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Frontiers in Microbiology 2023There are limited data on the efficacy of baloxavir marboxil (baloxavir) versus oseltamivir in Chinese patients with influenza A.
INTRODUCTION
There are limited data on the efficacy of baloxavir marboxil (baloxavir) versus oseltamivir in Chinese patients with influenza A.
METHODS
This study is an observational real-world investigation encompassing 246 patients (baloxavir, = 147; oseltamivir, = 99) confirmed positive for influenza A. The choice between baloxavir and oseltamivir antiviral treatments was determined collaboratively by the clinician and the patient. A thorough comparative analysis was undertaken between the two groups, examining parameters such as the duration of fever and symptoms, viral load dynamics, lymphocyte changes, and enhancements in health-related quality of life (QoL).
RESULTS
No significant differences were observed in demographic data between the two groups. The duration of fever was significantly shorter in the baloxavir group ( < 0.001). However, the duration of symptoms was not significant different ( = 0.167). Multivariable Cox analysis showed the independent factors affecting duration of fever were baloxavir treatment (HR = 2.033, < 0.001), fever on day 1 (HR = 0.741, = 0.010) and CRP level (HR = 1.009, = 0.039). Moreover, sex (HR= 0.660, = 0.019) and monocyte count (HR = 1.355, = 0.018) were independent factors affecting the duration of symptoms. No significant difference in change of health-related quality of life ( > 0.05), positive rate of viral antigen on day 3 ( = 0.477) between the two groups. Remarkably, a mutation was observed in one case on the third-day after baloxavir treatment compared with first-day, from cysteine to serine at position 384 of the PA subunit.
CONCLUSION
In the clinical setting, baloxavir demonstrated comparable clinical benefits to oseltamivir, establishing its efficacy as an effective antiviral therapy for Chinese patients with influenza.
PubMed: 38088961
DOI: 10.3389/fmicb.2023.1292735 -
Virology Feb 2024The possible emergence of drug-resistant avian flu raises concerns over the limited effectiveness of currently approved antivirals (neuraminidase inhibitors - NAIs) in...
The possible emergence of drug-resistant avian flu raises concerns over the limited effectiveness of currently approved antivirals (neuraminidase inhibitors - NAIs) in the hypothetical event of a zoonotic spillover. Our study demonstrated that the recombinant avian A(H6N1) viruses showed reduced inhibition (RI) by multiple NAI drugs following the introduction of point mutations found predominantly in the neuraminidase gene (NA) of NAI-resistant human influenza strains (E119V, R292K and H274Y; N2 numbering). Moreover, A(H6N1)-H274Y showed increased replication efficiency in vitro, and a fitness advantage over wild-type (WT) when co-inoculated into embryonated hen's eggs. The results presented in our study together with the zoonotic potential of the A(H6N1) virus as evidenced by the human infection from 2013, highlight the need for enhanced monitoring of NAI resistance-associated signatures in circulating LPAI (low pathogenic avian influenza) globally.
Topics: Animals; Female; Humans; Oseltamivir; Influenza in Birds; Chickens; Neuraminidase; Antiviral Agents; Enzyme Inhibitors; Influenza, Human; Mutation; Drug Resistance; Drug Resistance, Viral
PubMed: 38086284
DOI: 10.1016/j.virol.2023.109954 -
Med (New York, N.Y.) Jan 2024Recent outbreaks of avian influenza and ongoing virus reassortment have drawn focus on spill-over infections. The increase in human infections with highly pathogenic...
BACKGROUND
Recent outbreaks of avian influenza and ongoing virus reassortment have drawn focus on spill-over infections. The increase in human infections with highly pathogenic avian influenza H5N6 virus and its high fatality rate posed a potential threat, necessitating the search for a more effective treatment.
METHODS
Longitudinal clinical data and specimens were collected from five H5N6 patients after admission. All patients received antiviral treatment of either sequential monotherapy of oseltamivir and baloxavir or the two drugs in combination. Severity of illness; viral load in sputum, urine, and blood; and cytokine levels in serum and sputum were serially analyzed.
