Search Results (118)

(1) Background: The highly pathogenic avian influenza virus H5N1 clade 2.3.4.4b is an emerging threat that poses a great risk to the poultry industry. A few human cases have been linked to the infection with this clade in many parts of the world, including the USA. Unfortunately, there are no specific vaccines or antiviral drugs that could help prevent and treat the infection caused by this virus in birds. Our major objective is to identify/repurpose some (novel/known) antiviral compounds that may inhibit viral replication by targeting some key viral proteins. (2) Methods: We used state-of-the-art machine learning tools such as molecular docking and MD-simulation methods from Biovia Discovery Studio (v24.1.0.321712). The key target proteins such as hemagglutinin (HA), neuraminidase (NA), Matrix-2 protein (M2), and the cap-binding domain of PB2 (PB2/CBD) homology models were validated through structural assessment via DOPE scores, Ramachandran plots, and Verify-3D metrics, ensuring reliable structural representations, confirming their reliability for subsequent in silico approaches. These approaches include molecular docking followed by molecular dynamics simulation for 50 nanoseconds (ns), highlighting the structural stability and compactness of the docked complexes. (3) Results: Molecular docking revealed strong binding affinities for both sofosbuvir and GS441524, particularly with the NA and PB2/CBD protein targets. Among them, GS441524 exhibited superior interaction scores and a greater number of hydrogen bonds with key functional residues of NA and PB2/CBD. The MM-GBSA binding free energy calculations further supported these findings, as GS441524 displayed more favorable binding energies compared to several known standard inhibitors, including F0045S for HA, Zanamivir for NA, Rimantadine and Amantadine for M2, and PB2-39 for PB2/CBD. Additionally, 50 ns molecular dynamics simulations highlighted the structural stability and compactness of the GS441524-PB2/CBD complex, further supporting its potential as a promising antiviral candidate. Furthermore, hydrogen bond monitor analysis over the 50 ns simulation confirmed persistent and specific interactions between the ligand and proteins, suggesting that GS441524 may effectively inhibit the NA, and PB2/CBD might potentially disrupt PB2-mediated RNA synthesis. (4) Conclusions: Our findings are consistent with previous evidence supporting the antiviral activity of certain nucleoside analog inhibitors, including GS441524, against various coronaviruses. These results further support the potential repurposing of GS441524 as a promising therapeutic candidate against H5N1 avian influenza clade 2.3.4.4b. However, further functional studies are required to validate these in silico predictions and support the inhibitory action of GS441524 against the targeted proteins of H5N1, specifically clade 2.3.4.4b. Full article

Background: The advent of direct-acting antivirals (DAAs) has marked a significant milestone in the therapeutic landscape of hepatitis C, greatly improving treatment efficacy. A therapeutic regimen encompassing sofosbuvir (SOF), velpatasvir (VEL), and voxilaprevir (VOX) has demonstrated strong efficacy across all genotypes of the hepatitis C virus (HCV) and has recently been incorporated into the Korean healthcare system. This study aimed to evaluate the real-world efficacy and safety of these antivirals in the South Korean population. Methods: This prospective, multicenter, observational study enrolled patients with chronic HCV treated with SOF/VEL-based regimens at six hospitals between November 2022 and January 2024. DAA-naïve patients received SOF/VEL ± ribavirin for 12 weeks. Patients who had failed prior DAA therapy received SOF/VEL/VOX for 12 weeks. The primary endpoint was a sustained virological response at 12 weeks post-treatment (SVR12). Results: Among 101 patients treated with SOF/VEL, the mean age was 64.71 years, and 40.9% were male. Genotypes 1b and 2 were identified in 40.6% and 59.4% of patients, respectively. Two patients had a history of interferon-based treatment. The mean baseline HCV RNA level was 3,088,097 IU/mL. Cirrhosis was observed in 26.7% of patients (21.8% compensated; 5.0% decompensated). Of the 101 patients, 12 were lost to follow-up. Among the 89 patients who completed follow-up, SVR12 was achieved in 100.0% (89/89), including 5 patients with decompensated cirrhosis. In the SOF/VEL/VOX group, 17 patients were treated. The mean age was 61.84 years, 29.4% were male, and four had compensated cirrhosis. One patient was lost to follow-up. SVR12 was achieved in 100.0% (16/16) of the patients who completed follow-up. No serious adverse events (≥grade 3) were reported in either group during the DAA treatment period. Conclusions: In this first prospective real-world study in South Korea, SOF/VEL-based regimens demonstrated excellent efficacy and safety, achieving 100% SVR12 in the per-protocol population, including patients with cirrhosis and prior treatment failure. Full article

The combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is recommended as a salvage therapy for treatment-experienced chronic hepatitis C (CHC) patients. However, it is used in our country for treatment-naïve and treatment-experienced patients. This study aims to present real-world data from Türkiye on CHC patients treated with SOF/VEL/VOX. The present study was conducted by the Viral Hepatitis Study Group of the Turkish Society of Clinical Microbiology and Infectious Diseases (KLİMİK). It was a multicenter, retrospective, observational study. The data were collected from patients receiving SOF/VEL/VOX therapy at 12 medical centers in Türkiye between 1 June 2022 and 31 December 2024. The patients had received the treatment for 8 to 12 weeks. Of the 139 patients enrolled, 63.3% (n = 88) were male, with a mean age of 54.4 years. Most patients were non-cirrhotic (94.2%, n = 131) and treatment-naïve (92%, n = 128); 49.6% (n = 69) were infected with genotype 1b. Early virologic response (EVR) could be assessed in 126 patients, with an EVR rate of 82.5% (n = 104). End-of-treatment data were available for 113 patients, all achieving an end-of-treatment response. Among the 80 patients for whom week-12 post-treatment data were available, 97.5% sustained virologic response at week 12 (SVR12). Significant improvements were observed in AST, ALT, and platelet levels, along with reductions in APRI and FIB-4 scores (p = 0.001).” No serious adverse events leading to treatment discontinuation were reported. Mild adverse events included pruritus (2.1%, n = 3), fatigue (2.1%, n = 3), and nausea (1.4%, n = 2). The SOF/VEL/VOX combination is a highly effective and well-tolerated treatment option in treatment-naïve CHC patients, achieving an SVR12 rate of 97.5%. Full article

(1) Background: Hepatitis C virus (HCV) infection poses a significant health burden, particularly in Mongolia, where the HCV prevalence is notably high. This study evaluates the long-term outcomes of HCV treatment with ledipasvir/sofosbuvir, focusing on mortality, viral relapse, and hepatocellular carcinoma (HCC) development. (2) Methods: This prospective, longitudinal cohort study initially enrolled patients with chronic HCV in Mongolia between 2016 and 2017, focusing on those who completed the five-year follow-up (n = 303). The study measured long-term mortality, HCC development, and viral relapse, employing non-invasive methods to assess liver fibrosis and liver function. (3) Results: At the outset, 98.2% of the patients achieved undetectable HCV RNA levels. Over five years, 6.27% experienced viral relapse and 3.30% developed hepatocellular carcinoma (HCC), with a mortality rate of 5.94%. In a multivariable analysis, the significant predictors for HCC occurrence included age (OR = 1.081, 95% CI = 1.021–1.145), liver cirrhosis (OR = 5.866, 95% CI = 1.672–22.577), and GGT level (OR = 1.011, 95% CI = 1.004–1.018). The independent predictors of mortality included age (OR = 1.083, 95% CI = 1.024–1.147), liver cirrhosis (OR = 6.529, 95% CI = 1.913–22.281), and GGT (OR = 1.011, 95% CI = 1.004–1.017). (4) Conclusions: This study demonstrates that ledipasvir/sofosbuvir effectively suppresses HCV initially and maintains low viral relapse rates over the long term. However, it emphasizes the need for continued management to reduce the long-term risk of HCC and mortality, especially in patients with severe liver fibrosis or cirrhosis. Full article

