Covid-19 antiviral Molnupiravir not effective in preventing hospitalization and death among vaccinated patients with high risks.

Merck's drug improved recovery times, but failed to show benefit for its primary purpose. Still, this new study contains an unexpected trove of other good news.

There’s big news on Covid-19 therapeutics today. First, I’ll describe the basics you may be able to get from any decent news outlet. Then, I’ll highlight findings that I imagine very few people will have noticed, but which may be equally if not more important. 

The basics. A new study appearing in The Lancet today found that Molnupiravir—a Covid-19 antiviral similar to Paxlovid, but less widely used in the US—had no impact on hospitalization or mortality among vaccinated patients with high risks of severe Covid. The study did however find that patients who took the Merck drug (which runs around $700 per patient), shortened the time to recovery by around 4 days on average. 

An annotated version of data on whether Molnupiravir helped various categories of patients avoid hospitalization or death (Source: The Lancet). Any diamond in the pink area means that Molnupiravir did not help patients with the characteristic listed in that row. However, the attached horizontal lines that cross the vertical line (at 1.00) also mean that the finding was not statistically significant—meaning that the drug did not harm these people. Any diamonds in the blue are with horizontal lines that did not cross the vertical line would have meant a benefit for Molnupiravir patients. Unfortunately, that never happened for the main outcomes in this paper.

Molnupiravir’s lack of benefit in preventing hospitalization or death is in contrast to a blockbuster study of the drug last year which found that the drug appeared highly effective in preventing those outcomes. But that study, like the major Paxlovid study, assessed unvaccinated people with high risks. The new Lancet paper studied vaccinated people with high risks.

While disappointing, the authors bent over pretty far backwards to highlight the good news on recovery time. Reading the paper, you’d almost think that improving recovery time was the main objective of the trial, though it was not. So, many people will use the speedier recovery time as justification to keep using both Molnupiravir and Paxlovid for at-risk people with Covid-19. And that’s well and good, for people in the group studied here (older, higher-risk people). We don’t yet know whether these data will hold up in younger, standard risk people, and prior research suggests they may not. I have reason to think that these antiviral drugs likely help people with high risks across the age spectrum, albeit less and less as the pandemic goes on (as population immunity increases)

The Inside Medicine deeper dive. What caught my eye was that, to my knowledge, this is the first randomized controlled human trial that has studied Covid-19 outcomes among only vaccinated people that we’ve ever seen. That’s an absolutely astonishing fact, if you think about it. (Assuming I am correct here. Am I wrong?)

This gives us a chance to look at all-cause mortality and all-cause hospitalization among infected vaccinated people during the Omicron era, when the study occurred. In fact, after about a minute reading the paper, my thought was this: Forget whether Molnupiravir works or not! Let’s just ask what the hospitalization and death rate among the high-risk vaccinated Covid-19 patients who participated in this study were—and how do these numbers compare to data from the earlier trials which included unvaccinated high-risk people during the pre-Omicron era?

The news is absolutely excellent.

Among participants—people over the age of 50 with medical conditions placing them in the high-risk category and who had confirmed SARS-CoV-2 cases within 7 days of study enrollment—only 8 deaths occurred out of 25,054 patients. That’s an infection fatality rate of 0.032%, or 1 in 3,132 cases. The numbers were statistically similar, regardless of whether patients received Molnupiravir.

This is incredibly positive news. In the previous major study of this drug—which, again, assessed high-risk Covid-19 patients who were unvaccinated—the all-cause infection fatality rate in placebo recipients was a staggering 1.2%, or 1 in 78. And the prior study included adults of all ages; this latest one only studied older patients, which would tend to bias results towards more death in the newer dataset, not less.

By my math, this means that the all-cause death rate in Covid-infected, high-risk, vaccinated older patients (average age=57) during early 2022 appears to have been 97.5% lower than it was in 2021; this was despite the fact that the 2021 study included younger unvaccinated patients (average age=43) with high risks (who were not treated with anti-virals).

It’s not possible to know what share of the improvement can be attributed to vaccination, immunity from prior infections, or any changes in severity of illness due to variants (Omicron versus pre-Omicron). And it’s also a very sad and real possibility that death rates are now lower in part because many of the highest-risk people already died during the pre-Omicron era, and thus the “survivor population” is actually healthier on average—a horrible and predicted phenomenon called the “pull forward,” or “mortality displacement,” or “harvesting” effect—than the pre-pandemic population was.

Regardless, this all suggests that today, the risk of death from Covid-19 appears to be nearly two orders of magnitude lower in high-risk older groups than it was just a year ago—assuming they are vaccinated.

Of course, deaths are not everything.

But, more good news is that a similar reduction in hospitalization rates appears to have occurred too. Last year’s Molnupiravir study of unvaccinated high-risk Covid-19 patients recorded a hospitalization rate of 9.7% (68 out of 699 patients, just a little better than 1 out of 10 patients). In today’s study, the rate was just 0.78% in the control arm (98 out of 12,525, or around 1 out of 128 patients). While that’s still high on a population level, the risk of hospitalization in early 2022 (and with any luck, 2023) was again nearly two orders of magnitude better than that recorded in 2021, in this high-risk cohort.

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A few other key areas of interest to highlight: