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Lancet (London, England) May 2015Despite widespread use, questions remain about the efficacy of oseltamivir in the treatment of influenza. We aimed to do an individual patient data meta-analysis for all... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite widespread use, questions remain about the efficacy of oseltamivir in the treatment of influenza. We aimed to do an individual patient data meta-analysis for all clinical trials comparing oseltamivir with placebo for treatment of seasonal influenza in adults regarding symptom alleviation, complications, and safety.
METHODS
We included all published and unpublished Roche-sponsored randomised placebo-controlled, double-blind trials of 75 mg twice a day oseltamivir in adults. Trials of oseltamivir for treatment of naturally occurring influenza-like illness in adults reporting at least one of the study outcomes were eligible. We also searched Medline, PubMed, Embase, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov trials register for other relevant trials published before Jan 1, 2014 (search last updated on Nov 27, 2014). We analysed intention-to-treat infected, intention-to-treat, and safety populations. The primary outcome was time to alleviation of all symptoms analysed with accelerated failure time methods. We used risk ratios and Mantel-Haenszel methods to work out complications, admittances to hospital, and safety outcomes.
FINDINGS
We included data from nine trials including 4328 patients. In the intention-to-treat infected population, we noted a 21% shorter time to alleviation of all symptoms for oseltamivir versus placebo recipients (time ratio 0·79, 95% CI 0·74-0·85; p<0·0001). The median times to alleviation were 97·5 h for oseltamivir and 122·7 h for placebo groups (difference -25·2 h, 95% CI -36·2 to -16·0). For the intention-to-treat population, the estimated treatment effect was attenuated (time ratio 0·85) but remained highly significant (median difference -17·8 h). In the intention-to-treat infected population, we noted fewer lower respiratory tract complications requiring antibiotics more than 48 h after randomisation (risk ratio [RR] 0·56, 95% CI 0·42-0·75; p=0·0001; 4·9% oseltamivir vs 8·7% placebo, risk difference -3·8%, 95% CI -5·0 to -2·2) and also fewer admittances to hospital for any cause (RR 0·37, 95% CI 0·17-0·81; p=0·013; 0·6% oseltamivir, 1·7% placebo, risk difference -1·1%, 95% CI -1·4 to -0·3). Regarding safety, oseltamivir increased the risk of nausea (RR 1·60, 95% CI 1·29-1·99; p<0·0001; 9·9% oseltamivir vs 6·2% placebo, risk difference 3·7%, 95% CI 1·8-6·1) and vomiting (RR 2·43, 95% CI 1·83-3·23; p<0·0001; 8·0% oseltamivir vs 3·3% placebo, risk difference 4·7%, 95% CI 2·7-7·3). We recorded no effect on neurological or psychiatric disorders or serious adverse events.
INTERPRETATION
Our findings show that oseltamivir in adults with influenza accelerates time to clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admittance to hospital, but increases the occurrence of nausea and vomiting.
FUNDING
Multiparty Group for Advice on Science (MUGAS) foundation.
Topics: Adult; Aged; Antiviral Agents; Double-Blind Method; Humans; Influenza, Human; Middle Aged; Oseltamivir; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome
PubMed: 25640810
DOI: 10.1016/S0140-6736(14)62449-1 -
Anales de Pediatria May 2019Influenza is a generally a benign disease, but occasionally it can cause serious complications. There is controversy about the benefits of antiviral treatment. (Review)
Review
INTRODUCTION
Influenza is a generally a benign disease, but occasionally it can cause serious complications. There is controversy about the benefits of antiviral treatment.
OBJECTIVES
To provide some recommendations on the treatment with oseltamivir in paediatric patients with influenza, based on the best data available and valid in our environment.
METHODS
The Respiratory Infections Group of the Spanish Society of Paediatric Infectious Diseases carried out a review of the literature. The findings were analysed using the GRADE methodology, and recommendations were made.
