Paxlovid (nirmatrelvir/ritonavir) was touted as a “breakthrough” and a “wonder drug” for COVID-19 when Pfizer released their preliminary data in late 2021. Now that it is being widely used, cases of viral rebound or COVID 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 more than 40 kg body weight) with mild-to-moderate COVID-19 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 CDC.

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 are contraindicated. However, there are a variety of other drug interactions that should 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 percent reduction in hospitalization or death among unvaccinated patients with mild-moderate COVID-19 at high risk for severe disease. Paxlovid also led to faster viral clearance.

What is viral rebound or COVID rebound?

Viral rebound refers to a new positive test after testing negative, even if the patient remains asymptomatic. COVID rebound is a flare up of symptoms after resolution of acute illness. The timing of viral or COVID 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.   

COVID rebound is a flare up of symptoms after resolution of acute illness.

How many patients 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 two percent of EPIC-HR participants taking Paxlovid had a viral load rebound, but that it was about the same percentage in the placebo group. Therefore, their interpretation was that it was a natural progression of the viral infection and not caused by Paxlovid therapy.

One difference between the EPIC-HR study and current estimates of rebound 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 only included unvaccinated participants, while real-world use of Paxlovid includes many vaccinated individuals. However, one would hypothesize vaccination to reduce likelihood of rebound, not increase it, if it was contributing.

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

One obvious issue with viral rebound is the possibility that patients who rebound progress to severe COVID-19 requiring hospitalization despite treatment. While there are limited reports at this time, rebound does not appear to be associated with progression of disease. For patients with rebound, it is advised to monitor and reevaluate if symptoms persist. Retreatment with Paxlovid is not recommended. Also consider reporting the event to Pfizer Safety Reporting, FDA MedWatch or complete and submit FDA Form 3500 by fax (1-800-FDA-0178).

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

Finally, like the growth of bacteria in the presence of antibiotics, viruses can develop resistance to antiviral agents. Limited investigation so far does not support that rebounded SARS-CoV-2 virus 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 common it occurs and the clinical ramifications of viral rebound before changing advice for Paxlovid. Until that time, Paxlovid remains a first-line option for high-risk patients.