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1.
J Gen Virol ; 102(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34661516

RESUMO

The polymerase acidic (PA) I38T substitution is a dominant marker of resistance to baloxavir. We evaluated the impact of I38T on the fitness of a contemporary influenza A(H3N2) virus. Influenza A/Switzerland/9715293/2013 (H3N2) wild-type (WT) virus and its I38T mutant were rescued by reverse genetics. Replication kinetics were compared using ST6GalI-MDCK and A549 cells and infectivity/contact transmissibility were evaluated in guinea pigs. Nasal wash (NW) viral titres were determined by TCID50 ml-1 in ST6GalI-MDCK cells. Competition experiments were performed and the evolution of viral population was assessed by droplet digital RT-PCR. I38T did not alter in vitro replication. I38T induced comparable titres vs the WT in guinea pigs NWs and the two viruses transmitted equally by direct contact. However, a 50 %:50 % mixture inoculum evolved to mean WT/I38T ratios of 71 %:29 % and 66.4 %:33.6 % on days 4 and 6 p.i., respectively. Contemporary influenza A(H3N2)-I38T PA variants may conserve a significant level of viral fitness.


Assuntos
Vírus da Influenza A Subtipo H3N2/fisiologia , Infecções por Orthomyxoviridae/virologia , RNA Polimerase Dependente de RNA/genética , Proteínas Virais/genética , Células A549 , Substituição de Aminoácidos , Animais , Antivirais/farmacologia , Dibenzotiepinas/farmacologia , Cães , Farmacorresistência Viral , Cobaias , Humanos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/patogenicidade , Células Madin Darby de Rim Canino , Morfolinas/farmacologia , Nariz/virologia , Infecções por Orthomyxoviridae/transmissão , Piridonas/farmacologia , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/metabolismo , Genética Reversa , Triazinas/farmacologia , Carga Viral , Proteínas Virais/química , Proteínas Virais/metabolismo , Replicação Viral
2.
BMC Infect Dis ; 21(1): 777, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34372769

RESUMO

BACKGROUND: Children with influenza virus infections are prone to complications and are common sources of influenza transmission. Baloxavir marboxil inhibits cap-dependent endonuclease and was approved for influenza treatment in adolescent, adult, and pediatric patients in Japan. The miniSTONE-2 study included pediatric patients with influenza (1 to < 12 years) and demonstrated similar median times to alleviation of signs and symptoms of influenza with a single dose of baloxavir granules (weight < 20 kg: 2 mg/kg, ≥ 20 kg: 40 mg) and oseltamivir. Although the baloxavir dose in miniSTONE-2 was higher than the Japanese-approved dose, baloxavir exposure in miniSTONE-2 was similar to Japanese pediatric patients who receive the Japanese-approved dose. This study will be the first randomized active-controlled study in pediatric patients with influenza using the Japanese-approved dose of baloxavir. METHODS: This is a multicenter, open-label, randomized, active-controlled trial in which 200 Japanese subjects aged 6 to < 12 years with influenza virus infection are randomly allocated (2:1) to a single dose of baloxavir at the approved dose in Japan (weight ≥ 10 to < 20 kg: 10 mg, ≥ 20 to < 40 kg: 20 mg, ≥ 40 kg: 40 mg) or oseltamivir twice daily for 5 days. The primary clinical endpoint is the time to illness alleviation of influenza, from administration of baloxavir or oseltamivir until the following criteria were met and sustained for at least 21.5 h (24 h-10%): cough and nasal discharge/nasal congestion rated as absent or mild axillary body temperature < 37.5 °C. The primary analysis population is the intention-to-treat infected population, which includes all pediatric subjects who receive at least one dose of study drug and have confirmed influenza virus infection by reverse transcription-polymerase chain reaction. The safety population includes all subjects who receive at least one dose of study drug. DISCUSSION: No comparative studies have been conducted to confirm the efficacy and safety of baloxavir versus a comparator in pediatric patients with influenza infection in Japan. The outcomes from this trial will provide evidence on the efficacy and safety of baloxavir as an antiviral treatment option for Japanese pediatric patients with influenza infection. Trial registration Japan Registry of Clinical Trials: jRCTs011200011. Registered November 2020. ( https://rctportal.niph.go.jp/en/ ).


