To the publisher:
Researchers1 and in a Health Advisory from the Centers for Disease Control and Prevention reported cases of recurrence of clinical symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after completing treatment with nirmatrelvir-ritonavir.2 The frequency and clinical implications of the possible recurrence of coronavirus disease 2019 (Covid-19) are unknown.
We present data on the occurrence of viral load rebound from a randomized, double-blind, controlled, phase 2-3 trial (EPIC-HR3), which enrolled 2246 symptomatic, unvaccinated outpatient adults at high risk of progression to severe disease. by coronavirus 2019 (Covid-19) within 5 days after the onset of symptoms. Trial recruitment and sampling occurred from July 2021 to December 2021. Patients received nirmatrelvir (300 mg) plus ritonavir (100 mg) or placebo every 12 hours for 5 days. Over an average of 27 days, patients in the nirmatrelvir-ritonavir group had an 88% lower risk of COVID-19-related hospitalization or death from any cause than the placebo group; there were no deaths in the nirmatrelvir-ritonavir group and 13 deaths in the placebo group through day 34.
Nasopharyngeal swab samples were collected on the first day of enrollment (baseline) and then on testing days 3, 5, 10, and 14. (Details on sample collection are provided in Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) Recurrence of Covid-19 was defined according to prespecified criteria for viral load rebound: a half-log increase in viral load on day 10 or day 14 if only one value was available or on days 10 and 14 if both values were available. This definition was developed to assess resistance to nirmatrelvir.
Shown are changes in mean viral load among study patients who received a course of nirmatrelvir-ritonavir or placebo within 5 days of symptom onset of severe acute respiratory syndrome coronavirus 2 infection (Panel A). . Data from patients with present or persistent viral load rebound in the two groups are also shown (Panel B). In Panel B, the lower limit of quantitation for the reverse transcriptase-polymerase chain reaction assay was 2 log10 copies per milliliter; the blue line indicates hospitalization of the patient.
Data for patients whose viral load was measured at baseline and at least once after administration of nirmatrelvir-ritonavir or placebo were available for 1,106 patients in the nirmatrelvir-ritonavir group and for 1,110 patients in the nirmatrelvir-ritonavir group. placebo (Figure 1A). For the data cutoff in December 2021, data for patients whose viral load was measured on day 5 and during the rebound period were available for 990 patients in the nirmatrelvir-ritonavir group and for 980 patients in the nirmatrelvir-ritonavir group. placebo group. From baseline to day 14, viral load rebound occurred in 23 of 990 patients (2.3%) in the nirmatrelvir-ritonavir group and 17 of 980 (1.7%) in the placebo group (Figure 1B and Table S2). Results regarding viral load rebound were similar in the nirmatrelvir-ritonavir group and the placebo group in analyzes of presence of co-existing illness, exposure to nirmaterlvir, recurrence of moderate to severe Covid-19 symptoms (Fig. S1), the occurrence of hospitalization or death, initial SARS-CoV-2 serological status, and nirmatrelvir resistance (as assessed by SARS-CoV-2 Mpro gene or cleavage mutations). One patient in the nirmatrelvir-ritonavir group who had been admitted to hospital had a rebound in viral load after discharge. No hospitalizations occurred among patients with rebound viral load in the placebo group, and no deaths were observed in either rebound group.
Therefore, the incidence of viral load rebound was similar in the nirmatrelvir-ritonavir group and in the placebo group. The occurrence of viral load rebound was not retrospectively associated with low nirmatrelvir exposure, recurrence of moderate to severe symptoms, or development of nirmatrelvir resistance. A potential limitation of this analysis is that the clinical trial was conducted during a period of the pandemic when most infections were caused by the B.1.617.2 (delta) variant. However, more recent data indicate that nirmatrelvir-ritonavir is also effective against B.1.1.529 (omicron) variants.4 Another limitation of this analysis is the focus on identifying potential resistance to nirmatrelvir. Viral load determined by polymerase chain reaction assay does not directly translate to the presence of infectious virus and does not correlate perfectly with current or new clinical symptoms. Finally, recurrence of omicron has also been observed in untreated patients.5 In the ACTIV-2/A5401 study, rebounds in viral load and clinical symptoms were relatively common among participants who had not received any antiviral agent.6 Our findings suggest that rebound viral load may be a feature of some SARS-CoV-2 infections and that the natural history of Covid-19 requires continued study.
Annaliesa S. Anderson, Ph.D.
Pfizer, Pearl River, New York
Patrick Caubel, MD, Ph.D.
Pfizer, Collegeville, Pennsylvania
James M. Rusnak, MD, Ph.D.
Pfizer, Tampa, Fla.
for EPIC-HR Trial Investigators
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
This letter was published on September 7, 2022 on NEJM.org.
1. Gupta K, Strymish J., G-stack, Charness M. Rapid relapse of symptomatic SARS-CoV-2 infection after early nirmatrelvir/ritonavir suppression. April 26, 2022 (https://assets.researchsquare.com/files/rs-1588371/v1/48342d2c-b3ea-4228-b600-168fca1fded7.pdf?c=1650977883). prepress
two. Centers for Disease Control and Prevention Health Alert Network. COVID-19 rebound after Paxlovid treatment. May 24, 2022 (https://emergency.cdc.gov/han/2022/pdf/CDC_HAN_467.pdf).
3. HammondJ., Leister-Tebbe H., gardener a, et al. Oral nirmatrelvir for high-risk non-hospitalized adults with Covid-19. N English J Med 2022;386:1397–1408.
Four. Wong CKH, Au ICH, Lau K.T.K., Lau EHY, BJ Fairing, Leung General Manager. Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir against mortality, hospitalization, and hospital outcomes among outpatients with COVID-19 living in the community during the BA.2.2 wave in Hong Kong: an observational study. May 26, 2022 (https://www.medrxiv.org/content/10.1101/2022.05.26.22275631v1). prepress
5. Stegger M, Edslev SM, Sieber RN, et al. Occurrence and importance of infection by omicron BA.1 followed by reinfection by BA.2. February 22, 2022 (https://www.medrxiv.org/content/10.1101/2022.02.19.22271112v1). prepress
6. Deo R, Choudhary MC, moser c, et al. Viral and symptom rebound in untreated COVID-19 infection. August two, 2022 (https://www.medrxiv.org/content/10.1101/2022.08.01.22278278v1). prepress