RESUMO
Baloxavir marboxil (baloxavir), approved as an anti-influenza drug in Japan in March 2018, can induce reduced therapeutic effectiveness due to PA protein substitutions. We assessed PA substitutions in clinical samples from influenza-infected children and adults pre- and post-baloxavir treatment, examining their impact on fever and symptom duration. During the 2022-2023 influenza season, the predominant circulating influenza subtype detected by cycling-probe RT-PCR was A(H3N2) (n = 234), with a minor circulation of A(H1N1)pdm09 (n = 10). Of the 234 influenza A(H3N2) viruses collected prior to baloxavir treatment, 2 (0.8%) viruses carry PA/I38T substitution. One virus was collected from a toddler and one from an adult, indicating the presence of viruses with reduced susceptibility to baloxavir, without prior exposure to the drug. Of the 54 paired influenza A(H3N2) viruses collected following baloxavir treatment, 8 (14.8%) viruses carried E23 K/G, or I38 M/T substitutions in PA. Variant calling through next-generation sequencing (NGS) showed varying proportions (6-100 %), a polymorphism and a mixture of PA/E23 K/G, and I38 M/T substitutions in the clinical samples. These eight viruses were obtained from children aged 7-14 years, with a median fever duration of 16.7 h and a median symptom duration of 93.7 h, which were similar to those of the wild type. However, the delayed viral clearance associated with the emergence of PA substitutions was observed. No substitutions conferring resistance to neuraminidase inhibitors were detected in 37 paired samples collected before and following oseltamivir treatment. These findings underscore the need for ongoing antiviral surveillance, informing public health strategies and clinical antiviral recommendations for seasonal influenza.
Assuntos
Substituição de Aminoácidos , Antivirais , Dibenzotiepinas , Farmacorresistência Viral , Vírus da Influenza A Subtipo H3N2 , Influenza Humana , Morfolinas , Piridonas , Triazinas , Proteínas Virais , Humanos , Dibenzotiepinas/uso terapêutico , Dibenzotiepinas/farmacologia , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/enzimologia , Triazinas/uso terapêutico , Triazinas/farmacologia , Japão , Antivirais/farmacologia , Antivirais/uso terapêutico , Morfolinas/uso terapêutico , Farmacorresistência Viral/genética , Criança , Adulto , Pré-Escolar , Adolescente , Proteínas Virais/genética , RNA Polimerase Dependente de RNA/genética , Feminino , Masculino , Tiepinas/uso terapêutico , Tiepinas/farmacologia , Lactente , Pessoa de Meia-Idade , Estações do Ano , Piridinas/uso terapêutico , Piridinas/farmacologia , Adulto Jovem , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , IdosoRESUMO
We compared the duration of fever in children infected with A(H1N1)pdm09, A(H3N2), or influenza B viruses following treatment with baloxavir marboxil (baloxavir) or neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, or laninamivir). This observational study was conducted at 10 outpatient clinics across 9 prefectures in Japan during the 2012-2013 and 2019-2020 influenza seasons. Patients with influenza rapid antigen test positive were treated with one of four anti-influenza drugs. The type/subtype of influenza viruses were identified from MDCK or MDCK SIAT1 cell-grown samples using two-step real-time PCR. Daily self-reported body temperature after treatment were used to evaluate the duration of fever by treatment group and various underlying factors. Among 1742 patients <19 years old analyzed, 452 (26.0%) were A(H1N1)pdm09, 827 (48.0%) A(H3N2), and 463 (26.0%) influenza B virus infections. Among fours treatment groups, baloxavir showed a shorter median duration of fever compared to oseltamivir in univariate analysis for A(H1N1)pdm09 virus infections (baloxavir, 22.0 h versus oseltamivir, 26.7 h, P < 0.05; laninamivir, 25.5 h, and zanamivir, 25.0 h). However, this difference was not significant in multivariable analyses. For A(H3N2) virus infections, there were no statistically significant differences observed (20.3, 21.0, 22.0, and 19.0 h) uni- and multivariable analyses. For influenza B, baloxavir shortened the fever duration by approximately 15 h than NAIs (20.3, 35.0, 34.3, and 34.1 h), as supported by uni- and multivariable analyses. Baloxavir seems to have comparable clinical effectiveness with NAIs on influenza A but can be more effective for treating pediatric influenza B virus infections than NAIs.
