ETIDIOH - NEW

  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...

Highlights •  Antiviral susceptibility to NA inhibitors and PA inhibitor baloxavir was determined for seasonal and zoonotic influenza viruses circulating globally during 2020–2023. •  Low global frequencies (0.1-0.2%) of seasonal influenza viruses with reduced or highly reduced inhibition by NAI inhibitors were observed as in previous years. •  Low global frequencies of seasonal influenza viruses (∼ 0.1%) with reduced susceptibility to baloxavir were observed, with the rate in Japan elevated (3.3%) in 2022–2023, as has been seen previously. •  For zoonotic viruses, 2.7% contained genetic markers associated with reduced or highly reduced inhibition to NA inhibitors and none contained markers associated with reduced susceptibility for baloxavir. •  For the treatment of influenza , NA inhibitors and baloxavir remain suitable. ABSTRACT Antiviral susceptibility of influenza viruses is monitored by the World Health Organization Global Influenza Surveillance and Respon...

Abstract Since the first detection of highly pathogenic avian influenza (HPAI) H5N1 (clade 2.3.4.4b) in U.S. dairy cattle in early 2024, the virus has spread rapidly, posing a major public health concern as the number of human cases continues to rise. Although human-to-human transmission has not been confirmed, experimental data suggest that the bovine H5N1 virus can transmit via respiratory droplets in ferrets , highlighting its pandemic potential . With no vaccines currently available, antiviral drugs remain the only treatment option. Here, we investigate the efficacy of the polymerase inhibitor baloxavir marboxil (BXM) against this virus in mice. We find that early treatment post-infection is effective, but delayed treatment significantly reduces BXM efficacy and increases the risk of BXM resistance, underscoring the importance of timely BXM administration for effective treatment. Source: Nature Communications,  https://www.nature.com/articles/s41467-025-60791-5 ____

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...

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 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...

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 ____

Abstract In recent years, the influenza viruses have posed an increasingly severe threat to public health . It is essential to analyze the virulence and pathogenesis of influenza viruses to prevent and control them, as well as create antiviral drugs . Previous studies have revealed that influenza virus segment 3 codes for not only the PA protein but also a novel protein, PA-X . PA protein is one subunit of the polymerase of influenza viruses and plays a critical role in its life cycle. PA presented endonuclease activity , the transcription and replication of the viral genome , viral virulence , protein degradation , and host immune response by interacting with viral proteins, including PB2, PB1, and host factors, including ANP32A, CHD6, HAX1, hCLE, HDAC6, MCM complex. PA mutations were involved in the viral replication, pathogenicity, and transmission of influenza viruses in poultry, mammals, and humans . PA-X is an open reading frame generated by +1 ribosomal code shift at the N-termi...

Abstract Testing approved antivirals against A(H5N1) influenza viruses circulating in peridomestic species, including dairy cows , is critical to public health and pre-pandemic planning . It cannot be tested in humans due to A(H5N1) disease severity. Here, in mice, we demonstrate that US FDA-approved baloxavir treatment mediates improved disease outcomes ( survival and viral dissemination ) over oseltamivir after lethal intranasal and ocular challenge with A(H5N1)-contaminated cow milk. Source: Nature Microbiology,  https://www.nature.com/articles/s41564-025-01961-5 ____

Abstract During 2023-2024, highly pathogenic avian influenza A(H5N1) viruses from clade 2.3.2.1c caused human infections in Cambodia and from clade 2.3.4.4b caused human infections in the Americas . We assessed the susceptibility of those viruses to approved and investigational antiviral drugs . Except for 2 viruses isolated from Cambodia , all viruses were susceptible to M2 ion channel-blockers in cell culture-based assays. In the neuraminidase inhibition assay , all viruses displayed susceptibility to neuraminidase inhibitor antiviral drugs oseltamivir, zanamivir, peramivir, laninamivir , and AV5080. Oseltamivir was ≈4-fold less potent at inhibiting the neuraminidase activity of clade 2.3.4.4b than clade 2.3.2.1c viruses. All viruses were susceptible to polymerase inhibitors baloxavir and tivoxavir and to polymerase basic 2 inhibitor pimodivir with 50% effective concentrations in low nanomolar ranges. Because drug-resistant viruses can emerge spontaneously or by reassortment, close m...

Abstract Background Influenza is a pervasive respiratory infection which disproportionately burdens long-term care residents. To limit outbreaks, guidelines recommend antiviral prophylaxis, particularly oseltamivir or zanamivir , despite acknowledging the inadequate supporting evidence . Therefore, we aimed to review the literature on the efficacy of oseltamivir, zanamivir, and baloxavir prophylaxis for influenza in long-term care. Methods Medline, Embase, PubMed, and several other databases were searched from inception to August 16, 2023. For inclusion, observational studies or randomized controlled trials (RCTs) had to report influenza-like illness (ILI) or infection rates amongst adult long-term care populations receiving prophylaxis. Outcome values were meta-analyzed as intervention-specific pooled proportions (PPs) and risk ratios (RRs) when applicable. Risk of bias was assessed via the Cochrane risk of bias tool 2.0 and Joanna Briggs Institute checklist. Results In total, 14 stud...

To the Editor : Highly pathogenic avian influenza A(H5N1) viruses are circulating among wild birds and poultry in British Columbia, Canada .1 These viruses are also recognized to cause illness in humans . Here, we report a case of critical illness caused by influenza A(H5N1) virus infection in British Columbia. On November 4, 2024, a 13-year-old girl with a history of mild asthma and an elevated body-mass index (the weight in kilograms divided by the square of the height in meters) of greater than 35 presented to an emergency department in British Columbia with a 2-day history of conjunctivitis in both eyes and a 1-day history of fever . She was discharged home without treatment, but cough, vomiting, and diarrhea then developed, and she returned to the emergency department on November 7 in respiratory distress with hemodynamic instability. On November 8, she was transferred, while receiving bilevel positive airway pressure, to the pediatric intensive care unit at British Columbia Child...

Summary The purpose of this guidance is to outline CDC's recommendations for preventing exposures to highly pathogenic avian influenza (HPAI) A(H5N1) viruses, infection prevention and control measures including the use of personal protective equipment , testing, antiviral treatment , patient investigations , monitoring of exposed persons (including persons exposed to sick or dead wild and domesticated animals and livestock with suspected or confirmed infection with highly pathogenic avian influenza (HPAI) A(H5N1) virus), and antiviral chemoprophylaxis of exposed persons. These recommendations are based on available information and will be updated as needed when new information becomes available. (...) Source: US Centers for Disease Control and Prevention,  https://www.cdc.gov/bird-flu/prevention/hpai-interim-recommendations.html _____