Neuraminidase inhibitors for preventing and treating influenza in children (published trials only).
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ABSTRACT:
SUBMITTER: Wang K
PROVIDER: S-EPMC6599832 | biostudies-literature | 2012 Apr
REPOSITORIES: biostudies-literature
Publications
Neuraminidase inhibitors for preventing and treating influenza in children (published trials only).
Wang Kay K Shun-Shin Matthew M Gill Peter P Perera Rafael R Harnden Anthony A
The Cochrane database of systematic reviews 20120418 4
<h4>Background</h4>During epidemics, influenza attack rates in children may exceed 40%. Options for prevention and treatment currently include the neuraminidase inhibitors zanamivir and oseltamivir. Laninamivir octanoate, the prodrug of laninamivir, is currently being developed.<h4>Objectives</h4>To assess the efficacy, safety and tolerability of neuraminidase inhibitors in the treatment and prevention of influenza in children.<h4>Search methods</h4>For this update we searched the Cochrane Centr ...[more]
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Project description:ObjectivesIn British Columbia (BC), Canada, neuraminidase inhibitors (NIs) were publicly funded during the 2009 A(H1N1)pdm09 pandemic for treatment of high-risk patients and/or anyone with moderate-to-severe illness. We assessed antiviral effectiveness (AVE) against hospitalization in that context.MethodsA population-based cohort study was conducted using linked administrative data. The cohort included all individuals living in BC during the study period (1 September to 31 December 2009) with a diagnostic code consistent with influenza or pandemic H1N1. The main study period pertained to the second-wave A(H1N1)pdm09 circulation (1 October to 31 December 2009), with sensitivity analyses around the more specific pandemic peak (18 October to 7 November). Exposure was defined by same-day NI prescription. The main outcome was all-cause hospitalization within 14 days of the outpatient influenza diagnosis. Cox proportional hazards models assessed AVE with 1 : 1 propensity-score matching and covariate adjustment.ResultsAfter matching, there were 304/58,061 NI-exposed and 345/58,061 unexposed patients hospitalized during the main study period. The very young [<6 months (35.0; 95% CI 16.7-73.4)], the old [65-79 years (13.7; 95% CI 10.1-18.6)] and the very old [?80 years (38.7; 95% CI 26.6-56.5)] had the highest hospitalization rate per 1000 patients overall. Fully adjusted AVE against all-cause hospitalization during the main study period was 16% (95% CI 2%-28%), similar to the pandemic peak (15%; 95% CI -4%-30%).ConclusionsThe use of NIs was associated with modest protection against hospitalization during the 2009 pandemic, but appeared underutilized in affected age groups with the highest hospitalization risk.
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Project description:The fight against the emergence of mutant influenza strains has led to the screening of an increasing number of compounds for inhibitory activity against influenza neuraminidase. This study explores the chemical space of neuraminidase inhibitors (NAIs), which provides an opportunity to obtain further molecular insights regarding the underlying basis of their bioactivity. In particular, a large set of 347 and 175 NAIs against influenza A and B, respectively, was compiled from the literature. Molecular and quantum chemical descriptors were obtained from low-energy conformational structures geometrically optimized at the PM6 level. The bioactivities of NAIs were classified as active or inactive according to their half maximum inhibitory concentration (IC50) value in which IC50 < 1µM and ≥ 10µM were defined as active and inactive compounds, respectively. Interpretable decision rules were derived from a quantitative structure-activity relationship (QSAR) model established using a set of substructure descriptors via decision tree analysis. Univariate analysis, feature importance analysis from decision tree modeling and molecular scaffold analysis were performed on both data sets for discriminating important structural features amongst active and inactive NAIs. Good predictive performance was achieved as deduced from accuracy and Matthews correlation coefficient values in excess of 81% and 0.58, respectively, for both influenza A and B NAIs. Furthermore, molecular docking was employed to investigate the binding modes and their moiety preferences of active NAIs against both influenza A and B neuraminidases. Moreover, novel NAIs with robust binding fitness towards influenza A and B neuraminidase were generated via combinatorial library enumeration and their binding fitness was on par or better than FDA-approved drugs. The results from this study are anticipated to be beneficial for guiding the rational drug design of novel NAIs for treating influenza infections.
