Tuesday, 31 March 2020

Corona Virus Update: scientific studies on cures for COVID-19 (part 22)

This edition of the Corona Virus Update Podcast focusses on the scientific work on cures for COVID-19. What are the various substances and drugs that are currently being tested, how do they work and how promising are they? But starts with a clarification of yesterday's podcast on lateral-flow antibody tests.

This is part 22 of the Podcast recorded on Wednesday the 26th of March 2020. Science reporter Anja Martini of Germany public radio (NDR Info) talks to Professor Christian Drosten, the head of virology at the at a top German research hospital, the Charité in Berlin. He developed the first test for the virus, which was send to 150 countries by the WHO.

Antibody tests for the public

Anja Martini comes back to yesterday's topic of antibody tests because she received many questions:
Offers are accumulating in doctor's offices: Namely 50 tests at a unit price of 22 euros, please pay one hundred percent in advance. What do you say? Should you be more careful with these things, or what kind of thought comes to mind?
Christian Drosten:
Well, yeah, sure. Careful, definitely. It has to be said, these are lateral flow tests that can be manufactured in large quantities. That's a good thing that it' s technically possible. It's just that the current lateral-flow tests available ... have not yet been validated. So we do not know whether these antibody tests work as well as a real laboratory-based test, i.e. an ELISA test for antibodies, for one thing.

And on the other hand, there is something we already know for sure, namely that antibody tests are too late for acute diagnostics. These antibody tests can only become positive after about ten days of the disease. There are a few patients who have antibodies after only seven days. But in today's situation, when you have a test for the new virus and wants to be tested, then you ask actually always: Did I get infected? Did my symptoms come from this virus maybe? In this situation an antibody test is not useful.
These tests are mostly produced by Chinese companies. Racists abuse this situation to attack China by accusing them of producing bad tests to attack the West. This is Trumpian ignorance of people who should be attacking Xi for being an authoritarian like Trump. They should be attacking China for their concentration camps, for their lack of political freedom. But you do not get to complain that you are a gullible uninformed fool.

Anja Martini:
This antibody test, which might become available for the general public, namely the self-test, how should I imagine it technically? ... You put a prick in your finger and then you can put it on a piece of paper and see if you have antibodies or not?
Christian Drosten:
Yeah, that's pretty much how these tests work. There are several devices that extract a drop of blood from a fingertip. Then they record it. And then it runs from one side to the other in a test strip as a front, just like for a pregnancy test the urine. And at the end there is one stripe or two stripes. And if you see two stripes, the test is positive ... But as I said, all this is not yet technically validated. It will work somehow, maybe better or worse. But of course the normal laboratory-based test will also be widely available.

Polymerase Chain Reaction test

Also Polymerase Chain Reaction (PCR) tests for the virus itself were discussed in yesterday's podcast. There are cases where the patient clearly had COVID-19, which you can see in a lung x-ray, but that the test does detect it. For example patients who stayed at home as long as possible and only arrive in the hospital the second week they are ill. In this case the virus has sometimes disappeared in the throat and is only present in the lungs. Either by sampling sputum the patient coughs up or with a suction catheter a doctor can take a sample from the lungs and detect the virus that way.

Christian Drosten:
This has also caused great concern in China, in Wuhan. So much so that, from a combined impression of this apparent unreliability of PCR from the throat, and also of the laboratories being overburdened, that practically no more PCR capacity was available, they switched to a diagnosis based on the CT image at the peak of the epidemic in Wuhan, because on average, patients were seen relatively late. They stayed at home for a long time, they did not want to go to the hospital. And then they changed the diagnosis.

Remdesivir

Anja Martini:
We want to look at drugs today, because there are now several drugs that are tested in hospitals. ... Remdesivir, for example, is a drug that was originally developed for Ebola and is now being tested in two studies on corona patients in Germany. What do you currently know about these studies and how they are going?
Christian Drosten:
In the case of Remdesivir, for the time being, we have here a substance with a plausible and known mechanism. It's an inhibitor of viral RNA polymerase, the virus' replication enzyme. And we have had this substance in the literature for quite some time, it is clear that it is effective against corona viruses in cell culture and also in animal models. That's good. So not for every substance that is currently undergoing clinical trials, we do not have this convincing initial evidence. But for remdesivir it is very good, this initial evidence. There's a real mechanism.
The above paragraph may be a bit too much in the weeds, but I included it to show how a scientist assesses a situation and the likelihood that something will work before the evidence is conclusive. Having two options where test tube tests show they work similarly against viruses, one would first go for the option where one understands why. Even if test tube showed somewhat less good results, I would still go for the one where we understand why. This is one way to protect yourself against problems with purely empirical evidence, which has produced reproducibility problems.
And now the company that distributes Remdesivir, Gilead, has been allowing [[compassionate use]] protocols for quite some time. This means that in certain constellations, the drug is released for a single patient. This is a phase of the disease where the patient already needs oxygen but does not yet need catecholamines, i.e. drugs that support the circulation. This is already a critical phase in the course of the disease. This is the transition where they say soon the patient may have to go into intensive care. It's a critical time when you want to influence [the condition of] the patient.