Assuntos
Antivirais , Dibenzotiepinas , Febre , Guanidinas , Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A Subtipo H3N2 , Vírus da Influenza B , Influenza Humana , Morfolinas , Oseltamivir , Piranos , Piridonas , Ácidos Siálicos , Triazinas , Zanamivir , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Antivirais/uso terapêutico , Antivirais/farmacologia , Vírus da Influenza B/efeitos dos fármacos , Vírus da Influenza B/genética , Criança , Zanamivir/uso terapêutico , Zanamivir/análogos & derivados , Zanamivir/farmacologia , Triazinas/uso terapêutico , Triazinas/farmacologia , Guanidinas/uso terapêutico , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Piridonas/uso terapêutico , Dibenzotiepinas/uso terapêutico , Japão , Feminino , Masculino , Pré-Escolar , Oseltamivir/uso terapêutico , Febre/tratamento farmacológico , Febre/virologia , Adolescente , Morfolinas/uso terapêutico , Lactente , Estações do Ano , Tiepinas/uso terapêutico , Tiepinas/farmacologia , Oxazinas/uso terapêutico , Fatores de Tempo , Benzoxazinas/uso terapêuticoRESUMO
BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.
Assuntos
Antivirais , Dibenzotiepinas , Características da Família , Influenza Humana , Morfolinas , Oseltamivir , Profilaxia Pós-Exposição , Piridonas , Triazinas , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Influenza Humana/transmissão , Piridonas/uso terapêutico , Antivirais/uso terapêutico , Triazinas/uso terapêutico , Dibenzotiepinas/uso terapêutico , Feminino , Masculino , Oseltamivir/uso terapêutico , Adulto , Adolescente , Criança , Pessoa de Meia-Idade , Adulto Jovem , Profilaxia Pós-Exposição/métodos , Pré-Escolar , Morfolinas/uso terapêutico , Tiepinas/uso terapêutico , Método Duplo-Cego , Lactente , Piridinas/uso terapêutico , Idoso , Oxazinas/uso terapêuticoRESUMO
Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic bunyavirus with a fatality rate of up to 40%. Currently, there are no licensed antiviral drugs for the treatment of CCHF; thus, the World Health Organization (WHO) listed the disease as a priority. A unique viral transcription initiation mechanism called "cap-snatching" is shared by influenza viruses and bunyaviruses. Thus, we tested whether baloxavir (an FDA-approved anti-influenza drug that targets the "cap-snatching" mechanism) could inhibit CCHFV infection. In cell culture, baloxavir acid effectively inhibited CCHFV infection and targeted CCHFV RNA transcription/replication. However, it has weak oral bioavailability. Baloxavir marboxil (the oral prodrug of baloxavir) failed to protect mice against a lethal dose challenge of CCHFV. To solve this problem, baloxavir sodium was synthesized owing to its enhanced aqueous solubility and pharmacokinetic properties. It consistently and significantly improved survival rates and decreased tissue viral loads. This study identified baloxavir sodium as a novel scaffold structure and mechanism of anti-CCHF compound, providing a promising new strategy for clinical treatment of CCHF after further optimization.
