Development Of Direct-acting Antiviral Agents Research Articles

Inhibition of SARS-CoV-2 growth in the lungs of mice by a peptide-conjugated morpholino oligomer targeting viral RNA

Further development of direct-acting antiviral agents against human SARS-CoV-2 infections remains a public health priority. Here, we report that an antisense peptide-conjugated morpholino oligomer (PPMO), named 5’END-2, targeting a highly conserved sequence in the 5’UTR of SARS-CoV-2 genomic RNA, potently suppressed SARS-CoV-2 growth in vitro and in vivo. In Hela-ACE 2 cells, 5’END-2 produced IC50 values of between 40 nM and 1.15 μM in challenges using six genetically disparate strains of SARS-CoV-2, including JN.1. In vivo, using K18-hACE2 mice and the WA-1/2020 virus isolate, two doses of 5’END-2 at 10 mg/kg, administered intranasally on the day before and the day after infection, produced approximately 1.4 log10 virus titer reduction in lung tissue at 3 days post-infection. Under a similar dosing schedule, intratracheal administration of 1.0 to 2.0 mg/kg 5’END-2 produced over 3.5 log10 virus growth suppression in mouse lungs. Electrophoretic mobility shift assays characterized specific binding of 5’END-2 to its complementary target RNA. Further, using reporter constructs containing SARS-CoV-2 5’UTR leader sequence, in an in-cell system, we observed that 5’END-2 could interfere with translation in a sequence-specific manner. The results demonstrate that direct pulmonary delivery of 5’END-2 PPMO is a promising antiviral strategy against SARS-CoV-2 infections and warrants further development.

Therapeutic Intervention of Serine Protease Inhibitors against Hepatitis C Virus.

Hepatitis C virus (HCV) is a globally prevalent and hazardous disorder that is responsible for inducing several persistent and potentially fatal liver diseases. Current treatment strategies offer limited efficacy, often accompanied by severe and debilitating adverse effects. Consequently, there is an urgent and compelling need to develop novel therapeutic interventions that can provide maximum efficacy in combating HCV while minimizing the burden of adverse effects on patients. One promising target against HCV is the NS3-4A serine protease, a complex composed of two HCV-encoded proteins. This non-covalent heterodimer is crucial in the viral life cycle and has become a primary focus for therapeutic interventions. Although peginterferon, combined with ribavirin, is commonly employed for HCV treatment, its efficacy is hampered by significant adverse effects that can profoundly impact patients' quality of life. In recent years, the development of direct-acting antiviral agents (DAAs) has emerged as a breakthrough in HCV therapy. These agents exhibit remarkable potency against the virus and have demonstrated fewer adverse effects when combined with other DAAs. However, it is important to note that there is a potential for developing resistance to DAAs due to alterations in the amino acid position of the NS3-4A protease. This emphasizes the need for ongoing research to identify strategies that can minimize the emergence of resistance and ensure long-term effectiveness. While the combination of DAAs holds promise for HCV treatment, it is crucial to consider the possibility of drug-drug interactions. These interactions may occur when different DAAs are used concurrently, potentially compromising their therapeutic efficacy. Therefore, carefully evaluating and monitoring potential drug interactions are vital to optimize treatment outcomes. In the pursuit of novel therapeutic interventions for HCV, the field of computational biology and bioinformatics has emerged as a valuable tool. These advanced technologies and methodologies enable the development and design of new drugs and therapeutic agents that exhibit maximum efficacy, reduced risk of resistance, and minimal adverse effects. By leveraging computational approaches, researchers can efficiently screen and optimize potential candidates, accelerating the discovery and development of highly effective treatments for HCV, treatments.

Changes in clinical outcomes in Japanese patients with hepatocellular carcinoma due to hepatitis C virus following the development of direct-acting antiviral agents.

