Rare cases of COVID returning pose questions for Pfizer pill

Authors: MATTHEW PERRONE May 9, 2022 AP NEWS

As more doctors prescribe Pfizer’s powerful COVID-19 pill, new questions are emerging about its performance, including why a small number of patients appear to relapse after taking the drug.

Paxlovid has become the go-to option against COVID-19 because of its at-home convenience and impressive results in heading off severe disease. The U.S. government has spent more than $10 billion to purchase enough pills to treat 20 million people.

But experts say there is still much to be learned about the drug, which was authorized in December for adults at high risk of severe COVID-19 based on a study in which 1,000 adults received the medication.

WHY DO SOME PATIENTS SEEM TO RELAPSE?

Doctors have started reporting rare cases of patients whose symptoms return several days after completing Paxlovid’s five-day regimen of pills. That’s prompted questions about whether those patients are still contagious and should receive a second course of Paxlovid.

Last week, the Food and Drug Administration weighed in. It advised against a second round because there’s little risk of severe disease or hospitalization among patients who relapse.

Dr. Michael Charness reported last month on a 71-year-old vaccinated patient who saw his symptoms subside but then return, along with a spike in virus levels nine days into his illness.

Charness says Paxlovid remains a highly effective drug, but he wonders if it might be less potent against the current omicron variant. The $500 drug treatment was tested and OK’d based on its performance against the delta version of the coronavirus.

“The ability to clear the virus after it’s suppressed may be different from omicron to delta, especially for vaccinated people,” said Charness, who works for Boston’s VA health system.

Could some people just be susceptible to a relapse? Both the FDA and Pfizer point out that 1% to 2% of people in Pfizer’s original study saw their virus levels rebound after 10 days. The rate was about the same among people taking the drug or dummy pills, “so it is unclear at this point that this is related to drug treatment,” the FDA stated.

Some experts point to another possibility: The Paxlovid dose isn’t strong enough to fully suppress the virus. Andy Pekosz of Johns Hopkins University worries that could spur mutations that are resistant to the drug.

“We should really make sure we’re dosing Paxlovid appropriately because I would hate to lose it right now,” said Pekosz, a virologist. “This is one of the essential tools we have to help us turn the corner on the pandemic.”

HOW WELL DOES PAXLOVID WORK IN VACCINATED PEOPLE?

Pfizer tested Paxlovid in the highest-risk patients: unvaccinated adults with no prior COVID-19 infection and other health problems, such as heart disease and diabetes. The drug reduced their risk of hospitalization and death from 7% to 1%.

But that doesn’t reflect the vast majority of Americans today, where 89% of adults have had at least one shot. And roughly 60% of Americans have been infected with the virus at some point.

“That’s the population I care about in 2022 because that’s who we’re seeing — vaccinated people with COVID — so do they benefit?” asked Dr. David Boulware, a University of Minnesota researcher and physician.

There’s no clear answer yet for vaccinated Americans, who already have a hospitalization rate far below 1%.

That may come from a large, ongoing Pfizer study that includes high-risk vaccinated people. No results have been published; the study is expected to wrap up in the fall.

Pfizer said last year that initial results showed Paxlovid failed to meet the study’s goals of significantly resolving symptoms and reducing hospitalizations. It recently stopped enrolling anyone who’s received a vaccination or booster in the past year, a change Boulware says suggests those patients aren’t benefitting.

At a minimum, the preliminary data should be released to federal officials, Boulware said. “If the U.S. government is spending billions of dollars on this medicine, what’s the obligation to release that data so that they can formulate a good policy?”

CAN PAXLOVID BE USED TO HELP PREVENT COVID-19 INFECTION?

Pfizer recently reported that proactively giving Paxlovid to family members of people infected with COVID-19 didn’t significantly reduce their chances of catching it. But that’s not the end of the story. Pfizer is studying several other potential benefits of early use, including whether Paxlovid reduces the length and severity of COVID-19 among households.

“It’s a high bar to protect against infection but I’d love to see data on how Paxlovid did against severe disease because it may be more effective there,” said Pekosz.

FDA Investigating Reports Of COVID Relapses Following Use Of Pfizer’s Pill

Authors: Zachary Stieber  May 8, 2022

The U.S. Food and Drug Administration (FDA) is investigating reports of relapses among people who took Pfizer’s COVID-19 pill.