Assuntos
Antivirais , Dibenzotiepinas , Morfolinas , Piridinas , Piridonas , Triazinas , Replicação Viral , Animais , Morfolinas/farmacologia , Morfolinas/farmacocinética , Morfolinas/química , Antivirais/farmacologia , Antivirais/farmacocinética , Antivirais/química , Dibenzotiepinas/farmacologia , Dibenzotiepinas/farmacocinética , Camundongos , Piridinas/farmacologia , Piridinas/farmacocinética , Piridinas/química , Replicação Viral/efeitos dos fármacos , Triazinas/farmacologia , Triazinas/farmacocinética , Triazinas/química , Triazinas/uso terapêutico , Piridonas/farmacologia , Piridonas/farmacocinética , Piridonas/química , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Tiepinas/farmacocinética , Tiepinas/química , Carga Viral/efeitos dos fármacos , Chlorocebus aethiops , Células Vero , Feminino , Oxazinas/farmacologia , Oxazinas/farmacocinética , Oxazinas/uso terapêutico , Camundongos Endogâmicos BALB C , Humanos , Tiazóis/farmacologia , Tiazóis/farmacocinética , Tiazóis/químicaRESUMO
Influenza viruses (IFVs) have caused several pandemics and have claimed numerous lives since their first record in the early 20th century. While the outbreak of COVID-19 seemed to expel influenza from the sight of people for a short period of time, it is not surprising that it will recirculate around the globe after the coronavirus has mutated into a less fatal variant. Baloxavir marboxil (1), the prodrug of baloxavir (2) and a cap-dependent endonuclease (CEN) inhibitor, were approved by the FDA for the first treatment in almost 20 years. Despite their high antiviral potency, drug-resistant variants have been observed in clinical trials. Herein, we report a novel CEN inhibitor 8 with a delicately designed macrocyclic scaffold that exhibits a significantly smaller shift of inhibitory activity toward baloxavir-resistant variants.
Assuntos
Dibenzotiepinas , Influenza Humana , Morfolinas , Tiepinas , Humanos , Influenza Humana/tratamento farmacológico , Oxazinas/farmacologia , Piridinas/farmacologia , Endonucleases , Antivirais/farmacologia , Antivirais/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Piridonas/farmacologia , Piridonas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêuticoRESUMO
Seasonal or pandemic illness caused by influenza A viruses (IAVs) is a major public health concern due to the high morbidity and notable mortality. Although there are several approved drugs targeting different mechanisms, the emergence of drug resistance calls for new drug candidates that can be used alone or in combinations. Small-molecule IAV entry inhibitor, ING-1466, binds to hemagglutinin (HA) and blocks HA-mediated viral infection. Here, we show that this inhibitor demonstrates preventive and therapeutic effects in a mouse model of IAV with substantial improvement in the survival rate. When administered orally it elicits a therapeutic effect in mice, even after the well-established infection. Moreover, the combination of ING-1466 with oseltamivir phosphate or baloxavir marboxil enhances the therapeutic effect in a synergistic manner. Overall, ING-1466 has excellent oral bioavailability and in vitro absorption, distribution, metabolism, excretion, and toxicity profile, suggesting that it can be developed for monotherapy or combination therapy for the treatment of IAV infections.
Assuntos
Dibenzotiepinas , Vírus da Influenza A , Morfolinas , Piridonas , Tiepinas , Triazinas , Animais , Camundongos , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Antivirais/uso terapêutico , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas , Tiepinas/farmacologia , Tiepinas/uso terapêuticoRESUMO
Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.