RESULTS
The systematic use of diagnostic tests for influenza in the outpatient setting, or in the emergency room, in immunocompetent patients with a compatible clinical picture is not recommended. If the aim is to prevent serious events, the use of antivirals is not recommended for the vast majority of healthy and asthmatic patients with influenza or suspected seasonal flu. The systematic use of oseltamivir in patients admitted to hospital with influenza is not recommended. Oseltamivir treatment is recommended in any patients with influenza and pneumonia or severe illness, and critically ill patients, especially during the first 48hours of illness. The treatment of patients with risk factors is recommended, considering their underlying disease. Influenza vaccination, together with basic isolation measures, continue to be the main tool in the prevention of influenza.
CONCLUSION
In some situations, there are sufficient data to issue clear recommendations. In other situations, the data are incomplete, and only allows weak recommendations.
Topics: Adolescent; Age Factors; Antiviral Agents; Child; Critical Illness; Humans; Influenza, Human; Oseltamivir; Risk Factors; Time Factors
PubMed: 30797703
DOI: 10.1016/j.anpedi.2019.01.009 -
JAMA Internal Medicine Jan 2024Despite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Despite widespread use, summary evidence from prior meta-analyses has contradictory conclusions regarding whether oseltamivir decreases the risk of hospitalization when given to outpatients. Several large investigator-initiated randomized clinical trials have not yet been meta-analyzed.
OBJECTIVE
To assess the efficacy and safety of oseltamivir in preventing hospitalization among influenza-infected adult and adolescent outpatients.
DATA SOURCES
PubMed, Ovid MEDLINE, Embase, Europe PubMed Central, Web of Science, Cochrane Central, ClinicalTrials.gov, and WHO International Clinical Trials Registry were searched from inception to January 4, 2022.
STUDY SELECTION
Included studies were randomized clinical trials comparing oseltamivir vs placebo or nonactive controls in outpatients with confirmed influenza infection.
DATA EXTRACTION AND SYNTHESIS
In this systematic review and meta-analysis, Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed. Two independent reviewers (R.H. and É.B.C.) extracted data and assessed risk of bias using the Cochrane Risk of Bias Tool 2.0. Each effect size was pooled using a restricted maximum likelihood random effects model. The quality of evidence was graded using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework.
MAIN OUTCOMES AND MEASURES
Hospitalization was pooled as risk ratio (RR) and risk difference (RD) estimates with 95% CIs.
RESULTS
Of 2352 studies identified, 15 were included. The intention-to-treat infected (ITTi) population was comprised of 6166 individuals with 54.7% prescribed oseltamivir. Across study populations, 53.9% (5610 of 10 471) were female and the mean age was 45.3 (14.5) years. Overall, oseltamivir was not associated with reduced risk of hospitalization within the ITTi population (RR, 0.79; 95% CI, 0.48 to 1.29; RD, -0.17%; 95% CI, -0.23% to 0.48%). Oseltamivir was also not associated with reduced hospitalization in older populations (mean age ≥65 years: RR, 1.01; 95% CI, 0.21 to 4.90) or in patients considered at greater risk of hospitalization (RR, 0.65; 0.33 to 1.28). Within the safety population, oseltamivir was associated with increased nausea (RR, 1.43; 95% CI, 1.13 to 1.82) and vomiting (RR, 1.83; 95% CI, 1.28 to 2.63) but not serious adverse events (RR, 0.71; 95% CI, 0.46 to1.08).
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis among influenza-infected outpatients, oseltamivir was not associated with a reduced risk of hospitalization but was associated with increased gastrointestinal adverse events. To justify continued use for this purpose, an adequately powered trial in a suitably high-risk population is justified.
Topics: Adult; Adolescent; Humans; Female; Aged; Middle Aged; Male; Oseltamivir; Influenza, Human; Outpatients; Hospitalization; Europe
PubMed: 37306992
DOI: 10.1001/jamainternmed.2023.0699 -
JAMA Pediatrics Nov 2022Oseltamivir is recommended for all children hospitalized with influenza, despite limited evidence supporting its use in the inpatient setting.
IMPORTANCE
Oseltamivir is recommended for all children hospitalized with influenza, despite limited evidence supporting its use in the inpatient setting.
