persisted at ≥100 IU/L in ∼40% of the participants for at least 32 weeks after combined treatment. Moreover, the neutralizing ability of the anti-HBs-positive sera was associated with HBsAg reduction. CONCLUSIONS:siRNA-induced HBsAg reduction may contribute to the persistence and efficacy of the humoral arm of HBV-specific adaptive immunity in CHB participants receiving the therapeutic vaccine BRII-179. CLINICALTRIALS:gov number: NCT04749368.

Hepatitis B virus (HBV) DNA integration into the host cell genome is reportedly a major cause of liver cancer, and a source of hepatitis B surface antigen (HBsAg). High HBsAg levels can alter immune responses which therefore contributes to the progression of HBV-related disease. However, to what extent integration leads to the persistent circulating HBsAg is unclear. Here, we aimed to determine if the extent of HBV DNA integration is associated with the persistence of circulating HBsAg in people exposed to HBV. We established a digital droplet quantitative inverse PCR (dd-qinvPCR) method to quantify integrated HBV DNA in patients who had been exposed to HBV (anti-HBc positive and HBeAg-negative). Total DNA extracts from both liver resections (n = 32; 14 HBsAg-negative and 18 HBsAg-positive) and fine-needle aspirates (FNA, n = 10; 2 HBsAg-negative and 8 HBsAg-positive) were analysed. Using defined in vitro samples for assay establishment, we showed that dd-qinvPCR could detect integrations within an input of <80 cells. The frequency of integrated HBV DNA in those who had undergone HBsAg loss (n = 14, mean ± SD of 1.514 × 10−3 ± 1.839 × 10−3 integrations per cell) was on average 9-fold lower than those with active HBV infection (n = 18, 1.16 × 10−2 ± 1.76 × 10−2 integrations per cell; p = 0.0179). In conclusion, we have developed and validated a highly precise, sensitive and quantitative PCR-based method for the quantification of HBV integrations in clinical samples. Natural clearance of HBV is associated with fewer viral integrations. Future studies are needed to determine if dynamics of integrated HBV DNA can inform the development of curative therapies.

The Australasian Virology Society (AVS) holds premier biennial virology meetings that foster multidisciplinary research and collaboration and promote equity and inclusion of early-career researchers. The 12th AVS meeting (AVS12), convened by M. Tate, J. Fraser, and G. Moseley, was held from 2 to 5 December 2024 on Dja Dja Wurrung country at the RACV Goldfields Resort in Creswick, Victoria, Australia. In this report, we give a brief overview of the history of AVS and outline the current and developing priorities for the society. We provide a summary of the insightful panel discussions held to address career development and Indigenous virology, highlight the presentations given by international plenary speakers Joe Grove and Chantal Abergel, and celebrate the recipients of the numerous awards.

BACKGROUND & AIMS:REP 2139-Mg (REP), a nucleic acid polymer, blocks HBV subviral particle assembly and HDV replication. We report the outcomes of REP treatment in patients with HDV enrolled in a compassionate access program (NCT05683548). METHODS:Thirty-three patients with HDV and advanced chronic liver disease received weekly subcutaneous REP 250 mg plus a nucleotide analogue for a planned 48-week treatment course. Pegylated interferon-α (PegIFN) 45-180 μg weekly was added in 20 patients without contraindications. Safety and efficacy were assessed regularly, and intrahepatic markers were evaluated in one liver explant. RESULTS:Among the 33 patients (age 21-69 years; 21 males), 85% (28/33) had prior treatment failure, and six had decompensated cirrhosis (ascites in five). Suboptimal responses to REP were managed with dose modifications (250 mg intravenously or 500 mg subcutaneously or intravenously) and/or treatment extension in 21 patients. At end of therapy, HDV RNA declined by >2 log10 in 70% (23/33) and became undetectable in 58% (19/33). HBsAg loss occurred in 27% (9/33). Among the 28 patients with available follow-up, HDV RNA and HBsAg remained undetectable in 46% (13/28) and 18% (5/28), respectively. ALT normalized in 50% (14/28). Responses were similar with or without PegIFN. Ascites improved in two of five affected patients. Three patients underwent liver transplantation while receiving REP without complications. In one liver explant, HDV RNA and HDAg were undetectable, and intrahepatic covalently closed circular DNA activity and HBsAg levels were very low. No REP-related serious adverse events were observed. CONCLUSIONS:REP treatment was safe and effective in patients with HDV and advanced chronic liver disease. REP may induce sustained virological response of HDV and functional cure of HBV, independent of PegIFN co-administration. Clinical improvement may also occur in patients with decompensated cirrhosis. IMPACT AND IMPLICATIONS:No approved antiviral therapy exists for patients with chronic hepatitis D (CHD) and decompensated cirrhosis, or for those who have failed bulevirtide and/or pegylated interferon. In the Replicor Compassionate Access Program, 33 patients with CHD and advanced chronic liver disease received REP 2139-Mg (REP) plus a nucleotide analogue, with or without pegylated interferon. HBsAg loss occurred in 27% at end of treatment and remained undetectable in 18% after 1 year, indicating sustained HDV virological response and HBV functional cure. Among six patients with decompensated cirrhosis, five achieved a virological response and two showed clinical improvement with reduced ascites. No REP-related serious adverse events were observed. Overall, REP demonstrated promising efficacy and acceptable tolerability in this difficult-to-treat population and warrants evaluation in a response-guided clinical trial.

