The early diagnosis of infections in acute-on-chronic liver failure (ACLF) is still difficult. mNGS(metagenomic next-generation sequencing) is a no-bias, sensitive pathogen diagnosis method, and further research on mNGS in ACLF is needed. A total of 275 ACLF patients with suspected or confirmed infections were recruited and divided into the mNGS group and the non-mNGS group. Differences between the two groups were assessed. The 1:1 Propensity score matching (PSM) for balancing the baseline variables produced 86 patients in each group. From these 86 patients in the mNGS group, 134 samples were collected and analyzed. The overall microbiological positive rate (103/134, 76.9

Introduction. The correlation between antibiotic exposure and adverse outcomes in patients with acute-on-chronic liver failure (ACLF) remains controversial, and the underlying mechanism is unclear. Hypothesis/Gap Statement. This study hypothesizes that antibiotic exposure in ACLF patients alters gut microbiota, which affects the outcome of ACLF. Aim. To explore the effect of antibiotic exposure on gut microbiota that affects the outcome of ACLF. Methodology. A retrospective matched study of ACLF patients and the ACLF rat model was used to assess adverse outcomes associated with antibiotic exposure. The gut microbiota of the ACLF patients and the ACLF rat model were sequenced using the Illumina MiSeq platform. Results. Twenty-three ACLF patients who were exposed to antibiotics and 46 matched controls who were not exposed to antibiotics were enrolled. The survival rates at 4, 12 and 24weeks were significantly lower in the exposure group than in the non-exposure group. In the ACLF rat model, hepatitis in the antibiotic-exposure group became more severe, and the alanine transaminase levels were higher than those of the non-exposure group. The gut microbiota diversity was decreased in the ACLF patients with antibiotic exposure, and the proportions of Enterococcaceae and Peptostreptococcaceae were increased, while those of Lachnospiraceae, Bifidobacteriaceae and Bacteroidaceae were decreased. In the rat model, antibiotic exposure induced Gram-positive and Gram-negative bacterial eradication, and Klebsiella became the dominant micro-organism. Conclusion. Antibiotic exposure aggravated hepatitis and had no survival benefit for ACLF. The underlying mechanism may be related to dysbiosis in the gut microbiota.