Assuntos
Antivirais , Dibenzotiepinas , Influenza Humana , Oseltamivir , Adolescente , Adulto , Antivirais/uso terapêutico , Criança , Dibenzotiepinas/uso terapêutico , Humanos , Influenza Humana/tratamento farmacológico , Morfolinas/uso terapêutico , Estudos Multicêntricos como Assunto , Oseltamivir/uso terapêutico , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Triazinas
3.
JAMA Netw Open ; 4(8): e2119151, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34387680

RESUMO

Importance: Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2; however, questions remain about which treatment is associated with the best outcomes and fewest adverse events. Objective: To compare the efficacy and safety of neuraminidase inhibitors and the endonuclease inhibitor for the treatment of seasonal influenza among healthy adults and children. Data Sources: Medline, Embase, and the Cochrane Register of Clinical Trials were searched from inception to January 2020 (the last search was updated in October 2020). Study Selection: Included studies were randomized clinical trials conducted among patients of all ages with influenza treated with neuraminidase inhibitors (ie, oseltamivir, peramivir, zanamivir, or laninamivir) or an endonuclease inhibitor (ie, baloxavir) compared with other active agents or placebo. Data Extraction and Synthesis: Two investigators identified studies and independently abstracted data. Frequentist network meta-analyses were performed; relative ranking of agents was conducted using P-score probabilities. Quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations criteria. Data were analyzed in October 2020. Main Outcomes and Measures: The time to alleviation of influenza symptoms (TTAS), complications of influenza, and adverse events (total adverse events, nausea, and vomiting). Results: A total of 26 trials were identified that investigated antiviral drugs at high or low doses; these trials included 11 897 participants, among whom 6294 (52.9%) were men and the mean (SD) age was 32.5 (16.9) years. Of all treatments comparing with placebo in efficacy outcomes, high-quality evidence indicated that zanamivir was associated with the shortest TTAS (hazard ratio, 0.67; 95% CI, 0.58-0.77), while baloxavir was associated with the lowest risk of influenza-related complications (risk ratio [RR], 0.51; 95% CI, 0.32-0.80) based on moderate-quality evidence. In safety outcomes, baloxavir was associated with the lowest risk of total adverse events (RR, 0.84; 95% CI, 0.74-0.96) compared with placebo based on moderate-quality evidence. There was no strong evidence of associations with risk of nausea or vomiting among all comparisons, except for 75 mg oseltamivir, which was associated with greater occurrence of nausea (RR, 1.82; 95% CI, 1.38-2.41) and vomiting (RR, 1.88; 95% CI, 1.47-2.41). Conclusions and Relevance: In this systematic review and network meta-analysis, all 4 antiviral agents assessed were associated with shortening TTAS; zanamivir was associated with the shortest TTAS, and baloxavir was associated with reduced rate of influenza-related complications.


Assuntos
Antivirais/uso terapêutico , Dibenzotiepinas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Influenza Humana/tratamento farmacológico , Morfolinas/uso terapêutico , Piridonas/uso terapêutico , Triazinas/uso terapêutico , Zanamivir/uso terapêutico , Adolescente , Adulto , Criança , Endonucleases/antagonistas & inibidores , Feminino , Humanos , Vírus da Influenza A/efeitos dos fármacos , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Metanálise em Rede , Neuraminidase/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Estações do Ano , Adulto Jovem
4.
Antiviral Res ; 194: 105158, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34363859

RESUMO

It is more than 20 years since the neuraminidase inhibitors, oseltamivir and zanamivir were approved for the treatment and prevention of influenza. Guidelines for global surveillance and methods for evaluating resistance were established initially by the Neuraminidase Inhibitor Susceptibility Network (NISN), which merged 10 years ago with the International Society for influenza and other Respiratory Virus Diseases (isirv) to become the isirv-Antiviral Group (isirv-AVG). With the ongoing development of new influenza polymerase inhibitors and recent approval of baloxavir marboxil, the isirv-AVG held a closed meeting in August 2019 to discuss the impact of resistance to these inhibitors. Following this meeting and review of the current literature, this article is intended to summarize current knowledge regarding the clinical impact of resistance to polymerase inhibitors and approaches for surveillance and methods for laboratory evaluation of resistance, both in vitro and in animal models. We highlight limitations and gaps in current knowledge and suggest some strategies for addressing these gaps, including the need for additional clinical studies of influenza antiviral drug combinations. Lessons learned from influenza resistance monitoring may also be helpful for establishing future drug susceptibility surveillance and testing for SARS-CoV-2.


