ETIDIOH - NEW

Key Points -- Question:   In adults with influenza requiring admission to hospital, is oseltamivir treatment within the first 2 days of admission, when compared with supportive care without oseltamivir, associated with a decreased risk of death in hospital? -- Findings:  In this cohort study of 11 073 patients hospitalized with influenza, oseltamivir treatment was associated with an adjusted risk reduction of 1.8% for in-hospital mortality when compared with supportive care. -- Meaning:  The findings of this study support current guidelines that recommend oseltamivir treatment for patients admitted to hospital with influenza; clinical trials should be conducted to generate better quality evidence. Abstract Importance    Current guidelines recommend oseltamivir treatment for all patients hospitalized with influenza, but this guidance is based on suboptimal evidence. Objective    To evaluate outcomes associated with oseltamivir treatment when compared wi...

Summary Background Onradivir (ZSP1273) is a potent inhibitor of the PB2 subunit of influenza A virus (IAV) polymerase . Our previous, phase 2 clinical trial showed that a 600 mg regimen of onradivir initiated within 48 h of symptom onset can expedite the recovery of adult patients from acute, uncomplicated influenza. Here, we aimed to evaluate the safety and therapeutic efficacy of onradivir in a larger group with acute, uncomplicated influenza. Methods This randomised, double-blind, multicentre, placebo-controlled and oseltamivir-controlled, phase 3 trial was conducted at 68 clinical sites in China . Eligible participants were adults (aged 18–64 years) with an influenza-like illness who screened positive by rapid IAV antigen testing at the first clinical visit, and had a fever (axillary temperature ≥38·0°C) with at least one moderate systemic and one moderate respiratory symptom within 48 h of symptom onset. Patients were randomly assigned into three treatment groups, stratified by in...

Abstract Avian influenza viruses (AIVs) pose a growing global health threat , particularly in low- and middle-income countries (LMICs), where limited surveillance capacity and under-resourced healthcare systems hinder timely detection and response. Migratory birds play a significant role in the transboundary spread of AIVs, yet data from key regions along migratory flyways remain sparse. To address these surveillance gaps, we conducted a study between December 2021 and February 2023 using fresh bird guano collected across 10 countries in the Global South . Here, we show that remote, uninhabited regions in previously unsampled areas harbor a high diversity of AIV strains , with H5N1 emerging as the most prevalent . Some of these H5N1 samples also carry mutations that may make them less responsive to the antiviral drug oseltamivir . Our findings documented the presence of AIVs in several underrepresented regions and highlighted critical transmission hotspots where viral evolution may be ...

ABSTRACT Background and Objectives This randomised controlled trial evaluated whether higher doses of oseltamivir would improve virological and clinical outcomes in severe influenza patients requiring invasive mechanical ventilation. Methods Forty intubated adult patients with severe influenza A or B from four intensive care units in Hong Kong were enrolled and randomised to receive either a double dose (300 mg/day) or a triple dose (450 mg/day) of oseltamivir for 10 days. Baseline data were collected, and outcomes were assessed daily using SOFA and Murray scores. Viral RNA was quantified from nasopharyngeal and tracheal aspirates. The primary outcome was the viral clearance rate after 5 days of treatment; secondary outcomes included 28-day and hospital mortality rates, changes in viral load, and serial SOFA and Murray scores. Results Viral clearance rates after 5 days of treatment were low and similar between the double (3/20, 15%) and triple-dose groups (2/20, 10%). No significant di...

Abstract The COVID-19 pandemic has had a significant impact and continues to alarm the entire world due to the rapid emergence of new variants , even after mass vaccinations . There is still an urgent need for new antivirals or strategies to combat the SARS-CoV-2 infections; however, we have success stories with nirmatrelvir . Drug repurposing and drug discovery may lead to a successful SARS-CoV-2 antiviral; however, rapid drug use may cause unexpected mutations and antiviral drug resistance. Conversely, novel variants of the SARS-CoV-2 can diminish the neutralizing efficacy of vaccines, thereby enhancing viral fitness and increasing the likelihood of drug resistance emergence. Additionally, the disposal of antivirals in wastewater also contributes to drug resistance. Overall, the present review summarizes the strategies and mechanisms involved in the development of drug resistance in SARS-CoV-2. Understanding the mechanism of antiviral resistance is crucial to mitigate the significant...

