Antiviral Research Articles

Effectiveness and safety of tenofovir amibufenamide in chronic hepatitis B patients

This letter to the editor relates to the study entitled “Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B: A real-world study”, which was recently published by Peng et al . Hepatitis B virus infection represents a significant health burden worldwide and can lead to cirrhosis and even liver cancer. The antiviral drugs currently used to treat patients with chronic hepatitis B infection still have many side effects, so it is crucial to identify safe and effective drugs to inhibit viral replication.

Effectiveness and safety of tenofovir amibufenamide in chronic hepatitis B patients

This letter to the editor relates to the study entitled “Tenofovir amibufenamide vs tenofovir alafenamide for treating chronic hepatitis B: A real-world study”, which was recently published by Peng et al . Hepatitis B virus infection represents a significant health burden worldwide and can lead to cirrhosis and even liver cancer. The antiviral drugs currently used to treat patients with chronic hepatitis B infection still have many side effects, so it is crucial to identify safe and effective drugs to inhibit viral replication.

Safety, tolerability and pharmacokinetics of ASC10, a novel oral double prodrug of a broad-spectrum antiviral agent, β-d-N4-hydroxycytidine: results from a randomized, double-blind, placebo-controlled phase 1 study in Chinese healthy subjects

ABSTRACT Background Considering the rise of new SARS-CoV-2 variants that have reduced the efficacy of COVID-19 vaccines, the development of new antiviral medications for the disease has become increasingly necessary. In this study, ASC10, a novel antiviral prodrug, was studied in a phase 1 trial in healthy Chinese participants. Research design and methods Part 1 involved 60 participants, receiving 50–800 mg ASC10 or placebo twice daily for 5.5 days. Part 2, with 12 participants, explored ASC10 dosing in the fed/fasting states. Results ASC10-A, the main pharmacologically active metabolite, rapidly appeared in plasma (Tmax: 1.00–2.00 h) and decreased (t1/2: 1.10–3.04 h) without accumulation. The Cmax and area under the plasma concentration – time curve (AUC) of ASC10-A increased dose-dependently (50–800 mg BID) over 5.5 days, with no accumulation. The Tmax was slightly delayed in the fed state; however, the Cmax and AUC were similar between the fed and fasting states. Adverse events (AEs) were comparable (ASC10/placebo, 66.7%) and mostly mild (95%). Conclusion ASC10 was demonstrated to be safe and well tolerated and exhibited dose-proportional exposure and minimal food effects. Clinical trial registration www.clinicaltrials.gov identifier is NCT05523141.

Amphiphilic Heparinoids as Potent Antiviral Agents against SARS-CoV-2.

Herein, we report the synthesis and biological evaluation of a novel series of heparinoid amphiphiles as inhibitors of heparanase and SARS-CoV-2. By employing a tailor-made synthetic strategy, a library of highly sulfated homo-oligosaccharides bearing d-glucose or a C5-epimer (i.e., l-idose or l-iduronic acid) conjugated with various lipophilic groups was synthesized and investigated for antiviral activity. Sulfated higher oligosaccharides of d-glucose or l-idose with lipophilic aglycones displayed potent anti-SARS-CoV-2 and antiheparanse activity, similar to or better than pixatimod (PG545), and were more potent than their isosteric l-iduronic acid congeners. Lipophilic groups such as cholestanol and C18-aliphatic substitution are more advantageous than functional group appended lipophilic moieties. These findings confirm that fine-tuning of higher oligosaccharides, degree of sulfation, and lipophilic groups can yield compounds with potent anti-SARS-CoV-2 activity.

The antiherpetic and anti-inflammatory activity of the frog-derived peptide Hylin-a1.

