Maybe Antivirals aren’t a Useful Priority for Pandemics?

by Davidmanheim5 min read20th Jun 202113 comments

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Existential RiskBiology
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PLEASE KEEP COMMENTS GENERALLY ON THE TOPIC OF ANTIVIRALS.

Epistemic status: Building a better gears-level understanding of why antivirals don’t work very well, explaining why portfolio construction for technology isn’t the same as investing in markets, then speculating on implications. 
Note: Crossposted to the EA Forum

The public conversation around COVID-19 response, especially pre-vaccine, prominently featured the idea that there are treatments which we just need to find. The claim is that if we found good, broad-spectrum antivirals, we could treat COVID. 

But there is no guarantee that the thing we’re looking for exists. We might be searching up and down the street, under the lamps and elsewhere, for keys that are figments of our collective hopes and imaginations. There are words that describe things that do not exist. Like unicorns. Or antigravity. Fortunately, antivirals definitely exist. They just aren’t what I assumed when I was looking into the issue. And investing in them seems like a less promising avenue than I assumed. 

NOTE: I am not arguing against any investment in antivirals. I’m discussing the relative promise and synergies or anti-synergies of the approaches for fighting a pandemic.

Antibiotics versus Antivirals

Antibiotics, i.e. antibacterial drugs, are definitely a thing. Actually, around a dozen things. They prevent basic things that bacteria need to do, such as forming cell walls, using a specific protein synthesis pathway, or unwinding their DNA to replicate. Thankfully, some of the things bacteria need to do are unique to bacteria - their cell walls are different from animal cell walls, so interrupting formation of bacterial cell walls doesn’t kill human cells. Other things are the same. Protein synthesis and DNA unwinding are critical for human cells, but they happen inside of the cell, so we can use drugs that human cells keep out, but bacterial cells don’t. Those drugs are a bit more toxic, but if you need to kill off bacteria, sometimes it’s worth it.

Viruses are different. They use our cells to replicate, so they don’t do many things which human cells don’t. There just aren’t as many targets - and interfering with the ones that exist are more likely to hurt the human hosts. 

We want to find a useful antiviral, but we have good reasons to think that safe ones might not exist.

To be clear, we know of drugs that are effective at fighting viruses. Idoxuridine was the first antiviral, in the 1960s, and it is effective in fighting herpes. And by fighting, we mean slowing replication. It doesn’t actually eliminate herpes - nor do the other newer antivirals used for herpes and related viruses. Humanity had great success in finding cures for HIV. And by cures, we mean semi-toxic combinations of drugs that when taken indefinitely, slow viral replication enough that the hosts can live indefinitely and, due to very low viral load, not spread the virus. The drugs take months to work, but they are effective enough.

Other, newer antivirals fight things like influenza. Maybe. But not well. So where are we pinning our hopes, and why are we pursuing antivirals(1)?

Value of Information versus Portfolio Construction

I want to be incredibly clear; looking for antivirals is worth the money spent. 

We spend a few tens of billions of dollars per year looking for them, we learn more about viral biology and immunology, and we can treat HIV and herpes better. We might even find new treatments for other diseases. Value of Information here is really hard to compute, but it seems pretty high. At the very least, we have no fundamental reason to think we won’t find something that works.

But in constructing portfolios for investment, we aren’t just looking for positive returns, we are looking for a coherent plan, hopefully with synergies and risk mitigation. Unlike financial investments in the market, there are places where investing in one technology accelerates our returns in other places, or unnecessarily duplicates effort and wastes money, or actually makes success impossible. 

If we’re in the stock market and banking stocks are highly correlated, splitting our money among them is typically a bit better than investing all of it in any one, because we’re diversifying, with little or no cost in terms of returns. If we want to eliminate malaria and spend half our money on bed-nets and half on gene-drive mosquitoes, we mitigate risks of either approach, but they aren’t complementary or even parallel. Instead, there is likely to be wasted effort. If we’re SpaceX and invest in reusable spacecraft and also batteries for ion drives, we’re probably wasting the money on batteries. They aren’t compatible with the approach we’ve picked. And if we’re building a PC and invest half our money on an awesome graphics card, and the other half on a huge SSD, we end up with no CPU, and we’ve wasted all of our money by failing to get everything we need.

The above examples are talking about very different strategies, in different domains, with different failure modes. Which one seems to describe investing in antivirals alongside other parts of pandemic response?