Abstract Background Every year, more than one billion people around the world are infected with influenza , an acute infection of the respiratory tract. Influenza spreads from person to person through air, contaminated hands or objects. Antiviral and immunomodulatory drugs are available for treatment of patients and prophylaxis of exposed persons. Reverse transcription polymerase chain reaction (RT-PCR), nucleic acid amplification tests (NAATs) and rapid tests are available for the diagnosis of influenza.  Objective   The aim of this World Health Organization (WHO) guideline is to provide recommendations for the diagnosis, drug treatment and prophylaxis of influenza. Method This updated guideline has been developed in accordance with standards for trustworthy guidelines. The recommendations are based on systematic reviews on safety and effectiveness. They take into account the magnitude of benefits and harms of treatments, the reliability of the evidence, and the needs of pati...

Summary Background Molnupiravir and nirmatrelvir–ritonavir are oral antivirals that have shown efficacy in preventing disease progression in outpatients with COVID-19. We aimed to evaluate these treatments for patients hospitalised with COVID-19 pneumonia, for whom data on these antivirals are scarce. Methods The RECOVERY trial is a randomised, controlled, open-label, adaptive platform trial testing treatments for COVID-19 . In this study we report the molnupiravir and nirmatrelvir–ritonavir comparisons from the RECOVERY trial. In each comparison, participants aged 18 years and older were randomly allocated (1:1) to the relevant antiviral (5 days of molnupiravir 800 mg twice daily or 300 mg nirmatrelvir and 100 mg ritonavir twice daily) in addition to usual care, or to usual care alone. The molnupiravir comparison was conducted at 75 hospitals in the UK, two in Nepal, and two in Indonesia ; the nirmatrelvir–ritonavir comparison was conducted at 32 hospitals in the UK. Participants coul...

Abstract The SARS-CoV-2 papain-like protease (PLpro) is a cysteine protease that cleaves viral polyproteins and antagonizes the host immune response during viral replication. Jun12682 and PF-07957472 are the first-in-class PLpro inhibitors showing potent in vivo antiviral efficacy in mouse models . In this study, we characterize naturally occurring mutations at residues located at the drug-binding site of Jun12682. The results reveal several PLpro mutants showing significant drug resistance while maintaining comparable enzymatic activity as the wild-type PLpro. The physiological relevance of the identified drug-resistant mutants, including E167G and Q269H, is validated through independent serial viral passage experiments. Molecular dynamics simulations and perturbative free energy calculations show that drug-resistant PLpro mutants weaken hydrogen bonding and π-π stacking interactions. Collectively, this study identifies E167, Y268, and Q269 as drug-resistant hotspots for PLpro inhibit...

Abstract Thousands of outbreaks of the highly pathogenic avian influenza A(H5N1) virus in birds and an increasing number of mammal infections are registered annually. In 2023, multiple avian influenza outbreaks were registered among wild birds, poultry and seals in Russia . The genetic characterization of seventy-seven avian viruses and three viruses from seals showed that they belonged to the 2.3.4.4b clade and represented four distinct reassortant genotypes . The majority of viruses represented genotype BB , which was widespread in Europe in 2023. Viruses from seals and four viruses from birds , isolated from outbreaks in the Far East region , belonged to the G1 (A3) genotype and had the amino acid substitution N319K in the NP protein , previously associated with an increased virulence for mammals . In addition, one virus of the G10 genotype and two viruses, representing a previously undescribed genotype (designated as Ru-23-G4) were identified. The viruses analyzed showed normal inh...

