Background
The primary rationale for urgent deployment of antivirals to treat SARS-CoV-2 infection was originally to reduce the severity of acute disease and prevent hospitalization and death in highest-risk persons. In such groups, nirmatrelvir/ritonavir (Paxlovid) demonstrated high efficacy against severe outcomes (Hammond, February 2022). However, with population-wide reductions in acute disease severity owing to accumulated immunity, other antiviral use cases have been explored. These include: (i) reducing acute disease outcomes in lower-risk individuals (including shortening symptom duration), (ii) reducing incidence of post-acute complications or syndromes (e.g., long COVID) and (iii) preventing infections following a high-risk exposure (post-exposure prophylaxis).
In this series, we will review recent clinical trials assessing several of these potential Paxlovid use cases. Understanding the contemporary role(s) for this antiviral remains important given increasing cost and ongoing challenges related to major drug-drug interactions.
Reducing Symptoms of Acute COVID-19
The Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients
study was an industry-sponsored randomized clinical trial of 5 days of Paxlovid versus placebo conducted August 2021 to July 2022 among 1,300 adult outpatients with COVID-19 (Hammond, April 2024). It was designed to assess differences in time to sustained alleviation of all COVID-19 signs and symptoms. Participants were eligible if they had either (i) received a full primary COVID-19 vaccine series and had ≥1 condition associated with severe disease or (ii) were unvaccinated and did not have high-risk comorbidities or characteristics.
Participants were a median age of 42 years old (5% age ≥ 65), 54% were women, 18% had a BMI ≥30, 5% had diabetes, and 2% had lung disease; ultimately, half were labeled as “high risk” based on clinical characteristics, but eligible to participate in this “standard-risk” trial due to complete vaccination. Notably, 57% had received prior COVID-19 vaccination, and 74% had baseline positive SARS-CoV-2 serological testing indicating prior infection or vaccination. The plurality (~50%) had moderate COVID-19 symptoms, whereas 30% had mild disease, and 20% had severe disease; there was a wide range of SARS-CoV-2 viral loads on study entry. Most (73%) enrolled within ≤3 days of symptom onset, with a median (range) of 3 (0-6) days.
Primary Finding: The overall median time to sustained symptom alleviation did not differ significantly between the Paxlovid versus placebo groups (12 versus 13 days, p=0.60).
Secondary Findings: Analysis of severe COVID-19 outcomes showed a non-statistically significant lower risk of hospitalization or death among Paxlovid recipients (5/654 or 0.8%) as compared to placebo recipients (10/634 or 1.6%); none of the five Paxlovid recipients experienced ICU admission or death, whereas 3/10 placebo recipients required ICU admission. Additionally, average hospital stays were shorter among Paxlovid recipients than placebo recipients (5 days per 100 participants versus 18 days per 100 participants, respectively). There was only one death on trial, which occurred in the placebo group. Overall, medical visits were less frequent among Paxlovid versus placebo recipients (6 [1.9%] versus 17 [5.4%] of high-risk participants, respectively).
Otherwise, virological rebound was observed in ~4% of participants in both treatment groups, with symptom rebound rates of 11% in the Paxlovid group versus 16% in the placebo group. Adverse event rates were similar between treatment groups, albeit with more reported treatment-related AEs in the Paxlovid group, mostly driven by dysgeusia (5.8% versus 0.2%).
Bottom line: In a large RCT, Paxlovid was not found to alleviate acute COVID-19 symptoms in lower-risk adults — ultimately, about 75% of both Paxlovid and placebo participants had symptom resolution. Notably, the study population was predominantly <65 years old, with evidence of prior SARS-CoV-2 immunity and mild-moderate disease in the Delta and early Omicron variant eras. Although rare, secondary analyses showed some reduction in severe disease within the higher-risk subset of participants, supporting earlier Paxlovid studies in this group. Given further increases in population immunity since the conduct of EPIC-SR, it appears unlikely that Paxlovid will improve acute symptomatic disease outcomes for younger, healthy adults, particularly those with prior vaccination and/or infection history.