Background: There is still debate whether ribavirin should be added to direct-acting antivirals (DAAs) for the management of treatment-experienced individuals with non-genotype-1 hepatitis C. This study compared the efficacy and safety of adding ribavirin to sofosbuvir-based combinations compared to sofosbuvir-based regimens alone in treating non-genotype 1 hepatitis C virus (HCV) in individuals who have been previously treated. Methods: We searched Cochrane CENTRAL, PubMed, SCOPUS, CINAHL and preprint databases from inception to September 2023 for randomized controlled trials (RCTs) that compared sofosbuvir-based regimens with ribavirin to sofosbuvir-based regimens alone in previously treated individuals with non-genotype 1 HCV infection. Data extraction and quality of study assessments were performed by two independent authors, and synthesis was performed using bias-adjusted models, heterogeneity using I2, and publication bias using funnel plots. Results: Eight RCTs compared sofosbuvir-based combinations with and without ribavirin were included. Overall, the addition of ribavirin to sofosbuvir, compared to sofosbuvir alone, did not show a benefit in achieving sustained virological response (SVR) (OR 0.91, 95% CI 0.26–3.17, I2 = 70.0%) with moderate certainty in Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence. In subgroup analysis, there was no benefit of adding ribavirin to sofosbuvir in individuals with non-genotype 1 HCV. The additional ribavirin was associated with increased adverse events (OR 2.03, 95% CI 1.58–2.6, I2 = 8.0%) and treatment discontinuation (OR 1.81, 95% CI 0.78–4.28, I2 = 0.0%). Conclusions: The moderate certainty evidence suggests that adding ribavirin to sofosbuvir-based regimens may not confer benefit in achieving SVR in previously treated individuals with non-genotype 1 HCV but increases the odds of adverse events and treatment discontinuation. More evidence is needed on the effect of additional ribavirin in achieving SVR in individuals with decompensated cirrhosis. Registration: The protocol is registered on the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42022368868). Full article

The enzymatic resolution of chiral sofosbuvir precursors is a critical step in producing stereoisomerically pure ProTide drugs, essential for their therapeutic efficacy. In this study, a mutated phosphotriesterase (W131M-PTE) was immobilized onto various polymeric macroporous beads, including commercial immobead 150P (IB), modified (IB-EDA and IB-MTD), and synthetic polyacrylamide (PAM) beads functionalized with glutaraldehyde (PAM-GA) or 1-Ethyl-3-(3-dimethyl aminopropyl) carbodiimide (PAM-EDC). The immobilization efficiency, stability, and reusability of the enzyme were systematically evaluated. Among the tested supports, PAM-EDC demonstrated superior performance, retaining high enzymatic activity across multiple cycles and achieving a 92% yield of the (Sp)-diastereomer. The study highlights the potential of immobilized W131M-PTE as a cost-effective and scalable solution for chiral separation in pharmaceutical manufacturing, with implications for broader applications in ProTide drug production. Full article

Background: The aim of this study was to assess the cost effectiveness of a screening and treatment intervention approach for chronic HCV infection in Zimbabwe. Methods: Using a decision tree and a validated Markov model, we estimated the lifetime costs and health effects of screening for and treating HCV infections from a healthcare perspective. We evaluated three screening strategies, namely the following: i. no screening; ii. screening among the general population; and iii. screening among high-risk groups. Incremental cost effectiveness ratios were calculated for the strategies that were not dominated. We used deterministic and probabilistic sensitivity analyses to explore the impacts of parameter uncertainty on cost effectiveness outcomes. Results: The strategy of screening among high-risk groups and treating with sofosbuvir/velpatasvir had an incremental cost of USD 1201 and incremental quality-adjusted life years (QALY) of 2.01, yielding an incremental cost effectiveness ratio (ICER) of USD 604 per QALY gained as compared to no screening. The ICER was below the 0.5 times the gross domestic product per capita parameter (USD 796), making the intervention potentially cost effective. The strategy to screen among the general population was dominated, because it costed more and resulted in fewer QALYs than its comparators. Conclusions: Screening for HCV among high-risk populations followed by treatment using sofosbuvir/velpatasvir is cost effective under the assumptions made in this study. Full article

