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On paper, the list of outpatient treatments for Covid-19 seems reassuring.

Two oral antivirals have arrived, companies have churned out monoclonal antibody treatments, and all of them, to varying degrees, can help prevent patients from getting so sick they need to be hospitalized.

But shortages and setbacks have undercut those options — at a time when more people than ever are getting sick. Supply of some of the treatments, particularly the prized new oral treatment Paxlovid, is extremely constrained. The ascendance of the Omicron variant has nullified the power of some of the monoclonal antibodies.

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“It’s very concerning as you see the number of new cases per day going up, and you feel helpless because you don’t have much to give,” said Rachael Lee, an infectious diseases physician at the University of Alabama at Birmingham.

In the first week of Paxlovid’s availability, Alabama received just 780 courses of the pills. Some Walmart locations that received doses quickly ran through their entire supply, Lee said.

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There may be great medications, Lee said, “but it’s very difficult to find any.”

Many people who are contracting the coronavirus at this point don’t have much to worry about, thanks in large part to the protection conferred by vaccinations and past infections. But clinicians are still dealing with huge numbers of unvaccinated people, as well as people whose health conditions place them at risk for severe illness even if they’ve received their shots. Doctors and pharmacists are scrambling to match patients with treatments — and to decide which patients should be prioritized over others. Providers say the Omicron surge will present a serious crunch, as cases snowball and supplies fall further behind.

“We’re at a very odd time in terms of outpatient therapies,” said Andrew Badley, an infectious diseases physician and chair of the Mayo Clinic’s Covid-19 Task Force. “There’s a number of approved products, but the supply chain for them is tenuous and is being overwhelmed by the number of cases.”

The Biden administration is trying to expand treatment access and secure more doses, even as it acknowledges ample amounts won’t be available for some time. As he announced this week that his administration had doubled its purchase of Pfizer’s Paxlovid to 20 million courses, President Biden tempered the news with the reality that “it takes months, literally, to make a pill” and that supply would ramp up over months.

There are more courses of the other oral antiviral that also won Food and Drug Administration authorization last month, Merck’s molnupiravir. Some 300,000 doses went out nationwide in its first week of availability, compared to 65,000 doses of Paxlovid. But molnupiravir’s less impressive data and safety profile led the FDA to say it should be used when other treatments aren’t available.

The federal government is still overseeing the allocation of the monoclonal treatments as well as the two oral medications, distributing them to state agencies to be meted out. In some cases, states are shipping the pills to pharmacies to provide to patients with prescriptions, while others are distributing them to clinics directly, similar to the approach with the monoclonal therapies.

Treatment guidelines from the National Institutes of Health show just how much the landscape of outpatient therapies has changed in a few short weeks. As of early December, the expert panel recommended three monoclonal antibody treatments for high-risk Covid-19 patients. Then, in late December, the FDA authorized the oral antivirals, which the NIH added to its guidelines. During the same stretch, as Omicron exploded, the panel dropped two of the monoclonal treatments — one from Regeneron, and one from Lilly — from its general recommendations because they don’t work against the new variant. (The panel noted those two monoclonals would still work for a Delta variant infection.)

The third antibody treatment, GlaxoSmithKline and Vir Biotechnology’s sotrovimab, has maintained its activity against Omicron, and remains on the NIH guidelines.

But sotrovimab, which received emergency authorization last May, is also in limited supply. Even before Omicron took over, some clinics were getting few, if any, doses. This week, not even 50,000 doses were distributed nationally.

Because of Omicron, the federal government on Dec. 23 halted shipments of the Lilly and Regeneron products. But, facing criticism from some Republicans and in acknowledgement that the previously dominant Delta variant was still accounting for a fraction of cases, it reversed course on Dec. 31 and restarted distribution of the Lilly and Regeneron treatments. “The prevalence of Covid-19 variants remains dynamic,” the notice said.

But that might not be an option for long. National data indicate that Omicron is accounting for some 95% of cases. A slow and limited sequencing infrastructure also means that doctors don’t typically know which variant the person in front of them is infected with.

