To Paxlovid or not to Paxlovid

That is the question... with more answers.

Here is one more post about Paxlovid, and then I’ll switch lanes for a while. But with the holidays coming, a noticeable uptick in cases in the office this week, and a lot of questions from patients trying to decide what to do when they get Covid - I feel compelled to share a few thoughts about a promising new study out this week. It found that patients (with at least one risk factor for developing severe Covid) who took Paxlovid had a 25% reduction in their risk of developing Long Covid.

I think this will hold true of other antiviral treatments like remdesivir, too.

This is what I hoped would be shown one day, and if you read my post back in March of this year, you’ve been hoping this, too. Many doctors have been holding back on prescribing, and many patients are reluctant to take Paxlovid. Here’s what I wrote 8 months ago:

I also suspect (prescribing Paxlovid) will decrease the frequency and severity of Long Covid (that nasty lingering array of possible symptoms like fatigue, cough, shortness of breath, cognitive problems, muscle weakness, and pain just to name a few). Paxlovid reduces viral loads in the body by 10-fold, and we are learning that part of Long Covid pathogenesis is direct cell invasion by the virus… so it would make intuitive sense that reducing the amount of virus early in infection, and helping the body to clear it out faster, might help low, average, and high risk individuals avoid long Covid.

Once again, the new study found that Paxlovid was associated with 25% less risk of Long Covid. That’s a 25% reduction in people experiencing problems with the cardiovascular system (dysrhythmia and ischemic heart disease), coagulation and hematologic disorders (deep vein thrombosis, and pulmonary embolism), fatigue, liver disease, acute kidney disease, muscle pain, neurocognitive impairment, and shortness of breath.

That sounds worth taking. Long Covid is still most effectively prevented by trying not to get sick, or sick again. Vaccination and boosters reduce the risk by 30-50%. Add in Paxlovid for another 25% reduction at least.

However, I must put those shiny percentages into a less eye-catching perspective. Here are the absolute numbers:

*In the untreated group, Long Covid symptoms persisted in 9.43 out of every 100 patients evaluated at 90 days after infection.

*In the treated group, Long Covid persisted in 7.11 out of every 100 patients at 90 days.

*7.11 / 9.43 = 0.75, or a 25% reduction. That’s only a difference of 2.32 cases per 100 people infected.

But that 7.11 is sure to keep dropping faster than that 9.43 if we follow the curves and project out to 120 days, or even 365 days.

And using bigger numbers - that 2.32 less cases of Long Covid per 100 patients becomes 2.3 million less cases of Long Covid per 100 million Americans infected.

And don’t forget - early antiviral treatment with Paxlovid or remdesivir also has that up front reduction in hospitalization and death by 90%+ in the first month after treatment. This study found an additional 48% reduction in death during the next 1-3 months after recovery.

But will future studies find an even greater benefit? This study involved mostly older male veterans with an average age in the 60’s. In that previous post I said that Paxlovid “might help low, average, and high risk individuals avoid long Covid.” We can now take the “might” out of the sentence for high risk individuals. They were the ones identified by the FDA as appropriate for receiving Paxlovid (given proven benefits against hospitalization and death).

But what about those people at average and low risk? I think it will be determined that they can reduce their risk of Long Covid as well, especially the middle age crowd that seems to be developing Long Covid more frequently than older people. Here’s a nasty table that I have cropped down to the essentials, and then I will further explain:

This comes from a CDC survey last month of people who have ever experienced Long Covid after infection. What is paradoxical is that the percentages are highest in 40-49 year olds at 17.9%. People over age 80 complained of Long Covid at a rate of only 5.4%! What’s going on?

The CDC further states that based on a survey in June 2022 of present complaints:

• Overall, 1 in 13 adults in the U.S. (7.5%) have “long COVID” symptoms, defined as symptoms lasting three or more months after first contracting the virus, and that they didn’t have prior to their COVID-19 infection.

• Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older.

