Buzz over ‘Rebound COVID’ casts doubt on anti-viral treatments, but that’s not what the data shows

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When COVID-19 first appeared, the version that circulated through China, Europe, and then around the globe appeared to very rarely cause reinfection. For most people with a healthy immune system, the response to this initial version of COVID-19, and to the alpha and beta variants, provided a response that, while less powerful than the response generated by vaccines, was still broadly effective in preventing reinfection over a period of weeks to months. Researchers combed carefully through the initial wave of cases in China, looking for possible reinfections, and they did find a few. But “few” was the defining term.

That changed somewhat with the delta variant, where those who had been infected with past variants found that their previous illness offered little protection against the just-different-enough newcomer. Even so, infections with delta seemed to provide good protection against another infection with delta, so while those who had already suffered with a previous variant found themselves vulnerable a second time, it wasn’t the start of an endless round-robin.

With omicron, that’s changed again. Almost from the first appearance of the variant, there have been reports that not only were those who had previous forms of COVID-19 more open to infection by omicron, but that reinfections from omicron were much more common than with previous variants. There were frequent accounts of people being reinfected weeks, or even days, after their first experience with omicron.

Some of this remains true—omicron is more capable of causing reinfection, even among those who have had previous infections from omicron—but there was another factor that wasn’t initially recognized. On Dec. 20, 2021, the CDC first noted that omicron had become the dominant variant of COVID-19 in the United States, accounting for about three-quarters of new cases. On Dec. 22, 2021, the Food and Drug Administration (FDA) provided an emergency use authorization to Paxlovid as an oral treatment for those already infected by COVID-19.

One of the things that was happening wasn’t that omicron was so much better at causing reinfection. It was Paxlovid rebound.

As with many antiviral drugs, Paxlovid can rapidly drive down the viral load to an undetectable point. Researchers saw, and continue to see, this same phenomenon with HIV. But with the end of the five-day treatment, a small number of remnant viruses can come roaring back, generating a rebound infection.

Please note: It’s not that Paxlovid is causing the second infection. It’s that the infection never went away. The treatment merely masked the fact that some virus remained in system, and that the immune system response was not strong enough to fight it off when treatment ended. This doesn’t change the recommendation that Paxlovid be taken to address COVID-19 infections. In fact, those people experiencing rebound infections are likely to be those who benefited the most from the anti-viral treatment, as their immune systems were unable to suppress even a low level of SARS-CoV-2 infection.

The CDC continues to recommend Paxlovid and notes that in their review of rebound cases: “Both the recurrence of illness and positive test results improved or resolved (median of 3 days) without additional anti-COVID-19 treatment. Based on information from the case reports, COVID-19 rebound did not represent reinfection with SARS-CoV-2 or the development of resistance to Paxlovid.”

Paxlovid continues to be an effective treatment with good outcomes. A clinical study in preprint shows that “there was no evidence of severe disease or impaired antibody and T-cell responses in people with rebound symptoms.” A report from earlier this month conducted the first broad review of outcomes from Paxlovid and found that “Among 5,287 persons over 12” who received Paxlovid in the last six months, 39 were treated in emergency departments and just six were admitted for hospitalization.” That’s well under 1% of patients treated with Paxlovid. That report concluded just what the CDC and FDA have said from the beginning:

When administered as an early-stage treatment, Paxlovid might prevent COVID-19–related hospitalization among persons with mild to moderate cases of COVID-19 who are at risk for progression to severe disease.

In fact, the original studies on over 1,000 patients showed that “Paxlovid significantly reduced the proportion of people with COVID-19 related hospitalization or death from any cause by 88% compared to placebo among patients treated within five days of symptom onset.”

So, Paxlovid drastically cuts the incidence of severe illness or death. Less than 1% of patients experience rebound symptoms strong enough to seek treatment. Less than 0.1% of patients in rebound following Paxlovid were hospitalized.

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