ETIDIOH - NEW

  Abstract Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication . Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes . Model simulations suggested lower antiviral potency against pre-Omicron SARS-CoV-2 variants than against Omicron . We estimated that in vitro assays underestimated in vivo potency by 6- to 7-fold against Omicron variants. Our model suggested that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA was underestimated by approximately 0.4 log10 in the two trials conducted while Omicron variants dominated. Viral area under the curve estimates differed significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in...

  Abstract Since 2020, high pathogenicity avian influenza virus (HPAIV) infections in wild birds have been frequently reported . Because HPAIV infection has occasionally caused outbreaks in captive rare birds , application of antiviral drugs for treatment purposes against them has been considered from the perspective of conservation medicine . In this study, the therapeutic efficacy of baloxavir marboxil (BXM) was evaluated using a duck model to help establish the post-infection treatment for rare birds . Sixteen four-week-old ducks were divided into four groups and intranasally inoculated with the HPAIV strain A/crow/Hokkaido/0103B065/2022 ( H5N1 ). BXM was orally administered once daily at doses of 12.5, 2.5, 0.5, and 0 mg/kg to each of the four groups from 2 to 6 days post-infection. Blood samples were collected at 2, 8, and 24 hours after the initial BXM administration to measure the plasma concentrations of its active form, baloxavir acid (BXA). All ducks were monitored until ...

  Abstract Currently, no immunomodulatory agents have been conclusively shown to benefit severe influenza . The World Health Organization conditionally advises against the use of systemic corticosteroids, macrolides, plasma therapy, mechanistic target of rapamycin inhibitors , and nonsteroidal anti-inflammatory drugs for such patients. High-dose systemic corticosteroids may increase mortality and morbidity in severe influenza ; the potential of low-dose corticosteroids merits further study given survival benefits in patients with severe coronavirus disease 2019 ( COVID-19 ). Passive immunotherapy using convalescent plasma or intravenous immunoglobulin (IVIG) from healthy donors has not proven effective , suggesting that future research should focus on hyperimmune plasma or IVIG from recent infections . An open-label randomized controlled trial (RCT) found that a triple combination of oseltamivir, clarithromycin, and naproxen improved outcomes in severe influenza. One RCT has indica...

  Abstract The SARS outbreak and influenza A(H5N1) infections (2003–2004) prompted WHO to establish a global influenza antiviral stockpile , enabling rapid distribution to 72 countries during the 2009 A(H1N1) pandemic. To improve access in low- and middle-income countries, WHO added antivirals to the WHO Model List of Essential Medicines and included them in the Prequalification Programme . The 2011 Pandemic Influenza Preparedness Framework refined strategies for equitable access and rapid response. Lessons from COVID-19 led to a new WHO-led mechanism—the Interim Medical Countermeasures Network (i-MCM-net)— which supports integrated supply chains, real-time data sharing, research and development, and equitable access. WHO continues to emphasise equity and global solidarity , highlighting the need for accessible, effective, and affordable antivirals alongside vaccines to protect vulnerable populations and mitigate the impact of future pandemics. Source: Journal of Infectious Disease...

  Abstract This supplement contains 17 articles addressing various aspects of advances in influenza therapeutics and related strategies (e.g., diagnostics, rapid access strategies , and resistance monitoring ) for preventing and treating seasonal, zoonotic, and pandemic influenza . In addition to briefly introducing each article, we highlight shortcomings in current use, knowledge gaps requiring further study, and therapeutics of interest entering or advancing in clinical development. Source: Journal of Infectious Diseases,  https://academic.oup.com/jid/article/232/Supplement_3/S169/8287899?login=false ____

  Abstract Influenza antivirals play an important role in the prevention and control of influenza. We reviewed data on the effectiveness of influenza antivirals for reducing influenza transmission . We found that antiviral prophylaxis , whether given pre- or postexposure , has been shown to reduce the risk of symptomatic influenza in a variety of settings and populations . During pandemic responses, antiviral prophylaxis could play an important role, as demonstrated by the use of amantadine in the 1968–1969 influenza A(H3N2) pandemic and oseltamivir during the 2009–2010 influenza A(H1N1)pdm09 pandemic. Antiviral treatment reduces symptom severity, prevents complications, and can reduce onward transmission of infection. However, resistance, accessibility, and timing pose challenges. Future research directions include innovative therapies and combination treatments. Continued research and stewardship are crucial to optimize antiviral impact. Source: Journal of Infectious Diseases,...