Abstract Nipah virus, a zoonotic pathogen, can cause debilitating disease and death in humans. Currently, countermeasures are limited , with several in various stages of testing but none yet FDA-approved for human use. Evaluation of countermeasure candidates requires safety testing in humans, as well as efficacy testing against lethal challenge in animal models . Herein, we describe the characterization and comparison of the intraperitoneal and intranasal Syrian golden hamster models for Nipah virus strains Malaysia and Bangladesh . Overall, the intraperitoneal route of exposure resulted in a more consistent lethal outcome, regardless of virus strain. Therefore, the IP model was subsequently used to evaluate the use of Favipiravir as a potential positive control for future studies investigating NiV countermeasures. In contrast to prior reported results regarding Favipiravir in Nipah virus-infected hamsters, Favipiravir was only fifty percent effective at preventing death following leth...

Abstract Seasonal influenza continues to be a global health problem . Current existing vaccines and antivirals against influenza have limited effectiveness, and typically do not stay ahead of the viral evolutionary curve. Broad-spectrum antiviral agents that are effective therapeutically and prophylactically are much needed. We have created a promising new broad-spectrum anti-influenza agent using molecular engineering of a lectin from bananas , H84T, which is well-tolerated and protective in small animal models . However, the potency and effect of H84T on human immune cells and influenza-specific immune responses are undetermined. We found that H84T efficiently inhibited influenza A virus (IAV) replication in primary human dendritic cells (DCs) isolated from blood and tonsil, preserved DC viability and allowed acquisition and presentation of viral antigen. Excitingly, H84T-treated DCs subsequently initiated effective expansion of IAV-specific CD8 T cells. Furthermore, H84T preserved t...

Highlights •  Reconstituted human airway epithelia (HAE) are more effective than cell lines or mouse models for generating and predicting resistance-conferring mutations. •  The resistance barrier of oseltamivir is superior to baloxavir or HA targeting compounds in HAE or mouse model. •  HA-targeting therapeutics quickly led to resistant HA mutations without compromising viral fitness. •  A baloxavir-resistant virus with PA mutations E23G and C241Y was isolated in HAE. •  Combined therapy using clinical antiviral compounsd and HA-targeting compounds did not prevent the emergence of HA mutations. Abstract Influenza viruses pose a significant threat due to annual epidemics and pandemic potential . Resistance to current antivirals underscores the need for new drugs and strategies to prevent its emergence. We previously developed two novel HA-targeting compounds (CD-6’SLN and CD-SA) with demonstrated efficacy against influenza A and B strains . Here, we compared the...

Abstract Influenza remains a global public health concern, and although the antiviral drug oseltamivir is widely used to treat infections , questions regarding its actual antiviral efficacy and clinical benefits remain. Here, we evaluated the effects of oseltamivir on viral shedding dynamics in the context of experimental influenza infection . We analyzed individual participant data, including viral load, time to symptom alleviation, and laboratory test measurements, obtained from three publicly available clinical trials involving experimental infections with influenza A and B viruses. We applied mathematical modeling and estimated parameters using a nonlinear mixed-effects model to capture viral infection dynamics. Our analysis revealed that, compared with placebo groups, the oseltamivir-treated groups tended to have lower values in terms of viral load area under the curve , duration of infection, peak viral titer, and time to peak; however, most of these differences were not signific...

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 ...

Abstract Background Baloxavir marboxil (baloxavir) rapidly reduces influenza virus shedding , which suggests that it may reduce transmission. Studies of treatment with neuraminidase inhibitors have not shown sufficient evidence that they prevent transmission to contacts. Methods We conducted a multicountry, phase 3b trial to assess the efficacy of single-dose baloxavir treatment to reduce influenza transmission from index patients to household contacts. Influenza-positive index patients 5 to 64 years of age were randomly assigned in a 1:1 ratio to receive baloxavir or placebo within 48 hours after symptom onset. The primary end point was transmission of influenza virus from an index patient to a household contact by day 5. The first secondary end point was transmission of influenza virus by day 5 that resulted in symptoms. Results Overall, 1457 index patients and 2681 household contacts were enrolled across the 2019–2024 influenza seasons; 726 index patients were assigned to the baloxa...