OBJECTIVE
To determine whether early oseltamivir use is associated with improved outcomes in children hospitalized with influenza.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter retrospective study included 55 799 children younger than 18 years who were hospitalized with influenza from October 1, 2007, to March 31, 2020, in 36 tertiary care pediatric hospitals who participate in the Pediatric Health Information System database. Data were analyzed from January 2021 to March 2022.
EXPOSURES
Early oseltamivir treatment, defined as use of oseltamivir on hospital day 0 or 1.
MAIN OUTCOMES AND MEASURES
The primary outcome was hospital length of stay (LOS) in calendar days. Secondary outcomes included 7-day hospital readmission, late (hospital day 2 or later) intensive care unit (ICU) transfer, and a composite outcome of in-hospital death or use of extracorporeal membrane oxygenation (ECMO). Inverse probability treatment weighting (IPTW) based on propensity scoring was used to address confounding by indication. Mixed-effects models were used to compare outcomes between children who did and did not receive early oseltamivir treatment. Outcomes were also compared within high-risk subgroups based on age, presence of a complex chronic condition, early critical illness, and history of asthma.
RESULTS
The analysis included 55 799 encounters from 36 hospitals. The median (IQR) age of the cohort was 3.61 years (1.03-8.27); 56% were male, and 44% were female. A total of 33 207 patients (59.5%) received early oseltamivir. In propensity score-weighted models, we found that children treated with early oseltamivir had shorter LOS (median 3 vs 4 days; IPTW model ratio, 0.52; 95% CI, 0.52-0.53) and lower odds of all-cause 7-day hospital readmission (3.5% vs 4.8%; adjusted odds ratio [aOR], 0.72; 95% CI, 0.66-0.77), late ICU transfer (2.4% vs 5.5%; aOR, 0.41; 95% CI, 0.37-0.46), and the composite outcome of death or ECMO use (0.9% vs 1.4%; aOR, 0.63; 95% CI, 0.54-0.73).
CONCLUSIONS AND RELEVANCE
Early use of oseltamivir in hospitalized children was associated with shorter hospital stay and lower odds of 7-day readmission, ICU transfer, ECMO use, and death. These findings support the current recommendations for oseltamivir use in children hospitalized with influenza.
Topics: Humans; Male; Female; Child; Child, Preschool; Oseltamivir; Influenza, Human; Child, Hospitalized; Retrospective Studies; Hospital Mortality; Antiviral Agents; Length of Stay; Hospitalization
PubMed: 36121673
DOI: 10.1001/jamapediatrics.2022.3261 -
Lancet (London, England) Jan 2020Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups.
METHODS
We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921.
FINDINGS
Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20-1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74-1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30-1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00-5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group.
INTERPRETATION
Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2-3 days sooner.
FUNDING
European Commission's Seventh Framework Programme.
Topics: Adolescent; Adult; Aged; Antiviral Agents; Child; Child, Preschool; Combined Modality Therapy; Europe; Female; Humans; Infant; Influenza, Human; Male; Middle Aged; Oseltamivir; Primary Health Care; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult
PubMed: 31839279
DOI: 10.1016/S0140-6736(19)32982-4 -
FEBS Open Bio Jun 2022Influenza A and B viruses are among the most prominent human respiratory pathogens. About 3-5 million severe cases of influenza are associated with 300 000-650 000... (Review)
Review
Influenza A and B viruses are among the most prominent human respiratory pathogens. About 3-5 million severe cases of influenza are associated with 300 000-650 000 deaths per year globally. Antivirals effective at reducing morbidity and mortality are part of the first line of defense against influenza. FDA-approved antiviral drugs currently include adamantanes (rimantadine and amantadine), neuraminidase inhibitors (NAI; peramivir, zanamivir, and oseltamivir), and the PA endonuclease inhibitor (baloxavir). Mutations associated with antiviral resistance are common and highlight the need for further improvement and development of novel anti-influenza drugs. A summary is provided for the current knowledge of the approved influenza antivirals and antivirals strategies under evaluation in clinical trials. Preclinical evaluations of novel compounds effective against influenza in different animal models are also discussed.