Applying Portfolio Theory to Antivirals

I’m not sure exactly how this applies, but the new 100-day plans for response seems to be either split-the-money, and hope one approach works, or pick-incompatible-approaches, waste lots of money. Why?

If effective vaccines are available in 100 days, and we can scale up manufacturing, the game is over, we win. Treatment of the cases that happen later is either useful as a mitigation measure to slightly reduce impact, or a backup plan in case we don’t manage to make vaccines.

Perhaps these are independent resources, and we can spend money and research effort on antivirals without reducing the investments in vaccines? That seems implausible. Budgets are limited, and vaccine manufacturing is expensive. An extra couple million dollars might only expand production of vaccines by 5%, but if antivirals and vaccines show up at the same time, per the 100 day goal, that’s probably a better investment than antivirals.

Conclusion

Please correct me if I’m wrong on any of this. Otherwise, I’m interested in figuring out what we should do differently in the future for pandemic preparedness on the basis of this partial/tentative analysis.

  1. An aside: The investment in antivirals isn’t confusing as an outcome. There are reasons that vested interests push for the approaches they can make money with, and reasons for both clinicians and regulators to push for better treatments, even if they are only marginal improvements or are unlikely to succeed. There is no guarantee that markets pursue socially optimal policies - quite the opposite. So this is an expected failure mode.

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Antivirals, at the current level, can't extinguish a disease. They can at best drastically improve the outcome of individuals, but to do that you need to diagnose said individuals, make a cost-benefit judgement, put them on antivirals and wait for their contagiousness to drop. Compare this to prophylactics like vaccines, or even what an ivermectin / hydrochloride style drug might do. 

You don't really want to be 100% reactive to the disease. Assume you have the perfect antiviral, and every time somebody gets moderately sick they go to the local pharmacy, pay $1 and get better in 24 hours. This will still allow a new virus billions of hosts to spread and evolve, and you get Alpha, Delta, and god forbid an Omega variant. Old viruses have been playing this game with our immune system for millennia - we don't know how far a new virus might get if we give it room enough to evolve. Prophylactic solutions (no matter what their mechanism) work by cutting the spread along with disease severity, and by cutting spread you cut the possibility for the virus to evolve. 

Ivermectin is an antiviral in the context of COVID-19 (provided it works of course). 

I read through the ivermectin research in the last days. General strategy, search Google scholar for metareviews and put them on Wikidata to be listed on (https://www.wikidata.org/wiki/User%3AChristianKl%2Fivermectin). 

It seems to me like it's has the potential to be an antiviral. At the moment we don't have studies to be certain whether it has significant clinical benefit with high certainty but the studies we have does suggest it's has a significant clinical benefit. 

A recent meta analysis concludes:

Our study suggests that ivermectin may offer beneficial effects towards Covid-19 outcomes. More randomized clinical trial studies are still needed to confirm the results of our study.

Kory who advocated ivermectin for a while things it might be a broad spectrum antiviral and also be useful against other viruses. 

The potential of ivermectin to be a day one preventative measure for viral pandemics seems to warrent the research to validate whether it is.

As far as general risk prevention goes it's worth noting that Coronaviruses seem to be a type of virus that's releatively easy to vaccinate against. Having antivirals is important in the face of a pandemic caused by a virus that isn't easy to vaccinate against.

For any pandemic (especially bioengineered pandemics), the worst case scenario should be assumed:

1) Any treatment or prophylactic will either not work or not be able to be scaled up quickly enough.
2) Some viruses will spread completely asymptomatically and have very long incubation periods.
3) Some viruses will kill effectively regardless of age or health status.

The strategy that has the best chance of successfully dealing with this threat is to develop 1) a global pathogen surveillance system and 2) cheap and effective personal aerosol filtration systems. The surveillance system should ideally be decentralized for data collection and data access. An example of this kind of system is the demonpore platform. The filtration system would be (or similar to) an elastomeric respirator or PAPR. Everyone will need to possess and know how to correctly use the filtration system before a pandemic hit.

https://www.demonpore.com
https://wefunder.com/demonpore

First, you don't want to assume the worst case and then plan for only that, or you won't have prepared for the less bad cases. You are advising not bothering to develop treatments and prophylactics because in the worst case they won't work. That seems obviously wrong, and not worth discussing.

Second, yes, we need surveillance and PPE, but these don't relate to my questions. And if we're concerned about bioengineered pandemics, the bioengineering will explicitly attempt to build around the known countermeasures, so I'm not sure why the first and second paragraphs are combined into a single comment.