The high incidence of virus-related infections and the large diffusion of drug-resistant pathogens stimulate the search and identification of new antiviral agents with a broad spectrum of action. Antivirals can be designed to act on a single target by interfering with a specific step in the viral lifecycle. On the contrary, antiviral peptides (AVPs) are known for acting on a wide range of viruses, with a diversified mechanism of action targeting virus and/or host cell. In the present study, we evaluated the antiviral potential of the peptide Hylin-a1 secreted by the frog Hypsiobas albopunctatus against members of the Herpesviridae family. The inhibitory capacity of the peptide was evaluated in vitro by plaque assays in order to understand the possible mechanism of action. The results were also confirmed by Real-Time PCR and Western blot evaluating the expression of viral genes. Hylin-a1 acts to block the herpetic infection interfering at the early stages of both herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) infection. Its mechanism is mainly directed on the membrane, probably by damaging the viral envelope. The same effect was also observed against HSV-1 strains resistant to acyclovir. The data presented in this study, such as the increased activity of the peptide when combined to acyclovir, a weak hemolytic profile, an anti-inflammatory effect, and a tolerable half-life in serum, indicates Hylin-a1 as a novel antiherpetic molecule with promising potential in the clinical setting.

Aprotinin (I): Understanding the Role of Host Proteases in COVID-19 and the Importance of Pharmacologically Regulating Their Function

Proteases are produced and released in the mucosal cells of the respiratory tract and have important physiological functions, for example, maintaining airway humidification to allow proper gas exchange. The infectious mechanism of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), takes advantage of host proteases in two ways: to change the spatial conformation of the spike (S) protein via endoproteolysis (e.g., transmembrane serine protease type 2 (TMPRSS2)) and as a target to anchor to epithelial cells (e.g., angiotensin-converting enzyme 2 (ACE2)). This infectious process leads to an imbalance in the mucosa between the release and action of proteases versus regulation by anti-proteases, which contributes to the exacerbation of the inflammatory and prothrombotic response in COVID-19. In this article, we describe the most important proteases that are affected in COVID-19, and how their overactivation affects the three main physiological systems in which they participate: the complement system and the kinin–kallikrein system (KKS), which both form part of the contact system of innate immunity, and the renin–angiotensin–aldosterone system (RAAS). We aim to elucidate the pathophysiological bases of COVID-19 in the context of the imbalance between the action of proteases and anti-proteases to understand the mechanism of aprotinin action (a panprotease inhibitor). In a second-part review, titled “Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions”, we explain in depth the pharmacodynamics, pharmacokinetics, toxicity, and use of aprotinin as an antiviral drug.

A small molecule compound targeting hemagglutinin inhibits influenza A virus and exhibits broad-spectrum antiviral activity.

Influenza A virus (IAV) is a widespread pathogen that poses a significant threat to human health, causing pandemics with high mortality and pathogenicity. Given the emergence of increasingly drug-resistant strains of IAV, currently available antiviral drugs have been reported to be inadequate to meet clinical demands. Therefore, continuous exploration of safe, effective and broad-spectrum antiviral medications is urgently required. Here, we found that the small molecule compound J1 exhibited low toxicity both in vitro and in vivo. Moreover, J1 exhibits broad-spectrum antiviral activity against enveloped viruses, including IAV, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human coronavirus OC43 (HCoV-OC43), herpes simplex virus type 1 (HSV-1) and HSV-2. In this study, we explored the inhibitory effects and mechanism of action of J1 on IAV in vivo and in vitro. The results showed that J1 inhibited infection by IAV strains, including H1N1, H7N9, H5N1 and H3N2, as well as by oseltamivir-resistant strains. Mechanistic studies have shown that J1 blocks IAV infection mainly through specific interactions with the influenza virus hemagglutinin HA2 subunit, thereby blocking membrane fusion. BALB/c mice were used to establish a model of acute lung injury (ALI) induced by IAV. Treatment with J1 increased survival rates and reduced viral titers, lung index and lung inflammatory damage in virus-infected mice. In conclusion, J1 possesses significant anti-IAV effects in vitro and in vivo, providing insights into the development of broad-spectrum antivirals against future pandemics.

