With the vast majority of humanity having had COVID-19, been vaccinated against it, or both, treatment of SARS-CoV-2 infection is mostly focused on outpatients. The antivirals nirmatrelvir/ritonavir, remdesivir, and molnupiravir are recommended outpatient COVID-19 therapeutics, especially for those at greatest risk of severe disease, but each of these medications has limitations that temper their use. For nirmatrelvir /ritonavir, the most commonly prescribed of the three, drug-drug interactions, altered taste, gastrointestinal disturbances, and high pill burden have reduced uptake by healthcare providers and patients.
Ensitrelvir, which like nirmatrelvir, is an oral inhibitor of the SARS-CoV-2 protease but does not require pharmacological boosting, is administered once daily rather than twice a day for five days and has slightly fewer drug-drug interactions. In the placebo-controlled SCORPIO-SR trial that enrolled people with mild to moderate COVID-19 in Japan, Vietnam, and South Korea, ensitrelvir started within three days of symptom onset reduced the time to symptom resolution by about a day and shortened the time to clearance of the virus from the nose. The medication also appeared to reduce the risk of Long-COVID. These results led to its approval in Japan for the treatment of COVID-19.
In the follow-on SCORPIO-HR trial (A5407, ACTIV-2d), ACTG investigators again studied ensitrelvir in outpatients with mild to moderate COVID-19, expanding recruitment to participants in 16 countries in Africa, Asia, Europe, North America, and South America. The trial’s primary outcome was time to sustained resolution (at least two days) of 15 common COVID-19 symptoms as reported using participant diaries. Viral clearance rates from the nasopharynx, as assessed by RNA detection and culture, were key secondary outcomes.
The trial enrolled 2,093 participants: 55% female, 42% White, 45% Hispanic/Latino. Three-quarters had received at least the primary COVID-19 vaccine series. In all but the U.S., people considered to be at high risk for progression based on comorbid conditions were enrolled and 33% had at least one risk factor for progression to severe disease.
As reported in Clinical Infectious Diseases, the study found the time to symptom resolution to not be significantly different between the ensitrelvir and placebo groups (12.5 days versus 13.1 days). A pre-planned analysis suggested ensitrelvir reduced the time to resolution for at least one day of a set of symptoms restricted to stuffy nose, runny nose, sore throat, cough, low energy or tiredness, and feeling hot or feverish but only by less than a day. In contrast, ensitrelvir led to significantly reduced SARS-CoV-2 RNA levels in nasopharyngeal swabs at day four of the study. Among those with positive cultures for the virus at entry, at the four-day time point 96% receiving ensitrelvir were culture negative compared to 75% of those receiving placebo. Rebound of virus was rare and similar in both study arms. Only four participants were hospitalized during the trial (three were in the ensitrelvir arm). Overall, ensitrelvir was well tolerated and there were no significant differences in adverse events between study arms.
SCORPIO-HR demonstrates how a network designed to address the HIV pandemic can pivot to confront a new and fast-moving global health crisis. Skilled investigators, highly experienced research sites, and a rigorous clinical trials infrastructure served as a launching pad for an ambitious trial of a promising COVID-19 treatment in five continents. The trial also made clear that the study of a dynamic emerging pathogen can be a challenge. In the paper, the investigators discuss how with vaccinations and prior infection, potential participants in COVID-19 therapeutics studies are now much less at risk for severe COVID-19 pneumonitis and also more likely to have fewer COVID-19 symptoms and to resolve them quicker. The antiviral effects of ensitrelvir and the findings of prior studies suggest the medication may be of most value in those who are truly at high risk for severe COVID-19, such as people who are much older and have more comorbid conditions than those studied here.
Anne F Luetkemeyer, Kara W Chew, Stuart Lacey, Michael D Hughes, Linda J Harrison, Eric S Daar, Joseph Eron, Courtney V Fletcher, Alexander L Greninger, Diane Hessinger, Jonathan Z Li, David Mailhot, David Wohl, Methee Chayakulkeeree, Jose Luis Accini Mendoza, Polina Elistratova, Oluwaseun Makinde, Gareth Morgan, Simon Portsmouth, Takeki Uehara, Davey Smith, Judith S Currier
Clinical Infectious Diseases, ciaf029, https://doi.org/10.1093/cid/ciaf029