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Lancet (London, England) Sep 2015
Topics: Antiviral Agents; Humans; Influenza, Human; Oseltamivir; Randomized Controlled Trials as Topic
PubMed: 26461899
DOI: 10.1016/S0140-6736(15)00202-0 -
Lancet (London, England) Sep 2015
Topics: Antiviral Agents; Humans; Influenza, Human; Oseltamivir; Randomized Controlled Trials as Topic
PubMed: 26461897
DOI: 10.1016/S0140-6736(15)00200-7 -
Antiviral Research Apr 2022A total of 3425 influenza B viruses collected from the Asia-Pacific region were tested against the four registered neuraminidase inhibitors (NAIs) (oseltamivir...
A total of 3425 influenza B viruses collected from the Asia-Pacific region were tested against the four registered neuraminidase inhibitors (NAIs) (oseltamivir carboxylate, zanamivir, peramivir and laninamivir) as part of the routine surveillance work at the WHO Collaborating Centre for Research and Reference on Influenza, Melbourne between 2016 and 2020. Forty-five influenza B viruses with reduced susceptibility to one or more NAIs were identified. While the majority of these had neuraminidase (NA) mutations that were known to confer NAIs resistance, fifteen had NA mutations that had not been confirmed as being responsible for reduced NAIs susceptibility. Eleven of these NA mutations of concern were investigated using reverse genetics (RG) techniques to verify that these mutations were the cause of the reduced NAI susceptibility. All mutations were introduced separately into the NA of B/Brisbane/27/2016 (a B Victoria-lineage virus) or B/Yamanashi/166/98 (a B Yamagata-lineage virus) and the effects of these were analysed by an in vitro NAI assay. The T146K substitution in the NA of B Victoria and Yamagata-lineages resulted in a large increase in the IC for peramivir (>1000-fold increase in the mean IC of sensitive viruses with T146) with smaller increases for zanamivir and oseltamivir. A proline substitution (T146P) had a slightly lower (>700-fold) effect on the peramivir IC and also on the other NAIs. The presence of a second NA mutation at N169S combined with the T146P further increased the IC of peramivir (>7000-fold) and the other NAIs. A synergistic effect was also confirmed for dual NA mutations with G247D + I361V which showed a modest increase in the IC for oseltamivir (6-fold). Only one of two RG-viruses with the mutation G108E could be rescued and it had a high IC against zanamivir (>4000-fold) and laninamivir (>7000-fold), but a lower IC against oseltamivir (>200-fold). NA mutations H101L, A200T, D432G, H439P and H439R were also confirmed to somewhat reduce the in vitro susceptibility of influenza B viruses to the NAIs. Overall, this study identifies the potential impact of selected mutations on the clinical performance of NAIs when used to treat influenza B infection in humans.
Topics: Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza B virus; Influenza, Human; Neuraminidase; Oseltamivir; Zanamivir
PubMed: 35304163
DOI: 10.1016/j.antiviral.2022.105280 -
Journal of Medical Virology Sep 2022H1N1 influenza has brought serious threats to people's health and a high socioeconomic burden to society. Oseltamivir, a kind of neuraminidase (NA) inhibitor, is the...
H1N1 influenza has brought serious threats to people's health and a high socioeconomic burden to society. Oseltamivir, a kind of neuraminidase (NA) inhibitor, is the second-generation specific drug that is broadly used currently. However, H1N1 influenza viruses have exhibited oseltamivir resistance in the past decades, which might be a hidden danger. To understand the frequency and distribution laws of oseltamivir-resistant viruses, we conducted a thorough and deep analysis of the available NA protein sequences of H1N1 influenza viruses worldwide from 1918 to 2020. The differences and similarities before and after 2009 were also considered since the dominant viruses changed in this period. Results showed that 3.76% of H1N1 viruses harbored oseltamivir resistance currently. Among various significative mutations, H274Y had the highest frequency of 3.30%, while the frequencies of the other mutations were far below this whether before or after 2009. The oseltamivir resistance was mainly found in three hosts, humans, swine, and avian. Different mutation sites could exhibit different distributions in each host. Our results showed that the resistance level reached a peak during the 2007-2008 influenza season and then quickly decreased in 2009. The resistance also displayed a global distribution. The densely populated countries usually had a high resistance level. However, frequent significative mutations were also found in some small countries. Our findings indicated the necessity of monitoring oseltamivir resistance around the world. The study could provide a unique perspective toward the cognition of viruses and facilitate the future study of both pandemic and drug development.
