Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.
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SUBMITTER: Jefferson T
PROVIDER: S-EPMC3981975 | biostudies-literature | 2014 Apr
REPOSITORIES: biostudies-literature
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Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments.
Jefferson Tom T Jones Mark M Doshi Peter P Spencer Elizabeth A EA Onakpoya Igho I Heneghan Carl J CJ
BMJ (Clinical research ed.) 20140409
<h4>Objective</h4>To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments ("regulatory information").<h4>Design</h4>Systematic review of regulatory information.<h4>Data sources</h4>Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.<h4>Eligibility criteria for ...[more]
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Project description:ObjectivesTo describe the potential benefits and harms of zanamivir.DesignSystematic review of clinical study reports of randomised placebo controlled trials and regulatory informationData sourcesClinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.Eligibility criteria for selecting studiesRandomised placebo controlled trials in adults and children who had confirmed or suspected exposure to natural influenza.Main outcome measuresTime to first alleviation of symptoms, influenza outcomes and complications, admissions to hospital, and adverse events in the intention to treat (ITT) population.ResultsWe included 28 trials in stage 1 (judgment of appropriate study design) and 26 in stage 2 (formal analysis). For treatment of adults, zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by 0.60 days (95% confidence interval 0.39 to 0.81, P<0.001, I(2)=9%), which equates to an average 14.4 hours' reduction, or a 10% reduction in mean duration of symptoms from 6.6 days to 6.0 days. Time to first alleviation of symptoms was shorter in all participants when any relief drugs were allowed compared with no use. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia (risk difference 0.17%, -0.73% to 0.70%) or radiologically confirmed pneumonia (-0.06%, -6.56% to 2.11%) in adults. The effect on pneumonia in children was also not significant (0.56%, -1.64% to 1.04%). There was no significant effect on otitis media or sinusitis in both adults and children, with only a small effect noted for bronchitis in adults (1.80%, 0.65% to 2.80%), but not in children. There were no data to assess effects on admissions in adults and children. Zanamivir tended to be well tolerated. In zanamivir prophylaxis studies, symptomatic influenza in individuals was significantly reduced (1.98%, (0.98% to 2.54%); reducing event rates from 3.26% to 1.27%, which means 51 people need to be treated to prevent one influenza case (95% confidence interval, 40 to 103). In contrast, the prophylaxis effect on asymptomatic influenza cases was not significant in individuals (risk difference 0.14%, -1.10% to 1.10%) or in households (1.32%, -2.20% to 3.84%). In households treated prophylactically there was an effect on symptomatic influenza (14.84%, 12.18% to 16.55%), but this was based on only two small studies including 824 participants. Prophylaxis in adults reduced unverified pneumonia (0.32%, 0.09% to 0.41%; NNTB (number needed to treat to benefit) 311, 244 to 1086) but had no effect on pneumonia in children or on bronchitis or sinusitis in adults or children (risk difference 0.32%, 0.09% to 0.41%; NNTB 311, 244 to 1086).ConclusionsBased on a full assessment of all trials conducted, zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability.
| S-EPMC3981976 | biostudies-literature
Project description:Objective: To estimate the clinical effectiveness of oseltamivir in children with different subtypes of influenza virus infection. Methods: A total of 998 children with acute respiratory infection were enrolled from January to March 2018, and were divided into influenza A, influenza B, influenza A + B, and non-influenza infection (IV-negative) groups. Influenza-like symptoms and duration of fever were evaluated and compared between oseltamivir-treated and non-treated groups. Results: There were no significant differences in the reduction in total febrile period and duration of fever from the onset of therapy between the oseltamivir treated and non-treated children infected with influenza A (p = 0.6885 for total febrile period and 0.7904 for the duration of fever from the onset of treatment), influenza B (p = 0.1462 and 0.1966), influenza A + B (p = 0.5568 and 0.9320), and IV-negative (p = 0.7631 and 0.4655). The duration of fever in children received oseltamivir therapy within 48 h was not significantly shorter than that beyond 48 h (p > 0.05). Additionally, percentages and severities of influenza-like symptoms, including headache, myalgia, fatigue, bellyache, vomiting, diarrhea, sore throat, cough, and coryza were not decreased and alleviated after treatment of oseltamivir. Conclusion: Oseltamivir treatment does not significantly shorten the duration of fever, nor does it significantly relieve influenza-like symptoms in children with infection of influenza.
