Having a rebound of Covid-19 after taking Paxlovid is not exactly the same as having a rebound relationship. Although both could make you sick in different ways. A post-Paxlovid rebound may come after you feel better from taking Paxlovid for a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rebound is when at some point after the five-day course of the medication is completed, you experience a relapse of Covid-19 symptoms. And it seems like more and more people have been reporting such relapses.

For example, there’s that pre-print case report uploaded to Research Square on April 26, 2022, of a 71-year-old man who had been fully vaccinated and boosted against Covid-19. He began taking Paxlovid as soon as he tested positive for Covid-19, two days after he had gotten exposed to the virus. His Covid-19 symptoms essentially disappeared after two days of Paxlovid. Yet, nine days after he had first tested positive and four days after he had completed the five-day course of Paxlovid, his runny nose, sore throat, and difficulty breathing returned, along with his SARS-CoV-2 levels going up again. Viral genome sequencing showed that during his initial symptoms and his return of symptoms, he was infected with the BA.1 Omicron subvariant of the SARS-CoV-2. Of course, a pre-print is not the same as a peer-reviewed article, and anyone with opposable thumbs, a laptop, and Internet access could in theory upload a pre-print. But the authors of the case report (Kalpana Gupta, Judith Strymish, Gary Stack, and Michael Charness) are legitimate doctors from legitimate healthcare systems, the VA Connecticut and Boston Healthcare Systems.

Plus this certainly hasn’t been the only report of such a rebound. For example, here’s what Tatiana Prowell, MD, an Associate Professor of Oncology at the Johns Hopkins School of Medicine tweeted:

And Peter Hotez, MD, PhD, Dean of the National School of Tropical Medicine at Baylor Medical College, tweeted about his case of post-Paxlovid relapse:

As a reminder, Paxlovid received emergency use authorization (EUA) back on December 22, 2021, from the U.S. Food and Drug Administration (FDA) as a treatment for those 12 years and older with mild-to-moderate Covid-19. These antivirals are supposed to keep the SARS-CoV-2 from doing the nasty in your body, which is a non-technical way of saying reproducing in your cells. While Paxlovid doesn’t put tiny condoms of the viruses’ spikes, it is actually the combination of two different antiviral tablet, nirmatrelvir and ritonavir, packaged together. The recommended dose of these antivirals is two 150 mg tablets of nirmatrelvir along with one 100 mg tablet of ritonavir twice a day for five days, assuming that you have normal kidney function.

Like Hall & Oates, these two medications work together. Nirmatrelvir can block the action of an enzyme called MPRO, not to be confused with GoPro. MPRO cleaves two different viral polyproteins, which may not sound very sexy but is an important step when the SARS-CoV-2 wants to reproduce. Meanwhile, ritonavir inhibits cytochrome P450 (CYP) 3A4 enzymes in the liver that can break down nirmatrelvir and thus allows nirmatrelvir to hang out in your body longer.

And just like condoms, Paxlovid doesn’t work after reproduction has already occurred. That’s why it’s important to take Paxlovid as soon as you’ve learned that you are positive for Covid-19. Waiting beyond five days after symptoms first appeared may allow the virus to reproduce too much for Paxlovid to make much of a difference. So there is a finite window, less than half a Scaramucci, during which taking Paxlovid will help.

As this NBC News segment shows, the FDA is currently investigating the reports of Covid-19 rebound cases:

Do these rebound cases then mean that Paxlovid is not doing its job? No, not necessarily. Just because symptoms return doesn’t mean that things wouldn’t have been even worse without the medication. Plus, it’s not yet clear what percentage of people have been experiencing such relapses. Again stories on Twitter and a pre-print case report ain’t the same as peer-reviewed studies. While Pfizer’s clinical trial did show possible rebound Covid-19 occurring in about 2% of those who had received Paxlovid, around 1.5% of those who had received only placebo also suffered similar relapses. With these two percentages not being statistically significantly different from each other, the conclusion from the clinical trial was that these rebounds weren’t specific to Paxlovid. Of course, what happens or doesn’t happen in a clinical trial doesn’t necessarily mean the same will apply exactly in the real world.

So what’s going on, in the words of Marvin Gaye? One possibility is that the five-day course of the medication is turning out to be not long enough for everyone. The medication is supposed to suppress viral replication long enough for your immune system to clear the virus from your body. It’s kind of like smearing deodorant on yourself until you’ve had a chance to take a real shower. Remember Paxlovid doesn’t clear the virus from your body. It just keeps it from replicating. The amount of time needed for your immune system to accomplish this virus clearing task may vary depending on how much virus happens to be in your body and the status of your immune system. It could be that your immune system hasn’t geared up enough before the five-day course of the medication has been completed. So one question is whether the course of Paxlovid should be longer than five days.

Another possibility is that the Omicron variant may be different enough from previous versions of the virus that the medication may not be quite as effective. Remember Pfizer’s clinical trial occurred last year while the Delta variant was dominant. So all results may be more Delta-specific.

A third possibility is that the virus has been developing resistance to the antiviral medication. While resistance may not be futile, it can reduce the effectiveness of the medication. Resistance is why flu antivirals such as Tamiflu may not be as effective against certain strains of the flu. And with the Covid-19 coronavirus replicating so much, resistance could very well develop. Each time the SARS-CoV-2 replicates, it can be like a drunk person making photocopies of his or her butt. Mistakes can result when the virus tries to copy its genetic code leaving resulting progeny with mutations and thus different genetic sequences. Some of these mutations may alter virus proteins enough to allow the virus to better evade the antiviral.

Many people using the antiviral medication could then end up selecting for viruses with such resistance mutations, because they are better able to survive. These resistant versions could then eventually become the dominant version of the virus. That’s why antiviral medications shouldn’t be overused.

While there was no clear evidence of resistance developing during the Pfizer Paxlovid clinical trial, the trial may not have gone on long enough to see this possibility. It will be important for public health officials to track the possible emergence of resistant virus strains and potentially limit the use of Paxlovid if such resistance is found.

A fourth possibility is re-infection. Could some of the supposed relapse cases actually be people getting infected and then re-infected in a short period of time? I did cover for Forbes a case of someone getting infected with the Omicron variant within 20 days of getting infected with the Delta variant. But it’s not clear how common such getting two separate infections within such a short time period may be.

So if you do have a rebound case of Covid-19 after taking Paxlovid, what should you do? Should you take more of this antiviral medication? Well, currently, things are about as clear as Nutella soup. There is not enough evidence about what to do. And the EUA only covers taking the medication for five days.

Ultimately, more studies, more data, and more drug surveillance are needed. All of this is a reminder that while Paxlovid may be a very useful part of dealing with the pandemic, it is not a magical pill. Nothing in life is a magical solution with the possible exception of avocados or chocolate. Relying solely on a medication to “rescue you” if you were to get Covid-19 could be like relying on finding a soul mate to rescue you from your current life. Don’t think that the existence of Covid-19 treatments can allow you forego other Covid-19 precautions such as face mask wearing and vaccination against Covid-19. Remember Covid-19 interventions are like Swiss cheese, not that you should start putting them on your ham sandwich. Rather, this means that each individual precaution or treatment has its specific set of holes. And the hole thing means that you should always be layering at least several Covid-19 precautions on top of each other as long as the pandemic is still going on and the virus is circulating widely around you. If you don’t maintain other Covid-19 precautions and rely solely on getting Paxlovid when needed, the Covid-19 coronavirus could very well catch you on the rebound.

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