22 abril, 2022

Should We Prescribe Nirmatrelvir/r (Paxlovid) to Low-Risk COVID-19 Patients?

The top recommended treatment for high-risk outpatients with COVID-19 in the NIH Guidelines is nirmatrelvir/r (Paxlovid). It’s quite clear why.

In the EPIC-HR study, unvaccinated people at high risk for severe outcomes had an 89% reduction in the risk for hospitalization or death compared to placebo. If we just look at mortality — another important endpoint, don’t you think? — nirmatrelvir/r beat out placebo by a score of 0 (nirmatrelvir/r) to 13 (placebo).

Let’s add to this very favorable outcome several other benefits:

  • The reliable activity against all variants
  • The relatively good safety profile
  • The short course of treatment (5 days)
  • The substantial reduction in viral load, the most of any drug tested to date
  • That it is pills rather than an IV

Yes, folks, we have a winner! Sure, it has lots of drug interactions and it tastes terrible, but it’s far and away the best choice out there right now.

So if we recommend this treatment for high-risk people with COVID, what about for symptomatic people who are not at high risk? Not now, but imagine a time when we had sufficient supply. Should we also recommend it for them?

I thought the answer was straightforward, and will give my views below. But I had an inkling that this wasn’t so clear a few weeks ago when one of my smart colleagues held the opposite opinion.

To test these choppy waters, I posted this poll online:

Wow. Not only is there a pretty even split, but responses are so interesting, and quite strongly held. It’s fascinating to read them.

(And, by the way Dr. Titanji, good call.)

My own view? Given sufficient supply — and we’re not there yet — I’d certainly recommend nirmatrelvir/r even for low-risk symptomatic people. The motivation lies in the already summarized favorable results of the high-risk study, and hinted at even in the interim analysis of EPIC-SR, the study in low-risk people.

Remember, some low-risk younger people get severe disease. (Here’s a notable recent example — speedy recovery!) The reasons are poorly understood why this happens to some unlucky few (OK, not understood at all), and it’s rare, but all of us have seen these unfortunate cases. Could nirmatrelvir/r reduce the risk for severe disease even in this population?

Highly plausible. Look at the interim results of EPIC-SR which, though not showing benefit in the primary endpoint of time to symptom resolution, did appear to yield clinical benefits for this prespecified clinical endpoint:

A further advantage is the virologic response, which should reduce the likelihood of onward transmission. For those needing negative antigen tests prior to returning to work or school, it’s another plus to hasten this process.

Also, there’s the theoretical benefit that treatment will reduce the risk for long COVID, or other prolonged post-infectious symptoms. Both most certainly occur in people at low-risk for severe disease. Since at its genesis these are virus-induced complications, it’s not crazy to think that inhibiting and shortening viral replication will make these dreaded outcomes less likely. It will be challenging (and take some time) to prove, but it’s an important part of the research agenda.

Finally, treating symptomatic COVID-19 falls right in line with the first principles of our specialty. If there’s a safe, effective, and readily available treatment or prevention strategy for a symptomatic infection that is potentially serious, we treat it — even if most people will do fine.

I’m not alone in my view, obviously — 52% of respondents agreed. One respected ID researcher (who recently experienced her own household outbreak that was “not fun”), emailed me:

I agree with you 100%! I almost commented on that poll to say I thought it was a no-brainer but then saw how many people disagreed and stayed quiet! If it cuts short viral replication, the impact on secondary transmission could be enormous — far more than our vaccine responses are doing. What a huge benefit that could be!

The opposing view says it’s not yet been shown to benefit this population of lower-risk people. That these clinical endpoint results are “fragile” — so few outcomes that it could be an accident (and maybe motivated the increased sample size in the EPIC-SR study). That even if there is a clinical benefit, the number needed to treat will be gigantic. That resistance may develop. That the reduction in transmission effect isn’t proven. That there are places that don’t have this treatment at all, and our indiscriminate prescribing of nirmatrelvir/r will prevent it from being available abroad.

Lots of echoes of the oseltamivir controversies over the years. These are valid concerns, all of them. So I really do get this opposing view.

Créditos: Comité científico Covid

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