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The Cochrane Database of Systematic... Apr 2014Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide.
OBJECTIVES
To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments.
SEARCH METHODS
We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database.
SELECTION CRITERIA
Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza.
DATA COLLECTION AND ANALYSIS
We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers.
MAIN RESULTS
We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported. Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children. Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children. Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I(2) statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I(2) = 0%). Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116).
AUTHORS' CONCLUSIONS
Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.
Topics: Adult; Antiviral Agents; Child; Drug Evaluation; Enzyme Inhibitors; Europe; Health Status; Humans; Influenza, Human; Japan; Legislation, Drug; Neuraminidase; Oseltamivir; Pneumonia; Publication Bias; Randomized Controlled Trials as Topic; United Kingdom; United States; Zanamivir
PubMed: 24718923
DOI: 10.1002/14651858.CD008965.pub4 -
Cold Spring Harbor Perspectives in... Jan 2022The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic)... (Review)
Review
The neuraminidase (NA) of influenza A and B viruses plays a distinct role in viral replication and has a highly conserved catalytic site. Numerous sialic (neuraminic) acid analogs that competitively bind to the NA active site and potently inhibit enzyme activity have been synthesized and tested. Four NA inhibitors are now licensed in various parts of the world (zanamivir, oseltamivir, peramivir, and laninamivir) to treat influenza A and B infections. NA changes, naturally occurring or acquired under selective pressure, have been shown to reduce drug binding, thereby affecting the effectiveness of NA inhibitors. Drug resistance and other drawbacks have prompted the search for the next-generation NA-targeting therapeutics. One of the promising approaches is the identification of monoclonal antibodies (mAbs) targeting the conserved NA epitopes. Anti-NA mAbs demonstrate Fab-based antiviral activity supplemented with Fc-mediated immune effector functions. Antiviral Fc-conjugates offer another cutting-edge strategy that is based on a multimodal mechanism of action. These novel antiviral agents are composed of a small-molecule NA inhibitor and an Fc-region that simultaneously engages the immune system. The significant advancements made in recent years further support the value of NA as an attractive target for the antiviral development.
Topics: Antibodies, Monoclonal; Antiviral Agents; Drug Resistance, Viral; Enzyme Inhibitors; Humans; Influenza, Human; Neuraminidase; Oseltamivir; Zanamivir
PubMed: 32152244
DOI: 10.1101/cshperspect.a038455 -
Journal of Medicinal Chemistry Oct 2022Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By... (Review)
Review
Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.
Topics: Humans; Neuraminidase; Zanamivir; Oseltamivir; N-Acetylneuraminic Acid; Enzyme Inhibitors; Sialic Acids; Antiviral Agents; Biological Products
PubMed: 36252951
DOI: 10.1021/acs.jmedchem.2c01258 -
The Lancet. Respiratory Medicine May 2014Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a... (Meta-Analysis)
Meta-Analysis Review
Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.
BACKGROUND
Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection.
METHODS
We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling.
FINDINGS
We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay).
INTERPRETATION
We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection.
FUNDING
F Hoffmann-La Roche.
Topics: Adolescent; Adult; Antiviral Agents; Child; Enzyme Inhibitors; Female; Hospitalization; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Neuraminidase; Oseltamivir; Pandemics; Proportional Hazards Models; Treatment Outcome; Young Adult; Zanamivir
PubMed: 24815805
DOI: 10.1016/S2213-2600(14)70041-4 -
JAMA Network Open Aug 2021Antiviral treatment of influenza is recommended for patients with influenza-like illness during periods of community cocirculation of influenza viruses and SARS-CoV-2;... (Meta-Analysis)
Meta-Analysis
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.
Topics: Adolescent; Adult; Antiviral Agents; Child; Dibenzothiepins; Endonucleases; Enzyme Inhibitors; Female; Humans; Influenza A virus; Influenza, Human; Male; Middle Aged; Morpholines; Network Meta-Analysis; Neuraminidase; Pyridones; Randomized Controlled Trials as Topic; Seasons; Triazines; Young Adult; Zanamivir
PubMed: 34387680
DOI: 10.1001/jamanetworkopen.2021.19151 -
International Journal of Molecular... Dec 2022The use of vaccines is the most effective and reliable method for the prevention of viral infections. However, research on evaluation of effective therapeutic agents for...
