Aminoquinoline drugs, key drugs used for treating malaria, are showing promise in the fight against COVID-19. But they shouldn't be put into widespread use at this point until more definitive research is done, and a variety of safety and efficacy concerns are addressed, researchers say.
But the good news is, "We could have the answers we need in two weeks to a month if good quality randomized controlled trials are done," said , a clinical pharmacologist and professor emeritus at the University of British Columbia in Vancouver.
While the anti-malarials hydroxychloroquine and chloroquine have a long history of use in malaria, and for rheumatologic conditions such as lupus and rheumatoid arthritis, much remains unknown about their effects and potential risks for patients with COVID-19.
Media hype is already causing concern, and there have been three reports to date of deaths of people self-medicating; two from and one in . The American Society of Health-System Pharmacists (ASHP) offered this : "Inappropriate prescribing of these experimental treatments to have 'just in case' or for patients who are not at high risk of severe illness may lead to an inadequate supply of medications for those who need them most."
Already, at least one major health system appears to be committing to hydroxychloroquine for treating COVID-19: BuzzFeed News reported that Kaiser Permanente told a California woman with lupus that it because it was "conserving the current supply for those who are critically ill with COVID-19."
The Rationale
How did the aminoquinolines get on the radar as possible treatments for COVID-19?
Part of that came from clinical experience using chloroquine with SARS and MERS, as well as the in vitro and experimental use of these drugs against both those diseases. These "provided the rationale for the use of these drugs for SARS-CoV2, which is a related coronavirus," said Raymund Razonable, MD, an infectious diseases specialist and professor of medicine at the Mayo Clinic in Rochester, Minnesota. But it is not known exactly how they behave in patients with COVID-19.
They are promising because they have anti-inflammatory and immunomodulatory activity. There have also been promising in vitro studies and compelling anecdotal evidence.
For example, a from China indicated the combination of remdesivir -- an antiviral drug with its own hype/hope issue -- and chloroquine inhibited COVID-19 infection in cultured cells, mice, and nonhuman primate models, though such findings do not necessarily translate to clinical efficacy in humans.
, researchers from China suggested hydroxychloroquine would be preferable to chloroquine because of its better safety profile in malaria. "We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients," they wrote. But, they added, "Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection."
And a from another Chinese group stated that clinical trials are being conducted in more than 10 hospitals in China to test the efficacy and safety of both agents for the treatment of COVID-19-associated pneumonia.
Said the authors, "Thus far, results from more than 100 patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course according to the news briefing."
However, the letter provided no details about protocols, doses, patient characteristics, or adverse events.
But Is it Safe?
One key safety issue is that both drugs can prolong QT intervals, increasing the risk of cardiac events -- not a good thing for very sick patients. "If patients are already on medication which prolongs QT intervals, the anti-malaria drugs would enhance that," Wright told 51˶.
Another issue is medication interaction. One online reference lists a total of 329 medications as having potential interactions with , with 58 being major, and 375 for , including 65 major. Among the drugs with serious interactions are certain antibiotics, antiepileptics, and heart and diabetes medications.
Both drugs also increase the risk of cardiac failure. Chloroquine is known to pass through the placenta in pregnant women, and both drugs pass into breast milk.
"There are numerous reasons rigorous, randomized placebo controlled clinical trials need to be conducted," said Wright. With the large numbers of people contracting COVID-19, a variety of trials investigating use of the drugs, alone or in combination, for treatment and prevention, could be assembled and conducted fairly quickly.
"With its increasing number of patients, New York City would be a good location for a large trial. Now would be the time to start," said Wright. "Results could come in quickly, and we'd have the answers we need about safety and efficacy, in particular whether they decrease or increase mortality."
Trials would answer whether they'd work in some situations and not others, help define which patients might experience greater harm, and show whether there is potential for use in prevention.
Answers may come soon for both agents, according to Razonable.
They "are being tested currently under multiple clinical trials across various centers, including the large WHO [World Health Organization] sponsored mega-trial worldwide. Currently, they remain investigational for the treatment of COVID-19, and should be used under clinical study protocol," he said. The WHO trial will help show how they compare to investigational drugs such as lopinavir-ritonavir and remdesivir.
Just this week, Columbia University , in which researchers hope to recruit 1,600 patients for randomization to hydroxychloroquine or placebo. But the group expects the trial to take at least a full year.
One reason for caution could be a by Chinese researchers in the Journal of Zhejiang University (Medical Sciences). They randomized 30 patients to receive hydroxychloroquine plus conventional treatment or standard care alone for 5 days. No benefit for the drug was seen for clinical measures or viral clearance.