Does Paxlovid cause Covid rebound?

Some patients who have been prescribed Pfizer’s pill regimen Paxlovid to tackle Covid-19 have reported feeling cured of the disease after several days of treatment only to then suffer a relapse, a puzzling phenomenon that has been dubbed “Paxlovid rebound”.

The most famous victim to date is US President Joe Biden, who recently contracted the coronavirus, was immediately treated with the drug and duly tested negative, before subsequently testing positive again four days later, albeit this time without symptoms.

First lady Dr Jill Biden and Dr Anthony Fauci, the White House’s chief medical officer, have likewise reported similar experiences.

“We’re all seeing people who are taking Paxlovid doing really well and then suddenly they’re getting sick again,” Dr Michael Charness, a scientist at VA Boston Healthcare in Massachusetts, told the journal Nature.

“There are so many unanswered questions.”

So what exactly is Paxlovid and how common is the rebound?

The drug itself is an oral, three-pill antiviral regimen prescribed to those believed to be at severe risk after catching Covid – for instance, the elderly, the unvaccinated or those with a prior underlying health condition – and is taken daily over five days.

The first two pills consist of nirmatrelvir, which targets enzymes specific to the coronavirus and halts their replication, while the third is ritonavir, which supports that first medication by slowing its breakdown within the human body, as it proved so successful in doing when tackling HIV/Aids, the condition for which it was first developed.

Paxlovid proved a success in Pfizer’s clinical trials, cutting hospitalisation and death by 89 per cent in participants compared to those who were given a placebo, although the virus was spotted recurring shortly afterwards in 1-2 per cent of cases.

For comparison, another study of Covid recurrence in people who were not treated with Paxlovid by Brigham and Women’s Hospital in Boston, Massachusetts, found that 27 per cent of those involved reported their symptoms returning after an initial improvement while 12 per cent saw the virus return at high levels.

“The main take-home message is that recovery from Covid-19 is not going to be a linear process,” said Professor Jonathan Li, who led that research.

Paxlovid was approved by the US Food and Drug Administration (FDA) for general release in late 2021 for adults and children aged 12 and older who were considered to be at advanced risk because of outstanding conditions like obesity, diabetes and heart disease.

At the time of the FDA’s ruling, there were no treatments for Covid that could be administered at home and the drug outperformed a rival offering from Merck so was readily taken up, with the Biden administration spending more than $10bn purchasing Paxlovid and making it available through pharmacies nationwide as part of its test-and-treat initiative.

More than 3.9 million prescriptions have since been filled, according to federal records.

But the rebound phenomenon has gradually become apparent and is recognised by the US Centers for Disease Control (CDC), which warns that, while the treatment is still recommended, it can lead to “a brief return of symptoms” in some instances, while also noting that such an occurrence is possible “in some persons, independent of treatment with Paxlovid and regardless of vaccination status”.

Suffering the rebound might mean experiencing the “virus without symptoms, symptoms without virus, and you can have the two together,” Dr Davey Smith, the head of infectious diseases and global public health at the University of California, San Diego, told Scientific American.

“If your patient needs it, the drug works, even in the setting of some people [experiencing a] rebound,” he added.

“The clinical trials were very clear that this was a great drug to keep people out of hospital and from dying. So don’t be scared of the rebound.”

As proved to be the case with President Biden, when a rebound does occur it can be asymptomatic, making it difficult to determine whether the patient who has taken Paxlovid has truly suffered a recurrence of the virus or is just taking longer to recover than others.

Quite what causes the relapse is uncertain, with both evolving resistance from the virus and weak immune system response in those given the drug broadly rejected as unlikely.

One hypothesis is that the patients in question require greater quantities of nirmatrelvir to see off the sickness once and for all, an argument for the treatment being administered over a longer period.

Ultimately, only a small percentage of those treated with Paxlovid tend to suffer a rebound, according to the experts, who stress that more research is needed to put a definite round number on it, and the second bout may only amount to a minor case of Covid, given that your immune system will already be acquainted with its attack.

That said, the treatment is only given to those thought to be at risk in the first place, so any encounter with the coronavirus is a cause for concern and those to whom it does happen are reminded to isolate, wear a mask and take regular lateral flow tests because they remain infectious, with or without visible symptoms.

“I want to emphasise that the good thing is, even if you have a rebound, outcomes are good,” said Dr Adi Shah, an infectious disease specialist at the Mayo Clinic in Minnesota.

“You’re not needing additional Covid therapies, you’re not needing hospitalisation, and you’re not experiencing high mortality or morbidity.”