BACKGROUND AND AIM:Chronic hepatitis B virus (HBV) infection persists due to the dysfunction of virus-specific CD8+ T cells. High HBV antigen levels impair the success of therapeutic vaccination. The influence of viral titers on vaccine-induced immunity remains to be fully elucidated. We compared the kinetics of vaccine responses in low- and high-titer HBV carrier mice to identify tipping points and dissect the decisive steps determining the outcome of therapeutic vaccination. METHODS:We established low- and high-titer persistent HBV replication in the livers of immunocompetent C57BL/6J mice using adeno-associated-virus (AAV)-HBV and administered TherVacB, a heterologous protein prime-modified vaccinia Ankara boost vaccine. Serum and liver samples were collected during vaccination and subsequently longitudinally to analyze HBV-specific immune responses and viral parameters. RESULTS:HBV antigen levels before vaccination did not significantly influence the anti-HBs response (p>0.9); however, they had a significant effect on the vaccine-induced CD8 T-cell response. TherVacB induced, activated core-specific CD8+ T cells efficiently infiltrated into the liver in low- and high-titer HBV carriers. Low-titer HBV carrier mice achieved sustained viral clearance and memory T-cell formation, whereas high-titer mice exhibited only transient viral reduction, followed by CD8+ T-cell dysfunction and failure to clear the infection. The persistence of HBV infection and constant exposure to high antigen levels led to the overexpression of exhaustion markers, such as PD-1 and TOX (p<0.01), as well as the co-stimulatory receptor 4-1BB (p<0.01). Core-specific CD8+ T cells remained trapped in the liver, progressively lost their effector function, and were eventually eliminated. CONCLUSIONS:These findings identify critical time points that influence vaccine-induced CD8 T-cell responses, suggesting that early intervention targeting T-cell dysfunction may enhance therapeutic vaccination outcomes in chronic HBV infection. IMPACT AND IMPLICATIONS:This study demonstrates that baseline HBV antigen load critically determines the durability of vaccine-induced CD8+ T-cell immunity. While therapeutic vaccination initially elicited liver-infiltrating, HBV-specific CD8+ T cells irrespective of the viral titer, only low-titer infection permitted sustained viral clearance and memory T-cell formation. In high-titer HBV carriers, persistent antigen exposure drove progressive T-cell exhaustion and deletion, resulting in transient viral control and treatment failure. Importantly, the data identify a critical time window in which early intervention to prevent or reverse T-cell dysfunction may be decisive. Clinically, these findings support combining therapeutic vaccination with antigen-lowering or immunomodulatory strategies applied early to achieve durable immune control in chronic HBV infection.
BACKGROUND AND AIMS:Extrahepatic organ failures are key determinants of acute-on-chronic liver failure (ACLF). While the role of systemic inflammation and mitochondrial dysfunction in the pathogenesis of ACLF is well known, the contribution of the liver itself is less understood. We therefore performed transcriptome and functional analyses of the liver in order to identify hepatic drivers of ACLF. METHODS:Bulk-RNA sequencing and spatial transcriptomics were performed in liver specimens from patients with compensated cirrhosis, decompensated cirrhosis or ACLF. In addition, detailed analyses of genes involved in energy metabolism, as well as a metabolome analysis and functional analyses were performed. RESULTS:In total, 39 patients were included (9 compensated cirrhosis, 15 decompensated cirrhosis, 15 ACLF). ACLF was associated with changes in the hepatic transcriptome, clearly distinct from compensated and decompensated cirrhosis. Most strongly downregulated in ACLF were pathways involved in substrate metabolism and mitochondrial function, including downregulation of multiple genes of glucose and amino acid metabolism. In line, spatial transcriptomics revealed a breakdown of the functional liver zonation in ACLF, with decreasing proportions of hepatocytes specialized in gluconeogenesis/β-oxidation (compensated cirrhosis 68%, decompensated cirrhosis 52%, ACLF 12%; P<0.03). Branched chain ketoacid dehydrogenase kinase (BCKDK), a key regulator of branched-chain amino acid catabolism, was strongly downregulated in ACLF (0,33- fold expression vs. compensated cirrhosis, P<0.05) and may link dysregulation of branched-chain amino acid and glucose metabolism. CONCLUSION:ACLF is characterized by distinct changes in the hepatic transcriptome, which affect key pathways in substrate metabolism and mitochondrial function and are associated with loss of functional liver zonation. Downregulation of BCKDK in ACLF might be of particular interest, as it links altered branched-chained amino acid metabolism to impaired glucose production. IMPACT AND IMPLICATIONS:Extrahepatic organ failures are well known features of acute-on-chronic liver failure (ACLF), but the contribution of the liver itself to their pathogenesis is not well understood. By RNA sequencing and spatial transcriptomics of liver specimens, we could identify profoundly impaired metabolic and mitochondrial hepatic programs, suggesting that the liver might play a key role in the development of extrahepatic organ failures by compromising the body's energy supply. These findings are important since they provide a rationale for further studying molecular targets in the liver as therapeutic strategies for ACLF.
