Yale Researchers Discover Possible ‘Brain Fog’ Treatment for COVID-19

[Originally published: March 10, 2022. Updated: August 11, 2022] 

Note: Information in this article was accurate at the time of original publication. Because information about COVID-19 changes rapidly, we encourage you to visit the websites of the Centers for Disease Control & Prevention (CDC), World Health Organization (WHO), and your state and local government for the latest information.

Paxlovid is the latest COVID-19 treatment that’s been all over the news. The drug was granted an emergency use authorization (EUA) by the Food and Drug Administration (FDA) in December for anyone ages 12 and older who weighs at least 88 pounds, and is at high risk for severe disease. 

Paxlovid is an oral antiviral pill that can be taken at home to help keep high-risk patients from getting so sick that they need to be hospitalized. So, if you test positive for the coronavirus and you are eligible to take the pills, you can take them at home and lower your risk of going to the hospital. 

The drug, developed by Pfizer, has a lot of positives: It had an 89% reduction in the risk of hospitalization and death in the clinical trial that supported the EUA, a number that was high enough to prompt the National Institutes of Health (NIH) to prioritize it over other COVID-19 treatments; and it’s cheaper than many other COVID-19 drugs (it’s provided for free by the U.S. government while there is a public health emergency); and, perhaps most reassuring, it is expected to work against the Omicron variant.

“I think it is the beginning of a ‘game-changer,’” says Scott Roberts, MD, a Yale Medicine infectious diseases specialist. “It's really our first efficacious oral antiviral pill for this virus. It shows clear benefit, and it really can prevent hospitalization and death in people who are at high risk.”

It’s important to note that Paxlovid (the brand name for the drug, which is made up of two generic medications—nirmatrelvir and ritonavir) isn’t the only pill available to treat COVID-19. The FDA also granted an EUA in December to a pill from Merck called molnupiravir (Lagevrio), but some studies suggest that molnupiravir has only a 30% reduction in the risk for hospitalization and death from COVID-19. 

And as far as convenience, this medication is considered an improvement over treatments like remdesivir (approved by the FDA in October 2020), which is administered by intravenous (IV) injection.

We asked Yale Medicine infectious diseases experts common questions about Paxlovid. Below are their responses.

Paxlovid is an antiviral therapy that consists of two separate medications packaged together. When you take your three-pill dose, two of those pills will be nirmatrelvir, which inhibits a key enzyme that the COVID virus requires in order to make functional virus particles. After nirmatrelvir treatment, the COVID virus that is released from the cells is no longer able to enter uninfected cells in the body, which, in turn, stops the infection. The other is ritonavir, a drug that was once used to treat HIV/AIDS but is now used to boost levels of antiviral medicines. 

As a COVID-19 treatment, ritonavir essentially shuts down nirmatrelvir’s metabolism in the liver, so that it doesn’t move out of your body as quickly, which means it can work longer—giving it a boost to help fight the infection.

You have to take Paxlovid within five days of developing symptoms.

Like all antivirals, Paxlovid works best early in the course of an illness—in this case, within the first five days of symptom onset, says Jeffrey Topal, MD, a Yale Medicine infectious diseases specialist who is involved in determining COVID-19 treatment protocols for Yale New Haven Hospital patients.

“Once you’ve been ill with the virus for more than a week, the damage done to the body in a severe case can’t be undone by the antiviral,” he says.

You take three Paxlovid pills twice daily for five days for a full course that adds up to 30 pills. It helps that the pills are packaged in a “dose card,” basically a medication blister pack that allows you to punch out the pills as needed. 

“I think it's a good comparison,” says Dr. Roberts. Tamiflu is an antiviral drug that reduces flu symptoms. Both are prescription-only oral antiviral pills given early in illness.

Tamiflu is taken twice a day for five days, and it must be started within 48 hours of flu onset. “When you give a patient Tamiflu beyond that, it doesn’t really change the course of their flu,” Dr. Roberts says.

