Impact of oseltamivir treatment on influenza A and B dynamics in human volunteers

Mapping Intimacies ◽

10.1101/2020.11.13.20231357 ◽

2020 ◽

Author(s):

Kyla L. Hooker ◽

Vitaly V. Ganusov

Keyword(s):

Clinical Trials ◽

Influenza Virus ◽

Influenza A ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

Virus Shedding ◽

Viral Shedding ◽

Human Volunteers ◽

The Impact

AbstractInfluenza viruses infect millions of humans every year causing an estimated 400,000 deaths globally. Due to continuous virus evolution current vaccines provide only limited protection against the flu. Several antiviral drugs are available to treat influenza infection, and one of the most most commonly used drugs is oseltamivir (Tamiflu). While the mechanism of action of oseltamivir as a neuraminidase inhibitor is well understood, the impact of oseltamivir on influenza virus dynamics in humans has been controversial. Many clinical trials with oseltamivir have been done by pharmaceutical companies such as Roche but the results of these trials until recently have been reported as summary reports or papers. Typically, such reports included median virus shedding curves for placebo and drug-treated influenza virus infected volunteers often indicating high efficacy of the early treatment. However, median shedding curves may be not accurately representing drug impact in individual volunteers. Importantly, due to public pressure clinical trials data testing oseltamivir efficacy has been recently released in the form of redacted PDF documents. We digitized and re-analyzed experimental data on influenza virus shedding in human volunteers from three previously published trials: on influenza A (1 trial) or B viruses (2 trials). Given that not all volunteers exposed to influenza viruses actually start virus shedding we found that impact of oseltamivir on the virus shedding dynamics was dependent on i) selection of volunteers that were infected with the virus, and ii) the detection limit in the measurement assay; both of these details were not well articulated in the published studies. By assuming that any viral measurement is above the limit of detection we could match previously published data on median influenza A virus (flu A study) shedding but not on influenza B virus shedding (flu B study B) in human volunteers. Additional analyses confirmed that oseltamivir had an impact on the duration of shedding and overall shedding (defined as area under the curve) but this result was varied by the trial. Interestingly, treatment had no impact on the rates at which shedding increased or declined with time in individual volunteers. Additional analyses showed that oseltamivir impacted the kinetics of the start and end of viral shedding and in about 20-40% of volunteers treatment had no impact on viral shedding duration. Our results suggest an unusual impact of oseltamivir on influenza viruses shedding kinetics and caution about the use of published median data or data from a few individuals for inferences. Furthermore, we call for the need to publish raw data from critical clinical trials that can be then independently analyzed.

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Impact of Oseltamivir Treatment on Influenza A and B Virus Dynamics in Human Volunteers

Frontiers in Microbiology ◽

10.3389/fmicb.2021.631211 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kyla L. Hooker ◽

Vitaly V. Ganusov

Keyword(s):

Clinical Trials ◽

Influenza Virus ◽

Influenza A ◽

Influenza Viruses ◽

Influenza B ◽

Virus Dynamics ◽

Virus Shedding ◽

Viral Shedding ◽

Human Volunteers ◽

B Virus

Influenza viruses infect millions of humans every year causing an estimated 400,000 deaths globally. Due to continuous virus evolution current vaccines provide only limited protection against the flu. Several antiviral drugs are available to treat influenza infection, and one of the most commonly used drugs is oseltamivir (Tamiflu). While the mechanism of action of oseltamivir as a neuraminidase inhibitor is well-understood, the impact of oseltamivir on influenza virus dynamics in humans has been controversial. Many clinical trials with oseltamivir have been done by pharmaceutical companies such as Roche but the results of these trials until recently have been provided as summary reports or papers. Typically, such reports included median virus shedding curves for placebo and drug-treated influenza virus infected volunteers often indicating high efficacy of the early treatment. However, median shedding curves may be not accurately representing drug impact in individual volunteers. Importantly, due to public pressure clinical trials data testing oseltamivir efficacy has been recently released in the form of redacted PDF documents. We digitized and re-analyzed experimental data on influenza virus shedding in human volunteers from three previously published trials: on influenza A (1 trial) or B viruses (2 trials). Given that not all volunteers exposed to influenza viruses actually start virus shedding we found that impact of oseltamivir on the virus shedding dynamics was dependent on (i) selection of volunteers that were infected with the virus, and (ii) the detection limit in the measurement assay; both of these details were not well-articulated in the published studies. By assuming that any non-zero viral measurement is above the limit of detection we could match previously published data on median influenza A virus (flu A study) shedding but not on influenza B virus shedding (flu B study B) in human volunteers. Additional analyses confirmed that oseltamivir had an impact on the duration of shedding and overall shedding (defined as area under the curve) but this result varied by the trial. Interestingly, treatment had no impact on the rates at which shedding increased or declined with time in individual volunteers. Additional analyses showed that oseltamivir impacted the kinetics of the end of viral shedding, and in about 20–40% of volunteers that shed the virus treatment had no impact on viral shedding duration. Our results suggest an unusual impact of oseltamivir on influenza viruses shedding kinetics and caution about the use of published median data or data from a few individuals for inferences. Furthermore, we call for the need to publish raw data from critical clinical trials that can be independently analyzed.