Objectives: GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that inhibits HBV replication by interfering with assembly and disassembly of the virus nucleocapsid, this prospective, open-label, comparative, phase 2b trial evaluated the antiviral activity and safety of GLS4/ritonavir (RTV) combined with entecavir in hepatitis B e antigen-positive patients. Methods: 250 CHB patients were enrolled, including treatment-na & iuml;ve patients and those interrupted anti-HBV drugs for >= 6 months (Part A, n=125), and patients who had taken ETV for >= 1 year and had achieved viral suppression (Part B, n=125). Patients were randomly allocated to receive 120 mg GLS4/100 mg RTV plus 0.5 mg ETV or 0.5 mg ETV monotherapy for 96 weeks. Results: In the mid-term, in Part A (n=122), greater least-squares mean (LSM) changes from baseline were observed in the GLS4/RTV plus ETV cohort than in ETV monotherapy cohort in HBV DNA (-6.28 vs -5.72 log10 IU/ml, p=0.0005), HBsAg (-0.87 vs -0.65 log10 IU/ml, p=0.0653), HBV pgRNA (-3.83 vs -1.91 log10 copies/ml, p<0.0001); The proportions of both HBV DNA and pgRNA negative patients were 17.3% (13/75, GLS4/RTV plus ETV) and 0% (0/30, ETV monotherapy). In Part B (n=123), greater mean LSM reductions in HBsAg (-0.17 vs -0.06 log10 IU/ml, p=0.0013), HBV pgRNA (-1.61 vs -0.28 log10 copies/ml, p<0.0001) were also observed in the GLS4/RTV+ETV cohort. the proportions of both HBV DNA and pgRNA-negative patients were 71.6% (48/67, GLS4/RTV plus ETV) and 18.9% (7/37, ETV monotherapy), respectively. No patients achieved HBsAg loss at week 48. GLS4/RTV + ETV were well tolerated, the most common adverse events were elevated alanine aminotransferase levels and hypertriglyceridemia, which were reversed by temporary GLS4/RTV discontinuation. Conclusions: The primary analysis at week 48 showed that the antiviral efficacy of GLS4/RTV with ETV was clearly superior to that of ETV monotherapy. GLS4/RTV with ETV was well tolerated; further studies evaluating its safety and efficacy are ongoing. (clinical trial identifier: NCT04147208). (c) 2025 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Sarcopenia is the progressive loss of muscle mass that worsens the clinical outcomes of cirrhosis. Here, we aimed to investigate the changes in skeletal muscle index (ΔSMI) over an intermediate period of time to comprehensively elucidate its prognostic value for long-term mortality in cirrhosis. MATERIALS AND METHODS:This ambispective cohort study included patients with cirrhosis who underwent abdominal computed tomography (CT) between January 2012 and December 2021. SMI was obtained from annual CT scans at the third lumbar vertebra. The effect of the first 3 y of the annual rate of change in SMI (∆SMI/yr%) was calculated and its prognosis at the next long-term follow-up was analyzed. RESULTS:Overall, 384 patients who underwent at least two CT examinations during the first 3 y were enrolled. Here, 120 men (31.3%) and 44 women (11.5%) had sarcopenia at baseline. At an average follow-up of 71.52 mo, 257 (66.9%) patients were with liver transplantation (LT)-free. Sarcopenia defined status at 1 to 3 y tended to be a prognostic factor. Patients with a change in sarcopenia status from normal to sarcopenic had worse outcomes in terms of LT-free survival. Based on Cox and competing risk model analyses, ∆SMI/yr% was independently associated with poor survival. When separated by a cutoff of ∆SMI/yr% -2.08 derived from the receiver operating characteristic (ROC) analysis, ∆SMI/yr% < -2.08 was not associated with age, but it did significantly discriminate the patients with decompensation, bacterial infection, and severe liver dysfunction (P value < 0.05). CONCLUSIONS:SMI/yr% performs as an effective index for predicting poor long-term outcomes in patients with cirrhosis, independent of age. Early short-term monitoring of SMI could guide clinical decision-making regarding nutritional interventions in cirrhosis.

Background:As the most abundant protein in plasma, albumin (ALB) presents close association with prognosis of septic patients. Whereas, the benefit and the target level of ALB infusion remain controversial. Methods:We conducted a retrospective investigation to assess whether on-treatment ALB levels could predict 28-day mortality and try to identify the optimal level for ALB infusion. All patients diagnosed as sepsis from January 2016 to December 2020 were recruited and re-evaluated using Sepsis-3 criteria. Results:A total of 199 eligible patients were enrolled in this study. Compared with the survival group, the non-survival group had more males (73.97 vs. 56.35%), older patients (62.78 ± 15.93 vs. 56.43 ± 18.46), and a higher proportion of Gram-positive bacterial infection (27.40 vs. 23.02%), higher Sequential Organ Failure Assessment (SOFA) score (7.00-13.00 vs. 6.00-12.00), higher APACHE II score (18.25-29.00 vs. 15.00-26.00), higher PCT (2.84-49.18 vs. 2.43-19.14), more patients with septic shock (65.75%vs. 43.65%), shorter ICU-stay days (11.04 ± 6.28 vs. 14.83 ± 8.58), longer mechanical ventilation days (7.23 ± 7.07 vs. 5.04 ± 8.52), with statistically significant differences (p < 0.050). Furthermore, we identified that the ALB level on day 7 (HR, 0.920; 95% CI, 0.847 to 0.999; p = 0.046) and the maximum ALB level within the first 14 days (HR, 0.900; 95% CI, 0.838 to 0.967; p = 0.004) were independent protective factor for the 28-day prognosis in septic patients. Moreover, ROC curve analysis indicated that optimal target level for first 14-day maximum and on day 7 were 33.45 g/L and 27.85 g/L, respectively. Correspondingly, a negative correlation between ALB level and mortality was defined with Kaplan-Meier survival curve analysis. Further subgroup analysis showed that the group with ALB above the cut-off value was associated with favorable outcomes in female patients under 60 years, with SOFA score less than 7, and APACHE II score less than 19. Conclusion:ALB levels on day 7 and the maximum ALB level within first 14 days after ICU admission were closely associated with 28-day mortality. 27.85 g/L would work as the target level of ALB infusion on 7 day to improve the prognosis of sepsis patients.

