Politics aside, hydroxychloroquine could (maybe) help fight COVID-19e5902294bf45f7097abdd3d7d50161c6

President Donald Trump’s announcement
that he is taking the
drug hydroxychloroquine
as a precaution against the coronavirus has once
again thrown a decades-old antimalarial drug into the headlines.

There’s currently not enough data to say
whether the drug can protect people from catching COVID-19 or from getting very
ill if they do get infected with the virus. Studies of its use in treating very
sick patients have shown mixed results and, in some cases, have led to
dangerous side effects.

But now, with the president touting hydroxychloroquine
even as scientists issue cautions about its use, the drug has found itself at
the center of political divides, to the possible detriment of figuring out
whether it works.

Nevertheless, researchers are busy
testing hydroxychloroquine and a related drug called chloroquine to see if they
can either prevent infection or keep illness from worsening. Nearly 200
clinical trials are under way or planned around the world to test the drugs,
either alone or in combination with other medications. That includes at least
28 trials examining whether either drug can protect healthcare workers and
others at high risk of getting COVID-19.

Here’s what scientists know about the drugs
and their potential.

Why do researchers think chloroquine or hydroxychloroquine may prevent coronavirus infections?

Both are antimalarial drugs that also have
well-known antiviral activity against many viruses, including SARS and MERS. At
least they work against those viruses in lab dishes.

In lab tests, hydroxychloroquine can
also stop
SARS-CoV-2
, the coronavirus that causes COVID-19, from infecting cells and
decreases replication of viruses that do get inside cells, researchers report
March 18 in Cell Reports. A February
4 report in Cell Research found that chloroquine also
inhibits the virus
.

The drugs are thought to block viruses
from entering cells by changing the pH, or acidity, of cellular compartments
called lysosomes. That “creates a less friendly environment for the virus, so
it might be more difficult for the virus to get into human cells in the first
place,” says Michael Avidan, an anesthesiologist at Washington University
School of Medicine in St. Louis. Avidan is involved in a clinical trial testing
whether chloroquine can protect healthcare workers from infection or from
developing serious disease.

In addition, hydroxychloroquine and
chloroquine disrupt
interactions
between some of SARS-CoV-2’s proteins with proteins called
sigma receptors in human cells, researchers report April 30 in Nature. Interrupting those protein
interactions may make it difficult for the virus to replicate, says study
coauthor Adolfo Garcia-Sastre, a microbiologist who directs the Global Health
and Emerging Pathogens Institute of Icahn School of Medicine at Mount Sinai in
New York City. 

Together, those antiviral capabilities
make the drugs attractive for use against the coronavirus. But there’s another
important reason chloroquine and hydroxychloroquine were some of the first
drugs pressed into action: They’re available. Doctors have been prescribing the
drugs, already approved by the U.S. Food and Drug Administration, for decades
and they’re generally safe, although there are some serious side effects.

“Time is of the essence,” says Adam
Spivak, an infectious-disease doctor at the University of Utah in Salt Lake
City. “When you have a drug that you understand and can safely administer
that’s on the shelf, that’s the drug you reach for first.”

Hydroxychloroquine is better tolerated
by most people, so is the one researchers are testing more often.

Nurse at a hospital in St. Louis
Charge nurse Caroline Becker adjusts her face shield before entering a patient’s room at Barnes-Jewish Hospital in St. Louis. Several studies are testing hydroxychloroquine or chloroquine’s ability to protect healthcare workers from COVID-19, including a chloroquine study headed by researchers at Washington University School of Medicine in St. Louis.Matt Miller/Washington Univ.

But isn’t taking hydroxychloroquine or chloroquine dangerous?

It can be for some people, such as those
prone to heart problems, or when taken in combination with other drugs that can
alter heart rhythms.

While hydroxychloroquine latches on
sigma receptors proteins that are used by the virus, it can also bind to other
proteins in the heart, Garcia-Sastre said in a news conference May 15. “It may
not be the best drug that we can use right now to inhibit viral replication in
people because of this.” Some other drugs also interrupt the coronavirus’s
interactions with sigma receptors, but don’t bind to the heart proteins, which
may make them safer alternatives
to hydroxychloroquine
, Garcia-Sastre said (SN: 4/30/20).

In trials with very sick people, hydroxychloroquine
has caused sometimes fatal heart-rhythm problems. People with existing heart
problems, those with low potassium levels or low oxygen levels in their blood
are especially vulnerable to these serious side effects, says Raymond Woosley,
a pharmacologist the University of Arizona in Phoenix.

The largest study to date, published May
22 in the Lancet, found that the
drugs raised
the risk of death
for hospitalized COVID-19 patients. The findings are
based on data from more than 96,000 coronavirus patients in 671 hospitals on
six continents. Of those, nearly 15,000 received either chloroquine or
hydroxychloroquine, either alone or in combination with a type of antibiotic
called macrolides — usually azithromycin.

The researchers accounted for risk
factors, including age, obesity, sex, underlying diseases, smoking and the
severity of COVID-19 at the start of treatment. Among people taking
hydroxychloroquine alone, 18 percent died; 16.4 percent of those taking
chloroquine alone died; and combining either drug with a macrolide was
associated with even higher numbers of deaths. In comparison, only 9.3 percent
of people taking neither drug died.  The drugs were also associated with heart rhythm
irregularities.

