#Antiviral Susceptibility of Clade 2.3.4.4b #H5N1 and #H5N5 #Influenza Viruses Detected in #Birds in #Russia During 2021–2022

 

Abstract

In this study, we aimed to analyze the antiviral susceptibility of clade 2.3.4.4b H5N1 and H5N5 influenza viruses detected in Russia during 2021–2022. During this period, we investigated 40 avian influenza outbreaks in wild and domestic birds, isolating 109 H5N1 and 9 H5N5 strains. Using a genetic approach, we analyzed the presence of markers associated with reduced susceptibility to baloxavir and M2 blockers, as well as markers of reduced inhibition by neuraminidase inhibitors (NAIs). Additionally, the isolated strains were tested in a functional assay to evaluate the inhibitory activity of oseltamivir, zanamivir, and peramivir against viral neuraminidase. None of the isolates harbored genetic markers of reduced susceptibility to M2 blockers and baloxavir or reduced inhibition by NAIs. Functional assay showed that the median IC50 values of oseltamivir, zanamivir, and peramivir were 1.73, 0.49, and 0.16 nM for the H5N1 subtype, and 0.65, 1.13, and 0.12 nM for the H5N5 subtype, respectively. None of the tested strains demonstrated a ≥10-fold increase in NAI IC50 values compared to the corresponding subtype medians, and were thus classified as having a normal level of inhibition. The median IC50 values of the NAIs determined for the tested avian viruses were comparable to those of a susceptible seasonal A(H1N1)pdm09 strain, except for a slight reduction in oseltamivir activity against H5N1 viruses (4.3-fold) and zanamivir activity against H5N5 viruses (3.4-fold). Our study revealed a group of H5N1 viruses whose NA belonged to the ea5.1 genetic subclade, characterized by NA-Y253H and T452I amino acid substitutions, which exhibited a 28.8-fold decrease in oseltamivir IC50 values compared to the subtype median. These strains were detected in the European and Ural regions of Russia between May 2022 and January 2023, with no subsequent detections in the available surveillance data. To the best of our knowledge, such strains have not been identified outside Russia.

Source: 

Link: https://doi.org/10.3390/v18101126

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Integrated in vivo and transcriptomic analyses of lethal #Oropouche virus #infection reveal suppression of pathogenic host responses by #antiviral therapy

 

Abstract

Oropouche virus (OROV) is an emerging arbovirus responsible for large outbreaks of febrile illness in Central and South America, with increasing reports of severe neurological disease and fatal outcomes. Despite its growing public health impact, no approved antiviral therapies or vaccines are currently available. Here, we show that favipiravir, a broad-spectrum nucleoside analogue, robustly suppresses OROV replication and disease in vivo. In a lethal Syrian hamster model, favipiravir treatment provided complete protection against OROV infection, preventing viral dissemination to peripheral organs and the central nervous system, and remained highly effective when administration was initiated after infection. In contrast, insufficient antiviral control resulted in viral neuroinvasion and fatality. To define host responses associated with OROV pathogenesis and their modulation by antiviral therapy, we performed transcriptomic profiling of liver and brain tissues. OROV infection induced interferon-driven inflammatory programs accompanied by marked disruption of metabolic and tissue homeostatic pathways, whereas these transcriptional signatures were largely abrogated by favipiravir treatment. Together, our findings identify favipiravir as a potent antiviral candidate against OROV and provide the first in vivo, tissue-resolved transcriptomic framework of OROV infection, linking effective viral suppression with the prevention of neuroinvasion and pathogenic host responses. These results highlight antiviral intervention as a viable strategy to mitigate OROV-associated disease and mortality.

Source: 

Link: https://doi.org/10.1371/journal.ppat.1014647

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Persistent #influenza A #RNA detection in a #fatal #pediatric case of influenza-associated #encephalopathy

 

Abstract

Influenza-associated encephalopathy (IAE) is a life-threatening complication of influenza. We report a case of a 9-year-old boy diagnosed with fulminant IAE. The patient received life-sustaining support, intensive immunomodulatory therapy, and antiviral therapy. Following an initial single dose of baloxavir marboxil, persistent influenza A (H3N2) RNA detection prompted a multi-targeted antiviral regimen (oseltamivir, baloxavir marboxil, peramivir, and onradivir) as salvage therapy. Nevertheless, influenza A RNA remained detectable for more than 1 month, potentially reflecting severe neurological injury, immunosuppression, and impaired airway clearance.

