We aren’t using all of our tools to treat Covid-19

As record daily Covid-19 hospitalizations and deaths this month in the US have pushed the pandemic to new crisis levels, senior government health officials have lamented that many patients are not getting the drugs — including monoclonal antibodies, antivirals, and corticosteroids — available to treat the disease, leaving many doses unused.

There are still questions about how well many of these drugs work. One recent report found that a mix of monoclonal antibodies developed by Eli Lilly could reduce Covid-19 hospitalizations and deaths by 70 percent, though some researchers cautioned that the findings were drawn from a small number of events.

And with the new, potentially more contagious variants of the virus that causes Covid-19 now spreading, a few of these therapies could prove even less effective.

After some stumbles earlier with drugs like hydroxychloroquine, regulators have authorized monoclonal antibodies, antivirals, and corticosteroids. Doctors say these drugs have helped them save lives, putting them in a far better position than they were last year and cushioning the blow of this pandemic.

Yet US health officials say hospitals are still struggling to get them administered, and to get patients to the hospital in time to take advantage of them. In particular, they noted earlier this month that less than 25 percent of available doses of monoclonal antibodies have been administered.

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“Even with a vaccine, we know we will not prevent every infection,” said US Surgeon General Jerome Adams on January 14 during a press conference. “So today we want to remind everyone that for those of you who do contract Covid, we have excellent treatments to keep you out of the hospital, to keep you out of the ICU, to help you recover quickly.”

Administering these treatments most effectively also requires good timing. Some, like corticosteroids, work best in later stages of the disease; others, like monoclonal antibodies, need to be administered to patients early in the course of their illness, often before someone is even sick enough to go to the hospital.

That means testing to confirm that someone is carrying the virus and getting the results quickly is crucial, particularly for people at the highest risk of severe disease, like those over the age of 65. Then those patients need to get to a hospital that has the capacity to treat them in time. Many of these treatments also need medical supervision, adding further stress to hospitals reaching capacity. And as health facilities get overwhelmed, fatality rates are rising.

The Department of Health and Human Services has put together a website highlighting the tools available to control the pandemic and where people can receive treatments near them.

Here is how doctors think about treating Covid-19 patients, some of the most common treatments they have at their disposal, and their drawbacks.

Several tools and strategies for treating Covid-19 have emerged, with varying effectiveness

There are two main approaches for dealing with Covid-19. One is to constrain the virus, and the other is to temper the immune system’s response to it.

In the early stages of the disease, the SARS-CoV-2 virus itself is the main culprit behind the damage, leading to symptoms like coughing and a loss of smell. But as the disease progresses, the body’s immune system starts to overreact, causing problems like inflammation and, later, organ damage.

Figuring out what works to tamp down this often deadly disease has been tricky. Ideally, scientists would conduct randomized controlled trials, but in the face of an overwhelming pandemic, it’s been hard to recruit people into these studies and get adequate results in time. Much of the evidence for drugs to treat Covid-19 comes from weaker observational studies, leaving some therapies under a frustrating cloud of uncertainty. And doctors have been inclined to prescribe drugs that have already been approved for other uses and have an established safety record.

“We don’t have time to find a new drug in a test tube and do years of studying to make sure it’s safe,” said Matthew McCarthy, an associate professor at Weill Cornell Medicine who has been treating Covid-19 patients since the start of the pandemic. “We want to take drugs that we know are safe and see if they can help with Covid.”

But research is still underway to find better treatment options, and more therapies, from repurposed existing drugs to novel drugs, could become available soon.

Treatments include the following:

Convalescent plasma: The idea here is to use plasma, the liquid part of blood plus the proteins used for clotting, harvested from patients who survived Covid-19. During an infection, the immune system generates proteins called antibodies. They stick to a part of the virus or to an infected cell. That attachment can then block the virus from invading hosts, or it can flag the virus or infected cell for destruction by other immune cells.

After a patient successfully defeats the virus, their blood contains a variety of antibodies that stick to all different parts of the virus. Doctors then transfer those remaining antibodies via plasma to a patient with an active infection. Without outside help, the immune system can take several days to produce antibodies, so getting some from outside can bolster defenses, particularly for people at high risk.

This technique has been used in the past to treat other infections, but the evidence of how well it works against SARS-CoV-2 is mixed. The Food and Drug Administration granted an emergency use authorization to convalescent plasma last year, but the National Institutes of Health reported at the time that the evidence for its effectiveness was weak. Subsequent studies seemed to show that it helps slow the disease when administered early, particularly in older adults. More recent results have also been conflicting, with one study in the UK reporting no benefit and another finding that convalescent plasma rich in antibodies lowered the risk of death. Revised FDA guidelines allow convalescent plasma to be used to treat hospitalized patients.