Background & Aims Despite growing consensus of guidelines supporting screening for MASLD using non-invasive tests (NITs) in high-risk populations, access to NITs remains limited across the U.S. and E.U. Cost-effectiveness analyses of multimodal NIT strategies are needed to support implementation, address access challenges and inform coverage decisions. Methods A decision-analytic Markov model was developed to evaluate the cost-effectiveness of five multimodal NIT strategies for MASLD in hypothetical cohorts of patients with type 2 diabetes across six U.S. and European markets, compared with no screening; univariate and probabilistic sensitivity analyses were conducted to assess uncertainty. Results Multi-step non-invasive screening strategies were cost-effective compared with no screening across all countries, with ICERs ranging from dominance to £18,572 per QALY gained. In Germany, France, Italy and the US, at least one strategy dominated no screening. Probabilistic sensitivity analysis demonstrated robust cost-effectiveness, with multi-step non-invasive strategies demonstrating a 90-100% probability of cost-effectiveness across countries. Screening strategies involving liver biopsy were dominated by no screening in all settings. Conclusion Multi-step non-invasive screening strategies represent a cost-effective approach to improving adherence to guideline-based MASLD care in high-risk populations. As therapeutics capable of reversing fibrosis stages enter the market, the value of screening may increase further. Future research should focus on evaluating the economic impacts of longer-term care and emerging MASH therapeutics. Impact and Implications This paper uses a Markov model to evaluate five strategies for the screening and treatment of MASH in a hypothetical cohort of patients with T2DM in the UK, France, Germany, Spain, Italy, and the US. Despite professional guidelines recommending the use of non-invasive tests to screen and inform care delivery for patients high-risk for advanced fibrosis due to MASH, adoption and payer coverage of non-invasive tests remain limited in many markets. Clinicians, payers, and policymakers may consider the findings presented within this paper, which validate the cost-utility of guidelines-recommended non-invasive screening approaches in high-risk populations, when developing institutional protocols or coverage policies. As approved therapeutics (e.g., resmetirom, semaglutide) enter the market, the value proposition for cost-effective screening strategies will likely continue to grow.
Autoimmune hepatitis (AIH) is a rare, complex and chronic immune-mediated disease in which loss of tolerance to hepatocyte antigens leads to T-cell-driven liver inflammation, typically associated with autoantibodies and elevated IgG. The understanding of disease mechanisms is limited, patient presentations are heterogeneous, and clinical care varies. Predniso(lo)ne and azathioprine or mycophenolate mofetil are the first-line treatments. These medications are life-saving, but lack specificity, and are marred by side-effect profiles that negatively affect adherence and quality of life. Less than 70% of patients achieve a complete biochemical response (normalization of aminotransferases and IgG) by 6 months, and more than 20% develop side effects that require discontinuation. In addition, current medications have high rates of relapse after discontinuation. Evidence of second- and third-line treatments is mainly built on real-world studies without control groups. In addition, people with AIH experience symptoms that affect their well-being, such as fatigue, depression, anxiety, cognitive dysfunction and mood changes. Several gaps in AIH management persist, including a lack of validated questionnaires to capture specific symptoms and complaints, lack of recognized endpoints for clinical trials supported by regulatory agencies, and special AIH populations are understudied and outcomes beyond liver enzymes are underrepresented. In this review, we provide a detailed appraisal of current gaps in the management, discuss special populations, and recent advancements of new agents for AIH, summarizing evidence regarding how these agents could reduce the side effects of current treatment, potentially improving the quality of life of people living with AIH.
