A new study conducted by researchers from Brigham and Women’s Hospital, Harvard Medical School,Massachusetts-USA and Harvard T.H. Chan School of Public Health-Massachusetts-USA involving a randomized clinical trial has surprisingly found that untreated COVID-19 infected individuals tend to fair better than those treated with Paxlovid (nirmatrelvir–ritonavir) in terms of symptoms and viral rebound.
The study findings were published in the peer reviewed journal: Annals Of Internal Medicine.
Isolated cases of symptom and viral rebound and recurrence of culture-positive virus have been reported after nirmatrelvir–ritonavir treatment (3–5, 15). However, much of the literature has described the co-occurrence of symptom and viral rebound in noncontrolled settings or with limited sampling.
To help improve the understanding of the natural course of COVID-19, we analyzed the symptom and viral rebound dynamics of participants receiving placebo in the randomized, placebo-controlled ACTIV-2/A5401 trial for outpatients.
Overall, we found that viral or symptom rebound after initial improvement was relatively common, with 1 in 4 participants having symptom rebound and almost 1 in 3 having viral rebound during their infection, as assessed by daily symptom and nasal virus sampling. However, both symptom and viral rebound were short, lasting only 1 day in most participants.
In addition, the combination of symptom and high-level viral (≥5.0 log10 RNA copies/mL) rebound occurred in only 3% of study participants receiving placebo. Together, these results show that although a waxing and waning symptom course may be common during recovery from acute COVID-19, symptom relapse with high-level viral rebound is rare in untreated persons.
In the analysis of the EPIC-HR phase 3 outpatient study of nirmatrelvir–ritonavir for mild to moderate COVID-19, an increase of 0.5 log10 copies/mL or greater in nasal SARS-CoV-2 RNA levels from posttreatment levels was detected in approximately 4% of participants receiving placebo and 7% of participants receiving nirmatrelvir–ritonavir (8).
However, viral RNA levels were quantified at only 2 follow-up time points (5 and 9 days after the end of nirmatrelvir–ritonavir treatment or placebo). In the ACTIV-2/A5401 trial, nasal RNA was quantified daily between days 0 and 14, which likely explains the substantially higher rates of viral rebound (31%) in our analysis.
We could also define rates of viral rebound at differing viral load thresholds, with a 13% rate of high-level viral rebound using a viral load threshold associated with culture positivity (14).
Our finding that symptom rebound after initial improvement is also common during the disease course of untreated COVID-19 aligns with a prior analysis evaluating a smaller group of patients after complete symptom resolution (11). We also identified characteristics associated with the occurrence of symptom rebound, including female sex, having risk factors for severe disease, and having higher levels of nasal SARS-CoV-2 RNA shedding and symptom scores at study enrollment.
The relapsing symptoms described here during acute SARS-CoV-2 infection have several potential causes. One possibility is that viral dissemination into different anatomical compartments over time could cause an evolving series of symptoms (12, 13). Another explanation is infection with 2 separate SARS-CoV-2 variants, which has been described but is still believed to be a rare occurrence (16).
In addition, co-infection with another respiratory virus is a possibility, along with symptom rebound from a noninfectious cause. Given its high frequency, symptom rebound during acute COVID-19 is likely to be multifactorial. It should be noted that the duration of symptom and viral rebound observed in this study was short, 1 day in most cases.
This is in contrast to the more prolonged symptom and viral rebound after nirmatrelvir–ritonavir treatment in previous case reports (3, 4, 15) that may indicate differences in the characteristics of the rebound episodes occurring with or without antiviral therapy, or bias in reported cases.
This study has limitations. In general, our observations could be affected by the underlying study population because the ACTIV-2/A5401 study enrolled a largely unvaccinated population infected with pre-Omicron variants. Of note, recently published studies have reported that neither vaccination nor Omicron variants substantially alter viral decay kinetics (14, 17).
In addition, we did not include anosmia or ageusia in the symptom scoring because they have been reported to be of prolonged duration and may not resolve during the early recovery period. Because the ACTIV-2/A5401 study did not enroll participants receiving nirmatrelvir–ritonavir, we cannot define rates of posttreatment viral or symptom rebound associated with this treatment.
Another limitation is that this study did not include assessments of immune responses, and a maturing immune response reacting to the sudden reappearance of viral antigen could be an important contributory factor in symptomatic rebound (3, 5).
In summary, we observed that symptom and viral RNA rebound are individually common in participants who are not treated with antiviral agents. Our results highlight the importance of accounting for underlying rates of symptom relapse in the absence of antiviral therapy when evaluating the effects of antiviral treatments.
However, in the absence of antiviral therapy, the co-occurrence of both symptom and high-level viral rebound was rare and the observed short-term symptom relapses were not generally indicative of greater infectivity. These results provide insight into the natural trajectory of viral rebound and symptom relapses during COVID-19, which is critical in the interpretation of studies reporting biphasic disease courses after nirmatrelvir–ritonavir or other antiviral treatment.
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