San Diego—The CDC recently issued a health advisory for Paxlovid, the leading oral medication for preventing severe cases of COVID-19 in high-risk patients.

The caution was issued because symptoms returned in some patients after treatment was completed. In an effort to determine what was going on with "COVID-19 rebound," a study accepted for publication in Clinical Infectious Diseases sought to determine what was behind the phenomenon.

Researchers at the University of California San Diego School of Medicine evaluated one patient with a rebound of COVID-19 and determined that the symptom relapse was not caused by the development of resistance to the drug or impaired immunity against the virus. Instead, they suggested that the COVID-19 rebound was the result of insufficient exposure to the drug.

"We isolated a SARS-CoV-2 BA.2 variant from a person with COVID-19 recrudescence after nirmatrelvir/ritonavir treatment. Antiviral sensitivity and neutralizing antibody testing were performed with both parental SARS-CoV-2 and multiple variants of concern. We found that neither NM resistance nor absence of neutralizing immunity were likely causes of the 6 recrudescence," the researchers wrote.

Background information in the article pointed out that early administration of the oral protease inhibitor nirmatrelvir combined with ritonavir (NM/r), marketed as Paxlovid, can reduce severe disease due to COVID-19. Even though NM inhibits SARS-CoV-2 main protease, thereby blocking viral replication, virologic and symptomatic rebound after NM/r treatment was recently reported.

"The phenomenon of relapse after NM/r has been described in a limited number of individuals, all of which developed virologic rebound approximately 9-14 days after symptom onset and were likely infected with omicron variants," the authors added.

The study team evaluated whether NM resistance or impaired humoral immunity contributed to a case of COVID-19 recrudescence after NM/r treatment. Researchers described how three boosted adult travelers acquired COVID-19 after returning to the United States from South Africa and were treated with NM/r 300/100 mg taken orally twice daily for 5 days.

"All cases resolved quickly except one who experienced initial improvement with NM/r followed by rebounding symptoms," the authors recounted. "Progressively worsening fatigue, sore throat, nasal congestion, and diarrhea were associated with high viral shedding and culturable virus 5 days after the NM/r course."

Researchers isolated SARS-CoV-2 from a nasopharyngeal swab following the development of worsening symptoms and determined it was of SARS-CoV2 BA.2 lineage. "Our main concern was that the coronavirus might be developing resistance to Paxlovid, so to find that was not the case was a huge relief," stated first author Aaron F. Carlin, MD, PhD, assistant professor at University of San Diego School of Medicine.

The study team then evaluated the susceptibility of the viral panel to the neutralizing antibody response in the plasma from the patient and two controls. Researchers stated that their study suggests that neither development of NM resistance nor the absence of neutralizing antibodies was the likely cause of the observed recrudescence.

Because the patients' antibodies were still effective at blocking the virus from entering and infecting new cells, lack of antibody-mediated immunity was determined not to be the cause of the recurring symptoms.

"Although we were unable to measure T cell responses or serum drug concentrations, we believe the most likely possibility for the observed recrudescence is insufficient drug exposure by individual pharmacokinetics or insufficient duration," the researchers explained. "Further, the clinical significance of COVID-19 recrudescence after treatment remains unclear, so additional studies are needed to define the etiology, frequency, and clinical consequences (e.g., hospitalizations, deaths, transmissions) of such recrudescence."

After a clinical trial showed that Paxlovid could reduce the risk of hospitalization and death from COVID-19 by 89%, the drug was made available under an Emergency Use Authorization from the FDA in December 2021.

The Paxlovid treatment consists of two drugs (nirmatrelvir and ritonavir) that work together to suppress SARS-CoV-2 by blocking an enzyme that allows the virus to replicate in the body. Paxlovid can be taken at home, unlike drugs such as remdesivir, which require intravenous injection. Paxlovid treatment should be initiated within 5 days of symptom onset and taken twice daily for 5 consecutive days, the study noted.

Dr. Carlin said he hopes that physicians soon will be able to test whether patients require a longer duration of Paxlovid treatment or might be best treated by a combination of drugs.

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