Is viral rebound more common that previously thought?

Viral rebound may not be a consequence of antiviral treatment, but rather may be part of a more complex viral/host system paradigm. Some initial thoughts based on a recent LA times article.

Cover image from Singapore Paincare.

Edit 11/17/2022: In the post from today (11/17/2022) I made comment that prior confirmed cases may have been in regards to people unaware that they previously had COVID. In reality, the likely possibility is that the current individuals may have been people who were early seroconverters as Brian Mowrey pointed out.

Due to Brian Mowrey being more adept at the immunological aspects I’m relegating this idea to his hypothesis.

A few days ago the LA Times posted a rather interesting article, with a headline suggesting that rebound after PAXLOVID use may not, in fact, be attributed to PAXLOVID.

From LA Times

Upon first glance the article may seem like a defense of Big Pharma, and at some points this may appear to be the case:

It's also a story about how looks can be deceiving.

Americans have been quick to embrace the idea that the antiviral drug is to blame for COVID-19 relapses in people just days after they've seemingly recovered. President Biden was said to have experienced Paxlovid rebound this summer, after White House doctors declared him coronavirus-free. The same thing happened to Dr. Anthony Fauci and Stephen Colbert, among others.

It's tempting to presume a cause-and-effect relationship between two things that occur in quick succession. And even when events are completely random, we tend to see the patterns we expect to find.

Given everything going on, it’s certainly true that Big Pharma shouldn’t be given the big thumbs up as if everything is alright. Their role in the COVID craziness should obviously not be overlooked.

However, it’s always important to look at things through the lens of rationality, and after the whole PAXLOVID viral rebound affair I’ve been curious if other factors may be at play than just PAXLOVID use and vaccination status.

Apparently the writers at the LA Times thought the same as well:

But researchers are not so sure Paxlovid rebound is real. Relapses have occurred in COVID-19 patients who didn't take the drug — they just didn't get as much attention when there wasn't a new medicine to blame.

I probably wouldn’t use the phrase “Paxlovid rebound is real“, but rather if the rebound seen is due to PAXLOVID or some other factors.

Several researchers have raised some questions after the whole PAXLOVID viral rebound onset and whether this is unique to antiviral treatment¹ or part of a more complex system.

Fortunately the LA Times piece actually provides some interesting studies that, on the surface, may indicate that viral rebound may occur in individuals irrespective of their antiviral treatment.

While the studies do provide a bit of insight, they are also leaving me heavily wanting in their actually significance.

For instance, one of the studies cited was a correspondence released in the NEJM from Pfizer scientists² which looked back at the EPIC-HR PAXLOVID trial and compared viral load in a select few patients given PAXLOVID and a few given the placebo.

Remember that these patients were unvaccinated and exclusion criteria for the study included those who had no evidence of a previous infection. Essentially all of the participants should have been immunologically naïve to SARS-COV2.

Viral measures were taken at baseline and on Day 3, 5, 10, and 14 via nasopharyngeal swabs.

The researchers’ assessment suggests that the rebound between the treatment and the placebo group were similar, although incidences of rebound were slightly higher in the PAXLOVID group:

From baseline through day 14, viral load rebound occurred in 23 of 990 patients (2.3%) in the nirmatrelvir–ritonavir group and in 17 of 980 (1.7%) in the placebo group (Figure 1B and Table S2). Results regarding viral load rebound were similar in the nirmatrelvir–ritonavir group and the placebo group in analyses of the presence of coexisting illnesses, nirmatrelvir exposure, recurrence of moderate-to-severe Covid-19 symptoms (Fig. S1), the occurrence of hospitalization or death, baseline SARS-CoV-2 serologic status, and nirmatrelvir resistance (as assessed by SARS-CoV-2 Mpro gene or cleavage mutations).

The definition of viral rebound here is actually not as direct, and rather than be a definition that infers a negative PCR test before turning positive again, it actually infers a viral load which increases by at least half a log on Day 10 or Day 14 (Day 10 is used when Day 14 data was unavailable):

Recurrence of Covid-19 was defined according to prespecified criteria for viral load rebound: a half-log increase in viral load on day 10 or day 14 if only one value was available or on days 10 and 14 if both values were available. This definition was developed to evaluate resistance to nirmatrelvir.

This creates some weird assessments of the data, as this definition may not properly apply to the features seen in actual people who have taken PAXLOVID (i.e. the negative test followed by the positive rebound). This lack of proper definition means that the use of a phrase such as “viral rebound” may not translate across other studies, and in regards to this study may not provide any actual insight.