Direct-acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCV-HCC) changed before and after DAA development. A retrospective analysis of 1949 Japanese HCV-HCC patients from January 2000 to January 2023 categorized them into pre-DAA (before 2013, n=1169) and post-DAA (after 2014, n=780) groups. Changes in clinical features and prognosis were assessed. Despite no significant differences in BCLC stage between groups, the post-DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69years), lower levels of AST (40 vs 56IU/L), ALT (31 vs 46IU/L), and AFP (11.7 vs 23.6ng/mL), higher platelet count (13.5 vs 10.8×104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (-2.54 vs -2.36) (all P<0.001). The post-DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence-free survival (median 2.8 vs 2.1years). Adjusted for inverse probability weighting, overall survival was superior in the post-DAA group (median 7.4 vs 5.6years, P<0.001). Subanalysis within the post-DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8years vs NA vs NA) compared to pre-SVR or post-SVR patients (both P<0.001). No significant difference in OS was observed between the pre-SVR and post-SVR groups (P=1.0). The development of DAA therapy has dramatically improved the prognosis of HCV-HCC patients.

Mechanisms and Clinical Significance of Pharmacokinetic Drug Interactions Mediated by FDA and EMA-approved Hepatitis C Direct-Acting Antiviral Agents.

The treatment of patients infected with the hepatitis C virus (HCV) has been revolutionised by the development of direct-acting antiviral agents (DAAs) that target specific HCV proteins involved in viral replication. The first DAAs were associated with clinical problems such as adverse drug reactions and pharmacokinetic drug-drug interactions (DDIs). Current FDA/EMA-approved treatments are combinations of DAAs that simultaneously target the HCV N5A-protein, the HCV N5B-polymerase and the HCV NS3/4A-protease. Adverse events and DDIs are less likely with these DAA combinations but several DDIs of potential clinical significance remain. Much of the available information on the interaction of DAAs with CYP drug-metabolising enzymes and influx and efflux transporters is contained in regulatory summaries and is focused on DDIs of likely clinical importance. Important DDIs perpetrated by current DAAs include increases in the pharmacokinetic exposure to statins and dabigatran. Some mechanistic information can be deduced. Although the free concentrations of DAAs in serum are very low, a number of these DDIs are likely mediated by the inhibition of systemic influx transporters, especially OATP1B1/1B3. Other DDIs may arise by DAA-mediated inhibition of intestinal efflux transporters, which increases the systemic concentrations of some coadministered drugs. Conversely, DAAs are victims of DDIs mediated by cyclosporin, ketoconazole, omeprazole and HIV antiretroviral drug combinations, especially when boosted by ritonavir and, to a lesser extent, cobicistat. In addition, concurrent administration of inducers, such as rifampicin, carbamazepine and efavirenz, decreases exposure to some DAAs. Drug-drug interactions that increase the accumulation of HCV N3/4A-protease inhibitors like grazoprevir may exacerbate hepatic injury in HCV patients.

Best practice recommendations for the use of hepatitis C viremic donor organs for hepatitis C virus naïve recipients.

The combination of the transplant organ deficit, the increase in HCV nucleic acid positive donors (HCV NAT+), and the development of direct-acting antiviral agents (DAAs) has resulted in a rapid increase in HCV NAT+ organ transplants into HCV naïve recipients. Early clinical experience with HCV NAT+ donor organs has shown promising outcomes; however, best practices are lacking to guide transplant programs during all phases of patient care. Transplant programs developing protocols for the utilization of HCV NAT+ organs will need a multidisciplinary team to address all aspects of pre-transplant and post-transplant patient care. Reports of fibrosing cholestatic hepatitis in HCV NAT+ organ transplant recipients receiving delayed DAA initiation highlight the need for the transplant community to develop safe and effective protocols. A failure to do so will inevitably lead to the erosion of public trust from cases of missed or inadequately treated donor-derived HCV infections. Herein, we provide best practice guidelines for the utilization of HCV NAT+ organs into HCV-negative recipients based on literature review and expert opinion from the faculty of the ASTS Standards and Quality Committee.