The prompt and accurate prognostication of acute-on-chronic liver failure (ACLF) patients is crucial for clinical intervention and reducing mortality. This study aimed to develop a novel prognostic model based on pathological changes, with a specific focus on portal vein which is correlated with hepatic pathology. A cohort of 127 ACLF patients was enrolled to develop the prognostic model for 90-day mortality, which was validated in a prospective cohort of 105 ACLF patients. Demographic characteristics, laboratory indicators, and imaging factor portal vein diameter (PVD) were screened, and a nomogram prognostic model was developed using logistic regression. Patients with PVD ≥ 13.4 mm had significantly higher mortality (P = 0.047). PVD, age, neutrophil percentage, sex and total bilirubin were identified as independent predictors for the new PVD-based nomogram prognostic model, PANST. The C-index (0.878) of PANST score was higher than Chronic Liver Failure-Consortium-ACLF (CLIF-C ACLF), end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) scores (0.691, 0.687, 0.639, respectively; P < 0.001). The ROC and decision curves demonstrated that the PANST score was superior to CLIF-C ACLF, MELD and CTP scores. Furthermore, after subgroup analysis, the C-indices of PANST score for hepatitis B virus-related ACLF (HBV-ACLF) and non-HBV-ACLF patients (0.842,0.950) were significantly higher than those of CLIF-C ACLF score (0.772, 0.750; P < 0.05), MELD score (0.730, 0.608; all P < 0.05) and CTP score (0.701,0.513; all P < 0.05). These results were confirmed in the validation cohort. PVD was an independent predictor, and the PANST score, a novel prognostic model based on PVD can accurately predict 90-day mortality in ACLF patients.

Hemorrhagic fever with renal syndrome (HFRS) is caused by Hantavirus infection, with a case fatality rate of 0.1%-1%. We longitudinally monitored HTNV RNA kinetics in 345 plasma samples from 137 HFRS patients, with serial viral load measurements every 3 days until the virus was cleared. Our analysis showed no correlation between viremia duration and disease severity. However, the viral load during the febrile phase was identified as an independent predictor of HFRS severity. Significant differences (p < 0.001) were observed between mild and severe cases in white blood cell (WBC), procalcitonin (PCT), C-reactive protein(CRP), platelet (PLT), urea nitrogen (BUN), and creatinine (Cr). These findings suggest that immune dysregulation triggered by the virus, rather than direct cytopathic effects might drive the tissue injury. Further investigation of virus-host immune interactions is critical for informing therapeutic strategies.

Acute‐on‐chronic liver failure (ACLF) is a syndrome characterized by systemic inflammation with a high short-term mortality rate. Syndecan-1 (SDC-1) can independently predict the 90-day mortality of patients with septic shock. However, the role of SDC-1 in ACLF remains unknown. In this study, serum SDC-1 levels were examined in 2 cohorts, which included 174 ACLF patients. And a mouse ACLF model induced by tetrachloride, lipopolysaccharide, and D-galactosamine was established, to evaluate the effects of sulodexide and heparan sulfate (side chains of SDC-1) on ACLF in vivo. Baseline serum SDC-1 levels in 101 ACLF patients (847.72, 499.79–1511.37 ng/ml) were significantly higher than in healthy controls (33.58, 27.08–43.34 ng/ml) (P < 0.0001). The baseline SDC-1 levels of patients who died or accepted a liver transplantation within 90 days were markedly higher than those of patients who survived (P < 0.05). A novel prognostic model (UIAS) based on upper gastrointestinal bleeding, INR, age, and SDC-1 was developed. The AUROC of the UIAS score for 28-day deterioration in ACLF patients was 0.884, indicating an obviously greater predictive performance for the outcomes of ACLF than those of the Child‐Pugh (AUROC = 0.646), MELD (AUROC = 0.713), and COSSH‐ACLF II scores (AUROC = 0.713). Moreover, we found that heparan sulfate and sulodexide could increase the expression of SDC-1 and attenuate liver injury, by promoting liver regeneration and inhibiting cell apoptosis through the activation of JAK1/STAT3 signalling. Collectively, our findings suggest that SDC-1 represents a potential prognostic and therapeutic target for ACLF and should be further investigated.

The Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT) identifies nutritional risk in patients with liver disease, an important factor in cirrhosis outcomes. Recognizing the gap in existing prognostic models, which often overlook malnutrition, we developed and validated an RFH-NPT-based model for predicting outcomes of patients with cirrhosis. This study included inpatients with cirrhosis from a single center between February and July 2016 (training cohort) and patients from six other medical centers admitted between December 2011 and May 2022 (validation cohort). RFH-NPT assessment was conducted at admission, followed by a 5-year follow-up. A nomogram was created using prognostic variables from Cox modeling, best subset regression (BSR), and least absolute shrinkage and selection operator (LASSO) regression. Its performance was evaluated using various statistical methods and compared with that of existing models such as the Child‒Pugh, MELD, and MELD-Na. A total of 152 patients were included in the training cohort. The nutritional risk was significantly greater in nonsurvivors (81.1

The incidence of Invasive pulmonary aspergillosis (IPA) in acute-on-chronic liver failure (ACLF) population is increasing, and its diagnosis and treatment is still a major clinical conundrum. This study aimed to characterize disease-stage-specific patterns and identify independent risk factors for IPA development in ACLF. A cohort of 835 ACLF patients (Jan 2014-Aug 2023) was retrospectively analyzed. IPA diagnosis followed Invasive Fungal Infections Group of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG). Comparative analysis included 55 ACLF-IPA cases versus 163 pulmonary infection controls without IPA. Multivariate logistic regression established risk factors, with predictive performance evaluated by ROC analysis. The rate of clinical diagnosis of IPA in 835 ACLF patients was 6.6

As immunotherapy gains increasing attention and clinical application, the immune modulation therapy has been widely used in the treatment of infectious and critical diseases. Clinical evidence has been accumulated for application of thymosin alpha 1 (T alpha 1), a classical immune modulator, in related domains. The National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases and other institutions invited multidisciplinary experts to develop this expert consensus on clinical application of T alpha 1 in infectious diseases and critical care medicine. Based on the latest domestic and international research findings and considering relevant factors, including economics, patient preferences and values, tradeoffs, accessibility, fairness and acceptability, the consensus assesses the quality levels of current evidence and forms 10 recommendations on the application of T alpha 1 in treatment of liver diseases, viral infections, bacterial infections and critical illnesses. This consensus aims to enhance understanding of T alpha 1 and improving its standardized application for clinicians.

Despite the significant advances in autoimmune research, primary biliary cholangitis (PBC) remains a clinically challenging and incompletely understood disease, with its exact causes and molecular mechanisms still elusive. The immune system exerts crucial pathogenic effects throughout PBC development, from initial biliary injury to end-stage cirrhosis. Despite decades of investigation, the current understanding of PBC pathogenesis remains fragmented, particularly regarding the immune mechanisms involved in the disease. To address this, we conducted a bibliometric analysis of immunological studies on PBC, utilizing data from the Web of Science database, which covers publications from 1970 to 2023, and identified 2,042 studies for analysis. The findings revealed a steady increase in research activity over the decades. Our analysis revealed a consistent upward trend in PBC-related studies, with an average growth rate of 14.45%. The United States leads as the top contributing country, with the University of California, Davis, and Dr. Gershwin M. Eric emerging as the most influential institution and author, respectively. Among journals, Hepatology is the most prominent, with the highest number of citations and co-citations. Recent advances in diagnostic techniques have substantially improved early detection rates of PBC while dramatically decreasing instances of disease decompensation. This paradigm shift has redirected research priorities toward innovative disease management strategies and patient-centered care approaches. This synthesis presents a unified framework for PBC immunopathogenesis, pinpointing critical knowledge gaps and high-potential research trajectories in disease mechanisms and therapeutic innovation.

