A new study by Harvard Medical School researchers at Massachusetts General Hospital and Brigham and Women’s Hospital has found that one in five individuals taking nirmatrelvir-ritonavir therapy, commonly known as Paxlovid, to treat severe symptoms of COVID-19 had a positive test result and shed live potentially contagious virus following an initial recovery and negative test — a phenomenon known as virologic rebound. By contrast, people not taking Paxlovid experienced rebound only about 2 percent of the time.
The results indicate that viral rebound may occur more often than previously believed and raise questions about the risk of viral transmission by those who do experience a return of the virus.
“We found that the virologic rebound phenomenon was much more common than expected and that individuals shed live virus when experiencing a rebound, which means they may be contagious after initial recovery.”
“We conducted this study to address lingering questions about Paxlovid and virologic rebound in COVID-19 treatment,” said senior author Mark Siedner, associate professor of medicine at HMS and an infectious disease clinician and researcher at Mass General. “We found that the virologic rebound phenomenon was much more common than expected — in over 20 percent of people taking Paxlovid — and that individuals shed live virus when experiencing a rebound, which means they may be contagious after initial recovery.”
Paxlovid is an oral antiviral medication used to treat COVID-19. Previous studies demonstrate the medication’s effectiveness in reducing hospitalization and death in cases of severe COVID-19. Since the integration of Paxlovid into COVID-19 treatment, some patients have reported virologic rebound. A previous phase 3 clinical trial known as EPIC-HR suggested that only 1 to 2 percent of patients taking Paxlovid experienced virologic rebound.
The findings should not discourage clinicians from prescribing the medication, the researchers noted, but they should prompt them to counsel patients who take the medication about the risk for viral rebound and spreading the virus to others.
“Paxlovid remains a lifesaving drug I prescribe to high-risk patients,” said co-senior author Jonathan Li , associate professor of medicine at HMS and an infectious disease physician at Brigham and Women’s. “This study, while informative, does not change the fact that this drug is very effective at preventing hospitalizations and death. Instead, it offers valuable insights to Paxlovid patients, helping them understand what to expect and how long they might be contagious.”
The researchers caution that the study relied on observation and was not a randomized controlled trial, so the scientists cannot be certain that the increased rebound rate seen in people taking Paxlovid was solely due to use of the drug.
Assessment and analysis
The team used a positive viral culture as a marker for the risk of transmitting the virus but did not formally measure exactly how contagious someone experiencing virologic rebound was. Nonetheless, they note, live viral shedding is a well-established factor in transmission for other respiratory viruses so clinicians should counsel patients to be vigilant and isolate during rebound.
“This study does not change the fact that this drug is very effective at preventing hospitalizations and death. Instead, it offers valuable insights to Paxlovid patients, helping them understand what to expect and how long they might be contagious.”
The researchers collected data from the Post-vaccination Viral Characteristics Study (POSITIVES), which follows individuals diagnosed with acute COVID-19. Between March 2022 and May 2023, 142 individuals were selected for the study based on positive COVID-19 tests, medication prescriptions, or physician referrals.
Sorting participants by those who took a five-day Paxlovid regimen versus those who did not, the researchers closely tracked patients’ symptoms, analyzed viral loads, lab culture results, and viral samples and performed viral genome sequencing.
Patients who tested positive for COVID-19 after previously testing negative and those who exhibited two consecutive increases in viral loads — the amount of virus detected in nasal swabs — following an initial reduction were classified as experiencing virologic rebound.
The analysis showed that 20.8 percent of those who took Paxlovid experienced virologic rebound, while only 1.8 percent of those who did not take the drug had a rebound. Individuals with rebound also had prolonged viral shedding, for an average of 14 days compared with fewer than five days in those who did not experience rebound, indicating they may remain contagious for longer. Reassuringly, there was no evidence that the virus is developing resistance to the medication among patients with rebound.
The original EPIC-HR study assessed outcomes for patients at only two time points, while the new study tracked patients more frequently. When the researchers on the current study aligned their data with the select time points from the first EPIC-HR study, they too found virologic rebound in only 2.4 percent of participants, a finding that suggests that the previous study did not capture the full extent of virologic rebound.
“Unlike in the EPIC-HR study, which only assessed outcomes at two time points, we followed up with patients three times a week, sometimes for months, and performed in-home sample collection,” Li said. “Having both viral RNA levels and viral culture data also allowed us to paint a more comprehensive and nuanced picture of a patient’s experience with Paxlovid.”
The findings raise several intriguing questions, the researchers said.
For example, the research was not designed to determine why some people experienced rebound while others did not — something they aim to explore with future studies. They also plan to investigate the biological mechanism behind the rebound phenomenon seen with Paxlovid and determine whether changing the treatment duration might help combat the rebound effect.
Authorship, funding, disclosures:
Co-lead authors of the study include Gregory E. Edelstein, Julie Boucau. Additional researchers include Rockib Uddin, Caitlin Marino, May Y. Liew, Mamadou Barry, Manish C. Choudhary, Rebecca F. Gilbert, Zahra Reynolds, Yijia Li, Dessie Tien, Shruti Sagar, Tammy D. Vyas, Yumeko Kawano, Jeffrey A. Sparks, Sarah P. Hammond, Zachary Wallace, Jatin M. Vyas, co-senior author Amy K. Barczak, and co-senior author Jacob E. Lemieux.
This work was supported by the National Institutes of Health (U19 AI110818 and R01 AI176287), the Massachusetts Consortium for Pathogen Readiness SARS-CoV-2 Variants Program, and the MGH Department of Medicine. Additional support was provided by the Ragon Institute BSL3 core, which is supported by the NIH-funded Harvard University Center for AIDS Research (P30 AI060354). Sparks and Wallace are supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR080659). Sparks is also supported by the Llura Gund Award for Rheumatoid Arthritis Research and Care. The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the manuscript; or in the decision to submit the manuscript for publication.
AKB reports consulting for ICON Government and Public Health Solutions. JZL reports consulting for AbbVie and receives research funding from Merck. SPH reports research funding from GlaxoSmithKline and has served on an advisory board for Pfizer.