The FDA “is evaluating the reports of viral load rebound after completing paxlovid treatment and will share recommendations if appropriate,” an agency spokesperson told The Epoch Times in an email.

In a recent preprint case report, Veterans Affairs researchers reported that a 71-year-old male who took the pill, also known as nirmatrelvir, experienced a “rapid and progressive reduction” in the viral load of SARS-CoV-2, the virus that causes COVID-19.

But four days after completing the treatment course, there was a “surprising rebound of viral load and symptoms,” they reported.

The report “highlights the potential for recurrent, symptomatic SARS-CoV-2 replication after successful early treatment” with the pill, the researchers said.

A number of others have said they saw renewed symptoms after taking paxlovid.

In the FDA’s evaluation (pdf) of data on paxlovid, which the agency cleared on an emergency basis in 2021, the agency reported that in an ongoing phase 2/3 trial run by Pfizer, several participants “appeared to have a rebound” in viral load five to nine days after completing their treatment courses.

In light of the new reports, additional analyses of the paxlovid trial data were performed and showed that 1 to 2 percent of the patients had one or more positive COVID-19 tests after testing negative, or an increase in the amount of viral load, after completing the treatment, Dr. John Farley of the FDA said in an interview the agency published on May 4.

“This finding was observed in patients treated with the drug as well as patients who received placebo, so it is unclear at this point that this is related to drug treatment,” he said, adding that, at this time, the reports “do not change the conclusions from the paxlovid clinical trial which demonstrated a marked reduction in hospitalization and death.”

As part of the authorization agreement, the FDA said Pfizer must later submit information regarding “prolonged virologic shedding or rebound in clinical trials.”

Pfizer did not respond to a request for comment.

The company told Bloomberg that the rate of rebound in its trial was not higher among people who took paxlovid than in people who took a placebo.

“This suggests the observed increase in viral load is unlikely to be related to paxlovid,” the company said.

Dr. Clifford Lane, deputy director for clinical research at the National Institute of Allergy and Infectious Diseases, told the outlet that the agency will study the issue, calling it “a priority.”

Lane and the agency did not return queries.

The FDA authorized paxlovid for the treatment of mild to moderate COVID-19 in Americans 12 years or older. To get the pill, a person must test positive for COVID-19 and be deemed at high risk of progressing to severe disease.

Pfizer’s Covid-19 Pill Failed Study Testing Its Preventive Use

Paxlovid, authorized to treat high-risk people early in infection, didn’t meaningfully reduce illness in exposed adults

Authors: Jared S. Hopkins Apr. 29, 2022 The Wall Street Journal

The Covid-19 pill from Pfizer Inc. failed to prevent symptomatic infections in adults who had been exposed to the pandemic virus, a late-stage study found.

Pfizer said Friday that the drug, named Paxlovid, failed the study’s main objective of meaningfully reducing the risk of confirmed and symptomatic Covid-19 infections in adults who were exposed to the virus by someone in their household.

Paxlovid was cleared for use in December by U.S. health regulators to treat people 12 years and older early in the course of their disease who are at high risk of developing severe Covid-19.

The treatment consists of two components, nirmatrelvir and a widely used generic antiviral, and is taken twice daily for five days.

The pill’s key advantage over other Covid-19 treatments has been that it can be taken at home to avoid hospitalization. Another antiviral pill, from Merck & Co. and Ridgeback Biotherapeutics LP, has also been cleared for use.

Paxlovid’s authorization was based on a late-stage study finding the pill was highly effective at safely cutting the risk of hospitalization or death when taken within five days of symptoms.

Pfizer has also been studying the drug for other uses, including whether it could prevent disease.

In a 2,957-subject trial testing whether Paxlovid could also work preventively, researchers found that the risk of developing an infection declined by 32% in subjects who received Paxlovid for five days compared with people who got a placebo, and declined 37% in people who received treatment for 10 days, Pfizer said.

The results weren’t statistically significant and failed the study’s primary endpoint, Pfizer said.

“While we are disappointed in the outcome of this particular study, these results do not impact the strong efficacy and safety data we’ve observed in our earlier trial for the treatment of Covid-19 patients at high risk of developing severe illness, and we are pleased to see the growing global use of Paxlovid in that population,” Pfizer Chief Executive Albert Bourla said.

