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Is There a Risk for Rebound COVID-19 with Antiviral Therapy?

  • Authors: News Author: Lisa O’Mary; CME Author: Charles P. Vega, MD
  • CME / ABIM MOC / CE Released: 3/24/2023
  • Valid for credit through: 3/24/2024
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  • Credits Available

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Target Audience and Goal Statement

This activity is intended for primary care physicians, infectious disease specialists, nurses, pharmacists, physician assistants, and other clinicians who care for adults with COVID-19 infection.

The goal of this activity is for learners to be better able to evaluate the risk for viral rebound of SARS-CoV-2 after treatment with oral antiviral therapy vs no antiviral therapy.

Upon completion of this activity, participants will:

  • Describe the currently approved antiviral therapies for infections with SARS-CoV-2 virus
  • Evaluate the risk for viral rebound of SARS-CoV-2 after treatment with oral antiviral therapy or no antiviral therapy
  • Outline implications for the healthcare team


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News Author

  • Lisa O’Mary

    Freelance writer, Medscape


    Lisa O’Mary has no relevant financial relationships.

CME Author

  • Charles P. Vega, MD

    Health Sciences Clinical Professor of Family Medicine
    University of California, Irvine School of Medicine


    Charles P. Vega, MD, has the following relevant financial relationships:
    Consultant or advisor for: GlaxoSmithKline; Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Editor/Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


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  • Leigh Schmidt, MSN, RN, CNE, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Leigh Schmidt, MSN, RN, CNE, CHCP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Is There a Risk for Rebound COVID-19 with Antiviral Therapy?

Authors: News Author: Lisa O’Mary; CME Author: Charles P. Vega, MDFaculty and Disclosures

CME / ABIM MOC / CE Released: 3/24/2023

Valid for credit through: 3/24/2024


Note: The information on the coronavirus outbreak is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available. It is the policy of Medscape Education to avoid the mention of brand names or specific manufacturers in accredited educational activities. However, manufacturer names related to the approved COVID-19 vaccines are provided in this activity in an effort to promote clarity. The use of manufacturer names should not be viewed as an endorsement by Medscape of any specific product or manufacturer.

Clinical Context

Individuals infected with the SARS-CoV-2 virus may experience bothersome symptoms lasting a few to several days. With antiviral medications, the severity of these symptoms may be lessened, and the duration may be shortened. Approved antivirals for the treatment of SARS-CoV-2 may be administered through intravenous infusion or given orally.

Nirmatrelvir-ritonavir and molnupravir are the two approved oral antiviral agents for SARS-CoV-2. Both inhibit viral replication through different viral targets. Nirmatrelvir-ritonivir targets the main protease of SARS-CoV-2, while molnupiravir targets the viral RNA-dependent RNA polymerase. While current guidelines recommend the use of these agents within 5 days of symptom onset for adult patients with mild to moderate COVID-19 who are at high risk of disease progression, nirmatrelvir-ritonavir is recommended over molnupravir unless it is not available, feasible to use, or clinically appropriate.

Utilizing antiviral therapy can be beneficial for patients infected with SARS-CoV-2, but it does not come without limitations. One such limitation is the possibility of rebound infection, as defined by a viral load that increases after an initial reduction. A recent study examines this issue.

Antivirals in the Omicron Era

A recent study by Aggarwal and colleagues examined the efficacy of nirmatrelvir-ritonavir against subvariants of the Omicron variant, using a retrospective analysis of outpatients with COVID-19 diagnosed in Colorado between March and August 2022. This study period included infections with the BA.4 and BA.5 variants of SARS-CoV-2. The results of their study were published February 10, 2023, in the Lancet Infectious Diseases.[1]

A total of 9881 patients treated with nirmatrelvir-ritonavir were compared with 11,612 patients who were untreated. The adjusted odds ratio (OR) for hospitalization within 28 days of a positive COVID-19 test was 0.45 (95% CI, 0.33-0.62) in comparing the nirmatrelvir-ritonavir vs placebo groups. Nirmatrelvir-ritonavir was also associated with a lower risk for mortality at 28 days (OR, 0.15; 95% CI, 0.03-0.50), as well as a slight reduction in subsequent visits to the emergency department.

As of the date of publication of this article, a similar study with molnupravir has not been published.

Current Study Synopsis and Perspective

People who received the antivirals nirmatrelvir-ritonavir or molnupiravir to treat COVID-19 infections were not more likely to get back-to-back bouts of the virus, a new study shows.