Bacillus velezensis HN-2: a potent antiviral agent against pepper veinal mottle virus

Bacillus velezensis HN-2: a potent antiviral agent against pepper veinal mottle virus

In silico homology modeling of dengue virus non-structural 4B (NS4B) protein and its molecular docking studies using triterpenoids

BackgroundDengue fever has become a significant worldwide health concern, because of its high morbidity rate and the potential for an increase in mortality rates due to lack of adequate treatment. There is an immediate need for the development of effective medication for dengue fever.MethodsHomology modeling of dengue virus (DENV) non-structural 4B (NS4B) protein was performed by SWISS-MODEL to predict the 3D structure of the protein. Structure validation was conducted using PROSA, PROCHECK, Ramachandran plot, and VERIFY-3D. MOE software was used to find out the in-Silico inhibitory potential of the five triterpenoids against the DENV-NS4B protein.ResultsThe SWISS-MODEL was employed to predict the three-dimensional protein structure of the NS4B protein. Through molecular docking, it was found that the chosen triterpenoid NS4B protein had a high binding affinity interaction. It was observed that the NS4B protein binding energy for 15-oxoursolic acid, betulinic acid, ursolic acid, lupeol, and 3-o-acetylursolic acid were − 7.18, − 7.02, − 5.71, − 6.67 and − 8.00 kcal/mol, respectively.ConclusionsNS4B protein could be a promising target which showed good interaction with tested triterpenoids which can be developed as a potential antiviral drug for controlling dengue virus pathogenesis by inhibiting viral replication. However, further investigations are necessary to validate and confirm their efficacy.

Discovery of L15 as a novel Vif PROTAC degrader with antiviral activity against HIV-1

Viral infectivity factor (Vif) has been recognized as a new therapeutic target for human immunodeficiency virus-1 (HIV-1) infected patients. In our previous work, we have synthesized a novel class of Vif inhibitors with 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold, which show obvious activity in HIV-1 infected cells and are also effective against drug-resistant strains. Proteolytic targeting chimera (PROTAC) utilizes the ubiquitin–proteasome system to degrade target proteins, which is well established in the field of cancer, but the antiviral PROTAC molecules are rarely reported. In order to explore the effectiveness of PROTAC in the antiviral area, we designed and synthesized a series of degrader of HIV-1 Vif based on 2-amino-N-(5-hydroxy-2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide scaffold. Among them, L15 can degrade Vif protein obviously in a dose-dependent manner and shows certain antivirus activity. Meanwhile, molecular dynamics simulation indicated that the ternary complex formed by L15 Vif, and E3 ligase adopted a reasonable binding mode and maintained a stable interaction. This provided a molecular basis and prerequisite for the selective degradation of the Vif protein by L15. This study reports the HIV-1 Vif PROTAC for the first time and represents the proof-of-concept of PROTACs-based antiviral drug discovery in the field of HIV/ acquired immune deficiency syndrome (AIDS).

Characterization of Exopolysaccharides Having Potential Antiviral Properties from Priestia Aryabattai Strain MK1 and Bacillus sp. Strain MK2.

Viral diseases are a serious threat to humans while themost antiviral drugs have low efficiency and side effects on human health. Therefore, using microbial biopolymers as the drugs alternate to treat viral infections seems cost-effective and human friendly option. In the present study, thirty-four exopolysaccharides (EPSs) producing bacteria were isolated, and EPSs production capacity of five salt-tolerant isolates was determined under 0, 100 and 150 mM NaCl. Among these, two isolates exhibiting high anti-coliphage activity were identified through 16S rRNA gene analysis. Moreover, the EPSs were characterized by Fourier-transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) analysis, and their composition was determined. Five salt-tolerant bacteria (MK1, MK2, MK10, MK22 and MK29) exhibited higher production of EPSs at 100 mM NaCl compared to that under non-saline control. At 100 mM NaCl, the yield of EPSs ranged between 105 and 330mg 100 mL-1 broth. The EPSs produced by the isolates MK1 and MK2 exhibited higher anti-coliphage activity (plaque forming unit decreased from 43 × 106 mL-1 to 3 × 106 and 4 × 106 mL-1, respectively), and were comprised of glucose, fructose, galactose, sucrose, lactose and xylose sugars. FTIR spectroscopy depicted that EPSs are mainly composed of hydroxyl, aliphatic, carboxyl, sulfate and phosphate functional groups, which could have bound coliphage and thus conferred higher anti-coliphage activities to the EPSs. Phylogenetic analysis revealed that MK1 and MK2 isolates formed clades within genus Priestia and Bacillus sequences, respectively. High EPSs production capacity of bacterial isolates under saline condition and high anti-coliphage activity of the EPSs implies that bacterial biopolymers could be useful in antiviral drugs therapy.