Assuntos
Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Dibenzotiepinas/farmacologia , Farmacorresistência Viral , Inibidores Enzimáticos/farmacologia , Humanos , Influenza Humana/virologia , Conhecimento , Morfolinas/farmacologia , Neuraminidase/uso terapêutico , Oseltamivir/farmacologia , Piridonas/farmacologia , SARS-CoV-2/efeitos dos fármacos , Triazinas/farmacologia , Replicação Viral/efeitos dos fármacos , Zanamivir/farmacologia
5.
Antimicrob Agents Chemother ; 65(11): e0113721, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34424039

RESUMO

Clinical efficacy of the influenza antiviral baloxavir marboxil (baloxavir) is compromised by treatment-emergent variants harboring a polymerase acidic protein I38T (isoleucine-38-threonine) substitution. However, the fitness of I38T-containing influenza B viruses (IBVs) remains inadequately defined. After the pharmacokinetics of the compound were confirmed in ferrets, animals were injected subcutaneously with 8 mg/kg of baloxavir acid (BXA) at 24 h postinoculation with recombinant BXA-sensitive (BXA-Sen, I38) or BXA-resistant (BXA-Res, I38T) B/Brisbane/60/2008 (Victoria lineage) virus. BXA treatment of donor ferrets reduced virus replication and delayed transmission of the BXA-Sen but not the BXA-Res IBV. The I38 genotype remained dominant in the BXA-Sen-infected animals, even with BXA treatment. In competitive-mixture experiments, no transmission to aerosol contacts was seen from BXA-treated donors coinfected with the BXA-Sen and BXA-Res B/Brisbane/60/2008 viruses. However, in parallel mixed infections with the B/Phuket/3073/2013 (Yamagata lineage) virus background, BXA treatment failed to block airborne transmission of the BXA-Res virus, and the I38T genotype generally predominated. Therefore, the relative fitness of BXA-Res IBVs is complex and dependent on the virus backbone and within-host virus competition. BXA treatment of single-virus-infected ferrets hampers aerosol transmission of the BXA-Sen virus and does not readily generate BXA-Res variants, whereas mixed infections may result in propagation of BXA-Res IBVs of the Yamagata lineage. Our findings confirm the antiviral potency of baloxavir against IBVs, while supporting optimization of the dosing regimen to maximize clinical benefit.


Assuntos
Influenza Humana , Preparações Farmacêuticas , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas , Farmacorresistência Viral/genética , Furões , Humanos , Vírus da Influenza B/genética , Influenza Humana/tratamento farmacológico , Morfolinas , Piridonas/uso terapêutico , Tempo para o Tratamento , Triazinas/uso terapêutico
6.
J Microbiol Immunol Infect ; 54(5): 767-775, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34253490

RESUMO

Despite aggressive efforts on containment measures for the coronavirus disease 2019 (COVID-19) pandemic around the world, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuously spreading. Therefore, there is an urgent need for an effective antiviral agent. To date, considerable research has been conducted to develop different approaches to COVID-19 therapy. In addition to early observational studies, which could be limited by study design, small sample size, non-randomized design, or different timings of treatment, an increasing number of randomized controlled trials (RCTs) investigating the clinical efficacy and safety of antiviral agents are being carried out. This study reviews the updated findings of RCTs regarding the clinical efficacy of eight antiviral agents against COVID-19, including remdesivir, lopinavir/ritonavir, favipiravir, sofosbuvir/daclatasvir, sofosbuvir/ledipasvir, baloxavir, umifenovir, darunavir/cobicistat, and their combinations. Treatment with remdesivir could accelerate clinical improvement; however, it lacked additional survival benefits. Moreover, 5-day regimen of remdesivir might show adequate effectiveness in patients with mild to moderate COVID-19. Favipiravir was only marginally effective regarding clinical improvement and virological assessment based on the results of small RCTs. The present evidence suggests that sofosbuvir/daclatasvir may improve survival and clinical outcomes in patients with COVID-19. However, the sample sizes for analysis were relatively small, and all studies were exclusively conducted in Iran. Further larger RCTs in other countries are warranted to support these findings. In contrast, the present findings of limited RCTs did not indicate the use of lopinavir/ritonavir, sofosbuvir/ledipasvir, baloxavir, umifenovir, and darunavir/cobicistat in the treatment of patients hospitalized for COVID-19.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Amidas/uso terapêutico , Carbamatos/uso terapêutico , Cobicistat/uso terapêutico , Darunavir/uso terapêutico , Dibenzotiepinas/uso terapêutico , Combinação de Medicamentos , Quimioterapia Combinada , Humanos , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Irã (Geográfico) , Lopinavir/uso terapêutico , Morfolinas/uso terapêutico , Pirazinas/uso terapêutico , Piridonas/uso terapêutico , Pirrolidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Ritonavir/uso terapêutico , SARS-CoV-2 , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Triazinas/uso terapêutico , Valina/análogos & derivados , Valina/uso terapêutico
7.
J Infect Chemother ; 27(8): 1223-1229, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34045119

