N Engl J Med
Can a 5-day antiviral prevent COVID after household exposure?
Clinical Takeaway: A 5-day course of ensitrelvir started within 72 hours of symptom onset in a household index case reduced the risk of symptomatic, RT-PCR–confirmed COVID-19 by about two-thirds vs. placebo, with no major safety concerns identified.
No oral antivirals have been approved for postexposure prophylaxis of COVID-19—leaving a key prevention gap in high-risk household settings.
A global phase 3, double-blind, randomized trial (SCORPIO-PEP) evaluated ensitrelvir, an oral SARS-CoV-2 protease inhibitor, for postexposure prophylaxis among household contacts. Among 2041 participants in the modified intention-to-treat cohort (1030 ensitrelvir; 1011 placebo), symptomatic, RT-PCR–confirmed COVID-19 by day 10 occurred in 2.9% of those receiving ensitrelvir vs. 9.0% with placebo (risk ratio [RR], 0.33; 95% confidence interval, 0.22–0.49; P<0.001).
Results were consistent in the full intention-to-treat population (4.4% vs. 10.2%; RR, 0.43), translating to relative risk reductions of 67% and 57%, respectively. Benefits extended across subgroups, including higher-risk individuals, among whom infection developed in 2.4% vs. 9.9%. Ensitrelvir also reduced overall SARS-CoV-2 infection (symptomatic or not) from 21.5% to 14.0% (RR, 0.66).
Treatment was initiated within 72 hours of index case symptom onset, with 71% enrolled within 48 hours—highlighting the importance of early intervention. Adverse events were similar between groups (15.1% vs. 15.5%), with serious adverse events rare (0.2% in both groups) and no COVID-related hospitalizations or deaths reported.
“Prompt initiation of oral ensitrelvir postexposure prophylaxis was effective in preventing Covid-19 in household contacts…without apparent safety concerns,” the authors noted.
These findings suggest a potential new role for oral antivirals in interrupting transmission in high-risk settings, though considerations such as drug interactions and real-world uptake remain.
Source: Hayden FG, et al; SCORPIO-PEP Study Team. (2026, May 13). N Engl J Med. Ensitrelvir for Covid-19 Postexposure Prophylaxis in Household Contacts