Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts.

Summary

In a double-blind RCT of 2041 household contacts, ensitrelvir reduced symptomatic, PCR-confirmed COVID-19 from 9.0% to 2.9% (RR 0.33) when started within 72 hours of index case symptom onset. Adverse events and serious adverse events were similar to placebo, with no COVID-19-related hospitalizations or deaths.

Key Findings

• Symptomatic, PCR-confirmed COVID-19 by day 10: 2.9% with ensitrelvir vs 9.0% with placebo (RR 0.33, 95% CI 0.22–0.49, P<0.001).
• Adverse events similar between groups (15.1% vs 15.5%) and serious adverse events 0.2% in each arm; no COVID-19 hospitalizations or deaths.
• Most participants randomized within 48 hours of index onset (71.1%); 37% had at least one risk factor for severe COVID-19.

Clinical Implications

Ensitrelvir can be considered for postexposure prophylaxis in household contacts, particularly within 72 hours of index symptom onset and among those at higher risk for severe disease, potentially informing guideline updates.

Limitations

• Trial conducted in a single country context, which may limit generalizability across variants and settings.
• Primary endpoint limited to day 10; longer-term outcomes and transmission effects were not assessed.

Future Directions

Evaluate real-world effectiveness across variants and vaccination statuses, assess impact on secondary transmission, and define optimal target populations and timing.