Severe InfluenzaAntivirals for Treatment of Severe Influenza: A Systematic Review and Network Meta-Analysis of Randomised Controlled Trials

Influenza typically presents with mild to moderate upper respiratory symptoms that resolve within a week. Certain populations, however — young children under five, adults aged 65 and above, pregnant women, and individuals with chronic medical conditions — carry an increased risk of developing severe illness from the infection.

In patients hospitalised with seasonal influenza, complications such as severe pneumonia, respiratory failure, multi-organ failure and secondary bacterial infection can lead to significant mortality, with case-fatality rates for adults ranging from 4% to 8%. Among immunocompromised individuals, the mortality rate can be as high as 10% to 15%. Identifying effective therapies for severe influenza is therefore essential for global public health.

Antivirals, particularly the neuraminidase inhibitors, are recommended for patients with severe influenza. Systematic reviews and meta-analyses suggest that these treatments, when administered early, may reduce mortality and shorten hospital stay. Most of that earlier work, however, focused on the relative effects of neuraminidase inhibitors alone — neglecting to assess the impact of antivirals on zoonotic influenza, or to evaluate the certainty of the evidence.

The authors searched for randomised controlled trials published up to 20 September 2023. Trials were eligible if they enrolled hospitalised patients with suspected or confirmed influenza and compared direct-acting influenza antivirals against placebo, standard care, or other antivirals.

The systematic search covered Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, Global Health, Epistemonikos and ClinicalTrials.gov.

Two coauthors independently extracted data on study characteristics, patient demographics, antiviral types and clinical outcomes, with any differences resolved by discussion or by consultation with a third coauthor.

Outcomes of interest

• Time to symptom alleviation
• Duration of hospitalisation
• ICU admission
• Progression to invasive mechanical ventilation
• Duration of mechanical ventilation
• Mortality
• Emergence of antiviral resistance
• Serious adverse events

The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.

Learn moreAntivirals for post-exposure prophylaxis of influenza: a systematic review and network meta-analysisZhao, Y., Gao, Y., Guyatt, G., Uyeki, T. M., Liu, P., Liu, M., Shen, Y., Chen, X., Luo, S., Li, X., Huang, R., & Hao, Q. (2024). Antivirals for post-exposure prophylaxis of influenza: a systematic review and network meta-analysis. Lancet (London, England), 404(10454), 764–772. https://doi.org/10.1016/S0140-6736(24)01357-6

Eight trials with 1,424 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.^1-8 The proportion of patients with laboratory-confirmed influenza ranged from 79% to 100%.

The interventions in the trials included oseltamivir, peramivir, zanamivir, rimantadine, zanamivir combined with rimantadine, and baloxavir combined with neuraminidase inhibitors. Three trials directly compared oseltamivir and peramivir to standard care or placebo.^2,3,8

The remaining five trials compared different antivirals against each other:

• Two trials compared oseltamivir with peramivir^1,5
• One trial compared oseltamivir with zanamivir⁷
• One compared zanamivir and rimantadine with rimantadine alone⁴
• One trial compared baloxavir plus neuraminidase inhibitors with neuraminidase inhibitors alone⁶

Standard care varied, based on local hospital protocols or the doctor's choice, and usually did not involve neuraminidase inhibitors.

Table 1 · Click to enlarge

Mortality

A network meta-analysis encompassing four trials evaluated the impact of oseltamivir, peramivir and zanamivir on mortality among 813 patients with severe seasonal influenza. The findings revealed a range of risk differences, indicating that these antiviral agents could potentially decrease mortality by up to 18 fewer deaths per 1,000 patients for seasonal influenza, and by as much as 232 fewer deaths per 1,000 for zoonotic influenza. Some comparisons, however, indicated a slight increase in risk, and the certainty of this evidence remains very low.^4,5,6,7,8

ICU admission

In a separate analysis focused on ICU admissions, two trials involving 235 patients with severe seasonal influenza compared the effects of oseltamivir and peramivir.^3,5 The risk differences for ICU admission varied, showing 29 fewer to 43 more admissions per 1,000 patients, again with very low certainty in the evidence.

