Scientists and doctors are beginning to eye Paxlovid, the antiviral medicine developed by Pfizer to protect vulnerable people from severe disease, as a potential treatment for lingering COVID-19 symptoms after single patients report that the medicine has helped to reduce their symptoms.

Long COVID affects as many as one in five people infected by the virus, according to a recent report by the US Centers for Disease Control and Prevention.

The US Food and Drug Administration granted the drug emergency use authorization in December last year to prevent severe disease in high-risk patients.

“We need to be studying antiviral therapy [for the treatment of long COVID] as soon as possible,” said HIV expert Dr Steven Deeks, a professor of medicine at the University of California, San Francisco (UCSF). He told Health Policy Watch that single-patient case studies have helped drive HIV cure research and Deeks believes that the same could prove true for long COVID.

In May, researchers from Deeks’ university published a report on the Research Square preprint platform of three vaccinated individuals in their 40s who developed long COVID. Two of them were treated with Paxlovid and reported that their symptoms substantially improved.

“While single anecdotes must be interpreted with caution, these cases emphasize the urgent need for carefully designed studies to assess the impact of antiviral therapy beyond the acute window,” the researchers wrote in their report.

Anti-viral therapy

They added that the stories further suggest that antiviral therapy could “potentially impact the complex interplay between viral replication and the host immune response that likely underlies this syndrome but raise concern that brief early antiviral therapy alone may be insufficient to prevent the development of long COVID.”

A similar report was published in April on Research Square of a patient who was infected with the virus in the summer of 2021 and suffered from severe fatigue, brain fog and body aches, among other symptoms, for months afterwards. The symptoms were so severe that she could no longer work.

Six months later, she was reinfected with COVID-19. This time, her doctor prescribed a five-day course of Paxlovid. By day three she noted rapid improvement, not only in her acute symptoms resulting from reinfection, but in her long COVID symptoms.

“Her acute flu-like symptoms had already begun to self-improve by day three, but she noticed rapid improvement of her pre-existing PASC [Post-Acute Sequelae of SARS-CoV-2] symptoms after taking the antivirals,” according to the report.

“At seven months post-initial infection, her PASC symptoms had resolved, and she reported being back to her normal, pre-COVID health status and function including working fulltime and exercising rigorously.”

These cases are not proof that Paxlovid caused the relief these patients experienced as there were other factors, but Deeks said they should be enough to encourage research into the matter.

“These patient stories of people having lingering symptoms who go on Paxlovid for whatever reason and feel better, that strikes me as clearly not definitive, but clearly makes these things necessary to study right away,” Deeks said.

However, there are only a couple of handfuls of clinical trials studying any treatments for long COVID, he said, and certainly no “rigorous assessment for Paxlovid or any other antiviral drug for long COVID.”

To Deeks’ argument, in the HIV space, there has been much attention on individual cures and they “inspired the field,” he said, “they showed it could work.”

Deeks spoke to Health Policy Watch ahead of a visit to Israel for the Medicine 2042 conference in Tel Aviv, where he is expected to be speaking about “Curing HIV. What’s next?”

Long COVID is a ‘vague syndrome’

One of the challenges with researching the treatment of long COVID is that scientists are still unsure about what causes it. One theory is that long COVID may be the result of the virus persisting in part of the body at low levels that can cause local inflammation or clotting and contribute to excess morbidity.

“The dogma is that SARS causes short-term infections and goes away very quickly,” Deeks said. “But data is emerging that, if you look in the right place, you can find evidence that the virus is there.”

A recent study by the CDC showed that one in five people over the age of 18 (and one in four people over the age of 65) who recovered from COVID-19 experienced at least one symptom or condition that could be attributable to the virus. The study analyzed electronic health records of more than 60 million Americans between March 2020 and November 2021.

The long COVID symptoms were diverse and affected multiple symptoms including the cardiovascular, pulmonary, hematologic, renal, endocrine, gastrointestinal, musculoskeletal and neurologic systems, and also included psychiatric signs and symptoms.

Specifically, among those over 18, 38% of people experienced a condition compared with 16% of controls. People who recovered from COVID-19 were twice as likely to develop respiratory issues or pulmonary embolism than their virus-free counterparts.

Deeks said that such studies need to be taken for what they are: retrospective analyses based not on scientific or consistent medical testing but on how people feel.

“Long COVID is, right now, an extremely vague syndrome and that also makes it really hard for companies to invest in and regulatory bodies like the FDA to approve drugs to treat it,” he said.

Deeks said people who get COVID sometimes report incidents that are unrelated to the virus but blame the virus anyway. For example, he said that he lost his hair very quickly when he was in his 20s. If Deeks had COVID then, he said that he is sure he would have blamed the virus.