Source: 

Link: https://doi.org/10.1016/j.jiph.2026.103380

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Increased circulation of #influenza #H1N1pdm09 viruses with reduced susceptibility to #oseltamivir, #Germany 2024–2026

 

Highlights

    • The National Influenza Center for Germany (Germany NIC) detected an increase in the prevalence of A(H1N1)pdm09 viruses carrying the neuraminidase substitution NA-S247N, rising from 1.16% circulating in the 2024/25 influenza season to 56.8% in the 2025/26 season.

    • The NA-S247N substitution reduced oseltamivir susceptibility slightly; combined NA-S247N/NA-I223V/T substitutions showed reduced inhibition according WHO criteria.

    • Continuous molecular and phenotypic surveillance is essential for public health and the early detection of viruses with reduced susceptibility to antiviral drugs.

    • Rapid pyrosequencing supports the routine surveillance of neuraminidase substitutions associated with reduced susceptibility to antivirals.

    • The findings illustrate the Germany NIC's 30-year contribution to antiviral susceptibility monitoring.

Abstract

Background

Oseltamivir is still considered to be the first-line antiviral treatment for severe seasonal influenza. However, resistance to neuraminidase (NA) inhibitors poses significant challenges to influenza management. Since the 2023/24 season, A(H1N1)pdm09 viruses carrying neuraminidase substitutions (NA-I223V and/or NA-S247N) have emerged in Germany, other EU/EEA countries, and some of the World Health Organization (WHO) regions. These viruses have been linked to reduced oseltamivir susceptibility.

Methods

A rapid RT-PCR/pyrosequencing assay was developed and validated to detect NA-I223X and NA-S247X substitutions. Subsequently, a total of 765 A(H1N1)pdm09 viruses detected in Germany during the 2024/25 and 2025/26 influenza seasons were characterized phenotypically using fluorometric NA inhibition testing and/or genotypically using next-generation sequencing and pyrosequencing.

Results

The prevalence of A(H1N1)pdm09 viruses bearing the NA-S247N substitution increased from 1.2% in the 2024/25 season to 56.8% in the 2025/26 season, accounting for up to 80% of analyzed viruses by March 2026. Viruses carrying NA-S247N exhibited higher oseltamivir IC50 values than wild-type viruses. Combinations of NA-S247N with substitutions at position 223 demonstrated an additional increase. In viruses carrying the combined NA-S247N and NA-I223V/T substitutions oseltamivir showed reduced inhibition with increased IC50 values of up to 17-fold compared to wild type viruses.

Conclusions

The accumulation of NA substitutions in A(H1N1)pdm09 influenza viruses, particularly NA-S247N in combination with NA-I223V/T, substantially reduces susceptibility to oseltamivir. The marked increase in NA-S247N prevalence suggests that this substitution is becoming persistent rather than transient. Targeted pyrosequencing is a practical tool for the early detection of emerging resistance-associated substitutions.

Source: 

Link: https://doi.org/10.1016/j.ijmm.2026.151745

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N70S/Y155H Combined #Mutation of #Neuraminidase of Avian #Influenza #H9N2 Virus confers #oseltamivir and #zanamivir #resistance and pathogenicity to Mice

 

Highlights

    • H9N2 viruses recently circulating in China harbors novel N70S/Y155H dual mutations in N2;

    • H9N2 viruses with N70S/Y155H mutations exhibit high pathogenicity to BALB/c mice.

    • N70S/Y155H linked mutations in N2 confer resistance to oseltamivir and zanamivir, rather than peramivir.

    • Neuraminidase inhibitors exhibited limited efficacy on H9N2 virus with novel N70S /Y155H dual mutations.

Abstract

Recently, H9N2 avian influenza virus (AIV) poses a significant threat to both the poultry industry and public health. Therefore, investigating the impact of its neuraminidase mutations on susceptibility to neuraminidase inhibitors (NAIs) is of great importance for clinically preventing potential cross-species transmission of H9N2. In this study, our results revealed that NAI resistance-related mutations of most H9N2 viruses isolated from China during 1998 to 2024 mainly occurred at positions N70S, E119A/D/G/V, Q133K, Q136A, D151E, Y155H, I222V, R224K, E276D, R292K, N294S, and R371K. Among them, the combined N70S and Y155H mutations are common characteristics of H9N2 viruses circulating in recent years. In vivo experiments demonstrated that these H9N2 viruses harboring the combined N70S and Y155H mutations exhibit high pathogenicity to BALB/c mice without prior adaption. In vitro neuraminidase inhibition assays confirmed that these H9N2 viruses bearing the N70S/Y155H mutations exhibited greater reduced inhibition than their counterparts bearing the N70S or Y155H single mutation to oseltamivir and zanamivir, but remained highly sensitive to peramivir. Notably, the in vivo protective effect of NAIs against H9N2 virus with combined N70S and Y155H mutations is limited, possibly due to the restricted ability of these drugs to ameliorate the excessive inflammatory responses. Therefore, there is an urgency to strengthen research on epidemiological surveillance and prevention strategies for avian influenza H9N2 harboring these mutations.