The use of vaccines is the most effective and reliable method for the prevention of viral infections. However, research on evaluation of effective therapeutic agents for use in treatment after infection is necessary. Zanamivir was administered through inhalation for treatment of pandemic influenza A/H1N1 in 2009. However, the emergence of drug-resistant strains can occur rapidly. Alloferon, an immunomodulatory drug developed as an NK cell activator, exerts antiviral effects against various viruses, particularly influenza viruses. Therefore, alloferon and zanamivir were administered in combination in an effort to improve the antiviral effect of zanamivir by reducing H1N1 resistance. First, we confirmed that administration of combined treatment would result in effective inhibition of viral proliferation in MDCK and A549 cells infected with H1N1. Production of IL-6 and MIP-1α in these cells and the activity of p38 MAPK and c- that are increased by H1N1 were inhibited by combined treatment. Mice were then infected intranasally with H1N1, and examination of the antiviral efficacy of the alloferon/zanamivir combination was performed. The results showed that combined treatment after infection with H1N1 prevented weight loss, increased the survival rate, and improved lung fibrosis. Combined treatment also resulted in reduced infiltration of neutrophils and macrophages into the lungs. Combined treatment effectively inhibited the activity of p38 MAPK and c- in lung tissue, which was increased by infection with H1N1. Therefore, the combination of alloferon/zanamivir effectively prevents the development of H1N1-mediated inflammation in the lungs by inhibiting the production of inflammatory mediators and migration of inflammatory cells into lung tissue.
Topics: Animals; Humans; Mice; Antiviral Agents; Drug Resistance, Viral; Influenza A Virus, H1N1 Subtype; Neuraminidase; Oseltamivir; Zanamivir; Orthomyxoviridae Infections
PubMed: 36614125
DOI: 10.3390/ijms24010678 -
Journal of Infection and Public Health 2009The recent outbreak of human infection with a novel Swine-Origin Influenza A (H1N1) virus is spreading rapidly through sustained human-to-human transmission in multiple... (Review)
Review
The recent outbreak of human infection with a novel Swine-Origin Influenza A (H1N1) virus is spreading rapidly through sustained human-to-human transmission in multiple countries. Human-to-human transmission occurs by inhalation of infectious droplets and droplet nuclei, and by direct contact, which is facilitated by air and land travel and social gatherings. The most frequently reported symptoms are fever, cough, myalgia, and sore throat. Detailed contact and travel histories and knowledge of viral activity in community are essential for prompt case detection by the health personnel. Real-time Reverse Transcriptase-Polymerase Chain Reaction analysis of throat swabs or lower respiratory samples is a sensitive means of diagnosis. Use of oral oseltamivir may be warranted for the treatment of severe illness.
Topics: Antiviral Agents; Contact Tracing; Humans; Influenza A Virus, H1N1 Subtype; Influenza Vaccines; Influenza, Human; Oseltamivir; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Travel; Zanamivir
PubMed: 20701877
DOI: 10.1016/j.jiph.2009.08.006 -
Acta Biochimica Polonica 2014Influenza virus infection is a major source of morbidity and mortality worldwide. Due to the variable effectiveness of existing vaccines, especially in the early stages... (Review)
Review
Influenza virus infection is a major source of morbidity and mortality worldwide. Due to the variable effectiveness of existing vaccines, especially in the early stages of an epidemic, antiviral drugs represent the first line of defense against the virus. Currently, there are two major classes of anti-influenza drugs approved by the FDA for clinical use: M2 protein inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (zanamivir and oseltamivir). However, increasing resistance to these available influenza antivirals among circulating influenza viruses highlights the need to develop alternative approaches for the prevention and/or treatment of influenza. This review presents an overview of currently available drugs for influenza treatment as well as summarizes some new antiviral strategies that are now being tested covering agents targeting both the viral proteins and the host-virus interaction. We discuss their mechanisms of action, resistance and the therapeutic potential as new antiviral drug for use in future influenza pandemics. Additionally, combination therapy based on these drugs is also described.
Topics: Amantadine; Antiviral Agents; Disease Outbreaks; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Influenza A virus; Influenza, Human; Neuraminidase; Oseltamivir; Rimantadine; Viral Matrix Proteins; Zanamivir
PubMed: 25180220
DOI: No ID Found