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Yonsei Medical Journal Jul 2017Peramivir is the first intravenously administered neuramidase inhibitor for immediate delivery of an effective single-dose treatment in patients with influenza. However,... (Comparative Study)
Comparative Study Meta-Analysis Review
PURPOSE
Peramivir is the first intravenously administered neuramidase inhibitor for immediate delivery of an effective single-dose treatment in patients with influenza. However, limited data are available on intravenous (IV) peramivir treatment compared to oral oseltamivir for these patients.
MATERIALS AND METHODS
With a systematic review and meta-analysis, we compared the efficacy of IV peramivir with oral oseltamivir for treatment of patients with seasonal influenza. MEDLINE, EMBASE, and Cochrane Central Register were searched for relevant clinical trials.
RESULTS
A total of seven trials [two randomized controlled trials (RCTs) and five non-randomized observational trials] involving 1676 patients were finally analyzed. The total number of peramivir- and oseltamivir-treated patients was 956 and 720, respectively. Overall, the time to alleviation of fever was lower in the peramivir-treated group compared with the oseltamivir-treated group [mean difference (MD), -7.17 hours; 95% confidence interval (CI) -11.00 to -3.34]. Especially, pooled analysis of observational studies (n=4) and studies of outpatients (n=4) demonstrated the superiority of the peramivir-treated group (MD, -7.83 hours; 95% CI -11.81 to -3.84 and MD, -7.71 hours; 95% CI -11.61 to -3.80, respectively). Mortality, length of hospital stay, change in virus titer 48 hours after admission, and the incidence of adverse events in these patients were not significantly different between the two groups.
CONCLUSION
IV peramivir therapy might reduce the time to alleviation of fever in comparison with oral oseltamivir therapy in patients with influenza; however, we could not draw clear conclusions from a meta-analysis because of the few RCTs available and methodological limitations.
Topics: Acids, Carbocyclic; Administration, Intravenous; Administration, Oral; Antiviral Agents; Cyclopentanes; Guanidines; Humans; Influenza, Human; Odds Ratio; Oseltamivir; Publication Bias; Randomized Controlled Trials as Topic; Risk Factors; Treatment Outcome
PubMed: 28540991
DOI: 10.3349/ymj.2017.58.4.778 -
Annals of Family Medicine Mar 2018Studies examining the association between use of oseltamivir and neuropsychiatric events (including suicide) among children have had mixed findings and have been limited...
PURPOSE
Studies examining the association between use of oseltamivir and neuropsychiatric events (including suicide) among children have had mixed findings and have been limited by small sample size, reliance on older data, and potential confounding. We undertook an analysis that addresses these limitations.
METHODS
Using a national administrative claims database and a case-crossover design that minimized confounding, we analyzed data from 5 contemporary influenza seasons (2009-2013) for individuals aged 1 to 18 years and ascertained oseltamivir exposure from pharmacy dispensing.
RESULTS
We identified 21,407 suicide-related events during this study period, 251 of which were in oseltamivir-exposed children. In case-crossover analysis, we did not find any significant association with suicide either for oseltamivir exposure (odds ratio = 0.64; 95% CI, 0.39-1.00; = .05) or for influenza diagnosis alone (odds ratio = 0.63; 95% CI, 0.34-1.08; = .10).
CONCLUSION
Our findings suggest that oseltamivir does not increase risk of suicide in the pediatric population.
Topics: Adolescent; Antiviral Agents; Child; Child, Preschool; Cross-Over Studies; Databases, Factual; Female; Humans; Infant; Influenza, Human; Logistic Models; Male; Odds Ratio; Oseltamivir; Suicide; United States
PubMed: 29531106
DOI: 10.1370/afm.2183 -
Postepy Higieny I Medycyny... Sep 2015Influenza virus neuraminidase inhibitors (NAIs), including oseltamivir, zanamivir and peramivir, are important antivirals for the treatment and prophylaxis of influenza.... (Review)
Review
Influenza virus neuraminidase inhibitors (NAIs), including oseltamivir, zanamivir and peramivir, are important antivirals for the treatment and prophylaxis of influenza. Increasing use of NAIs brings into focus the risk of drug resistance. The problem of resistance is of high clinical and epidemiological importance. There are generally three levels of antiviral resistance according to the way that resistance can be detected or inferred: genotypic, phenotypic and clinical resistance. Recently the problem of resistance to NAIs, although still rare (<2% of influenza isolates), has been rising. It should be underlined that NAI resistance in influenza viruses is relative, and despite its presence patients with resistant viruses may still benefit from receiving NAIs. The clinical resistance and the response to treatment with antivirals remain the most important proof of antiviral effectiveness. Currently, there has not been observed cross-resistance between oseltamivir and zanamivir, which may be a consequence of the number of given doses, differences in drug structure and duration of the drug concentrations in the site of infection. Early treatment with appropriate doses of NAI is necessary to minimize the likelihood of a resistant virus arising.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antiviral Agents; Child; Child, Preschool; Drug Resistance, Viral; Enzyme Inhibitors; Female; Humans; Infant; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Middle Aged; Neuraminidase; Oseltamivir; Young Adult; Zanamivir
PubMed: 26400894
DOI: No ID Found -
International Journal of Infectious... Jul 2008
Topics: Antiviral Agents; Female; Humans; Infant; Milk, Human; Oseltamivir
PubMed: 18243025
DOI: 10.1016/j.ijid.2007.11.009 -
BMJ (Clinical Research Ed.) Apr 2014To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
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").