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Haemagglutination-inhibition antibodies against influenza A and influenza B in maternal and neonatal sera

Journal of Hygiene ◽

10.1017/s0022172400053353 ◽

1978 ◽

Vol 80 (1) ◽

pp. 13-19 ◽

Cited By ~ 6

Author(s):

N. Masurel ◽

J. I. de Bruijne ◽

H. A. Beuningh ◽

H. J. A. Schouten

Keyword(s):

Influenza Virus ◽

Maternal Age ◽

Influenza A ◽

Haemagglutination Inhibition ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

B Virus ◽

Duration Of Pregnancy ◽

Pregnancy And Birth

SUMMARYHaemagglutination inhibition (HI) antibodies against the influenza viruses A/Hong Kong/8/68 (H3N2) and B/Nederland/77/66 were determined in 420 paired sera from mothers and newborns (umbilical cord sera), sampled in 1970–1.A higher concentration of antibodies against influenza A virus was found more frequently in neonatal than in maternal sera. By contrast, low titres against influenza B virus were more frequently observed in neonatal than in maternal sera. Maternal age, duration of pregnancy, and birth-weight did not affect the results of the tests.It is suggested that the titre of the newborn against an epidemic influenza virus can be predicted from that of the mother. Furthermore, the maternal titre may be an indication of the susceptibility of the newborn infant to influenza infections.

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Detection of severe acute respiratory syndrome coronavirus 2 and influenza viruses based on CRISPR-Cas12a

Experimental Biology and Medicine ◽

10.1177/1535370220963793 ◽

2020 ◽

pp. 153537022096379

Author(s):

Oraphan Mayuramart ◽

Pattaraporn Nimsamer ◽

Somruthai Rattanaburi ◽

Naphat Chantaravisoot ◽

Kritsada Khongnomnan ◽

...

Keyword(s):

Influenza Virus ◽

Severe Acute Respiratory Syndrome ◽

Influenza A ◽

Limit Of Detection ◽

Cross Reactivity ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

Influenza Virus A ◽

B Virus

Due to the common symptoms of COVID-19, patients are similar to influenza-like illness. Therefore, the detection method would be crucial to discriminate between SARS-CoV-2 and influenza virus-infected patients. In this study, CRISPR-Cas12a-based detection was applied for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A virus, and influenza B virus which would be a practical and attractive application for screening of patients with COVID-19 and influenza in areas with limited resources. The limit of detection for SARS-CoV-2, influenza A, and influenza B detection was 10, 103, and 103 copies/reaction, respectively. Moreover, the assays yielded no cross-reactivity against other respiratory viruses. The results revealed that the detection of influenza virus and SARS-CoV-2 by using RT-RPA and CRISPR-Cas12a technology reaches 96.23% sensitivity and 100% specificity for SARS-CoV-2 detection. The sensitivity for influenza virus A and B detections was 85.07% and 94.87%, respectively. In addition, the specificity for influenza virus A and B detections was approximately 96%. In conclusion, the RT-RPA with CRISPR-Cas12a assay was an effective method for the screening of influenza viruses and SARS-CoV-2 which could be applied to detect other infectious diseases in the future.

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Bacterial Sinusitis and Otitis Media following Influenza Virus Infection in Ferrets

Infection and Immunity ◽

10.1128/iai.74.5.2562-2567.2006 ◽

2006 ◽

Vol 74 (5) ◽

pp. 2562-2567 ◽

Cited By ~ 59

Author(s):

Ville T. Peltola ◽

Kelli L. Boyd ◽

Julie L. McAuley ◽

Jerold E. Rehg ◽

Jonathan A. McCullers

Keyword(s):

Influenza Virus ◽

Otitis Media ◽

Influenza A ◽

Bacterial Colonization ◽

Influenza Virus Infection ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

Complication Rates ◽

Pneumococcal Infections

ABSTRACT Streptococcus pneumoniae is the leading cause of otitis media, sinusitis, and pneumonia. Many of these infections result from antecedent influenza virus infections. In this study we sought to determine whether the frequency and character of secondary pneumococcal infections differed depending on the strain of influenza virus that preceded bacterial challenge. In young ferrets infected with influenza virus and then challenged with pneumococcus, influenza viruses of any subtype increased bacterial colonization of the nasopharynx. Nine out of 10 ferrets infected with H3N2 subtype influenza A viruses developed either sinusitis or otitis media, while only 1 out of 11 ferrets infected with either an H1N1 influenza A virus or an influenza B virus did so. These data may partially explain why bacterial complication rates are higher during seasons when H3N2 viruses predominate. This animal model will be useful for further study of the mechanisms that underlie viral-bacterial synergism.

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Clinical Evaluation of the SD Bioline Influenza Virus Antigen Test for Rapid Detection of Influenza Viruses A and B in Children and Adults during the Influenza Season

Clinical and Vaccine Immunology ◽

10.1128/cvi.00465-06 ◽

2007 ◽

Vol 14 (8) ◽

pp. 1050-1052 ◽

Cited By ~ 14

Author(s):

Young Yoo ◽

Jang Wook Sohn ◽

Dae Won Park ◽

Jeong Yeon Kim ◽

Hye Kyung Shin ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Influenza Season ◽

Virus Detection ◽

Virus Antigen ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

Antigen Test ◽

Test Kit

ABSTRACT The performance of the SD Bioline rapid antigen test kit for influenza virus detection was evaluated with 295 respiratory specimens during the influenza season. The overall sensitivity and specificity of the SD Bioline test were 61.9% and 96.8% for the influenza A virus antigen and 54.5% and 100% for the influenza B virus antigen, respectively. The results were consistent with peak influenza activities.

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AMINO ACID COMPOSITION OF HIGHLY PURIFIED VIRAL PARTICLES OF INFLUENZA A AND B

Journal of Experimental Medicine ◽

10.1084/jem.86.2.125 ◽

1947 ◽

Vol 86 (2) ◽

pp. 125-129 ◽

Cited By ~ 25

Author(s):

C. A. Knight

Keyword(s):

Amino Acids ◽

Influenza Virus ◽

Influenza A ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

Isoleucine Leucine ◽

Viral Particles ◽

B Virus ◽

Microbiological Assays

Microbiological assays for amino acids were made on hydrolysates of four to five highly purified preparations each of influenza A virus (PR8 strain) and influenza B virus (Lee strain). The results of the assays indicated that these strains of influenza virus contain approximately the same amounts of alanine, aspartic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, and valine. However, significant differences were found in the values for arginine, glutamic acid, lysine, tryptophane, and tyrosine. It is believed that these differences may provide, at least in part, a chemical explanation for some of the differing properties of the PR8 and Lee strains of influenza viruses.

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Inhibitory effects of aprotinin on influenza A and B viruses in vitro and in vivo

Scientific Reports ◽

10.1038/s41598-021-88886-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eun-Jung Song ◽

Erica Españo ◽

Sang-Mu Shim ◽

Jeong-Hyun Nam ◽

Jiyeon Kim ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Lethal Dose ◽

Influenza Viruses ◽

Influenza B Virus ◽

Influenza B ◽

Inhibitory Effects ◽

Compound Libraries ◽

Wide Range

AbstractInfluenza viruses cause significant morbidity and mortality worldwide. Long-term or frequent use of approved anti-influenza agents has resulted in drug-resistant strains, thereby necessitating the discovery of new drugs. In this study, we found aprotinin, a serine protease inhibitor, as an anti-influenza candidate through screening of compound libraries. Aprotinin has been previously reported to show inhibitory effects on a few influenza A virus (IAV) subtypes (e.g., seasonal H1N1 and H3N2). However, because there were no reports of its inhibitory effects on the other types of influenza viruses, we investigated the inhibitory effects of aprotinin in vitro on a wide range of influenza viruses, including avian and oseltamivir-resistant influenza virus strains. Our cell-based assay showed that aprotinin had inhibitory effects on seasonal human IAVs (H1N1 and H3N2 subtypes), avian IAVs (H5N2, H6N5, and H9N2 subtypes), an oseltamivir-resistant IAV, and a currently circulating influenza B virus. We have also confirmed its activity in mice infected with a lethal dose of influenza virus, showing a significant increase in survival rate. Our findings suggest that aprotinin has the capacity to inhibit a wide range of influenza virus subtypes and should be considered for development as a therapeutic agent against influenza.

