The Lancet: Antivirals for Post-Exposure Prophylaxis & Treatment of Influenza

 

#18,264

During the opening months of the 2020 COVID pandemic we found ourselves with few pharmaceutical options, since the first coronavirus vaccine wouldn't become widely available until early 2021, and the first experimental monoclonal antibody (Bamlanivimab) didn't receive a EUA until November 2020.

Available treatment was mainly supportive (ventilation, O2, IV fluids, etc.) with a few desperate attempts to incorporate `off-label' drugs, many of which proved to be of little value (see WHO Solidarity Therapeutics Trial: Remdesivir, HCQ, Lopinar/Ritonavir & Interferon Disappoint).

While we might have to wait 6 months or longer for a strain-specific flu vaccine, in an influenza pandemic we already have a range of antivirals in stock, including Oseltamivir (Tamiflu) and the newer Baloxavir (Xofluza). 

Granted, supplies are limited (see CIDRAP report Half of US states had antiviral shortages in 2022-23 flu season) and anti-viral resistance is always a concern (see EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition), but there are also questions of just how effective these drugs really are.

While there is a good deal of anecdotal evidence (from observational studies) to support their use, more compelling data - from randomized controlled trials (RCTs) - is limited.  Such studies can be difficult to mount since it would be unethical to deny potentially life-saving antivirals to a `placebo group'. 

Since `purists' often dismiss observational studies as being unreliable, the evidence we have for - or against - their use is often considered `weak'.  

Despite these gaps in our knowledge the CDC (and other public health agencies) continue to urge early treatment with influenza antivirals for severe seasonal and novel flu infections.

CDC Interim Guidance on the Use of Antiviral Medications for Treatment of Human Infections with Novel Influenza A Viruses Associated with Severe Human Disease). 

In an attempt to better quantify the available evidence, on Friday The Lancet published two reports on antiviral effectiveness as both a treatment and a post-exposure prophylaxis. 

The first, and shorter of the two, is the following editorial which cites evidence that  `. . . oseltamivir and peramivir, relative to placebo or standard care, might reduce the length of hospitalisation for patients with severe seasonal influenza . . .', but also cautions that `Many knowledge gaps remain that need to be filled.'

Antiviral treatment and prophylaxis for influenza

David S C Hui

Published:August 24, 2024 DOI:https://doi.org/10.1016/S0140-6736(24)01698-2

The larger analysis (excerpts below), looks primarily at the use of antivirals as a post-exposure prophylaxis, although it discusses treatment as well.  I've reproduced the summary and interpretation, but you'll want to follow the link for the details.

Antivirals for post-exposure prophylaxis of influenza: a systematic review and network meta-analysis

Yunli Zhao, MD,Ya Gao, PhD, Prof Gordon Guyatt, MD, Prof Timothy M Uyeki, MD, Ping Liu, MD, Ming Liu, MD et al.

Summary

Background

Antiviral post-exposure prophylaxis with neuraminidase inhibitors can reduce the incidence of influenza and the risk of symptomatic influenza, but the efficacy of the other classes of antiviral remains unclear. To support an update of WHO influenza guidelines, this systematic review and network meta-analysis evaluated antiviral drugs for post-exposure prophylaxis of influenza.

Methods

We systematically searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos, and ClinicalTrials.gov for randomised controlled trials published up to Sept 20, 2023 that evaluated the efficacy and safety of antivirals compared with another antiviral or placebo or standard care for prevention of influenza. Pairs of reviewers independently screened studies, extracted data, and assessed the risk of bias. We performed network meta-analyses with frequentist random effects model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. The outcomes of interest were symptomatic or asymptomatic infection, admission to hospital, all-cause mortality, adverse events related to antivirals, and serious adverse events. This study is registered with PROSPERO, CRD42023466450.

Findings

Of 11 845 records identified by our search, 33 trials of six antivirals (zanamivir, oseltamivir, laninamivir, baloxavir, amantadine, and rimantadine) that enrolled 19 096 individuals (mean age 6·75–81·15 years) were included in this systematic review and network meta-analysis. Most of the studies were rated as having a low risk of bias.

Zanamivir, oseltamivir, laninamivir, and baloxavir probably achieve important reductions in symptomatic influenza in individuals at high risk of severe disease (zanamivir: risk ratio 0·35, 95% CI 0·25–0·50; oseltamivir: 0·40, 0·26–0·62; laninamivir: 0·43, 0·30–0·63; baloxavir: 0·43, 0·23–0·79; moderate certainty) when given promptly (eg, within 48 h) after exposure to seasonal influenza.