RESUMO

INTRODUCTION: Baloxavir marboxil is an oral anti-influenza drug with demonstrated safety and efficacy in pediatric patients when a 2% granules formulation is administered at 1 mg/kg. This study assessed safety, effectiveness, and pharmacokinetics of a higher dose (2 mg/kg) of baloxavir marboxil 2% granules in pediatric patients weighing <20 kg. METHODS: This multicenter, open-label, noncontrolled study was conducted at 15 sites in Japan (January 2019-March 2020; JapicCTI-194577). Patients aged <12 years with confirmed influenza received a single oral dose of baloxavir marboxil at 2 mg/kg if body weight was <10 kg or 20 mg if ≥ 10 to <20 kg. Safety, pharmacokinetics, effectiveness (time to illness alleviation [TTIA] of influenza; time to resolution of fever; virus titer), and polymerase acidic protein (PA) substituted viruses were assessed over 22 days. RESULTS: 45 patients, all aged ≤6 years, were enrolled. Adverse events were reported in 24 (53.3%) patients, most commonly nasopharyngitis, diarrhea, and upper respiratory tract infection. Median (95% confidence interval [CI]) TTIA was 37.8 (27.5-46.7) hours; median (95% CI) time to resolution of fever was 22.0 (20.2-28.6) hours. A >4 log decrease in mean viral titer occurred at day 2 and a subsequent temporary 1-2 log increase in patients with influenza A(H3N2) and B. Treatment-emergent PA/I38X-substituted virus was detected in 16/39 (41.0%) patients, but no prolonged TTIA or time to resolution of fever was associated with its presence. CONCLUSIONS: Baloxavir granules administered at 2 mg/kg in children <20 kg were well tolerated, with symptom alleviation similar to 1 mg/kg.


Assuntos
Dibenzotiepinas , Influenza Humana , Antivirais/efeitos adversos , Criança , Dibenzotiepinas/uso terapêutico , Humanos , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/tratamento farmacológico , Japão , Morfolinas/uso terapêutico , Oxazinas , Piridonas/uso terapêutico , Triazinas
8.
PLoS Pathog ; 17(5): e1009527, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33956888

RESUMO

Baloxavir is approved in several countries for the treatment of uncomplicated influenza in otherwise-healthy and high-risk patients. Treatment-emergent viruses with reduced susceptibility to baloxavir have been detected in clinical trials, but the likelihood of widespread occurrence depends on replication capacity and onward transmission. We evaluated the fitness of A/H3N2 and A/H1N1pdm09 viruses with the polymerase acidic (PA) I38T-variant conferring reduced susceptibility to baloxavir relative to wild-type (WT) viruses, using a competitive mixture ferret model, recombinant viruses and patient-derived virus isolates. The A/H3N2 PA/I38T virus showed a reduction in within-host fitness but comparable between-host fitness to the WT virus, while the A/H1N1pdm09 PA/I38T virus had broadly similar within-host fitness but substantially lower between-host fitness. Although PA/I38T viruses replicate and transmit between ferrets, our data suggest that viruses with this amino acid substitution have lower fitness relative to WT and this relative fitness cost was greater in A/H1N1pdm09 viruses than in A/H3N2 viruses.


Assuntos
Antivirais/farmacologia , Dibenzotiepinas/farmacologia , Modelos Animais de Doenças , Farmacorresistência Viral , Vírus da Influenza A/genética , Morfolinas/farmacologia , Infecções por Orthomyxoviridae/tratamento farmacológico , Piridonas/farmacologia , Triazinas/farmacologia , Replicação Viral , Substituição de Aminoácidos , Animais , Feminino , Furões , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/isolamento & purificação , Masculino , Infecções por Orthomyxoviridae/virologia
9.
Expert Rev Clin Pharmacol ; 14(7): 901-918, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33861168

RESUMO

BACKGROUND: Scarce evidence verifying the clinical impact of baloxavir on influenza complications is found. METHODS: PubMed, Cochrane Library, and Web of Science databases were searched through December 2020. Randomized-controlled trials (RCT) that enrolled patients with laboratory-confirmed influenza receiving neuraminidase inhibitors (NAI) or baloxavir comparing to placebo were assessed. PROSPERO Registration-number: CRD42021226854. RESULTS: Twenty-one RCTs (11,697 patients) were included. Antiviral administration significantly reduced time to clinical resolution (mean difference: -21.3 hours) and total influenza-related complications (OR:0.55, 95%CI: 0.42-0.73). Specifically, antivirals significantly decreased bronchitis (OR:0.54, 95%CI: 0.38-0.75), sinusitis (OR:0.51, 95%CI: 0.33-0.78), acute otitis media (OR:0.48, 95%CI: 0.30-0.77), and antibiotic prescription (OR:0.62; 95%CI: 0.48-0.80). A positive trend favored antivirals administration to reduce pneumonia (OR:0.47, 95%CI: 0.16-1.33), or hospitalization rates (OR:0.65; 95%CI: 0.34-1.24) compared to placebo, but did not reach statistical significance. Adverse events (AE) were reported in 11%, 8.9%, and 5.1% of NAIs, placebo and baloxavir recipients, respectively. Compared with NAIs, administration of baloxavir showed non-significantly reduced AEs (OR:0.74, 95%CI: 0.53-1.04). CONCLUSIONS: Single-dose baloxavir and NAIs were superior to placebo to reduce complications in uncomplicated influenza, with 40% significant reduction in antibiotic prescription. Safety and efficacy of single-dose baloxavir were non-inferior to NAIs.


