These findings may be useful to clinical laboratory professionals when physicians want guidance in effective treatments for COVID-19 patients, particularly when there are concerns about a rebound of the infection

Drug interactions are a major concern for physicians and clinical laboratories. That is especially true given the push for nearly universal COVID-19 vaccinations and boosters. Now, a study conducted in Denmark may show that the use of Paxlovid as an antiviral drug to treat early SARS-CoV-2 infection could trigger drug-drug interactions (DDI) in some patients.

For clinical laboratory managers, insights into the issues associated with Paxlovid may be useful in helping client physicians diagnose their patients and anticipate possible negative drug reactions where other anti-viral drugs are involved.

Also of interest to medical laboratory leaders is the fact that the federal Centers for Disease Control and Prevention (CDC) in May released a Health Alert Network (HAN) Health Advisory about the potential for COVID-19 rebound after Paxlovid treatment.

COVID-19 Rebound, according to the CDC, “has been reported to occur between two and eight days after initial recovery and is characterized by a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative.”

The Danish researchers published their findings in the International Journal of Infectious Diseases, titled, “Assessing the Proportion of the Danish Population at Risk of Clinically Significant Drug-Drug Interactions with New Oral Antivirals for Early Treatment of COVID-19.”

Joan Susan Bregstein, MD

In an article she penned for STAT, Joan Susan Bregstein, MD (above), a pediatric emergency medicine physician and professor of pediatrics at Columbia University Irving Medical Center in New York, wrote, “Is Paxlovid worth it? The CDC advisory states in black, bold, and no uncertain terms that, despite the risk of rebound COVID, ‘Paxlovid continues to be recommended for early-stage treatment of mild to moderate COVID-19 among persons at high risk for progression to severe disease.’ But the definition of ‘high risk’ in this situation has been a moving target since the first days of COVID-19.” Clinical laboratory leaders can attest to the accuracy of that statement. (Photo copyright: Columbia University.)

Do Anti-Viral Drugs Interact with Other Medications?

Paxlovid is the retail name for a combination of two anti-viral drugs: nirmatrelvir and ritonavir. The medication for COVID-19 was developed by American pharmaceutical company Pfizer (NYSE:PFE) and received Emergency Use Authorization from the US Food and Drug Administration in August of this year.  

The drug is taken orally for five days by people who test positive for the SARS-CoV-2 coronavirus to head off disease progression as well as serious illness, according to the CDC advisory.

But a “sizeable proportion” of elderly people are on medications that could interact with Paxlovid, Reuters reported.

“Two oral antiviral drugs—nirmatrelvir/ritonavir (NMV/r) and molnupiravir—have been approved for early outpatient treatment of COVID-19 to prevent severe disease. Ritonavir, contained in NMV/r is known to have significant DDI with several drugs frequently used by the elderly. This communication puts the problem with DDI with oral antiviral COVID-19 treatment into perspective,” the study authors wrote.

Their analysis of prescription data from Denmark residents found “extensive use of drugs likely to interact with NMV/r” as follows:

  • Anticoagulants (blood thinners): used by 20% of people over age 65 and by 30% of people over 80.
  • Statins (cholesterol-lowering medications): taken by 15% to 18% of people over 65.
  • Analgesics (for pain), calcium channel blockers (used to decrease blood pressure in patients with hypertension), or digoxin (used to treat heart conditions): taken by 20% of those studied.

In their paper, the researchers offered guidance to physicians. “Before prescribing NMV/r, the patient’s full medical history, including herbals and over-the-counter and recreational drugs, must be known and co-treatment carefully managed by the treating physician or by a specialist to avoid detrimental effects.” 

However, one infectious disease specialist told Scientific American it may just take the elderly who were taking Paxlovid more time to completely get over COVID-19.

“Being of an elderly age and then having other risk factors—like diabetes, heart disease, kidney disease, or some sort of cancer—does put you at higher risk of rebound,” Aditya Shah, MBBS, Mayo Clinic Infectious Disease Physician and Researcher, told Scientific American.

Rebounding after Molnupiravir, Too

COVID-19 rebound is not exclusive to people who took Paxlovid, according to a paper published on medRxiv, titled, “Rebound after Paxlovid and Molnupiravir during January-June 2022.”

That study’s researchers retrospectively reviewed 92 million electronic health records (EHR) from US patients. They found most people (11,270) had been treated with Paxlovid. However, 2,374 patients took molnupiravir, which also was granted EUA status by the FDA and is marketed as Lagevrio.

That COVID-19-rebound study found:

  • After nirmatrelvir/ritonavir (Paxlovid) treatment: 3.53% had rebound infections, 2.3% with rebound symptoms, and .44% were hospitalized.
  • After molnupiravir (Lagevrio) treatment: 5.86% had rebound infections, 3.75% with rebound symptoms, and .84% were hospitalized.

“Patients who took molnupiravir were significantly older and had more comorbidities than those who took Paxlovid,” the researchers wrote. “Results further suggest that rebound was not unique to Paxlovid and may be associated with persistent viral infection in some patients treated with either of these two antivirals. There has been more attention to COVID-19 rebound following Paxlovid treatment than molnupiravir, which may be attributable to more people being treated with Paxlovid,” they concluded.

Clinical Laboratories Can Guide Doctors

In an article she penned for STAT, titled, “Paxlovid Rebound Happens, Though Why and to Whom Are Still a Mystery,” Joan Susan Bregstein, MD, a pediatric emergency medicine physician and professor of pediatrics at Columbia University Irving Medical Center in New York, wrote of COVID-19 rebound, “My emergency medicine physician colleagues are seeing tons of it. Although people tend to think of medical care as something that is certain, it is actually a real-time experiment. Paxlovid, like a lot of COVID-19 care, is a reminder of this.”

Similarly, Mayo Clinic’s Shah acknowledged difficulty in identifying a COVID-19 rebound case. “You need real documentation of three tests—a positive, a negative, a positive—and clear documentation of symptoms—all symptoms gone, symptoms come back,” Shah told Scientific American.

Thus, clinical laboratories play a vital role in diagnosing and treating COVID-19 rebound patients, because that is what clinical labs do: test, document, and report. And as the study of the Danish population pointed out, doctors need guidance as they prescribe oral antivirals to COVID-19 patients who are on other drugs and at possible risk of drug-drug interactions. 

Donna Marie Pocius

Related Information:

Assessing the Proportion of the Danish Population at Risk of Clinically Significant Drug-Drug Interactions with New Oral Antivirals for Early Treatment of COVID-19

CDC Health Advisory: COVID-19 Rebound after Paxlovid Treatment

Wastewater Study Technique Finds Virus Variants Sooner; Many Patients Are Using Meds Affected by Paxlovid

What Is Paxlovid Rebound and How Common Is It?

COVID-19 Rebound after Paxlovid and Molnupiravir during January-June 2022

Paxlovid Rebound Happens, Though Why and To Whom are Still a Mystery