2. Merck reports that a regimen of 40 pills over five days confers a 30% reduction in hospitalization and death in unvaccinated COVID cases. The US has ordered three million so courses of the drug to be delivered by early 2022.
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3. However, I'm somewhat concerned about the drug's safety — not so much for those taking it, as for the rest of the community. Let me explain. I've written in the past about how disease interventions can create externalities: effects on individuals beyond the person treated.
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4. For example, vaccines generate positive externalities. When I get vaccinated against measles, it benefits me because I won't get measles, and it benefits you because I won't spread measles to you.
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5. Antibiotics, by contrast, can generate negative externalities in the form of antibiotic resistance. If I take an antibiotic, that may increase the chance that antibiotic resistance evolves and that the same drug later fails to work for you.
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6. At least in the case of antibiotic resistance (or antiviral resistance), the negative externalities "only" undermine the use of the drug itself. They doesn't put people who will never take the drug at any greater risk.
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7. I worry that molnupiravir may be different, and may create even more extensive negative externalities. The problem is that molnupiravir works by inducing *lethal mutagenesis*: it causes lots of mutations in the virus, weakening it & allowing the immune system to clear it.
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8. But there's a risk of *sublethal mutagenesis*: the virus mutates extensively but isn't cleared. In that event, the virus creates new genotypes involving large number of mutations. That process of accelerated mutation without eliminating the virus might be trouble.
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9. A number of lines of evidence suggest that sublethal mutagenesis may occur with molnupiravir, not the least of which is the limited efficacy shown against hospitalization. See e.g. Bill Haseltine https://www.forbes.com/sites/williamhaseltine/2021/11/01/supercharging-new-viral-variants-the-dangers-of-molnupiravir-part-1/?sh=bcdb7016b15a … and this
@michaelzlin thread https://twitter.com/michaelzlin/status/1464424333246447620 ….Show this thread -
10.
@chasewnelson and@sarperotto make very much the same point in this letter to Virological:https://virological.org/t/mutagenic-antivirals-the-evolutionary-risk-of-low-doses/768 …Show this thread -
11. Recall that >6% of patients on molnupiravir require hospitalization. During chronic infections, the drug could in principle drive viral evolution toward new and more dangerous strains that spread better, cause more severe illness, or both. We don't want another omicron.
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12. Moreover, the pill regimen for molnupiravir is a difficult one: 40 pills spaced across a mere 5 days. In patients who missed multiple doses or failed to complete the regimen, sublethal mutagenesis could be particularly likely.
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13. This sets up a potential conflict between patient and the public: taking molnupiravir benefits the patient, on average. But in the unlikely event that something goes wrong, and the drug helps the virus evolve to a new variant of concern, the entire public pays the price.
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14. It is also worth considering the drug's efficacy vs. alternatives. The molnupiravir trial results are a bit odd. I'm troubled that the difference between placebo groups is greater than the difference between either placebo and the treatment group. Seehttps://twitter.com/jpogue1/status/1464371651164966921 …
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15. Meanwhile, Pfizer's forthcoming antiviral works by inhibiting protein synthesis rather than generating mutations. Trials of this drug report a 90% reduction in hospitalization and death. That might be better for the patient and safer for all.
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16. Other drug candidates work by generating mutations, but do so in a safer way. For example, one causes the polymerase to stall, but shouldn't generate large numbers of non-specific mutations the way molnupiravir does.https://twitter.com/VirusWhisperer/status/1466543750000177153 …
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17. I want to stress that all of this is speculative. We don't know that molnupiravir will accelerate adaptive evolution of virus and I don't know whether the FDA made the right call. But it seems worth considering the externalities in addition to efficacy and patient safety.
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18. Very important correction from
@leonidkruglyak:https://twitter.com/leonidkruglyak/status/1467616834237046787 …Show this thread -
19. NB: the degree to which a manufacturer internalizes risk is greater for an antibiotic, where resistance evolution takes out the drug but doesn't cause broader harm, and a mutagenic antiviral, where evolution can have effects that spill far beyond the market for the drug.
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4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication