A phase 2 trial led by Pfizer suggests that extending the antiviral regimen of nirmatrelvir–ritonavir (Paxlovid) beyond the standard 5-day course may help reduce the risk of viral rebound in immunocompromised individuals with COVID-19, though longer treatment durations did not significantly improve overall viral suppression rates.
Edward Weinstein, MD, who leads Antivirals in Global Product Development at Pfizer and author for the study, emphasized the potential clinical relevance of the findings. "The results from this study have implications for the clinical management of the overall immunocompromised and the severely immunocompromised populations, who are at high risk of prolonged infection leading to viral resistance and poor clinical outcomes, and for whom little guidance is available regarding optimal dosing of treatments for COVID-19," Weinstein said.
Study Design and Patient Population
The placebo-controlled, randomized, double-blind trial, known as EPIC-IC, enrolled 156 non-hospitalized, symptomatic COVID-19 patients aged 12 and older who were immunocompromised. Conducted across 73 sites in nine countries, participants were randomly assigned to receive Paxlovid (300 mg nirmatrelvir + 100 mg ritonavir, orally twice daily) for either 5, 10, or 15 days.
The primary endpoint measured the proportion of participants who maintained SARS-CoV-2 RNA levels below the lower limit of quantification in nasopharyngeal swabs (2·0 log₁₀ copies/mL) from day 15 to day 44.
Efficacy Results
Sustained viral suppression was achieved in:
- 61.5% (95% CI 48.3–74.8) of participants in the 5-day group
- 70.8% (95% CI 58–83.7) in the 10-day group
- 66% (95% CI 52.9–79.1) in the 15-day group
Though differences in the primary endpoint were not statistically significant, extended courses showed a sharp drop in viral rebound rates:
- 17.3% (95% CI 8.2–30.3) in the 5-day group
- 2.1% (95% CI .1–11.1) in the 10-day group
- 2% (95% CI .1–10.6) in the 15-day group
Clinical Implications for High-Risk Patients
Weinstein noted that this reduction in viral rebound may offer added value for certain high-risk patients. "A post-hoc analysis suggested that extending Paxlovid treatment beyond 5 days might improve time to SARS-CoV-2 viral clearance for patients with severe immunocompromise," he said. "That said, additional studies are needed to confirm whether extended Paxlovid treatment durations might better control viral load and rebound risk compared with the standard 5-day treatment course among severely immunocompromised patients."
Safety Profile
Adverse events were reported in:
- 52.8% of participants in the 5-day group
- 66.7% in the 10-day group
- 60.8% in the 15-day group
Most side effects were manageable, and only two COVID-19-related hospitalizations occurred, both in the 5-day group.
Despite the promising signals, Weinstein emphasized that the 5-day course remains appropriate for many. "For most immunocompromised patients, the approved 5-day course of Paxlovid treatment is likely to promote sustained viral clearance and sufficiently control disease progression."
Future Research Directions
To better define optimal treatment duration, Pfizer is advancing further research through the ASPIRE-IC trial (ClinicalTrials.gov Identifier: NCT07013474), which aims to explore antiviral strategies for severely immunocompromised patients with symptomatic COVID-19.
Weinstein concluded, "We would welcome additional studies to confirm whether extended Paxlovid treatment durations might better control viral load and rebound risk compared with the standard 5-day treatment course among severely immunocompromised patients."
