As the SARS-CoV-2 pandemic continues to evolve, efforts to understand variability in COVID-19 recovery, as well as the impact of factors including viral variants, vaccine status, and COVID-19 treatment on the development and persistence of Long COVID symptoms have intensified. This case series demonstrates that variability in the timing of antiviral therapy may be associated with different outcomes and underscores the need for systematic study of antiviral therapy for this disease condition during both the acute and convalescent stages.
It has been suggested that the viral burden during acute infection may be an important determinant of Long COVID,1 and that early antiviral therapy might mitigate this risk. In Case 1, the individual took nirmatrelvir/ritonavir according to the recent Emergency Use Authorization (EUA) criteria2 and shortly thereafter experienced rebound symptoms, which were associated with physiologic changes measured using a fitness device. Symptomatic relapses of SARS-CoV-2 infection are just now starting to be reported.3 Although he was not re-tested during this period, it is possible that this coincided with viral rebound upon the completion of therapy. Concerningly, he subsequently experienced worsening post-infectious symptoms which now meet U.S. Centers for Disease Control (CDC) criteria for Long COVID.4 This suggests that although a short course of early antiviral therapy is adequate to prevent severe acute disease in high-risk patients,5 it may be insufficient to prevent the development of Long COVID, and those experiencing rebound symptoms could remain at risk.
A related hypothesis is that SARS-CoV-2 may persist for weeks to months in some individuals, causing inflammation, local tissue damage and end-organ disease.6–8 If this turns out to be the case, antiviral therapy during the acute and post-acute stages may prevent or even reverse Long COVID. Although not approved under the EUA,2 there are reports emerging about individuals accessing oral antiviral therapy at later points in the disease course and the potential effects of these therapies.9 We present two cases in which individuals were able to access nirmatrelvir/ritonavir for clinical care in the setting of persistent COVID-19 symptoms. There were notable differences between these cases, including the timing of antiviral therapy from initial infection (> 60 days and < 30 days, respectively), as well as potential lineage differences based on the timing of infection (Winter 2021–2022 versus Spring 2022). While single anecdotes must be interpreted with caution, these cases emphasize the urgent need for carefully designed studies to assess the impact of antiviral therapy beyond the acute window. Confirmation of a benefit in the context of such studies would support the hypothesis that persistent viral activity, particularly in the tissues, could be one contributor to ongoing symptoms in Long COVID.
An additional factor in one of these cases was a clear re-exposure and potential re-infection event, after which the individual began to experience improvement in Long COVID symptoms which had until that point been escalating. Although vaccines are likely to reduce the risk of developing Long COVID,10 there are numerous, but inconsistent, reports of the impact of SARS-CoV-2 vaccination on pre-existing Long COVID symptoms.11,12 A dysregulated immune response has been proposed as a potential mechanism underlying Long COVID pathophysiology.1,13,14 The fact that re-exposure to viral antigen may have led to symptomatic improvement is intriguing, suggesting the possibility that a dysregulated immune response, if present, could be recalibrated.
Although this case series is limited by a lack of intensive physiologic and laboratory measurements throughout the disease course, we believe these clinical anecdotes are informative as investigators try to understand the pathophysiology that drives the development and persistence of Long COVID. They suggest that antiviral therapy and/or antigen re-exposure could potentially impact the complex interplay between viral replication and the host immune response that likely underlies this syndrome but raise concern that brief early antiviral therapy alone may be insufficient to prevent the development of Long COVID.