#Antiviral treatment for #influenza

 

Abstract

Seasonal influenza is a widespread acute respiratory infection that causes significant illness and death worldwide. Two major antiviral classes are neuraminidase inhibitors (NAIs) and polymerase inhibitors. NAIs, including oseltamivir, zanamivir, peramivir and laninamivir, block viral release, while polymerase inhibitors such as baloxavir disrupt viral RNA replication. Early administration within 48 h of symptom onset reduces illness duration, severity and complications, particularly in high-risk groups. Oseltamivir is the most widely studied NAI, demonstrating reduced viral shedding, faster symptom resolution and lower complication rates, though gastrointestinal side effects are common. Higher doses generally do not improve outcomes compared to standard dosing. Zanamivir is more effective against influenza B and is inhibitory for most influenza A viruses resistant to oseltamivir, but the inhaled formulation is less suitable for patients with severe illness or airway disease. Intravenous (IV) zanamivir is approved for hospitalized influenza patients in some countries. Peramivir offers IV treatment options, while laninamivir is mainly used in Japan. Baloxavir shows superior viral load reduction and comparable symptom relief to oseltamivir in outpatients, though resistance variants can emerge. Favipiravir and newer polymerase inhibitors are under investigation. Combination therapies may enhance recovery, with limited evidence. Overall, timely antiviral use is critical to reducing influenza’s burden.

This article is part of the Theo Murphy meeting issue ‘Evaluating anti-infective drugs’.

Source: 

Link: https://royalsocietypublishing.org/rstb/article/381/1949/20240344/481548/Antiviral-treatment-for-influenza

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Optimal Dose and #Safety of Intravenous #Favipiravir in Hospitalized Patients With #COVID19: A Dose-Escalating, Randomized Controlled Phase Ib Study

 

Abstract

AGILE (NCT04746183) is a Phase Ib/IIa platform, evaluating candidates to treat COVID-19. Candidate Specific Trial 6 evaluated the safety and optimal dose of a novel intravenous formulation of favipiravir in a dose-escalating, open-label, randomized, controlled, Bayesian adaptive Phase Ib trial. Hospitalized adults with PCR-confirmed SARS-CoV-2 infection, within 14 days of symptomatic COVID-19 were randomized 2:1 in groups of 6 (n = 4 favipiravir, n = 2 standard of care) to ascending doses of intravenous favipiravir twice daily (b.i.d.) for 7 days or standard of care. Clinical data, safety evaluations, virology and pharmacokinetic samples were collected. The primary outcome was safety. Secondary outcomes included clinical, pharmacokinetic and virological endpoints. Twenty-four participants enrolled between September 10, 2022 and November 1, 2023 [10/24 female; median age 74 years (range 52–93)]. Favipiravir was well tolerated despite a high background rate of unrelated adverse events. No dose limiting toxicities were observed, with a model-predicted dose limiting toxicity risk of 16.8% and probability of unacceptable toxicity of 2.7% at the highest dose level. No serious adverse events were deemed related to favipiravir but an expected association with asymptomatic, transient hyperuricemia was observed. Favipiravir exposures increased disproportionally to dose with significant accumulation in plasma, but with marked variability between participants within each cohort. This novel formulation of favipiravir was safe at sustained high doses that reached pre-specified pharmacokinetic targets in a study group with frailty and complex health profiles. We consider doses up to 2,400 mg b.i.d. to be safe for further evaluation.

Study Highlights

-- WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

- Pre-clinical studies of favipiravir describe broad spectrum antiviral activity, positioning it as a therapeutic candidate for many RNA viruses. An oral formulation of favipiravir has been widely studied as a treatment for COVID-19 in clinical trials. Pharmacokinetic modeling suggests the doses used in many of these trials may not have reached effective plasma concentrations.

-- WHAT QUESTION DID THIS STUDY ADDRESS?

- Was a novel intravenous formulation of favipiravir safe and well tolerated in patients hospitalized with COVID-19? Were pre-specified pharmacokinetic parameters met at doses modeled to be effective for the treatment of COVID-19?

-- WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

- We demonstrate that high doses of intravenous favipiravir are safe and well tolerated in a frail and co-morbid population who are likely to be eligible for antiviral treatment but are often excluded from early phase clinical trials. We characterize the pharmacokinetic profile of intravenous favipiravir at high doses and recommend an optimal dose to be used in future Phase II studies.

-- HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

- There is an ongoing unmet need for antivirals to effectively treat COVID-19; however, the significance of these safety and pharmacokinetic data go beyond COVID-19. High doses of favipiravir have a use case against RNA viruses with pandemic potential including viral hemorrhagic fevers and pandemic influenza. The intravenous formulation may be particularly relevant in severely unwell patients for whom oral dosing is not possible or in whom GI absorption is affected. The pharmacokinetic characterization from this study will be used to inform doses for use against a range of significant pathogens. Early phase clinical trials of IV favipiravir in Crimean-Congo Haemorrhagic Fever are ongoing.

Source: 

Link: https://ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.70261

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#SARS-CoV-2 Error Catastrophe Under #Molnupiravir: #Mutagenic Enhancement Enables Viral #Persistence with Impaired Fitness

 

Abstract

Molnupiravir induces mutations that render severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication-competent through error catastrophe mechanisms. Previous studies showed no resistant virus emergence during prolonged molnupiravir treatment, with no resistant variants reported. However, these approaches were limited by genetic uniformity at passage initiation. To investigate viral population dynamics under enhanced genetic diversity, we employed mutagenic pre-treatment using 5-fluorouracil (5-FU) and favipiravir to generate diverse quasi-species populations before molnupiravir selection pressure. Viral populations were treated with stepwise increasing molnupiravir concentrations (10 μM ⟶ 25 μM ⟶ 40 μM) over ten serial passages. Viral detectability, plaque morphology, and mutation accumulation were analyzed using molecular and sequencing approaches. Only high-concentration favipiravir (1000 μM) pre-treatment maintained detectable viral RNA through ten passages under 40 μM molnupiravir, while favipiravir (500 μM) and 5-FU groups became undetectable after passage 6. Surviving populations formed extremely small plaques with markedly reduced replication capacity. Next-generation sequencing revealed extensive mutation accumulation across viral proteins, including polymerase proteins. Individual viable virus isolation was unsuccessful, and large-scale propagation could not be achieved. These findings demonstrate apparent survival rather than true resistance to molnupiravir, characterized by severely compromised viral fitness.

Source: 

Link: https://www.mdpi.com/1999-4915/18/2/273

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#Baloxavir outperforms #oseltamivir, #favipiravir, and #amantadine in treating lethal #influenza #H5N1 HA clade 2.3.4.4b #infection in #mice

 

Abstract

Intercontinental spread of highly pathogenic avian influenza A(H5N1) viruses poses significant pandemic risks and necessitates strong protective countermeasures. We evaluated the therapeutic efficacy of the neuraminidase inhibitor oseltamivir, the polymerase inhibitors baloxavir and favipiravir, and an ion-channel blocker amantadine, against severe influenza A(H5N1) virus infection in female BALB/c mice. Baloxavir (≥10 mg/kg, 1 dose) fully protected mice from death, significantly reduced virus respiratory replication, and prevented neuroinvasion. Oseltamivir (≥100 mg/kg/day for 5 days) provided limited survival benefits, reduced lung titers but failed to prevent viral neuroinvasion. Favipiravir (≥100 mg/kg/day for 5 days) provided partial protection, although did not reduce viral titers in lungs and brain. Amantadine provided no benefits. Although all drugs inhibited A(H5N1) viruses in vitro, in vivo correlations did not extend beyond baloxavir. Our results indicate that baloxavir is the most reliable treatment to address both respiratory replication and systemic spread of contemporary A(H5N1) viruses in mice and should be considered in pandemic planning.

