One in five people taking nirmatrelvir-ritonavir treatment were found to experience rebound COVID

A new study by researchers at Mass General Brigham found that one in five people taking Nirmatrelvir-ritonavir treatment, commonly known as Paxlovid, to treat severe symptoms of COVID-19 experienced a positive test result and excretion of live and potentially contagious virus after initial recovery and negative test; a phenomenon known as virological rebound. In contrast, people who didn’t take Paxlovid experienced a rebound only about 2 percent of the time. Results are published in Annals of Internal Medicine.

We conducted this study to answer lingering questions about Paxlovid and virologic rebound in the treatment of COVID-19. We found that the virological rebound phenomenon was much more common than expected – in more than 20% of people taking Paxlovid – and that individuals shed live virus when they experience a rebound, indicating the potential for transmission after initially recovering were from the virus.”

Mark Siedner, MD, MPH, Corresponding author, physician and infectious disease researcher at the Division of Infectious Diseases at Massachusetts General Hospital

Paxlovid is an oral antiviral medication used to treat COVID-19. Previous studies show the drug’s effectiveness in reducing hospitalizations and deaths in cases of severe COVID-19 infection. Since the integration of Paxlovid into the treatment of COVID-19, some patients have reported a virological rebound. A previously conducted phase 3 clinical trial, known as EPIC-HR, suggested that only 1% to 2% of patients taking Paxlovid experienced a virological rebound. However, research by Siedner and colleagues shows that this phenomenon is much more common than previously suspected.

Paxlovid remains a life-saving drug that I prescribe to high-risk patients. This study, while informative, does not change the fact that this drug is highly effective in preventing hospitalizations and death. Instead, it provides valuable insights to Paxlovid patients, helping them understand what to expect and how long they may remain contagious.”

Jonathon Li, MD, co-senior author, infectious disease physician and investigator in the Division of Infectious Diseases at Brigham and Women’s Hospital

Siedner, Li, and other researchers from Mass General Brigham collected data from the Post-vaccination Viral Characteristics Study (POSITIVES), an ongoing study of individuals diagnosed with acute COVID-19 infections. 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 into those who followed a five-day Paxlovid regimen and those who did not, they closely monitored patients’ viral loads and symptoms, cultured virus samples and performed whole genome sequencing. Patients who tested positive for COVID-19 after previously testing negative and those who showed two consecutive increases in viral load after an initial reduction were classified as having virological rebound.

Researchers found that 20.8% of participants taking Paxlovid experienced a virological rebound, while only 1.8% of those not taking Paxlovid had a similar rebound effect. Those with a rebound also showed prolonged virus shedding – an average of 14 days compared to less than 5 days in those who did not experience a rebound – suggesting they were potentially contagious for much longer. Importantly, Siedner’s team found no evidence of drug resistance in these patients.

The findings should not deter doctors from prescribing the medication, the researchers noted, but they should prompt them to counsel patients taking the medication about the risk of viral rebound and spreading the virus to others. Advising patients to retest and isolate in case of a rebound should be part of that conversation, the team said.

The original EPIC-HR study assessed patient outcomes at only two time points. When the Mass General Brigham researchers matched their data analysis to selected time points from the EPIC-HR study, they found virologic recovery in only 2.4% of participants, suggesting that the previous study did not capture the full extent of represented virological recovery.

“In our study, we were able to closely monitor patients from the onset of COVID-19 infection through treatment and rebound,” Li explains. “Unlike the EPIC-HR study, which assessed outcomes at only two time points, we followed up with patients three times a week, sometimes for months, and performed sample collection at home. We also had both viral RNA levels as viral culture data. have allowed us to paint a more comprehensive and nuanced picture of a patient’s experience with Paxlovid.”

This study is limited in that it was an observational study and not a randomized, controlled trial. Thus, the authors cannot be certain that the increased rebound rate observed in people taking Paxlovid was solely due to use of the drug. The team used a positive virus culture as a measure of risk of transmitting the virus, but could not formally measure how contagious someone was who experienced a virological rebound. Furthermore, the team could not explain why some people experienced a rebound and others did not. something they want to explore with future studies. They also plan to investigate the biological mechanism behind the rebound phenomenon associated with Paxlovid and determine whether changing the duration of treatment can help combat this rebound effect.