Chronic hepatitis B (CHB) remains a major global health burden because nucleos(t)ide analogues (NAs), although highly effective in suppressing viral replication, rarely achieve functional cure. A central barrier is the exhaustion of HBV-specific T cells, a multilayered state driven by persistent antigen exposure, inhibitory receptor signaling, mitochondrial and metabolic dysfunction, transcriptional and epigenetic fixation, and the tolerogenic hepatic microenvironment. Single-target checkpoint blockade, effective in oncology, is limited in CHB by redundant inhibitory networks, providing a rationale for multi-target strategies. Traditional Chinese medicine (TCM), characterized by multicomponent and multitarget pharmacology, has been widely used as an adjunctive strategy in CHB, but its relationship to antiviral immunity remains incompletely defined. This review synthesizes mechanistic, preclinical, and clinical evidence on TCM-derived phytochemicals and compound formulas in the context of HBV-specific T cell exhaustion. The novelty of this review lies in using T cell exhaustion as the organizing framework to distinguish five mechanistic axes of TCM action: reduction of viral antigen burden, modulation of checkpoint and costimulatory pathways, restoration of metabolic fitness, regulation of transcriptional or epigenetic programs, and remodeling of the hepatic immune microenvironment. Current evidence suggests that many TCM-related benefits are more readily explained by suppression of HBV replication and indirect reduction of antigen-driven T cell dysfunction than by definitive T cell-intrinsic reprogramming. Clinical studies indicate that TCM combined with NAs may improve virological, biochemical, and serological outcomes, including HBeAg seroconversion and HBsAg decline, but functional cure rates remain limited and immunological endpoints are rarely assessed. Key challenges include mechanistic ambiguity, variable formulation quality, pharmacokinetic uncertainty, and region-specific clinical evidence. Future biomarker-driven studies integrating standardized formulations, pharmacokinetic validation, and HBV-specific T cell profiling are needed to establish whether, and under what conditions, TCM can contribute to durable immune control and functional cure in CHB.

Chronic liver diseases and periodontitis are prevalent inflammatory disorders that impose substantial global health and economic burdens. Increasing evidence supports an oral-hepatic axis through which periodontal dysbiosis and chronic oral inflammation may influence hepatic homeostasis and disease progression. Epidemiologic studies have linked periodontitis with metabolic dysfunction-associated steatotic liver disease (MASLD), nonalcoholic fatty liver disease (NAFLD), viral hepatitis, cirrhosis, and hepatocellular carcinoma. Although many associations persist after adjustment for shared risk factors, including obesity, diabetes, smoking, nutritional status, and socioeconomic factors, the independent contribution of periodontitis to liver disease remains unclear. Experimental and translational studies indicate that periodontal pathogens and their virulence factors promote systemic inflammation, endotoxemia, microbial translocation, immune dysregulation, and alterations in gut microbial ecology. Nutritional factors may further influence these interactions through their effects on host immunity, inflammation, and microbial communities. Together, these mechanisms converge along the oral-gut-liver axis to activate hepatic inflammatory, oxidative stress and profibrotic pathways that contribute to steatosis, immune activation, and fibrogenesis. Emerging evidence suggests that trained immunity, driven by metabolic and epigenetic reprogramming, may represent an additional mechanism linking periodontitis and liver disease warranting future studies. Preliminary studies indicate that periodontal therapy may reduce systemic inflammatory burden and improve hepatic biomarkers; however, evidence for an effect on liver disease progression or clinical outcomes remains limited. Similarly, hepatic dysfunction may exacerbate immune dysregulation and periodontal breakdown, reinforcing an inflammatory loop. However, overall causal relationships remain to be established. This review summarizes current epidemiological, clinical, and mechanistic evidence linking periodontitis and chronic liver diseases, highlighting the oral-gut-liver axis, shared immunometabolic and nutritional pathways. Understanding these interactions shows the significance of integrated dental-medical care and opens new avenues for prevention and adjunctive therapy to sustain oral and hepatic health.

