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Review 1: "The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants"

Published onJan 17, 2023
Review 1: "The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants"
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key-enterThis Pub is a Review of
The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants

AbstractIntroductionThe uptake of Paxlovid in individuals infected with COVID-19 has been significantly limited by concerns around the Paxlovid rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of Paxlovid rebound in treated and untreated participants with acute COVID-19 infectionMethodsWe designed a decentralized, digital, prospective observational study in which participants who tested positive for COVID-19 using eMed Test-to-Treat telehealth kits and were clinically eligible for Paxlovid were recruited to be evaluated for viral and symptom clearance, as well as rebound. Participants were assigned to a Paxlovid or control group based on their decision to take Paxlovid. Following initial diagnosis based on a telehealth proctored test both groups were provided 12 telehealth proctored rapid antigen home tests and asked to test on a regular frequent schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient reported symptoms were evaluated.ResultsViral rebound incidence was 14.2% in the Paxlovid group (n=127) and 9.3% in the control group (n=43). COVID-19 symptom rebound incidence was higher in the Paxlovid group (18.9%) compared to the control group (7.0%). There were no notable differences in viral rebound by age, gender, pre-existing conditions, or major symptom groups during the acute phase or at the 1-month interval.ConclusionThis preliminary report of our prospective study suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, we observed a similar rate of rebound in both in the Paxlovid and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.



In their paper entitled “The Paxlovid Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences Between Paxlovid and Untreated COVID-19 Participants”, Pandit et al. performed a decentralized prospective observational study of Paxlovid versus placebo rebound in patients acutely diagnosed with COVID-19. They found higher COVID19 viral and symptom rebound incidence among Paxlovid group compared to placebo. The study, however, did not have enough sample size and power to draw statistical conclusions which is a major limitation.

The main limitation of the study is the lack of racial diversity among patients as 81% of patients were white. This is mentioned in the limitation paragraph of the manuscript. Acknowledging the difficulty of digitally recruiting a more racially diverse group of patients, prior studies have reported more severe COVID-19 outcomes amongst certain racial groups, particularly Latinx. Including more diverse groups of patients would have increased the impact of this study.

Additionally, in the results section of the manuscript, authors mentioned notably higher symptom rebound incidence among the Paxlovid group compared to placebo, however, these differences were not statistically significant, as noted in Table 1. The authors should note that the results were “not statistically significant” in paragraph 4 of the results section.

Furthermore, in the first paragraph of the discussion section, it would be in the best interest of the authors to move the following sentence to paragraph 5 to help with the flow of ideas: “In addition to the study results reported, this study demonstrates the feasibility of offering a test to treatment approach, collecting patient reported outcomes and clinical outcomes in a decentralized fashion, which is ideal for participants acutely infected with COVID-19 and complements public health prevention measures”.

Ultimately, the authors bring up an interesting point in the discussion section about the COVID-19 isolation period and “test to exit” technique — this is much appreciated. It fits well in the scope of this study and is currently relevant.

Alex Badinici:

Thank you for this detailed review assessing the strengths and limitations of the Paxlovid rebound study. You highlight several key areas where the authors could strengthen the reporting and contextualization of their results.

Regarding the diversity limitation, I agree that calling out the lack of racial representation more prominently is important. As you note, given the differential COVID-19 outcomes across groups, including a more ethnically diverse cohort would increase generalizability and impact of the findings. The difficulty of digital recruitment is valid but warrants emphasis.

You also astutely point out the need to explicitly state non-significant differences between Paxlovid and placebo arms in Results paragraph 4. Table 1 data alone doesn't suffice - directly blank calendar qualifying effect sizes is crucial to avoid misinterpretation.

The structural suggestion to move the feasibility statement to Discussion paragraph 5 is also well-taken. Reorganizing to keep focus on direct study results first would indeed improve flow.

Finally, I'm likewise glad the authors addressed implications for isolation policies and re-testing practices. Examining those downstream effects helps translate the Paxlovid rebound data into actionable guidance.

Some minor limitations aside, I agree this study provides a potentially informative first look at an important clinical question. Hopefully future work can build on this foundation with larger, more diverse cohorts to further elucidate the rebound phenomenon. Thank you again for the insightful, constructive analysis!