BACKGROUND AND AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to severe forms such as metabolic dysfunction-associated steatohepatitis (MASH). Effective treatments for MASH are urgently needed. This study aimed to evaluate the efficacy and safety of chiglitazar, a PPAR pan-agonist, in MASLD with hypertriglyceridemia and insulin resistance. APPROACH AND RESULTS:In this phase II multicenter, randomized, double-blind and placebo-controlled study, 104 patients with MASLD with hypertriglyceridemia and insulin resistance were randomized 2:2:1 to receive 48 mg, 64 mg of chiglitazar, or placebo once daily for 18 weeks. The primary endpoint was the percentage change in liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) at week 18. Chiglitazar significantly reduced liver fat content, with percentage change from baseline at week 18 of -28.1% (95% CI -37.5 to -18.7) in the 48 mg group and -39.5% (95% CI -49.0 to -30.0) in the 64 mg group, compared with -3.2% (95% CI -16.8 to 10.4) in placebo group. The differences compared with placebo were -24.9% ( p <0.05) for the 48 mg group and -36.3% ( p <0.001) for the 64 mg group. Chiglitazar also significantly improved liver injury-related biomarkers such as ALT, AST, and γ-GT. Liver fibrosis indicators, lipid parameters, insulin resistance, and metabolic syndrome showed an improved trend. Both doses of chiglitazar were well tolerated, with most adverse events being mild to moderate. CONCLUSIONS:Chiglitazar significantly reduced liver fat content in MASLD with hypertriglyceridemia and insulin resistance, with a dose-dependent effect and a favorable safety profile.

Hemorrhagic Fever with Renal Syndrome (HFRS) is a zoonotic disease caused by hantaviruses, remains a significant public health challenge in China. Despite a decline in national incidence, persistent regional outbreaks highlight a need to understand how scientific research corresponds to these evolving epidemiological patterns to better inform public health strategies. We aimed to identify the spatiotemporal correlations between HFRS incidence and research publication output in China, identifying trends and disparities to inform future research priorities. We conducted a bibliometric and spatial analysis of 3,304 Chinese articles from the China National Knowledge Infrastructure (CNKI) and 556 English articles from Web of Science (WOS) from 1981 to 2023. Provincial HFRS incidence data were correlated with publication output using Spearman’s correlation and the Geographical Detector model across distinct analytical phases. HFRS incidence declined nationally but remained concentrated in specific regions. Domestic publications (CNKI) peaked during Phase 2 (1992–2006; 120–226/year), while international publications (WOS) surged in Phase 3 (2007–2023). A strong and consistent spatial correlation was found between HFRS incidence and CNKI publication output (q > 0.49). In contrast, the correlation with WOS publications only became significance in Phase 3 (q = 0.271). Thematic analyses revealed differing research priorities: CNKI publications emphasized clinical and epidemiological research, while WOS focused more on epidemiological and mechanistic research. Collaboration networks became increasingly international in Phase 3, with Beijing and Shaanxi emerging as central hubs. This study reveals a strong spatial correspondence between research output and disease incidence in high-incidence province. However, it also underscores significant research gaps in some highly affected yet under-resourced regions. The diverging thematic focus and collaboration patterns between domestic and international publications reflect the evolution of China’s research ecosystem. Integrating bibliometric with epidemiological analysis provides a robust, evidence-based framework to help guide equitable resource allocation and foster collaborations that address the persistent challenges of HFRS.

Background: Acute liver failure (ALF) is marked by a substantial generation of reactive oxygen species (ROS), which can induce both cellular senescence and a pronounced inflammatory response. Senescent cells secrete factors collectively termed the senescence-associated secretory phenotype (SASP), which exacerbate inflammation, while inflammation can reciprocally promote cellular senescence. Quercetin (Que), recognized for its ROS-scavenging capabilities, holds the potential for anti-inflammatory and anti-senescent effects. However, its extremely low aqueous solubility constrains its clinical efficacy in treating inflammation. Methods: We employed a simple and stable coordination method to synthesize ultra-small quercetin-Fe nanoparticles (QFN) by complexing quercetin with iron ions. The ROS-scavenging, anti-inflammatory, and anti-senescent effects of QFN were evaluated in vitro. A lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced ALF mice model was used to investigate the therapeutic effects of QFN in vivo, and transcriptomic analysis was conducted to elucidate the mechanisms underlying QFN-mediated hepatoprotection. Results: Our findings demonstrate that QFN possesses remarkable water solubility and highly efficient ROS-scavenging properties. In vitro, QFN effectively inhibits macrophage-mediated inflammation and mitigates hepatocyte senescence. In vivo, QFN significantly attenuates LPS/D-GalN-induced ALF by protecting against macrophage inflammation and cellular senescence, thereby disrupting the self-perpetuating cycle of inflammation and aging. Moreover, its potent ROS scavenging capacity not only suppresses cellular apoptosis but also facilitates liver regeneration. Transcriptomic analyses further reveal that QFN exerts its protective effects through the modulation of key pathways involved in cellular senescence and inflammation. Conclusions: In summary, our study characterizes QFN as a potent ROS-scavenging modulator that exhibits both anti-inflammatory and anti-senescent properties, effectively disrupting the detrimental feedback loop between inflammation and cellular senescence. QFN holds considerable potential as a therapeutic agent for the treatment of ALF and other pathologies associated with inflammation and aging.