Source: 

Link: https://doi.org/10.1016/j.antiviral.2026.106540

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Comparison of #Baloxavir-Based Combinations and Monotherapies for Treating #Influenza #H5N1 Clade 2.3.4.4b Virus #Infection in Mice

 

Abstract

Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause animal outbreaks and sporadic zoonotic infections. In a mouse model of lethal influenza disease, we compared oseltamivir, baloxavir, and molnupiravir monotherapies with 2-drug combinations. Baloxavir-based combinations improved survival, reduced lung viral loads, and prevented extrapulmonary dissemination, supporting H5N1 preparedness strategies.

Source: 

Link: https://doi.org/10.3201/eid3210.260186

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Occurrence of #influenza #antivirals and #resistance development in #influenza A viruses in aquatic #environments: A risk assessment

 

Abstract

Influenza antivirals (IAs) have been detected in aquatic environments inhabited by dabbling ducks, the natural reservoir of influenza A virus (IAV), raising concerns about the development of antiviral resistance. Because novel human IAV strains often contain genetic material of avian origin, this may contribute to resistance in viruses with pandemic potential. This study aimed to assess the environmental risk posed by four IAs—oseltamivir carboxylate (OC), zanamivir (ZA), peramivir (PE), and amantadine (AM)—based on their potential for environmental release, environmental stability, and induction of antiviral resistance. The assessment combined data from new experiments on (1) environmental release and (2) environmental stability of PE, AM, OC, and ZA, with results from previously published in vivo experiments in a mallard model examining (3) resistance development to OC, PE, and ZA in IAV. The risk of environmental release was assessed as high for OC, AM, and PE, and very high for ZA. Environmental stability ranged from very high to low, in the order PE > AM > OC > ZA. The potential to induce resistance in IAV was similar for PE and OC, and lower for ZA. Overall, the environmental risk ranking was PE > OC > ZA, with PE and OC posing the highest risks. Prudent use of IAs requires balancing the risk of resistance development against clinical benefit. In cases of complicated influenza or in high-risk patient groups, the clinical benefits are substantial and justify IA use. However, in uncomplicated influenza among otherwise healthy individuals, the clinical benefit is limited, and the risk of resistance development should be carefully considered. Among the evaluated antivirals, ZA showed the lowest environmental risk and should be preferred when feasible.

Source: 

Link: https://doi.org/10.1371/journal.pone.0358447

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A Decade of Chronic #Hepatitis E #Treatment: #Ribavirin Effectiveness, Safety, and the Association of Torque Teno Virus Load With Treatment Outcomes

 

Highlights

    • Ribavirin achieved 81% SVR in immunocompromised patients with chronic HEV.

    • Adverse events occurred in 56% and led to discontinuation in 17%.

    • Ribavirin dose reduction was associated with failure to achieve SVR.

    • Higher baseline HEV RNA levels were associated with non-SVR.

    • Baseline TTV load showed a nonsignificant trend toward higher levels in non-SVR patients.

Abstract

Background

Hepatitis E virus (HEV) affects immunocompromised individuals. Unlike immunocompetent hosts, who rarely develop chronic infection, up to two-thirds of immunocompromised patients progress to chronicity. Ribavirin is the recommended antiviral therapy, yet predictors of sustained virological response (SVR) remain unclear. Torque Teno Virus (TTV), a marker of immunosuppression, has been proposed as a potential predictor of viral clearance.

Objectives

We evaluated ribavirin treatment outcomes and adverse effects in immunocompromised patients with HEV infection, and assessed whether TTV load predicts SVR.

Study Design

A retrospective cohort study was conducted at the University Medical Center Groningen including solid organ transplant recipients (SOTR) and haematology patients treated with ribavirin for HEV infection between 2010 and 2022. Clinical data and stored serum samples were analysed to determine infection duration and TTV load at treatment initiation and after three months. TTV loads in treated patients were compared with TTV loads of transplant recipients who spontaneously cleared HEV.

Results

Fifty-two patients received ribavirin; 27 had confirmed chronic infection. SVR was achieved in 81% of chronic cases. Adverse events occurred in 56%, leading to dose reduction in 25% and discontinuation in 17%. Non-SVR was associated with ribavirin dose reduction, lower mean daily dose, higher baseline HEV RNA, and lower ALT. Baseline TTV load showed a nonsignificant trend toward higher levels in non-SVR patients. TTV loads did not differ between treated patients and spontaneous clearers.