Assuntos
Dibenzotiepinas , Influenza Humana , Morfolinas , Tiepinas , Humanos , Oxazinas , Piridinas/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Endonucleases/genética , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Piridonas/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Zanamivir/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêuticoRESUMO
Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness, but the susceptibility of zoonotic IAVs to the cap-dependent endonuclease inhibitor baloxavir acid (BXA) has not been thoroughly researched. Although an amino acid substitution at position 38 in the polymerase acidic protein (PA/I38) in seasonal IAVs reduces BXA susceptibility, PA polymorphisms at position 38 are rarely seen in zoonotic IAVs. Here, we examined the impact of PA/I38 substitutions on the BXA susceptibility of recombinant A(H5N1) viruses. PA mutants that harbored I38T, F, and M were 48.2-, 24.0-, and 15.5-fold less susceptible, respectively, to BXA than wild-type A(H5N1) but were susceptible to the neuraminidase inhibitor oseltamivir acid and the RNA polymerase inhibitor favipiravir. PA mutants exhibited significantly impaired replicative fitness in Madin-Darby canine kidney cells at 24 h postinfection. In addition, in order to investigate new genetic markers for BXA susceptibility, we screened geographically and temporally distinct IAVs isolated worldwide from birds and pigs. The results showed that BXA exhibited antiviral activity against avian and swine viruses with similar levels to seasonal isolates. All viruses tested in the study lacked the PA/I38 substitution and were susceptible to BXA. Isolates harboring amino acid polymorphisms at positions 20, 24, and 37, which have been implicated in the binding of BXA to the PA endonuclease domain, were also susceptible to BXA. These results suggest that monitoring of the PA/I38 substitution in animal-derived influenza viruses is important for preparedness against zoonotic influenza virus outbreaks.
Assuntos
Dibenzotiepinas , Virus da Influenza A Subtipo H5N1 , Vírus da Influenza A , Influenza Humana , Morfolinas , Orthomyxoviridae , Piridonas , Tiepinas , Triazinas , Animais , Cães , Humanos , Suínos , Vírus da Influenza A/genética , Oxazinas/farmacologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Virus da Influenza A Subtipo H5N1/genética , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Orthomyxoviridae/genética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Substituição de Aminoácidos , Endonucleases/genética , Farmacorresistência Viral/genéticaRESUMO
Influenza remains a worldwide health concern. Antiviral drugs are considered as one of the useful options for its prevention as a complementary measure to vaccination. Baloxavir acid selectively inhibits the cap-dependent endonuclease of influenza viruses and exhibits marked viral titre reduction in patients. Here, we describe the prophylactic potency of baloxavir acid against lethal infection with influenza A and B viruses in mice. BALB/c mice were subcutaneously administered once with baloxavir acid suspension, or orally administered once daily for 10 days with oseltamivir phosphate solution at human relevant doses. Next, the mice were intranasally inoculated with A/PR/8/34 (H1N1) or B/Hong Kong/5/72 strain at 24 to 96 h after the initial dosing. Prophylactic treatment with the antiviral drugs significantly reduced the lung viral titres and prolonged survival time. In particular, baloxavir acid showed a greater suppressive effect on lung viral titres compared to oseltamivir phosphate. In this model, baloxavir acid maintained significant prophylactic effects against influenza A and B virus infections when the plasma concentration at the time of infection was at least 0.88 and 3.58 ng/mL, respectively. The significant prophylactic efficacy observed in our mouse model suggests the potential utility of baloxavir marboxil for prophylaxis against influenza in humans.
Assuntos
Herpesvirus Cercopitecino 1 , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Tiepinas , Humanos , Animais , Camundongos , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/uso terapêutico , Piridinas/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Camundongos Endogâmicos BALB C , FosfatosRESUMO
A community cluster of influenza A(H3N2) caused by viruses with an E199G substitution in PA was detected in Nara, Japan, between February and March 2023. The three patients with these mutant viruses had not received antiviral treatment before specimen collection but patients in the same hospital had. The sequences of the mutant viruses were closely related, suggesting clonal spread in Nara. They showed reduced susceptibility to baloxavir in vitro; however, the clinical significance of the PA E199G substitution remains unclear.