BACKGROUND:Current literature informs us that bivalent vaccines will generate a broader serum neutralizing antibody response to multiple SARS-CoV-2 variants, but studies on how this breadth relates to the memory B cell (MBC) and T cell responses are sparse. This study compared breadth of neutralising antibody, and memory B and T cell responses to monovalent or a bivalent ancestral/Omicron BA.1 COVID-19 booster vaccine. METHODS:At baseline and 1-month post-booster, neutralisation activity and frequencies of receptor binding domain (RBD)-specific MBCs and Spike-specific memory T cells were measured against a panel of variants. FINDINGS:Both vaccines boosted neutralising antibodies to 5 variants - Wuhan-Hu-1, Delta, BA.1, BA.5 and JN.1, the latter of which had not yet emerged at the time of sample collection. The bivalent vaccine induced a significantly larger increase in nAb against BA.1 and JN.1. Both vaccines boosted RBD-specific MBC responses to Wuhan-Hu-1, Delta, BA.1 and BA.5 variants with a significantly greater increase for BA.1 in the bivalent group. The breadth of MBCs was significantly higher in those who received the bivalent boost and correlated with nAb breadth. Both vaccines significantly boosted Spike-specific T cell responses to the Wuhan-Hu-1 and BA.5 variants, but only the bivalent vaccine boosted BA.1 responses. INTERPRETATION:These results suggest that the bivalent vaccine confers an advantage against future novel variants due to increased frequency of broadly reactive RBD-specific B cells. FUNDING:Work supported by NSW Health for the NSW Vaccine, Infection and Immunology Collaborative (VIIM).

Background The COVID-19 pandemic impacted patients with substance use disorder (SUD) more than the general population and resulted in substantially increased emergency department admissions. Routine care of patients attending drug health services during the pandemic transitioned, with telehealth being important in delivering appropriate care. However, telehealth introduces unique risks such as privacy, confidentiality, and data safety. Providing health care through telehealth may fail if the legal impacts are not fully identified and acted on by health professionals. It also poses unintended risks for patients and can result in ineffectiveness, damages, medical negligence, and detracts from the best intentions of governments and health professionals. Understanding the legal framework ensures that medical professionals operate health care through telehealth within the law. Providing health care successfully through telehealth depends on the balance between innovation and legal compliance. By considering these aspects, clinicians and practitioners can provide effective and safe telehealth services during pandemics or any other natural disaster. Objective We aimed to explore the legal impact of autonomy consent, confidentiality, privacy, data security, professional indemnity, and liability when delivering telehealth to patients with SUD. The scoping review also aimed to provide legal, ethical, and clinical considerations to minimize legal risks with using telehealth in drug health service outpatient settings. Methods We performed a scoping review to provide an overview of existing research, statutes, and case laws for the incorporation of clinical, ethical, and legal considerations into telehealth use. Six databases for medical and 6 databases for legal publications were searched, as well as Australian national and selected international regulatory standards. Medical articles published up to June 2022 were included in this review. Our search yielded 1436 publications, 614 abstracts were reviewed, and 80 published studies met the inclusion criteria from 614 legal and medical search results. Current regulations related to technology use in drug health services, relevant cases, and international regulatory standards are discussed. Results In total, 43 legal documents including 15 statutes, 4 case laws, and 37 medical publications were reviewed. The themes arising from the literature were consent and autonomy (20/80, 25%), confidentiality (8/80, 10%), privacy (8/80, 10%), data security (7/80, 9%), and professional indemnity issues (3/80, 4%) in telehealth use. Further, 24 studies identified legal issues associated with telehealth use in patients with SUD. Conclusions Our review identified potential legal issues associated with telehealth use in patients with SUD. Several legal and medical research articles provide frameworks, codes of conduct, or suggestions for clinicians to consider, but there was little discussion or evidence of how legal considerations are being applied when providing telehealth consultations at drug health services. Clinicians should be aware of the medicolegal implications when providing health care via telehealth at drug health services.

Chronic viral hepatitis is caused by hepatitis B virus (HBV), hepatitis C virus (HCV), or hepatitis D virus (HDV). Despite different replication strategies, all of these viruses rely on secretion through the host endoplasmic reticulum-Golgi pathway, providing potential host targets for antiviral therapy. Knockdown of transmembrane 6 superfamily member 2 (TM6SF2) in virus cell culture models reduced secretion of infectious HCV virions, HDV virions, and HBV subviral particles. Moreover, in a cohort of people with hepatitis B, a TM6SF2 polymorphism (rs58542926 CT/TT, which causes protein misfolding and reduced TM6SF2 in the liver) correlated with lower concentrations of subviral particles in blood, complementing our previous work showing decreased HCV viral load in people with this polymorphism. In conclusion, the host protein TM6SF2 plays a key role in secretion of HBV, HCV, and HDV, providing the potential for novel pan-viral agents to treat people with chronic viral hepatitis. Chronic hepatitis viruses HBV, HCV, and HDV all rely on endoplasmic reticulum-Golgi secretion. Knocking down the host gene TM6SF2 in cell culture models reduces secretion of HBV, HCV, and HDV particles, offering the potential for pan-viral therapies to treat chronic hepatitis. Graphical Abstract

Objectives: Bacille Calmette-Gu & eacute;rin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. Design: Phase III double-blind randomised controlled trial. Setting: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. Participants: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. Intervention: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). Main outcome measures: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARSCoV-2 na & iuml;ve at inclusion). Results: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12- month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for >= 3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. Conclusions: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).