Conclusions

Ribavirin is effective for chronic HEV, but treatment-limiting toxicity is common. Adequate dosing appears critical for achieving SVR. TTV load did not reliably predict treatment outcome, underscoring the need for further research into immunological and virological predictors of response.

Source: 

Link: https://doi.org/10.1016/j.jcv.2026.106003

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Notes from the Field: #Clinical Characteristics of Patients with #Ebola Disease Caused by #Bundibugyo Virus — #Uganda, 2026

 

Summary

    ° What is already known about this topic?

        § Clinical and epidemiologic descriptions of Bundibugyo virus disease (BVD) are rare; case-fatality rates in previous outbreaks have ranged from 32% to 55%. Effective treatments have not been described.

    ° What is added by this report?

        § Among the first 21 cases (20 confirmed; one probable) in the 2026 Uganda BVD outbreak, 18 were admitted to the Mulago National Referral Hospital Ebola Treatment Unit (ETU). Among these 18, all had elevated liver enzymes, hypoalbuminemia, and hyponatremia on ETU admission. All 18 received treatment with remdesivir through an off-label, compassionate-use protocol. Among 20 confirmed cases, 18 (90%) patients survived; two deaths occurred among patients with confirmed cases whose infections were recognized late. Seeking care promptly might have reduced the number of deaths.

    ° What are the implications for public health practice?

        § Communicating with the public about the benefits of seeking health care promptly when BVD is suspected might improve patient outcomes. Clinical trials of remdesivir for patients with BVD might be warranted.

Abstract

    Ebola disease is a viral hemorrhagic fever caused by viruses of the genus Orthoebolavirus. Bundibugyo virus (Orthoebolavirus bundibugyoense), first identified in 2007 in Bundibugyo District, Uganda, is one of four orthoebolaviruses known to cause Ebola disease in humans; only two previous Bundibugyo virus disease (BVD) outbreaks have been documented. Transmission occurs through direct contact with infectious blood or other body fluids. Common signs and symptoms include fever, abdominal pain, diarrhea, vomiting, weakness, and bleeding from orifices and injection sites. Case-fatality rates (CFRs) among confirmed cases in the two previous outbreaks ranged from 32% to 55% (1,4). No licensed vaccine or specific treatment is available for BVD; clinical management is primarily supportive. On May 15, 2026, the Uganda Ministry of Health confirmed an outbreak of BVD imported from the neighboring Democratic Republic of the Congo (DRC). On August 26, 2026, the outbreak was declared over in Uganda with 20 confirmed BVD cases and one probable case reported, although the outbreak in DRC is ongoing. This report describes the clinical and epidemiologic characteristics of all 21 cases. This activity was reviewed by CDC, deemed not research, and conducted consistent with applicable federal law and CDC policy.*

Source: 

Link: http://dx.doi.org/10.15585/mmwr.mm7535a2

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Emergence and spread of NA-I223V and NA-S247N double-mutant #H1N1pdm09 #influenza viruses with reduced #oseltamivir susceptibility in the #Netherlands and beyond, 2023 to 2026

 

Abstract

In 2023/24, A(H1N1)pdm09 influenza viruses with neuraminidase (NA)-S247N emerged in NA-clade C.5.3.3 carrying NA-I223V, spread internationally, then faded. Such double mutants reappeared sporadically in 2024/25. They expanded again in 2025/26 in NA-clade D.3 viruses carrying NA-S247N after acquiring NA-I223V in Europe – notably Spain, the Netherlands, Finland and France, and beyond. Dutch double mutants from both seasons showed median 12- and 13-fold reduced inhibition by oseltamivir. These findings underscore the need for ongoing genomic and phenotypic monitoring of antiviral susceptibility.

© Creative Commons License. This work is licensed under a Creative Commons Attribution 4.0 International License.

Source: 

Link: https://doi.org/10.2807/1560-7917.ES.2026.31.36.2600733

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Updated #H1N1pdm09 #influenza virus #ferret infection #model permits refined #antiviral #assessment using aerosol inhalation challenge

 

Abstract

Seasonal influenza viruses continue to pose a significant threat to human health. As influenza viruses exhibit sustained genetic drift, it is imperative that animal studies utilize challenge strains that reflect contemporary, currently circulating viruses when evaluating pathogenicity, viral tropism, transmissibility, and antiviral sensitivity to better inform public health responses. Ferrets are considered the gold-standard small animal model for assessing currently circulating influenza viruses. Seasonal influenza A(H1N1)pdm09 viruses replicate well in both the upper and lower respiratory tract of ferrets, providing an important model for developing improved vaccination and therapeutic strategies; however, many of these studies have relied on a 2009 virus isolate. Utilising representative influenza A(H1N1)pdm09 virus strains from 2009 to 2022, we explored virus replication kinetics and lung pathogenesis in ferrets following intranasal inoculation with these contemporary strains. Our results revealed strain specific differences, with greater lung viral loads and pathogenesis following inoculation with A/Sydney/5/2021 compared to other strains. Efficient transmissibility of A/Sydney/5/2021 virus to naïve recipients was also observed following both contact and airborne exposure to infected donor ferrets. To refine this updated model, we performed side-by-side evaluation of oseltamivir antiviral efficacy following traditional intranasal or aerosol inhalation influenza challenges. Pre-treatment with oseltamivir demonstrated greater reductions in viral shedding from the upper respiratory tract than post-infection treatment of ferrets infected by aerosol inhalation, while the intranasal route showed reduced oseltamivir efficacy independent of the timing of antiviral treatment. These findings provide the basis for using an updated A(H1N1)pdm09 challenge virus for ferret studies as an alternative to the commonly used, but now less relevant 2009 early pandemic viruses. It also highlights how different methods of virus inoculation can influence outcomes of ferret antiviral studies, with an aerosol challenge model able to demonstrate differences between therapeutic and prophylactic treatments, which were not apparent with an intranasal challenge model.

Source: 

Link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014604

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#Report on #influenza viruses received and tested by the #Melbourne #WHO Collaborating Centre for Reference and Research on Influenza during 2025

 

Abstract

As part of its role in the World Health Organization (WHO) Global Influenza Surveillance and Response System (GISRS), the WHO Collaborating Centre for Reference and Research on Influenza in Melbourne (the Centre) received 13,817 human influenza-positive samples during 2025. Viruses were analysed for their antigenic, genetic, and antiviral susceptibility properties. Selected viruses were propagated in qualified cells or embryonated hens’ eggs for potential use in seasonal influenza virus vaccines. Of the 13,817 samples received or processed, influenza A(H1N1)pdm09 viruses predominated, accounting for 46.1% of samples, compared to 21.2% for A(H3N2) viruses and 19.5% for influenza B viruses; one influenza C virus was received. Among viruses analysed at the Centre, the majority of A(H1N1)pdm09 (> 99%) and influenza B (98%) viruses were antigenically similar to their respective WHO recommended vaccine strains for the Southern Hemisphere in 2025. In contrast, only 43% of A(H3N2) viruses were antigenically similar to their respective WHO recommended vaccine strains. Of 3,307 samples tested for susceptibility to the neuraminidase inhibitors oseltamivir and zanamivir, 37 A(H1N1)pdm09 viruses showed highly reduced inhibition by oseltamivir and no influenza viruses tested showed highly reduced inhibition by zanamivir. Of 5,080 samples with sequencing of the polymerase acidic (PA) gene, no genetic markers associated with highly reduced susceptibility to baloxavir marboxil were identified.

Source: 

Link: https://ojs.cdi.cdc.gov.au/index.php/cdi/article/view/3489

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#Nirmatrelvir–ritonavir targeting viral #persistence in post-COVID-19 condition (long #COVID) in the #USA (RECOVER-VITAL): a randomised, double-blind, placebo-controlled, phase 2 trial

 

Summary

Background

Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir–ritonavir improved long COVID symptoms.

Methods

We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir–100 mg ritonavir twice daily, then 100 mg ritonavir–placebo); 25 days of active intervention (300 mg nirmatrelvir–100 mg ritonavir twice daily); or 25 days of placebo–ritonavir (100 mg ritonavir–placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete.

Findings

Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38–59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI –10·4 to 16·8, p=0·65) for the 25-day regimen and –2·2% (–15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were –6·4% (–18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and –0·1% (–12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were –7·8% (–19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (–11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study.

Interpretation

Nirmatrelvir–ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed.

Funding

National Institutes of Health.

Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00406-8/fulltext

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Evaluating the #impact of #antiviral post-exposure #prophylaxis for health-care workers during #orthoebolavirus outbreaks: a modelling study

 

Summary

Background

Orthoebolavirus outbreaks place health-care workers (HCWs) at substantial risk, and HCW illness or death can weaken response capacity. The 2026 Bundibugyo virus outbreak in DR Congo highlights the need for deployable countermeasures when species-specific vaccines are unavailable. With candidate antivirals under evaluation, we aimed to estimate the impact of HCW-targeted antiviral post-exposure prophylaxis (PEP) across different readiness, disruption, and allocation scenarios.

