SARS-CoV-2 particles (blue, artificially colored) infect a cell.Credit: Steve Gschmeissner/SPL
COVID-19 can inflict days of misery even on people who don’t develop serious illness. Now trial data shows an antiviral called ensitrelvir shortens symptoms of mild to moderate COVID-19 by about a day – and is the first drug to statistically significantly reduce the number of days of testing positive for SARS -CoV-2.
The drug’s maker, Shionogi in Osaka, Japan, says the data also shows ensitrelvir has the potential to prevent long COVID. But scientists are skeptical of this claim and criticize the design of the clinical trial. The research was presented at the Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington on Feb. 21, and has not yet been peer-reviewed.
Two oral antivirals are already widely used to treat COVID-19: Paxlovid (nirmatrelvir/ritonavir) and molnupiravir. Both target people at high risk of serious illness. But ensitrelvir has been tested in people at all risk levels, which could have implications for its use in low-risk people. No drug has been conclusively shown to reduce the risk of long COVID, although preliminary evidence suggests Paxlovid may have this effect.
A COVID cough pill
Organizers of the ensitrelvir trial surveyed about 1,200 people, with the primary goal of determining whether the drug could speed recovery. The results showed that participants who took 125-milligram ensitrelvir pills recovered from five specific symptoms — stuffy or runny nose, sore throat, cough, feeling hot or feverish, and lack of energy or fatigue — about 24 hours earlier than those in the control group.
Participants who took the 125 milligram dose also tested negative for SARS-CoV-2 about 29 hours earlier than those who took a placebo. According to Shionogi, the study was the first to show a statistically significant reduction in the time to a negative test result.
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A subset of participants were asked about their COVID-19 symptoms three and six months after trial enrollment as well as during their period of acute infection. Those who reported two or more of the same symptoms at least twice in a row during this period were defined as having developed long COVID. Participants who had a relatively high number of symptoms in the early stages of the disease had a 14% risk of developing long COVID if they took the antiviral, compared to a 26% risk for similar participants in the placebo group. . This led Shionogi to conclude that participants who received ensitrelvir had a reduced risk of developing long-lasting COVID.
Doubts about the design
But scientists who were not involved in the study point out that the trial was not specifically intended to investigate long-term COVID risk. This means that the pre-trial research plan did not describe any method for analyzing long COVID data.
That means, for example, it’s unclear if Shionogi’s definition of long COVID was determined before the trial began, notes physician Eric Topol, director of the Scripps Research Translational Institute in San Diego, in California. As this was an exploratory phase of the study, it is not possible to draw firm conclusions, he adds.
Simon Portsmouth, clinical development manager at Shionogi in Florham Park, New Jersey, said the company could not specify the long COVID data analysis plan in advance because long COVID was less clearly defined in the past. than today. He says these results, while not definitive, will shape an ongoing trial assessing the effect of ensitrelvir on COVID-19 symptoms.
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Scientists say it’s plausible that antivirals can prevent long COVID. A recent analysis found that people who took Paxlovid had a reduced risk of developing long-lasting COVID compared to those who took no antiviral drugs.1. The study, published as a preprint, has not yet been peer-reviewed. Study co-author Ziyad Al-Aly, head of research and development at the VA St Louis Health Care System in Missouri, says the ensitrelvir data makes him more optimistic that attacking the virus early in an infection “seems to hold the key to reducing the risk of prolonged COVID.
Topol agrees that the data Shionogi has made public supports the idea that antivirals protect against long COVIDs, at least when residual virus is implicated in causing prolonged symptoms.
Persistent Questions
But there is no consensus that the lingering virus causes long COVID. “It’s entirely possible that the virus has nothing to do with the long COVID,” says Edward Mills, a health researcher at McMaster University in Hamilton, Canada. The long COVID could be caused, for example, by the immune response to the virus, he notes.
The optimal study to determine whether antivirals prevent long COVID would involve selecting only participants whose illness might be caused in part by persistent SARS-CoV-2, says immunologist Danny Altmann of Imperial College London . If scientists don’t separate these people from those whose symptoms don’t have the same cause, the trials could yield “obscure answers,” Altmann says.