A five-day course of the oral antiviral ensitrelvir significantly reduced the risk of developing symptomatic COVID-19 among household contacts of individuals who were infected, according to results from the phase 3 SCORPIO-PEP trial published in The New England Journal of Medicine.1 The findings provide some of the strongest evidence to date that pharmacologic postexposure prophylaxis may help prevent COVID-19 following a known household exposure.
In the randomized, double-blind, placebo-controlled trial, investigators led by Frederick G. Hayden, MD, Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, enrolled household contacts of patients with confirmed COVID-19 who were symptomatic. Participants who tested negative for SARS-CoV-2 and were enrolled within 72 hours of symptom onset in the index case received either ensitrelvir or a placebo.
The primary analysis included 2,041 participants with centrally confirmed negative baseline results for COVID-19 infection. By day 10, laboratory-confirmed COVID-19 developed in 2.9% of participants who received ensitrelvir compared with 9.0% of those assigned to placebo, representing a 67% relative risk reduction (RR, 0.33; 95% CI, 0.22-0.49; P < .001).
“The key finding is that COVID-19 can be prevented pharmacologically after a recognized household exposure,” said investigator Paul E. Sax, MD, the Bruce A. Beal and Robert L. Beal Endowed Chair in Infectious Diseases at Brigham and Women’s Hospital and Professor of Medicine at Harvard Medical School. “A five-day course of ensitrelvir reduced symptomatic COVID-19 by approximately two-thirds, establishing postexposure prophylaxis as a potentially useful addition to vaccination, testing, and treatment.”
The benefit was also observed in the broader intention-to-treat population, where symptomatic COVID-19 occurred in 4.4% of participants receiving ensitrelvir vs 10.2% of those receiving a placebo through day 10 with a RR reduction of 57% (RR, 0.43; 95% CI, 0.32 to 0.59; P < .001). Investigators further reported lower rates of confirmed infection, regardless of symptoms, with infection occurring in 14.0% of the ensitrelvir group compared with 21.5% of the placebo group through day 10.
The findings are particularly notable because previous studies evaluating postexposure prophylaxis with nirmatrelvir-ritonavir and molnupiravir did not meet their primary efficacy end points, the authors noted.
“We cannot know definitively, but several factors may have contributed,” Dr. Sax said when asked why ensitrelvir succeeded where earlier antiviral prophylaxis studies did not. “Ensitrelvir is a potent antiviral, treatment began early, within 72 hours of symptom onset in the index case, and the trial enrolled household contacts, a group with a well-defined and substantial risk of exposure.”
He added that the drug’s long half-life may have helped maintain protection during the period of ongoing exposure beyond the five-day administration period.
Subgroup analyses suggested that the benefit extended across a range of populations, including older adults and individuals at increased risk for severe COVID-19. Among household contacts with risk factors, symptomatic COVID-19 developed in 2.4% of those receiving ensitrelvir compared with 9.9% of those receiving a placebo.
Patients at high risk may be among the most appropriate candidates for postexposure prophylaxis, Dr. Sax said.
“The strongest rationale is for household contacts who are at increased risk for severe COVID-19, including older adults, [patients who are immunocompromised], and people with certain underlying medical conditions,” he said. “The high-risk subgroup had an approximately 76% reduction in symptomatic COVID-19.”
He cautioned, however, that the trial was not designed to determine whether prophylaxis prevents hospitalization or death.
Safety findings were generally reassuring. Overall adverse event rates were similar between groups, occurring in 15.1% of participants receiving ensitrelvir and 15.5% of those receiving a placebo. Serious adverse events were uncommon, affecting 0.2% of participants in each group. No COVID-19-related hospitalizations or deaths were reported during the study.
Investigators also observed reversible reductions in high-density lipoprotein (HDL) cholesterol levels among participants who received ensitrelvir.
“The HDL reductions were transient and reversible, and a short-lived laboratory change of this kind is unlikely to have meaningful cardiovascular consequences,” Dr. Sax said. “More critically, the drug has several important drug-drug interactions, so clinicians should review concomitant medications carefully before prescribing ensitrelvir.”
Additionally, several important questions remain to be answered, he said.
“The priorities are to determine which [patients who have been exposed] derive the greatest absolute benefit, whether prophylaxis reduces severe outcomes and onward transmission, and whether effectiveness is maintained against future variants,” Dr. Sax said.
Additional data are also needed in patients who are pregnant, younger children, and other populations typically underrepresented in research.
References
1. Hayden FG, Shinkai M, Clark TW, et al. Ensitrelvir for COVID-19 postexposure prophylaxis in household contacts. N Engl J Med. 2026;394(19):1905-1915. doi:10.1056/NEJMoa2509306
