The Rise and Fall of Paxlovid - HIV and ID Observations HIV and ID Observations

APRIL 8TH, 2024

The Rise and Fall of Paxlovid

It’s been quite the ride for our “preferred” outpatient therapy for COVID-19, nirmatrelvir with ritonavir — much better known as Paxlovid, so allow me the license to use the licensed name.

Let’s recap the astonishing success and now failure of this intervention (some dates approximate):

1. December 2021, the FDA issued an Emergency Use Authorization for Paxlovid:  Action is based on the efficacy shown in the EPIC-HR study of high-risk outpatients with COVID-19. Compared to those receiving placebo, Paxlovid-treated participants had an 89% reduction in risk of hospitalization or death. Exciting times.
2. Early 2022, that annoying rebound thing. No, it’s never been quite clear whether Paxlovid caused rebounds, or just didn’t prevent them, or whether it just happened in those people for whom COVID-19 illness lasted longer than the treatment’s 5 days (a large group!), but regardless — it was a major disincentive to clinicians and providers alike.
3. December 2022, the protocol for the EPIC-SR in “standard risk” outpatients was amended to increase the sample size. Though an interim analysis suggested such patients would benefit from treatment, the change in sample size signaled that such a benefit observed in this analysis might be small — or nonexistent.
4. August 2023, the negative results of EPIC-SR were posted on clinicaltrials.gov. Yes, these results have been in the public domain since last summer.
5. Last week, the disappointing EPIC-SR results appeared in the New England Journal of Medicine. This is the primary endpoint (from the Research Summary):

It wasn’t all bad news for treatment: Risks of severe outcomes (hospitalizations, ICU admissions, or deaths) were very low overall — hooray! — and numerically lower in the Paxlovid group; medical visits were significantly lower as well. However, as anyone who has taken Paxlovid can attest, the taste alone could have made study participants aware that they were already on treatment, hence discouraging them from seeking further evaluations.

What about rebounds? From these limited data, it appeared there was no difference:

By day 14, viral load rebound had occurred in 4.3% of the participants in the nirmatrelvir–ritonavir group and 4.1% of those in the placebo group; symptom rebound occurred in 11.4% and 16.1%, respectively, and symptom and viral load rebound together occurred in 1.2% and 0.5%, respectively.

So where does that leave us right now? There’s no doubt that the EPIC-SR data further confirm that this treatment has many limitations. Here’s a teaching slide I recently made:

But before we completely abandon Paxlovid for outpatient use, let’s remember that our options for outpatient treatment of COVID-19 remain highly limited. Furthermore, people at high risk for adverse outcomes still require hospitalization and still die from this infection — as they do from other viral respiratory illnesses. As a result, based on EPIC-HR, these EPIC-SR data, and the observational studies, I’d still recommend treatment for this very high-risk group.

The Rise and Fall of Paxlovid - HIV and ID Observations HIV and ID Observations