Virtual Screening of Indonesian Herbal Compounds with Neuraminidase Inhibitor Activity against N2 Influenza Virus Protein: An in silico Study

Background: Neuraminidase inhibitor (NAI) is one of anti-influenza drugs recommended for use by the World Health Organization (WHO). However, after treatment with NAI drugs in human, resistance to influenza antiviral drugs is begun to rise. Therefore, identification of compounds from Indonesian herbal plants as natural inhibitors of the influenza virus neuraminidase protein needs to be conducted for the development of new anti-influenza drugs.Materials and methods: The crystal structure of the neuraminidase protein complex used in this study was obtained from the Protein Data Bank (PDB). Structure-based pharmacophore modeling was performed using LigandScout version 4.4.5 software. Indonesian herbal plant compounds were collected from the HerbalDB database. Protein and ligand processing was carried out using Autodock 4.2 software. The 3D interaction visualization was carried out with Autodock software, while 2D interaction visualization was carried out with LigPlot software. To determine the toxicity and drug-likeliness of the ligand, the test ligands that had the best docking results were predicted using SwissADME and AdmetSAR.Results: From the virtual screening results, 24 hits were found, and five compounds had the best binding energy among the 24 tested compounds, these were pollenitin (ΔG=-7.22 kcal/mol), OPC-4:0 (ΔG=-7.11 kcal/mol), 6-hydroxykaempferol (ΔG=-7.08 kcal/mol), 5,8-dihydroxy-7,4'-dimethoxyflavone (ΔG=-7.07 kcal/mol), and 3,5,6,7-tetrahydroxy-4'-methoxyflavone (ΔG=-6.95 kcal/mol). The best five compounds were then chosen for further analysis.Conclusion: OPC-4:0 is found to be the best compound for the NAI based on its binding energy, pharmacokinetics, toxicity, and drug-likeliness. Thus, OPC-4:0 might be a potential candidate as a NAI of HxN2 virus. Keywords: influenza, molecular docking, neuraminidase, resistance, virtual screening

Virtual Screening of Indonesian Herbal Compounds with Neuraminidase Inhibitor Activity against N2 Influenza Virus Protein: An in silico Study

Background: Neuraminidase inhibitor (NAI) is one of anti-influenza drugs recommended for use by the World Health Organization (WHO). However, after treatment with NAI drugs in human, resistance to influenza antiviral drugs is begun to rise. Therefore, identification of compounds from Indonesian herbal plants as natural inhibitors of the influenza virus neuraminidase protein needs to be conducted for the development of new anti-influenza drugs.Materials and methods: The crystal structure of the neuraminidase protein complex used in this study was obtained from the Protein Data Bank (PDB). Structure-based pharmacophore modeling was performed using LigandScout version 4.4.5 software. Indonesian herbal plant compounds were collected from the HerbalDB database. Protein and ligand processing was carried out using Autodock 4.2 software. The 3D interaction visualization was carried out with Autodock software, while 2D interaction visualization was carried out with LigPlot software. To determine the toxicity and drug-likeliness of the ligand, the test ligands that had the best docking results were predicted using SwissADME and AdmetSAR.Results: From the virtual screening results, 24 hits were found, and five compounds had the best binding energy among the 24 tested compounds, these were pollenitin (ΔG=-7.22 kcal/mol), OPC-4:0 (ΔG=-7.11 kcal/mol), 6-hydroxykaempferol (ΔG=-7.08 kcal/mol), 5,8-dihydroxy-7,4'-dimethoxyflavone (ΔG=-7.07 kcal/mol), and 3,5,6,7-tetrahydroxy-4'-methoxyflavone (ΔG=-6.95 kcal/mol). The best five compounds were then chosen for further analysis.Conclusion: OPC-4:0 is found to be the best compound for the NAI based on its binding energy, pharmacokinetics, toxicity, and drug-likeliness. Thus, OPC-4:0 might be a potential candidate as a NAI of HxN2 virus. Keywords: influenza, molecular docking, neuraminidase, resistance, virtual screening

