Viral and Symptom Rebound in Untreated COVID-19 Infection

Abstract

Background: There are reports of viral RNA and symptom rebound in people with COVID-19 treated with nirmatrelvir/ritonavir. Since the natural course of viral and symptom trajectories of COVID-19 has not been well described, we evaluated the incidence of viral and symptom rebound in untreated outpatients with mild-moderate COVID-19.

Methods: The study population included 568 participants enrolled in the ACTIV-2/A5401 platform trial who received placebo. Anterior nasal swabs were collected for SARS-CoV-2 RNA testing on days 0-14, 21 and 28. Participants recorded the severity of 13 targeted symptoms daily from day 0 to 28. Viral rebound was defined as ≥0.5 log₁₀ viral RNA copies/mL increase and symptom rebound was defined as a 4-point total symptom score increase from baseline. Baseline was defined as study day 4 (primary analysis) or 8 days from symptom onset (secondary analysis).

Findings: In both the primary and secondary analyses, 12% of participants had viral rebound. Viral rebounders were older than non-rebounders (median 54 vs 47 years, P=0.04). Symptom rebound occurred in 27% of participants after initial symptom improvement and in 10% of participants after initial symptom resolution. The combination of high-level viral rebound to ≥5.0 log₁₀ RNA copies/mL and symptom rebound after initial improvement was observed in 1-2% of participants.

Interpretation: Viral RNA rebound or symptom relapse in the absence of antiviral treatment is common, but the combination of high-level viral and symptom rebound is rare.

Keywords: COVID-19; Paxlovid; symptom rebound; viral rebound.

Figure 1:. Description of anterior nasal (AN) SARS-CoV-2 RNA rebound.

(A) Bar graph shows percentage of participants having ≥0.5 log₁₀ AN SARS-CoV-2 RNA rebound at a follow-up time point relative to baseline using the primary (study day 4) and secondary analysis (8 days from symptom onset). The frequencies of viral rebound were assessed with a minimum rebound viral load of either ≥3.0 or ≥5.0 log₁₀ RNA copies/mL. (B) The left and right graphs show log₁₀ AN SARS-CoV-2 RNA in copies/ml by study day in rebounders and non-rebounders respectively using primary definition of baseline i.e, study day 4 and rebound viral load value ≥3 log AN SARS-CoV-2 RNA copies/ml. Median AN SARS-CoV-2 RNA copies/ml for each day is shown with thick black line. Y-axis shows log₁₀ AN SARS-CoV-2 RNA in copies/ml while x-axis denotes study day.

Figure 2:. Heat map of symptom score rebound.

The heat map shows participants with hospitalization or symptom rebound (≥4-point increase from baseline in symptom score) after demonstrating initial symptom improvement using (A) study day 4 as baseline, (B) day 8 after symptom onset as baseline. Baseline time point is shown as dotted black line. Individual participants are shown in rows while study day is shown in columns. Red squares represent days meeting symptom rebound criteria and orange squares represent days of hospitalization. Blue squares denote days that did not meet symptom rebound criteria.