Methods

We adapted a previously published stochastic branching-process model of orthoebolavirus transmission, representing health care, community, and funeral transmission; time-varying non-pharmaceutical interventions; and HCW-targeted PEP. The model was calibrated to two historical outbreaks using sequential approximate Bayesian computation: the 2013–16 west Africa epidemic, to define a high-burden, reasonable worst-case scenario archetype (west Africa-like archetype); and the 2018–20 North Kivu and Ituri outbreak in eastern DR Congo, to define an archetype with longer transmission under conflict-related response disruption (DR Congo-like archetype). The primary outcome was HCW deaths averted. For both archetypes, we simulated three antiviral deployment readiness scenarios (scenario 1: 100% coverage on day 0; scenario 2: scaled up to 80% coverage over 180 days; and scenario 3: scaled up to 50% coverage over 1 year) and compared their impact on HCW deaths with a scenario of no antiviral. For the DR Congo-like archetype only, we simulated four disruption scenarios: no antiviral PEP, ideal delivery (100% coverage and no dosing delay), delayed dosing with coverage preserved, and delayed dosing with delayed coverage. As a secondary outcome, we assessed number of PEP doses required per HCW death averted under different allocation scenarios.

Findings

At baseline (no antiviral PEP), cumulative HCW deaths reached a median of 553 (IQR 208–983) in the west Africa-like archetype by week 60, compared with 61 (19–125) in the DR Congo-like archetype by week 80. Assuming 80% efficacy and 80% coverage with antiviral PEP in the same timeframe in a central analysis, cumulative HCW deaths fell to 200 (68–349; equivalent reduction of 64% [63–66] relative to baseline) in the west Africa-like archetype and 22 (10–44; equivalent reduction of 64% [60–68]) in the DR Congo-like archetype. Under different scenarios of deployment readiness at 80% antiviral efficacy, the median reduction in HCW deaths compared with no PEP was 80% (95% CrI 79–81) in the west Africa-like archetype and 80% (76–84) in the DR Congo-like archetype for scenario 1; 60% (57–62) and 52% (41–58), respectively, for scenario 2; and 19% (16–22) and 22% (7–29), respectively, for scenario 3. In the DR Congo-like operational disruption analyses, an ideal scenario (PEP delivered at 100% coverage without a delay after exposure) averted 83% (79–87) of HCW deaths compared with no antiviral; maintaining 100% coverage but introducing delayed dosing (1–5 days post-exposure) reduced this finding to 50% (40–55) compared with no antiviral. Delayed coverage and dosing resulted in only 35% (25–47) of the ideal scenario impact. At 80% antiviral efficacy with same-day dosing, targeted allocation of recognised high-risk exposures (such as personal protective equipment breaches or direct body-fluid contact) required 44 doses (95% Crl 43–44) per HCW death averted versus 109 doses (85–161) with broad allocation.

Interpretation

HCW-targeted antiviral PEP could substantially reduce HCW deaths during orthoebolavirus outbreaks if efficacious antivirals can be delivered rapidly and high operational coverage is maintained. Comparisons of antiviral use cases and alternative response investments are needed to determine how resources can best support outbreak response.

Funding

Gilead Sciences, UK National Institute for Health and Care Research, Oxford Martin School, Miller Institute, EU Global Health EDCTP3, and Coalition for Epidemic Preparedness Innovations.

Translations

For the French and Swahili translations of the abstract see Supplementary Materials section.

Source: 

Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00437-8/fulltext?rss=yes

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COMbination #therapy with #baloxavir and #oseltamivir 1 for hospitalized patients with #influenza: The pragmatic COMBO 1 randomized controlled trial

 

Abstract

Background

COMBO 1 compared time to cessation of viral shedding (TCVS) among hospitalized influenza patients treated with oseltamivir plus a single dose of baloxavir vs. oseltamivir alone.

Methods

In a quadruple-blinded, placebo-controlled parallel group multicenter randomized controlled trial, hospitalized patients with laboratory-confirmed influenza were randomly enrolled in a 1:1 ratio to Group 1 (oseltamivir+placebo) or Group 2 (oseltamivir+baloxavir). All patients were treated with oseltamivir for 5 days; one dose of baloxavir or placebo was given in identical capsules. Primary efficacy and safety outcomes were TCVS by virus titer with qCulture TCID50 agglutination and 30-day severe adverse event (SAE) rate, respectively. Secondary virology, clinical, and safety outcomes were assessed. Continuous and categorical data were analyzed with Wilcoxon Rank-Sum and Fisher’s Exact Tests, respectively.

