Antivirals for treatment of severe influenza: a systematic review and network meta-analysis of randomized controlled trials

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Summary Background The optimal antiviral drug for treatment of severe influenza remains unclear. To support updated WHO influenza clinical guidelines, this systematic review and network meta-analysis evaluated antivirals for treatment of patients with severe influenza. Methods We systematically searched Medline, Embase, CENTRAL, CINAHL, Global Health, Epistemonikos, and ClinicalTrials.gov for randomized controlled trials published through 20 September 2023, that enrolled hospitalized patients with suspected or laboratory-confirmed influenza and compared direct-acting influenza antivirals against placebo, standard care, or another antiviral. We conducted frequentist network meta-analyses to summarize the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We registered the protocol with PROSPERO, CRD42023456650. Findings Of 11,878 records, 8 trials with 1,424 participants were included. The effects of oseltamivir, peramivir or zanamivir on mortality compared with placebo or standard care without placebo for seasonal and zoonotic influenza are uncertain. Compared with placebo or standard care, oseltamivir (mean difference (MD) 1.63 days lower, 95% CI 2.81 lower to 0.45 lower) and peramivir (MD 1.73 days lower, 95% CI 3.33 lower to 0.13 lower) may reduce duration of hospitalization for seasonal influenza (low certainty evidence). There were few or no differences between oseltamivir (MD 0.34 days higher, 95% CI 0.86 lower to 1.54 higher; low certainty evidence), peramivir (MD 0.05 days lower, 95% CI 0.69 lower to 0.59 higher; low certainty evidence) and standard care in time to alleviation of symptoms. There were no differences in adverse events or serious adverse events among oseltamivir, peramivir and zanamivir (very low certainty evidence). Interpretation In hospitalized patients with severe influenza, oseltamivir and peramivir may reduce duration of hospitalization compared with standard care or placebo. The effects of all antivirals on mortality and other important patient outcomes are very uncertain. Funding WHO. Research in context Evidence before this study Antivirals are frequently used in the clinical management of people with severe influenza. Previous systematic reviews and meta-analyses have reported that early initiation of neuraminidase inhibitor (NAI) treatment in hospitalized influenza patients may be associated with reduced mortality and length of hospital stay compared with later or no NAI treatment. However, these pairwise meta-analyses mainly focused on the relative effects of one specific class of antivirals (NAIs), did not evaluate the effects of antivirals on severe zoonotic influenza, and did not assess the certainty of evidence. No network meta-analysis has evaluated all available antiviral treatments for severe influenza. The optimal antiviral drug for treatment of patients with severe influenza remains uncertain. Added value of this study We found low certainty evidence that oseltamivir and peramivir may reduce the duration of hospitalization in patients with severe seasonal influenza compared with placebo or standard care. Great uncertainty remains regarding the effects of oseltamivir, peramivir, and zanamivir on mortality in patients with severe seasonal influenza or zoonotic influenza. There are no important differences in adverse events or serious adverse events associated with oseltamivir, peramivir, or zanamivir for treatment of patients with severe influenza, although the evidence is of very low certainty. The effects of other antivirals, including baloxavir, in patients with severe influenza, on mortality and other important patient outcomes are very uncertain. Implications of all the available evidence Our study provides evidence that oseltamivir and peramivir, relative to placebo or standard care, may reduce the duration of hospitalization for patients with severe seasonal influenza. These findings primarily highlight the uncertainty regarding effects of antivirals for treatment of patients with severe influenza but do provide some justification for their use.