| S-EPMC9020783 | biostudies-literature
Project description:BackgroundThe Cochrane risk of bias tool is a prominent instrument used to evaluate potential biases in clinical trials. In three updates of our Cochrane review on neuraminidase inhibitors, we assessed risk of bias on the same trials using different levels of detail: the trials in journal publications, in core reports, and in full clinical study reports. Here we analyse whether progressively greater amounts of information and detail in full clinical study reports (including trial protocols, statistical analysis plans, certificates of analyses, individual participant data listings and randomisation lists) affected our risk of bias assessments.Methods and findingsWe used the Cochrane risk of bias tool to assess and compare risk of bias in 14 oseltamivir trials (reported in 10 clinical study reports) obtained from the European Medicines Agency (EMA) and the manufacturer, Roche. With more detailed information, reported in clinical study reports, no previous assessment of 'high' risk of bias was reclassified as 'low' or 'unclear' in the main analysis, and over half (55%, 34/62) of the previous assessments of 'low' risk of bias were reclassified as 'high'. Most assessments of 'unclear' risk of bias (67%, or 28/42) were reclassified as 'high' risk of bias when our judgements were based on full clinical study reports. The limits of our study were our relative inexperience in dealing with large information sets, sometimes subjective bias judgements and focus on industry trials. Comparison with journal publications was not possible because of the low number of trials published.ConclusionsWe found that as information increased in the document, this increased our assessment of bias. This may mean that risk of bias has been insufficiently assessed in Cochrane reviews based on journal publications.
| S-EPMC4179405 | biostudies-literature
Project description:Immunocompromised patients are highly susceptible to influenza infection and can have prolonged viral shedding, which is a risk factor for the development of antiviral resistance.We investigated the emergence of oseltamivir-resistant influenza variants in children and young adults with cancer during the 2002-2008 influenza seasons. The demographic and clinical features of influenza infections in 12 patients who had viral isolates obtained before and after oseltamivir therapy was initiated were studied. Antiviral susceptibilities were determined by the fluorescence-based neuraminidase (NA) enzyme inhibition assay and by sequencing genes encoding NA and matrix M2 proteins.The mean age of patients was 10.5 (range, 1.1-23.0) years. Ten patients had hematologic malignancies, 4 were recipients of hematopoietic stem cell transplants, and all patients were receiving immunosuppressive therapy. Eleven patients had prolonged respiratory symptoms and 8 had prolonged viral shedding. Serial viral isolates were available for 8 of 12 patients. Oseltamivir-resistant influenza viruses were isolated from 4 children (3 influenza A [H3N2] and 1 influenza B virus): before the initiation of antiviral therapy in 2 patients and during therapy in the other 2 patients. Three resistant influenza A (H3N2) viruses shared a common E119V NA mutation. One patient was infected with oseltamivir-resistant influenza B virus (IC50, 731.86 ± 155.12 nM) that harbored a N294S NA mutation, the first report of this mutation in influenza B viruses.Oseltamivir-resistant influenza viruses can exist before or rapidly emerge during antiviral therapy in immunocompromised individuals, and this has important implications for therapy and infection control.
| S-EPMC3070406 | biostudies-literature
Project description:BackgroundDuration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding.MethodsFrom January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18-64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3.ResultsOf 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of -12.2% [-21.4%, -3.0%], P =; .010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34) in those with confirmed influenza infection.ConclusionsOseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms.Clinical trials registrationNCT01314911.
| S-EPMC7245154 | biostudies-literature
Project description:ObjectiveTo investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza.DesignDouble blind randomised trial.SettingThirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam.ParticipantsPatients aged ≥ 1 year admitted to hospital with confirmed severe influenza.InterventionsOral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent).Main outcome measureViral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five.ResultsOf 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (-5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.ConclusionsThere were no virological or clinical advantages with double dose oseltamivir compared with standard dose in patients with severe influenza admitted to hospital.RegistrationClinical Trials NCT00298233.
| S-EPMC3668094 | biostudies-literature
Project description:BackgroundChildren <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown.MethodsThe National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure.ResultsFrom 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment.ConclusionsThe appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.