I wonder if part of this discrepancy can be attributed to the fact that older people have a lot of baseline complaints and symptoms that were present before and after Covid infection? How many 80 year-olds won’t admit to some degree of fatigue, brain fog, or feeling winded? Just a thought. Or it could be that the strength and balance between constructive and destructive inflammation/immune system activation tilts unfavorably in middle age.

One more sampling of data trends. A study out of the UK found this:

The proportion of people with symptoms for 12 or more weeks generally rose with increasing age, ranging from 7.8% in younger adults to 17% in middle-aged people.

Using a stricter definition of long COVID as impacting routine daily activities, the researchers found that it affected 1.2% of 20-year-olds who had COVID-19, but 4.8% of people in middle age.

Women were 50% more likely to report long COVID than men.

I think future studies will find that treatment with Paxlovid reduces the incidence of Long Covid even in people who are not currently encouraged to take it - namely those without that one risk factor for severe disease. Consider middle-aged people, who are developing Long Covid at higher rates than even the elderly. Dr.

Eric Topol

, an expert on this stuff, states succinctly:

…it is possible/likely that the acute phase benefit in the younger age groups is minimal (with low acute phase risk), but reduction of Long Covid, which mostly occurs in younger people, age 30-50 years, is equal to (or potentially greater) than the older age groups.

If so, then the low utilization of Paxlovid should look better than this:

The oldest patients are being prescribed/taking Paxlovid at alarmingly low rates, especially considering the primary benefit is to reduce hospitalization and death in this highest risk group. Medication interactions are a prime reason, but would not completely explain this phenomenon.

Like most illnesses, younger, healthier people tend to bounce back more completely and with greater speed. But for many people, including young and healthy ones I have seen, the after effects of Covid can really be a debilitating problem. So by taking Paxlovid, the theory is that we are sweeping away the virus more completely, reducing its armies by 90%, preventing the accumulation of viral remnants and persistent pockets of infection, and reducing the potential chronic inflammatory state that can develop and lead to Long Covid.

An article in National Geographic reviews how many viruses have been causing “Long Syndromes” all along. Doctors like myself are starting to realize and acknowledge that this post-viral phenomenon has been more prevalent than we would care to admit to our frustrated patients with chronic, unexplained symptoms and syndromes:

“It is not surprising to find viruses encountered during the lifetime” surviving in human tissues, says Kei Sato, a virologist at the University of Tokyo. Indeed, Sato’s work has shown that humans frequently accumulate viruses such as Epstein-Barr virus, varicella zoster virus (which causes chicken pox), and many herpes viruses in dormant forms. These persisting viruses are typically present at low levels, so only extensive genetic sequencing can identify them...Likewise, lingering SARS-CoV-2 could cause long-term health problems. Henrich thinks when the virus is seeded in deep tissues, it potentially causes the immune system to shift into a dysregulated inflammatory state. Such a state is “probably evidence that the virus is capable of persisting, and maybe getting down into sort of an uneasy truce with the body,” says VanElzakker.“

~

In summary, Paxlovid (and remdesivir) have already been proven to reduce the risk of hospitalization and death, primarily in older and higher risk individuals. Prescribing them more liberally to lower risk patients has generally been frowned upon, even by doctors. But some (like me!) have hoped that early treatment with antivirals would also reduce the rates of Long Covid, which can be mild to debilitating. This was intuitive, as reducing the viral load by 90% leaves much less viral mess for the immune system to clean up. This first major study provides good evidence that Paxlovid does indeed reduce the risk of Long Covid. By at least 25% in older individuals. Further speculation logically extends to younger and healthier individuals who are not the usual targets for antivirals, but who actually have higher rates of Long Covid. It seems likely that they would also benefit from taking this medication early in the course of disease. Longer term studies are needed. And maybe Long Covid persistence will be reduced by even more, say 50%, at 6 months? Just a guess. We are not seeing Paxlovid resistance in the real world yet, but antiviral stewardship needs to be considered, especially if we do start to see resistance.

Would I still take Paxlovid? Yes. Should doctors pay attention to all this emerging nuance? Yes.