Canadian Medical Association

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Paxlovid (nirmatrelvir/ritonavir) was touted as a “breakthrough” and a “wonder drug” to treat COVID-19 when Pfizer released preliminary data in late 2021. Now that it is being widely used, cases of viral rebound or COVID-19 rebound have been reported. Here’s what we know about Paxlovid efficacy and rebound.

What is Paxlovid?

Paxlovid consists of two separate agents: nirmatrelvir and ritonavir. Nirmatrelvir prevents the SARS-CoV-2 virus from replicating by blocking its protease enzyme. Ritonavir is a boosting agent that helps nirmatrelvir last long enough in the body to be effective.

Paxlovid is taken orally twice daily for five days and should be initiated as soon as possible after diagnosis of COVID-19 in select patients described below, and within five days of symptom onset. Dysgeusia (altered sense of taste) and diarrhea are the most common adverse effects.

Who is eligible for Paxlovid?

Paxlovid is the first-line option for non-hospitalized patients at least 12 years old (and weighing over 40 kg) with mild-to-moderate COVID-19 and at high risk for severe disease. High risk includes people over the age of 64, persons with obesity, pregnant individuals and patients with other underlying conditions outlined by the Public Health Agency of Canada and the US Centers for Disease Control and Prevention.

Medication interactions are an issue with Paxlovid and a careful review of a patient’s current medications for potential interactions is necessary before initiating treatment. Concomitant use of rivaroxaban or salmeterol is contraindicated. A variety of other drug interactions should also be considered, and adjustments and monitoring may be necessary. Importantly, Paxlovid is also contraindicated in patients with severe renal or hepatic dysfunction.

How effective is Paxlovid?

In the EPIC-HR trial, Paxlovid resulted in nearly 90% reduction in hospitalization or death among unvaccinated patients with mild-to-moderate COVID-19 and at high risk for severe disease. Paxlovid also led to faster viral clearance.

What is viral rebound or COVID-19 rebound?

Viral rebound is the phenomenon in which a patient has a new positive test result after testing negative, even if they remain asymptomatic. COVID-19 rebound is a flare-up of symptoms after resolution of acute illness. The timing of viral or COVID-19 rebound seems to be about two to eight days after recovery, and both recurrence of illness and positive test results have resolved in the few case reports documenting rebound. 

How many patients experience rebound after Paxlovid?

There is no concrete answer to this question and estimates vary widely. It is thought to be a rare occurrence.

Interestingly, the EPIC-HR trial researchers measured viral load out to 14 days but chose to report mean change in viral load per group, which may conceal viral rebound among a subset of patients. In a Pfizer earnings call, William Pao, executive VP and chief development officer, stated that about 2% of EPIC-HR participants taking Paxlovid had a viral load rebound but that it was about the same percentage in the placebo group. Therefore, Pfizer’s interpretation was that viral load rebound was a natural progression of the viral infection and not caused by Paxlovid therapy.

One difference between the EPIC-HR study and the current situation could be the SARS-CoV-2 virus. The EPIC-HR trial was conducted during the Delta wave, while we are currently in the midst of various Omicron subvariant surges. Another difference could be vaccination status. The EPIC-HR trial included only unvaccinated participants, while real-world use of Paxlovid includes many vaccinated individuals. However, one would hypothesize that vaccination reduces the likelihood of rebound and doesn’t increase the risk.

What should I do if my patient has COVID-19 rebound and what are the concerns?

One obvious issue with viral rebound is the possibility that, despite treatment, patients who rebound progress to severe COVID-19 requiring hospitalization. While there are limited reports at this time, rebound does not appear to be associated with progression of disease. Patients with rebound should be monitored and reevaluated if symptoms persist. Retreatment with Paxlovid is not recommended. Health care providers should consider reporting the event to Health Canada’s Canada Vigilance adverse reaction online database.

Another problem with viral rebound is the potential for patients to become infectious again and unknowingly contribute to transmission. Thus, if a patient has been diagnosed with viral or COVID-19 rebound they should isolate themselves for at least five days and continue to wear a mask for 10 days (isolation can end after five days if symptoms have improved and there is no fever for 24 hours without fever-suppressing medications).

Finally, like the growth of bacteria in the presence of antibiotics, viruses can develop resistance to antiviral agents. Limited investigation so far does not indicate that the SARS-CoV-2 virus in rebound infections contains additional mutations that would confer resistance. In the long term, viral resistance remains a possibility and will continue to be monitored.

Ultimately, we need to understand how commonly viral rebound occurs and its clinical ramifications before changing the advice for Paxlovid. Until that time, Paxlovid remains a first-line option for high-risk patients.

Related articles

Outpatient therapy for COVID-19: What are the options and who is eligible?

An antiviral pill for COVID-19 — is molnupiravir too good to be true?

PrEP and PEP: Can medications work to prevent COVID-19? (cma.ca)


Original article published on EBM Focus. Written by:

  • Heather D. Marshall, PhD, Public Health Content Manager at DynaMed; and
  • Vito Iacoviello, MD, Deputy Editor for Infectious Disease, Allergy, and Immunology at DynaMed.

CMA members have access to DynaMed, a point-of-care reference tool valued at US$399 per year, as part of their membership.

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