  Summary Background Ensitrelvir is an oral antiviral treatment for COVID-19 with the same molecular target (the main protease ) as ritonavir-boosted nirmatrelvir —the current oral first-line treatment. We aimed to compare the clinical antiviral effects of the two drugs. Methods In an open-label, phase 2, randomised, controlled, adaptive pharmacometric platform trial, low-risk adult outpatients aged 18–60 years with early symptomatic COVID-19 (<4 days of symptoms) were recruited from hospital acute respiratory infection clinics in Thailand and Laos . Patients were randomly assigned in blocks (block sizes depended on the number of interventions available) to one of eight treatment groups, including oral ensitrelvir and oral ritonavir-boosted nirmatrelvir at standard doses, both given for 5 days, and no study drug. The primary endpoint was the oropharyngeal SARS-CoV-2 viral clearance rate assessed between day 0 and day 5 in the modified intention-to-treat population (defined as pa...

  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 The polymerase acidic (PA) protein is a subunit of the trimeric influenza A virus (IAV) RNAdependent RNA polymerase and the target of the anti-influenza drug baloxavir marboxil (BXM). As with other direct-acting antivirals , treatment with BXM can lead to selection of viruses carrying resistance mutations . If these mutations have negligible fitness costs , resistant viruses can spread widely and render existing treatments obsolete. Multiple BXM resistance mutations in the nuclease domain of PA have been identified, with I38T and I38M amino acid substitutions occurring frequently. These mutations have minimal to no effects on viral polymerase activity , virus replication , or transmission . However, for reasons that are not well understood, viruses with BXM resistance substitutions have not been able to compete with parental wild-type strains . The IAV genome segment encoding PA also encodes the host shutoff nuclease PA-X , which shares the endonuclease domain with PA bu...

  Context and significance The avian influenza A virus subtype H10N3 is a possible candidate for causing a fatal flu and may present a serious public health threat . Research increasingly shows that the avian influenza virus H10N3 can be transmitted from birds to humans , causing severe viral pneumonia and potentially leading to acute respiratory distress syndrome and respiratory failure . Researchers at the Fourth People’s Hospital of Nanning (China) provide evidence supporting the cross-species transmission of the avian influenza virus H10N3 to humans, which can give rise to severe pneumonia. The authors report that a female patient with avian influenza virus H10N3 infection, who was suffering from severe pneumonia , respiratory failure, pneumothorax , and numbness and dysesthesia in her feet , recovered after receiving appropriate therapy and was discharged from the hospital. Highlights •  A young woman contracted the avian influenza virus H10N3 •  Secondary infections...

  ABSTRACT Oropouche virus (OROV), Rift Valley fever virus (RVFV), and Dabie bandavirus (DBV) are significant re-emerging and emerging human pathogens with major public health implications. Notably, the ongoing OROV disease epidemic spanning South America, Central America, and the Caribbean now exceeds 11,000 cases, including several fatalities and reports of neurological disease and congenital abnormalities associated with infection. Rift Valley fever outbreaks continue to plague sub-Saharan Africa , and DBV, the etiologic agent of severe fever with thrombocytopenia syndrome (SFTS), is expanding its reach throughout several Asian countries . No vaccines or approved therapies are available to prevent or treat these viral infections. Here, we report on the antiviral activity and protective efficacy of the ribonucleoside analog , 4′-fluorouridine (4′-FlU), against OROV, RVFV, and DBV in cell culture and murine models of infection and disease. In cell culture, the potency of 4′-FlU wa...

  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 Bourbon virus (BRBV) is an emerging tick-borne virus that can cause severe and fatal disease in humans . BRBV is vectored via the Amblyomma americanum tick , which is widely distributed throughout the central, eastern, and southern United States . Serosurveillance studies in Missouri and North Carolina identified BRBV-neutralizing antibodies in approximately 0.6% of tested individuals . To date, no specific antiviral therapy exists. As part of an initial screen, several nucleoside analogs were tested for their ability to inhibit BRBV replication in cell culture. Among the compounds assessed, molnupiravir , an antiviral drug with oral availability and broad spectrum antiviral activity against RNA viruses, showed antiviral activity against BRBV production in vitro. In vivo, pre-exposure administration of molnupiravir protected susceptible type I interferon receptor knockout (Ifnar1-/-) mice against lethal BRBV infection. The protection by molnupiravir was associated with l...

  Key Points -- Question:  Is regular application of azelastine nasal spray associated with reduced risk of SARS-CoV-2 infections? - Findings:  In this randomized placebo-controlled clinical trial that included 450 participants , the incidence of laboratory-confirmed SARS-CoV-2 infections was significantly lower with application of azelastine nasal spray compared with placebo treatment. -- Meaning:  The use of azelastine nasal spray may help to reduce the risk of SARS-CoV-2 infections. Abstract Importance    Limited pharmaceutical options exist for preexposure prophylaxis of COVID-19 beyond vaccination. Azelastine, an antihistamine nasal spray used for decades to treat allergic rhinitis, has in vitro antiviral activity against respiratory viruses, including SARS-CoV-2. Objective    To determine the efficacy and safety of azelastine nasal spray for prevention of SARS-CoV-2 infections in healthy adults. Design, Setting, and Participants   ...

