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

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, 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 enrolled hospitalised patients with suspected or laboratory-confirmed influenza and compared direct-acting influenza antivirals against placebo, standard care, or another antiviral. Pairs of coauthors independently extracted data on study characteristics, patient characteristics, antiviral characteristics, and outcomes, with discrepancies resolved by discussion or by a third coauthor. Key outcomes of interest were time to alleviation of symptoms, duration of hospitalisation, admission to intensive care unit, progression to invasive mechanical ventilation, duration of mechanical ventilation, mortality, hospital discharge destination, emergence of antiviral resistance, adverse events, adverse events related to treatments, and serious adverse events. We conducted frequentist network meta-analyses to summarise the evidence and evaluated the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. This study is registered with PROSPERO, CRD42023456650. Findings Of 11 878 records identified by our search, eight trials with 1424 participants (mean age 36–60 years for trials that reported mean or median age; 43–78% male patients) were included in this systematic review, of which six were included in the network meta-analysis. The effects of oseltamivir, peramivir, or zanamivir on mortality compared with placebo or standard care without placebo for seasonal and zoonotic influenza were of very low certainty. Compared with placebo or standard care, we found low certainty evidence that duration of hospitalisation for seasonal influenza was reduced with oseltamivir (mean difference –1·63 days, 95% CI –2·81 to –0·45) and peramivir (–1·73 days, –3·33 to –0·13). Compared with standard care, there was little or no difference in time to alleviation of symptoms with oseltamivir (0·34 days, –0·86 to 1·54; low certainty evidence) or peramivir (–0·05 days, –0·69 to 0·59; low certainty evidence). There were no differences in adverse events or serious adverse events with oseltamivir, peramivir, and zanamivir (very low certainty evidence). Uncertainty remains about the effects of antivirals on other outcomes for patients with severe influenza. Due to the small number of eligible trials, we could not test for publication bias. Interpretation In hospitalised patients with severe influenza, oseltamivir and peramivir might reduce duration of hospitalisation compared with standard care or placebo, although the certainty of evidence is low. The effects of all antivirals on mortality and other important patient outcomes are very uncertain due to scarce data from randomised controlled trials. Funding World Health Organization.

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Details of risk of bias assessment
piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti.and animal experiment/ OR Radavirsen or AVI-7100 OR cap-dependent endonuclease inhibitor* OR "Baloxavir marboxil" or Baloxavir or S-033188 or Xofluza OR Umifenovir or Arbidol or Arbidole OR Amantadine or Symmetrel or Symetrel or Rimantadine orTo evaluate the risk of bias of eligible RCTs, we used a modified Cochrane risk of ).ti. (nonrandom$ not random$).ti,ab."Random field$".ti,ab.(random cluster adj3 sampl$).ti,ab.(review.ab.and review.pt.) not trial.ti."we searched".ab.and (review.ti.or review.pt.) "update review".ab.(databases adj4 searched).ab.(rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or or GS-4071 or zanamivir or relenza or "GG 167" or GG167 or GG-167 or CS-8958 or Dectova or Laninamivir or R-125489 or R125489 or "R 125489" or Inavir or peramivir or "BCX 1812" or BCX1812 or BCX-1812 or "RWJ 270201" or RWJ270201 or RWJ-270201 or Rapivab or rapiacta ) OR AB ( oseltamivir or tamiflu or "GS 4104" or GS4104 or GS-4104 or "GS 4071" or GS4071 or GS-4071 or zanamivir or relenza or "GG 167" or GG167 or GG-167 or CS-8958 or Dectova or Laninamivir or R-125489 or R125489 or "R 125489" or Inavir or peramivir or "BCX 1812" or BCX1812 or BCX-1812 or "RWJ 270201" or RWJ270201 or RWJ-270201 or Rapivab or rapiacta ) discontinuation).Pairs of reviewers independently rated each domain at the outcome level as: high, probably high, probably low, or low risk of bias.Because lack of blinding is unlikely to bias assessment of mortality, admission to ICU, progression to invasive mechanical ventilation, and emergence of antiviral resistance, we rated the blinding for these outcomes as low risk of bias, regardless of blinding status.Reviewers resolved discrepancies by discussion or, if necessary, with adjudication by a third party.Appendix 3.

Additional characteristics of eligible RCTs
5.2.

Network plot for duration of hospitalization 5.3. Network plot for time to alleviation of symptoms 5.4. Network plot for any adverse events Appendix 8. Direct, indirect, and network treatment estimates 8.1. Direct, indirect, and network treatment estimates for mortality
Comparison: treatment comparison; k: number of studies providing direct evidence; prop: direct evidence proportion; NMA: estimated treatment effect (RR) in network meta-analysis; direct: estimated treatment effect (RR) derived from direct evidence; indirect: estimated treatment effect (RR) derived from indirect evidence; RoR: Ratio of Ratios (direct versus indirect); z: z-value of test for disagreement (direct versus indirect); Incoherence p-value: p-value of test for disagreement (direct versus indirect).NA: not applicable.8.2.

Direct, indirect, and network treatment estimates for admission to ICU
z: z-value of test for disagreement (direct versus indirect); Incoherence p-value: p-value of test for disagreement (direct versus indirect).NA: not applicable.8.

Direct, indirect, and network treatment estimates for time to alleviation of symptoms
z: z-value of test for disagreement (direct versus indirect); Incoherence p-value: p-value of test for disagreement (direct versus indirect).NA: not applicable.8.

5. Direct, indirect, and network treatment estimates for any adverse events
NMA: estimated treatment effect (RR) in network meta-analysis; direct: estimated treatment effect (RR) derived from direct evidence; indirect: estimated treatment effect (RR) derived from indirect evidence; RoR: Ratio of Ratios (direct versus indirect); z: z-value of test for disagreement (direct versus indirect); Incoherence p-value: p-value of test for disagreement (direct versus indirect).NA: not applicable. 9.2.

GRADE summary of findings for time to alleviation of symptoms for different comparisons
There may be little or no difference between oseltamivir and peramivir in time to alleviation of symptoms.†Rated down 1 level for risk of bias.‡Rated down 1 level for imprecision.