Results

14 participants were randomized and received study drug (Group 1: n=6, Group 2: n=8); the study was stopped early due to slow accrual. Baseline characteristics were balanced. Median TCVS with qCulture was 53.3 hours in Group 1 and 25.3 hours in Group 2 (p=0.13). 30-day overall SAE rates were 16.7% and 12.5%, respectively. All patients achieved negative qCulture. Median TCVS with quantitative PCR (RT-qPCR) was 115.6 and 34.4 hours (p=0.24); % achieving viral negative by RT-qPCR was 33.3% and 75.0% (p=0.28), respectively.

Conclusions

Combination therapy with oseltamivir and a single dose of baloxavir was inconclusive with non-significant trends towards shorter median TCVS vs. monotherapy with oseltamivir in hospitalized patients with influenza. Interpretation is limited by small sample size and early termination.

Source: 

Link: https://journals.sagepub.com/doi/10.1177/13596535261479944

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A randomised, open-label clinical study on the efficacy of #baloxavir marboxil and #oseltamivir for post-exposure #prevention of #influenza in a #hospital setting: a study protocol

 

Abstract

Introduction 

Healthcare settings are high-risk environments for the transmission of respiratory viruses. Effective strategies to prevent hospital-acquired influenza, particularly post-exposure prophylaxis for close contacts (CCs), are urgently needed. This study aims to assess the effectiveness of baloxavir marboxil (baloxavir) and oseltamivir in preventing influenza virus infection among CCs who have been exposed to confirmed influenza cases and are unable to be immediately isolated in the hospital ward.

Methods and analysis 

This multicentre, randomised, open-label, parallel-controlled trial involves hospitalised patients with laboratory-confirmed influenza (index patients) and their CCs. CCs will be randomised into three groups: baloxavir marboxil, oseltamivir or placebo. Baloxavir (40 mg or 80 mg for ≥80 kg) will be administered as a single dose on day 1, while oseltamivir (75 mg) will be given once a day for 5 days. CCs will be monitored for influenza-like symptoms, with respiratory samples collected for rapid antigen test or reverse-transcription PCR testing at baseline, day 5±1 and day 10±1 or earlier if symptoms develop. The primary outcome is the 5-day incidence of clinical influenza, defined as laboratory-confirmed infection with concurrent fever and at least one respiratory symptom. Secondary outcomes will include the 5-day incidence of laboratory-confirmed influenza, the 10-day incidence of clinical influenza and the percentage of CCs infected with resistance-associated treatment-emergent influenza variants.

Ethics and dissemination 

The study has been approved by the Clinical Research Ethics Committee of China-Japan Friendship Hospital (2024-KY-401). The results of the study will be submitted for publication in a peer-reviewed journal with online accessibility. The full protocol, de-identified participant data and statistical code will be openly available in a public repository within 12 months after trial completion.

Trial registration number NCT06762587. 

https://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/.

Source: 

Link: https://bmjopen.bmj.com/content/16/8/e118748

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#Treatment of #CCHF with supportive care, #favipiravir, and avatrombopag

 

Abstract

We report a severe Crimean-Congo Hemorrhagic Fever case treated with favipiravir and avatrombopag in a high-level isolation unit. This multimodal approach was associated with rapid platelet recovery, reduced transfusion requirements, and viral clearance. Combining targeted antivirals with thrombopoietin receptor agonists represents a promising strategy for managing severe CCHF coagulopathy.

Source: 

Link: https://academic.oup.com/cid/advance-article-abstract/doi/10.1093/cid/ciag415/8765585?redirectedFrom=fulltext

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#Maraviroc Inhibits #SARS-CoV-2 Through Variant-Dependent Effects on Viral Entry and #Mpro Activity Using Single-Round Infectious Particle and Virus-like Particle Models

 

Abstract

Maraviroc (MVC), a CCR5 antagonist, has been proposed as a potential antiviral agent against SARS-CoV-2; however, its mechanism of action across viral variants remains unclear. Here, we evaluated the antiviral activity of MVC against SARS-CoV-2 wild-type (WT) and Omicron BA.1 variants using single-round infectious particles (SRIPs), virus-like particles (VLPs), and cell-based assays, with a focus on its impact on viral entry and Mpro function. MVC potently inhibited infection of both WT and BA.1 SRIPs in Vero E6 cells, exhibiting EC50 values of 0.0065 μM and 0.016 μM, respectively. Time-of-addition assays revealed that MVC primarily targets the early phase of infection, with the strongest inhibition observed at the viral entry stage, while moderate effects were detected during attachment and post-entry stages. Fluorescence-labeled VLP imaging demonstrated distinct entry pathways, with WT predominantly entering via plasma membrane fusion and BA.1 via endocytosis, independent of cell type. MVC altered WT-VLP trafficking by promoting internalization and lysosomal localization, whereas it had minimal impact on BA.1 internalization. In spike-mediated cell–cell fusion assays, MVC preferentially inhibited WT spike-driven syncytium formation but showed limited effects on BA.1 or BA.4 fusion, while more effectively reducing Omicron spike-mediated binding. At the post-entry stage, MVC inhibited SARS-CoV-2 main protease (Mpro) activity, with BA.1 Mpro (P132H) exhibiting greater sensitivity (IC50 = 0.496 µM) than WT (1.869 µM). Collectively, these findings demonstrate that MVC exerts variant-dependent antiviral effects by targeting viral entry, modulating trafficking pathways, and inhibiting Mpro activity. This study highlights MVC as a multi-stage inhibitor with differential efficacy against SARS-CoV-2 variants, providing insights into its potential therapeutic application.