Topics: Animals; Antiviral Agents; Humans; Influenza A Virus, H1N1 Subtype; Influenza, Human; Models, Animal; Oseltamivir
PubMed: 35451200
DOI: 10.1002/2211-5463.13416 -
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 -
Science Immunology Jun 2023The immune system eliminates pathogen intruders such as viruses and bacteria. To recruit immune effectors to virus-infected cells, we conjugated a small molecule, the...
The immune system eliminates pathogen intruders such as viruses and bacteria. To recruit immune effectors to virus-infected cells, we conjugated a small molecule, the influenza neuraminidase inhibitor zanamivir, to a nanobody that recognizes the kappa light chains of mouse immunoglobulins. This adduct was designed to achieve half-life extension of zanamivir through complex formation with the much-larger immunoglobulins in the circulation. The zanamivir moiety targets the adduct to virus-infected cells, whereas the anti-kappa component simultaneously delivers polyclonal immunoglobulins of indeterminate specificity and all isotypes. Activation of antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity promoted elimination of influenza neuraminidase-positive cells. A single dose of the conjugate protected mice against influenza A or B viruses and was effective even when given several days after infection with a lethal dose of virus. In the absence of circulating immunoglobulins, we observed no in vivo protection from the adduct. The type of conjugates described here may thus find application for both anti-influenza prophylaxis and therapy.
Topics: Mice; Animals; Humans; Zanamivir; Oseltamivir; Immunoglobulin Light Chains; Neuraminidase; Influenza, Human; Mice, Inbred BALB C
PubMed: 37352373
DOI: 10.1126/sciimmunol.adg9459 -
Enzyme and Microbial Technology Oct 2023Shikimate, a precursor to the antiviral drug oseltamivir (Tamiflu®), can influence aromatic metabolites and finds extensive use in antimicrobial, antitumor, and... (Review)
Review
Shikimate, a precursor to the antiviral drug oseltamivir (Tamiflu®), can influence aromatic metabolites and finds extensive use in antimicrobial, antitumor, and cardiovascular applications. Consequently, various strategies have been developed for chemical synthesis and plant extraction to enhance shikimate biosynthesis, potentially impacting environmental conditions, economic sustainability, and separation and purification processes. Microbial engineering has been developed as an environmentally friendly approach for shikimate biosynthesis. In this review, we provide a comprehensive summary of microbial strategies for shikimate biosynthesis. These strategies primarily include chassis construction, biochemical optimization, pathway remodelling, and global regulation. Furthermore, we discuss future perspectives on shikimate biosynthesis and emphasize the importance of utilizing advanced metabolic engineering tools to regulate microbial networks for constructing robust microbial cell factories.
Topics: Antiviral Agents; Metabolic Engineering; Microbial Consortia; Oseltamivir
PubMed: 37598506
DOI: 10.1016/j.enzmictec.2023.110306 -
Seminars in Perinatology Dec 2014Pregnancy predisposes women to disproportionate morbidity and mortality from influenza infections. This is true for both seasonal epidemics as well as occasional... (Review)
Review
Pregnancy predisposes women to disproportionate morbidity and mortality from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Inactivated yearly influenza vaccines are the best available method of disease prevention and are recommended for all pregnant women in any trimester of pregnancy and postpartum. Oseltamivir (Tamiflu(®)) is currently the first-line recommended and most commonly used pharmaceutical agent for influenza prophylaxis and treatment. Oseltamivir has been demonstrated to prevent disease among exposed individuals, as well as to shorten the duration of illness and lessen the likelihood of complications among those infected. The physiologic adaptations of pregnancy may alter the pharmacokinetics and pharmacodynamics of this important drug. Updated evidence regarding these potential alterations, current knowledge gaps, and future investigative directions is discussed.
Topics: Antiviral Agents; Female; Humans; Influenza, Human; Oseltamivir; Pregnancy; Pregnancy Complications, Infectious
PubMed: 25281358
DOI: 10.1053/j.semperi.2014.08.015