Trends in treatment for hepatocellular carcinoma in Japan

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer deaths in Japan, and it has gradually decreased in the last quarter century. The reason for the decrease in HCC patients is the decrease of patients with hepatitis C virus due to avoiding unnecessary blood transfusions and development of direct-acting antiviral agents (DAAs), which have been available since 2014, along with interferon and oral antiviral agents in Japan. On the other hand, the numbers of HCC patients with non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD) are increasing. In the treatment strategy for HCC in the Japanese guideline, the algorithm involves five clinicopathological factors: liver function (assessed using the Child-Pugh classification, liver damage score, and the ICG-R15 value), presence of extrahepatic metastases, presence of vascular invasion, number of tumors (within 3 or more than 4), and tumor size (within 3 cm or over 3 cm). Surgical resection is sometimes indicated for extrahepatic metastases in patients with well-controlled intrahepatic HCC, and for advanced HCC with vascular invasion, hepatectomy is also recommended as one of the treatment options according to the results of a nationwide survey in Japan. In the latest Japanese guideline, the recommended chemotherapy for advanced HCC is lenvatinib or sorafenib as first-line and regorafenib as second-line therapy. Currently, based on the results of various clinical trials for advanced HCC, the therapeutic options for advanced HCC have increased, such as combination therapy of atezolizumab and bevacizumab, ramucirumab, and cabozantinib. Reports of conversion surgery after chemotherapy have also increased, and the development of multidisciplinary treatment for advanced HCC will be of further interest in the future.

Development of diffuse large B-cell lymphoma after sofosbuvir-ledipasvir treatment for chronic hepatitis C: A case report and literature review.

Recently, treatments for chronic hepatitis C virus (HCV) infection have significantly improved by the development of direct-acting antiviral agents (DAAs) and almost all patients with HCV can complete antiviral treatment without apparent adverse events. Malignant lymphoma, particularly B-cell non-Hodgkin's lymphoma, is one of the extrahepatic manifestations associated with chronic HCV infection. The effectiveness of anti-HCV therapy with DAAs for B-cell non-Hodgkin's lymphoma has been demonstrated in recent reports, whereas late-onset B-cell non-Hodgkin's lymphoma after HCV eradication with DAAs has occasionally been reported. In the present study, a 77-year-old man with chronic hepatitis C and intermediate liver cancer risk received sofosbuvir-ledipasvir treatment for 12 weeks. Two months following the end of antiviral therapy, he had achieved sustained virologic response for 8 weeks. However, the patient occasionally found swelling of the right cervical lymph nodes without any subjective symptoms. Lymph node biopsy revealed diffuse large B-cell lymphoma and whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography showed increased FDG uptake in the right cervical, right submandibular, mediastinal and mesenteric lymph nodes. The patient received six courses of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy and achieved complete response at 8 months after chemotherapy initiation. Thus, the development of lymphoid malignancies may arise, even after HCV eradication with DAAs. Therefore, clinicians should be aware of such risks during and after antiviral treatment with DAAs.

Construction and characterization of Genotype-3 hepatitis C virus replicon revealed critical genotype-3-specific polymorphism for drug resistance and viral fitness

Hepatitis C virus (HCV), a major causative agent of chronic hepatitis, is a positive-stranded RNA virus and has a high degree of genetic diversity due to its error-prone RNA-dependent RNA polymerase. Development of direct-acting antiviral agents (DAAs) has greatly improved the therapeutic outcome of chronic hepatitis C patients. However, naturally existing resistance-associated variants (RAVs) or occurrence of resistance-associated substitutions (RASs) in the HCV genome may impose a challenge to the long-term success of the DAA-based therapies. Genotype-3 HCV is the most difficult genotype to treat by DAAs, but the underlying molecular mechanisms remain to be explored. Here we developed a novel genotype-3a subgenomic replicon PR87A7 by screening a HCV cDNA pool amplified from a patient serum RNA. PR87A7 replicon displayed strong resistance to anti-NS3 DAAs, mainly owing to a genotype-3-specific polymorphism 168Q in NS3. Introduction of NS3 168Q into a genotype-2a JFH1 strain rendered resistance to anti-NS3 DAAs while greatly diminished the viral replication, and yet this fitness defect can be rescued by additional genotype-3-specific polymorphism. In conclusion, we developed a novel genotype-3a subgenomic replicon by a functional screening approach, and revealed genotype-3-specfic amino acid residues that confer resistance to anti-NS3 DAAs while retaining viral fitness.

Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses.

Dengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridae family. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world's population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2'-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.

Long-Term Impact of Direct-Acting Antiviral Agent Therapy in HCV Cirrhosis: Critical Review.

