Covid Rebound: How can I be positive again, what is Covid Rebound, and should I be worried?

Paxlovid, an anti-viral medicine used to treat SARS-CoV-2 infection, is available in the UK for patients at high risk for progression to severe disease, but in the USA, it can be given to anyone over 65.  Dr. Fauci (81 years old) and President Biden (79 years old) are both prime candidates for treatment.  Upon testing positive, both men were prescribed the standard five day course.  According to Dr. Fauci, his symptoms were initially mild and after taking Paxlovid, he felt much better.  He continued to test negative for three days in a row after finishing the course.  On day four, he got a shock.  He tested positive and his symptoms returned.  President Biden’s second positive test occurred on day five after completing treatment.  So what’s going on?

What is Covid Rebound?

Covid Rebound is a phenomenon whereby a person diagnosed with Covid-19, appears to recover, even to the point of testing negative for the virus, then experiences a recurrence of symptoms and retests positive two to fourteen days later.  This is not the same as a case of reinfection, which usually has a little more time between first and second positive tests (the shortest case so far being recorded at 19 days). 

Research into Covid Rebound is in its infancy, but data is trickling through.  For a while, many of the reports of Covid Rebound were anecdotal – doctors using social media to describe incidences of it in their patients.  However, as the numbers grew, the US Centers for Disease Control and Prevention (CDC) were prompted to issue a health advisory in May 2022, suggesting that people continue to test after treatment and to isolate if they return a second positive test.  This is important because people with Covid Rebound could potentially spread the virus.

What Does the Research Say?

The US Food and Drug Administration (FDA; main body authorising drugs for clinical use in the United States) had, in light of the reports of rebound, conducted additional analyses of the Paxlovid clinical trial data.  They found that 1 to 2 percent of patients experienced rebound, but concluded that it was unclear if this is due to treatment with Paxlovid, since they also observed rebound in the placebo group at a similar rate.  More research is needed, so they also request that if anyone experiences rebound due to Paxlovid treatment, they can report it to the Pfizer adverse events site.  

Not all doctors agree about the low incidence and given that the clinical trials conducted on Paxlovid occurred well before Omicron ever hit the scene, it is possible that this is an effect of Omicron variants.  One preliminary study, not yet peer reviewed, conducted during the Omicron predominant period puts the incidence slightly higher, at around 5 percent within 30 days.

Scientists are intrigued by Covid Rebound and have begun to examine its mechanisms.  One case study involved a scientist who became ill with Covid-19, was treated with Paxlovid and then experienced Covid Rebound.  He was savvy enough to sequence the genetic code of the virus, both before taking the medication and again after.  He observed that the genetic sequences pre- and post-treatment were identical, suggesting that Covid Rebound is not due to the development of drug resistance.  This data should be treated cautiously as it is not yet peer reviewed and is only one case.  However, a similar result has been observed in another case study that has been published in a peer reviewed journal, where genetic sequencing data from a patient experiencing Covid Rebound also demonstrates that the rebound is not due to drug resistance.  Indeed, this data also supports the conclusion that it is not a case of reinfection, because studies of genome sequencing showed that reinfections occur with genetically distinct SARS-CoV-2 strains. 

A Theory

One theory of why Covid Rebound occurs is that Paxlovid works so well at reducing the replication of SARS-CoV-2 that after five days of treatment, a patient’s immune system doesn’t get the opportunity to mount its own response.  After the removal of Paxlovid (when the treatment is finished) any remaining virus is able to replicate unchecked by the immune system and after a few days, is back at ‘make you sick, or at least test positive’ levels.  This would imply that the timing of use of the drug or the length of the course may need to be adjusted.  However, and this is a big however…this is theory and data is still being collected.  We cannot conclude anything until the numbers are crunched and results are verified, which is likely to take months.

When Dr. Fauci experienced Covid Rebound, he received a second course of Paxlovid, which he says is relatively common among those who suffer rebounds.  However, the CDC has noted that there is no evidence that additional treatment is required, and in most cases, the rebound resolves in a few days and is not severe.  The bigger concern comes from the possibility of transmission of the virus.  Hence those with Covid Rebound should take precautions against infecting others until they test negative again.  And yes, President Biden is back in isolation for another five days.

Should I Worry About Covid Rebound and Taking Paxlovid?

So, in light of the hype around Covid Rebound, remember that it is relatively rare but does occur.  Whether it is a phenomenon of Covid or Paxlovid remains to be determined.  However, it is not a reason to avoid using Paxlovid if you are at high risk of hospitalisation from SARS-CoV-2 infection.  In the words of Dr. Anthony Fauci…

If you are prescribed Paxlovid, don’t be put off using it.  Just remember, it may be wise to continue to test for a week after finishing the course to ensure that you do not rebound and possibly infect others.  If you have any questions, please ask your doctor.