DESIGN
Systematic review of regulatory information.
DATA SOURCES
Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza.
MAIN OUTCOME MEASURES
Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population.
RESULTS
From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval -0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for "pneumonia," and no clinical study reports reported laboratory or diagnostic confirmation of "pneumonia." The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined "on-treatment" and "off-treatment" periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two "pivotal" treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, -0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116).
CONCLUSIONS
In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.
Topics: Adult; Age Factors; Antiviral Agents; Child; Headache; Humans; Influenza, Human; Kidney Diseases; Nausea; Oseltamivir; Randomized Controlled Trials as Topic; Treatment Outcome; Vomiting
PubMed: 24811411
DOI: 10.1136/bmj.g2545 -
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 -
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 -
Health Technology Assessment... Feb 2009To evaluate the clinical effectiveness and incremental cost-effectiveness of amantadine, oseltamivir and zanamivir for seasonal and post-exposure prophylaxis of... (Review)
Review
OBJECTIVES
To evaluate the clinical effectiveness and incremental cost-effectiveness of amantadine, oseltamivir and zanamivir for seasonal and post-exposure prophylaxis of influenza.
DATA SOURCES
A MEDLINE search strategy was used and searches were carried out in July 2007.
REVIEW METHODS
An independent health economic model was developed based on a review of existing cost-effectiveness models and clinical advice.The model draws together a broad spectrum of evidence relating to the costs and consequences associated with influenza and its prevention. Where direct evidence concerning the effectiveness of prophylaxis within specific model subgroups was lacking, the model uses estimates from mixed subgroups or extrapolates from other mutually exclusive subgroups.
RESULTS
Twenty-six published references relating to 22 randomised controlled trials (RCTs) were included in the clinical effectiveness review, along with one unpublished report. Eight, six and nine RCTs were included for amantadine, oseltamivir and zanamivir respectively. The study quality was variable and gaps in the evidence base limited the assessment of the clinical effectiveness of the interventions. For seasonal prophylaxis, there was limited evidence for the efficacy of amantadine in preventing symptomatic, laboratory-confirmed influenza (SLCI) in healthy adults [relative risk (RR) 0.40, 95% confidence interval (CI) 0.08-2.03]. Oseltamivir was effective in preventing SLCI, particularly when used in at-risk elderly subjects (RR 0.08, 95% CI 0.01-0.63). The preventative efficacy of zanamivir was most notable in at-risk adults and adolescents (RR 0.17, 95% CI 0.07-0.44), and healthy and at-risk elderly subjects (RR 0.20, 95% CI 0.02-1.72). For post-exposure prophylaxis, data on the use of amantadine were again limited: in adolescents an RR of 0.10 (95% CI 0.03-0.34) was reported for the prevention of SLCI. Oseltamivir was effective in households of mixed composition (RR 0.19, 95% CI 0.08-0.45). The efficacy of zanamivir in post-exposure prophylaxis within households was also reported (RR 0.21, 95% CI 0.13-0.33). Interventions appeared to be well tolerated. Limited evidence was available for the effectiveness of the interventions in preventing complications and hospitalisation and in minimising length of illness and time to return to normal activities. No clinical effectiveness data were identified for health-related quality of life or mortality outcomes. With the exception of at-risk children, the incremental cost-utility of seasonal influenza prophylaxis is expected to be in the range 38,000-428,000 pounds per QALY gained (depending on subgroup). The cost-effectiveness ratios for oseltamivir and zanamivir as post-exposure prophylaxis are expected to be below 30,000 pounds per QALY gained in healthy children, at-risk children, healthy elderly and at-risk elderly individuals. Despite favourable clinical efficacy estimates, the incorporation of recent evidence of viral resistance to amantadine led to it being dominated in every economic comparison.