But the problem is that this is a direct antiviral substance, so we would like to administer it earlier. The virus attacks the respiratory tract in the first week of the disease. In the second week of the disease, when the virus deteriorates, we already have a combination of immune and viral effects that act in the lungs. This suggests that in this later phase you can't do as much if you specifically do something against the virus. You have to be careful that you might also do something against an excessive immune reaction. There are also clinical studies on this. And this is true for Remdesivir as well as for other substances where one could assume that there is a direct effect on the virus.
The rest of this section is background information on how RNA viruses work and how Remdesivir interferes, which you can skip if you just care about your health, but I find it fascinating.

Anja Martini:
How does Remdesivir work in this virus? What does it do?
Christian Drosten:
The virus is an RNA virus. And RNA viruses can't use the replication enzymes in the cell nucleus. Our cell nucleus has DNA. And when cells divide, the DNA has to be replicated.

And some viruses, DNA viruses often, they can use these multiplication enzymes for themselves. So they abuse the duplication enzymes of the cell nucleus for their own genetic material. But RNA viruses cannot do this because our cells do not need to duplicate RNA. Our cells do possess RNA. This RNA is only copied from DNA and is actually the template for proteins. This is the so-called messenger RNA, in the simplest approximation. There are of course other complicated subforms of RNA and so on. But let us now talk about the main case. This messenger RNA is not being replicated. It is simply copied once. But for viral replication, we need proper duplication. And in that process we need to have a step where RNA is copied from RNA. The viral genome consists of RNA, and the product consists again of RNA, we say the replicative intermediate, and from that again RNA has to be copied back again. After all, we have plus and minus and then again a positive sense of the genetic information in this multiplication.

All this leads us to the conclusion that the virus itself must bring along an RNA polymerase, an enzyme that carries out this multiplication, this transcription. There are different ways in which RNA viruses do this. Some RNA viruses have a functioning RNA polymerase in the virus particle. Polymerase is an enzyme that generates a polymer that transcribes. This takes a template, which is the genome of the virus, and makes a copy of it, a mirror image copy in the reading sense, and then takes this mirror image copy again and makes the next generation of genomes from it, which is then packaged. Some viruses bring this as a functioning enzyme, as a protein in the virus particle.

Other viruses simply encode this, they carry the enzyme as genetic information. This is then converted into protein in the cell by ribosomes. The protein that is produced there can then duplicate the viral RNA. Coronaviruses do it in the latter way. Corona viruses bring genetic information with them in order to create an RNA polymerase in the cell do-it-yourself, which is what the cell does, and this enzyme is inhibited with emdesivir. ...

We could also go back into detail here, because it is not quite so clear how things work exactly. We do not know whether the RNA polymerase itself is inhibited in its processivity, or whether the assembly of essential building blocks of the resulting RNA is inhibited, or whether the RNA polymerase continues to work, but makes so many copying errors that the viruses that come out of it are dead.

Chloroquin

Anja Martini:
Chloroquine, we still have to say, is an antimalarial drug that is not completely free of side effects, but also against the old SARS virus, at least in cell cultures, has been successful, right?
Christian Drosten:
Right, exactly. In cell cultures and against all kinds of viruses. ...

A lot of people who know about it, including myself, are very sceptical about chloroquine, whether it is really helpful in the end. But I also cannot say what it will look like in the end if a very large study is carried out with a large number of patients. And the up analyse the clinical fate of these patients, what would be the outcome for the patients? So there might be a very small effect.

This effect does not necessarily have to be directly related to the virus, because chloroquine also has a strong influence on inflammatory processes in general. These also play a role in lung damage, so that it is not possible to say exactly what to expect.However, one thing can be said: A resounding effect that really decides the fate of the clinical outcome can hardly be expected with chloroquine. ... Let's put it this way, then it would be very easy to observe it. Then there would be no such contradictory clinical studies. If the effects are quite clear, it is also quite easy to prove the clinical effect.