Assuntos
Influenza Humana , Tiepinas , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Vírus da Influenza A Subtipo H3N2/genética , Oxazinas/farmacologia , Piridinas/farmacologia , Japão , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral/genéticaRESUMO
Baloxavir marboxil (baloxavir) is a recently FDA-approved influenza virus polymerase acidic (PA) endonuclease inhibitor. Several PA substitutions have been demonstrated to confer reduced susceptibility to baloxavir; however, their impacts on measurements of antiviral drug susceptibility and replication capacity when present as a fraction of the viral population have not been established. We generated recombinant A/California/04/09 (H1N1)-like viruses (IAV) with PA I38L, I38T, or E199D substitutions and B/Victoria/504/2000-like virus (IBV) with PA I38T. These substitutions reduced baloxavir susceptibility by 15.3-, 72.3-, 5.4-, and 54.5-fold, respectively, when tested in normal human bronchial epithelial (NHBE) cells. We then assessed the replication kinetics, polymerase activity, and baloxavir susceptibility of the wild-type:mutant (WT:MUT) virus mixtures in NHBE cells. The percentage of MUT relative to WT virus necessary to detect reduced baloxavir susceptibility in phenotypic assays ranged from 10% (IBV I38T) to 92% (IAV E199D). While I38T did not alter IAV replication kinetics or polymerase activity, IAV PA I38L and E199D MUTs and the IBV PA I38T MUT exhibited reduced replication levels and significantly altered polymerase activity. Differences in replication were detectable when the MUTs comprised ≥90%, ≥90%, or ≥75% of the population, respectively. Droplet digital PCR (ddPCR) and next-generation sequencing (NGS) analyses showed that WT viruses generally outcompeted the respective MUTs after multiple replication cycles and serial passaging in NHBE cells when initial mixtures contained ≥50% of the WT viruses; however, we also identified potential compensatory substitutions (IAV PA D394N and IBV PA E329G) that emerged and appeared to improve the replication capacity of baloxavir-resistant virus in cell culture. IMPORTANCE Baloxavir marboxil, an influenza virus polymerase acidic endonuclease inhibitor, represents a recently approved new class of influenza antivirals. Treatment-emergent resistance to baloxavir has been observed in clinical trials, and the potential spread of resistant variants could diminish baloxavir effectiveness. Here, we report the impact of the proportion of drug-resistant subpopulations on the ability to detect resistance in clinical isolates and the impact of substitutions on viral replication of mixtures containing both drug-sensitive and drug-resistant variants. We also show that ddPCR and NGS methods can be successfully used for detection of resistant subpopulations in clinical isolates and to quantify their relative abundance. Taken together, our data shed light on the potential impact of baloxavir-resistant I38T/L and E199D substitutions on baloxavir susceptibility and other biological properties of influenza virus and the ability to detect resistance in phenotypic and genotypic assays.
Assuntos
Antivirais , Farmacorresistência Viral , Vírus da Influenza A Subtipo H1N1 , Influenza Humana , Replicação Viral , Humanos , Substituição de Aminoácidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Endonucleases/genética , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Nucleotidiltransferases/genética , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética , Mutação , Linhagem CelularRESUMO
Cap-dependent endonuclease (CEN) in the polymerase acidic protein (PA) of influenza A virus (IAV) represents a promising drug target due to its critical role in viral gene transcription. The CEN inhibitor, baloxavir marboxil (BXM), was approved in Japan and the US in 2018 and several other countries subsequently. Along with the clinical use of BXM, the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern. Herein, we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A, an analogue of BXM. The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes, including pH1N1, H3N2, H7N9 and H9N2, in MDCK cells, and the 50% effective concentration (EC50) was calculated to nanomole level and comparable to that of baloxavir acid (BXA), the active form of BXM. Furthermore, in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice, with reduced viral RNA loads and alleviated pulmonary damage. Importantly, serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage. Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA. Taken together, our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance, which provides critical clues for future drug development and drug resistance surveillance.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Subtipo H7N9 do Vírus da Influenza A , Vírus da Influenza A Subtipo H9N2 , Influenza Humana , Tiepinas , Animais , Camundongos , Humanos , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Endonucleases/genética , Endonucleases/química , Endonucleases/metabolismo , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N2 , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Farmacorresistência Viral/genéticaRESUMO
Although the prevalence of polymerase acidic (PA)/I38T strains of influenza virus with reduced susceptibility to baloxavir acid is low, there is a possibility of emergence under selective pressure. Furthermore, the virus may be transmitted between humans. We investigated the in vivo efficacy of baloxavir acid and oseltamivir phosphate against influenza A subtypes H1N1, H1N1pdm09, and H3N2, with PA/I38T substitution, at doses simulating human plasma concentrations. A pharmacokinetic/pharmacodynamic analysis was performed to strengthen the validity of the findings and the applicability in a clinical setting. Although the antiviral effect of baloxavir acid was attenuated in mice infected with PA/I38T-substituted viral strains compared with the wild type (WT), baloxavir acid significantly reduced virus titers at higher-but clinically relevant-doses. The virus titer reduction with baloxavir acid (30 mg/kg subcutaneous single dose) was comparable to that of oseltamivir phosphate (5 mg/kg orally twice daily) against H1N1 and H1N1pdm09 PA/I38T strains in mice, as well as the H3N2 PA/I38T strain in hamsters. Baloxavir acid demonstrated an antiviral effect against PA/I38T-substituted strains, at day 6, with no further viral rebound. In conclusion, baloxavir acid demonstrated dose-dependent antiviral effects comparable to that of oseltamivir phosphate, even though the degree of lung virus titer reduction was diminished in animal models infected with PA/I38T-substituted strains.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Vírus da Influenza A , Influenza Humana , Tiepinas , Humanos , Animais , Camundongos , Antivirais/farmacologia , Antivirais/uso terapêutico , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/farmacologia , Piridinas/farmacologia , Vírus da Influenza A Subtipo H3N2 , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Farmacorresistência Viral , Nucleotidiltransferases , FosfatosRESUMO
To aid understanding of the effect of antiviral treatment on population-level influenza transmission, we used a novel pharmacokinetic-viral kinetic transmission model to test the correlation between nasal viral load and infectiousness, and to evaluate the impact that timing of treatment with the antivirals oseltamivir or baloxavir has on influenza transmission. The model was run under three candidate profiles whereby infectiousness was assumed to be proportional to viral titer on a natural-scale, log-scale, or dose-response model. Viral kinetic profiles in the presence and absence of antiviral treatment were compared for each individual (N = 1000 simulated individuals); subsequently, viral transmission mitigation was calculated. The predicted transmission mitigation was greater with earlier administration of antiviral treatment, and with baloxavir versus oseltamivir. When treatment was initiated 12-24 hours post symptom onset, the predicted transmission mitigation was 39.9-56.4% for baloxavir and 26.6-38.3% for oseltamivir depending on the infectiousness profile. When treatment was initiated 36-48 hours post symptom onset, the predicted transmission mitigation decreased to 0.8-28.3% for baloxavir and 0.8-19.9% for oseltamivir. Model estimates were compared with clinical data from the BLOCKSTONE post-exposure prophylaxis study, which indicated the log-scale model for infectiousness best fit the observed data and that baloxavir affords greater reductions in secondary case rates compared with neuraminidase inhibitors. These findings suggest a role for baloxavir and oseltamivir in reducing influenza transmission when treatment is initiated within 48 hours of symptom onset in the index patient.
