Antivirals for Treatment of Influenza

Hsu, Jonathan C.; Santesso, Nancy; Mustafa, Reem A.; Brožek, Jan; Chen, Yao Long; Hopkins, Jessica; Cheung, Adrienne; Hovhannisyan, Gayane; Ivanova, Liudmila; Flottorp, Signe; Sæterdal, Ingvil; Wong, Arthur; Tian, Jianmin; Uyeki, Timothy M.; Akl, Elie A.; Alonso‐Coello, Pablo; Smaill, Fiona; Schünemann, Holger J.

doi:10.7326/0003-4819-156-7-201204030-00411

Cited by 240 publications

(93 citation statements)

References 79 publications

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“…Our findings that early initiation of NAI treatment (≤48 hours after illness onset) compared with later was associated with a significant reduction in IRP and ‘any pneumonia’ corroborate those previously reported from observational data on hospitalised influenza patients 9, 17, 19. These trends were consistently observed across multiple subgroups: laboratory‐confirmed influenza, adults, children, pregnant women and adults requiring critical care (but not children).…”

Section: Discussionsupporting

confidence: 90%

“…Neuraminidase inhibitors (NAIs), primarily oseltamivir and zanamivir, were widely recommended for patients with suspected or confirmed influenza A(H1N1)pdm09 virus infection 6, 7. However, prior to the 2009–2010 pandemic, evidence of their effectiveness in seasonal influenza, while strong for modest symptom alleviation, was less robust for reductions in pneumonia incidence or improvements in pneumonia outcome 8, 9, 10. The findings from meta‐analyses have been inconsistent.…”

Section: Introductionmentioning

confidence: 99%

“…The findings from meta‐analyses have been inconsistent. One study based on observational data from 150 660 patients with mainly seasonal influenza suggested no statistically significant reduced likelihood of pneumonia 9. Another used clinical trials data from 4452 community adult patients with uncomplicated seasonal influenza and concluded that oseltamivir significantly reduced ‘self‐reported, investigator‐mediated, unverified pneumonia’ by 45%, compared with placebo, but data on radiologically confirmed pneumonia were not available 11…”

Section: Introductionmentioning

confidence: 99%

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Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

Muthuri¹,

Venkatesan²,

Myles³

et al. 2016

Influenza Resp Viruses

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BackgroundThe impact of neuraminidase inhibitors (NAIs) on influenza‐related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection.MethodsA worldwide meta‐analysis of individual participant data from 20 634 hospitalised patients with laboratory‐confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) ‘pandemic influenza’. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids.ResultsOf 20 634 included participants, 5978 (29·0%) had IRP; conversely, 3349 (16·2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0·83 (95% CI 0·64–1·06; P = 0·136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0·72 (0·44–1·17; P = 0·180)] or likelihood of requiring ventilatory support [adj. OR = 1·17 (0·71–1·92; P = 0·537)], but early treatment versus later significantly reduced mortality [adj. OR = 0·70 (0·55–0·88; P = 0·003)] and likelihood of requiring ventilatory support [adj. OR = 0·68 (0·54–0·85; P = 0·001)].ConclusionsEarly NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

Muthuri¹,

Venkatesan²,

Myles³

et al. 2016

Influenza Resp Viruses

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“…Sudden death is another concern [5-7]. A causal association between oseltamivir use and abnormal behaviours or sudden death has not been established and it is considered negative [1,2] based on retrospective observational studies [8-12], systematic reviews of retrospective observational studies [13,14] and a systematic review and meta-analysis of randomized controlled trials of oseltamivir treatment for influenza of adults [15]. …”

