COVID-19 rebound occurs with or without antivirals, doesn't affect outcomes, studies find

Two new studies analyzed rebound of SARS-CoV-2 infection.

One study, published by Annals of Internal Medicine on Feb. 20, looked at symptomatic and viral rebound in outpatients with untreated COVID-19. It included 563 participants in the placebo group of a trial who recorded the severity of 13 symptoms daily and underwent RNA testing on days 0 to 14, 21, and 28. Symptom rebound, defined as a four-point increase in total symptom score after improvement, was found in 26% of participants, at a median of 11 days after initial symptom onset. Viral rebound (an increase ≥0.5 log₁₀ RNA copies/mL from the immediately preceding time point to a viral load ≥3.0 log₁₀ copies/mL) occurred in 31%, and high-level viral rebound (an increase ≥0.5 log₁₀ RNA copies/mL to a viral load ≥5.0 log₁₀ copies/mL) was found in 13% of participants.

Only 3% had both symptomatic and viral rebound, and most rebounds were transient, with 89% of symptom rebounds and 95% of viral rebounds occurring at only a single time point before improving. The study authors concluded that symptomatic or viral relapse in the absence of antiviral treatment is common but that the occurrence of both together is rare. They noted that the short duration of rebound observed in their study “is in contrast to the more prolonged symptom and viral rebound after nirmatrelvir–ritonavir treatment in previous case reports that may indicate differences in the characteristics of the rebound episodes occurring with or without antiviral therapy, or bias in reported cases.” Limitations of the study include that it was based on pre-omicron variants in unvaccinated patients.

The second study, published by The Lancet Infectious Diseases on Feb. 13, analyzed rebound during omicron predominance in Hong Kong. It included 4,592 patients who were hospitalized but not oxygen-dependent at baseline: 242 given nirmatrelvir-ritonavir (300 mg/100 mg twice a day for five days), 563 given molnupiravir (800 mg twice a day for five days), and 3,787 controls who received no oral antiviral. Viral rebound (defined as a reduction in cycle threshold value ≥3 on quantitative reverse transcriptase-polymerase chain reaction test between two consecutive measurements) occurred in statistically similar percentages of all three groups: 6.6% (95% CI, 4.1% to 10.5%), 4.8% (95% CI, 3.3% to 6.9%), and 4.5% (95% CI, 3.9% to 5.2%), respectively. Immunocompromised patients in all three groups had higher risk of rebound (odds ratios compared to nonimmunocompromised patients, 7.37, 3.05, and 2.21, respectively). Patients on either antiviral also had higher likelihood of rebound if they were ages 18 to 65 years (versus older) or concomitantly taking corticosteroids.

Viral rebound was not associated with any increase in risk of a composite clinical outcome of mortality, ICU admission, or need for ventilation initiation, the study found. The study authors concluded that rebound rates are similar with and without antiviral treatment and that rebound does not appear to be associated with adverse clinical outcomes. They noted that various mechanisms have been proposed for COVID-19 rebound, including a naturally biphasic pattern to SARS-CoV-2 infection or some relationship with the dosage, duration, or timing of antiviral therapy. An accompanying editorial observed that the study reinforces the importance of continuing to offer antivirals to patients who are at increased risk of progression to severe COVID-19. “A major advance from this study is the identification of risk predictors of viral burden rebound,” the editorialists said.