But there are also differences between the two, starting with the way they were studied, Dr. Topal adds. Researchers showed that Paxlovid can prevent hospitalization and death. But since influenza causes fewer severe cases, clinical trials focused on whether Tamiflu could shorten the length of flu illness—which it did, he says.

The FDA authorized Paxlovid for people ages 12 and older who weigh at least 88 pounds. But in order to qualify for a prescription, you must also have had a positive COVID-19 test result and be at high risk for developing severe COVID-19. 

That means you must either have certain underlying conditions (including cancer, diabetes, obesity, or others) or be 65 or older (more than 81% of COVID-19 deaths occur in in this group). The more underlying medical conditions a person has, the higher their risk for developing a severe case of COVID-19, according to the CDC.

The hope is that the restrictions on who can take Paxlovid will be relaxed over time. The FDA granted the EUA in December, just as a staggering number of people were infected with Omicron and the need for care skyrocketed, leading to supply issues.

If you are pregnant or breastfeeding, the FDA recommends discussing your options and specific situation with your health care provider, since there is no experience using the drug in these populations. If you could become pregnant, it’s recommended that you use effective barrier contraception or do not have sexual activity while taking Paxlovid. 

It’s important to note that although health care providers can write a prescription, pharmacists may also provide Paxlovid (with certain limitations) if they’ve opted to do so, provided you can share your electronic or printed medical records, including a list of medications you are already taking, and blood test results from the last 12 months.

When it applied for FDA authorization, Pfizer presented data from a clinical trial conducted between mid-July and early December in 2021. The data showed that participants (all of whom were unvaccinated) who were given Paxlovid were 89% less likely to develop severe illness and death compared to trial participants who received a placebo. (While the recommendation is to take Paxlovid within five days of symptom onset, participants in the clinical trial took the drug within three days.)

Scientists will continue to study the drug’s effectiveness as it is used to treat patients in the real world.

Pfizer launched a clinical trial in March to study the safety and efficacy of Paxlovid in children and teenagers ages 6 to 17 who have COVID-19 symptoms and test positive for the virus, and who are neither hospitalized nor at risk for severe disease.

While Paxlovid is authorized for use in adolescents and teenagers ages 12 and up, and weighing at least 88 pounds, that age group wasn’t tested in the original clinical trial. But because many children reach 88 pounds—considered to be an adult weight—the FDA has allowed extensions of EUAs for medications such as monoclonal antibodies and remdesivir in younger age groups, adds Dr. Topal.

“Based on the pharmacokinetics of the drugs in Paxlovid, the differences in metabolism and excretion—liver and kidney function specifically—of these drugs in this age group are thought to be similar to that of adults,” Dr. Topal says.

Paxlovid’s clinical trials took place before Omicron and later subvariants like BA.5 became predominant, but Pfizer says the drug works against the highly contagious variant. Three laboratory-based studies claim to back this up—two of those studies were conducted by Pfizer, while the third was done by Pfizer in partnership with the Icahn School of Medicine at Mount Sinai. These studies have not yet been published in peer-reviewed medical journals.

Most people who take Paxlovid should not experience serious side effects, explains Dr. Roberts. “Paxlovid is usually very well-tolerated,” he says. 

But people should stop taking Paxlovid and call a health care provider right away if they experience any of the following signs of an allergic reaction:

• hives
• trouble swallowing or breathing
• swelling of the mouth, lips, or face
• throat tightness
• hoarseness
• skin rash

Other possible side effects include:

• an altered or impaired sense of taste
• diarrhea
• increased blood pressure
• muscle aches
• abdominal pain
• nausea
• feeling generally unwell

Since Paxlovid is cleared by the kidneys, dose adjustments may be required for patients with mild-to-moderate kidney disease, explains Dr. Topal. “For patients with severe kidney disease—or who are on dialysis—or those with severe liver disease, Paxlovid is not recommended; the levels of the drug can become too high and could cause increased side effects,” he says. 