The supply of convalescent plasma is limited by the number of patients who donate. And it’s infused intravenously, so it has to be administered by a professional. The main concerning side effects are allergic reactions and circulation problems associated with transfusion.

Monoclonal antibodies: This approach takes the idea behind convalescent plasma one step further. Some antibodies are more effective than others at corralling a given pathogen, so if one clones the best antibodies, they could be used as the basis for a targeted drug.

There are now two monoclonal antibody therapies for Covid-19 that have received emergency use authorizations from the FDA. One is called bamlanivimab, developed by the pharmaceutical company Eli Lilly. The other is a cocktail of two monoclonal antibodies, casirivimab and imdevimab, created by Regeneron (the -mab suffix stands for “monoclonal antibody”). President Trump famously received a course of the Regeneron therapy when he was ill with Covid-19 last year.

Under Operation Warp Speed, more than 500,000 doses of these therapies have been distributed across the US. Only about 25 percent of these doses have been used, despite high levels of Covid-19 transmission.

Like convalescent plasma, these drugs require transfusion. But monoclonal antibodies are most effective in the early stages of the illness, rather than in patients who are already hospitalized.

“By the time you’re hospitalized, your immune system is kicked into high gear and it may simply be too late,” McCarthy said. Some hospitals around the country have reported good results using monoclonal antibodies, with the treatment reducing the likelihood of a high-risk patient needing hospitalization.

However, NIH has been more skeptical of the evidence provided to date. For both the Eli Lilly therapy and the Regeneron therapy, the agency said “there are insufficient data to recommend either for or against the use” of these drugs and that they “should not be considered the standard of care.” That doesn’t necessarily mean that these drugs don’t work — just that the research to date hasn’t yielded a definitive answer.

Side effects are similar to those of convalescent plasma, with allergic reactions being the main concern.

Antivirals: These are drugs that directly interfere with the reproductive cycle of a virus. Since viruses like SARS-CoV-2 use human cells to make copies of themselves, it’s tricky to come up with a drug that hampers the virus without causing any collateral damage.

Remdesivir has emerged as a leading antiviral drug against Covid-19. Sold under the brand name Veklury by Gilead Sciences, it was the first drug to receive full FDA approval to treat Covid-19, becoming the new standard of care. It works by imitating one of the molecules the virus uses to encode the instructions for making copies of itself. The impostor molecule causes the viral replication process to stall, but it doesn’t fool human cells, giving it a targeted effect.

It was initially developed to treat the Ebola virus. There are concerns about how well it works with Covid-19. The World Health Organization conducted one of the largest studies to date on antiviral drugs for Covid-19 and found that remdesivir had little to no effect on mortality. However, several smaller studies found that it could reduce the length of hospital stays in patients.

McCarthy said that means the drug can still be useful. Shorter hospital stays mean fewer beds occupied, which in turn allows health workers to treat more patients. The drug is mainly administered to Covid-19 patients who are hospitalized.

Side effects of remdesivir include elevated liver enzymes, which could indicate liver damage, as well as allergic reactions leading to fever, shortness of breath, wheezing, swelling, low blood oxygen, and changes in blood pressure. This is also a transfused drug, so the same concerns about circulation problems apply here, as well as the challenge of administering it under medical supervision.

Corticosteroids: As Covid-19 progresses, it can throw the immune system way off balance. Immune cells can start attacking healthy cells, and the strain of being on high alert can trigger dangerous immunological conditions like cytokine storms, even after the virus has been cleared from the body.

So drugs that tamp down on the immune system can help patients in more advanced stages of the disease. This seems to be the case with dexamethasone, a generic corticosteroid. It’s one of the few drugs that has been shown to actually reduce the mortality rate of Covid-19, and it costs as little as $1 per dose, administered orally.

That’s why it’s quickly become one of the most common drugs used to treat hospitalized Covid-19 patients who are ill enough to need oxygen support.

However, because it can slow the immune system, it could actually backfire in early stages of Covid-19 when the virus itself is the main concern. Dexamethasone can also leave patients vulnerable to other infections and may cause dizziness, an irregular heartbeat, and psychiatric problems like anxiety and suicidal ideation.

