As a leading physician working with COVID-19 patients at Columbia University Medical Center in New York City, Neil Schluger had creepy days.
"I would come to the room in the morning to go around and say to the intern, & # 39; How did we do last night? & # 39; And the intern said, & # 39; “It wasn’t like anything I experienced in my 35 years of being a doctor,” Schluger says.
When he first learned about hydroxychloroquine, he hoped it would work for his patients. He and his colleagues prescribed the antimalarial drug for 811 of the 1,446 patients hospitalized at the medical center from April 7-8. But the drug did not appear to help, Schluger and colleagues reported May 17 in the New England Journal of Medicine.
As a result, “we stopped giving hydroxychloroquine at some point in April,” he says.
And yet the number of cases and deaths from COVID-19 in New York City continued to fall. “If he took away a life-saving medicine from us, I wouldn’t expect this to happen,” he says. Instead, Schluger, now a critical lung care physician and clinical epidemiologist at New York Medical College and Westchester Medical Center in Valhalla, believes outdated public health measures – wearing masks, staying home and socializing away – for success of New York against the virus.
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Hydroxychloroquine has been tested more than any other potential drug COVID-19, but has repeatedly fallen short of expectations. Although study after study has shown no benefit from hydroxychloroquine in treating people with severe coronavirus infections, some people, including President Donald Trump, still insist the drug has merit. A viral video released on July 27 made the misleading claim that hydroxychloroquine is an effective treatment for the spread of COVID-19 as an online gunpowder.
But the vast majority of scientific evidence does not support that claim. It’s time to move from hydroxychloroquine to try other drugs that may have more promise against COVID-19, say Schluger and other experts.
Initial hope that hydroxychloroquine would be useful in combating coronavirus derived from laboratory tests that showed the drug inhibits the growth of monkey kidney cell virus by blocking its entry. But it turns out that the virus does not enter the cells of the human lung in the same way.
In these initial experiments, the researchers tested the drug using kidney cells from African green monkeys, known as Vero cells. These cells are useful for virologists because they allow the growth of a wide variety of viruses, says Stefan Pöhlmann, a virologist at the German Primate Center in Gothenburg. But the way SARS-CoV-2, the coronavirus that causes COVID-19, infects monkey kidney cells is different from the way it infects human lung cells, Pöhlmann and colleagues report July 22 in Nature.
To infect different cell types, the coronavirus has at least two possible possible entry pathways. In one, the virus ear protein (the abrupt structures on its surface) binds to the ACE2 protein in the cell membrane, and then an enzyme called TMPRSS2 cleaves the ear protein. That process allows the virus to inject its genetic material into the cell, where more copies of the virus are produced.
The second way the virus is introduced into cells is through a diversion through special mobile compartments called endosomes. After binding to ACE2, the virus is absorbed by an endosome, but the pathogen needs to extract its genetic material from the compartment and into the main part of the cell. So the ear protein has to be cut by an enzyme to allow viral and cell membranes to fuse, releasing the genetic material of the virus, says Markus Hoffmann, a virologist also at the German Primate Center.
In monkey Vero cells, that enzyme – called cysteine protease cathepsin L or CatL – performs a fusion-promoting portion. But the enzyme needs a certain level of acidity to make the cut. Hydroxychloroquine and chloroquine raise the pH too much for CatL to extract spike protein, thus inhibiting infection.
But when Hoffman, Pöhlmann, and colleagues tested the drugs on human lung cells grown in lab dishes, the virus easily slipped into the cells. This is because in lung cells, SARS-CoV-2 leads the most direct route using TMPRSS2, which is not found in monkey cells and is not inhibited by chloroquine and hydroxychloroquine, says Michael Farzan, a virologist and immunologist at the Scripps Research Institute in Jupiter, Fla.
He and his colleagues posted a prepress on bioRxiv.org on July 22, also showing that hydroxychloroquine does not block how SARS-CoV-2 enters human cells. That fact has not yet been reviewed by other scientists for publication in a scientific journal.
Pöhlmann says very little, if any, in the cells of the human lung. This mainly leaves the virus with the TMPRSS2 entry pathway, which is impermeable to hydroxychloroquine.
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Many other viruses, including the original SARS and MERS coronaviruses, use TMPRSS2 to activate their spike protein. But the entry of TMPRSS2 is much more important for the entry of SARS-CoV-2 into human lung cells than it was for the original SARS virus, Farzan’s study demonstrates. This is because SARS-CoV-2 also uses another enzyme called furin to extract the ear protein (SN: 26/03/20).
That cleavage point of furins was not present in the original SARS virus, and may facilitate the breakdown of SARS-CoV-2 in cells. These furin cleavage sites often help make the flu and other viruses more infectious. In Farzan’s study, furin cuts make the new coronavirus more dependent on TMPRSS2 for entry, relegating the CatL pathway to a distant plan B.
Both studies found a compound called camostat mesylate effectively inhibits the entry of SARS-CoV-2 into TMPRSS2-forming cells. That drug is being tested against the virus in some clinical trials.
Another study by researchers in France also found that hydroxychloroquine inhibits SARS-CoV-2 infection of Vero cells, but not human lung cells. In addition, the drug did not protect another type of monkey, the cynomolgus monkeys, from coronavirus infection, the researchers reported on July 22 in Nature.
