ETIDIOH - NEW

  Abstract Introduction Seasonal influenza causes significant global morbidity, mortality, and economic burden . Ongoing viral evolution can lead to vaccine mismatch and the emergence of antiviral resistance , highlighting the importance of genomic surveillance. The 2024–2025 influenza season was characterized by high incidence and increased hospitalizations. Methods We analyzed influenza A virus (IAV) genomes and clinical characteristics from the 2024–2025 season . Whole-genome sequencing was performed on 648 influenza A–positive clinical specimens collected between October 2024 and April 2025. Results Hemagglutinin (HA) sequences were recovered from 74.23% (481/648) of samples and used for subtyping and phylogenetic analysis. A(H1N1)pdm09 and A(H3N2) viruses co-circulated , representing 55.5% and 44.5% of cases, respectively. Among A(H1N1)pdm09 viruses, the HA1 substitution T120A , located near the Sa antigenic site , increased more than twofold compared with the prior season. Ci...

  Abstract Background Household transmission of SARS-CoV-2 remains a key driver of community spread , with secondary attack rates in Thai households reaching approximately 50 %. There is limited evidence supporting the efficacy of antiviral post-exposure prophylaxis (PEP) in this context. Methods The phase 2/3, open-label, (1:1) cluster-randomized controlled trial in Thailand , 168 household close contacts from 76 index cases were enrolled to receive either favipiravir-PEP (FPV-PEP) (1600–2000 mg/day for 7 days) or usual care. The efficacy of FPV-PEP was investigated in preventing SARS-CoV-2 infection after contact with index cases. Results The incidence of confirmed SARS-CoV-2 infection was lower in the FPV-PEP group than in the usual care group (7.32 % vs. 14.47 %), although the difference was not statistically significant . A trend toward fewer early positive rapid diagnostic test results on day 3 was observed in the FPV-PEP group. Symptom development was less frequent among FPV...

  Abstract Neuraminidase inhibitors (NAIs) and cap-dependent endonuclease inhibitors (CENIs) represent two classes of antiviral drugs recommended for early treatment of patients with seasonal influenza A virus (IAV) infections. However, only limited human data , particularly on combination antiviral treatment , are available to inform optimal dosing regimens against novel IAVs, including highly pathogenic avian influenza A(H5N1) virus , associated with severe disease . Clade 2.3.4.4b A( H5N1 ) viruses have caused outbreaks in avian and mammalian species worldwide , highlighting the need to assess antiviral drug efficacy against these strains. We challenged ferrets with a D1.1 genotype A(H5N1) virus and treated infected animals with the NAI oseltamivir phosphate (OST) and the CENI baloxavir acid (BXA), alone or in combination , with treatment onset commencing pre- or post-symptom onset (24- or 48-hours post-inoculation (p.i.), respectively). When administered pre- or post-illness on...

  Summary Highly pathogenic avian influenza A(H5N1) viruses have been circulating among wild birds and are enzootic in poultry in some areas of the world with spillover to a wide range of terrestrial and marine mammals. Since 1997, sporadic animal to human , primarily poultry to human, transmission of highly pathogenic avian influenza A(H5N1) viruses has been reported in 25 countries . More recently there have been locally acquired infections in the Americas due to the 2.3.4.4b clade of the virus. Most of the recently detected human infections in the USA have been relatively mild but there have been cases of critical illness reported in several countries. In this Grand Round we present the first locally acquired highly pathogenic avian influenza A(H5N1) virus infection in Canada , which was in a 13-year-old female, who developed severe disease requiring prolonged critical care . She was infected with a clade 2.3.4.4b, genotype D1.1 virus and developed evidence of cytokine storm and...

  Abstract Objective :  This systematic review aimed to assess the clinical effectiveness and safety profile of baloxavir marboxil for managing influenza in pediatric populations . Methods :  This review has been registered on the INPLASY platform (INPLASY2025110063). Designed in accordance with the PRISMA 2020 guidelines, we searched four major biomedical databases (PubMed, Embase, Web of Science, Cochrane Library) covering publications from January 1, 2015, to January 30, 2025 . Eligibility criteria encompassed both randomized controlled trials and observational cohort studies evaluating this antiviral agent in children with laboratory-confirmed influenza. Methodological rigor was appraised using the Cochrane Collaboration's risk of bias instrument for randomized controlled trials (RCTs) and the Newcastle-Ottawa Quality Assessment Scale for cohort studies. Statistical synthesis was conducted using RevMan 5.3 software (Version 5.3.5) with metafor package implementation. ...