Researchers didn’t observe any serious safety concerns and the safety profile was consistent with previous Paxlovid studies, Pfizer said.

Pfizer continues to study Paxlovid in patients who are at low risk of developing severe disease to see if it can reduce the risk of hospitalization and death.

An interim analysis last year found the drug failed to reach the trial’s goal of resolving or reducing symptoms among the people who took the pill within four days of infection. Results are expected as early as the third quarter, according to a company spokesman.

Another rare virus puzzle: They got sick, got treated, got covid again

Authors: Carolyn Y. Johnson  April 27, 2022 The Washington Post

Shortly after he served on a jury in March, Gregg Crumley developed a sore throat and congestion. The retired molecular biologist took a rapid test on a Saturday and saw a dark, thick line materialize — “wildly positive” for the coronavirus.

Crumley, 71, contacted his doctor two days later. By the afternoon, friends had dropped off a course of Paxlovid, a five-day regimen of antiviral pills that aims to keep people from becoming seriously ill.

The day he took his last dose, his symptoms were abating. He tested each of the next three days: all negative.

Then, in the middle of a community Zoom meeting, he started feeling sick again. Crumley, who is vaccinated and boosted, thought it might be residual effects of his immune response to the virus. But the chills were more prolonged and unpleasant. He tested. Positive. Again.

Crumley, like other patients who have experienced relapses after taking Paxlovid, is puzzled — and concerned. On Twitter, physicians and patients alike are engaged in a real-time group brainstorm about what might be happening, with scant evidence to work with.

It is the latest twist — and newest riddle — in the pandemic, a reminder that two years in, the world is still on a learning curve with the coronavirus.

Infectious-disease experts agree that this phenomenon of the virus rebounding after some patients take the drug appears to be real but rare. Exactly how often it occurs, why it happens and what — if anything — to do about it remain matters of debate.

What’s clear is that patients should be warned it is possible so they don’t panic — and so that they know to test again if they start feeling ill. More data is needed to understand what is going on. Paxlovid, made by the drug giant Pfizer, remains a useful drug, even though it has sparked a new mystery.Biden administration boosts access to antivirals as covid cases rise

“I’m not negative on Paxlovid,” said Crumley, who lives in Philadelphia and whose last positive test was a week after his second wave of illness began. “I don’t know whether it’s just stopping [viral] replication for that five-day period of time, and it comes back.”

One of the top worries accompanying antiviral drugs is the threat of resistance, when the virus evolves to evade the treatment. A Food and Drug Administration analysis of Pfizer’s clinical trial of the drug showed the virus rebounded in several subjects about 10 to 14 days after their initial symptoms but found no reason and no evidence that their infections were resistant to the treatment.

Michael E. Charness, chief of staff at the VA Boston Healthcare System, published a detailed case study of one 71-year-old patient who had a relapse. The man, who was vaccinated and boosted, received Paxlovid and quickly felt better. When he developed cold symptoms a week after his case of covid had resolved, researchers sequenced the virus’s genetic code and found it was the same virus surging back. That ruled out a reinfection, the emergence of a variant or the virus becoming resistant.

Charness would like to see more data and other questions answered. Should antivirals be given longer, to assure the virus is cleared? Should people be treated a second time? What are the implications for people returning to their normal lives?

“If you have a resurgence of viral load, and that happens on day 10, when CDC says you’re back to work, no mask, what are you supposed to do about isolation? Is that a moment when you’re contagious again?” Charness said. “The person we studied, we advised to isolate until their viral load was gone the second time.”

Pfizer is collecting data, in clinical trials and in real-world monitoring of the drug’s use. The company’s trial data indicates there is a late uptick in viral load in “a small number” of people who take the drug, but the rates appear to be similar among study participants given a placebo, according to company spokesman Kit Longley. The people who experienced such increases also did not develop severe disease the second time around.

Those findings suggest that Paxlovid isn’t the reason people are relapsing, because that’s happening in untreated people, too.

If that turns out to be true, it raises the concern that some people — whether they have taken the drug or not — could be infectious long after they think they are in the clear, and after guidelines suggest they can stop taking precautions.

“Although it is too early to determine the cause, this suggests the observed increase in viral load is unlikely to be related to Paxlovid,” Longley wrote in an email. “We have not seen any resistance to Paxlovid, and remain very confident in its clinical effectiveness.”

