HIV and ID Observations

Photo by Piret Ilver on Unsplash.

We turn now to the second of the controversial papers published in late 2022 on COVID-19 — namely the PANORAMIC study of molnupiravir versus usual care in outpatients with the disease. This one is controversial not because the study was poorly done, or unimportant, but because molnupiravir has, from the start, been a contentious treatment for this disease.

Conducted in the United Kingdom, PANORAMIC was impressively large, enrolling over 25,000 people. Eligible participants had symptoms for 5 days or fewer, and were either older than 50 or had comorbidities known to increase the severity of the disease. Randomization was to open-label molnupiravir or usual care. The primary endpoint was hospitalization or death. Importantly, 94% of the participants had already received three doses of a COVID-19 vaccine.

The main study results were negative — hospitalization or death occurred in only 1% of participants in both groups. Serious adverse events were evenly matched between arms.

On the plus side, people assigned to receive molnupiravir had a substantially faster time to recovery, 9 vs. 15 days, which yielded a >99% chance of the molnupiravir being superior to usual care for this protocol-specified endpoint. Active treatment also decreased healthcare utilization, and reduced viral load compared to usual care.

The critical view of molnupiravir:  Great study in a highly relevant population — those who are not just “fully vaccinated,” but also boosted. In this context, molnupiravir did nothing to reduce the serious outcomes of hospitalization or death.

And ignore those time to recovery results. It’s an open-label study, with people getting active treatment of course thinking that what they’re getting is working. The placebo effect in treatment trials can be massive.

Only this isn’t a harmless placebo — it’s an antiviral with a concerning mechanism of action, inhibiting viral replication by increasing the frequency of viral RNA mutations. Such a process could conceivably spawn more contagious or more immune evasive SARS-CoV-2 variants, something we definitely want to avoid.

Plus, there’s the ongoing concern about mutagenesis, which has implications for those of reproductive age, and might have other long-term safety issues.

Finally, molnupiravir isn’t cheap. Don’t be fooled that it’s “free”, or covered by insurance, or government programs. It’s $700 for a five-day course, another disadvantage it has compared to placebo.

Now that we know this giant, well-done study is negative, can we take molnupiravir off the treatment guidelines completely, please? Or consider withdrawing the Emergency Use Authorization?

For further concise, and (mostly) critical thoughts, read the responses to this post:

pic.twitter.com/5mx7i0Yy7y

— Patrick Kenney (@PatrickKenney7) January 13, 2023

The supportive view of molnupiravir:  Great study — helps put this treatment in the current-world context of COVID being milder in people who are vaccinated or who have immunity from prior disease, or both.

And though molnupiravir made no difference in the primary endpoint (which was reassuringly rare in both arms), that faster time to recovery sounds pretty great. It’s better than we’ve seen in open-label studies of influenza treatment, so it is unlikely just due to the unblinded study design.

Given the option of recovering from a nasty respiratory tract infection in 2 weeks with no treatment, versus less than 10 days with molnupiravir — and no major side effects — I’ll take the latter, thank you.

And dropping viral load might reduce household transmission, and speed time to being able to get back to work and other activities. Both big wins.

Plus, let’s look at molnupiravir in the context of other treatment options:

• Nirmatrelvir plus ritonavir has many drug interactions, so can’t be given to some of our patients at highest risk for severe COVID.
• Remdesivir in the outpatient setting sounds great, but anyone who’s tried to set up 3 consecutive days of intravenous treatment for patients in the ambulatory setting know this is a tall order, indeed.
• The monoclonal antibodies are toast.

Molnupiravir clearly has a role.

My take on molnupiravir:  We need to acknowledge that the clinical data on this drug are mixed — at best. In the blinded phase 3 study, MOVe-OUT, the patients receiving treatment who had pre-existing immunity to SARS-CoV-2 did not benefit at all — in fact, the placebo group did better. And the study on hospitalized patients, MOVe-IN, was also negative.

Also, there are legitimate concerns about its mechanism of action, both related to variant generation and mutagenicity.

In short, there are excellent reasons why the preferred treatments for non-hospitalized high-risk adults in the NIH Treatment Guidelines are not molnupiravir, but nirmatrelvir boosted with ritonavir or intravenous remdesivir. A footnote reads, “Molnupiravir appears to have lower efficacy than the other options.”

But as I wrote previously when the data from PANORAMIC were first released, this improvement in time to recovery does stand out, and it is plausible that secondary transmission would be reduced. So I don’t think that molnupiravir is useless — especially given the limitations of our other treatment options.

So back to the guidelines, which state molnupiravir should be used in high-risk outpatients with COVID “…when the preferred therapies are not available, feasible to use, or clinically appropriate.”

Perfect, and it’s exactly what I’ve been doing.

Meanwhile, can we get some further data on other treatment options that are easier or safer to use? I’m thinking in particular the unboosted protease inhibitors ensitrelvir* and EDP-235, interferon lambda — and maybe even cheap (and very safe) metformin.

(*A very wise ID PharmD has kindly informed me that the drug interactions with this protease inhibitor are likely to be just as complex as with nirmatrelvir plus ritonavir. Oh well.)