Actually, I didn't mean to advise against developing treatments and prophylactics, but in the context of a zero sum game or in a fund-only-the-best-approaches game, I would advise pursuing the surveillance/PPE strategy rather than treatments and prophylactics. To be clear, I should have wrote something like this: "While treatments and prophylactics might work for some pandemics, we should assume that they won't work for others, especially the bioengineered kind. Since we won't know ahead of time which pandemic we'll have to deal with next, we should assume that it will be the worst-case kind and plan accordingly." In a mild pandemic (like this one), a lot of people won't want to wear PPE, and that's why treatments and prophylactics should still be developed.

I don't see how any kind of virus (bioengineered or otherwise) could evade a surveillance system that could detect the presence of any unknown viruses and cause a pandemic even if nearly everyone wore PAPRs. That seems physically impossible.

If you're only concerned about how limited funding should be allocated between antivirals and vaccines, most of the funding should go to vaccines, because we already know that they can work well. However, with more development, antivirals have the potential to overtake vaccines in performance (e.g., DRACO), so a smaller but substantial amount of funding should be allocated for this research.

https://en.wikipedia.org/wiki/DRACO
https://www.fightaging.org/archives/2020/09/kimer-med-founded-to-develop-the-draco-antiviral-strategy/

I think we agree - I'm certainly in favor of massive investments in surveillance and in PPE. The key question was whether I was missing something in the push for vaccines and antivirals, as if both were similarly promising.

When talking about health care priorities, it's useful to look at which players would have which priorities. The question of "What should the NIH fund?", "What should a big pharma company fund?" and "What should venture capitalist who are interested in funding health?" are three different ones. 

If Pfizer thinks that they have a shoot at developing an antiviral, I think Pfizer should go for it. If there's a startup that wants to develop an antiviral and a venture capitalist sees it as a viable business it makes sense to fund it.

Budgets are limited, and vaccine manufacturing is expensive. 

Vaccine manufacturing is expensive when you do it with what are effectively cost-plus contracts. Synthesing peptides is cheap. Alhydrogel or similar adjuvants are cheap. The thing the RaDVaC people are doing is cheap.

The thing that's not cheap is running clinical trials that cost hundreds of millions. This prevents vaccines that are cheap to manufacture from being commercially viable. 

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I feel like 100 day plan goes completely around the real issues. Take for example:

We had a sophisticated international surveillance network that alerted the world to some unusual cases of “flu” in Wuhan, China in December 2019, that was able to share the genomic sequence and disease information even quicker than the 20 days it took.

A better question would be imagine a world where the organization that hosts our database of Coronavirus that we have for the purposes like vaccine development wouldn't take down the database and give the data to nobody.

Alternatively, imagine a world where an organization who acts like that would be publicly criticized for doing that.

Imagine a world where when the NSA hacks into a lab because they believe there's something fishy going on and they find that something fishy is going on, they would tell the US public. If we are to believe Shi who runs the WIV, the cyber attacks on the WIV started in September 2019 (she named the cyber attacks as the reason for why the database is down and it went down September 26 2019).

Given that this is UK policy and the UK is in the Five Eyes, the MI6 might have known and could have alerted the UK public.

We can discuss whether NSA/MI6 should generally have so much power to surveil everything but given that they do, saying nothing in the beginning and then telling journalists off the record that it was a lab leak seems like they are not doing the job they are supposed to

Imagine a world where when politicians speak about the dangers of the Delta variant we would immediately switch our vaccines to the spike protein of the Delta variant.

Their plan involves completely ignoring how screwed up the response was and still is. An abstract discussion doesn't really do anything about how dysfunctional the institutions happen to be.

The strongest argument against antivirals is likely that someone is going to use them as a pretext for gain of function research.

There are a lot of points here, many of which I agree with, several of which I don't, but none seem to address the questions I asked or points I made.

To very briefly respond, 

First, yes, warning is critical, and being discussed, but doesn't relate to the 100 day plan, which was formulated in case there is spread, i.e. warning systems failed.

Second, the plan expressly addresses the issues with slow clinical trials, and building new institutions to handle that.

And third, laboratory origins and the database deletion is so far off from the point I was thinking about deleting the comment.

And third, laboratory origins and the database deletion is so far off from the point I was thinking about deleting the comment.

That wouldn't be the first time you did something in defense of the institutions that looks suspect retrospect. 

