Antiviral agents such as zanamivir and baloxavir are associated with improved time to symptom alleviation for seasonal influenza

1. This network meta-analysis of randomized controlled trials (RCTs) concluded that four antiviral medications successfully reduce the duration of influenza symptoms, of which zanamivir was associated with the shortest time to alleviation of influenza symptoms (TTAS).

2. Baloxavir was associated with the lowest overall risk of influenza-related complications of the antivirals included.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Seasonal influenza is a common and potentially deadly illness in many parts of the world. Recently, Influenza A or B coinfection with the COVID-19 virus has increased the risk that each of these illnesses pose to individuals and healthcare systems globally. This systematic review and meta-analysis summarized high-quality evidence from RCTs evaluating antiviral medications recommended for influenza treatment: oseltamivir, oral baloxavir, inhaled zanamivir and intravenous peramivir. 26 studies were included with 11,897 participants in total. 15 trials were included in the analysis of antiviral efficacy for reduced symptom duration; 10mg zanamivir was associated with the shortest TTAS compared to placebo. Baloxavir reduced TTAS compared to placebo, but was the least effective of the evaluated antivirals at doing so. However, baloxavir was associated with the lowest risk of overall influenza-related complications as assessed through 21 trials, while zanamivir was associated with the highest complication rate. Finally, drug safety outcomes were assessed: Liu et al concluded that baloxavir was significantly associated with the lowest rate of treatment-related adverse events and peramivir with the highest. Sensitivity analysis was performed to remove studies with high risk of bias; this did not change the conclusions with regards to estimates of TTAS. Liu et al’s analysis of antiviral medications for the treatment of seasonal influenza provides thorough evidence for the advantages and disadvantages of several common agents. These findings are plausible given the known properties of the antiviral agents used in this study; this work strengthens the argument for early empiric treatment of influenza-like illnesses with antivirals to reduce symptom duration and complication rates with relatively few adverse events. The findings reported here are strengthened by the relatively large sample size and thorough statistical analysis. The authors conducted a rigorous evaluation of study quality & concluded that low quality studies had not introduced bias to their results. Interestingly, median TTAS durations were not reported in order to reduce bias due to missing data. Instead, hazard ratios were calculated for the relative differences in TTAS between drugs. A primary drawback of the study is the subjectivity of patient-reported data in defining influenza-like symptoms.

Click to read this study in JAMA Network Open

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In-depth [systematic review & meta-analysis]: Eligible studies were RCTs comparing neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, laninamivir) or endonuclease inhibitors (baloxavir) to each other and/or to placebo in otherwise healthy adults and children. Most trials included otherwise-healthy patients of all ages, with 12 (36%) focussing on only adults and 5 (15%) assessing only children. TTAS was defined as the time from the start of antiviral treatment to patient-reported relief of all influenza-like symptoms. Three databases were searched from their inception point until January, 2020, and data was extracted independently by two reviewers. The Cochrane Risk of Bias tool was used to assess study quality; a multivariate random effects model was used for the statistical analysis using R software. Study drugs are ranked according to shortest to longest TTAS compared with placebo, as follows: 10mg zanamivir (Hazard Ratio [HR] 0.67, 95% Confidence Interval [95CI] 0.58-0.77), 600mg peramivir (HR 0.69; 95CI, 0.54-0.88), 75mg oseltamivir (HR 0.74; 95CI, 0.70-0.79), 150 mg oseltamivir (HR 0.75; 95CI, 0.65-0.86), 300mg peramivir (HR 0.75; 95CI, 0.62-0.91), 40mg or 80mg baloxavir (HR 0.79; 95CI, 0.73-0.86). Influenza complication rates were assessed using the relative risk (RR) compared to placebo. Baloxavir (40mg or 80mg dose) was associated with a RR of 0.51 (95CI 0.32-0.80) for influenza-related complications. The RR for influenza complications amongst patients treated with zanamivir was 0.82 (95CI 0.72-0.92). An Egger test and funnel plot to assess for publication bias concluded that positive studies may have been more likely to be published.

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