Section: Introductionmentioning

confidence: 99%

The mechanisms of sudden-onset type adverse reactions to oseltamivir

Hama¹,

Bennett

2016

Acta Neurol Scand

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Oseltamivir is contraindicated for people aged 10 to 19 in principle in Japan, due to concern about abnormal behaviours. Sudden death is another concern. This review examines growing evidence of their association and discusses underlying mechanisms of these sudden-onset type reactions to oseltamivir. First the importance of animal models and the concept of human equivalent dose (HED) is summarised. Second, the specific condition for oseltamivir use: influenza infection, is reviewed. Third, findings from toxicity studies conducted prior to and after the marketing of oseltamivir are reported on to provide context on the observation of a possible causal association. Fourth, similarity and consistency of toxicity in humans with that in other animals is described. Finally, coherence of toxicokinetic and molecular-level of evidence (channels, receptors, and enzymes), including differences from the toxicity of other neuraminidase inhibitors, is reviewed. It is concluded that unchanged oseltamivir has various effects on the central nervous system (CNS) that may be related to clinical findings including hypothermia, abnormal behaviours including with fatal outcome, and sudden death. Among receptors and enzymes related to CNS action, it is known that oseltamivir inhibits nicotinic acetylcholine receptors, which are closely related to hypothermia, as well as human monoamine oxidase-A (MAO-A), which is closely related to abnormal or excitatory behaviours. Receptors such as GABAA, GABAB, and NMDA and their related receptors/channels including Na+ and Ca2+ channels are thought to be other candidates for investigation related to respiratory suppression followed by sudden death and psychotic reactions (both acute and chronic) respectively.

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“…Various observational studies have provided evidence of improved survival with prompt antiviral treatment within 48 hours of influenza symptom onset, however not all studies have found this clear benefit 8, 9, 10, 11. The purpose of this ecological analysis was, therefore, to examine the relationship of mortality specific to pandemic H1N1 influenza and NAI supply at the level of WHO Member States and provide further evidence of the aggregate role that NAIs may play in reducing influenza mortality in future pandemics.…”

Section: Introductionmentioning

confidence: 99%

Supply of neuraminidase inhibitors related to reduced influenza A (H1N1) mortality during the 2009–2010 H1N1 pandemic: summary of an ecological study

Miller

Rambachan

Hubbard

et al. 2013

Influenza Resp Viruses

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When the influenza A (H1N1) pandemic spread across the globe from April 2009 to August 2010, many WHO Member States used antiviral drugs, specifically neuraminidase inhibitors (NAIs) oseltamivir and zanamivir, to treat influenza patients in critical condition. Antivirals have been found to be effective in reducing severity and duration of influenza illness, and likely reduce morbidity; however, it is unclear whether NAIs used during the pandemic reduced H1N1 mortality. To assess the association between antivirals and influenza mortality, at an ecologic level, country‐level data on supply of oseltamivir and zanamivir were compared to laboratory‐confirmed H1N1 deaths (per 100 000 people) from July 2009 to August 2010 in 42 WHO Member States. From this analysis, it was found that each 10% increase in kilograms of oseltamivir, per 100 000 people, was associated with a 1·6% reduction in H1N1 mortality over the pandemic period [relative rate (RR) = 0·84 per log increase in oseltamivir supply]. Each 10% increase in kilogram of active zanamivir, per 100 000, was associated with a 0·3% reduction in H1N1 mortality (RR = 0·97 per log increase). While limitations exist in the inference that can be drawn from an ecologic evaluation, this analysis offers evidence of a protective relationship between antiviral drug supply and influenza mortality and supports a role for influenza antiviral use in future pandemics. This article summarises the original study described previously, which can be accessed through the following citation: Miller PE, Rambachan A, Hubbard RJ, Li J, Meyer AE, et al. (2012) Supply of Neuraminidase Inhibitors Related to Reduced Influenza A (H1N1) Mortality during the 2009–2010 H1N1 Pandemic: An Ecological Study. PLoS ONE 7(9): e43491.

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Antivirals for Treatment of Influenza

Cited by 240 publications

References 79 publications

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

The mechanisms of sudden-onset type adverse reactions to oseltamivir

Supply of neuraminidase inhibitors related to reduced influenza A (H1N1) mortality during the 2009–2010 H1N1 pandemic: summary of an ecological study

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