| S-EPMC3563309 | biostudies-literature
Project description:BackgroundData on oseltamivir treatment among hospitalized community-acquired pneumonia (CAP) patients are limited.MethodsPatients hospitalized with CAP at 6 hospitals during the 2010-2012 influenza seasons were included. We assessed factors associated with oseltamivir treatment using logistic regression.ResultsOseltamivir treatment was provided to 89 of 1627 (5%) children (<18 years) and 143 of 1051 (14%) adults. Among those with positive clinician-ordered influenza tests, 39 of 61 (64%) children and 37 of 48 (77%) adults received oseltamivir. Among children, oseltamivir treatment was associated with hospital A (adjusted odds ratio [aOR], 2.76; 95% confidence interval [CI], 1.36-4.88), clinician-ordered testing performed (aOR, 2.44; 95% CI, 1.47-5.19), intensive care unit (ICU) admission (aOR, 2.09; 95% CI, 1.27-3.45), and age ≥2 years (aOR, 1.43; 95% CI, 1.16-1.76). Among adults, oseltamivir treatment was associated with clinician-ordered testing performed (aOR, 8.38; 95% CI, 4.64-15.12), hospitals D and E (aOR, 3.46-5.11; 95% CI, 1.75-11.01), Hispanic ethnicity (aOR, 2.06; 95% CI, 1.18-3.59), and ICU admission (aOR, 2.05; 95% CI, 1.34-3.13).ConclusionsAmong patients hospitalized with CAP during influenza season, oseltamivir treatment was moderate overall and associated with clinician-ordered testing, severe illness, and specific hospitals. Increased clinician education is needed to include influenza in the differential diagnosis for hospitalized CAP patients and to test and treat patients empirically if influenza is suspected.
| S-EPMC5413989 | biostudies-literature
Project description:BackgroundInfluenza is a common viral respiratory infection that causes epidemics and pandemics in the human population. Oseltamivir is a neuraminidase inhibitor-a new class of antiviral therapy for influenza. Although its efficacy and safety have been established, there is uncertainty regarding whether influenza-like illness (ILI) in children is best managed by oseltamivir at the onset of illness, and its cost-effectiveness in children has not been studied in China.ObjectiveTo evaluate the cost-effectiveness of post rapid influenza diagnostic test (RIDT) treatment with oseltamivir and empiric treatment with oseltamivir comparing with no antiviral therapy against influenza for children with ILI.MethodsWe developed a decision-analytic model based on previously published evidence to simulate and evaluate 1-year potential clinical and economic outcomes associated with three managing strategies for children presenting with symptoms of influenza. Model inputs were derived from literature and expert opinion of clinical practice and research in China. Outcome measures included costs and quality-adjusted life year (QALY). All the interventions were compared with incremental cost-effectiveness ratios (ICER).ResultsIn base case analysis, empiric treatment with oseltamivir consistently produced the greatest gains in QALY. When compared with no antiviral therapy, the empiric treatment with oseltamivir strategy is very cost effective with an ICER of RMB 4,438. When compared with the post RIDT treatment with oseltamivir, the empiric treatment with oseltamivir strategy is dominant. Probabilistic sensitivity analysis projected that there is a 100% probability that empiric oseltamivir treatment would be considered as a very cost-effective strategy compared to the no antiviral therapy, according to the WHO recommendations for cost-effectiveness thresholds. The same was concluded with 99% probability for empiric oseltamivir treatment being a very cost-effective strategy compared to the post RIDT treatment with oseltamivir.ConclusionIn the Chinese setting of current health system, our modelling based simulation analysis suggests that empiric treatment with oseltamivir to be a cost-saving and very cost-effective strategy in managing children with ILI.
| S-EPMC4833415 | biostudies-literature
Project description:ImportanceOseltamivir is recommended for all children hospitalized with influenza, despite limited evidence supporting its use in the inpatient setting.ObjectiveTo determine whether early oseltamivir use is associated with improved outcomes in children hospitalized with influenza.Design, setting, and participantsThis 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.ExposuresEarly oseltamivir treatment, defined as use of oseltamivir on hospital day 0 or 1.Main outcomes and measuresThe 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.ResultsThe 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 relevanceEarly 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.
| S-EPMC9486642 | biostudies-literature