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Science: Long Covid treatment trials and lessons in persistence

Shelley Hayden became Patient No. 3 in a monoclonal antibody study, and part of a small but growing community: people with Long Covid enrolling in rigorously designed clinical trials of potential treatments…

Science by Jennifer Couzin-Frankel

Article extracts

Long Covid has been a vexing foe, but these clinical trials mark a new chapter. They’re the first targeting the syndrome’s underlying biology, and many of them, including the one Hayden joined, focus on a key question: Is lingering SARS-CoV-2 virus behind patients’ symptoms? A number of studies have indicated some people with Long Covid do not fully clear SARS-CoV-2 from their body. Viral “reservoirs” show up in the gut, blood, and elsewhere. Now, scientists want to know whether wiping out that virus brings relief.

The [American] trials are small in number, and most are modest in size. The monoclonal antibody study includes just 30 patients, two-thirds of whom will get treatment and one-third a placebo. But each enrollee holds clues about Long Covid that doctors hope to mine. Even if an approach fails, the knowledge gained could push science forward.

“It’s not going to happen overnight,” says Steven Deeks, a UCSF infectious disease doctor who began studying Long Covid in the spring of 2020 and helped design the antibody trial. “But it’s happening.”

Deeks describes Long Covid’s effects on the body as “chaos and mayhem,” and he’s circumspect about what most of these early trials can accomplish. “We’re not going to change the world,” he says. That’s partly because scientists’ grasp of Long Covid is still evolving. Clinical trials often hinge on objective measurements such as tumor size, brain lesions, or number of blood cells. Long Covid lacks these markers, making it tougher to determine whether a treatment is working. Relying on symptoms alone can be risky, because they shift unpredictably over time.

And so doctors labor alongside an advancing science, braiding discoveries into trials as they come. The trials, in turn, hunt not only for treatments, but also for signatures of Long Covid in the blood or elsewhere, which could guide future studies. The pressure is immense. Hayden knows fellow sufferers who say they’ve considered suicide but are holding off while waiting for results of the trial she’s part of. But for the first time, she’s hopeful that answers are on the horizon…

Chronic illness

From the pandemic's earliest days, some researchers worried this new virus would spawn chronic illness. In April 2020, Upinder Singh, an infectious disease specialist at Stanford University, was running a trial in acute COVID-19 with a colleague who worked in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), an amorphous chronic illness thought to arise after an infection.

One Saturday afternoon as they sat together enrolling patients, “He said, ‘Upi, do you think there’s going to be an ME/CFS after COVID?’” Overwhelmed by the crush of COVID-19 cases, Singh pushed the question away. “I remember thinking, ‘Why do you have to think like this?’ I said, ‘Let’s hope not.’”

Within a year, Stanford had established a Long Covid clinic and Singh was deep into caring for its patients. Recent estimates suggest at least 17 million people in the United States have Long Covid, along with millions more in other countries.

Long Covid is not the first syndrome to arise after infection, but it offers a unique study opportunity, because doctors typically know when patients were infected and that SARS-CoV-2 was the culprit. Soon after the syndrome emerged, scientists began to scrutinize its biology, documenting immune system abnormalities and blood clotting dysfunction in affected adults and children…

Taking aim at lingering virus

New trials, some listed below, use a range of weapons against traces of SARS-CoV-2, implicated in Long Covid. Some treatment trials are targeting immune dysfunction, for example with immune-modulating treatments such as the rheumatoid arthritis drug baricitinib. Others are now taking direct aim at lingering virus…

TREATMENTDescriptionLead institutionNumber of participantsAnticipated results
PaxlovidAntiviral approved for acute COVID-19Yale University1002024
Stanford University1552024
Karolinska Institute2202024
Duke University (RECOVER)9002025
AER002Monoclonal antibody for SARS-CoV-2 infectionUniversity of California San Francisco (UCSF)302024
LarazotideExperimental treatment for celiac disease, tightens gut junctionsMassachusetts General Hospital482025
EnsitrelvirAntiviral approved in Japan for acute COVID-19UCSF402025
Truvada/SelzentryAntivirals approved for HIV infectionIcahn School of Medicine at Mount Sinai90Late 2025/early 2026

The search for a biomarker

“We need a biomarker,” says Sara Cherry, a virologist at the University of Pennsylvania (UPenn). “It’s very challenging to run trials” without it.

For patients, a biomarker would have another benefit: validation. Despite overwhelming evidence to the contrary, “some doctors continue to believe that Long Covid is psychosomatic,” says Dominique Salmon, an infectious disease physician at the Fournier Institute who studies and treats the syndrome. Patients crave a measurable indicator of their illness…

“Being able to say, ‘I have Long Covid,’ and have a piece of paper that points” to that is invaluable, says Matthew Dunn, an 18-year-old in the Boston area who’s had Long Covid for 2 years. He’s now a research intern in Yonker’s lab, studying the syndrome…

Improved detection, along with analysis of the immune system, might clear up uncertainty in today’s test results. Right now, some Long Covid patients have detectable virus one month and not the next, and many don’t have it at all.

Current technologies may not be powerful enough to catch it, or the virus or viral RNA may be hiding in inaccessible tissues such as nerves or the brain. It’s also possible that certain people with Long Covid clear the virus while continuing to suffer from an aberrant immune response it initiated. But there’s another possibility: Maybe for some patients with Long Covid, lingering virus isn’t relevant.

“Do different patients have different disease,” wonders UPenn microbiologist Maayan Levy, “or are we missing” virus in lots of them?

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