FINDINGS
All patients developed acute respiratory distress syndrome (ARDS) and viral sepsis within 1 week after disease onset. When delayed oseltamivir showed poor effects, baloxavir was administered and rapidly decreased viral load. In addition, levels of IL-18, M-CSF, IL-6, and HGF in sputum and Mig and IL-18 in serum that reflected ARDS and sepsis deterioration, respectively, were also reduced with baloxavir usage. However, three patients eventually died from exacerbation of underlying disease and secondary bacterial infection. Nonsurvivors had more severe extrapulmonary organ dysfunction and insufficient H5N6 virus-specific antibody response.
CONCLUSIONS
For critical human cases of H5N6 infection, baloxavir demonstrated effects on viral load and pulmonary/extrapulmonary cytokines, even though treatment was delayed. Baloxavir could be regarded as a first-line treatment to limit continued viral propagation, with potential future application in avian influenza human infections and poultry workers exhibiting influenza-like illness.
FUNDING
This work was funded by the National Natural Science Foundation of China (81761128014).
Topics: Animals; Humans; Influenza in Birds; Oseltamivir; Influenza A Virus, H5N6 Subtype; Interleukin-18; Influenza, Human; Influenza A virus; Respiratory Distress Syndrome; Sepsis; Dibenzothiepins; Morpholines; Pyridones; Triazines
PubMed: 38070511
DOI: 10.1016/j.medj.2023.11.001 -
Antimicrobial Agents and Chemotherapy Jan 2024Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme...
Endocytosis, or internalization through endosomes, is a major cell entry mechanism used by respiratory viruses. Phosphoinositide 5-kinase (PIKfyve) is a critical enzyme for the synthesis of phosphatidylinositol (3, 5)biphosphate (PtdIns (3, 5)P2) and has been implicated in virus trafficking the endocytic pathway. In fact, antiviral effects of PIKfyve inhibitors against SARS-CoV-2 and Ebola have been reported, but there is little evidence regarding other respiratory viruses. In this study, we demonstrated the antiviral effects of PIKfyve inhibitors on influenza virus and respiratory syncytial virus and . PIKfyve inhibitors Apilimod mesylate (AM) and YM201636 concentration-dependently inhibited several influenza strains in an MDCK cell-cytopathic assay. AM also reduced the viral load and cytokine release, while improving the cell integrity of human nasal air-liquid interface cultured epithelium infected with influenza PR8. In PR8-infected mice, AM (2 mg/mL), when intranasally treated, exhibited a significant reduction of viral load and inflammation and inhibited weight loss caused by influenza infection, with effects being similar to oral oseltamivir (10 mg/kg). In addition, AM demonstrated antiviral effects in RSV A2-infected human nasal epithelium and mouse , with an equivalent effect to that of ribavirin. AM also showed antiviral effects against human rhinovirus and seasonal coronavirus . Thus, PIKfyve is found to be involved in influenza and RSV infection, and PIKfyve inhibitor is a promising molecule for a pan-viral approach against respiratory viruses.
Topics: Humans; Animals; Mice; Influenza, Human; Oseltamivir; Hemorrhagic Fever, Ebola; Antiviral Agents; Nasal Mucosa
PubMed: 38063402
DOI: 10.1128/aac.01050-23 -
ACS Omega Nov 2023Drug failure during experimental procedures due to low bioactivity presents a significant challenge. To mitigate this risk and enhance compound bioactivities, predicting...
