Protocol and Registration
This report describes the results of the SR following the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [8]. PICO (Population, Intervention, Comparator, Outcome) questions are detailed in the supplementary material 1. The protocol was published in the National Institute for Health Research International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42018110060.
This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.
Data Sources
A global search strategy was systematically performed in three databases: MEDLINE database through the PubMed search engine, the Cochrane Library Database, and Web of Science database. Websites from ClinicalTrials.gov and clinicaltrialsregister.eu were consulted for other ongoing trials. Search terms were detailed in the supplementary material 2. Restrictions in the search were applied regarding the language: only studies published in English, Spanish, French, Italian, and Portuguese were considered. Abstracts presented at scientific conferences, unpublished studies, and other unpublished data deriving from industry sites were excluded. A restriction was also applied to the publication period of time, between 2009 and 2019, partially because before 2009 there were no diagnostic tests of influenza and also since the outbreak of A/H1N1 in 2009 [9], the use of NAIs has increased. The first search was performed in January 2019 and repeated in November 2019.
Data Extraction and Study Selection Process
Two authors (ST and LC) independently evaluated all the studies identified in the literature search by screening their titles, abstracts, and full text. In case of disagreement, a third author (CSL) independently determined eligibility. A predesigned spreadsheet was used to collect study data in a standardized way. Data extracted from each trial included were the study design, quality assessment, characteristics of the study populations, method used for confirmation of the influenza infection, characteristics of compared treatment arms, the intention to treat (ITT) population and the subgroup of patients with laboratory-confirmed influenza infection, as well as data regarding the effectiveness and safety outcomes.
Studies were considered eligible for inclusion in the SR if they were a RCT that enrolled patients older than 1 year of age, requiring hospitalization with clinically diagnosed influenza (with H1N1, H3N2, or B) or influenza-like syndrome, with or without laboratory confirmation. Pre-defined treatments for inclusion were oseltamivir (oral administration), zanamivir (oral, intravenous, or inhaled administration), peramivir (oral or intravenous administration), and laninamivir (inhaled administration). Studies involving children less than 1 year old, NAIs against other serotypes of influenza such as H5N1, pregnant women, immunocompromised patients (more than 30% of the overall population), or outpatients were excluded. Also, observational cohort studies or studies with different intervention of NAIs such as polymerase inhibitors (baloxavir marboxil) treatment were excluded.
Definitions and Outcomes
Clinically suspected influenza was defined by the presence of respiratory symptoms (sore throat, cough, nasal congestion) and fever (≥ 37.7 °C) within 48 h of study enrollment, regardless of prior symptoms duration. Influenza infection was defined by the presence of a positive polymerase chain reaction (PCR), immunofluorescence assay, or rapid antigen test (RAT) for influenza virus. The ITT population included all patients randomized to receive the respective study regimens. The influenza-positive population included only patients with confirmed influenza. Time to clinical resolution (TTCR), defined by the individual study protocol as the time from initiation of the study treatment until resolution of vital sign abnormalities (the supplementary material 3), and overall mortality were considered as the primary effectiveness outcomes of this SR. Secondary effectiveness outcome was viral clearance, defined as the proportion of influenza virus-negative patients detected by PCR on nasopharyngeal samples at 5 day. Samples analyzed with different methods (e.g., viral culture) or at different time frames were excluded from the comparison. Safety was evaluated in terms of occurrence of respiratory and/or systemic drug-related adverse events (AEs) and serious adverse events (SAEs).
Quality Assessment
Risk of bias was assessed for each included study independently by ST on the basis of the Cochrane Handbook for Systematic Reviews of Interventions [10] and using the Cochrane Review Manager 5.3 risk of bias tool which takes account of allocation sequence generation, concealment of allocation, masking of participants and investigators, incomplete outcome reporting, selective outcome reporting, and other sources of bias. Each potential source of bias was graded to determine whether studies were considered at high, low, or moderate risk of bias. In case of disagreement, a second author (CSL) independently determined the quality assessments.
Data Analysis
For categorical outcomes, the numbers of patients who had each outcome and denominator were extracted, and for continuous outcomes, sample size, mean [standard deviation (SD)], or median [interquartile range (IQR)] were extracted on the basis of the information provided within studies. Where results were not reported in the same format for analysis, we used recommended methods from the Cochrane Collaboration to extract or estimate effects including contacting study authors and using formulae for conversion of medians (IQR) to estimated mean (SD) as previously described [11].