COVID-19 Recurrence After Paxlovid Treatment Not Likely Due to Resistance, Impaired Immunity

Researchers assessed whether treatment resistance or impaired humoral immunity were associated with the recurrence of COVID-19 infection following treatment with Paxlovid.

Neither treatment resistance nor a lack of neutralizing immunity were likely causes of recurrent COVID-19 infection in a patient who had received treatment with Paxlovid™ (nirmatrelvir/ritonavir), according to findings published in Clinical Infectious Diseases.

Investigators at the University of California, San Diego, evaluated humoral immunity and potential drug resistance in a patient who developed recurrent COVID-19 infection after treatment with Paxlovid.

Three patients who tested positive for COVID-19 infection after returning to the US from South Africa were also assessed. At the time of infection, all 3 patients were vaccinated against COVID-19 infection and had subsequently received a booster dose. Two patients recovered following receipt of Paxlovid twice daily for 5 days.

For 1 patient, initial symptom improvement occurred after receipt of Paxlovid but symptoms subsequently rebounded, evidenced by progressively worsening fatigue, sore throat, nasal congestion, and diarrhea.

The patient was found to have a high rate of virologic shedding and cultivable virus 5 days after treatment. Analysis of a nasopharyngeal swab sample showed that the patient was infected with an Omicron subvariant (BA.2 PRSDO1). The virus did not have any amino acid differences in any coding position compared with the Omicron BA.2 reference genome.

Using human lung epithelial cells, the half maximal inhibitory concentration (IC50) of Paxlovid against BA.2 PRSD01 was 2.0-times lower for the parental strain, 1.8-times lower for the Delta variant, and 1.7- and 2.0-times lower for the Omicron variant and the Omicron BA.2.3 subvariant, respectively.

In contrast, the IC50 for remdesivir was 2.0-times higher for the parental strain and 1.8-times higher for the Delta variant, and 1.1- and 1.3-times higher for the Omicron variant and Omicron BA.2.3 subvariant, respectively.

Compared with 2 control patients who were fully vaccinated, the average half maximal authentic virus neutralizing antibody concentrations (NT50) were 1668 for Omicron subvariant BA.2 PRSD01, 1170 for the Omicron variant, and 5239 for the parental SARS-CoV-2 strain for the patient in whom Paxlovid treatment was unsuccessful. Further analysis showed that this patient’s NT50 concentrations for BA.2 PRSD01, the Omicron variant, and the parental strain were, respectively, 8.9-, 7.1-, and 2.1-times higher than those observed in a control patient who had not recovered from symptomatic infection; and 2.0-, 1.7-, and 2.6-times lower than those observed in a control patient who had recovered from symptomatic infection, both of whom were fully vaccinated.

This study was limited by the inability to measure T-cell responses and serum drug concentrations.

According to the investigators, “…the clinical significance of COVID-19 [recurrence] after [Paxlovid] treatment remains unclear, so additional studies are needed to define the etiology, frequency, and clinical consequences (eg, hospitalizations, deaths, transmissions) of [recurrent COVID-19 infection].”

Disclosure: Multiple authors declared affiliations with industry. Please see the original reference for a full list of disclosures.


Carlin AF, Clark AE, Chaillon A, et al. Virologic and immunologic characterization of COVID-19 recrudescence after nirmatrelvir/ritonavir treatment. Clin Infect Dis. 2022;ciac496. doi:10.1093/cid/ciac496