The limited efficacy and tolerability of interferon (IFN)-based therapies make refining patient selection a critical step towards achieving a functional cure in chronic hepatitis B (CHB). The novel GOLDEN model, based on sequential changes in quantitative HBsAg (qHBsAg), accurately predicts hepatitis B surface antigen (HBsAg) loss in patients with CHB receiving nucleos(t)ide analogue (NA) therapy. However, it remains unvalidated in patients receiving sequential pegylated IFN α-2b (Peg-IFN α-2b)-based therapy. We aim to validate the GOLDEN model and the optimised cut-off value for the predictive index (Pi) to prospectively identify optimal candidates for clinical cure among patients receiving sequential Peg-IFN α-2b therapy using pre-IFN treatment qHBsAg kinetics across multiple centres.

Chronic hepatitis B virus (HBV) infection remains an important unmet medical need with 240 million patients worldwide. The HBV capsid assembly process has emerged as a key target for more efficient antiviral intervention. Pevifoscorvir sodium (ALG-000184), an oral prodrug of the potent HBV capsid assembly modulator (CAM) ALG-001075 showed significant reductions in HBV DNA, HBV RNA and other viral antigens (HBsAg, HBcrAg and HBeAg) in Phase I clinical participants with chronic HBV infection. We aim to characterize the antiviral properties of ALG-001075. ALG-001075 is a highly potent CAM that inhibited HBV DNA production in cellular settings with EC50 values below 1 nM and an EC99.9 value of only 22 nM. ALG-001075 was shown to induce the formation of empty, but not aberrant viral particles as demonstrated by fluorescence quenching, electron microscopy, size-exclusion chromatography, immunofluorescent staining and NMR analysis, thereby classifying it as a CAM-E. Notably, solid-state NMR spectra of wild-type capsids in the presence of ALG-001075 revealed a characteristic CAM-E fingerprint at atomic resolution. ALG-001075 showed potent antiviral activity against HBV strains from genotypes A-J, nucleoside analogue-resistant virus strains and known CAM-resistance mutations, with the exception of T33N, T33P and V124G, which induced 6-to-28-fold loss in ALG-001075 activity. The in vivo efficacy of ALG-001075 was confirmed in adeno-associated virus-HBV mice, where ALG-001075 demonstrated up to 5 log10 reduction in circulating HBV DNA levels. Because of its robust antiviral potency and favorable preclinical resistance profile, ALG-001075 was selected for further clinical development under the form of its prodrug pevifoscorvir sodium.

Although metabolic, viral, and drug- and alcohol-related etiologies are a familiar part of the evaluation of elevated liver enzymes, less common causes include autoimmune hepatitis, Wilson disease, and hereditary hemochromatosis. Each has a progressive course to end-organ damage underscoring the importance of early recognition, as effective therapies are available. Autoimmune hepatitis is an immune-mediated liver disease, with a female predominance and autoantibodies present in about 80% of cases. It can progress rapidly without treatment. Liver biopsy featuring lymphoplasmacytic hepatitis is needed for diagnosis and to determine the intensity of immunosuppression. Wilson disease is caused by biallelic variants in the ATP7B gene resulting in copper accumulation in the liver, brain, kidneys, and corneas. Diagnosis relies on clinical findings, laboratory data, and genetic testing results. Lifelong chelation therapy is required. Hereditary hemochromatosis is characterized by iron overload, usually due to a common variant in the HFE gene with variable disease penetrance; it is prevalent in people of Northern European ancestry. Untreated hemochromatosis leads to cirrhosis and hepatocellular carcinoma. Early diagnosis and initiation of phlebotomy can result in normal life expectancy. To facilitate early diagnosis, genetic testing of first-degree relatives is recommended for those with Wilson disease or hemochromatosis.