“It is hard to go back into these records and identify those individuals who have classic long COVID that we know is real. But the bad version of long COVID is not subtle. When you sit down in front of a person who six months ago was running marathons and now can barely leave the house that is long COVID,” Deeks said. “But that is not happening in 20% of the people who got COVID. My sense is that it is less than 5% with Delta. One of the most important questions on the table now is how common long COVID with Omicron is.”

Another challenge to understanding long COVID, he added, is that the world does not have enough information emanating about it from the Global South. Most of the data is coming out of the United Kingdom, United States and Israel – countries with complex electronic health records that are easy to manage and that have more resources.

Paxlovid reduced death by 81% in vaccinated patients over 65

Last week, a new observational, retrospective cohort study on Paxlovid was published on Research Square by a team of Israeli researchers that found that the antiviral drug works for people infected with the Omicron variant and individuals who have been vaccinated.

“Our study demonstrated that [Paxlovid] therapy was associated with a 67% reduction in COVID-19 hospitalizations and an 81% reduction in COVID-19 mortality in patients 65 years and above, during the Omicron surge,” explained Dr Ronen Arbel, a researcher at Clalit Health Services and Sapir College. Arbel led the study that ran from January to March, when the Omicron variant was the dominant strain in Israel.

The researchers examined the effectiveness of Paxlovid in preventing hospitalization and death from COVID-19 in patients over the age of 40 who had been identified as at high risk for COVID-19 complications. In Israel, the treatment was provided within days of diagnosis and administered for five days, per the Pfizer protocol.

There were more than 100,000 participants who were eligible for Paxlovid therapy in the study. Of the 42,819 eligible patients aged 65 years and above, 2,504 were treated with Paxlovid. Fourteen of the treated patients versus 762 of the untreated patients were hospitalized and two treated patients died while 151 of the untreated patients died.

“It was very important to us to understand if the drug also works for patients who were vaccinated or recovered,” Arbel told Health Policy Watch. “What we saw was very interesting. For people without prior immunity, we saw very similar results to the Pfizer trial – 86% reduction [in hospitalisation] while they had 89%. But the majority of real-world patients in most countries have some kind of immunity from recovery or vaccination. In these cases, we saw a 60% reduction in the older population.”

Paxlovid contraindications

Moreover, Paxlovid does have serious limitations. For starters, the drug can have contraindications with existing drugs, Arbel explained.

“We had to have a physician involved to see what drugs each patient was already getting and if they could get Paxlovid,” he explained. “Sometimes there was a recommendation to stop a few drugs for the course of the Paxlovid treatment, but some drugs you cannot stop, and this was a challenge.”

In addition, Paxlovid has uncomfortable side effects, including taste disturbance, diarrhea and vomiting. There is no long-term safety data on the drug nor any sign of what the results might be if taken for more than five days.

The FDA in May rebuked statements made by Pfizer CEO Albert Bourla in an interview with Bloomberg in which he proposed that if some patients experienced a relapse of COVID-19 symptoms after the first round of Paxlovid they could take another round.

“There is no evidence of benefit at this time for a longer course of treatment or repeating a treatment course of Paxlovid in patients with recurrent COVID-19 symptoms following completion of a treatment course,” Dr John Farley, director of the Office of Infectious Diseases, wrote.

Finally, Deeks said one of the drawbacks of Paxlovid is that while it prevents the virus from spreading it does not kill infected cells, which may be necessary in the case of people suffering from long COVID.

Vaccines offer partial protection against long COVID

Many people have asked if vaccination could prevent long COVID and most recent research is showing that vaccination only offers partial protection against persistent symptoms, so relying solely on vaccination to prevent long COVID is not likely to be enough.

A study published last month in Nature Medicine by researchers from Washington University in St Louis looked at 33,940 individuals who had been vaccinated and developed a breakthrough infection and 4,983,491 controls who had no record of a positive COVID-19 test between January 1 and October 31, 2021. The team found that being vaccinated reduced the risk of experiencing long COVID symptoms six months after diagnosis by only 15%.

However, when it came to some of the most severe long COVID symptoms – lung and blood-clotting disorders – the risks were reduced by 49% and 56%, according to the study.

“You cannot rely totally on vaccines to protect you,” Deeks stressed. “As society opens up, how you manage your COVID risk behavior will depend on how much of a concern long COVID is.”

But knowing whether or not Paxlovid may be an answer is likely a long time off.

“We don’t have so many patients that received the drug,” Arbel said. “The drug was given only to a minority of patients, so its effects on long COVID would be very interesting to look at, but it will take some time to have meaningful evidence.”

Image Credits: Pfizer , Centers for Disease Control and Prevention, Bobbi-Jean MacKinnon, "Long COVID after breakthrough SARS-CoV-2 infection" in Nature Medicine.