Synthesis and biological evaluation of novel coumarin derivatives bearing sulfonamide moiety in antiviral and antibacterial agent

20 novel 4-bromine-coumarin derivatives bearing sulfonamide moiety were designed and synthesized. Their antiviral activities and antibacterial were systematically evaluated. The test results show that all the target compounds possess moderate to excellent antiviral and antibacterial activities. Among all target compounds, compound I15 exhibited good antiviral activity against TMV, CMV, PVY. Which is superior to ribavirin. Moreover, target compounds I8 and I15 exhibited good in vitro antibacterial activity against Psa, with an EC50 value of 44.9 mg/L, 49.3 mg/L, respectively, which were better than thiodiazole copperand and zinc thiazoles, with an EC50 value of 56.3 mg/L, 50.2 mg/L, respectively. The results provides insights for the development of multi-functional pesticides.

Probenecid Inhibits Human Metapneumovirus (HMPV) Replication In Vitro and in BALB/c Mice

Human metapneumovirus (HMPV) is an important cause of acute respiratory tract infection and causes significant morbidity and mortality. There is no specific antiviral drug to treat HMPV or vaccine to prevent HMPV. This study determined if probenecid, a host-targeting antiviral drug, had prophylactic (pre-virus) or therapeutic (post-virus) efficacy to inhibit HMPV replication in LLC-MK2 cells in vitro and in the lungs of BALB/c mice. This study showed that ≥0.5 μM probenecid significantly inhibited HMPV replication in vitro, and 2–200 mg/kg probenecid prophylaxis or treatment reduced HMPV replication in BALB/c mice.

The Novel A-Type Proanthocyanidin-Rich Phytocomplex SP4™ Acts as a Broad-Spectrum Antiviral Agent against Human Respiratory Viruses.

The appearance of new respiratory virus infections in humans with epidemic or pandemic potential has underscored the urgent need for effective broad-spectrum antivirals (BSAs). Bioactive compounds derived from plants may provide a natural source of new BSA candidates. Here, we investigated the novel phytocomplex formulation SP4™ as a candidate direct-acting BSA against major current human respiratory viruses, including coronaviruses and influenza viruses. SP4™ inhibited the in vitro replication of SARS-CoV-2, hCoV-OC43, hCoV-229E, Influenza A and B viruses, and respiratory syncytial virus in the low-microgram range. Using hCoV-OC43 as a representative respiratory virus, most of the antiviral activity of SP4™ was observed to stem primarily from its dimeric A-type proanthocyanidin (PAC-A) component. Further investigations of the mechanistic mode of action showed SP4™ and its PAC-A-rich fraction to prevent hCoV-OC43 from attaching to target cells and exert virucidal activity. This occurred through their interaction with the spike protein of hCoV-OC43 and SARS-CoV-2, thereby interfering with spike functions and leading to the loss of virion infectivity. Overall, these findings support the further development of SP4™ as a candidate BSA of a natural origin for the prevention of human respiratory virus infections.

Phytochemical profiling of Livistona carinensis leaf extract via UHPLC-QTOF-MS/MS with assessment of its antiviral mechanisms.

