ETIDIOH - NEW

  Abstract SARS-CoV-2’s remarkable resistance to nucleotide analog antivirals such as remdesivir , which thwarts RNA synthesis by inhibiting viral polymerase (RdRp), challenges available therapies . We reveal that remdesivir incorporation destabilizes RdRp–RNA complex while enhancing RNA binding to the proofreading exoribonuclease (ExoN), facilitating remdesivir excision. Conserved ExoN determinants for remdesivir recognition and excision underpin ExoN-mediated resistance across all coronaviruses . These findings inform the design of next-generation antivirals and combination therapies capable of overcoming ExoN-mediated resistance. Source: Proceedings of the National Academy of Sciences of the United States of America,  https://www.pnas.org/doi/full/10.1073/pnas.2519755122 ____

  Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has impacted global health. Remdesivir was approved based on clinical trials demonstrating improved outcomes in hospitalized patients. The ReEs-COVID19 study provides real-world evidence on its effectiveness and safety across two periods: Pre-Omicron and Omicron. This retrospective, observational cohort study included 1610 patients hospitalized with COVID-19 , treated with remdesivir during Pre-Omicron (September 2020–February 2021; n = 606) and Omicron (June 2022–March 2023; n = 1004) periods. Primary endpoint: time to discharge; Hepatic/renal function abnormalities were also investigated. In the Omicron period patients were older and had more comorbidities but remdesivir was initiated earlier (median: 2 days from symptom onset) compared to the Pre-Omicron period (8 days). ICU admissions rates and direct COVID-19-related deaths were significantly lower , but overall 30-day mortality was higher during the Omicr...

  Abstract Background On September 27, 2024, Rwanda reported an outbreak of Marburg virus disease (MVD), after a cluster of cases of viral hemorrhagic fever was detected at two urban hospitals. Methods We report key aspects of the epidemiology, clinical manifestations, and treatment of MVD during this outbreak, as well as the overall response to the outbreak. We performed a retrospective epidemiologic and clinical analysis of data compiled across all pillars of the outbreak response and a case-series analysis to characterize clinical features, disease progression, and outcomes among patients who received supportive care and investigational therapeutic agents. Results Among the 6340 patients with suspected MVD who underwent testing, 66 had laboratory-confirmed MVD , 51 (77%) of whom were health care workers. The median estimated incubation period was 10 days (interquartile range, 8 to 13), and symptom onset occurred a median of 2 days (interquartile range, 1 to 3) before hospital ad...

Abstract Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking . We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC50 and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC50). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient . In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment . A comparison with known RAS showed that S759A, located in the ...

Abstract In 2018, a clinical trial of four investigational therapies for Ebola virus disease (EVD), known as the PALM trial , was conducted in the Democratic Republic of Congo . All patients received either the antiviral remdesivir (RDV) or a monoclonal antibody product : ZMapp, mAb114 (Ebanga), or REGN-EB3 (Inmazeb). The study concluded that both mAb114 and REGN-EB3 were superior to ZMapp and RDV in reducing mortality from EVD. However, the data suggested that some patients in the RDV and ZMapp groups might have been sicker at the time of treatment initiation. Here, we assessed the efficacy of each of these therapies in a uniformly lethal rhesus monkey model of EVD when treatment was initiated 5 days after Ebola exposure. Treatment with RDV, mAb114, REGN-EB3, and ZMapp each resulted in similar survival (approximately 40% ). Survival was associated with circulating viral load at treatment initiation. A trend of more escape mutants in the GP1 and GP2 domains was observed for the mAb114 ...

Summary The 2024 Nipah outbreak in Kerala, India —its fifth in six years—and the recurring annual outbreaks in Bangladesh underscore the persistent threat posed by the Nipah virus (NiV) in the region. With a high mortality rate, human-to-human transmission potential , and the widespread presence of Pteropus bats , the natural reservoir, NiV remains a significant epidemic threat . Despite being a WHO priority pathogen , there has been no systematic effort to improve patient care for NiVD, leading to consistently poor outcomes . Current care relies on supportive measures and the ‘ compassionate use ’ of unapproved drugs like ribavirin and remdesivir . Drugs used ‘off-label’ during outbreaks can become the ‘standard of care’ without robust evidence of their safety or efficacy, complicating the testing of new therapies and perpetuating uncertainty about their true effectiveness. To improve NiVD care, we propose four key strategies: 1) Enhance early case detection , 2) optimize supportive c...

Abstract As new SARS-CoV-2 variants continue to emerge , it is important to evaluate the potency of antiviral drugs to support their continued use. Remdesivir (RDV; VEKLURY®) an approved antiviral treatment for COVID-19, and obeldesivir (ODV) are inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase Nsp12. Here we show these two compounds retain antiviral activity against the Omicron variants BA.2.86, BF.7, BQ.1, CH.1.1, EG.1.2, EG.5.1, EG.5.1.4, FL.22, HK.3, HV.1, JN.1, JN.1.7, JN.1.18, KP.2, KP.3, LB.1, XBB.1.5, XBB.1.5.72, XBB.1.16, XBB.2.3.2, XBC.1.6, and XBF when compared with reference strains. Genomic analysis identified 29 Nsp12 polymorphisms in these and previous Omicron variants. Phenotypic analysis of these polymorphisms confirmed no impact on the antiviral activity of RDV or ODV and suggests Omicron variants containing these Nsp12 polymorphisms remain susceptible to both compounds. These data support the continued use of RDV in the context of circulating SARS-CoV-2 vari...