Drug failure during experimental procedures due to low bioactivity presents a significant challenge. To mitigate this risk and enhance compound bioactivities, predicting bioactivity classes during lead optimization is essential. The existing studies on structure-activity relationships have highlighted the connection between the chemical structures of compounds and their bioactivity. However, these studies often overlook the intricate relationship between drugs and bioactivity, which encompasses multiple factors beyond the chemical structure alone. To address this issue, we propose the BioAct-Het model, employing a heterogeneous siamese neural network to model the complex relationship between drugs and bioactivity classes, bringing them into a unified latent space. In particular, we introduce a novel representation for the bioactivity classes, called Bio-Prof, and enhance the original bioactivity data sets to tackle data scarcity. These innovative approaches resulted in our model outperforming the previous ones. The evaluation of BioAct-Het is conducted through three distinct strategies: association-based, bioactivity class-based, and compound-based. The association-based strategy utilizes supervised learning classification, while the bioactivity class-based strategy adopts a retrospective study evaluation approach. On the other hand, the compound-based strategy demonstrates similarities to the concept of meta-learning. Furthermore, the model's effectiveness in addressing real-world problems is analyzed through a case study on the application of vancomycin and oseltamivir for COVID-19 treatment as well as molnupiravir's potential efficacy in treating COVID-19 patients. The data and code underlying this article are available on https://github.com/CBRC-lab/BioAct-Het. However, data sets were derived from sources in the public domain.
PubMed: 38046344
DOI: 10.1021/acsomega.3c05778 -
Viruses Nov 2023Influenza remains a worldwide health concern. Antiviral drugs are considered as one of the useful options for its prevention as a complementary measure to vaccination....
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.
Topics: Humans; Animals; Mice; Influenza, Human; Oseltamivir; Herpesvirus 1, Cercopithecine; Influenza A Virus, H1N1 Subtype; Oxazines; Pyridines; Thiepins; Antiviral Agents; Mice, Inbred BALB C; Phosphates
PubMed: 38005940
DOI: 10.3390/v15112264 -
Journal of Global Antimicrobial... Mar 2024The neuraminidase (NA) mutations causing resistance to NA inhibitors (NAIs) mostly compromise the fitness of influenza viruses. Considering the importance of these...
OBJECTIVES
The neuraminidase (NA) mutations causing resistance to NA inhibitors (NAIs) mostly compromise the fitness of influenza viruses. Considering the importance of these mutations, constant monitoring of the effectiveness of available drugs is critical. This study aimed to identify NA mutations in the influenza A/H1N1 and A/H3N2 subtypes in the samples of Mazandaran, Iran from 2016 to 2020.
METHODS
In this cross-sectional study, 20 influenza A/H1N1 and 20 influenza A/H3N2 samples were included in the study. After design of appropriate primers for NA gene, all samples subjected to RT-PCR and electrophoresis. Then the PCR product was sequenced to determine the mutations.
RESULTS
In the present study, no oseltamivir resistance-related mutations were detected. Still, NA gene showed variations compared to the vaccine strains. In A/H1N1, a total of 43 mutations were detected. Similarly, in A/H3N2, a total of 66 mutations were observed. In all isolates of H1N1, N200S, N248D and I321V mutations were detected in the antigenic site of NA protein, which can affect vaccine incompatibility and virus escape from the host's immune system. Also, H150R mutation was observed in the NA active site of H3N2, which is the cause of agglutination by NA protein. Also, S245N mutation was identified as a new N-Glycosylation site of H3N2 subtype.
CONCLUSIONS
The study of NA gene sequences revealed no oseltamivir resistance mutations. In H1N1 isolates, ca. 97% identities and in the H3N2 subtype, 96% identities were observed compared to reference isolate of 2009, which indicates the importance of constant monitoring of the emergence of the drug resistance mutations.
Topics: Humans; Influenza, Human; Neuraminidase; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Iran; Cross-Sectional Studies; Oseltamivir; Mutation; Vaccines
PubMed: 37992963
DOI: 10.1016/j.jgar.2023.10.025 -
Journal of Enzyme Inhibition and... Dec 2023Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH position of oseltamivir to occupy 150-cavity contributes to...
Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound bearing 4-(()-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.