  Highlights •  Nonspecific early signs hinder prompt diagnosis of H10N3 infection. •  H10N3 human infection remains rare but with high clinical severity. •  All patients had bird exposure and developed fever, cough, and dyspnoea. •  Diagnosis was confirmed by sequencing; imaging revealed viral pneumonia. Abstract Background Since the first human case of H10N3 Avian Influenza in Jiangsu, China (April 2021), three cases have been reported globally. However, clinical and treatment data remain limited. Therefore, we describe the fourth patient’s epidemiology, clinical manifestations, diagnostics, treatment. Case presentation A 23-year-old woman, previously well , presented on 12 Dec 2024 with fever, dry cough and breathlessness after pig and chicken contact . CT showed bilateral pneumonia . Despite high-flow oxygen and broad-spectrum antibiotics she deteriorated , requiring intubation, lung-protective ventilation and VV-ECMO . Bronchoalveolar lavage isolated H10N3 ...

  Highlights •  We generated a recombinant reporter OROV that expresses the eGFP fluorescent protein in infected cells. •  We found that remdesivir efficiently inhibited the replication of Oropouche virus (OROV) using this reporter OROV. •  We demonstrated strain-dependent differences in the replication efficiency of OROV. Abstract The Oropouche virus (OROV), an orthobunyavirus transmitted by biting midges, is the causative agent of Oropouche fever , which has caused multiple outbreaks in South and Central America . During the most recent epidemic in 2023–2025, more than 25,000 laboratory-confirmed cases were reported in Brazil , and no licensed antivirals have been reported to be effective date. In this study, we generated a recombinant OROV-expressing enhanced green fluorescent protein (rOROV/GFP) to facilitate rapid and sensitive antiviral evaluation . Growth kinetics demonstrated that rOROV/GFP replicated less efficiently than wild-type rOROV and that the histori...

  Abstract We characterized influenza A(H1N1)pdm09, A(H3N2), and B/Victoria viruses circulating in Japan during 2023–2024 , focusing on lineage placement relative to WHO-recommended vaccine strains and on baloxavir resistance (PA/I38T substitutions). We enrolled 210 outpatients with influenza-like illness across eight clinics in six prefectures (October 2023–September 2024). Of these, 209 had an analyzable pre-treatment respiratory specimen for RT-PCR; hemagglutinin (HA) and neuraminidase (NA) genes were sequenced by next-generation sequencing (NGS). PA/I38T substitutions that confer baloxavir resistance were assessed by cycling-probe RT-PCR, Sanger sequencing, and NGS. HA phylogenies were constructed with global datasets and WHO vaccine reference strains. Of 209 pre-treatment specimens, 181 were influenza-positive (A(H1N1)pdm09 44.2%, A(H3N2) 37.6%, B/Victoria 18.2%); 51 follow-up specimens were collected ≈4–5 days after baloxavir or neuraminidase inhibitor therapy . HA phylogeny ...

  Abstract While treatment with nirmatrelvir/ritonavir or molnupiravir is effective in lowering the rate of severe COVID-19 , the effectiveness of these antivirals in reducing the risk of cardiovascular outcomes, especially among the hospitalized population, remains largely unknown . In this study, we assessed the real-world effectiveness of nirmatrelvir/ritonavir and molnupiravir on short- and long-term cardiovascular complications of COVID-19 using a target trial emulation design. Two target trials of COVID-19 antivirals were emulated by using a territory-wide, population-based, retrospective cohort of hospitalized patients in Hong Kong . Nine cardiovascular outcomes were evaluated in both short-term (day 0–21) and long-term (day 22–365) post-SARS-CoV-2 infection. Compared with the control group , the use of nirmatrelvir/ritonavir was associated with a significantly lower one-year risk of cardiovascular mortality , composite cardiovascular complications, major adverse cardiac eve...

  Abstract Maintaining tissue function while eliminating infected cells is fundamental, and inflammatory damage plays a major contribution to lethality after lung infection . We tested 50 immunomodulatory regimes to determine their ability to protect mice from lethal infection . Only neutrophil depletion soon after infection prevented death from influenza. This result suggests that the infected host passed an early tipping point after which limiting innate damage alone could not rescue lung function. We investigated treatments that could have efficacy when administered later in infection. We found that partial limitation of viral spread together with enhancement of epithelial repair, by interferon blockade or limiting CD8+ T cell–mediated killing of epithelial cells , reduced lethality . This finding highlights the importance of rebalancing repair and damage processes in the survival of pulmonary infections. Source:  Link:  https://www.science.org/doi/10.1126/science.adr4...

  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...