Antivirals for Treatment of Influenza A Systematic Review and Meta-analysis of Observational Studies

McMaster University, Hamilton, Ontario, Canada.
Annals of internal medicine (Impact Factor: 17.81). 02/2012; 156(7):512-24. DOI: 10.1059/0003-4819-156-7-201204030-00411
Source: PubMed


Systematic reviews of randomized, controlled trials in patients with influenza suggest a lack of evidence about the effects of antiviral therapy on several patient-important outcomes of influenza.
To systematically review observational studies for benefits and harms of oseltamivir, zanamivir, amantadine, or rimantadine in the treatment of influenza.
MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL, SIGLE, the Chinese Biomedical Literature Database, Panteleimon, and LILACS up to November 2010; contact with pharmaceutical companies; and reference lists.
Observational studies in any language that compared single antiviral therapy with no therapy or other antiviral therapy, or that had no comparator, for influenza or influenza-like illness.
Two independent investigators extracted data. Confidence in the estimates of the obtained effects (quality of evidence) was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation approach.
74 studies fulfilled the inclusion criteria. Meta-analyses of the few studies providing effects with adjustment for confounders suggest that, in high-risk populations, oral oseltamivir may reduce mortality (odds ratio, 0.23 [95% CI, 0.13 to 0.43]; low-quality evidence), hospitalization (odds ratio, 0.75 [CI, 0.66 to 0.89]; low-quality evidence), and duration of symptoms (33 hours [CI, 21 to 45 hours]; very low-quality evidence) compared with no treatment. Earlier treatment with oseltamivir was generally associated with better outcomes. Inhaled zanamivir may lead to shorter symptom duration (23 hours [CI, 17 to 28 hours]; moderate-quality evidence) and fewer hospitalizations (odds ratio, 0.66 [CI, 0.37 to 1.18]) but more complications than no treatment. Direct comparison of oral oseltamivir and inhaled zanamivir suggests no important differences in key outcomes. Data from 1 study suggest that oral amantadine may reduce mortality and pneumonia associated with influenza A. No included study evaluated rimantadine.
Mortality was assessed in high-risk patients, and generalizability is limited. The overall body of evidence is limited by risk for confounding and selection, reporting, and publication bias.
Therapy with oral oseltamivir and inhaled zanamivir may provide a net benefit over no treatment of influenza. However, as with the randomized trials, the confidence in the estimates of the effects for decision making is low to very low. PRIMARY FUNDING SOURCES: World Health Organization and McMaster University.