Duration of hospitalisation

Three trials, which included a total of 226 patients suffering from severe seasonal influenza, reviewed the difference in hospital stay between patients treated with either oseltamivir or peramivir. Results indicated that oseltamivir reduced hospitalisation by an average of 1.63 days compared to standard care or placebo, while peramivir led to a reduction of 1.73 days — though again, the evidence supporting these findings is classified as low certainty.^2,5,8

Adverse events

Two trials involving a total of 752 patients assessed adverse events associated with oseltamivir, peramivir and zanamivir in severe influenza cases. The analysis showed no significant differences in the occurrence of either adverse or serious adverse events among the three antivirals.^5,7

Mechanical ventilation and resistance

One study specifically examined the outcomes related to oseltamivir or zanamivir treatment, focusing on progression to mechanical ventilation, duration of mechanical ventilation, emergence of resistance and associated adverse events. Compared to zanamivir, oseltamivir presented relative risks ranging from 1.20 to 2.89 for these outcomes, with 95% confidence intervals overlapping the null effect. The average duration of mechanical ventilation was 0.89 days longer with oseltamivir, reinforcing the very low certainty of this evidence.⁷

Combination regimens

The researchers compared the combination of baloxavir and neuraminidase inhibitors to neuraminidase inhibitors alone. This study found minimal differences in hospitalisation duration (a mean difference of 0.31 days shorter) and a slight reduction in the emergence of antiviral resistance (25 fewer cases per 1,000 patients), both supported by low-certainty evidence. Very low certainty evidence also surrounded the effects of combination treatment on ICU admissions, mechanical ventilation, mortality or adverse events when compared to neuraminidase inhibitors alone.⁶

Finally, a single trial explored the effects of combining zanamivir with rimantadine against rimantadine alone. The evidence regarding this combination's impact on hospitalisation duration, mortality and adverse events was categorised as very low certainty.⁴

Learn moreInfluenza Treatment: Limitations of Antiviral Therapy and Advantages of Drug Combination TherapyBatool, S., Chokkakula, S., & Song, M. S. (2023). Influenza Treatment: Limitations of Antiviral Therapy and Advantages of Drug Combination Therapy. Microorganisms, 11(1), 183. https://doi.org/10.3390/microorganisms11010183

Antivirals play a crucial role in managing severe influenza, and previous studies have suggested that early treatment with neuraminidase inhibitors may lower mortality and shorten hospital stay. Those analyses, however, focused primarily on neuraminidase inhibitors, did not address severe zoonotic influenza, and lacked an evaluation of evidence certainty. To date, no network meta-analysis has comprehensively assessed all antiviral treatments for severe influenza, leaving the optimal antiviral drug uncertain.

This study presents low-certainty evidence indicating that oseltamivir and peramivir may reduce the duration of hospitalisation for patients with severe seasonal influenza compared to placebo or standard care. Despite this, significant uncertainty remains about the impact of oseltamivir, peramivir and zanamivir on mortality rates in both seasonal and zoonotic influenza cases.

Importantly, no significant differences were found in adverse or serious adverse events among the three antivirals, although this conclusion too is based on very low certainty evidence. The effects of other antivirals such as baloxavir on mortality and other critical outcomes in severe influenza patients remain unclear.

Learn moreUpdated Guidelines from the World Health Organization13 September 2024: the WHO has updated its guidelines for influenza therapeutics to reflect the evolving evidence from recent randomised controlled trials.

The researchers indicate that the study had a number of limitations. Only eight eligible trials were identified, with six included in the network meta-analyses, leading to uncertainty about the effects of antivirals on severe influenza outcomes.