These antivirals probably do not achieve important reductions in symptomatic influenza in individuals at low risk of severe disease when given promptly after exposure to seasonal influenza (moderate certainty). 

Zanamivir, oseltamivir, laninamivir, and baloxavir might achieve important reductions in symptomatic zoonotic influenza in individuals exposed to novel influenza A viruses associated with severe disease in infected humans when given promptly after exposure (low certainty).

Oseltamivir, laninamivir, baloxavir, and amantadine probably decrease the risk of all influenza (symptomatic and asymptomatic infection; moderate certainty). Zanamivir, oseltamivir, laninamivir, and baloxavir probably have little or no effect on prevention of asymptomatic influenza virus infection or all-cause mortality (high or moderate certainty). Oseltamivir probably has little or no effect on admission to hospital (moderate certainty). All six antivirals do not significantly increase the incidence of drug-related adverse events or serious adverse events, although the certainty of evidence varies.

Interpretation

Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir probably decreases the risk of symptomatic seasonal influenza in individuals at high risk for severe disease after exposure to seasonal influenza viruses. 

Post-exposure prophylaxis with zanamivir, oseltamivir, laninamivir, or baloxavir might reduce the risk of symptomatic zoonotic influenza after exposure to novel influenza A viruses associated with severe disease in infected humans.

Funding

World Health Organization.

Research in context

Evidence before this study

Antivirals can be used to prevent influenza in people who have been in close contact with people or animals infected with influenza viruses. Although previous systematic reviews have found that antivirals (oseltamivir or zanamivir) are effective in preventing symptomatic influenza, these reviews assessed selected antivirals and did not rate the quality of evidence or consider the importance of effects in their interpretation. Additionally, a randomised controlled trial of baloxavir for influenza post-exposure prophylaxis was not included in previous reviews.

Added value of this study

This systematic review and network meta-analysis of randomised controlled trials evaluating antiviral post-exposure prophylaxis for influenza was performed to support a WHO guideline development panel in formulating recommendations on the use of antivirals for influenza. We present analyses of the efficacy of antiviral post-exposure prophylaxis to prevent symptomatic influenza for high-risk or low-risk populations and to prevent symptomatic zoonotic influenza.

We found evidence of moderate certainty that zanamivir, oseltamivir, laninamivir, and baloxavir probably reduce the risk of symptomatic seasonal influenza in individuals at high risk when administered promptly after exposure (eg, within 48 h) after exposure, but probably have little or no important effect in low-risk populations.

Rimantadine probably has little or no effect on symptomatic seasonal influenza A virus infection (moderate certainty).

Zanamivir, oseltamivir, laninamivir, and baloxavir might decrease the risk of symptomatic zoonotic influenza (low certainty). We found little evidence that amantadine prevents influenza A virus infection. We found no important impact on adverse events with any of these antivirals.

Implications of all the available evidence

The findings of this systematic review and network meta-analysis support use of zanamivir, oseltamivir, laninamivir, or baloxavir for post-exposure prophylaxis of seasonal influenza in individuals at high risk of severe influenza, and also provide some support for the use of these antivirals for post-exposure prophylaxis of zoonotic influenza.

The findings do not support using these antivirals among low-risk populations for post-exposure prophylaxis of seasonal influenza and do not support the use of amantadine or rimantadine for preventing symptomatic influenza A virus infection.

         (Continue . . . )

Last May these same authors published a preprint (Antivirals for treatment of severe influenza: a systematic review and network meta-analysis of randomized controlled trials) which focused on the limited RCT data on antiviral treatment which is now available on The Lancet.

Despite this dearth of gold standard RCT data, observational studies continue to suggest that antiviral drugs such as Oseltamivir (aka Tamiflu ®), Zanamivir, Peramivir, and the relative newcomer Baloxavir - if taken within the first 48 hours of symptom onset - can reduce the both the length and severity of symptoms in adults and children.

While influenza antivirals are far from being a `cure', I personally would not hesitate to take them for seasonal or novel influenza.  For many patients, even a modest reduction in viral load, or duration of illness, may mean the difference between life and death.

And during a pandemic, even a small advantage is worth having.