What to Know About COVID Rebound

The Centers for Disease Control and Prevention (CDC) and US Food and Drug Administration (FDA) recently released studies examining whether there was an association between the use of oral antiviral treatments for COVID-19 and the occurrence of COVID-19 rebound. COVID-19 rebound is typically described as a recurrence of symptoms or a new positive viral test after testing negative. Researchers found that there was no consistent association between antiviral treatment for COVID-19 (eg, nirmatrelvir-ritonavir) and COVID-19 rebound. Among people at higher risk for progression to severe disease, the substantial benefits of treatment outweigh the risk for COVID-19 rebound.

What do we currently know about COVID-19 rebound?

Current evidence, including randomized controlled trial and observational data, suggests that SARS-CoV-2 rebound occurs initially as a mild illness 3-7 days after resolution of the initial acute illness, occurs in both treated and untreated patients, and is not associated specifically with receiving nirmatrelvir-ritonavir. There was no increased risk for hospitalization or death among people with rebound. Moreover, rebound occurs when there is variable, host-mounted immune response to infection during the course of illness.

What should clinicians know when treating patients?

A person's risk of experiencing rebound could be related to a range of factors, such as immunosuppression, delayed viral clearance, and overall immune response. Data are limited on risk factors for COVID-19 rebound. One study in the review found that COVID-19 rebound may occur more frequently among persons aged 18-65 years, persons with immunocompromising conditions, and persons who were taking steroids.

Rebound was not associated with drug resistance in the studies examined. It is important to ensure that use of antivirals does not accelerate viral evolution and result in resistant mutations, such as through counseling patients to complete antiviral treatment and monitoring for resistance using molecular analyses.

Two studies demonstrated the shedding of infectious virus during rebound, suggesting that patients with rebound are contagious. CDC recommends that people with rebound re-isolate per CDC guidelines.

For information on providing care to high-risk patients with COVID-19, please visit COVID-19 Treatment Guidelines.

Why do some studies show that rebound rates are higher among treated persons?

Some observational studies demonstrated a higher frequency of rebound among treated persons (10%-14%) than was reported by the randomized controlled trial EPIC-HR (Supplementary Table). Depending on the definition used, the prevalence of rebound varied. In four studies, including the randomized trial, no statistically significant difference in rebound rates was identified among persons receiving treatment and those not receiving treatment. Persons receiving antiviral treatment might be at higher risk for rebound compared with persons not receiving treatment because of host factors or treatment-induced viral suppression early in the course of illness. 

Viral rebound might occur in persons on antiviral treatment because they are at high risk for severe disease and might have host factors, such as immunosuppression, that contribute to the natural variability in viral dynamics. Risk factors for rebound appear to be similar to those for severe disease, but further studies are needed to understand whether persons with certain characteristics or underlying medical conditions are predisposed to experiencing rebound.

Another important consideration is that persons receiving antiviral treatment might be at higher risk of experiencing rebound given the viral suppression related to use of treatment early in the disease course and resumption of viral replication after completion of treatment because of delayed viral clearance. This elevated risk could be due to early discontinuation of antiviral treatment or the need for longer courses of treatment among certain persons, such as those who are immunocompromised.

Do patients who have rebound need longer treatment courses or additional treatment courses?

Two ongoing clinical trials of nirmatrelvir-ritonavir will further characterize the frequency of rebound after different durations of nirmatrelvir-ritonavir treatment among immunocompromised individuals and the potential benefit of nirmatrelvir-ritonavir retreatment among those with posttreatment rebound. The results of these trials should inform recommendations for treatment in the context of rebound.

Does the risk for rebound infection outweigh the clinical benefits of treatment?

No. The substantial benefit of antiviral COVID-19 treatment for people who are at high risk for severe disease and who do not have contraindications to the chosen treatment outweighs the risk for rebound. In cases wherein rebound does occur, rebound resolves quickly and is not associated with an increase in severity of symptoms, hospitalization, or drug resistance. Monitoring drug resistance is an important part of postmarketing surveillance of any new medication. To date, resistance to nirmatrelvir-ritonavir has been rare.

As recommended by the National Institutes of Health COVID-19 Treatment Guidelines Panel, rebound should not deter clinicians from prescribing lifesaving treatments that prevent severe illness and death from COVID-19 for eligible patients.

What are the implications for public health practice?

Clinicians should continue to prescribe antiviral treatments for eligible patients given the substantial benefit of reducing the risk for severe illness, hospitalization, and death.

