COVID-19 rebound risks similar for paxlovid and molnupiravir

In a recent article on the medRxiv* Preprint server, researchers in the United States showed that some patients experienced recurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after therapy with molnupiravir and Paxlovid SARS-CoV-2 can come.

Study: COVID-19 rebound after paxlovid and molnupiravir in January-June 2022. Image credit: NIAIDStudy: 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 people at high risk of developing serious disease. However, recent case reports show that some patients suffered from rebound CoV disease 2019 (COVID-19) and disease-related symptoms two to eight days after completing a five-day treatment with Paxlovid.

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

About the study

The present work aimed to assess the relative risks and rates of a COVID-19 rebound in SARS-CoV-2 patients receiving paxlovid or molnupiravir therapy and to compare the characteristics of individuals who experience a rebound suffered and have not suffered from the SARS-CoV-2 infection. Researchers used the TriNetX Analytics network system, a nationwide, multi-center database in the United States (US), to conduct a retrospective cohort analysis of electronic health records (EHRs) of approximately 92 million individuals.

The study population included 13,644 subjects ≥ 18 years of age who became COVID-19 positive between January 1 and June 8, 2022. Additionally, within five days of contracting SARS-CoV-2, 11,270 and 2,374 of these individuals received paxlovid and molnupiravir therapy, respectively. COVID-19 patients treated with both paxlovid and molnupiravir were excluded from the study. The International Classification of Diseases, 10th Revision (ICD-10) diagnostic 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 participants .

The primary findings and metrics of the research were three types of COVID-19 rebound events (SARS-CoV-2 infections, COVID-19 associated symptoms, and SARS-CoV-2 associated hospitalizations) occurring two days after the last day of molnupiravir or paxlovid therapy. In addition, the 95% confidence intervals (CI) and hazard ratios (HR) of the 7-day and 30-day likelihood of COVID-19 rebound in patients treated with paxlovid and molnupiravir before and after Propensity score matching calculated.


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

In the two groups in the present study, patients treated with Paxlovid differed significantly from those treated with molnupiravir, even though both drugs were approved for use in SARS-CoV-2 infected individuals at high risk of severe COVID-19. The median age of Paxlovid-treated patients was 56 compared to 62 for molnupiravir-treated patients, and the original cohort also had fewer co-existing health conditions. In addition, the Paxlovid arm included more Hispanic, female, Black and Asian patients.

The rates of COVID-19 rebound after 7-day and 30-day Paxlovid treatment 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 hospital admissions, respectively. After molnupiravir therapy, 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 propensity score matching: 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). Also, patients with SARS-CoV-2 rebound had a statistically higher prevalence of underlying health conditions compared to patients without SARS-CoV-2.


Study results indicated that SARS-CoV-2 rebound occurred after treatment with both molnupiravir and Paxlovid, particularly in patients with pre-existing conditions. This shows that the COVID-19 rebound was not specific to Paxlovid and that the risks were comparable for both Paxlovid and molnupiravir. The team suggests that the rebound in some people who received either antiviral drug could be related to a chronic viral infection. Additionally, SARS-CoV-2 rebound rates for both drugs increased over time after treatments.

The current results require continuous monitoring of COVID-19 rebound after treatments with molnupiravir and paxlovid. The authors stated that further studies are needed to identify the mechanisms underlying SARS-CoV-2 rebounds and to evaluate dosing and duration regimens that could halt them in susceptible patients.

*Important NOTE

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

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