On Friday, the World Health Organization (WHO) announced a large global trial, called SOLIDARITY, to find out if any can treat infections with the new coronavirus for the dangerous respiratory disease. The study, which could include many thousands of patients in dozens of countries, has been designed to be as simple as possible so that even hospitals overwhelmed by an onslaught of COVID-19 patients can participate.
Enrolling subjects in SOLIDARITY will be easy. When a person with a confirmed case of COVID-19 is deemed eligible, the physician can enter the patient’s data into a WHO website, including any underlying condition that could change the course of the disease, such as diabetes or HIV infection. The participant has to sign an informed consent form that is scanned and sent to WHO electronically. After the physician states which drugs are available at his or her hospital, the website will randomize the patient to one of the drugs available or to the local standard care for COVID-19.
The list of drugs to test first was put together for WHO by a panel of scientists who have been assessing the evidence for candidate therapies since January, says Ana Maria Henao-Restrepo, a medical officer at WHO’s Department of Immunization Vaccines and Biologicals. The group selected drugs that had the highest likelihood of working; had the most safety data from previous use; and are likely to be available in supplies sufficient to treat substantial numbers of patients if the trial shows they work.
Here are the treatments that SOLIDARITY will test:
Remdesivir
The new coronavirus is giving this compound a second chance to shine. Originally developed by Gilead to combat Ebola and related viruses, remdesivir shuts down viral replication by inhibiting a key viral enzyme, the RNA-dependent RNA polymerase.
The first COVID-19 patient diagnosed in the United States—a young man in Snohomish County, Washington—was given remdesivir when his condition worsened; he improved the next day, according to a case report in the New England Journal of Medicine (NEJM). A Californian patient who received remdesivir—and who doctors thought might not survive—recovered as well. Such evidence from individual cases doesn’t prove a drug is safe and effective.
Chloroquine and hydroxychloroquine
The WHO scientific panel designing SOLIDARITY had originally decided to leave the duo out of the trial as Hydroxychloroquine in particular might do more harm than good. The drug has a variety of side effects and can in rare cases harm the heart. Since people with heart conditions are at higher risk of severe COVID-19, that is a concern but had a change of heart at a meeting in Geneva on 13 March, because the drugs “received significant attention” in many countries, according to the report of a WHO working group that looked into the drugs’ potential.
The available data are thin. The drugs work by decreasing the acidity in endosomes, compartments inside cells that they use to ingest outside material and that some viruses can coopt to enter a cell. But the main entryway for SARS-Cov-2 is a different one, using its so-called spike protein to attach to a receptor on the surface of human cells. Studies in cell culture have suggested chloroquines have some activity against SARS-CoV-2, but the doses needed are usually high—and could cause serious toxicities.
Encouraging cell study results with chloroquines against two other viral diseases, dengue and chikungunya, didn’t pan out in people in randomized clinical trials. And non-human primates infected with chikungunya did worse when given chloroquine. “Researchers have tried this drug on virus after virus, and it never works out in humans. The dose needed is just too high,” says Susanne Herold, an expert on pulmonary infections at the University of Giessen, Germany.
More than 20 COVID-19 studies in China used chloroquine or hydroxychloroquine, WHO notes, but their results have been hard to come by.
Researchers in France have published a study in which they treated 20 COVID-19 patients with hydroxychloroquine. They concluded that the drug significantly reduced viral load in nasal swabs. But it was not a randomized controlled trial and it didn’t report clinical outcomes such as deaths.
Ritonavir/lopinavir
This combination drug, sold under the brand name Kaletra, was approved in the US in 2000 to treat HIV infections. Abbott Laboratories developed lopinavir specifically to inhibit the protease of HIV, an important enzyme that cleaves a long protein chain into peptides during the assembly of new viruses. Because lopinavir is quickly broken down in the human body by our own proteases, it is given with low levels of ritonavir, another protease inhibitor, that lets lopinavir persist longer.
The combination can inhibit the protease of other viruses as well, specifically coronaviruses. It has shown efficacy in marmosets infected with the MERS virus, and has also been tested in SARS and MERS patients, though results from those trials are ambiguous.
The first trial with COVD-19 was not encouraging, however. Doctors in Wuhan, China, gave 199 patients two pills of lopinavir/ritonavir twice a day plus standard care, or standard care alone. There was no significant difference between the groups, they reported in NEJM on 15 March. But the authors caution that patients were very ill—more than a fifth of them died—and so the treatment may have been given too late to help. While the drug is generally safe it may interact with drugs usually given to severely ill patients, and doctors have warned it could cause significant liver damage.
Ritonavir/lopinavir + interferon beta
SOLIDARITY will also have an arm that combines the two antivirals with interferon-beta, a molecule involved in regulating inflammation in the body that also has shown an effect in marmosets infected with MERS. A combination of the three drugs is now being tested in in MERS patients in Saudi-Arabia in the first randomized controlled trial for that disease.
But the use of interferon-beta on patients with severe COVID-19 might be risky, says Herold. “If it is given late in the disease it could easily lead to worse tissue damage instead of helping patients,” she says.
The design of the SOLIDARITY trial can change at any time. A global data safety monitoring board will look at interim results at regular intervals and decide whether any member of the quartet has a clear effect, or whether one can be dropped because it clearly does not. Several other drugs, including the influenza drug favipiravir, produced by Japan’s Toyama Chemical, may be added to the trial.
Reference: Science Magazine and WHO newsletter
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