These sorts of studies which track across various days can also make it difficult to see the actual viral rebound effects in individuals. Note the chart below where plots which cross over with a lot of the data not being clear aside from the blue line tracking the one hospitalized patient in this group.

From Anderson, et al. Figure 1. Viral load on both Day 10 and Day 14 were compared to viral load on Day 5. Increases in viral load by 0.5 was used as a determinant for “viral rebound”.

Granted, the fact that many of these samples did not meet the limit of quantification on Day 10 but appear to be quantifiable on Day 14 suggest more than just a half a log increase in viral load. As for why such a drastic increase in viral load was seen is not explained, and remember that PCR was being used as a proxy for viral load and may not infer actual infectious virions.

Pretty recently JAMA published an article³ which looked at placebo patients who were part of a platform trial named ACTIV-2/A5401. The trial was a phase 2/3 trial which looked at investigatory treatments for non-hospitalized patients.

This study took place in the months of August-November 2020, so note that this study took place prior to the release of the vaccines. However, the researchers do not make note of the immunity status of recruited individuals (the trial excluded people who previously were hospitalized for COVID, but there’s no mention of the actual vaccination status).

Recurrence of symptoms were marked for individuals who reported symptoms at least 2 days after being symptom-free, which was used to infer some form of viral rebound.

Unfortunately, the study asked participants to keep a journal and record their daily symptoms which were then mapped to infer some level of viral rebound, so there’s a huge assumption in the assessment of recrudescence in these individuals.

From Smith, et al. The above chart lists out information for some of the participants form the placebo arm of the ACTIV-2/A5401 study. The data is organized by duration of COVID symptoms with participants showing the longest duration of symptoms listed at the bottom (Participant 1). All of the above participants showed symptom recurrence at least 2 days after having no more symptoms. Note that the number and duration of symptoms vary greatly between participants and may not be an actual, appropriate measure of viral rebound.

The high subjectivity of these reports makes this data difficult to assess, especially given that many of the symptoms that returned were mild coughs, fatigue, or headaches (see the Table from the study⁴).

How exactly would a participant label a cough as being mild, or which symptom occurred on which day?

Note in the above chart that many of these symptoms appeared to have occurred continuously on and off for some individuals (e.g. Participant 6), or appeared only one day for many of the participants above (e.g. Participants 37-40).

So the actual utility of this study may be rather minimal since it’s hard to relate any of these results to anything of significance.

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The LA Times brought up an interesting argument, and it’s most certainly a possibility that complex systems are at play that are leading to viral rebound. However, the studies provided don’t move us closer to finding out the actual mechanisms that may be causing the viral rebound.

The fact that some of these incidences of viral rebound occurred even in individuals who were not vaccinated or had prior immunity is rather interesting, but more data would be needed that aren’t funded by the drug manufacturer to remove any of those blatant biases.

With that being said, this may serve as a reminder that a complex web of biochemical processes are all occurring at once, all of which play a role in the viral dynamics and this supposed rebound effect. It’s a reminder that there may be more than a dysfunction due to vaccination occurring, although further researcher would need to elucidate other potential dynamics.

It’s interesting that many reports of rebound don’t appear to show a rebound more severe than the initial infection. By all accounts, it appears that viral rebound tends to occur with more mild symptoms which would be worth investigating further. We also have to keep in mind that “rebound” testing measures either utilize PCR or antigen tests, and so these tests only serve as a proxy for infection as they are both only measuring how much “stuff” is there.

Note that this is just a preliminary glance into this topic spurred on by the report in the LA Times. However, this should serve as a reminder that much of the COVID discussion still remains ambiguous, and in fact much of science is still plagued with ambiguity and nuance.

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1. I have written about one study which suggests a possible rebound seen in Molnupiravir, although the study comes with many limitations that make the evidence not exactly conclusive.

Molnupiravir COVID rebound just as possible as PAXLOVID's

2. Anderson, A. S., Caubel, P., Rusnak, J. M., & EPIC-HR Trial Investigators (2022). Nirmatrelvir-Ritonavir and Viral Load Rebound in Covid-19. The New England journal of medicine, 387(11), 1047–1049. https://doi.org/10.1056/NEJMc2205944

3. Smith DM, Li JZ, Moser C, et al. Recurrence of Symptoms Following a 2-Day Symptom Free Period in Patients With COVID-19. JAMA Netw Open. 2022;5(10):e2238867. doi:10.1001/jamanetworkopen.2022.38867

4. Note that many of the symptom recurrence appears mild and were recorded as being either a cough, fatigue, or headache. There may be a few overlaps in symptoms, but given that these symptoms occurred only for a day or two and were mild it would be hard to argue that this data is relatable to an idea of COVID rebound.