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 Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: Symptomatic and virologic recrudescence after treatment of patients with COVID-19 with nirmatrelvir/ritonavir (Paxlovid) — Paxlovid rebound — occurs in a very small percentage of patients and generally is mild and self-limited.
SOURCES: Charness M, Gupta K, Stack G, et al. Rapid relapse of symptomatic omicron SARS-CoV-2 infection following early suppression with nirmatrelvir/ritonavir. Research Square2022. doi: https://doi.org/10.21203/rs.3.... [Preprint].
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. [Online ahead of print].
Charness and colleagues described symptomatic and virologic relapse of COVID-19 after what appeared to be successful treatment with nirmatrelvir/ritonavir (Paxlovid) in 10 patients. The relapses occurred nine to 12 days after symptom onset and four to seven days after completion of a five-day course. The viral load during relapse was similar to that seen during the initial illness, and there was no evidence of emergence of antiviral resistance in the three cases in which sequencing was performed. The illness was mild and similar to that seen with a common cold; all 10 patients recovered without further treatment. Transmission to family members occurred during relapse, one while the index patient was asymptomatic and one while presymptomatic.
Ranganath et al reported that, among a cohort of 483 high-risk patients treated with nirmatrelvir/ritonavir (Paxlovid) for coronavirus disease-2019, two patients (0.4%) required hospitalization by day 30. Four patients (0.8%), all of whom had been “fully vaccinated,” experienced rebound of symptoms, which generally were mild, at median of nine days after treatment, and all resolved without additional COVID-19-directed therapy.
Relying on spontaneous reporting, Coulson and colleagues in Wales identified spontaneous reports of rebound in just three patients, representing < 1% of nirmatrelvir/ritonavir recipients.1 All three were receiving immunosuppressive therapy for inflammatory disease; one patient was retreated with sotrovimab.
COMMENTARY
Paxlovid remains highly effective in the treatment of at-risk COVID-19 patients.2 Kaiser Permanente data from California showed that, among 5,287 individuals > 12 years of age (73% of whom had received > 3 vaccine doses), only six hospitalizations and 39 emergency department encounters related to SARS-CoV-2 infection occurred during a five- to 15-day interval after treatment. These 45 cases represent just 0.85% of those treated.
However, clinical and virological rebound after treatment occurs in a small proportion of patients after completion of the five-day course. The reason for the rebound remains uncertain. Limited data suggest it is not related to antiviral resistance or to new infection and, in a single reported case in which this was examined, it was not due to the absence of circulating neutralizing antibody.3 It has been suggested that higher drug dosage may be beneficial, but this appears to be contradicted by available pharmacokinetic/pharmcodynamic data. It also has been suggested that a more prolonged course of therapy could prevent rebound. This also leads to the question of whether retreatment should be used in rebound cases. However, the rebound illness generally is quite mild, and the Centers for Disease Control and Prevention states, “There is currently no evidence treatment is needed with Paxlovid or other anti-SARS-CoV-2 therapies in cases where COVID-19 rebound is suspected.” Similarly, the U.S. Food and Drug Administration states, “… there is no evidence of benefit at this time for a longer course of treatment (e.g., 10 days rather than the 5 days recommended in the Provider Fact Sheet for Paxlovid) or repeating a treatment course of Paxlovid in patients with recurrent COVID-19 symptoms following completion of a treatment course.”4
However, another question is whether this analysis applies to rebound in severely immunocompromised patients, about whom there are very limited data — possibly because of the frequent avoidance of Paxlovid in such patients because of the drug-drug pharmacokinetic interactions involving the ritonavir component.
As illustrated by the experience reported by Charness et al, patients experiencing rebound potentially may transmit infection and should isolate for at least five days, after which isolation may be ended if symptoms are improving and fever has been absent for at least 24 hours absent antipyretic use. However, mask wearing should continue for 10 days after onset of rebound symptoms. Of importance, it has been reported that virologic relapse may occur in the absence of symptoms.4 It must be recognized that clinical and virological rebound is not limited to patients treated with Paxlovid. A recent report indicates that the frequency of occurrence after treatment with molnupiravir is similar to that reported with Paxlovid.5 In addition, we have seen apparent rebound after remdesivir treatment. Finally, rebound also was observed in placebo recipients in the Paxlovid trial.
REFERENCES
- Coulson JM, Adams A, Gray LA, Evans A. COVID-19 “rebound” associated with nirmatrelvir/ritonavir pre-hospital therapy. J Infect 2022:S0163-4453(22)00363-2.
- 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 2022;71:830-833.
- Carlin AF, Clark AE, Chaillon A, et al. Virologic and immunologic characterization of COVID-19 recrudescence after nirmatrelvir/ritonavir treatment. Res Sq 2022 May 18:rs.3.rs-1662783. [Preprint].
- Food and Drug Administration. FDA Updates on Paxlovid for Health Care Providers. https://www.fda.gov/drugs/news-events-human-drugs/fda-updates-paxlovid-health-care-providers
- Zou R, Peng L, Shu D, et al. Antiviral efficacy and safety of molnupiravir against omicron variant infection: A randomized controlled clinical trial. Front Pharmacol 20225;13:939573.