I haven't speaking about the laboratory origins directly. 

If you don't want to start in September start in October. We are currently asking the EcoHealth alliance to account for the reduced cellphone traffic in the WIV within October. How would we know now that they had reduced cellphone traffic if not through surveillance of the WIV by some agency within the Five Eyes? It seems like the passed that organization along sometime in July 2020, so that we can ask the EcoHealth alliance and the Chinese for an explanation. 

Whether or not the WIV is the cause of the outbreak doesn't change the fact that information like that should be passed on. If we could have asked the EcoHealth alliance in December 2020 to explain itself, that would have been much better.

Whether or not the WIV is actually the cause doesn't change the fact that it's very bad that they took a database that was created with international fund to be useful in a pandemic offline. If we can't count of critical infrasturcture like that to be available during a pandemic, we can't count on anything we build for our 100 day plan to be available as well.

Even if the WIV didn't cause the outbreak both of those issues are relevant. Asking the EcoHealth alliance in 2021 about the anomalies is too late. The database not being available to defend ourselves against the pandemic is bad. 

I'm not defending any institutions, or disagreeing with the point. But I mostly agree with your substantive claim, and I'm happy to talk about the question more  - elsewhere.

I'm simply telling you it's off topic. As the commenting guidelines should have made clear by now.
 

I would like to point out a flaw in your reasoning or at least in the way you try to support your argument that antivirals may not work aswell as we'd like to (which btw is a pretty vague statement to begin with). You cite a study about neuraminidase inhibitors, which btw is largely concerned with prophylaxis, not treatment, while in your text you seem to be talking about antivirals as a treatment option.

In regards to treatment it states:"Pooled results showed that oseltamivir and zanamivir treatment alleviated the symptoms of influenza less than one day sooner. The time to return to normal activity could be reduced by one and half a days by oseltamivir and by less than half a day by zanamivir according to Burch et al."

Which to me sounds like a pretty good outconme, for example if we where to compare that to antibiotics and the time they need to alleviate symptoms.

If we where to talk about prophylaxis, I'd also argue that a 76% efficacy rate is, while obviously not perfect, nothing to sneeze at (pun intended): "In healthy adults, the seasonal prophylaxis against influenza showed a significant efficacy of 76% (95% CI 42–90) for oseltamivir"

 

However the far bigger issues is that you attempt to make an argument about antivirals in general, or antivirals in regards to Covid 19 treatment, none of which have much to do with the study you offer. Neuraminidase inhibitors are antivirals that use one out of 5 potential mechnisms to target the viral reproduction cycle (Attachment to a host cell, release of viral genes and possibly enzymes into the host cell, replication of viral components using host-cell machinery, assembly of viral components into complete viral particles, release of viral particles to infect new host cells). 

This means you try to make an argument about all antivirals, only using data for a fifth of them and worse you only estimnate that particular antiviral drug against influenza while trying to make an argument about either all viruses or Covid. In the first case, you would be ignoring most viruses, in the second case you would be simple looking at the wrong one.

 

On a more opinion based/speculative note: I recognize that you do not have a background in either statistics or microbiology, however one of those would certainly be helpfull in attempting to analyze data about microbiology. The fact that you try to argue from what is clearly an economical background about the usefullness of antiviral drugs is not only misguided, because you clearly lack some topic specific knowledge, I personally also see a problem with an economical approach towards making decisions about human life and death.

I guess I could have cited more data on the claim that antivirals work poorly - but I wasn't trying to write an academic paper, and I don't think you cited anything that refutes my point. 

You seem unconvinced about how much this generalizes, so in addition to the obvious relative lack of efficacy for HIV, noted earlier, it might be somewhat useful to note that, AFAIK, the entire set of viral diseases we have antivirals for is HIV, HPV, Flu, Hep-B and C, and various herpesviruses (HCMV,  HSV, VZV,) and that most of these (HIV, Hepatitis, and the herpesviruses,) seem to be  used mainly to treat chronic disease by reducing viral load, rather than cure the disease, and the the remainder aren't particularly effective as cures.

Some, in fact, only seem to work in studies funded by their manufacturers. You, and others, claim that Neuraminidase inhibitors like tamiflu seem to work. Some people, like the people who wrote the Cochrane review, disagree. That's fine - evidently you know lots about this, and I only looked into it briefly, though the evidence seems at best shaky to me. And I'm not going to try to convince you, or write a paper on this. But I was asking for feedback and corrections, so thanks.