Antiviral ensitrelvir cuts risk of COVID-19 in household contacts by two-thirds, study finds

The antiviral drug ensitrelvir prevents infection in household contacts of COVID-19 patients when given within 72 hours after symptom onset in the index patient, according to a Phase III randomized controlled trial published in the New England Journal of Medicine.

A team led by researchers from the University of Virginia and ensitrelvir maker Shionogi randomly assigned participants aged 12 years and older who tested negative for COVID-19 but lived with an infected patient to receive either oral ensitrelvir (375 milligrams [mg] on day 1 and 125 mg on days 2 through 5) or a placebo within 72 hours after the index patient developed symptoms.

Nasopharyngeal swabs were collected from participants for testing on days 1, 3, 6, 10, 15, 21, and 28. The trial was conducted in the United States, Japan, Argentina, South Africa, and Vietnam from June 2023 to September 2024.

Households ‘key sites for transmission’

The primary study end point was confirmed symptomatic COVID-19 infection by day 10 in a household member in the modified intention-to-treat population, which included all participants who received at least one dose of ensitrelvir (1,030 participants) or placebo (1,011).

The average participant age was 42.4 years, 71.1% underwent randomization within 48 hours after symptom onset in the index patient, and 37.0% had at least one risk factor for severe COVID-19.

Ensitrelvir is approved in Japan for the treatment of mild-to-moderate COVID-19 in people aged 12 years and older, and, based on the findings of this trial, it is also approved in that country for postexposure prevention in contacts.

“Households are key sites for transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, with secondary attack rates of up to 32 to 48% among household contacts during the omicron era,” the authors wrote.

“Nonpharmaceutical interventions (e.g., masking, isolation, and ventilation) may lower the risk of household transmission, but such interventions are not fully protective and their use in households varies widely.”

Similar adverse-event rates in two groups

Over 98% of household contacts were positive for SARS-CoV-2 antibodies, indicating previous exposure to the virus. Antiviral therapy—most often with ensitrelvir (13.6%)—was started in 18.7% of the 1,319 index patients. About 83% of index patients had multiple household contacts.

The COVID-19 infection rate was 67% lower in the ensitrelvir group than in placebo recipients (2.9% vs. 9.0%; risk ratio, 0.33). The incidence of adverse events was similar in the two groups (15.1% in ensitrelvir recipients and 15.5% in the placebo group), as was the rate of serious adverse events (0.2% in each group). No COVID-related hospitalizations or deaths occurred.

In the intention-to-treat population, the COVID-19 infection rate was significantly lower in ensitrelvir recipients than in the placebo group (4.4% vs. 10.2%; risk ratio, 0.43) through day 10.

In contrast to a rapid increase in illnesses by day 2 in placebo recipients, fewer events occurred in the ensitrelvir group by days 10 to 12; subsequently, new events occurred in a similar proportion of participants in the two groups, showing that the lower incidence of COVID-19 in the ensitrelvir group was maintained.

Ensitrelvir showed significant reductions in the relative risk of COVID-19 infection through day 10 of 67% in the modified intention-to-treat population and of 57% in the intention-to-treat population.

“In addition, in the subgroup analysis involving the household contacts with risk factors, the percentage of those in whom COVID-19 developed was 2.4% in the ensitrelvir group and 9.9% in the placebo group,” the authors wrote. “Ensitrelvir postexposure prophylaxis was also associated with a 34% relative risk reduction in SARS-CoV-2 transmission within households.”

Possible tool for congregate living

The benefits of ensitrelvir generally appeared consistent across most subgroups, including older adults and participants at risk for severe disease.

Post hoc analyses suggested that SARS-CoV-2 viral loads were lower in the ensitrelvir group than in placebo recipients in those infected at baseline or infected while they were receiving postexposure prevention. In both of these subgroups, ensitrelvir recipients appeared to have lower symptom scores early in their illness than the placebo group.

Among household contacts given ensitrelvir, genome sequencing identified viral variants with amino acid substitutions incurred during therapy in 1.9% of the modified intention-to-treat population and 14.9% of the intention-to-treat baseline COVID-positive population.

Of the associated index patients, 20 received no antiviral treatment, while 10 were given ensitrelvir, two received molnupiravir, and three received nirmatrelvir–ritonavir (Paxlovid).

“These findings suggest the potential effectiveness of ensitrelvir in reducing the risk of illness in other unprotected contexts, such as during outbreaks in acute and long-term care facilities,” the researchers conclude.

In a Shionogi news release, Aeron Hurt, Ph.D., the company’s vice president of global medical science, said, “By preventing COVID-19, people can avoid not only potentially serious consequences of acute disease, but also the risk of exacerbating pre-existing conditions or acquiring new conditions, such as long COVID.

“Ensitrelvir cuts the chances of developing COVID-19 by two-thirds, which is substantial, particularly in households where the risk of spread is high.”

Who’s behind this story?

Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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