Source: 

Link: https://www.nature.com/articles/s41467-026-69721-5

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Post-exposure #prophylaxis with #favipiravir among #household close contacts to confirmed #COVID19 cases: A cluster-randomized trial (PEPfavi)

 

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-PEP recipients, with fewer cases of fever, rhinorrhea, and myalgia. A significantly higher probability of remaining asymptomatic and delayed symptom onset was observed in the FPV-PEP group. No participants developed severe COVID-19 or required hospitalization.

Conclusion

FPV-PEP was associated with a lower incidence of fever, rhinorrhea, and myalgia among household contacts. While a reduction in secondary transmission was observed, it did not reach statistical significance. Further large-scale studies are warranted to clarify its role in preventing household transmission.

Source: 

Link: https://www.sciencedirect.com/science/article/pii/S1876034126000225?via%3Dihub

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#Placental transfer of #medications to treat #COVID19, #molnupiravir, #favipiravir and #nirmatrelvir/ritonavir, in the ex vivo human cotyledon model

 

Abstract

Objectives

There have been few studies in pregnant women of medications that are used to reduce severe complications from COVID-19 infection. Currently, nirmatrelvir/ritonavir (Paxlovid) is recommended by the National Institutes for Health to treat non-hospitalized pregnant patients with mild-to-moderate COVID-19 illness. The aim of this study was to determine the transplacental passage of molnupiravir, nirmatrelvir/ritonavir and favipiravir utilizing an ex vivo placental perfusion model.

Methods

Human placental cotyledons were continuously perfused in a double open circuit. The study molecules and antipyrine, a marker of placental viability, were dissolved in the maternal solution. The experiment was conducted over 90 minutes, and every 5 minutes, samples of the maternal solution and fetal exchange solutions were collected for analysis. We calculated the concentrations of study molecules, fetal transfer ratios and the clearance indexes to determine placental transfer.

Results

Of 18 placentas analysed, 14 were validated by antipyrine transfer. Nirmatrelvir alone had low placental transfer, with a fetal transfer ratio of 0.025. Its placenta transfer increased in the presence of ritonavir, with a fetal transfer ratio of 0.06. The molnupiravir metabolite, β-D-N-4-hydroxycytidine (EIDD 1931), showed low placental transfer, with an average fetal transfer ratio of 0.04. By contrast, favipiravir crossed the placenta with an average fetal transfer ratio of 0.425.

Conclusions

Placental transfer was high for the nucleoside analogue favipiravir, while it was low for molnupiravir and low for the protease inhibitor nirmatrelvir but increased by ritonavir. Clinical data are required to confirm the placental transfer and determine the safety of COVID antivirals in pregnancy.

Source: Journal of Antimicrobial Chemotherapy, https://academic.oup.com/jac/advance-article-abstract/doi/10.1093/jac/dkaf302/8245204?redirectedFrom=fulltext

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Dose response comparison of #Nipah virus #strains #Malaysia and #Bangladesh in #hamsters exposed by the intranasal or intraperitoneal route

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 lethal challenge, regardless of Nipah virus strain. The data suggest that Favipiravir is only partially protective against Nipah virus in hamsters, and, thus, would likely not be an ideal candidate as a positive control in future efficacy studies.

Source: PLoS One, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0318912

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#PA and #PAX: two key #proteins from segment 3 of the #influenza viruses

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-terminal amino acids of segment 3 and possesses the shutoff activity of host gene expression, regulating the host immune response, viral virulence and transmission. Therefore, PA is one ideal target for the development of antiviral drugs against influenza viruses. Baloxavir marboxil (BXM) and Favipiravir are two very effective anti-influenza virus drugs targeting the PA endonuclease domain of influenza A viruses. In this review, we summarized the structures, viral replication, virulent determinants and transmission, host factors, innate immunity, and antiviral drugs involved in PA and PA-X. The information is of great value for underlying the mechanism of viral replication and developing novel effective strategies to prevent and control influenza infection and the pandemic.

Source: Frontiers in Cellucal and Infection Microbiology, https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2025.1560250/full

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