Assuntos
Influenza Humana , Tiepinas , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Triazinas/farmacologiaRESUMO
BACKGROUND: Anti-influenza treatment is important for children and is recommended in many countries. This study assessed safety, clinical, and virologic outcomes of baloxavir marboxil (baloxavir) treatment in children based on age and influenza virus type/subtype. METHODS: This was a post hoc pooled analysis of two open-label non-controlled studies of a single weight-based oral dose of baloxavir (day 1) in influenza virus-infected Japanese patients aged < 6 years (n = 56) and ≥ 6 to < 12 years (n = 81). Safety, time to illness alleviation (TTIA), time to resolution of fever (TTRF), recurrence of influenza illness symptoms and fever (after day 4), virus titer, and outcomes by polymerase acidic protein variants at position I38 (PA/I38X) were evaluated. RESULTS: Adverse events were reported in 39.0 and 39.5% of patients < 6 years and ≥ 6 to < 12 years, respectively. Median (95% confidence interval) TTIA was 43.2 (36.3-68.4) and 45.4 (38.9-61.0) hours, and TTRF was 32.2 (26.8-37.8) and 20.7 (19.2-23.8) hours, for patients < 6 years and ≥ 6 to < 12 years, respectively. Symptom and fever recurrence was more common in patients < 6 years with influenza B (54.5 and 50.0%, respectively) compared with older patients (0 and 25.0%, respectively). Virus titers declined (day 2) for both age groups. Transient virus titer increase and PA/I38X-variants were more common for patients < 6 years. CONCLUSIONS: The safety and effectiveness of single-dose baloxavir were observed in children across all age groups and influenza virus types. Higher rates of fever recurrence and transient virus titer increase were observed in children < 6 years. TRIAL REGISTRATION: Japan Pharmaceutical Information Center Clinical Trials Information JapicCTI-163,417 (registered 02 November 2016) and JapicCTI-173,811 (registered 15 December 2017).
Assuntos
Dibenzotiepinas , Influenza Humana , Orthomyxoviridae , Tiepinas , Criança , Humanos , Antivirais/efeitos adversos , Dibenzotiepinas/uso terapêutico , Febre/tratamento farmacológico , Influenza Humana/tratamento farmacológico , Japão , Oxazinas/efeitos adversos , Piridinas/efeitos adversos , Piridonas , Tiepinas/uso terapêutico , Tiepinas/efeitos adversos , Triazinas/efeitos adversosRESUMO
In a post-hoc analysis of the phase 3 BLOCKSTONE study (JapicCTI-184180), we investigated household transmission of baloxavir-resistant (PA/I38X) influenza viruses. Using baloxavir resistance rates from prior clinical trials and the rate of influenza transmission observed in the study, the predicted number of PA/I38X transmission events was 4.8, assuming wild type and PA/I38X viruses were equally transmissible. However, no PA/I38X viruses were observed. These results suggest a low potential for baloxavir-resistant influenza virus transmission from treated to untreated individuals, potentially due to reduced viral/transmission fitness for PA/I38X viruses and/or low viral titres at the time when resistant viruses arise.
Assuntos
Antivirais , Influenza Humana , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Ensaios Clínicos Fase III como AssuntoRESUMO
Amino acid substitutions I38T and E23K in the influenza polymerase acidic (PA) protein lead to reduced susceptibility to the influenza antiviral drug baloxavir. The in vivo effectiveness of baloxavir and oseltamivir for treatment of these viruses is currently unknown. Using patient-derived influenza isolates, combination therapy was equally effective as monotherapy in reducing viral titers in the upper respiratory tract of ferrets infected with A(H1N1pdm09)-PA/E23K or A(H3N2)-PA/I38T. When treated with baloxavir plus oseltamivir, infection with a mixture of PA/I38T or PA/E23K and corresponding wild-type virus was characterized by a lower selection of viruses with reduced baloxavir susceptibility over the course of infection compared to baloxavir monotherapy. De novo emergence of the oseltamivir resistance mutation NA/H275Y occurred in ferrets treated with oseltamivir alone but not in ferrets treated with baloxavir plus oseltamivir. Our data suggest that combination therapy with influenza drugs with different mechanisms of action decreased the selection pressure for viruses with reduced drug susceptibility. IMPORTANCE Influenza viruses cause significant morbidity and mortality worldwide but can be treated with antiviral drugs. In 2018, a highly effective antiviral drug, baloxavir marboxil, was licensed. However, the selection of viruses with baloxavir resistance was relatively high following treatment, which may compromise the effectiveness of the drug. Here, we took two different influenza viruses that are resistant to baloxavir and tested the effectiveness alone and in combination with oseltamivir (a second influenza antiviral drug) in the ferret model. Our findings suggest that combination treatment may be a more effective method than monotherapy to reduce the selection of resistant viruses. These results may have important clinical implications for the treatment of influenza.