Remdesivir (RDV) and nirmatrelvir/ritonavir (NMVr) are among the most widely used antivirals in the treatment of COVID-19, aiming to reduce disease severity and progression. Adverse neuropsychiatric effects, such as anxiety, sleep disturbances, and movement disorders, have emerged as significant concerns associated with these treatments. To better understand the safety profiles of RDV and NMVr, this study performs a pharmacovigilance analysis of individual case safety reports (ICSRs) from the EudraVigilance (EV) database. Objectives: This study evaluates the risk of neuropsychiatric adverse events associated with RDV and NMVr. Comparisons with other antiviral drugs, including darunavir, sofosbuvir, ribavirin, tenofovir, ritonavir, and sotrovimab, are also performed to develop a comprehensive understanding of the safety profiles. Methods: A retrospective analysis of ICSRs submitted to EV until 7 July 2024, with data extraction on 12 July 2024, was conducted. Demographic characteristics (age, sex, geographic region, and reporter type) and case severity were included in the descriptive analysis. Disproportionality analysis using reporting odds ratio (ROR) and 95% confidence intervals (CI) was performed to compare adverse drug reaction (ADRs) frequencies across 27 system organ classes (SOCs), with emphasis on “Nervous system disorders” and “Psychiatric disorders. Results: The total number of ICSRs was significantly higher for NMVr (n = 8078) compared to RDV (n = 3934). Nervous system disorders accounted for 3.07% of the total RDV reports and for 17.31% of NMVr reports, while psychiatric disorders represented 0.92% of the total ADRs reported for RDV (n = 60) and 3.61% for NMVr (n = 672). On the other hand, RDV showed a significantly lower frequency of reporting headache compared to NMVr (ROR: 0.1057; 95% CI: 0.0676–0.1653). Conclusions: NMVr presents a higher risk of neuropsychiatric ADRs than RDV, underscoring the need for enhanced monitoring, particularly in patients with preexisting central nervous system (CNS) conditions. These findings contribute to optimizing antiviral safety and informing clinical decision making. Full article

While direct-acting antivirals (DAAs) are available for the treatment of chronic Hepatitis C virus (HCV) patients in Nepal, knowledge of the circulating genotypes/subtypes and drug target gene mutations of HCV is currently unavailable. Here, we describe HCV genotypes/subtypes and identify antiviral target gene mutations in patients at a tertiary care hospital using genome data. A cross-sectional study was conducted from December 2019 to February 2024, where PCR followed by whole genome sequencing was performed to identify HCV genotypes/subtypes and drug target gene mutations. Among all the patients who tested positive for anti-HCV, 70.6% (149/211) were HCV RNA positive, while 68.2% (30/44) were genotype/subtype 3a, followed by 1a (18.2%, 8/44) and others (13.6%, 6/44), including new subtypes 3g and 3i from Nepal. Subtype 3a was also the dominant subtype (≥70%) among intravenous drug users and sexual routes of transmission. We found 70.5% of the samples with resistant mutations in the NS3/4A region, 22.7% in NS5A, and 45.5% in NS5B. Resistant mutations against sofosbuvir, pibrentasvir, velpatasvir, daclatasvir, and dasabuvir were found at 25%, 18%, 16%, 16%, and 2%, respectively, mostly on subtype 3a. The predominant HCV genotype/subtype in our patient group was 3a, and resistance mutations against direct-acting antivirals were found in most untreated patients. Full article