Topics: Oseltamivir; Neuraminidase; Molecular Docking Simulation; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H1N1 Subtype; Glycoside Hydrolases
PubMed: 37955306
DOI: 10.1080/14756366.2023.2277135 -
Frontiers in Immunology 2023Influenza A, the most common subtype, induces 3 to 5 million severe infections and 250,000 to 500,000 deaths each year. Vaccination is traditionally considered to be the... (Review)
Review
Influenza A, the most common subtype, induces 3 to 5 million severe infections and 250,000 to 500,000 deaths each year. Vaccination is traditionally considered to be the best way to prevent influenza A. Yet because the Influenza A virus (IAV) is highly susceptible to antigenic drift and Antigenic shift, and because of the lag in vaccine production, this poses a significant challenge to vaccine effectiveness. Additionally, much information about the resistance of antiviral drugs, such as Oseltamivir and Baloxavir, has been reported. Therefore, the search for alternative therapies in the treatment of influenza is warranted. Recent studies have found that regulating the gut microbiota (GM) can promote the immune effects of anti-IAV via the gut-lung axis. This includes promoting IAV clearance in the early stages of infection and reducing inflammatory damage in the later stages. In this review, we first review the specific alterations in GM observed in human as well as animal models regarding IAV infection. Then we analyzed the effect of GM on host immunity against IAV, including innate immunity and subsequent adaptive immunity. Finally, our study also summarizes the effects of therapies using probiotics, prebiotics, or herbal medicine in influenza A on intestinal microecological composition and their immunomodulatory effects against IAV.
Topics: Animals; Humans; Influenza, Human; Orthomyxoviridae Infections; Gastrointestinal Microbiome; Lung; Influenza A virus
PubMed: 37928517
DOI: 10.3389/fimmu.2023.1147724 -
Clinical and Translational Science Jan 2024Kidney function-adjusted drug dosing is currently based solely on the estimated glomerular filtration rate (GFR), however, kidney drug handling is accomplished by a...
Kidney function-adjusted drug dosing is currently based solely on the estimated glomerular filtration rate (GFR), however, kidney drug handling is accomplished by a combination of filtration, tubular secretion, and re-absorption. Mechanistic physiologically-based pharmacokinetic (PBPK) models recapitulate anatomic compartments to predict elimination from estimated perfusion, filtration, secretion, and re-absorption, but clinical applications are limited by a lack of empiric individual-level measurements of these functions. We adapted and validated a PBPK model to predict drug clearance from individual biomarker-based estimates of kidney perfusion and secretory clearance. We estimated organic anion transporter-mediated secretion via kynurenic acid clearance and kidney blood flow (KBF) via isovalerylglycine clearance in human participants, incorporating these measurements with GFR into the model to predict kidney drug clearance. We compared measured and model-predicted clearances of administered tenofovir and oseltamivir, which are cleared by both filtration and secretion. There were 27 outpatients (age 55 ± 15 years, mean iohexol-GFR [iGFR] 76 ± 31 mL/min/1.73 m ) in this drug clearance study. The mean observed and mechanistic model-predicted tenofovir clearances were 169 ± 102 mL/min and 163 ± 80 mL/min, respectively; estimated mean error of the mechanistic model was 37.1 mL/min (95% confidence interval [CI]: 24-52.9), compared to a mean error of 41.8 mL/min (95% CI: 25-61.6) from regression model. The mean observed and model-predicted oseltamivir carboxylate clearances were 183 ± 104 mL/min and 179 ± 89 mL/min, respectively; estimated mean error of the mechanistic model was 42.9 mL/min (95% CI: 29.7-56.4), versus error of 48.1 mL/min (95% CI: 31.2-67.3) from the regression model. Individualized estimates of tubular secretion and KBF improved the accuracy of PBPK model-predicted tenofovir and oseltamivir kidney clearances, suggesting the potential for biomarker-informed measures of kidney function to refine personalized drug dosing.
Topics: Humans; Adult; Middle Aged; Aged; Oseltamivir; Kidney; Kidney Function Tests; Glomerular Filtration Rate; Biomarkers; Tenofovir
PubMed: 37921258
DOI: 10.1111/cts.13678