Most mutations are lethal or deleterious in viruses. In our work and also that of @Rafa_Sanjuan_ approx 30% are lethal and another 60% are deleterious. Very, very few are beneficial. (15/x)
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It is reasonable to think - but not entirely known - that mutations and mutational combinations in people with sublethal mutagenesis are deleterious and will result in reduced fitness of the virus. This is reassuring. (16/x)
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We also know that mutated viruses can sometimes interfere with unumutated ones through a process called "lethal defection." Here these mutated viruses run interference and gum up the replication machinery. This limits replication of sub-lethally mutated viruss. (17/x)
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Some other things that are also IMO overlooked in discussion of molnupiravir. Another drug, favirpiravir, works in a similar manner, and has been used for influenza in other countries. So there's experience here. (18/x)
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See this from
@cjriIllingworth on immunocompromised host with favirpiravir (in combination). (19/x)https://pubmed.ncbi.nlm.nih.gov/32124919/1 reply 3 retweets 46 likesShow this thread -
I suspect that many clinicians may choose to use molnupiravir in combination in immunocompromised hosts btw. (20/x)
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It's really hard to predict evolution - and the evolutionary impacts of drugs and vaccines. The discussion of molnupiravir reminds me a bit of the discussion about delayed vax second dose in early 2021 and whether that would lead to selection of variants. (21/x)
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There were theoretical risks, but also theoretical benefits. There were data from other viruses. The lessons from that experience are that evolution is complicated and that it's hard to capture all the upsides and downsides of an intervention like a drug or vaccine. (22/x)
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So, conclusions. 1. Great thread from
@CT_Bergstrom 2. There's more to molnupiravir than is getting discussed 3. I wish data were better, but think there's a place for it 4. We need to better define the risk of sublethal mutagenesis and variant generation. (23/x)4 replies 20 retweets 157 likesShow this thread -
5. Right now, largely theoretical. Need more data. Fin! (24/24)
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Question: Would this not suggest more data should be collected before approval? Especially given the benefit itself is under question? (Zero efficacy in second half looks like regression to the mean). Patient compliance certainly an issue with an at-home five days every 12h pill.
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Replying to @zeynep
Not necessarily. There's always post-approval data collection. FDA panel has evaluated risks and benefits from initial data. It's a question of whether you think FDA evaluation was adequate and appropriate.
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Replying to @LauringLab
Right, though FDA panel is advisory, the vote barely squeaked by, multiple no voters mentioned this and no approval yet. So question is what should the FDA do? The usual risk/benefit or adverse/event framework doesn't seem suited for this. Risk is to planet, not to patient. 1/2
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