A recent industry-sponsored randomized clinical trial, the Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients, has cast doubt on the efficacy of nirmatrelvir/ritonavir (Paxlovid) in alleviating acute COVID-19 symptoms among lower-risk adults. The study, conducted between August 2021 and July 2022, involved 1,300 adult outpatients and aimed to assess the time to sustained alleviation of COVID-19 signs and symptoms.
Study Design and Patient Population
Participants were eligible if they had either completed a primary COVID-19 vaccine series with at least one condition associated with severe disease or were unvaccinated without high-risk comorbidities. The median age of participants was 42 years, with only 5% aged 65 or older. The cohort was 54% female, with 18% having a BMI of 30 or greater, 5% with diabetes, and 2% with lung disease. Notably, 57% had prior COVID-19 vaccination, and 74% had baseline positive SARS-CoV-2 serological testing, indicating prior infection or vaccination. Approximately 50% had moderate COVID-19 symptoms, 30% had mild disease, and 20% had severe disease. The median time from symptom onset to enrollment was three days.
Primary and Secondary Findings
The primary finding indicated no significant difference in the median time to sustained symptom alleviation between the Paxlovid and placebo groups (12 versus 13 days, p=0.60). However, secondary analyses revealed a non-statistically significant lower risk of hospitalization or death among Paxlovid recipients (0.8%) compared to placebo recipients (1.6%). No Paxlovid recipients required ICU admission or died, whereas 3/10 placebo recipients needed ICU admission. Hospital stays were also shorter among Paxlovid recipients. Medical visits were less frequent in the Paxlovid group among high-risk participants (1.9% versus 5.4%).
Virological rebound occurred in approximately 4% of participants in both groups, with symptom rebound rates of 11% in the Paxlovid group versus 16% in the placebo group. Adverse event rates were similar, although treatment-related adverse events, mainly dysgeusia, were more reported in the Paxlovid group (5.8% versus 0.2%).
Implications and Context
"In a large RCT, Paxlovid was not found to alleviate acute COVID-19 symptoms in lower-risk adults," the study authors noted. About 75% of participants in both groups experienced symptom resolution. The study population's characteristics, including prior SARS-CoV-2 immunity and mild-moderate disease during the Delta and early Omicron variant eras, are crucial in interpreting these results. While rare, secondary analyses suggested some reduction in severe disease within the higher-risk subset, supporting earlier Paxlovid studies in this population. Given the increasing population immunity since the EPIC-SR trial, Paxlovid is unlikely to improve acute symptomatic disease outcomes for younger, healthier adults, especially those with prior vaccination or infection history.