Assuntos
Dibenzotiepinas/farmacologia , Influenza Humana/tratamento farmacológico , Morfolinas/farmacologia , Neuraminidase/antagonistas & inibidores , Piridonas/farmacologia , Triazinas/farmacologia , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacologia , Dibenzotiepinas/administração & dosagem , Dibenzotiepinas/efeitos adversos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacologia , Humanos , Influenza Humana/virologia , Morfolinas/administração & dosagem , Morfolinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Triazinas/administração & dosagem , Triazinas/efeitos adversos
10.
Curr Med Res Opin ; 37(7): 1135-1148, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33858277

RESUMO

OBJECTIVE: Baloxavir marboxil (baloxavir) is a single-dose antiviral which was previously found to be a cost-effective alternative to laninamivir in otherwise healthy adults in Japan. This study aimed at investigating the cost-effectiveness of baloxavir versus laninamivir in patients with influenza at high risk for complications. METHODS: A decision tree was utilized to estimate costs and health gains associated with the use of antivirals. A lifetime horizon was applied to capture the long-term impact of influenza complications, and other events with associated costs and health outcomes were accounted for one influenza season. The study population was stratified into three categories: adolescents and non-elderly adults with high-risk conditions (HRC), elderly without other HRC, and elderly with other HRC. The cost-effectiveness was assessed from a public healthcare payer's perspective. The duration of influenza symptoms, probabilities of complications and probabilities of adverse events were obtained from a clinical trial and network meta-analysis. The costs of influenza and adverse events management were derived from the JammNet claims database. Utility values were informed by the clinical trial data and literature. Sensitivity analyses were also performed. RESULTS: The baloxavir strategy was associated with higher costs (+¥144) and higher quality-adjusted life-years (QALYs) in adults with HRC, elderly without HRC and elderly with HRC (+0.00078, +0.00183 and +0.00350 respectively). The overall incremental cost/QALY for baloxavir versus laninamivir was ¥68,855, which was below the willingness-to-pay threshold of ¥5 million/QALY gained. Key drivers of the model results were the probability of pneumonia and bronchitis. The probability of baloxavir being cost-effective was 72%. CONCLUSIONS: This study suggests that influenza treatment with baloxavir is cost-effective compared with laninamivir in the adult high-risk population in Japan.


Assuntos
Dibenzotiepinas , Influenza Humana , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Análise Custo-Benefício , Dibenzotiepinas/uso terapêutico , Guanidinas , Humanos , Influenza Humana/tratamento farmacológico , Japão/epidemiologia , Pessoa de Meia-Idade , Morfolinas/uso terapêutico , Piranos , Piridonas/uso terapêutico , Ácidos Siálicos , Triazinas/uso terapêutico
11.
J Biol Chem ; 296: 100486, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33647314

RESUMO

Baloxavir marboxil (BXM) is an FDA-approved antiviral prodrug for the treatment of influenza A and B infection and postexposure prophylaxis. The active form, baloxavir acid (BXA), targets the cap-snatching endonuclease (PA) of the influenza virus polymerase complex. The nuclease activity delivers the primer for transcription, and previous reports have shown that BXA blocks the nuclease activity with high potency. However, biochemical studies on the mechanism of action are lacking. Structural data have shown that BXA chelates the two divalent metal ions at the active site, like inhibitors of the human immunodeficiency virus type 1 (HIV-1) integrase or ribonuclease (RNase) H. Here we studied the mechanisms underlying the high potency of BXA and how the I38T mutation confers resistance to the drug. Enzyme kinetics with the recombinant heterotrimeric enzyme (FluB-ht) revealed characteristics of a tight binding inhibitor. The apparent inhibitor constant (Kiapp) is 12 nM, while the I38T mutation increased Kiapp by ∼18-fold. Order-of-addition experiments show that a preformed complex of FluB-ht, Mg2+ ions and BXA is required to observe inhibition, which is consistent with active site binding. Conversely, a preformed complex of FluB-ht and RNA substrate prevents BXA from accessing the active site. Unlike integrase inhibitors that interact with the DNA substrate, BXA behaves like RNase H inhibitors that compete with the nucleic acid at the active site. The collective data support the conclusion that BXA is a tight binding inhibitor and the I38T mutation diminishes these properties.