Sparse data prevented subgroup analyses based on secondary bacterial infection or influenza type, and there was a lack of information on individuals over 60 and on children. Most trials focused on seasonal influenza, and concerns were raised about bias arising from inadequate allocation concealment and blinding. Consequently, the certainty of evidence for all comparisons was assessed as low or very low. Future trials may enhance evidence quality, prompting periodic updates to this systematic review.

1. Chen, H. D., Wang, X., Yu, S. L., Ding, Y. H., Wang, M. L., & Wang, J. N. (2020). Clinical effectiveness of intravenous peramivir compared with oseltamivir in patients with severe influenza A with primary viral pneumonia: a randomized controlled study. Open Forum Infectious Diseases, 8(1), ofaa562. https://doi.org/10.1093/ofid/ofaa562
2. Dawood, F. S., Jara, J., Gonzalez, R., Castillo, J. M., De León, T., Estripeaut, D., Luciani, K., Sujey Brizuela, Y., Barahona, A., Cazares, R. A., Lawson, A. M., Rodriguez, M., de Viana, D., Franco, D., Castillo, M., Fry, A. M., Gubareva, L., Tamura, D., Hughes, M., Gargiullo, P., … Widdowson, M. A. (2016). A randomized, double-blind, placebo-controlled trial evaluating the safety of early oseltamivir treatment among children 0–9 years of age hospitalized with influenza in El Salvador and Panama. Antiviral Research, 133, 85–94. https://doi.org/10.1016/j.antiviral.2016.07.007
3. de Jong, M. D., Ison, M. G., Monto, A. S., Metev, H., Clark, C., O'Neil, B., Elder, J., McCullough, A., Collis, P., & Sheridan, W. P. (2014). Evaluation of intravenous peramivir for treatment of influenza in hospitalized patients. Clinical Infectious Diseases, 59(12), e172–e185. https://doi.org/10.1093/cid/ciu632
4. Ison, M. G., Gnann, J. W., Jr, Nagy-Agren, S., Treanor, J., Paya, C., Steigbigel, R., Elliott, M., Weiss, H. L., Hayden, F. G., & NIAID Collaborative Antiviral Study Group. (2003). Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antiviral Therapy, 8(3), 183–190. https://pubmed.ncbi.nlm.nih.gov/12924534/
5. Ison, M. G., Hui, D. S., Clezy, K., O'Neil, B. J., Flynt, A., Collis, P. J., Simon, T. J., & Alexander, W. J. (2013). A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. Antiviral Therapy, 18(5), 651–661. https://doi.org/10.3851/IMP2442
6. Kumar, D., Ison, M. G., Mira, J. P., Welte, T., Hwan Ha, J., Hui, D. S., Zhong, N., Saito, T., Katugampola, L., Collinson, N., Williams, S., Wildum, S., Ackrill, A., Clinch, B., & Lee, N. (2022). Combining baloxavir marboxil with standard-of-care neuraminidase inhibitor in patients hospitalised with severe influenza (FLAGSTONE): a randomised, parallel-group, double-blind, placebo-controlled, superiority trial. The Lancet Infectious Diseases, 22(5), 718–730. https://doi.org/10.1016/S1473-3099(21)00469-2
7. Marty, F. M., Vidal-Puigserver, J., Clark, C., Gupta, S. K., Merino, E., Garot, D., Chapman, M. J., Jacobs, F., Rodriguez-Noriega, E., Husa, P., Shortino, D., Watson, H. A., Yates, P. J., & Peppercorn, A. F. (2017). Intravenous zanamivir or oral oseltamivir for hospitalised patients with influenza: an international, randomised, double-blind, double-dummy, phase 3 trial. The Lancet Respiratory Medicine, 5(2), 135–146. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(16)30435-0/abstract
8. Ramirez, J., Peyrani, P., Wiemken, T., Chaves, S. S., & Fry, A. M. (2018). A randomized study evaluating the effectiveness of oseltamivir initiated at the time of hospital admission in adults hospitalized with influenza-associated lower respiratory tract infections. Clinical Infectious Diseases, 67(5), 736–742. https://doi.org/10.1093/cid/ciy163