Reference: Ann Intern Med. 2023 Dec;176(12):1577
Practice Point: Treating COVID-19 with Paxlovid may have benefits, but also seems to increase viral rebound and the period of infectivity.
EBM Pearl: COVID “virologic rebound” may only be a surrogate outcome. Recurrent symptoms, increased infectivity, and potential need for extended isolation are clinically relevant outcomes that matter more.
As COVID-19 rebounds back into focus this winter (along with influenza and other respiratory viruses), the concept of viral rebound after treatment with nirmatrelvir–ritonavir (Paxlovid) has also reared its unwelcome head. An Annals of Internal Medicine article from November found that post-Paxlovid return of viral positivity and symptoms is both common and potentially more clinically relevant than previously thought, mostly in regards to increased infectivity.
The study was an observational cohort of 127 previously-vaccinated adults enrolled within five days of COVID-19 diagnosis. Participants were eligible for and were offered Paxlovid, and were analyzed according to whether they took the medication (72) or did not (55). The groups were quite different: the folks who elected to take it were older (57 years old vs 39 years old), had more comorbidities, and were more likely to have been diagnosed because of symptoms rather than through screening or exposure history. Nobody died during this study (that is so nice to say when we talk about COVID!), and the Paxlovid-treated patients generally did better. The primary outcome of this study, however, was virologic rebound within 20 days of the initial positive test, defined by either positive viral culture after a negative result or sustained elevated viral load. The headlines on this study all focused on the main conclusion, which was that rebound of COVID occurred about 21% of the time after Paxlovid, compared to 2% without treatment. However, we’d like to make four points that might have been missed without a closer reading of this study:
- The researchers used multiple methods to assess patients, asking them to fill out symptom surveys, having them obtain repeated nasal swabs during the course of their illness and recovery, and analyzing those results in several different ways. Additionally, they utilized a less common testing method, viral cultures, alongside molecular diagnostics. Viral cultures take days to result and are not routinely available clinically, but are the gold standard for infectivity in research studies. By using viral cultures to supplement molecular testing, researchers were able to differentiate those patients who had virus capable of replication (which presumably correlates with potential infectivity). As it turns out, culture was almost 4 times more sensitive for detecting rebound than molecular testing.
- One not-so-surprising finding was that many people who had a drop in their viral load followed by a definable resurgence were asymptomatic. We’ve known this. But interestingly, this study documented that most people who had rebound of symptoms did not have virologic rebound. We found that a little surprising.
- In a subgroup analysis, those that initiated Paxlovid 2-5 days after symptom onset or positive result were much less likely to have viral rebound than those who started therapy on days 0 or 1 (0% vs 26%). This seems like a really important phenomenon to study, and could potentially represent a needed change in prescribing (waiting 2 days to begin treatment) if born out in a trial.
- Last—and this is pretty important—it turns out that for the approximately 20% of patients who had viral rebound after taking Paxlovid, their period of infectivity was in total significantly longer than those who did not take medication. None of them got really sick, but if we can assume that in vitro viral replication (manifested by cytolysis) is the best surrogate marker for infectivity, these patients had about 10 more days of contagiousness to others (see the Kaplan Meiers curves in Figure 3 for the juicy details). On the other hand, none of the patients with a negative molecular test after five days of Paxlovid experienced rebound, and if this finding is replicated, negative molecular testing at five days may eventually allow the 80% of people who don’t experience rebound to end isolation.
Due to the limitations of this small, observational study with significant between-group differences, we can’t really draw many firm conclusions here. However, while viral rebound may not pose a significant clinical harm to individual patients taking Paxlovid, there may be important public health implications. If the 20% rebound risk is true, the associated prolonged period of infectivity may lead to the need for recommendations for extended isolation after completing Paxlovid, at least for those without a negative molecular test at day 5.
For more information, see the topic COVID-19 Management in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Elham Razmpoosh, PhD, Postdoctoral Fellow at McMaster University; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Associate Editor at DynaMed.