Other emerging treatments: So far, there is still no surefire way to knock out Covid-19 the way an antibiotic can wipe away a bacterial infection. That’s why many doctors often use several of these therapies in conjunction to treat Covid-19 patients, like remdesivir and dexamethasone for hospitalized patients. “Those two things are given so frequently together that some people as a shorthand call it ‘remdexavir,’” said McCarthy.

But researchers are also investigating other drugs, both off-the-shelf varieties and new designs, to see if they can make more gains against the virus. Clinical trials are underway for drugs that act as immune system modulators like abatacept and infliximab, for instance, which are already used for rheumatoid arthritis, to deal with immunological imbalances wrought by Covid-19. A small randomized trial found that fluvoxamine, an antidepressant, prevented symptoms from getting worse in Covid-19 patients within seven days of symptoms appearing. Large scale trials are also beginning for generic drugs like the anti-inflammatory drug colchicine and the anti-parasitic drug ivermectin.

Doctors are also developing protocols to deal with patients experiencing lasting problems from Covid-19, the so-called long-haulers. “I think what you’re going to see six months or a year from now, long Covid is not going to be one diagnosis but a series or collection of different conditions,” McCarthy said. Persistent fatigue, neurological problems, and breathing trouble can linger, and each set of symptoms may require its own course of treatment. Some Covid-19 patients have had strokes, while others are reeling from blood clotting disorders.

“It’s become clear to me that I’m going to be dealing with coronavirus and the sequelae of it for years and years,” McCarthy said. And more research is still needed to determine what will work best for these many survivors who are still suffering.

Why it’s still so hard to deploy treatments for Covid-19

Despite the growing variety of options, health officials are concerned that not enough people are getting them. “These medications, these therapeutics, are not being used as much as I, or the doctors on the task force, or the career experts here at HHS feel that they should be,” Adams said. “Tools that never leave the toolbox don’t get the work done.”

Officials say part of the problem is public awareness — people don’t know that these options are available to them. Many public health agencies are also not conveying that there are treatments that can help people before they are hospitalized.

Another issue is that many of these drugs have to be administered early in the course of the disease. That means people need to get tested for the virus and get results quickly. People in high-risk groups in particular should then seek treatment right away, especially if they begin to notice breathing issues.

Hospitals are also filling up with patients, and many can’t spare the personnel to treat people with less severe symptoms, particularly with drugs that require transfusions. “The antibodies are not in shortage,” said Janet Woodcock, director of the Center for Drug Evaluation and Research at the FDA, during a press call this month. “We have a shortage of ability to administer these to patients.”

There are other options, however. Patients can receive these therapies at dedicated transfusion centers, or can have nurses administer the therapy at home, but both of these alternatives pose their own logistical challenges.

Cost is another barrier. While off-the-shelf therapies like dexamethasone are cheap, and the government is fronting the cost of the drugs for monoclonal antibodies, health providers can still charge for using their facilities. Transfusions in particular can cost hundreds to more than $1,000 out of pocket, depending on insurance coverage.

The Covid-19 pandemic is also throwing some curveballs. New variants of the virus are now spreading in the United States. These variants contain mutations that could weaken prior immunity to the virus and may elude targeted therapies like monoclonal antibodies.

“We are actively looking at that question,” Woodcock said. “We can’t predict what variants will arise and will become prevalent, so we have to rely on sampling and testing that’s done across the United States” to continue studying the efficacy of these drugs.

A spokesperson for Regeneron told Vox that the company’s combination of two monoclonal antibodies still seems to be effective against the apparently more contagious B.1.1.7 variant first identified in the United Kingdom. The 501.V2 variant first detected in South Africa seems to elude one of the antibodies in the treatment regimen, but not the other.

“We’ll continue to test/replicate our data to confirm that is the case,” the spokesperson wrote in an email.

Drugs that aren’t specific to a given version of the virus like corticosteroids or antivirals are likely to remain as effective against the new SARS-CoV-2 variants.

To keep treatments viable, the full suite of public health tools to control the pandemic must be used. Relieving the stress on hospitals requires reducing transmission of the virus, which in turn demands social distancing, masking, and rigorous hand-washing. Reducing transmission also lowers the chances of mutations that could render treatments less effective.

Administering care away from hospitals whenever possible could also lift the burden on hospitals and allow them to focus on the most critically ill patients.

Though the coming weeks are likely to remain grim, with high levels of hospitalizations and deaths, the combination of treatments and vaccines does offer hope. Progress against the pandemic will continue to be slow, hard-fought, and fragile, but we now have tools that we didn’t before. It’s a matter of whether and how we wield them.