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Project description:BACKGROUND: Antivirals play a critical role in the prevention and the management of influenza. One class of antivirals, neuraminidase inhibitors (NAIs), is effective against all human influenza viruses. Currently there are two NAI drugs which are licensed worldwide: oseltamivir (Tamiflu®) and zanamivir (Relenza®); and two drugs which have received recent approval in Japan: peramivir and laninamivir. Until recently, the prevalence of antiviral resistance has been relatively low. However, almost all seasonal H1N1 strains that circulated in 2008-09 were resistant to oseltamivir whereas about 1% of tested 2009 pandemic H1N1 viruses were found to be resistant to oseltamivir. To date, no studies have demonstrated widespread resistance to zanamivir. It seems likely that the literature on antiviral resistance associated with oseltamivir as well as zanamivir is now sufficiently comprehensive to warrant a systematic review.The primary objectives were to systematically review the literature to determine the incidence of resistance to oseltamivir, zanamivir, and peramivir in different population groups as well as assess the clinical consequences of antiviral resistance. METHODS: We searched MEDLINE and EMBASE without language restrictions in September 2010 to identify studies reporting incidence of resistance to oseltamivir, zanamivir, and peramivir. We used forest plots and meta-analysis of incidence of antiviral resistance associated with the three NAIs. Subgroup analyses were done across a number of population groups. Meta-analysis was also performed to evaluate associations between antiviral resistance and clinical complications and symptoms. RESULTS: We identified 19 studies reporting incidence of antiviral resistance. Meta-analysis of 15 studies yielded a pooled incidence rate for oseltamivir resistance of 2.6% (95%CI 0.7% to 5.5%). The incidence rate for all zanamivir resistance studies was 0%. Only one study measured incidence of antiviral resistance among subjects given peramivir and was reported to be 0%. Subgroup analyses detected higher incidence rates among influenza A patients, especially for H1N1 subtype influenza. Considerable heterogeneity between studies precluded definite inferences about subgroup results for immunocompromised patients, in-patients, and children. A meta-analysis of 4 studies reporting association between oseltamivir-resistance and pneumonia yielded a statistically significant risk ratio of 4.2 (95% CI 1.3 to 13.1, p = 0.02). Oseltamivir-resistance was not statistically significantly associated with other clinical complications and symptoms. CONCLUSION: Our results demonstrate that that a substantial number of patients may become oseltamivir-resistant as a result of oseltamivir use, and that oseltamivir resistance may be significantly associated with pneumonia. In contrast, zanamivir resistance has been rarely reported to date.
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Project description:IntroductionInfluenza in hospitalized intensive care unit (ICU) patients with respiratory failure is associated with 25% mortality, despite timely oseltamivir treatment. A systematic review of randomized controlled trials (RCTs) was conducted to evaluate the efficacy and safety of alternative neuraminidase inhibitor (NAI) regimens compared to standard of care in patients hospitalized for H1N1, H3N2, or B influenza.MethodsThe Cochrane collaboration searching methods were followed in Cochrane Library, PubMed, and Web of Science databases (2009-2019). Eligibility criteria were RCTs comparing different regimens of NAIs in hospitalized patients (at least 1 year old) for clinically diagnosed influenza (H1N1, H3N2, or B). Pre-defined endpoints were time to clinical resolution (TTCR), overall mortality, hospital discharge, viral clearance, drug-related adverse events (AEs), and serious adverse events.ResultsSeven trials (1579 patients) were included. Two trials compared two regimens of oral oseltamivir therapy, and one trial compared two regimens of intravenous zanamivir therapy vs oral oseltamivir therapy. Four trials focused on intravenous peramivir therapy: two trials compared two different regimens and two trials compared two different regimens vs oral oseltamivir therapy. Overall, the different regimens were well tolerated, with no significant differences in AEs; nonetheless non-significant differences were reported among different regimens regarding TTCR, mortality, and viral clearance.ConclusionHigher compared to standard doses of NAIs or systemic peramivir therapy compared to oral oseltamivir therapy did not demonstrate benefit.
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