The limited evidence leaves most physicians favoring the idea that Paxlovid knocks the virus down but doesn’t knock it out completely. It’s possible that by holding the virus in check, the immune response doesn’t fully ramp up, because it doesn’t see enough virus. Once the treatment ends, the virus can start multiplying again in some people.

Philip Bretsky, a primary care doctor in Santa Monica, Calif., said he has encountered two cases among patients, both of whom were vaccinated and boosted at least once.

A double-boosted 72-year-old who had chronic medical conditions that raised his risk for severe illness started to feel unwell at the end of March. He tested positive and began a course of Paxlovid. He felt better and tested negative. Then, 12 days later, he started feeling crummy again — and tested positive.

Reinfection seemed improbable, and Bretsky thought resistance was unlikely with a five-day course of treatment.

In well-vaccinated people, being reinfected so quickly would be “like getting struck by lightning or winning the lottery,” Bretsky said. “I don’t think this is reinfection. I think this is recrudescence of the original infection.”

Experts don’t know how common this phenomenon is. Many people may not test if they get sick again after their initial infection has receded, making it hard to track.

That almost happened to Holly Teliska, 42, of San Francisco. Teliska got sick shortly after returning home from a trip to New York. She has a risk factor for severe illness and got access to Paxlovid right away. When she finished her treatment course, she took a home PCR test that was negative and felt much better, though remained fatigued.

Four days later, she came down with a runny nose and cough. She assumed she had caught her daughter’s cold and powered through. Five days later, with plans to visit an immunocompromised friend, she took a test.

Teliska almost felt silly testing herself. She had been vaccinated and boosted, then infected.

“We’ve been saying I’m her safest friend now, now that I’ve had covid, so for three months, I can go spend time with her pretty safely,” Teliska said. “That really threw that narrative out the window. … This entire experience has been a real reminder there is still so much to learn.”

Paxlovid is new. It only began to be used in December, so reports people share on social media of resurgent illness may be the tip of the iceberg — or might simply reflect the eagerness to learn more about a rare, intriguing outcome.

If such cases turn out to be exceedingly rare, then these case reports may be a sporadic curiosity — something to warn patients could happen. If more common, it could lead to tweaks in treatment regimens.

The mounting anecdotes are compelling to many physicians, but it’s also possible the virus might rarely rebound. Yonatan Grad, an associate professor of immunology and infectious diseases at the Harvard T.H. Chan School of Public Health, has studied the viral loads of NBA players and staff during the course of an infection. That data, he said, shows that viral loads can bounce around.

What’s “exceptionally uncommon,” Grad said, is for the viral load to plunge for a few days to a level that suggests they are negative and then go up again.

Paul Sax, an infectious-diseases specialist at Brigham and Women’s Hospital in Boston, recently shared the story of a patient who became infected and then relapsed after taking Paxlovid. He has heard from lots of colleagues with similar stories. But the anecdotes raise more questions than they answer.

Even if the virus has not been shown to develop resistance to the treatment during a resurgence, that’s doesn’t mean it won’t happen, he points out. Does the treatment knock the virus down so successfully that people aren’t generating a robust immune response? That could have implications for understanding whether being infected acts as a potent booster.

The phenomenon is so new that many doctors aren’t aware of it. Jennifer Charness, a 31-year-old nurse who lives in Brookline, Mass., had the benefit of knowing about her father’s work at the Boston VA.

Charness started sneezing in early April and got a blaringly positive coronavirus test. She has a history of asthma and was prescribed Paxlovid. As she took the drug, she saw her positive test line grow fainter and her symptoms resolve. She swabbed to make sure she was negative before going back to work, as a precaution. Then, two days later, she felt the symptoms come back and tested positive — again.

“I’m so frustrated,” Charness said. “I don’t think I’m going to get very sick. It’s the concern of what does this mean for my viral load, and how contagious am I? And when will I not be contagious? I’m stuck back in my home again.”

Charness’s primary concern is that she doesn’t pose a risk to anyone else. She consulted a doctor via telemedicine Friday. The practice hadn’t heard of any cases like hers and decided to treat it as a reinfection and reset the isolation clock.

“I’m Day 4,” she said. “Or am I Day 13?”