These results indicate the importance of using human lung cells to study the virus, the researchers say. “Many of these studies (favorable hydroxychloroquine) that came out don’t make sense because they were done in an incorrect cell (types),” says Katherine Seley-Radtke, a medical chemist at the University of Maryland, Baltimore County.
Farzan says he does not blame anyone for testing hydroxychloroquine first. “We were picking straws” at the beginning of the coronavirus outbreak, he says. "There were a lot of things to try things out initially in people … that ended up being essentially useless."
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The implications of the new studies are clear, says Seley-Radtke, who did not participate in any of the new studies. "We now have a lot more information about hydroxychloroquine and it doesn't work. It's not a direct-acting antiviral."
This means that chloroquine and hydroxychloroquine are also unlikely to prevent infection with the virus or protect people from developing serious illnesses, as some researchers have proposed. Some studies continue to test drugs to determine if they can prevent infection or decrease the risk of developing serious disease, although the results of such a study conducted at the University of Minnesota were not encouraging (SN: 6/4/20). That study showed that hydroxychloroquine did not prevent coronavirus infections after exposure to the virus.
No help for the hospitalized
Aside from antiviral activity, the researchers hoped that hydroxychloroquine could calm the hyperactive immune system's response, called a "cytokine storm," which leads to tissue damage and even death in some patients with COVID-19. The reason for this hope is that hydroxychloroquine is also used to treat rheumatoid arthritis and lupus, and may help regulate the immune system in those patients (SN: 22/05/20).
But hydroxychloroquine and chloroquine have not been released as effective COVID-19 therapies, Shmuel Shoham, an infectious disease specialist at the Johns Hopkins School of Medicine, said June 26 during a press conference sponsored by the Infectious Diseases Society of America that announced revised treatment guidelines. The proof that “passed is not encouraging that that is a great option,” he said. The U.S. Food and Drug Administration has withdrawn the emergency use authorization for hydroxychloroquine (SN: 15/06/20) and several large studies have stopped testing the drug for people hospitalized with COVID-19.
Compared to placebo, hydroxychloroquine did not relieve the symptoms of COVID-19 or prevent people from progressing to a serious illness to a statistically significant degree, the researchers reported on July 16 in the Annals of Internal Medicine. Similarly, a randomized trial in Brazil of more than 600 COVID-19 patients with mild to moderate symptoms found no statistically significant benefit for a hydroxychloroquine placebo alone or in combination with another drug called azithromycin, the researchers reported on 23 July in the New England Journal. of Medicine.
Some studies, published after the FDA withdrawal, have found what appears to be a benefit of taking the drug. At Henry Ford Hospital in Detroit, the researchers wanted to know the good state of the hospital with the treatment of COVID-19 patients. Epidemiologist Samia Arshad and colleagues at the infectious disease reviewed patient records from March 10 to May 2. Patients with moderate to severe disease were given hydroxychloroquine, and if a bacterial infection was suspected, they also obtained the antibiotic azithromycin. Overall, about 18 percent of patients with COVID-19 died. This percentage was lower in the hydroxychloroquine group, with 13.5 percent deceased, Arshad and colleagues reported on July 1 in the International Journal of Infectious Diseases. But about 20 percent of those who received hydroxychloroquine and azithromycin died.
Arshad says his results may differ from studies that showed no benefit because Henry Ford patients received treatment earlier (91 percent received the drug within 48 hours of being admitted to the hospital) and because a treatment algorithm doctors did not. Do not allow anyone with heart risk factors to take the medication. Who received the drug was closely monitored. The hospital stopped using the drug after the FDA withdrew the emergency use authorization.
Another retrospective study of nearly 6,500 COVID-19 patients in New York City from March 13 to April 17 also found a reduced risk of death among people taking hydroxychloroquine, the researchers reported on June 30 in the Journal of General Internal Medicine .
It is not enough to recommend hydroxychloroquine for use against coronavirus, says David Hsieh, an oncologist at Southwestern Medical Center at the University of Texas at Dallas, who has been examining clinical trials of COVID-19 worldwide.
He and his brother Antony Hsieh, of the Perelman School of Medicine at the University of Pennsylvania, and UT Southwestern colleague Magdalena Espinoza found that hydroxychloroquine had more coronavirus clinical trials dedicated to it and is mentioned in more publications than any other drug or targeted therapy. COVID-19, researchers reported on July 4 in Med.
Hsieh states that studies that look back at results, such as retrospective studies and meta-analyzes (studies that combine data from multiple studies) are excellent for generating hypotheses. "But we are in real danger if we start using them to change our practice."
This is because in retrospective or observational studies, there is no guarantee that patients who received the drug and those who did not will be the same. At Henry Ford's trial, patients who received hydroxychloroquine were about five years younger, on average, than those who did not, Schluger says. "We know that age is the single strongest predictor of mortality from this disease."
And patients who received hydroxychloroquine were also more likely than those who were not on the antimalarial drug to also have steroids, which other studies have shown can save lives (SN: 22/07/20). Thus, patients who received the drug were different from those who did not in significant ways.
The researchers “who looked at the data consider in detail the history of hydroxychloroquine as quite a bit,” Schluger says. "It would be a shame not to try other potentially promising things because we were pending to pursue something so there's a lot of evidence now that it doesn't really do much."
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