Hepatitis C virus (HCV) is a global public health problem, but advancements in HCV treatment have improved the cure rate. This study evaluated the effectiveness of direct-acting antivirals (DAAs) in HCV-infected patients from May 2021 to April 2023 in collaboration with tertiary care hospitals in West Bengal. The HCV viral load was monitored via qRT-PCR. Sanger sequencing was performed to determine the HCV genotypes. The clinicians prescribed the patient treatment regime. The maximum number of patients in the study population (N = 398) were compensated cirrhosis patients (46.28%). The overall SVR rate of the study population was 94.47%. The decompensated cirrhosis patients experienced the lowest SVR rate (88.89%). The maximum number of patients were prescribed sofosbuvir/daclatasvir (63.77%), and the lowest SVR rate (93.23%) was observed with this treatment regime. In the study population, GT-3 was the predominant (67.43%) circulating genotype, followed by GT-1 and -4. Among 398 patients, 22 (5.53%) were non-responsive to DAA treatment. Out of these 22 non-responder patients, 77.27% (n = 17) were GT-3-infected (3a:10; 3b:07), followed by GT-1 (1c: 04; 1b: 01). Thus, increasing numbers of DAA non-responsive cases among HCV GT-3-infected and decompensated cirrhosis patients may pose serious threats in the future. Full article

Background: Since the discovery of successful direct-acting antiviral (DAA) treatment, kidneys from hepatitis C virus (HCV) RNA-positive donors represent a new opportunity to expand the organ donor pool for HCV-negative recipients. Case presentation: In this paper, we describe a unique case of transplantation of an HCV genotype 3a-infected kidney into an HCV-negative recipient who was highly sensitized, with a virtual panel-reactive antibody level of 99.96%. Prior to the kidney transplantation, the recipient received DAA treatment with glecaprevir/pibrentasvir as a viable prophylactic strategy. Post-transplant, the recipient received a triple-combination DAA regimen with glecaprevir/pibrentasvir/sofosbuvir, which continued for 12 weeks. Subsequently, viral load was undetectable at 12 and 24 weeks after treatment, with no significant adverse events associated with DAA therapy. A 12-month post-transplantation biopsy revealed mixed rejection requiring treatment. The 19-month follow-up showed a favorable outcome regarding the function of the kidney allograft and the recipient’s quality of life. HCV-positive transplantation allowed our recipient to receive a kidney from an immunologically compatible donor without donor-specific antibodies and the need for desensitization strategies. Conclusions: Each transplant center should decide on the selection of candidates for kidney transplantation from HCV RNA-positive donors to HCV-negative recipients, the availability and choice of DAA treatment, and post-transplant follow-up. Our case emphasizes the need for early DAA treatment based on viral load and HCV genotyping, as well as for careful post-transplant surveillance including protocol biopsies. Full article

Hepatitis C virus (HCV) eradication is usually associated with dyslipidemia. Most studies in this field have focused on genotype-specific direct-acting antivirals (DAAs), with research on pangenotypic DAAs being limited. This study examined how two pangenotypic DAA regimens, glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/velpatasvir (SOF/VEL), affect lipid profiles and insulin resistance after viral eradication in chronic HCV patients. A total of 100 patients (57 with GLE/PIB and 43 with SOF/VEL) treated between September 2020 and January 2022 were included in the retrospective analysis. This study found a significant increase in LDL and TC levels after treatment (p < 0.001), but no significant changes in triglycerides, high-density lipoprotein, HbA1C, or the Homeostatic Model Assessment of Insulin Resistance. According to a logistic regression analysis, higher baseline LDL or TC and lower baseline glucose are predictors of the degree of increase in LDL or TC following a sustained virological response. Both pangenotypic DAA regimens significantly impact lipid profiles, particularly LDL and TC, but not insulin resistance. This study emphasizes the need for more research into the long-term metabolic effects of DAAs. Full article

The treatment landscape for hepatitis C virus (HCV) infection has transformed over the past few decades, evolving from the limited efficacy of interferon (IFN) monotherapy to the highly successful pan-genotypic direct-acting antivirals (DAAs) used today. Initially, alpha-interferon monotherapy, introduced in the 1990s, was the standard treatment, yet it provided low sustained virological response (SVR) rates and caused significant adverse effects, limiting its utility. The development of pegylated interferon (peg-IFN) improved the pharmacokinetic profile of IFN, allowing for less frequent dosing and modestly improved response rates. When combined with ribavirin, peg-IFN achieved higher SVR rates, especially in non-genotype 1 HCV infections, but the combination also brought additional side effects, such as anemia and depression. The advent of the first-generation DAAs, such as telaprevir and boceprevir, marked a significant milestone. Combined with peg-IFN and ribavirin, these protease inhibitors boosted response rates in patients with genotype 1 HCV. However, high rates of adverse effects and drug resistance remained challenges. Second-generation DAAs, like sofosbuvir and ledipasvir, introduced IFN-free regimens with improved safety profiles and efficacy. The most recent advances are pan-genotypic DAAs, including glecaprevir-pibrentasvir and sofosbuvir-velpatasvir, which offer high SVR rates across all genotypes, shorter treatment durations, and fewer side effects. Current pan-genotypic regimens represent a cornerstone in HCV therapy, providing an accessible and effective solution globally. Full article