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Available from: Signe Agnes Flottorp, Oct 14, 2014
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    • "According to the guidelines released based on recommendations from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC), treatment is warranted for all hospitalized patients, and for confirmed and probable outpatient cases. Treatment should ideally be initiated within 48 h of the onset of illness as it has been shown to reduce disease severity as well as mortality (Jain et al., 2009; Siston et al., 2010; Hiba et al., 2011; Kumar, 2011; Rodríguez et al., 2011; Yu et al., 2011; Chemaly et al., 2012; Hsu et al., 2012; Louie et al., 2012; Muthuri et al., 2013). However, treatment should be initiated even if 48 h has lapsed. "
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    ABSTRACT: The novel avian influenza A H7N9 virus which caused the first human infection in Shanghai, China; was reported on the 31st of March 2013 before spreading rapidly to other Chinese provinces and municipal cities. This is the first time the low pathogenic avian influenza A virus has caused human infections and deaths; with cases of severe respiratory disease with pneumonia being reported. There were 440 confirmed cases with 122 fatalities by 16 May 2014; with a fatality risk of ∼28%.The median age of patients was 61 years with a male-to-female ratio of 2.4:1. The main source of infection was identified as exposure to poultry and there is so far no definitive evidence of sustained person-to-person transmission. The neuraminidase inhibitors, namely oseltamivir, zanamivir, and peramivir; have shown good efficacy in the management of the novel H7N9 virus. Treatment is recommended for all hospitalized patients, and for confirmed and probable outpatient cases; and should ideally be initiated within 48 h of the onset of illness for the best outcome. Phylogenetic analysis found that the novel H7N9 virus is avian in origin and evolved from multiple reassortments of at least four origins. Indeed the novel H7N9 virus acquired human adaptation via mutations in its eight RNA gene segments. Enhanced surveillance and effective global control are essential to prevent pandemic outbreaks of the novel H7N9 virus.
    Frontiers in Microbiology 03/2015; 6(140):1-11. DOI:10.3389/fmicb.2015.00140 · 3.99 Impact Factor
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    • "Influenza A virus (IAV) remains a global health concern because of the emergence of novel virus subtypes or strains potentially capable of causing pandemics [1] [2] [3]. Due to high mutation rate during IAV replication, emergence of antiviral drug resistance is a major concern in influenza antiviral treatment [4], and highlights the need for new drug development. To avoid antiviral drug resistance, more attention is paid to find new targets for antiviral therapy that targeting host cell factors. "
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    ABSTRACT: Influenza A virus (IAV) assembly and budding on host cell surface plasma membrane requires actin cytoskeleton reorganization. The underlying molecular mechanism involving actin reorganization remains unclarified. In this study, we found that the natural antiviral compound petagalloyl glucose (PGG) inhibits F-actin reorganization in the host cell membrane during the late stage of IAV infection, which are associated with the suppression of total cofilin-1 level and its phosphorylation. Knock-down of cofilin-1 reduces viral yields. These findings provide the first evidence that cofilin-1 plays an important role in regulating actin reorganization during IAV assembly and budding. Copyright © 2014 Elsevier Inc. All rights reserved.
    Biochemical and Biophysical Research Communications 10/2014; 453(4). DOI:10.1016/j.bbrc.2014.10.036 · 2.30 Impact Factor
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    • "The uncertainty about the evidence-base for effectiveness of PEP with oseltamivir in nursing homes is reflected in the literature [17-24]. While acknowledging the absence of sufficient data, both the Dutch Association of Nursing Homes [25] and the Dutch National Centre for Infectious Disease Control [26] recommended in 2004 implementation of PEP with oseltamivir in nursing home units with a laboratory confirmed influenza patient, but also recommended that if PEP was used, it should be scientifically evaluated. "
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    ABSTRACT: Background Oseltamivir has been registered for use as post-exposition prophylaxis (PEP) following exposure to influenza, based on studies among healthy adults. Effectiveness among frail elderly nursing home populations still needs to be properly assessed. Methods We conducted a randomised double-blind placebo-controlled trial of PEP with either oseltamivir (75 mg once daily) or placebo among nursing home units where influenza virus was detected; analysis was unblinded. The primary outcome was laboratory-confirmed influenza among residents in units on PEP; the secondary outcome was clinical diagnosis of influenza-like illness (ILI). Results 42 nursing homes were recruited, in which 17 outbreaks occurred from 2009 through 2013, two caused by influenza virus B, the others caused by influenza virus A(H3N2). Randomisation was successful in 15 outbreaks, with a few chance differences in baseline indicators. Six outbreaks were assigned to oseltamivir and nine to placebo. Influenza virus positive secondary ILI cases were detected in 2/6 and 2/9 units respectively (ns); secondary ILI cases occurred in 2/6 units on oseltamivir, and 5/9 units on placebo (ns). Logistical challenges in ensuring timely administration were considerable. Conclusion We did not find statistical evidence that PEP with oseltamivir given to nursing home residents in routine operational settings exposed to influenza reduced the risk of new influenza infections within a unit nor that of developing ILI. Power however was limited due to far fewer outbreaks in nursing homes than expected since the 2009 pandemic. (RCT nr NL92738)
    Emerging Themes in Epidemiology 09/2014; 11(1):13. DOI:10.1186/1742-7622-11-13 · 2.59 Impact Factor
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