Assuntos
Dibenzotiepinas/farmacologia , Endonucleases/antagonistas & inibidores , Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Influenza Humana/virologia , Morfolinas/farmacologia , Piridonas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Triazinas/farmacologia , Replicação Viral/efeitos dos fármacos , Antivirais/farmacologia , Domínio Catalítico , Endonucleases/metabolismo , Humanos , Vírus da Influenza B/enzimologia , Vírus da Influenza B/isolamento & purificação , Influenza Humana/enzimologia , RNA Polimerase Dependente de RNA/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo
13.
Antiviral Res ; 188: 105036, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33577807

RESUMO

Baloxavir marboxil has been used for influenza treatment since March 2018 in Japan. After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses. To rapidly investigate the frequency of PA/I38T in influenza A (H1N1)pdm09 and A (H3N2) viruses in clinical samples, we established a rapid real-time system to detect single nucleotide polymorphisms in PA, using cycling probe real-time PCR. We designed two sets of probes that were labeled with either 6-carboxyfluorescein (FAM) or 6-carboxy-X-rhodamine (ROX) to identify PA/I38 (wild type strain) or PA/I38T, respectively. The established cycling probe real-time PCR system showed a dynamic linear range of 101 to 106 copies with high sensitivity in plasmid DNA controls. This real-time PCR system discriminated between PA/I38T and wild type viruses well. During the 2018/19 season, 377 influenza A-positive clinical samples were collected in Japan before antiviral treatment. Using our cycling probe real-time PCR system, we detected no (0/129, 0.0%) influenza A (H1N1)pdm09 viruses with PA/I38T substitutions and four A (H3N2) (4/229, 1.7%) with PA/I38T substitution prior to treatment. In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A (H3N2) that afflicted the entire family. Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited. Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PA/I38T.


Assuntos
Antivirais/farmacologia , Dibenzotiepinas/farmacologia , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/genética , Morfolinas/farmacologia , Piridonas/farmacologia , RNA Polimerase Dependente de RNA/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Triazinas/farmacologia , Proteínas Virais/genética , Substituição de Aminoácidos , Animais , Linhagem Celular , Humanos , Vírus da Influenza A/enzimologia , Vírus da Influenza A/isolamento & purificação , Testes de Sensibilidade Microbiana , RNA Viral/biossíntese , Replicação Viral/efeitos dos fármacos
14.
Pharmacoepidemiol Drug Saf ; 30(6): 779-786, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33608939

RESUMO

PURPOSE: Baloxavir marboxil is a novel antiviral agent for influenza, introduced into clinical practice in 2018. A concern remains about the variant virus with reduced susceptibility after baloxavir exposure and its clinical consequences such as healthcare-seeking behavior. METHODS: Using a healthcare database in Japan, we compared the medical resource use following baloxavir and neuraminidase inhibitors (NAIs) treatment among children aged 7-15 years. The study period was from December 2018 to March 2019. The primary endpoint was the composite of hospitalization, laboratory and radiological tests, and antibiotic use over 1-9 days of antiviral treatment. As exploratory analyses, secondary outcomes being each single component of the primary composite were assessed and subgroup analyses comparing baloxavir with each NAI were done. RESULTS: Data from 115 867 prescriptions in 115 238 children were analyzed (median age: 10 years; severe influenza risk in 26%; baloxavir accounting for 43%). Overall, baloxavir use did not increase subsequent medical resource utilization in the composite endpoint (adjusted odds ratio [aOR]: 1.04; 95% confidence interval [CI]: 0.99-1.09; P = 0.14), as were likelihoods of other secondary outcomes. In the subgroup analysis, baloxavir use was associated with higher medical resource use than oseltamivir (aOR: 1.21; 95% CI: 1.13-1.31; P < 0.001) and lower resource use than zanamivir (aOR: 0.93; 95% CI 0.86-1.00; P = 0.040). CONCLUSIONS: Based on a single-year experience in Japan, prescribing baloxavir rather than NAIs did not increase medical resource utilization within 9 days of treatment, except in one exploratory comparison with oseltamivir.


Assuntos
Dibenzotiepinas , Influenza Humana , Antivirais/uso terapêutico , Criança , Dibenzotiepinas/uso terapêutico , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Morfolinas/uso terapêutico , Prescrições , Piridonas/uso terapêutico , Instituições Acadêmicas , Triazinas
15.
J Med Econ ; 24(1): 244-254, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33470138

