Relapse of COVID-19 symptoms and SARS-CoV-2 viral load following nirmatrelvir/ritonavir treatment

In a recent study posted to Research Square*, researchers reported rapid relapse of coronavirus disease 2019 (COVID-19) symptoms following the administration of nirmatrelvir/ritonavir in adults.

Nirmatrelvir inhibits the main protease (M^pro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and blocks viral replication. The antiviral drug markedly lowers disease severity in at-risk individuals.

The study and findings

The present study observed the relapse of COVID-19 symptoms and viral load after an early nirmatrelvir/ritonavir treatment. A 71-year-old male with intermittent asthma developed a sore throat, rhinorrhea, cough, coryza, chills, fever, and fatigue on day 0, with a positive SARS-CoV-2 antigen test. Oral nirmatrelvir/ritonavir was started twice daily from day 0 until day 5.

Symptoms subsided rapidly with only asthma and mild rhinorrhea on day 1 and resolved completely by day 8. While still being isolated, the patient developed rhinorrhea, coryza, sore throat, and asthma on day 9. Peak symptoms were evident on day 10, which resolved by day 12. Antigen tests returned negative on day 16 and day 35. The Biofire respiratory pathogen screen panel was positive for SARS-CoV-2 and negative for remaining respiratory viruses on day 10.

Molecular sequencing revealed the infecting variant to be SARS-CoV-2 Omicron BA.1.20 from day 1 to 11. A P132H substitution in non-structural protein 5 (nsp5), found in 98% of BA.1.20 sequences, was consistently present throughout. Serum anti-spike immunoglobulin G (IgG) was positive on day 13, and anti-nucleocapsid IgG was positive on day 21.

Another patient (aged 69) had cold symptoms and tested positive for SARS-CoV-2 on an antigen test on day 0. Nirmatrelvir/ritonavir course was started on day 1 for five days; symptoms resolved on day 4. Between days 4 and 9, daily antigen tests and two polymerase chain reaction (PCR) tests returned negative. The patient developed mild symptoms on day 10, and the relapse was confirmed by antigen and PCR tests. The relapse lasted for three days.

The third patient was a 50-year-old female and the household member of the second patient. The patient had a similar pattern of relapse following complete symptom resolution post-treatment of nirmatrelvir/ritonavir. Sequencing of second and third patients’ specimens identified Omicron BA.2.9 as the infecting variant.

Additionally, seven (presumptive) cases were identified with relapse, including two household members of the first patient. All patients were vaccinated and received a COVID-19 mRNA vaccine booster two weeks to six months before SARS-CoV-2 infection. No patient was immunocompromised; the antiviral course was initiated on days 0 to 2, with symptoms resolving three to eight days after starting the treatment.

Symptoms relapsed five median days after completing the nirmatrelvir/ritonavir treatment. Cold symptoms were the most frequent during relapse, albeit some patients experienced fatigue and headache. In these patients, relapse symptoms were milder than during acute/initial infection. Fever was not recorded in any patient. All patients recovered without requiring antiviral therapy.

Antigen tests were positive during relapse on days 9 – 13 and remained positive for six median days until day 18, beyond the recommended isolation period. Two events of SARS-CoV-2 transmission were identified during relapse. Two family members of one patient (aged 63) were in close contact when the patient experienced a relapse. Contacts developed symptoms and tested SARS-CoV-2-positive within three days.

While pre-symptomatic on day 12, a patient (aged 67) had been in close contact with a six-month-old family member for 15 to 20 minutes. The infant tested positive three days later and developed symptoms. Subsequently, the child’s parents were symptomatic after two/three days and tested positive on antigen tests. Notably, the infant and parents had no other close contacts.

Conclusions

The study noted the rapid recurrence of COVID-19 symptoms following the early and effective nirmatrelvir/ritonavir treatment. Sequencing of specimens from three patients suggested that the relapse was not a result of treatment-emergent mutation or a different infecting variant. However, more investigations are needed to study the etiology, duration, spectrum, and frequency of relapsing symptoms and their association with nirmatrelvir/ritonavir treatment. 

*Important notice

Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Tarun Sai Lomte

Tarun is a writer based in Hyderabad, India. He has a Master’s degree in Biotechnology from the University of Hyderabad and is enthusiastic about scientific research. He enjoys reading research papers and literature reviews and is passionate about writing.