Dendritic cells (DCs) play a crucial role in controlling viral infections. Little is known about the changes in frequencies of the DC subsets in patients with chronic hepatitis C (CHC), particularly in the era of interferon-free regimens. We aimed to evaluate the impact of sofosbuvir/daclatasvir on the frequency of different peripheral DC subsets, the expression of the inhibitory CD200R and its ligand CD200 on DC, and their relation to the treatment outcome. A total of 1000 patients with CHC were enrolled and treated with a fixed oral dose of 400 mg of sofosbuvir and 60 mg of daclatasvir for 12 weeks. A total of 940 patients achieved sustained virologic response (SVR), and only 60 patients were non-responders (NRs). The frequencies of the peripheral plasmacytoid (pDC) and myeloid (mDCs) subsets and their surface expressions of CD200R and CD200 molecules were analyzed using flow cytometry. This analysis included 60 non-responders (NR group), 60 randomly selected sustained virologic responders (SVR group) at baseline, and at the end of treatment, and 60 healthy controls. HCV infection was associated with a down-regulation in the frequency of mDC, compared to healthy controls. In addition, mDC in HCV-infected patients showed lower levels of CD200R. However, neither the pDC frequency nor their CD200R expression was significantly altered. Interestingly, by the end of therapy, the frequencies of circulating mDCs and CD200R⁺mDC increased significantly in the SVR group and were even comparable to healthy controls. The levels of these cells were not normalized in the NR group. Percentages of mDCs and CD200R⁺mDC subsets showed good prognostic accuracy for predicting virologic response to therapy. Our results showed that HCV infection was associated with modulation of the mDC frequency and their surface expression of CD200R. Successful daclatasvir and sofosbuvir combined therapy was associated with the normalization of the percentages of mDC and CD200R⁺mDC. Full article

The COVID-19 pandemic has intensified the development of new antiviral agents specifically intended for the SARS-CoV-2 virus, but has also increased the use of some already known antiviral agents originally intended for other viruses. Although the pandemic has ended, the SARS-CoV-2 virus is expected to be present in the human population forever, as is the case with the influenza virus, for example. Such a scenario guarantees the continued use of SARS-CoV-2 antivirals and, accordingly, their continued release into the environment. Unfortunately, there is little or no information on the adverse potential of most of these antiviral agents. In this study, the acute toxicity of six antiviral agents used in the treatment of SARS-CoV-2 infections was determined. These are atazanavir, ribavirin, emtricitabine, nirmatrelvir, sofosbuvir and oseltamivir, sorted according to their toxicity, starting with the most toxic agent. Toxicity was determined using the marine bacterium Aliivibrio fischeri according to the ISO 11348-1:2007 standard. In addition to the toxicities of the individual antiviral solutions, the toxicities of binary antiviral mixtures were also determined. By comparing the experimentally determined toxicities of the mixtures with the values estimated by the concentration addition model and the independent action model, we analyzed the mode of joint toxic activity of these antiviral agents. Additive behavior was observed for most binary combinations. The combination of nirmatrelvir and sofosbuvir led to an antagonistic deviation from the concentration addition model, while a synergistic deviation was observed for the combinations of emtricitabine with atazanavir and with nirmatrelvir, as well as for the combinations of ribavirin with atazanavir, oseltamivir and sofosbuvir. All tested binary combinations showed a synergistic deviation from the independent action model. Full article