Source: 

Link: https://www.mdpi.com/1999-4915/18/8/911

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#Lassa fever and Argentine hemorrhagic fever #treatment in guinea pigs using broad-spectrum cap-dependent #endonuclease #inhibitors

 

ABSTRACT

The class Bunyaviricetes encompasses several highly pathogenic viruses that cause lethal hemorrhagic fevers. Due to their limited prevention and treatment options and high pathogenicity, these viruses require handling in biosafety level-4 facilities. Within the bunyaviruses, arenaviruses are particularly notable for their pathogenicity and ability to cause severe hemorrhagic disease in humans. The cap-dependent endonuclease (CEN) is a unique and crucial enzyme involved in the replication cycle of these viruses. As humans do not possess a similar enzyme, CEN represents an ideal target for antiviral drug development with reduced risk of side effects. Recently, we identified a promising CEN inhibitor (CENi) demonstrating potent inhibition of virus replication. In this manuscript, we demonstrate the successful therapeutic efficacy of CENis against Lassa fever and Argentine hemorrhagic fever virus infections in guinea pig models of lethal hemorrhagic fever. In addition, we identified several CENis with antiviral activity against other highly pathogenic arenaviruses. These findings further support the potential of CENis as therapeutic agents for arenavirus infections that cause severe and often lethal hemorrhagic fever. Collectively, our results suggest that CENis are promising candidates for pan-arenavirus therapy and may also have broader utility against other CEN-containing viruses for which no approved antiviral treatments currently exist.

Source: 

Link: https://journals.asm.org/doi/10.1128/mbio.00880-26

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The association of empirical #treatment with #oseltamivir with the #outcome of critically ill patients admitted with severe acute respiratory illness (#SARI)

 

Abstract

Objective

Neuraminidase inhibitors (NAIs) are widely used empirically in critically ill patients with suspected influenza; however, their effect on mortality remains uncertain. This multicenter study evaluates the association between empirical treatment with oseltamivir and the outcome of critically ill patients with Severe Acute Respiratory Infection (SARI) admitted to the Intensive Care Unit (ICU).

Methods

This was a retrospective cohort study conducted in the ICUs of four hospitals in Saudi Arabia, involving adult patients with SARI from September 2012 to December 2018. Data collected were: demographics, comorbidities, clinical presentation, and outcomes among patients treated with oseltamivir and those who were not. The primary outcome was 90-day mortality. The association of oseltamivir and mortality was evaluated adjusting for propensity score.

Results

During the study period, 456 patients with SARI were included in the study, 301 were treated with empirical oseltamivir within a median of 1 day from presentation (interquartile range, 0-1 day) and a median of 4 days after symptom onset, while 155 patients were not. No significant differences were observed in baseline characteristics between the two groups. Of the included patients, 334 (73%) were tested for influenza using PCR, and 87 (26%) had a confirmed diagnosis of influenza. Patients on oseltamivir were less likely to require rescue oxygen therapy (22.9% vs. 34.8%, p=0.007), and had shorter hospital stay (20 days vs. 27 days, p=0.01). Patients treated with oseltamivir had significantly reduced 90-day mortality on adjusted analyses (aOR: 0.87, 95% CI: 0.81-0.94, p=0.0002). Subgroup analysis revealed that the association with reduced mortality extends to patients >70 years old (aOR: 0.94, 95% CI: 0.89-0.99, p=0.02) and those with negative influenza tests (aOR: 0.81, 95% CI: 0.79, 0.84, p<0.0001).

Conclusion

Among critically ill patients with SARI, empirical treatment with oseltamivir was associated with lower mortality. These results add to the body of evidence suggesting clinical benefits of oseltamivir in managing critically ill patients with influenza-like illnesses.

Source: 

Link: https://journals.sagepub.com/doi/10.1177/20503121261478401

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