Topics: Animals; Antiviral Agents; Drug Resistance, Viral; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Mutation; Neuraminidase; Oseltamivir; Swine; Viral Proteins
PubMed: 35585032
DOI: 10.1002/jmv.27870 -
The Medical Letter on Drugs and... Oct 2023
Topics: Humans; Influenza Vaccines; Influenza, Human; Antiviral Agents; Oseltamivir; Neuraminidase; Enzyme Inhibitors
PubMed: 37871115
DOI: 10.58347/tml.2023.1687a -
PLoS Pathogens May 2022Antiviral drugs are an important measure of control for influenza in the population, particularly for those that are severely ill or hospitalised. The neuraminidase... (Review)
Review
Antiviral drugs are an important measure of control for influenza in the population, particularly for those that are severely ill or hospitalised. The neuraminidase inhibitor (NAI) class of drugs, including oseltamivir, have been the standard of care (SOC) for severe influenza illness for many years. The approval of drugs with novel mechanisms of action, such as baloxavir marboxil, is important and broadens potential treatment options for combination therapy. The use of antiviral treatments in combination for influenza is of interest; one potential benefit of this treatment strategy is that the combination of drugs with different mechanisms of action may lower the selection of resistance due to treatment. In addition, combination therapy may become an important treatment option to improve patient outcomes in those with severe illness due to influenza or those that are immunocompromised. Clinical trials increasingly evaluate drug combinations in a range of patient cohorts. Here, we summarise preclinical and clinical advances in combination therapy for the treatment of influenza with reference to immunocompromised animal models and clinical data in hospitalised patient cohorts where available. There is a wide array of drug categories in development that have also been tested in combination. Therefore, in this review, we have included polymerase inhibitors, monoclonal antibodies (mAbs), host-targeted therapies, and adjunctive therapies. Combination treatment regimens should be carefully evaluated to determine whether they provide an added benefit relative to effectiveness of monotherapy and in a variety of patient cohorts, particularly, if there is a greater chance of an adverse outcome. Safe and effective treatment of influenza is important not only for seasonal influenza infection, but also if a pandemic strain was to emerge.
Topics: Animals; Antiviral Agents; Enzyme Inhibitors; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Pyridones
PubMed: 35551301
DOI: 10.1371/journal.ppat.1010481 -
Yakugaku Zasshi : Journal of the... 2019Although the anti-influenza virus drug oseltamivir ameliorates the fever of influenza, adverse events related to its hypothermic effect have been reported. We found that... (Review)
Review
Although the anti-influenza virus drug oseltamivir ameliorates the fever of influenza, adverse events related to its hypothermic effect have been reported. We found that oseltamivir causes dose-dependent hypothermia in normal mice, and have been studying the pharmacological mechanisms responsible for 12 years. Oseltamivir blocks nicotinic cholinergic transmission at sympathetic ganglia and reduces sympathetic modulation of brown adipose tissue (BAT), a heat generator. Oseltamivir was found to target the ion channels of nicotinic acetylcholine receptors, as demonstrated by patch clamp experiments with cells expressing the human α3β4 nicotinic receptor. Metabolized oseltamivir carboxylate, which inhibits the influenza virus neuraminidase, did not elicit hypothermia and ion channel suppression. Body temperature was decreased by intracerebroventricular administration of oseltamivir. Because this hypothermic effect was inhibited by dopamine D receptor blockade, it was suggested that oseltamivir centrally stimulates the D receptor. In Japan, the package inserts for oseltamivir and amantadine indicate very similar adverse neuropsychiatric reactions for the two drugs (abnormal behavior, consciousness disturbance, convulsion, delirium, delusion, hallucination). A literature search revealed that in some previous studies, oseltamivir and amantadine were shown to block the ion channel systems and activate the dopaminergic nervous system via several mechanisms. Therefore the similarity of the adverse reactions elicited by oseltamivir and amantadine was considered attributable to their similar pharmacological effects.
Topics: Adipose Tissue, Brown; Amantadine; Animals; Antipyretics; Antiviral Agents; Body Temperature; Dose-Response Relationship, Drug; Humans; Hypothermia; Mice; Oseltamivir; Rats; Receptors, Dopamine D2; Receptors, Nicotinic
PubMed: 31061347
DOI: 10.1248/yakushi.18-00191 -
The Pediatric Infectious Disease Journal Aug 2023Advances in multiplex polymerase chain reaction (PCR) methods have enabled the simultaneous detection of multiple respiratory viruses. We aimed to estimate the clinical...