Hepatitis C virus (HCV) remains a major global public health concern due to the absence of an effective vaccine and its diversity, which complicate diagnosis, genotyping, and clinical management despite the widespread use of direct-acting antivirals (DAAs). In regions where multiple HCV genotypes co-circulate, inter-genotypic recombination represents an additional challenge for accurate classification and molecular surveillance. In this study, we investigate the presence and characterize inter-genotypic recombinant strains of HCV in Cameroon. Among 512 chronically infected patients initially genotyped by Sanger sequencing of Core and NS5B regions, 10 samples (1.9%) showed genotypic discordance, suggesting putative recombination. Whole-genome sequencing using Oxford Nanopore technology, combined with phylogenomic and recombinant analysis, confirmed the recombinant nature of all 10 isolates. Most recombinant (7/10) shared a unique breakpoint in the NS2/NS3 region, primarily displaying a genotype 2/1 genomic profile, while one group had a breakpoint in the E2/p7 region (genotype 4/1 genomic profile). One isolate exhibited a more complex structure with two successive breakpoints (4/2 followed by 2/1). Genotypes 1 and 2 were the most frequently involved parental lineages. These findings demonstrate the ongoing circulation of diverse natural HCV recombinant forms in Cameroon and identify genomic regions that appear preferentially involved in recombination events. Our results highlight the limitations of genotypic approaches based on partial genomes and underscore the importance of comprehensive genomic characterization to improve HCV genotype classification, surveillance, and therapeutic strategies in Central Africa.

Autoimmune hepatitis (AIH) is a chronic immune-mediated liver disease diagnosed by the clustering of compatible biochemical, serological, and histological features after exclusion of competing causes. Concurrent biliary obstruction or drug-induced injury can obscure the underlying autoimmune process and misdirect the initial diagnosis toward a purely obstructive or toxic cause. A 65-year-old woman with a remote cholecystectomy presented with one week of painless jaundice, dark urine, fatigue, and pruritus on a background of a year of slowly progressive aminotransferase elevation. She had also completed an unprescribed two-week course of oral ivermectin shortly before presentation. Admission studies showed marked hepatocellular injury (aspartate aminotransferase (AST): 2,109 U/L, alanine aminotransferase (ALT): 1,652 U/L), conjugated hyperbilirubinemia (total bilirubin: 8.4 mg/dL), mildly elevated alkaline phosphatase (ALP) (253 U/L), hypergammaglobulinemia (globulin: 5 g/dL; subsequent immunoglobulin G (IgG): 2,925 mg/dL), and an international normalized ratio (INR) of 1.6. With a negative viral hepatitis panel, a normal acetaminophen level, and bland cross-sectional imaging, empiric intravenous corticosteroids were begun on hospital day 2. Aminotransferases and bilirubin fell briskly over the next 72 hours, before any mechanical relief of obstruction. Magnetic resonance cholangiopancreatography (MRCP) on hospital day 4 revealed a 7-mm common bile duct stone, extracted at endoscopic retrograde cholangiopancreatography on hospital day 5. Smooth muscle antibody (SMA) returned at a titer of ≥1:640, with negative antinuclear antibodies (ANA) and antimitochondrial antibodies (AMA), a profile consistent with type 1 AIH. By a simplified International Autoimmune Hepatitis Group (IAIHG) score of 6, the combination of high-titer SMA, markedly elevated IgG, and a corticosteroid response that preceded biliary decompression identified AIH as the most likely dominant driver of injury, with choledocholithiasis as a concurrent second insult and ivermectin as a possible contributor of indeterminate magnitude. Obstructive imaging findings can anchor clinicians away from a concurrent, treatable autoimmune process, and a corticosteroid response that precedes mechanical decompression carries genuine diagnostic weight. Because histology was not obtained during the index admission, the relative contributions of the biliary stone and ivermectin cannot be fully excluded; long-term follow-up, including confirmatory biopsy and a structured trial of corticosteroid withdrawal, will clarify whether the disease is best classified as idiopathic AIH unmasked by concurrent insults or as a drug-related variant.