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

Abstract

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.

Figure 1

Study selection

Figure 2

Network plots of trials included in meta-analyses (A) Trials evaluating laboratory-confirmed symptomatic influenza. (B) Trials evaluating laboratory-confirmed influenza. The size of the circle represents the number of participants. The connecting lines represent direct comparisons. The width of the line represents the number of trials.

Figure 3

Summary of effects of interventions compared with placebo Absolute risk estimates for each outcome are presented in comparison with standard care or placebo. Numbers in the coloured cells are point estimates per 1000 people and their 95% CIs. MID=minimal important difference. NA=not applicable due to no available data. *For low-risk populations, these antivirals probably have little to no important effect on symptomatic influenza; however, zanamivir, oseltamivir, laninamivir, and baloxavir probably have an important effect on symptomatic influenza in high-risk populations. †Baseline risk estimates for for symptomatic influenza, admission to hospital, and adverse events related to drugs were from the control (placebo or standard care) group of eligible studies; various indicates that no single estimate was used and the absolute risk reductions were calculated as the risk differences. ‡MID values were established based on discussion with the WHO guideline development panel; they were used to support judgements of imprecision. §Low-risk and high-risk populations were defined based on the 2022 WHO influenza guidelines (appendix p 18). ¶Baseline risk estimates for symptomatic influenza, admission to hospital, mortality, and serious adverse events were informed by the WHO guideline panel discussion; baseline risk estimates for adverse events related to drugs were from the control group of eligible studies.