Among 36 species of the genus Livistona (family Palmae or Arecaceae), L. carinensis is considered the only species native to Africa. Previous studies showed the richness of Livistona fruits in phenolic compounds. The goal of the current study was to investigate the phytochemical composition and assess the antiviral mechanisms of the L. carinensis leaves' ethanolic extract cultivated in Egypt for the first time. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS/MS) was applied. Moreover, the total crude extract was fractionated using ethyl acetate and n-butanol for phytochemical investigations by various chromatographic and spectroscopic techniques. Besides, the antiviral activity of L. carinensis leaves was assessed using three protocols in vitro using MTT assay compared to acyclovir. UHPLC-QTOF-MS/MS-based analysis resulted in identification of 72 metabolites tentatively. They belonged to diverse phytochemical classes, mainly including flavonoids (29), organic acids (10), and phenolic acids (7). The antiviral activity investigations revealed a direct Adeno virus inactivation mechanism rather than inhibition of virus replication or blocking its attachment to Vero cells. Hence, the plant leaves may be a potential candidate for discovery of novel antiviral drugs owing to the diversity of identified phytochemical classes.

The ATP-Binding Cassette Transporter-Mediated Efflux Transport of Ganciclovir at the Blood-Brain Barrier.

Recent studies have highlighted the key role of the ATP-binding cassette (ABC) transporters, including theP-glycoprotein (P-gp), the breast cancer resistance protein (BCRP), and the multi-drug resistance protein 4 (MRP4) in limiting the brain distribution of several antiviral agents. In this study, we investigated whether the inhibition of these transporters increases the permeability of the blood-brain barrier (BBB) to ganciclovir. A microdialysis and high-performance liquid chromatographic method was developed to monitor the concentrations of unbound ganciclovir in the brain interstitial fluid and plasma, with and without the administration of ABC transporter inhibitors. Pharmacokinetic parameters, including the area under the plasma concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC0-t,plasma), the area under the brain interstitial fluid concentration-time curve from time 0 to time of the last measurable analyte concentration (AUC0-t,brain), and the unbound brain-to-plasma concentration ratio (Kp,uu,brain) were calculated. The mean AUC0-t,plasma, AUC0-t,brain, and Kp,uu,brain in rats who received ganciclovir (30 mg/kg, intraperitoneal) alone were 1090 min·µg/mL, 150 min·µg/mL, and 14%, respectively. After the administration of tariquidar (inhibitor of P-gp), Ko143 (inhibitor of BCRP), or MK-571 (inhibitor of MRP4), the Kp,uu,brain of ganciclovir increased to 31 ± 2.1%, 26 ± 1.3%, and 32 ± 2.0%, respectively. The findings of this studysuggest that ABC transporters P-gp, BCRP, and MRP4 mediate the efflux of ganciclovir at the BBB and that the inhibition of these transporters facilitates the penetration of the BBB by ganciclovir.

Antiviral Effect of Ferula Plants and their Potential for Treatment of COVID-19: A Comprehensive Review.

Viral diseases have always been a threat to mankind throughout history, and many people have lost their lives due to the epidemic of these diseases. In recent years, despite the progress of science, we are still witnessing a pandemic of dangerous diseases such as COVID-19 all over the world, which can be a warning for humanity. Ferula is a genus of flowering plants commonly found in Central Asia, and its species have shown antiviral activity against a variety of viruses, including respiratory syncytial virus, Herpes simplex virus type 1, influenza, human immunodeficiency virus, hepatitis B, and coronaviruses. In this study, we intend to review the antiviral effects of Ferula plants, emphasizing the therapeutic potential of these plants in the treatment of COVID-19. Google, PubMed, Web of Science, and Scopus databases were searched to review the relevant literature on the antiviral effect of Ferula or its isolated compounds. The search was performed using the keywords Ferula, antiviral, Coronaviruses, respiratory syncytial virus, Herpes simplex virus type 1, influenza, human immunodeficiency virus, and hepatitis B. According to the reviewed articles and available scientific evidence, it was determined that the plants of this genus have strong antiviral effects. Also, clinical studies have shown that some species, such as Ferula assa-foetida, can be used effectively in the treatment of COVID-19. Ferula plants have inhibitory effects on various viruses, making them an attractive alternative to conventional antiviral agents. Therefore, these plants are a natural source of valuable compounds that can help us fight infectious diseases.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4weeks for new-onset LC and liver-related events. Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.