CONCLUSIONS
All three interventions showed some efficacy for seasonal and post-exposure prophylaxis. However, weaknesses and gaps in the clinical evidence base are directly relevant to the interpretation of the health economic model and rendered the use of advanced statistical analyses inappropriate. These data limitations should be borne in mind in interpreting the findings of the review.
Topics: Amantadine; Antiviral Agents; Cost-Benefit Analysis; Humans; Influenza, Human; Models, Economic; Oseltamivir; Practice Guidelines as Topic; Premedication; Randomized Controlled Trials as Topic; Seasons; Treatment Outcome; Zanamivir
PubMed: 19215705
DOI: 10.3310/hta13110 -
The Journal of Antimicrobial... Apr 2010Seasonal influenza viruses cause annual disease epidemics that affect individuals at low and high risk for secondary illnesses. Influenza vaccines are widely used in... (Review)
Review
Seasonal influenza viruses cause annual disease epidemics that affect individuals at low and high risk for secondary illnesses. Influenza vaccines are widely used in high-risk patients to prevent infection, but the protection afforded varies by population; uptake is also limited in some groups. Antiviral drugs for influenza are now readily available. Oseltamivir is the most widely used antiviral for the treatment and prophylaxis of seasonal influenza, and its efficacy and safety are now well established in a variety of populations. In addition to decreasing the severity and duration of the symptoms of influenza, clinical and epidemiological studies demonstrate that oseltamivir significantly reduces the frequency of secondary illnesses and exacerbation of underlying conditions; survival is also significantly improved in seriously ill patients who are hospitalized with severe influenza. Resistant viruses are isolated with a low frequency during oseltamivir treatment (0.33% in adults and 4.0% in children among almost 2000 oseltamivir-treated patients enrolled onto Roche-sponsored clinical trials of oseltamivir treatment during the oseltamivir development programme). However, an oseltamivir-resistant influenza A (H1N1) virus emerged in Europe during the 2007-08 season and circulated in the southern and northern hemispheres in 2008-09. No link with oseltamivir usage could be detected, and the clinical impact of these viruses was limited. Oseltamivir-susceptible pandemic (H1N1) 2009 viruses now predominate in many countries. Oseltamivir is generally well tolerated, with a similar adverse event profile to placebo.
Topics: Amino Acid Substitution; Antiviral Agents; Chemoprevention; Clinical Trials as Topic; Drug Resistance, Viral; Humans; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza B virus; Influenza, Human; Mutation, Missense; Oseltamivir; Seasons; Treatment Outcome
PubMed: 20215131
DOI: 10.1093/jac/dkq012 -
Antimicrobial Agents and Chemotherapy Nov 2009Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite...
Oseltamivir, a potent and selective inhibitor of influenza A and B virus neuraminidases, is a prodrug that is systemically converted into the active metabolite oseltamivir carboxylate. In light of reported neuropsychiatric events in influenza patients, including some taking oseltamivir, and as part of a full assessment to determine whether oseltamivir could contribute to, or exacerbate, such events, we undertook a series of nonclinical studies. In particular, we investigated (i) the distribution of oseltamivir and oseltamivir carboxylate in the central nervous system of rats after single intravenous doses of oseltamivir and oseltamivir carboxylate and oral doses of oseltamivir, (ii) the active transport of oseltamivir and oseltamivir carboxylate in vitro by transporters located in the blood-brain barrier, and (iii) the extent of local conversion of oseltamivir to oseltamivir carboxylate in brain fractions. In all experiments, results showed that the extent of partitioning of oseltamivir and especially oseltamivir carboxylate to the central nervous system was low. Brain-to-plasma exposure ratios were approximately 0.2 for oseltamivir and 0.01 for oseltamivir carboxylate. Apart from oseltamivir being a good substrate for the P-glycoprotein transporter, no other active transport processes were observed. The conversion of the prodrug to the active metabolite was slow and limited in human and rat brain S9 fractions. Overall, these studies indicate that the potential for oseltamivir and oseltamivir carboxylate to reach the central nervous system in high quantities is low and, together with other analyses and studies, that their involvement in neuropsychiatric events in influenza patients is unlikely.
Topics: Aged; Aged, 80 and over; Animals; Antiviral Agents; Biological Transport, Active; Brain; Carboxylesterase; Female; Humans; Liver; Male; Nucleotidyltransferases; Oseltamivir; Rats; Rats, Sprague-Dawley
PubMed: 19721074
DOI: 10.1128/AAC.01541-08