Update April 13: Why finding a drug is so difficult
- April 13, 2020
April 13, 2020
Does quinine or hydroxychloroquine work as a medication? Are there other medications for the coronavirus? We all know from the internet that dozens of substances are discussed and there are debates even in the White House about the efficacy of certain drugs. We have used different antiviral treatment strategies in our patients at Hannover Medical School when we were desperate.
But what do we know about antiviral treatment? We know that treatment of a virus is difficult, but we had some spectacular successes with antiviral treatment strategies in the past. One of those successes is the treatment of the AIDS virus and the other is the successful treatment of hepatitis. Especially with the latter, treatment strategy has successfully eliminated the disease. We can learn two important lessons:
- So far, this is treatment of a chronic viral disease.The treatment must be for some time to eliminate a virus in the body so that its detrimental effect on immune cells or liver cells disappears.
- We need a combination therapy where we block the replication of the virus at different stages of the replication cycle.We know that viruses are slippery fiends which escape easily and only when we catch them at different time points of their life cycles can we be successful in treating them.
In principal, we have several possible ways to interfere with the virus:
- Inhibition of binding to cell surfaces. We can interfere with glycoproteins on epithelial cells and prevent/reduce the binding of the virus.
- Blockade of cell entry.After the virus binds to a cell the regulated uptake is necessary. This uptake can be blocked.
- Replication within the cell.There are several ways we can block this process. We can interfere with the production of the virus particles or the transport of the particles within the cells. The infamous hydroxychloroquine seems to interfere with the endosomal transport.
We obviously have several molecules which interfere with these pathways and effectively reduce virus entry or virus replication. A lot of research groups are working on these mechanisms. Here at MDIBL we may even start research in this direction: my lab has experience with glycoproteins which are important for binding of the virus to cell surfaces. Maybe we can inhibit binding of virus proteins to cell surfaces with small molecules.
The real problem is demonstrating that these possible drugs work in patients in real life in a way that is scientifically significant. We used several of these drugs over the last couple of weeks when we had severely sick patients. Other doctors have done the same and, in some cases, reports have been published. In a few cases several patients were treated, and the treated patients were compared with non-treated patients. However, these were isolated cases with small numbers of patients and the results were always the same: in principle it could work, however, some patients got better, and others did not. We have to do a larger controlled trial where we can actually compare the results in a manner that can be reproduced again. And this is a very difficult study to do. There are so many variables to be decided: At what point do we treat a patient? Only in severe cases or everybody with a fever? Is it for everybody who has the virus or everybody who has clinical symptoms of the disease? This kind of study needs time, and time is something we do not have. The epidemic will be over before these trials could even begin.
This is why antiviral strategies with medications are so difficult. Reports about successful treatments are stories, not science. They are reports from doctors without evidence from controlled studies. As medical doctors we are not immune to this temptation. We want to talk about our successes, we want to show that we have helped patients. I too, have fallen into this trap — about nine years ago, we had another epidemic in Germany. There was infection with a dangerous strain of E. coli leading to kidney failure and death. I was using a novel drug in the hospital with spectacular success. I was on national news; I was the miracle doctor who could save the lives of patients. I gave grand rounds at Yale and at Duke. I was talking about novel mechanism and a few patient cases. But then, when we tried to analyze the data in a scientific fashion after the epidemic, we could not verify that the drug made a difference. In some patients yes, it helped, but in others, it had no effect.
In the present COVID-19 epidemic we will use some drugs based on our personal experience in patients with life-threatening symptoms. We have yet to find a recommended medication for the disease that has a positive result for all patients. Quinine may help; we have used (Gin and) Tonic for the prevention of malaria for a long time… but right now, we don’t rightly know.
We are waiting for a vaccine. I believe in science and Bill Gates.