BACKGROUND
Advances in multiplex polymerase chain reaction (PCR) methods have enabled the simultaneous detection of multiple respiratory viruses. We aimed to estimate the clinical and virologic impacts of influenza and other respiratory virus co-infection in children.
METHODS
We enrolled 38 and 35 children diagnosed with influenza and treated with baloxavir marboxil (baloxavir) and oseltamivir, respectively. We performed quantitative reverse transcription-PCR to detect and measure the levels of noninfluenza viruses from 3 nasopharyngeal swab samples collected before and on days 3 and 5 after the initial antiviral dose. We assessed patients' clinical information using questionnaires.
RESULTS
One or more respiratory viruses other than influenza virus were detected in 26 (35.6%) of 73 children before antiviral treatment. The influenza virus load and clinical characteristics on the day of influenza onset were similar between children with and without virus co-infections. Of the 26 and 32 children without the emergence of the reduced baloxavir and oseltamivir susceptible variants after treatment, 8 (30.8%) and 7 (21.9%) children were dually co-infected with human rhinovirus only, respectively. The level of human rhinovirus RNA on day 0 in these children was less than -3 log 10 that of influenza virus RNA, and the human rhinovirus co-infection had no impact on the disease course either clinically or virologically.
CONCLUSIONS
When multiple respiratory viruses are detected in the same patient, it is necessary to assess clinical symptoms as well as the levels of detected viruses to determine which virus contributes to the development of illness.
Topics: Humans; Child; Influenza, Human; Oseltamivir; Coinfection; Antiviral Agents; Viruses; Virus Diseases
PubMed: 37079571
DOI: 10.1097/INF.0000000000003940 -
Viruses May 2023Although the prevalence of polymerase acidic (PA)/I38T strains of influenza virus with reduced susceptibility to baloxavir acid is low, there is a possibility of...
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.
Topics: Humans; Animals; Mice; Antiviral Agents; Oseltamivir; Influenza A virus; Oxazines; Pyridines; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H1N1 Subtype; Thiepins; Drug Resistance, Viral; Influenza, Human; Nucleotidyltransferases; Phosphates
PubMed: 37243240
DOI: 10.3390/v15051154 -
Antiviral Research Apr 2022Global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) and the polymerase acidic (PA) inhibitor (PAI) baloxavir was conducted... (Review)
Review
Global analysis of the susceptibility of influenza viruses to neuraminidase (NA) inhibitors (NAIs) and the polymerase acidic (PA) inhibitor (PAI) baloxavir was conducted by five World Health Organization Collaborating Centres for Reference and Research on Influenza during two periods (May 2018-May 2019 and May 2019-May 2020). Combined phenotypic and NA sequence-based analysis revealed that the global frequency of viruses displaying reduced or highly reduced inhibition (RI or HRI) or potential to show RI/HRI by NAIs remained low, 0.5% (165/35045) and 0.6% (159/26010) for the 2018-2019 and 2019-2020 periods, respectively. The most common amino acid substitution was NA-H275Y (N1 numbering) conferring HRI by oseltamivir and peramivir in A(H1N1)pdm09 viruses. Combined phenotypic and PA sequence-based analysis showed that the global frequency of viruses showing reduced susceptibility to baloxavir or carrying substitutions associated with reduced susceptibility was low, 0.5% (72/15906) and 0.1% (18/15692) for the 2018-2019 and 2019-2020 periods, respectively. Most (n = 61) of these viruses had I38→T/F/M/S/L/V PA amino acid substitutions. In Japan, where baloxavir use was highest, the rate was 4.5% (41/919) in the 2018-2019 period and most of the viruses (n = 32) had PA-I38T. Zoonotic viruses isolated from humans (n = 32) in different countries did not contain substitutions in NA associated with NAI RI/HRI phenotypes. One A(H5N6) virus had a dual substitution PA-I38V + PA-E199G, which may reduce susceptibility to baloxavir. Therefore, NAIs and baloxavir remain appropriate choices for the treatment of influenza virus infections, but close monitoring of antiviral susceptibility is warranted.
Topics: Amino Acid Substitution; Antiviral Agents; Dibenzothiepins; Drug Resistance, Viral; Endonucleases; Enzyme Inhibitors; Humans; Influenza A Virus, H1N1 Subtype; Influenza B virus; Influenza, Human; Morpholines; Neuraminidase; Oseltamivir; Pyridones; Triazines
PubMed: 35292289
DOI: 10.1016/j.antiviral.2022.105281