But safety concerns about
hydroxychloroquine have mainly come from use of the drug in people who are sick
in the hospital with COVID-19, says Susanna Naggie, an infectious disease
doctor at Duke University School of Medicine. She is leading a clinical trial
testing hydroxychloroquine as a prophylactic to protect healthcare workers
exposed to COVID-19 patients. Because of reports of harm in very sick COVID-19
patients, “people have kind of forgotten about the decades of safety data that
we do have in an ambulatory, healthy population,” she says.

In places where malaria is a problem,
people often take the drugs without any serious side effects, says Ira
Baeringer, chief operations officer of Rising Pharmaceuticals, a company based
in East Brunswick, N.J. that donated hydroxychloroquine and chloroquine for
several large clinical trials.

So far, studies looking at hydroxychloroquine
use before or early in infection haven’t produced any of the heart rhythm
problems seen in studies of seriously ill patients. “When used alone, we’re not
seeing major issues,” says Sarah Lofgren, an infectious disease doctor at the
University of Minnesota Medical School in Minneapolis, where researchers are
testing hydroxychloroquine’s ability to prevent COVID-19. “Out of our thousands
of patients, we’re not seeing things people are quite concerned about,
particularly the heart arrhythmias.”

Still, researchers are taking
precautions when giving the drug to healthy people. People with existing heart
problems, kidney disease or who are taking other drugs that may alter heart
rhythms aren’t allowed to participate in the trials.

Isn’t there already evidence that hydroxychloroquine doesn’t work against COVID-19?

Yes, and no. Very few rigorous trials of
the drug have reported data. Some people were given the drug in studies in
which there wasn’t a control group that got placebos, and results from some of
those studies have been mixed, with some reporting benefits, others showing no
effect, and some indicating that the drugs may even be harmful for some
patients. Even the latest data from the large multinational study in the Lancet combined studies that used the
drugs in different doses and in different ways that may not be directly
comparable.  

Hydroxychloroquine is also used to treat
rheumatoid arthritis and lupus. It is effective against those diseases because
it helps regulate the immune system’s responses, pushing away from harmful
inflammation.

It’s clear that the immune system also
plays an important role in COVID-19, Spivak says. So researchers thought that
hydroxychloroquine might be able to calm overactive immune reactions that do
damage to people with severe cases of COVID-19.

Early evidence from tests of the drug
points to hydroxychloroquine having no
effect in combatting the disease
in seriously ill patients (SN: 4/21/20).
The large Lancet study also failed
to show any benefit
.

But just because the drug didn’t seem to
help in late stages of the disease, that doesn’t mean it won’t be effective if
given early, perhaps even before people are exposed to the virus, Avidan says.

“If you bring on a star player
consistently [only] in the last minute of a game and you’re still losing, you
might say, ‘This star player is no good,’” Avidan says. “But that’s not a good
use of your star player, because most of the outcome is already established at
that very late stage.” Bringing a star in early to play the whole game, he
says, may produce a much better outcome.

That’s exactly what researchers are
attempting in multiple trials testing the drugs effectiveness as a
preventative, or prophylactic, treatment for the coronavirus.

Some of those trials are just wrapping
up — including two trials at the University of Minnesota — but aren’t reporting
results yet. Others are still under way.

In Utah, Spivak and colleagues have
begun testing 40 people of the planned 400 for a trial to determine whether
hydroxychloroquine can shorten the duration of virus production in people who
have tested positive. “If we get results by February, I’m going to be
ecstatic,” Spivak says. “Although, February feels like a century away given all
that is going on.”

For now, there’s no evidence that
hydroxychloroquine or chloroquine can prevent COVID-19, but there’s also no
evidence that they can’t.

So what’s the big deal about the president saying he’s taking hydroxychloroquine?

Doctors and researchers worry that based
on the president’s endorsement, people will take the medications without
medical supervision and could do harm to themselves. When President Trump first
touted hydroxychloroquine in March, internet searches seeking places to buy the
drug increased
1,389 percent
, researchers report April 29 in JAMA Internal Medicine. Interest in buying the drug peaked again
after reports of a fatal poisoning resulting from taking a fish tank treatment
containing chloroquine, the researchers found.

“These drugs have been villainized and
politicized,” Baeringer says. “That leads to hyperbole on both sides of the
debate.”

Some researchers have voiced concern
that so many people would take hydroxychloroquine on their own that researchers
wouldn’t be able to find enough people not taking the drug to participate in
clinical trials. That hasn’t happened, Spivak says. “The public has been
appropriately wary of it,” he says. “The pendulum has swung. There was huge
interest, then there was a lot of negative press and warnings. We’ve had a lot
of local press stories where people came to us said, ‘Hey, wait, you’re still
doing that?’ The science follows the pace of the news cycle.”

In Minnesota, enrollment in the studies has
both fallen, and risen, with greater media and political attention, Lofgren
says. One study recruited volunteers via the internet. Initially there was
excitement and quick enrollment, but “as it became a political, partisan
medication, our enrollment really dropped down,” she says. “This week we’ve had
a bump in enrollment.”

And soon, researchers hope to have data
that will say whether the drugs are effective or not.

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