Important Considerations

Are antivirals a replacement for COVID-19 vaccination?

No. It is very important to stay up-to-date with COVID-19 vaccines. COVID-19 vaccination substantially reduces the risk for disease, hospitalization, and death. Antiviral treatments further reduce this risk and provide additional benefits for people who are at higher risk for severe COVID-19 outcomes, regardless of vaccination status. Persons at risk for severe disease include older adults, especially patients aged 65 years or older, patients who aren't up-to-date on COVID-19 vaccinations, and people with certain medical conditions that make them more likely to get very sick with COVID-19, such as weakened immune systems. CDC recommends that everyone aged 6 months or older get an updated (2023-2024 formula) COVID-19 vaccine.

The JN.1 variant continues to increase in proportion across the United States. Are antivirals effective against illness caused by emerging variants?

It's important to know that existing vaccines, tests, and treatments still work well against JN.1 as well as other currently circulating variants. Recent laboratory data (here and here) show that the updated 2023-2024 COVID-19 vaccines produce antibodies that protect against JN.1, further indicating that our vaccines should work against this variant. At this time, the spread of JN.1 does not appear to pose additional risks to public health beyond that of other recent variants. CDC is closely monitoring COVID-19 increases domestically and internationally.

All available COVID-19 antivirals are effective against currently circulating variants. FDA provides information about how variants affect SARS-CoV-2 tests on their webpage.

COVID-19 antivirals have recently transitioned to the commercial market. How will eligible individuals, including those who are uninsured or underinsured, continue to access antivirals?

Clinicians should continue to order and dispense US Government (USG)–procured nirmatrelvir-ritonavir to allow sufficient time for the specific patient assistance programs to ramp-up.

On November 1, 2023, ritonavir-boosted nirmatrelvir and molnupiravir became commercially available. Eligible patients can get COVID-19 antivirals for free or at a reduced cost even if they do not have insurance. For more information, please visit COVID-19 Therapeutics Commercialization Transition Guide.

Patients with Medicare and Medicaid as well as those who are uninsured will continue to receive nirmatrelvir-ritonavir at no charge through 2024 through the USG Patient Assistance Program (PAP) operated by Pfizer. This includes all patients who are publicly insured through Medicare (with or without Part D, Part B, or Part C and inclusive of Medicare Advantage), Medicaid/Children's Health Insurance Program, TRICARE, and patients insured through the Veteran's Affairs Community Care Network. The USG PAP using USG-procured supply (commercial, New Drug Application–labeled) started December 1, 2023 and will end December 31, 2024.

Patient assistance programs that help pay for these drugs are available to people who are underinsured, uninsured, or publicly insured through Medicaid, Medicare, or other programs.

Once they have a prescription, patients may be eligible for reduced or no-cost antivirals through:

• Manufacturer access programs such as PAXCESS (nirmatrelvir-ritonavir), including the USG PAP operated by Pfizer, Merck Helps (molnupiravir), and Gilead's Advancing Access (remdesivir)

• Home Test to Treat program: free tests, a telehealth appointment with a healthcare provider, and treatment if eligible, shipped directly to the patient

Patients that use certain federal entities, including Health Resource & Services Administration–supported health centers such as Federally Qualified Health Centers, Indian Health Service sites, and others, will have continued access to free USG-procured nirmatrelvir-ritonavir and molnupiravir.

Will the COVID-19 oral antiviral treatments be covered by commercial insurers, or will the cost need to be covered entirely by the patient?

Federal law does not require commercial plans to cover all possible COVID-19 treatments or put any limits on patient cost-sharing for any commercial plans if the treatments are covered. Patients should contact their insurer or clinician for more information on treatment coverage. For more information, see COVID-19 Therapeutics Transition to Commercial Distribution: Frequently Asked Questions.

With COVID-19 hospitalizations remaining elevated, it is important that people who get sick and are eligible for antivirals get treatment in the first days of illness because symptoms can change and worsen quickly. Though these antivirals are effective at preventing severe disease, not enough people are taking them. If more eligible people get treatment in a timely manner, we will save lives. Clinicians should continue to prescribe antiviral treatments for eligible patients given the substantial benefit of reducing the risk for severe illness, hospitalization, and death.

Credits:
Lead image: Medscape composite/Dreamstime

Public Information from the CDC and Medscape

Cite this: What to Know About COVID Rebound - Medscape - Feb 21, 2024.