Editor’s Note:
The rapidly changing information about COVID-19 and its management is apparent and difficult to manage. The observation of recurrent symptoms and viral presence shortly after completing treatment with Paxlovid is one such example — and one that has caused concern. The following two items deal with this issue. Dr. Winslow provides his assessment of the situation based on the initial published report, while a second assessment based on that and subsequently published reports provides a further evaluation — but comes to similar conclusions.
By Dean L. Winslow, MD, MACP, FIDSA, FPIDS
Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine
SYNOPSIS: A cohort of 483 high-risk patients was treated with nirmatrelvir/ritonavir for COVID-19. Two of the patients (0.4%) required hospitalization by day 30, and four patients (0.8%) experienced a rebound of symptoms (generally mild) at median of nine days after treatment. All resolved without additional COVID-19-directed therapy.
SOURCE: Ranganath N, O’Horo JC, Challener DW, et al. Rebound phenomenon after nirmatrelvir/ritonavir treatment of coronavirus disease-2019 in high-risk persons. Clin Infect Dis 2022; Jun 14:ciac481. doi: 10.1093/cid/ciac481. [Online ahead of print].
This study included 483 patients with a median age of 63 years. Their median Monoclonal Antibody Screening Score was 3 (interquartile range [IQR], 1-5), suggesting a high risk for severe disease progression. Most patients (n = 448; 93%) were fully vaccinated against COVID-19.
The time from a positive SARS-CoV-2 test to receiving a prescription for nirmatrelvir/ritonavir was one day (IQR, 1-2). None of the patients died. Four patients (0.8%) had a rebound of symptoms at a median of nine days (IQR, 7-14.5) after treatment with nirmatrelvir/ritonavir. All four of these patients were fully vaccinated, and none needed hospitalization. All of the patients improved without needing further COVID-19-directed therapies. No alternative diagnoses were found.
COMMENTARY
Nirmatrelvir inhibits the coronavirus protease that is necessary for polyprotein processing in the later stages of the viral replication cycle. Ritonavir (which also inhibits the human immunodeficiency virus aspartyl protease but has little activity against coronavirus protease) is co-formulated with nirmatrelvir since it is a potent inhibitor of CyP 3A/4 (and other cytochrome P450 isoforms) and boosts the levels of nirmatrelvir. While the potential drug-drug interactions posed by ritonavir need to be considered, one reason I like nirmatrelvir/ritonavir (Paxlovid) is that the SARS-CoV-2 protease is conserved and not influenced by the rapid evolution of mutations in spike protein that has characterized emerging variants, which reduce their inhibition by monoclonal antibody treatments.
For the past several weeks, because of anecdotal reports of rebound infection after a five-day course of nirmatrelvir/ritonavir, a lot of doctors and others have expressed concern about “Paxlovid rebound.”1 Unfortunately, the internet has amplified this concern to the point that many doctors are reluctant to prescribe nirmatrelvir/ritonavir to high-risk patients despite conclusive evidence from prospective randomized controlled trials that nirmatrelvir/ritonavir is safe and very effective in preventing progression of disease, hospitalization, and death in high-risk patients with confirmed infection with SARS-CoV-2. In this observational study from Mayo Clinic, the four patients (0.8% of those treated) who experienced recurrence of symptoms after a five-day course of nirmatrelvir/ritonavir treatment all had mild symptoms, and these resolved with symptomatic treatment. A recent Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report supports the reassurance that the Mayo Clinic experience provides.2
REFERENCES
- Charness M, Gupta K, Stack G, et al. Rapid relapse of symptomatic Omicron SARS-CoV-2 infection following early suppression with nirmatrelvir/ritonavir. Research Square May 23, 2022. [Pre-Print].
- Malden DE, Hong V, Lewin BJ, et al. Hospitalization and emergency department encounters for COVID-19 after Paxlovid treatment — California, December 2021–May 2022. MMWR Morb Mortal Wkly Rep ePub: 21 June 2022. doi: https://dx.doi.org/10.15585/mmwr.mm7125e2