Assuntos
Influenza Humana , Tiepinas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Furões , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Morfolinas , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridonas/farmacologia , Piridonas/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêuticoRESUMO
New antiviral influenza treatments can effectively alleviate illness while reducing viral shedding. However, how such effects can translate into lower population infections of seasonal influenza in China remains unknown. To shed light on the public health impacts of novel antiviral agents for influenza, we constructed a dynamic transmission model to simulate the seasonal influenza epidemics in China. Two antivirus treatments, baloxavir and oseltamivir, were evaluated by estimating their impacts on the incidences of influenza infection in a single flu season. In the base-case analysis of a 10% antiviral treatment uptake rate, 2760 and 3420 per 10 000 persons contracted influenza under the treatment of baloxavir and oseltamivir, respectively. These incidence rates amounted to an 18.90% relative risk reduction (RRR) of infection associated with baloxavir in relation to oseltamivir. The corresponding RRR was 82.16% when the antiviral treatment uptake rate was increased to 35%. In addition, the peak of the prevalence of infected individuals per 10 000 persons under the baloxavir treatment was 177 (range: 93-274) fewer than that of oseltamivir. Our analyses suggest that the baloxavir treatment strategy reduces the incidence of influenza in China compared with oseltamivir in the setting of a seasonal flu epidemic. Also, increasing the uptake rate of antiviral treatment can potentially prevent millions of infections during a single flu season.
Assuntos
Influenza Humana , Tiepinas , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Morfolinas , Oseltamivir/uso terapêutico , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridonas , Estações do Ano , Tiepinas/farmacologia , Tiepinas/uso terapêutico , TriazinasRESUMO
In our ongoing efforts to identify baloxavir resistance markers, we demonstrated that the influenza A polymerase acidic (PA) protein E23R substitution is genetically stable, increases baloxavir EC50 values (13- to 19-fold vs. wild-type), synergizes with PA I38T, and only modestly decreases viral fitness. E23R is, therefore, a potential threat to baloxavir treatment efficacy.
Assuntos
Vírus da Influenza A , Influenza Humana , Tiepinas , Substituição de Aminoácidos , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Humanos , Vírus da Influenza A/genética , Influenza Humana/tratamento farmacológico , Morfolinas , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Piridinas/farmacologia , Piridonas/farmacologia , Piridonas/uso terapêutico , Tiepinas/farmacologia , Tiepinas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêuticoRESUMO
The first licensed polymerase inhibitor, baloxavir marboxil was recently approved for the treatment of influenza A and B viruses. Furthermore, there is growing interest in testing the antiviral activity of baloxavir marboxil against Coronavirus. Despite its critical clinical value, there is no information on the degradation products, pathways, or kinetics of baloxavir marboxil under various stress conditions. In this study, a new high-performance liquid chromatography-ultraviolet detection method for accurately quantifying baloxavir marboxil in the presence of its degradation products was developed. A study of degradation kinetics revealed that acidic, thermal neutral, and photolytic degradation reactions have zero-order kinetics, whereas basic and oxidative degradation reactions have first-order kinetics. The structural characterization of baloxavir marboxil degradation products was performed by coupling the optimized high-performance liquid chromatography method to the triple-quadrupole tandem mass spectrometer. The proposed approach was validated according to the International Council for Harmonisation Q2 (R1) requirements for accuracy, precision, robustness, specificity, and linearity. The validated new method was successfully used to analyze baloxavir marboxil as raw material and its pharmaceutical dosage form, Xofluza.