Background Hemorrhagic fever with renal syndrome (HFRS) research has undergone significant global transformation over the past decades. A comprehensive scientometric overview of research trends and scholarly cooperation in HFRS is absent. This study employs scientometric analysis to map the evolution of research themes, identify widely and scarcely explored areas, and anticipate future research directions. Methods We searched Web of Science Core Collection from inception until July 31, 2023, identifying 3,908 HFRS-related studies published for analysis. Utilizing CiteSpace, VOSviewer, and Bibliometrix, we performed co-authorship, co-occurrence, and co-citation analyses, and visualized research networks. Results Our analysis revealed a consistent upward trend in HFRS publications since 1980, with an average growth rate of 11.34%. The United States led in publication and citation counts, followed by China, Finland, Germany, and Sweden. Through co-occurrence analysis, we categorized keywords into eight clusters and 24 sub-clusters, revealing six predominant research themes: Clinical Features, Epidemiology, Mechanisms, Virus, Evolution, and Host. Notably, while themes such as Virus and Pathogenesis have been extensively studied, others, including certain aspects of Host research and Environmental Factors, remain less explored. Conclusion This scientometric synthesis provides a global perspective on the breadth and depth of HFRS research, highlighting well-trodden and understudied areas. It offers a roadmap for researchers to navigate the evolving landscape of HFRS studies and prioritize areas ripe for future investigation.

Hemorrhagic fever with renal syndrome (HFRS) was Hantaviruses infectious disease with a mortality rate of 1-10%. In the previous studies, the duration of the virus and the relationship between the virus and the severity of the disease were still unclear. 137 patients with HFRS were enrolled in this study, patients were followed up every three days until the virus load was negative. Virus quantification was performed using RT-PCR method. Of all the 137 patients, 38 patients (28%) were classified as severe/critical cases. We found that the duration of the virus lasted much longer than we thought before. Most patients still have virus during the polyuria phase, and some patients even have virus in recovery phase. We confirmed that viral load in febrile phase rather than the duration of virus associated with the severity of Hantaan virus caused HFRS. This indicates that tissue damage in HFRS may not related to the virus, virus activated immune response in the early stages may responsible for the pathogenesis. Understanding the mechanism of virus in HFRS will provide ideas and guidance for better clinical treatment.

ABSTRACT:Chronic hepatitis B virus (HBV) infection is a global public health concern. Existing antiviral drugs, including nucleos(t)ide analogs and interferon-α, can suppress HBV replication and improve the prognosis. However, the persistence of covalently closed circular DNA (cccDNA), the integration of HBV-DNA into the host genome, and compromised immune responses impede the successful treatment of hepatitis B. While achieving a functional cure of HBV remains elusive with the current treatment methods, this is the goal of new therapeutic approaches. Therefore, developing novel antiviral drugs is necessary for achieving a functional or complete cure for chronic hepatitis B. In recent years, substantial progress has been made in drug discovery and development for HBV infection. Direct-acting antiviral agents such as entry inhibitors, capsid assembly modulators, subviral particle release inhibitors, cccDNA silencers, and RNA interference molecules have entered clinical trials. In addition, several immunomodulatory agents, including toll-like receptor agonists, therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also making their way toward clinical use. In this review, we summarize the recent progress and limitations of chronic hepatitis B treatment and discuss perspectives on approaches to achieving functional cure. Although it will take some time for these new antiviral drugs to be widely used in clinical practice, combination therapy may become a preferable treatment option in the future.