RESUMO

AIMS: Estimating the monetary value of the convenience of using influenza antivirals approved in Japan from a patient perspective using a conjoint analysis. METHODS: An online survey (August 2020) was performed on individuals aged 20-64 years living in Japan who had taken oral or inhalant antivirals for influenza treatment in the 2018/19 or 2019/20 seasons. Efficacy and safety were assumed to be equivalent among the antivirals. The attributes for the conjoint analysis included route (oral or inhalant), duration, frequency of administration, and out-of-pocket expenses. A conditional logit model was applied as a baseline model. The monetary value of each attribute was calculated by comparing the same utility of the linearly interpolated level of the out-of-pocket attribute. Another survey to determine the experiences of the latest antiviral intake was also conducted on the same respondents. RESULTS: Of the respondents, 1,550 were men and 1,587 were women. The monetary value for oral antivirals was estimated to be higher, saving JPY 741 (USD 7.06, as of August 2020), compared with inhalant. Regarding the length and frequency of administration, five days corresponds to an increase of JPY 2,072, compared with one day, and twice a day corresponds to a JPY 574 increase compared to once a day. CONCLUSIONS: The results suggest that - among the antivirals approved in Japan - the monetary value of the utility is the highest in the single dose oral antiviral, baloxavir marboxil (baloxavir). Although the drug cost was highest in baloxavir among the brand antivirals, the difference in the value of utility for influenza patient was estimated to be larger than the difference in the drug costs. LIMITATIONS: Although individuals with diverse attributes from all over the country were included in the survey, they are not necessarily a representative population of the Japanese society.


Assuntos
Dibenzotiepinas , Influenza Humana , Adulto , Antivirais/uso terapêutico , Dibenzotiepinas/uso terapêutico , Feminino , Humanos , Influenza Humana/tratamento farmacológico , Japão , Masculino , Pessoa de Meia-Idade , Morfolinas/uso terapêutico , Neuraminidase/uso terapêutico , Piridonas/uso terapêutico , Triazinas/uso terapêutico , Adulto Jovem
16.
J Pharm Pharm Sci ; 24: 37-40, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33460556

RESUMO

BACKGROUND: Baloxavir marboxil (BM) is a novel drug with a cap-dependent endonuclease inhibitory action for influenza A or B; it is highly safe and requires just a single oral dose. Patients with severe heart failure use implantable ventricular assist device (iVAD) until transplantation, but they have an increased risk of thrombosis development. Their warfarin is administered based on point-of-care testing (POCT) with a strict control of prothrombin time-international normalized ratio (PT-INR). CASE REPORT: Here, we report a case of a patient with iVAD whose PT-INR was significantly increased from the target range after BM administration. The patient was a 45-year-old man and transplanted with iVAD; warfarin treatment was started when his PT-INR target range was 3.0-3.5. At home, he frequently self-measured PT-INR by POCT and precisely controlled the warfarin dose. He had a fever, was diagnosed with influenza A and was administered BM 40 mg. Thereafter, his PT-INR continued to increase, reaching 4.8 on day 12 of BM administration, exceeding his target range; warfarin was skipped for 1 day. In this case, based on the history of BM administration and clinical course, the increase in PT-INR could be due to BM. Considering the interaction between warfarin and BM, we suspected a possibility of competition for protein-binding sites. Increased PT-INR in the patient was detected early by POCT and thus severe bleeding was avoided. CONCLUSION: Strict monitoring of PT-INR when using BM in patients taking warfarin is of clinical importance.


Assuntos
Anticoagulantes/uso terapêutico , Dibenzotiepinas/uso terapêutico , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Morfolinas/uso terapêutico , Piridonas/uso terapêutico , Triazinas/uso terapêutico , Varfarina/uso terapêutico , Anticoagulantes/administração & dosagem , Dibenzotiepinas/administração & dosagem , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Morfolinas/administração & dosagem , Tempo de Protrombina , Piridonas/administração & dosagem , Triazinas/administração & dosagem , Varfarina/administração & dosagem
17.
Am J Nurs ; 121(2): 26-27, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33497124

RESUMO

Baloxavir marboxil (Xofluza), an antiviral flu treatment, has now been approved to prevent influenza.Patients should avoid taking calcium, aluminum, or magnesium products while receiving baloxavir as this will lead to a loss of antiviral efficacy.


Assuntos
Dibenzotiepinas/farmacologia , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Morfolinas/farmacologia , Piridonas/farmacologia , Triazinas/farmacologia , Antivirais/farmacologia , Antivirais/uso terapêutico , Dibenzotiepinas/uso terapêutico , Humanos , Morfolinas/uso terapêutico , Piridonas/uso terapêutico , Triazinas/uso terapêutico
18.
Nucleic Acids Res ; 49(3): 1609-1618, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33469660