{Excerpt} Highlights •  A new strain of Lassa virus (LASV) was successfully isolated and characterized. •  The combination of ribavirin and LHF-535 has been demonstrated to exhibit synergistic effects in inhibiting LASV. •  The findings provide new directions for the development of antiviral drugs and vaccines for Lassa fever. Dear Editor, Lassa virus (LASV) is the causative agent of the acute viral hemorrhagic Lassa fever (LF), which is classified into Mammarenavirus within the Arenaviridae family , with a single-stranded, negative-sense, bi-segmented RNA genome. Due to its high pathogenicity and lethality , LASV is considered as a priority threat to public health , with an estimated cases of 300,000 infections and 5,000 deaths annually . LASV was first isolated and described as a clinical entity in 1969 in Lassa, Nigeria (Garry, 2023). LASV isolates of different geographic and host origins are highly diverse in genomic sequences and phylogenetically classified into up t...

Significance Anti-influenza therapeutics remain essential for the control of influenza infections , which may require hospitalization for the most severe cases. Hemagglutinin (HA) and neuraminidase (NA), the two membrane glycoproteins of the influenza virus, play crucial roles in the viral replication cycle. While many monoclonal antibodies and small-molecule inhibitors target HA or NA, each faces limitations tied to their individual properties. We developed an antibody–drug conjugate (ADC) by covalently linking the NA inhibitor zanamivir to MEDI8852, an HA stem-specific monoclonal antibody . The MEDI8852–zanamivir conjugate targets both HA and NA and offers robust and long-lasting protection in mice against lethal infections with influenza A and B viruses. This approach represents an addition to anti-influenza therapy. Abstract Influenza remains a significant public health threat . Both monoclonal antibodies and small-molecule inhibitors can target the influenza surface glycoproteins ...

Summary Background The substantial burden of post-COVID-19 condition (also known as long COVID) underscores the need for effective pharmacological interventions. Given that viral persistence has been hypothesised as a potential cause of long COVID, antiviral therapy might offer a promising approach to alleviating long COVID symptoms. We therefore investigated the efficacy, safety, and tolerability of nirmatrelvir–ritonavir for treating long COVID. Methods In this phase 2, decentralised, double-blind, randomised controlled trial , adults (aged ≥18 years) from the 48 states across the contiguous USA, with previous documented SARS-CoV-2 infection and long COVID symptoms starting within 4 weeks of initial infection and persisting for at least 12 weeks, were eligible for inclusion. Key exclusion criteria were use of nirmatrelvir–ritonavir within the previous 2 months, CYP3A4-dependent medications, or strong CYP3A4 inducers; acute medical illness such as SARS-CoV-2 infection within the past ...

Abstract Influenza A(H1N1)pdm09 virus carrying an I38N substitution was detected in an untreated teenager in Japan . The I38N mutant virus exhibited reduced susceptibility to baloxavir but remained susceptible to neuraminidase inhibitors and showed reduced growth capability . Monitoring antiviral drug susceptibility of influenza viruses is necessary to aid public health planning and clinical recommendations. Source: US Centers for Disease Control and Prevention,  https://wwwnc.cdc.gov/eid/article/31/5/24-1123_article ____

Highlights •  Phylogenetic analysis of genotype B3.13 and D1.1 across the species. •  Mutations on the receptor binding sites related to receptor preferring. •  Host adaptability differences between B3.13 and D1.1. •  Antivirals resistance mutations emergence of genotype B3.13 and D1.1. Abstract The recent report of the first fatality associated with infection by influenza virus H5N1 clade 2.3.4.4b, identified as genotype D1.1, which is distinct from the B3.13 genotype, has sparked fears of a potential human pandemic . However, the genetic relationships between B3.13 and D1.1, as well as their origins, host adaptability, and antiviral resistance, remain poorly understood . Here we conducted a comprehensive phylogenetic and comparative analysis of H5N1 clade 2.3.4.4b across multiple species , in order to identify the molecular characteristics and frequency of resistance mutations in these two genotypes, elucidate their evolutionary trajectories , and assess their impl...