Updated EPIC-HR data bolster nirmatrelvir/ritonavir role against COVID-19

Updated data from the EPIC-HR* trial show reduced duration of COVID-19 symptoms and utilization of healthcare resources with nirmatrelvir/ritonavir (NMV/r) in high-risk, unvaccinated, nonhospitalized, symptomatic adults with COVID-19.

Compared with placebo, NMV/r significantly reduced median time to sustained symptom alleviation (13 vs 15 days; hazard ratio [HR], 1.27; p<0.0001) and resolution through day 28 (16 vs 19 days; HR, 1.20; p=0.0022). The benefits remained significant with or without accounting for COVID-19-related hospitalizations or all-cause deaths. [Clin Infect Dis 2025;80:323-330]

The reduced median time to sustained alleviation with NMV/r was seen across all subgroups, with more apparent effects in patients with moderate or severe symptoms at baseline (13 vs 17 days; p=0.0001), baseline viral load ≥7 log₁₀ copies/mL (14 vs 19 days; p<0.0001), aged >60 years (13 vs 18 days; p=0.0011), and those who were seronegative (13 vs 17 days; p=0.0001).

A similar trend was observed in the same subgroups of patients for median time to sustained symptom resolution: 20 vs 23 days (p=0.010), 19 vs 25 days (p=0.027), 18 vs 22 days (p=0.022), and 19 vs 23 days (p=0.0086), respectively.

Healthcare utilization

COVID-19-related medical visits were substantially lower in the NMV/r vs placebo arm (64.3-percent rate reduction; p<0.0001). Through day 34, fewer NMV/r vs placebo recipients reported any COVID-19-related medical visit (2.3 percent and 8.4 percent); this corresponded to a 73.2-percent relative risk reduction (RRR) in favour of NMV/r (p<0.0001).

There were also fewer NMV/r vs placebo recipients hospitalized for COVID-19 through day 28 (0.9 percent vs 6.4 percent; RRR, 85.5 percent; p<0.0001). Among hospitalized patients, none in the NMV/r arm were admitted to the intensive care unit (ICU) or required mechanical ventilation (MV); in the placebo arm, the respective incidences of ICU admission and MV were 14.3 percent and 6.3 percent.

On average, NMV/r-treated patients spent 8.7 days in the hospital per 100 patients; the corresponding number of days in the placebo arm was 76.6. The average number of days in the hospital dropped by 88.6 percent with NMV/r (67.9 days per 100 patients; p<0.0001).

All NMV/r recipients with a known discharge status were discharged to home self-care; in the placebo arm, the corresponding rate was 54.7 percent. The rest of placebo recipients either died in the hospital, were discharged to home and required assistance (home healthcare, family, or friends), or were transferred to a nursing or rehabilitation facility.

Fewer NMV/r vs placebo recipients required supplemental O₂ support for COVID-19 (1 percent vs 5.2 percent; RRR, 80.6 percent).

Through week 24, no deaths were reported in the NMV/r arm; in the placebo arm, there were 15. Fourteen of the deaths were COVID-19-related, three were reported after day 28, and one was attributed to sepsis tied to relapsed acute myeloid leukaemia.

Severe illness remains a serious threat

The current results build on the initial EPIC-HR findings. [N Engl J Med 2022;386:1397-1408] In this study, 1,966 patients were randomized 1:1 to receive NMV/r 300 mg/100 mg or placebo Q12H for 5 days.

“[S]evere illness from [SARS-CoV-2] infection remains a serious public health threat,” said the researchers. “In addition to the key goal of preventing progression to severe disease, accelerating symptom recovery is a potential therapeutic goal as described in the NIH** therapeutic management guidelines for nonhospitalized patients; this is a particularly relevant efficacy outcome for patients, given the declining rate of severe COVID-19.”

Evidence shows that of the >50M COVID-19 cases in the US between December 2021 and February 2023, ~48,000 deaths and 135,000 hospitalizations could have been prevented at 50-percent uptake of NMV/r. [medRxiv (Preprint) 2023;doi:10.1101/2023.05.26.23290602] COVID-19 also caused a significant strain on healthcare systems in various countries during its peak. [JAMA Network Open 2022;5:e221760; J Pers Med 2022;12:1295]

“Thus, the efficacy of NMV/r in the post-Delta era remains relevant … The importance of having effective COVID-19 treatments, such as NMV/r, to reduce healthcare system burden (both ambulatory and hospital-based), should not be underestimated,” the researchers said.