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Establishment of the Haemadsorption-Based Colorimetric Assay for the Screening of Anti-Influenza Compounds

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029300400402 ◽

1993 ◽

Vol 4 (4) ◽

pp. 201-206 ◽

Cited By ~ 1

Author(s):

H. Takeuchi ◽

M. Baba ◽

S. Shigeta

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Mdck Cells ◽

Colorimetric Assay ◽

Influenza Viruses ◽

Assay System ◽

The Other ◽

Influenza B Virus ◽

Influenza B ◽

Other Hand

We established a haemadsorption-based colorimetric assay system, which may be used to screen a large number of anti-influenza compounds. Madin Darby canine kidney (MDCK) cells infected with influenza virus were cultured in the presence of test compounds and after 3 days of infection guinea pig erythrocytes (GPE) were added to infected MDCK cells. After 4 washings of the cells the adsorbed GPE were lysed with distilled water, and peroxidase activities contained in GPE were measured using o-phenylendia-mine and H2O2 as substrates. The peroxidase activity that was read as optical density of oxidized o-phenylendiamine (quinoid form) correlated well with the dose of virus and day of infection in MDCK cells. Fifty per cent inhibitory concentration (IC50) of 1-(β-D-ribofuranosyl)-1,2,4-triazole-3-carboxamide (ribavirin) and adamantanamine hydrochloride (amantadine) against influenza virus A/H3N2/lshikawa and influenza B/Singapore, the IC50s of ribavirin to influenza A and B were 0.5 μg ml−1 to 1.0 μg ml−1 respectively. On the other hand, the IC50 of amantadine for influenza A was 1 μg ml−1 but was more than 100 μg ml−1 for influenza B virus. By this method, ribavirin, 5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide (EICAR), 3-(β-D-ribofuranosyl)-4-hydroxypyrazole-5-carboxamide (pyrazofurin) have shown inhibitory effects for virus replication at lower concentrations than their cytotoxic doses. On the other hand carbocyclic citidine (carbodine) was cytotoxic at the concentration of virus inhibition. Ribavirin and pyrazofurin showed one tenth or less EC50 for influenza A and B viruses by the haemadsorption-based colorimetric assay compared with the ECso by TCID50 method. It is possible to estimate the inhibitory effect of antiviral compounds against influenza viruses rapidly and quantitatively by this colorimetric assay system.

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Influenza: An Emerging and Re-emerging Public Health Threat in Nepal

Annals of Clinical Chemistry and Laboratory Medicine ◽

10.3126/acclm.v3i2.20737 ◽

2018 ◽

Vol 3 (2) ◽

pp. 1-2

Author(s):

Bishnu Prasad Upadhyay

Keyword(s):

Influenza Virus ◽

Influenza A ◽

Winter Season ◽

Emerging Infectious Diseases ◽

Influenza Viruses ◽

Influenza B ◽

Influenza A Viruses ◽

Influenza A H1n1 ◽

New Variant ◽

Seasonal Epidemics

Influenza virus type A and B are responsible for seasonal epidemics as well as pandemics in human. Influenza A viruses are further divided into two major groups namely, low pathogenic seasonal influenza (A/H1N1, A/H1N1 pdm09, A/H3N2) and highly pathogenic influenza virus (H5N1, H5N6, H7N9) on the basis of two surface antigens: hemagglutinin (HA) and neuraminidase (NA). Mutations, including substitutions, deletions, and insertions, are one of the most important mechanisms for producing new variant of influenza viruses. During the last 30 years; more than 50 viral threat has been evolved in South-East Asian countriesof them influenza is one of the major emerging and re-emerging infectious diseases of global concern. Similar to tropical and sub-tropical countries of Southeast Asia; circulation of A/H1N1 pdm09, A/H3N2 and influenza B has been circulating throughout the year with the peak during July-November in Nepal. However; the rate of infection transmission reach peak during the post-rain and winter season of Nepal.

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