The findings offer clarity amid concerns that the use of antivirals, which work by stopping the spread of the virus in the body, increased the risk for COVID-19 rebound.

“Rebound is a re-emergence of symptoms and an uptick in viral load after a period of recovery,” the Center for Infectious Disease Research and Policy explained in a summary of the study.

The researchers found that patients who received nirmatrelvir-ritonavir, another antiviral called molnupiravir, or no antiviral medication had rebounds at similar rates, ranging from 4.5% to 6.6%.

The study was published February 13 in the Lancet Infectious Diseases and included 4592 people in Hong Kong who were hospitalized within 3 days of a COVID diagnosis.[2] The study period was from February 26, 2022, to July 3, 2022, which is the time that the Omicron subvariant BA.2.2 was predominant.

The study further found that the risk for rebound was tied to being 18 to 65 years old (compared with older patients), having chronic medical conditions, and receiving steroid treatment. Another finding, which the authors noted was important, was that it appeared that the use of antivirals did not make rebounds more severe. People who received antivirals and had a rebound infection were not more likely to be admitted to the intensive care unit, need a ventilator to help them breathe, or die.

In a commentary published alongside the study, infectious disease expert Nicola Petrosillo, MD, noted that an unexpected finding was the relationship between vaccination status and rebound.[3]

“Surprisingly, the odds of viral burden rebound in patients receiving nirmatrelvir-ritonavir were significantly reduced in individuals who were not fully vaccinated,” he noted. 

Dr Petrosillo, who treated some of the earliest COVID cases in Rome, said that the takeaway from the study is the importance of continuing to offer antivirals to people at high risk of developing severe COVID.

Lancet Infect Dis. Published online February 13, 2023.

Study Highlights

  • The study was conducted using a retrospective cohort design. Research examined adults at least 18 years old with COVID-19 diagnosed in Hong Kong, China, between February and July 2022. This corresponded with high prevalence of the Omicron BA.2.2 variant.
  • Patients were admitted to the hospital for COVID-19 within 3 days of a positive test. The current study was limited to individuals who did not require oxygen therapy.
  • Patients who received molnupiravir and nirmatrelvir-ritonavir were compared with adults not receiving treatment.
  • The main study outcome was cycle threshold values on subsequent quantitative RT-polymerase chain reaction tests after the initial test. Researchers considered a decrease in cycle threshold values of at least 3 units to correspond with an 8 times increase in viral RNA, signifying viral rebound.
  • The main study outcome was adjusted to account for demographic variables, as well as comorbid illnesses, vaccination status, concomitant steroids, and especially immunocompromised status.
  • 4592 patients were evaluated; 56.5% of patients were men and 86% of patients were older than 65 years. Less than 5% of the cohort was fully vaccinated against SARS-CoV-2.
  • 563 patients received molnupiravir and 242 received nirmatrelvir-ritonavir. The remaining 3787 patients were not treated for SARS-CoV-2.
  • The second polymerase chain reaction test was completed on average about 10 days after the first positive test.
  • The rates of rebound were 6.6% in the nirmatrelvir-ritonavir group, 4.8% in the molnupiravir group, and 4.5% in the untreated control group. There was no significant difference between groups in the rate of viral rebound.
  • Viral rebound was more common in both active treatment groups among individuals aged 18 to 65 years and among those receiving concomitant corticosteroids. Incomplete vaccination history was associated with a lower risk for viral rebound.
  • There was no evidence that viral rebound increased the rate of complications of COVID-19.

Clinical Implications

  • Oral antiviral agents nirmatrelvir-ritonavir and molnupiravir may lessen the severity and shorten the duration of SARS-CoV-2 infection. Current guidelines recommend nirmatrelvir-ritonavir over molnupiravir when available, feasible, and clinically appropriate. Concerns of viral rebound after the use of oral antivirals have previously been reported.
  • The current study finds a similar rate of viral rebound among hospitalized patients treated with nirmatrelvir-ritonavir, molnupiravir, and no antiviral treatment. The overall rebound rate was around 5% and was not associated with any clinical deterioration. Age 18 to 65 years and a history of the use of corticosteroids were associated with higher rates of rebound.
  • Implications for the healthcare team: The health care team should answer questions that patients may have about the possibility of rebound after treatment for COVID-19 with reassuring results from the current study.


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