RESUMO

The endonuclease activity within the influenza virus cap-snatching process is a proven therapeutic target. The anti-influenza drug baloxavir is highly effective, but is associated with resistance mutations that threaten its clinical efficacy. The endonuclease resides within the N-terminal domain of the PA subunit (PAN) of the influenza RNA dependent RNA polymerase, and we report here complexes of PAN with RNA and DNA oligonucleotides to understand its specificity and the structural basis of baloxavir resistance mutations. The RNA and DNA oligonucleotides bind within the substrate binding groove of PAN in a similar fashion, explaining the ability of the enzyme to cleave both substrates. The individual nucleotides occupy adjacent conserved pockets that flank the two-metal active site. However, the 2' OH of the RNA ribose moieties engage in additional interactions that appear to optimize the binding and cleavage efficiency for the natural substrate. The major baloxavir resistance mutation at position 38 is at the core of the substrate binding site, but structural studies and modeling suggest that it maintains the necessary virus fitness via compensating interactions with RNA. These studies will facilitate the development of new influenza therapeutics that spatially match the substrate and are less likely to elicit resistance mutations.


Assuntos
Endorribonucleases/química , Vírus da Influenza A Subtipo H1N1/enzimologia , Proteínas Virais/química , Antivirais/química , DNA/química , Dibenzotiepinas/química , Endorribonucleases/metabolismo , Modelos Moleculares , Morfolinas/química , Piridonas/química , RNA/química , Especificidade por Substrato , Triazinas/química , Proteínas Virais/metabolismo
19.
Curr Med Res Opin ; 37(2): 225-244, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33079575

RESUMO

OBJECTIVES: Previous network meta-analysis (NMA) demonstrated advantageous or similar efficacy of baloxavir marboxil (baloxavir) over neuraminidase inhibitors in otherwise healthy (OwH) influenza patients. This analysis assessed the efficacy and safety of baloxavir in the subgroup of high-risk (HR) patients and in the population of uncomplicated influenza consisting of OwH and HR patients with influenza. METHODS: A systematic literature review (SLR) was performed in Medline, Embase, CENTRAL and ICHUSHI up to August 8th, 2018. A Bayesian NMA was conducted to compare baloxavir with oseltamivir, zanamivir, laninamivir and peramivir in HR patients and all uncomplicated patients. RESULTS: Based on the SLR, a total of 32 studies were identified as pertinent for the analysis, including 7 studies on HR patients, 13 trials on OwH patients and 14 studies on OwH + HR population. NMA of 10 trials assessing HR patients demonstrated comparable time to alleviation of symptoms for all treatments. Mean decline in virus titer from baseline at 24 h after treatment was significantly greater for baloxavir compared with oseltamivir and peramivir. The risks of total complications and drug-related adverse events were comparable between baloxavir and zanamivir, oseltamivir and laninamivir. These findings were highly consistent with results of the NMA using pooled evidence on the uncomplicated population of OwH and HR patients.Conclusions: Baloxavir was significantly more effective than placebo regarding all outcomes except for the risk of pneumonia. Besides, baloxavir was associated with similar clinical efficacy and safety, and superior antiviral activity compared to other antivirals in HR patients, as well as in the entire population of uncomplicated patients with influenza.


Assuntos
Dibenzotiepinas/efeitos adversos , Dibenzotiepinas/uso terapêutico , Influenza Humana/tratamento farmacológico , Morfolinas/efeitos adversos , Morfolinas/uso terapêutico , Piridonas/efeitos adversos , Piridonas/uso terapêutico , Triazinas/efeitos adversos , Triazinas/uso terapêutico , Humanos , Metanálise em Rede
20.
Antiviral Res ; 185: 104970, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33159999

RESUMO

Influenza B viruses cause significant morbidity and mortality, particularly in children, but the awareness of their impact is often less than influenza A viruses partly due to their lack of pandemic potential. Here, we summarise the biology, epidemiology and disease burden of influenza B, and review existing data on available antivirals for its management. There has long been uncertainty surrounding the clinical efficacy of neuraminidase inhibitors (NAIs) for influenza B treatment. In this article, we bring together the existing data on NAIs and discuss these alongside recent large randomised controlled trial data for the new polymerase inhibitor baloxavir in high-risk influenza B patients. Finally, we offer considerations for the clinical management of influenza B, with a focus on children and high-risk patients where disease burden is highest.


Assuntos
Efeitos Psicossociais da Doença , Gerenciamento Clínico , Vírus da Influenza B/patogenicidade , Influenza Humana/prevenção & controle , Antivirais/uso terapêutico , Criança , Ensaios Clínicos Fase III como Assunto , Dibenzotiepinas/farmacologia , Dibenzotiepinas/uso terapêutico , Farmacorresistência Viral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Vírus da Influenza B/efeitos dos fármacos , Influenza Humana/tratamento farmacológico , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Pandemias/prevenção & controle , Piridonas/farmacologia , Piridonas/uso terapêutico , Triazinas/farmacologia , Triazinas/uso terapêutico
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