More than 70 million people are chronically infected with hepatitis C virus (HCV) worldwide. Chronic hepatitis C is associated with progressive liver fibrosis, which can result in cirrhosis, liver failure, and hepatocellular carcinoma (HCC). HCV-related liver disease has been the most common indication for liver transplantation in the past decade. The development of direct-acting antiviral agents (DAAs) that are simple, well-tolerated, and highly effective means that most people living with hepatitis C can now be cured, leading the World Health Organization to set targets for reduction in deaths due to viral hepatitis by 2030. In this review, the authors will consider the emerging data showing that curative therapy with DAAs can prevent HCV-related morbidity and mortality, with a focus on patients with HCV-related cirrhosis.

An Update On the Management of Hepatitis C Virus and Human Immunodeficiency Virus co-infection

An estimated 2.3 million people globally are co-infected with HIV and HCV. Liver disease is now a leading cause of non-AIDS-related mortality among HIV-infected patients. The development of direct-acting antiviral agents has revolutionized the treatment of HIV/HCV co-infection with sustained virologic response response rates above 95% in most patient populations. This article provides an update on the management of acute and chronic HCV in patients co-infected with HIV including a section on drug–drug interactions.

Identification of novel small molecule inhibitors against the NS3/4A protease of hepatitis C virus genotype 4a.

Hepatitis C virus (HCV) infection poses a considerable threat to the public health. The current standard of care treatment with pegylated interferon-alpha in combination with ribavirin (PEG-IFN- α+RBV) is associated with significant side effects, poorly tolerated, and provides limited efficacy. The development of direct-acting antiviral agents (DAAs) targeting key viral enzymes essential for viral replication represents a significant milestone in the treatment of chronic HCV infection. Given its critical role in the viral polyprotein processing and the evasion of the host innate immunity, the NS3/4A protease has emerged as a promising drug target for the development of anti-HCV therapies. Although several potent NS3/4A protease inhibitors (PIs) have been approved or are in clinical development, the majority of currently available PIs have significant limitations related to untoward adverse events and a lack of pan-genotypic activity, indicating a continuing unmet medical need for the development and optimization of novel PIs with improved efficacy and tolerability, convenient dosing schedules, and shorter treatment durations. The inhibitory efficacy of four computer-designed chemically-synthesized compounds was evaluated against in vitro-expressed NS3/4A protease from HCV genotype 4a, the most prevalent genotype in Egypt, using a fluorescence-based enzymatic assay. We successfully identified two non-macrocyclic small molecules, BE113 (7a) and BE114 (7b), which exhibited inhibitory activity against HCV NS3/4A protease from HCV genotype 4a. The two compounds presented in this study may be promising inhibitors against NS3/4A protease of HCV genotype 4a and could be novel lead compounds for developing new therapeutics for the treatment of chronic HCV infection.

Pathophysiology and Treatment of Hepatitis B and C Infections in Patients With End-Stage Renal Disease.

An in-depth understanding of viral hepatitis is important to the care of patients with end-stage renal disease undergoing hemodialysis. Both hepatitis B and C viruses are acquired through hematogenous spread and can lead to horizontal transmission. Concurrent hepatic and renal injuries have ominous outcomes with significant morbidity. Hepatitis B incidence has decreased through practices including vaccination of nonimmune individuals and isolation of patients with the disease. The pathogenesis of hepatitis B leads to various symptoms and serologic changes with unique temporal associations dictating an acute or chronic presentation. Chronic hepatitis B develops when there is persistence of surface antigen for more than 6months. Occult hepatitis B is an enigmatic form of the chronic disease where viral DNA is present despite the patient remaining seronegative. Nucleoside analogs are used as a treatment for individuals with hepatitis B who have comorbid CKD; however, the mainstay of infection control relies on immunization. Hepatitis C, an RNA virus, has increased in prevalence. Strict universal precautions with sound infection-control practices are important to prevent seroconversion. Recent therapeutic advances involving the development of direct-acting antiviral agents have broadened treatment options for patients with renal impairment and hepatitis C, offering the potential for a definitive cure. Controversy on the timeliness of treatment for transplant options has also risen with the advent of these newer therapies. We review the epidemiology, pathophysiology, and updates in treatment of these viral entities as they relate to the hemodialysis population.