  Abstract Objectives There have been few studies in pregnant women of medications that are used to reduce severe complications from COVID-19 infection. Currently, nirmatrelvir/ritonavir (Paxlovid) is recommended by the National Institutes for Health to treat non-hospitalized pregnant patients with mild-to-moderate COVID-19 illness. The aim of this study was to determine the transplacental passage of molnupiravir, nirmatrelvir/ritonavir and favipiravir utilizing an ex vivo placental perfusion model. Methods Human placental cotyledons were continuously perfused in a double open circuit. The study molecules and antipyrine, a marker of placental viability, were dissolved in the maternal solution. The experiment was conducted over 90 minutes, and every 5 minutes, samples of the maternal solution and fetal exchange solutions were collected for analysis. We calculated the concentrations of study molecules, fetal transfer ratios and the clearance indexes to determine placental transfer. R...

  ABSTRACT Mpox, caused by monkeypox virus (MPXV) infection, has emerged as a significant global health threat . The World Health Organization (WHO) has twice declared a Public Health Emergency of International Concern for mpox: first for the 2022–2023 global outbreak and subsequently for concurrent outbreaks in Africa. Beyond MPXV, other members of the Orthopoxvirus genus also pose growing risks of zoonotic spillover , with the potential to jump from animal reservoirs to humans . Clinically, mpox is distinguished from other Orthopoxvirus infections by its propensity to cause severe systemic manifestations alongside localized skin lesions , disproportionately affecting vulnerable groups such as children, pregnant women, and immunocompromised individuals . Although vaccines are available, effective therapeutics are equally essential in combating the mpox crisis. Current antiviral agents , including tecovirimat and brincidofovir , have demonstrated uncertain or disappointing efficacy...

Abstract Effective and reliable treatments for SARS-CoV-2 infections are a key part of global COVID-19 management . Based on vitro studies, niclosamide has been considered as a potential drug candidate for SARS-CoV-2, but its clinical development has been limited due to poor solubility and bioavailability. Here we report results from a randomized, double-blind, placebo-controlled clinical trial involving 300 patients (Clinical Trial Registration Number: KCT0007307) that assessed the efficacy and safety of the niclosamide nanohybrid CP-COV03 at two different doses. Oral CP-COV03 was well tolerated, with no serious adverse events reported in any treatment group. The primary endpoints demonstrated that CP-COV03 significantly alleviated all 12 FDA-recommended COVID-19 symptoms , with symptom improvement sustained for more than 48 h. Additionally, CP-COV03 reduced SARS-CoV-2 viral load by 56.7% within 16 h of the initial dose compared to baseline. Secondary endpoints, including time to sust...

Abstract Influenza A virus (IAV) poses a significant global health risk, with highly pathogenic strains like H5N1 (CFR ~52%) causing severe disease compared to less lethal but more transmissible strains like H1N1 (CFR 0.01-0.03%). Although IAV primarily infects lung epithelial cells , causing cell death and tissue damage , the molecular basis of strain-specific pathogenesis remains poorly understood. Here we show that in cell culture , H5N1 induced more rapid and extensive cell death than H1N1. Since Interferon (IFN) signaling is key to innate immunity, we examined its role in virus-induced cell death using STAT1-knockout A549 cells and JAK/STAT pathway inhibitors like Baricitinib . Both approaches reduced cell death across various IAV strains, including H1N1, H5N1, H7N9 , and H3N2 . However, inhibition increased viral titers , raising concerns about its clinical use in isolation. To overcome this, we tested a combination of Oseltamivir (antiviral) and Baricitinib (anti-inflammatory). ...

Highlights •  Mol shows greater antiviral effects against IAV and IBV in cell cultures. •  Mol and Ose together showed a synergistic effect against IAV. •  In mice, Mol alone or with Ose reduced lung injury and viral load. Abstract Oseltamivir, a neuraminidase inhibitor, is widely used in the clinic for treating influenza virus infections . However, suboptimal efficacy and risk of drug resistance development remain major challenges. Molnupiravir , a ribonucleoside analog, was originally developed to treat influenza, but was repurposed and first approved for treating COVID-19 in 2021. Considering their complementary mode-of-actions, this study aimed to investigate the combinatorial activities of oseltamivir and molnupiravir against influenza virus infections . In cell culture models, we found that β-d-N4-hydroxycytidine (NHC), the active form of molnupiravir, exerted more potent antiviral activities against influenza A and B viruses , when compared to oseltamivir treatment...