Speeding COVID-19 symptom recovery may not fall within the realm of nirmatrelvir–ritonavir

Treating COVID-19 patients who had been vaccinated or did not have risk factors for severe disease with ritonavir-boosted nirmatrelvir (nirmatrelvir–ritonavir) did not expedite the time to symptom alleviation, reported investigators in the EPIC-SR trial.

There appears to be "a gradient of benefit for nirmatrelvir–ritonavir”, as commented in the accompanying editorial. The benefit does not extend to those at lower risk for severe COVID-19, despite being observed in a previous trial involving unvaccinated high-risk individuals. [N Engl J Med 2024;390:1234-1236]

From the day of randomization through day 28, the median time to sustained alleviation of all targeted signs or symptoms of COVID-19 was 12 days with nirmatrelvir–ritonavir vs 13 days with placebo (log-rank p=0.60). Therefore, the primary endpoint of EPIC-SR was not met. [N Engl J Med 2024;390:1186-1195]

The key secondary endpoint of COVID-19–related hospitalization or death from any cause through day 28 was also similar between the treatment arms (difference, −0.81 percentage points, 95 percent confidence interval [CI], −2.00 to 0.37), which was descriptive in nature due to the nonsignificant primary endpoint.

Different trial populations, endpoints, and prevalent variants

EPIC-SR enrolled two groups of patients per protocol: fully vaccinated individuals at an increased risk for severe COVID-19, and individuals who had never been vaccinated or had not received a COVID-19 vaccine within the previous 12 months but were not at an increased risk for severe COVID-19. The total population of 1,296 individuals (median age 42 years, 5.0 percent aged ≥65 years) had both groups equally distributed (high-risk but vaccinated, 49.1 percent vs standard-risk, 50.1 percent). Severe COVID-19 at baseline was permitted (18.8 percent).

The trial was conducted from August 2021 to July 2022, a time when the Omicron variant was emerging and became prevalent. Nearly three-quarters of the participants were randomized within 3 days after symptom onset (72.5 percent), with nirmatrelvir–ritonavir or placebo dosed every 12 hours for 5 days (total of 10 doses).

EPIC-SR focused on symptom alleviation, mirroring trials of influenza treatments. [Lancet 2000;355:1845-1850; N Engl J Med 2018;379:913-923] This is in stark contrast to the previous EPIC-HR trial conducted among unvaccinated high-risk persons, where the met primary endpoint was COVID-19–related hospitalization or death from any cause by day 28. [N Engl J Med 2022;386:1397-1408]

Patients in EPIC-HR were older (median age 46 years, 12.8 percent aged ≥65 years), and only those with mild-to-moderate COVID-19 at baseline were enrolled. Importantly, the trial was performed between mid-July and early December 2021, during the prevalence of the Delta variant and the emergence of Omicron. [N Engl J Med 2022;386:1463-1464; N Engl J Med 2022;387:475-476]

A global perspective

“The safety of nirmatrelvir–ritonavir in this trial is consistent with that in the EPIC-HR trial, with no new safety findings,” stated the investigators. Frequencies of adverse events (AEs) of any cause were similar: 25.8 percent in the nirmatrelvir–ritonavir group and 24.1 percent in the placebo group, as were those of overall grade 3 or 4 AEs (3.7 percent vs 3.9 percent). Investigators in both EPIC-SR and EPIC-HR concluded that nirmatrelvir–ritonavir was associated with mild dysgeusia and diarrhoea.

It is worth noting that in the vaccinated high-risk subgroup, fewer COVID-19–related medical visits resulted in the nirmatrelvir–ritonavir arm (total number, 6 vs 26; least-squares mean ratio, 0.18, 95 percent CI, 0.06–0.56). The mean duration of hospitalization overall was 0.23 days shorter with nirmatrelvir–ritonavir (95 percent CI, 0.04–0.39).

The editorialists contrasted EPIC-SR with the trials of ritonavir-boosted simnotrelvir, ensitrelvir, and mindeudesivir, which have shown clinical benefit in terms of symptom resolution, despite not being globally available. [N Engl J Med 2024;390:230-241; JAMA Netw Open 2024;7:e2354991; Lancet Infect Dis 2024;24:129-139]

The key takeaway is that, as the investigators concluded, "the usefulness of nirmatrelvir–ritonavir in patients who are not at high risk for severe [COVID-19] has not been established."