Grazoprevir/elbasvir treatment for the relapse of HCV genotype 1b infection after ledipasvir/sofosbuvir: A case report.

The treatment of chronic hepatitis C has radically changed due to the development of direct-acting antiviral agents (DAAs). Twelve-week treatment with ledipasvir and sofosbuvir (LDV/SOF), a combination of DAAs, is highly effective in patients with hepatitis C virus (HCV) genotype 1 infection. However, the overall sustained virological response rate 12 weeks after the end of treatment (SVR12) is not 100%. Elbasvir (EBR) combined with grazoprevir (GZR) is the latest approved therapy for patients with genotype 1 or 4 chronic hepatitis C. However, to the best of our knowledge no case reports have described retreatment with GZR/EBR in patients with a history of failed LDV/SOF treatment. The present case report indicated a case in which GZR/EBR was effective for the retreatment of a patient with a history of failed LDV/SOF treatment and chronic hepatitis C. The present study indicated a 55-year-old Japanese male with a history of chronic hepatitis C and compensated liver cirrhosis. The patient exhibited the amino acid mutation Y93H in NS5A. Therefore, treatment with LDV/SOF was initiated, which was effective and suppressed the virus during oral administration. However, 4 weeks after treatment, the patient's viral load relapsed and returned to its original level. After the patient provided informed consent, treatment with GZR/EBR was initiated. No problems related to GZR/EBR were observed during treatment and the patient's SVR12 was evaluated at 12 weeks posttreatment. In conclusion, GZR/EBR treatment was useful for treating a relapse of HCV genotype 1b infection in the present case after LDV/SOF treatment, despite liver fibrosis, in the presence of the high-frequency amino acid mutation Y93H in NS5A. Although it will be necessary to examine a large number of cases, the present findings suggest that GZR/EBR may be a potential treatment option for relapse of HCV genotype 1b infection after LDV/SOF treatment.

Viral Hepatitis C: Treatment

Infection with the hepatitis C virus (HCV) leads to chronic infection in the majority, and is associated with the development of complications including cirrhosis, end-stage liver failure, hepatocellular carcinoma and death. HCV is curable, and successful viral eradication is associated with a reduction in cirrhosis and liver-related mortality. However, previous HCV therapy, consisting of pegylated interferon plus ribavirin, was associated with poor cure rates and significant adverse events. The development of direct-acting antiviral agents (DAAs) that specifically target HCV replication has revolutionized the treatment of HCV. Current regimens are now highly potent, all-oral, interferon-free combinations of these DAAs. The Food and Drug Administration has now approved many of these regimens. The changing management of HCV infection, including recent advances in HCV therapy, are discussed. This review contains 1 figure, 5 tables and 59 references Key words: direct-acting antiviral agents, hepatitis C virus, interferon-free therapy, management, treatment

Viral Hepatitis C: Treatment

Infection with the hepatitis C virus (HCV) leads to chronic infection in the majority, and is associated with the development of complications including cirrhosis, end-stage liver failure, hepatocellular carcinoma and death. HCV is curable, and successful viral eradication is associated with a reduction in cirrhosis and liver-related mortality. However, previous HCV therapy, consisting of pegylated interferon plus ribavirin, was associated with poor cure rates and significant adverse events. The development of direct-acting antiviral agents (DAAs) that specifically target HCV replication has revolutionized the treatment of HCV. Current regimens are now highly potent, all-oral, interferon-free combinations of these DAAs. The Food and Drug Administration has now approved many of these regimens. The changing management of HCV infection, including recent advances in HCV therapy, are discussed. This review contains 1 figure, 5 tables and 59 references Key words: direct-acting antiviral agents, hepatitis C virus, interferon-free therapy, management, treatment

Viral Hepatitis C: Treatment

Infection with the hepatitis C virus (HCV) leads to chronic infection in the majority, and is associated with the development of complications including cirrhosis, end-stage liver failure, hepatocellular carcinoma and death. HCV is curable, and successful viral eradication is associated with a reduction in cirrhosis and liver-related mortality. However, previous HCV therapy, consisting of pegylated interferon plus ribavirin, was associated with poor cure rates and significant adverse events. The development of direct-acting antiviral agents (DAAs) that specifically target HCV replication has revolutionized the treatment of HCV. Current regimens are now highly potent, all-oral, interferon-free combinations of these DAAs. The Food and Drug Administration has now approved many of these regimens. The changing management of HCV infection, including recent advances in HCV therapy, are discussed. This review contains 1 figure, 5 tables and 59 references Key words: direct-acting antiviral agents, hepatitis C virus, interferon-free therapy, management, treatment

Interferon-Free Regimen for Hepatitis C: Insight and Management.

