BACKGROUND: Oseltamivir is recommended for the treatment of adults hospitalized with influenza, but adherence is often suboptimal. This may be due to doubts about the reliability of the evidence supporting its benefits, particularly when initiation is delayed. We aimed to assess the effectiveness of oseltamivir in reducing mortality in older adults hospitalized with influenza, with a focus on the timing of initiation. METHODS: The CIRN-SOS Network gathered data on severe respiratory illnesses across 5 Canadian provinces during the influenza seasons 2012-2019. Individuals aged ≥65 years with confirmed influenza and available antiviral prescription data were included. We compared the 30-day survival rates of hospitalized patients based on oseltamivir prescription status. Kaplan-Meier estimated survival probability and inverse probability of treatment (IPT)-weighted Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality. The analyses considered the time to antiviral initiation (>
48 vs ≤48 hours). RESULTS: Among the 8135 influenza patients studied, 2126 did not receive antiviral treatment, whereas 6009 were treated with oseltamivir. A total of 395 patients were hospitalized for >
30 days. The overall mortality rate was 8.32 per 1000 person-days, with 53.9% of the deaths occurring within the first week. Oseltamivir recipients had a 18% lower risk of 30-day mortality (IPT-weighted HR, 0.82 [95% CI, .69-.98]). The benefit was significant for influenza A (IPT-weighted HR, 0.74 [95% CI, .61-.91]) but not for influenza B (IPT-weighted HR, 1.12 [95% CI, .81-1.56]). Oseltamivir remained effective even when initiated after 48 hours (IPT-weighted HR, 0.66 [95% CI, .49-.90]). Influenza vaccination did not mediate the effectiveness of oseltamivir in reducing mortality. CONCLUSIONS: Oseltamivir significantly reduces mortality risk in older adults hospitalized with influenza, even when administered after 48 hours, independent of vaccination status.