Study: COVID-19 rebound after Paxlovid and Molnupiravir during January-June 2022. Image Credit: NIAID

COVID-19 rebound risks similar for Paxlovid and Molnupiravir

In a recent article posted on the medRxiv* preprint server, researchers in the United States have shown that some patients may experience a rebound of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after treatment with molnupiravir and Paxlovid SARS-CoV-2.

Study: COVID-19 rebound after Paxlovid and Molnupiravir in January-June 2022† ​​​​​​​Image credit: NIAID


In December 2021, the Food and Drug Administration (FDA) approved Paxlovid (nirmatrelvir) and Lagevrio (molnupiravir) for the treatment of mild to moderate SARS-CoV-2 infection in individuals at high risk of developing serious disease. However, recent case reports show that two to eight days after finishing a five-day treatment with Paxlovid, some patients suffered rebound 2019 CoV disease (COVID-19) and disease-related symptoms.

To educate the public about the possibility of a rebound from COVID-19 after Paxlovid therapy, the Centers for Disease Control and Prevention (CDC) recently released a Health Alert Network Health Advisory. Nevertheless, the prevalence of COVID-19 rebound in the general population remains uncertain, whether Paxlovid is the only drug causing the rebound of SARS-CoV-2 infection, or whether some people are more sensitive than others.

About the study

The current work focused on assessing the relative risks and rates of COVID-19 rebound in SARS-CoV-2 patients receiving Paxlovid or molnupiravir therapy and comparing the characteristics of individuals who did and did not rebound. of SARS-CoV-2 infection. The researchers used the TriNetX Analytics network system, a nationwide, multicenter database in the United States (U.S.), to perform a retrospective cohort analysis on the electronic health records (EHRs) of approximately 92 million individuals.

The study population consisted of 13,644 subjects aged 18 years and older who became COVID-19 positive between January 1 and June 8, 2022. Furthermore, within five days of contracting SARS-CoV-2, 11,270 and 2,374 of these subjects received therapy with Paxlovid and molnupiravir, respectively. † COVID-19 patients treated with both Paxlovid and molnupiravir were excluded from the study. The International Classification of Diseases, 10th Revision (ICD-10) diagnosis code for COVID-19, i.e. U07.1, or laboratory-confirmed SARS-CoV-2 infection, was used to determine the status of COVID-19 among the participants.

The primary results and statistics of the study were three types of COVID-19 rebound events (SARS-CoV-2 infections, COVID-19-related symptoms, and SARS-CoV-2-associated hospitalizations) that occurred two days after the last day of molnupiravir or Paxlovid therapy. In addition, the 95% confidence interval (CI) and hazard ratios (HR) of the seven-day and 30-day probability of COVID-19 rebound in patients treated with Paxlovid and molnupiravir were calculated before and after propensity score matching.


Overall, the study results showed that more COVID-19 patients were treated with Paxlovid compared to molnupiravir, which may be related to the two drugs’ differing effectiveness in preventing SARS-CoV-2 related hospitalizations or deaths. high-risk patients compared to placebo (88% for Paxlovid vs. 30% for molnupiravir).

In the two groups in the current study, patients treated with Paxlovid were significantly different from patients treated with molnupiravir, despite both drugs being approved for use in SARS-CoV-2 infected individuals at high risk of serious COVID-19. The mean age of the Paxlovid-treated patients was 56 compared to 62 for the molnupiravir-treated patients, and the initial cohort also had fewer co-existing health problems. In addition, the Paxlovid arm included more Hispanics, women, black and Asian patients.

The rates of COVID-19 rebound after seven-day and 30-day treatment with Paxlovid were 3.53% and 5.40%; 2.31% and 5.87%; and 0.44% and 0.77% for SARS-CoV-2 infection, Covid-19 symptoms, and SARS-CoV-2 related hospitalizations, respectively. Following molnupiravir treatment, the 7-day and 30-day SARS-CoV-2 rebound rates were 5.86% and 8.59%; 3.75% and 8.21%; and 0.84% ​​and 1.39% for SARS-CoV-2 infection, SARS-CoV-2 symptoms, and COVID-19-related hospitalizations, respectively.

There were no significant changes in the probability of COVID-19 rebound for SARS-CoV-2 infection between molnupiravir and Paxlovid after matching the propensity score: SARS-CoV-2 infection (HR 0.90 and 95% CI: 0.73-1.11), SARS-CoV-2 symptoms (HR: 1.03 and 95% CI: 0.83-1.27), or COVID-19-related hospitalizations (HR: 0, 92 and 95% CI: 0.56-1.55). In addition, compared with those without, patients with SARS-CoV-2 rebound had a statistically higher prevalence of underlying health problems.


The study results indicated that SARS-CoV-2 rebound occurred after treatment with both molnupiravir and Paxlovid, particularly in patients with pre-existing medical conditions. This shows that the COVID-19 rebound was not specific to Paxlovid and that the risks were similar for both Paxlovid and molnupiravir. The team suggests that the rebound may be related to a chronic viral infection in some individuals who received one of the antiviral drugs. In addition, the rates of SARS-CoV-2 rebound for both drugs increased over time after treatments.

The current results mandate continued monitoring of the COVID-19 rebound after molnupiravir and Paxlovid treatments. The authors stated that further studies were needed to identify the mechanisms underlying SARS-CoV-2 rebounds and to assess dosing and duration regimens that could arrest them in susceptible patients.

*Important announcement

medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, that should guide clinical practice/health-related behavior or be treated as established information.

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