In a fraction of SARS-CoV-2 infected individuals treated with the oral antiviral Paxlovid, the virus rebounds following treatment. The mechanism driving rebound is not understood. Here, we show that viral dynamic models based on the hypothesis that Paxlovid treatment near the time of symptom onset halts the depletion of target cells, but may not fully eliminate the virus, which can lead to viral rebound. We also show that the occurrence of viral rebound is sensitive to model parameters, and the time treatment is initiated, which may explain why only a fraction of individuals develop viral rebound. Finally, the models are used to test the therapeutic effects of two alternative treatment schemes. These findings also provide a possible explanation for rebounds following other antiviral treatments for SARS-CoV-2.

ASP owns stock in Pfizer. He was also on a Pfizer advisory committee and received an honorarium. The other authors declare that they have no competing interests.

This work was performed under the auspices of the US Dept. of Energy under contract 89233218CNA000001 and supported by National Institutes of Health grant R01-OD011095 (ASP) National Institutes of Health grant R01-AI116868 (RMR) National Institutes of Health grant U54-HL143541-04 (RMR) Los Alamos National Laboratory LDRD 20200743ER, 20200695ER, and 20210730ER.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used only openly available human data that were originally reported by M. E. Charness et al., Rebound of SARS CoV 2 Infection after Nirmatrelvir Ritonavir Treatment. N. Engl. J. Med. 387, 1045-1047 (2022).

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There are no original data underlying this work. Only previously published data were used for this study by Charness et al. (2022). The viral load values used in this study are given in the Supplementary Materials. M. E. Charness et al., Rebound of SARS CoV 2 Infection after Nirmatrelvir Ritonavir Treatment. N. Engl. J. Med. 387, 1045-1047 (2022).