Favipiravir

Christian Drosten:
There is another substance called favipiravir. ... It is approved for use against influenza in several countries. So you can buy it in pharmacies against influenza, for example in Japan. ... This substance is also available in China against influenza. There is now a first study, which has been published, so perhaps we can clarify where we stand. So in case of Favipiravir, we know exactly what the mechanism is.

But I have to say that when it came up to give favipiravir against the new virus, I was surprised, because years ago, when this substance was still in the experimental phase, we did not call it favipiravir, but T-705, which was the short name for a chemical substance at that time. And it did not work well in cell culture. We didn't pursue it further. ...

Favipiravir is now being used in China after all. And a first study has just come out. ...

And in contrast to the French study, which we discussed for chloroquine last week, here it is the case that they really looked at a clinical starting criterion. They simply asked: How is the improvement of the clinical picture seven days after starting the administration of the drug? Clinical picture means for example respiratory rate, fever and other general symptoms of the disease. ...

Most of the cases here are quite normal initial cases, they are not intensive care cases. For example, there were only 18 severe cases here with pneumonia in a total of 116 people who were treated, so the overwhelming majority were not severe cases. And of course they have been included at an earlier stage accordingly.

So now we can say that the difference that can be obtained in this rather optimal situation is that clinical symptoms improve in 56 percent of the cases where no treatment is given, and in 72 percent of the cases where treatment is given. That is a significant difference, a significant difference statistically.

And that's amazing to me. I have to say that in view of the fact that we never actually saw a good effect of this substance in cell culture, I am still skeptical if this is real or if there's some kind of flaw in the clinical study. Now we have to see what other studies indicate. It's certainly not enough, to take one study and even more so one study that has not even been formally reviewed yet.

Camostat

Anja Martini:
I believe that you yourself are also working with Göttingen researchers on a drug at the moment. How does it work?
Christian Drosten:
That's right. There are studies that we have done together with Stefan Pöhlmann's group in Göttingen, a really absolute specialist in virus entry. Stefan has seen that it is possible to reduce virus entry with a substance called camostat. ...

So it is the case that this virus, this new SARS 2 virus, uses a certain transmembrane protease in a stronger way than the old known SARS virus. And that is, as the name suggests, a protein-cleaving enzyme, but this time it is not an enzyme from the virus but an enzyme from the cell. So the cell itself has this protein on its outer membrane. And with this protein, the cell involuntarily helps the virus enter the cell, by the passage through the membrane. This works in such a way that the surface protein of the virus is cut at one point, is clipped, and this clipping of the surface protein is the first step for the virus to pass through the cell membranes. This virus uses this cellular protein for this purpose.

There is a drug that inhibits this cellular protein and this drug is called camostat. I am deliberately saying drug and not substance, because this substance is approved as a drug for chronic pancreatitis. And it is only approved in Japan. So in Japan you can buy it in the pharmacy. This much we know. We know it works in cell culture, and we know the drug is available in Japan. That's all we know.

But on this basis we can now of course do something that cannot be done with other substances. Namely, we can say that we do not have time for large-scale animal experiments, but we have an approved substance here. In certain cases, we can now test this in clinical controlled trials to see whether patients benefit from it if they get this substance. This is a typical off-label use study. And we're going to do something like this start now.
That sounds promising. Do note that Drosten is here talking about his own research. It is always harder to be just as sceptical about your own work, any scientist will be able to attest.


Other podcasts

Part 28: Corona Virus Update: exit strategy, masks, aerosols, loss of smell and taste.

Part 27: Corona Virus Update: tracking infections by App and do go outside

Part 26: Corona Virus Update on Vaccines: clinical trials, various types, for whom and when.

Part 23: Corona Virus Update: need for speed in funding and publication, virus arrival, from pandemic to endemic

Part 21: Corona Virus Update: tests, tests, tests and how they work.

Part 20: Corona Virus Update: Case-tracking teams, slowdown in Germany, infectiousness.

Part 19: Corona Virus Update with Christian Drosten: going outside, face masks, children and media troubles.

Part 18: Leading German virologist Prof. Dr. Christian Drosten goes viral, topics: Air pollution, data quality, sequencing, immunity, seasonality & curfews.


Related reading

The Corona Virus Update podcast and its German transcript. Part 22.

Nature Magazine on the various possibilities where the virus comes from: The proximal origin of SARS-CoV-2. "This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation."

European Medicines Agency: COVID-19: chloroquine and hydroxychloroquine only to be used in clinical trials or emergency use programmes. "The European Medicines Agency (EMA) is a decentralised agency of the European Union (EU) responsible for the scientific evaluation, supervision and safety monitoring of medicines in the EU."

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