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CT_Bergstrom's profile
Carl T. Bergstrom
Carl T. Bergstrom
Carl T. Bergstrom
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@CT_Bergstrom

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Carl T. BergstromVerified account

@CT_Bergstrom

#BlackLivesMatter Information flow in bio, society, & science. Book *Calling Bullshit*: http://tinyurl.com/y7ekfkhx  I love crows & ravens. he/him

Coast Salish Lands (Seattle)
carlbergstrom.com
Joined June 2015

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    Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

    1. The FDA recently approved Merck's new COVID treatment, an antiviral known known as molnupiravir. The drug works by mimicking the cytidine and uridine nucleosides and thereby inducing frequent mutations in replicating virus.

    1:46 PM - 5 Dec 2021
    • 732 Retweets
    • 2,150 Likes
    • さけずき みやざけ スモォ提督 タナカサオリ Arakawa カエサル ANISH KAR Sriram Sunil Mason 8_octp
    73 replies 732 retweets 2,150 likes
      1. New conversation
      2. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        6 replies 38 retweets 288 likes
        Show this thread
      3. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        6 replies 67 retweets 542 likes
        Show this thread
      4. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        3 replies 32 retweets 383 likes
        Show this thread
      5. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        4 replies 39 retweets 458 likes
        Show this thread
      6. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        4 replies 27 retweets 281 likes
        Show this thread
      7. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        4 replies 102 retweets 605 likes
        Show this thread
      8. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        10 replies 105 retweets 776 likes
        Show this thread
      9. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        Carl T. Bergstrom Retweeted Michael Lin, MD PhD  🧬

        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 ….

        Carl T. Bergstrom added,

        Michael Lin, MD PhD  🧬 @michaelzlin
        In conclusion, it would be highly irresponsible to approve molnupiravir unless the possibility of sublethal accelerated viral mutagenesis is thoroughly addressed and satisfactorily rejected, especially within the target population of patients at risk of hospitalization.
        Show this thread
        4 replies 112 retweets 596 likes
        Show this thread
      10. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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 …

        1 reply 49 retweets 372 likes
        Show this thread
      11. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        7 replies 64 retweets 436 likes
        Show this thread
      12. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        3 replies 54 retweets 474 likes
        Show this thread
      13. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        3 replies 48 retweets 413 likes
        Show this thread
      14. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        Carl T. Bergstrom Retweeted Jason Pogue

        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 …

        Carl T. Bergstrom added,

        Jason Pogue @jpogue1
        This may be an unpopular opinion, but I think there should be a confirmatory #molnupiravir study prior to EUA. The outlier here (not just internally, but also externally with other outpatient industry RCTs) is the event rate in the 1st half of plac pts. https://www.fda.gov/advisory-committees/advisory-committee-calendar/november-30-2021-antimicrobial-drugs-advisory-committee-meeting-announcement-11302021-11302021#event-materials … pic.twitter.com/kyI03idX58
        Show this thread
        3 replies 38 retweets 370 likes
        Show this thread
      15. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        5 replies 97 retweets 800 likes
        Show this thread
      16. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        Carl T. Bergstrom Retweeted Prof. Dr. Benhur Lee, MD  🦠 🧬 🔬

        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 …

        Carl T. Bergstrom added,

        Prof. Dr. Benhur Lee, MD  🦠 🧬 🔬Verified account @VirusWhisperer
        #COVID19 #Omicron New ORAL anti-SARS-CoV-2 drug by Richard Plemper & colleagues! A chain terminator, NOT a mutagen. AND resistance is futile! 👍👏 4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication https://www.science.org/doi/10.1126/science.abj5508#.YalP9iHq1to.twitter …
        Show this thread
        2 replies 33 retweets 328 likes
        Show this thread
      17. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        8 replies 54 retweets 422 likes
        Show this thread
      18. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        Carl T. Bergstrom Retweeted Leonid Kruglyak

        18. Very important correction from @leonidkruglyak:https://twitter.com/leonidkruglyak/status/1467616834237046787 …

        Carl T. Bergstrom added,

        Leonid Kruglyak @leonidkruglyak
        Replying to @CT_Bergstrom
        Unless I missed it, the FDA hasn’t actually approved it yet. There was a narrow 13-10 advisory committee vote in favor, which the agency is now considering. They could still decline so concerns are worth bringing up.
        7 replies 28 retweets 378 likes
        Show this thread
      19. Carl T. Bergstrom‏Verified account @CT_Bergstrom 5 Dec 2021

        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.

        22 replies 20 retweets 244 likes
        Show this thread
      20. End of conversation

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