The rapid development of direct-acting antiviral agents (DAA) for hepatitis C virus (HCV) therapy dramatically altered the treatment landscape of this disease. The DAA regimen is associated with various advantages including high sustained virological response (SVR) with minimum side effects and low pill load and specific inhibition of viral replication, which lowers dependence on the host cell. This regimen has substantially replaced conventional (interferon) therapy with high cure rates (> 90%) in most HCV populations. This review provides insight into clinical studies of NS3/4A protease inhibitors, NS5B viral polymerase inhibitor (nucleotide and non-nucleotide), and NS5A inhibitors, alone and in combination.

Retreatment of patients with treatment failure of direct-acting antivirals: Focus on hepatitis C virus genotype 1b.

The recent development of direct-acting antiviral agents (DAAs) against hepatitis C virus (HCV) infection could lead to higher sustained virological response (SVR) rates, with shorter treatment durations and fewer adverse events compared with regimens that include interferon. However, a relatively small proportion of patients cannot achieve SVR in the first treatment, including DAAs with or without peginterferon and/or ribavirin. Although retreatment with a combination of DAAs should be conducted for these patients, it is more difficult to achieve SVR when retreating these patients because of resistance-associated substitutions (RASs) or treatment-emergent substitutions. In Japan, HCV genotype 1b (GT1b) is founded in 70% of HCV-infected individuals. In this minireview, we summarize the retreatment regimens and their SVR rates for HCV GT1b. It is important to avoid drugs that target the regions targeted by initial drugs, but next-generation combinations of DAAs, such as sofosbuvir/velpatasvir/voxilaprevir for 12 wk or glecaprevir/pibrentasvir for 12 wk, are proposed to be potential solution for the HCV GT1b-infected patients with treatment failure, mainly on a basis of targeting distinctive regions. Clinicians should follow the new information and resources for DAAs and select the proper combination of DAAs for the retreatment of HCV GT1b-infected patients with treatment failure.

Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C

Although treatment for hepatitis C virus has been dramatically improved by the development of direct-acting antiviral agents (DAAs), whether interferon (IFN)-free therapy reduces hepatocarcinogenesis in an equivalent manner to IFN-based therapy remains controversial. The aims of this study were to evaluate the occurrence and recurrence of hepatocellular carcinoma (HCC) in chronic hepatitis C (CHC) patients treated with DAAs and to identify biomarkers of HCC development after antiviral treatment. A restrospective review of a prospective database of 1,897 CHC patients who were treated with IFN-based (1,145) or IFN-free therapies (752) was carried out. Cumulative HCC occurrence and recurrence rates were compared using propensity score-matched analysis. Predictors of HCC development after viral eradication were identified by multivariate analysis. Propensity score-matched analysis showed no significant difference in HCC occurrence (p=0.49) and recurrence rates (p=0.54) between groups treated with IFN-based or IFN-free therapies. In multivariate analysis, higher levels of post-treatment α-fetoprotein (AFP) or Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+M2BP) were independently associated with HCC occurrence and recurrence after viral eradication. Only post-treatment WFA+M2BP level was significantly associated with HCC occurrence and recurrence among patients without severe fibrosis. The area under the receiver operating characteristic (ROC) curve for WFA+M2BP levels was greater than that for AFP levels in ROC analysis. The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy. Patients with high WFA+M2BP levels after antiviral treatment, even without severe fibrosis, must be followed up carefully for HCC development. Lay summary: The risks of early HCC occurrence and recurrence after viral eradication were similar between IFN-based and IFN-free therapies. Post-treatment levels of WFA+M2BP may be helpful screening biomarkers for assessing the risk of HCC after IFN-free therapy.