“Given the epidemiological trends, because of the predominance of Omicron in our community, we’re treating everyone as if they have Omicron,” said Mayo’s Badley.

Last month, the FDA authorized another monoclonal therapy, AstraZeneca’s Evusheld, as a pre-exposure treatment for people with compromised immune systems, to reduce their risk of contracting the coronavirus. It appears to work against Omicron, but, again, supply is an issue. The government distributed about 50,000 doses of Evusheld this week, on top of about 100,000 doses in December.

At Mayo, which treats thousands of patients who might not mount a robust response to vaccines, clinicians are trying to devise an ethical system for which patients should get any Evusheld the health system receives, Badley said. One idea is a lottery.

The treatment shortages have further underscored how crucial it is to be vaccinated, clinicians stress. Lee, of UAB, said some unvaccinated Covid-19 patients have asked specifically for Regeneron’s antibody treatment, which former President Trump received when he had Covid-19 before he was vaccinated. They don’t realize the therapy they’ve viewed as a crutch will no longer help them as the pandemic — and the pathogen — evolves.

“That’s what a lot of people who haven’t been vaccinated have been banking on,” Lee said. “But based on everything we’re seeing, about 95% of cases are Omicron. It’s really hard for patients to understand why we’re not giving [the Regeneron treatment], but it won’t work.”

Given the constraints with the oral antivirals and monoclonals, some clinics are trying to expand and accelerate the use of another therapy that itself has had a bumpy ride during the pandemic: remdesivir.

The Gilead Sciences antiviral, also known as Veklury, won approval from the FDA for people hospitalized with Covid-19 in October 2020, and it’s been a regular tool in hospitals. But its reputation has been dogged by research questioning its effectiveness. The World Health Organization in late 2020 recommended against its use because studies failed to demonstrate that it could save lives.

But more recent data, initially presented last fall and published in the New England Journal of Medicine last month, indicated that three days of remdesivir could, if it was given early to people at high risk for severe Covid-19, reduce hospitalizations. (Antivirals work better generally when given earlier in infections.) The data, combined with the Omicron surge, pushed some clinicians to move the drug out of hospital wards into outpatient settings, including at Mayo, Badley said.

The latest NIH clinical guidelines support using three days of remdesivir for outpatients, noting that it can be used “off label,” meaning doctors can prescribe it for outpatients even though its FDA green light was for hospitalized patients.

“We have a medicine on the shelf that can be used as a bridge during this gap” when there are shortages of other treatments, said Robert Gottlieb, a cardiologist at Baylor Scott & White Health in Dallas and one of the investigators for the Gilead-funded trial of outpatient remdesivir.

The challenge with remdesivir is one of logistics. It’s given intravenously, which is not an issue for hospitalized patients but presents one in outpatient settings. Moreover, it has to be given over several days, compared to single treatment of monoclonal antibodies, so there are questions about how to ensure patients come in three days in a row.

Still, some clinics have explored piggybacking on the infrastructure built for the monoclonal therapies to find ways to offer remdesivir to outpatients, or are exploring other pathways.

At Massachusetts General Hospital, clinicians have started a pilot offering outpatient remdesivir to pregnant Covid-19 patients who are unvaccinated or undervaccinated and have another risk factor for serious illness, said Ilona Goldfarb, a maternal-fetal medicine specialist. The team started the pilot because pregnant patients often weren’t chosen for the limited supply of other treatments in the hospital’s prioritization process, given the number of high-risk patients the hospital was treating.

“We were finding that when we referred our patients to the central process, that they weren’t getting selected,” Goldfarb said.

Emily Heil, a University of Maryland pharmacist focused on infectious diseases, said she heard that a number of clinics were considering starting outpatient remdesivir programs before Paxlovid was authorized. But the promise of the oral drugs — combined with the hurdles of committing space, resources, and nurses to providing outpatient remdesivir — led some to give up those plans.

“We’re on a shoestring staff as it is,” Heil said, “with so many people being out and isolated with Covid.” 

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