The FDA says that anyone who takes Paxlovid should contact their health provider right away if they have any signs and symptoms of liver problems: loss of appetite, yellowing of the skin and whites of the eyes (jaundice), dark-colored urine, pale-colored stools and itchy skin, or stomach-area (abdominal) pain.

It’s worth noting that because Paxlovid is still being monitored in the real world, it is possible that all of the risks are not yet known. (The FDA has provided a fact sheet on Paxlovid with a full list of known side effects.)

There is a long list of medications Paxlovid may interact with, and in some cases, doctors may not prescribe Paxlovid because these interactions may cause serious complications.

The list of drugs that Paxlovid interacts with includes some organ anti-rejection drugs that transplant patients take, as well as more common drugs like some used to treat heart arrhythmias. Paxlovid also decreases the metabolism of anticoagulants, or blood thinners, that many older adults depend on, driving up levels of those medications in the body to a point where they are unsafe, Dr. Topal explains.

It also interacts with cholesterol-lowering medications like Lipitor, but that’s less challenging for patients to overcome. “If you stop taking your Lipitor for five days, nothing bad is going to happen,” he adds.

There have been reports of a “rebound” of COVID-19 symptoms in some people within 2 to 8 days after completing the five-day course of Paxlovid; in those cases, some have tested positive again but have no symptoms; others have a recurrence of symptoms. Pfizer had said that in the clinical trial for Paxlovid, several participants appeared to have a rebound in virus levels, although this also occurred in some people who were given a placebo.  

Scientists are still studying the Paxlovid rebound. The CDC says a rebound does not mean a person was resistant to Paxlovid, nor does it mean they were reinfected with the virus. In June, the CDC released guidance for clinicians, saying a brief return of symptoms may be part of the natural history of SARS-CoV-2 infection in some people, independent of treatment with Paxlovid, adding that there is no evidence additional treatment is needed. A CDC study reported that rebound symptoms tended to be unlikely to require hospitalization and milder than symptoms experienced during the primary infection.

“The hypothesis is that the immune system didn’t have a chance to see the full extent of the virus, since Paxlovid suppressed replication early in disease,” Dr. Roberts says. Scientists are studying the effects of longer treatment durations, longer periods of isolation, and other ways of managing the problem, he adds.

 For anyone who experiences a rebound, the CDC advises people “restart isolation” for five days, following its isolation guidance. Pfizer recommends reporting it to them on its portal for adverse events associated with Paxlovid.

There are other therapies for COVID-19, and anyone who cannot take Paxlovid—perhaps because it would interact with another medication—should talk to their doctor about the best approach for their situation.

Vaccination, testing, and mitigation efforts such as masking, remain a key part of prevention, even as more drugs become available, says Dr. Topal. 

“Early testing is key to making these drugs work,” he says. “It’s always been the Achilles’ heel of these antiviral drugs that most people don’t get tested—or they don’t have access to testing.”

He encourages taking a test even if you think you only have a cold or allergies—and if you can get one. “Home testing is a huge part of the way to really ‘operationalize’ these medications,” he says, adding that while home tests may not be as highly sensitive as the laboratory-based polymerase chain reaction (PCR) tests, they are still very helpful in making a diagnosis.

Dr. Topal says people also should remember that Paxlovid, even with its high efficacy, is not perfect, and even if it were, viruses can mutate and develop resistance to antiviral medications. “Will some people still be hospitalized? Yes—no medication is perfect,” he says. “But for many high-risk patients, this medication can really reduce that risk.”

If you are experiencing symptoms of COVID-19 and think you are eligible for a treatment, you can visit the government Test-to-Treat Locater. You can use the site to search for the places near you where you can fill a COVID-19 prescription, or identify sites that provide testing, medical care, and COVID-19 medications. 

Information provided in Yale Medicine articles is for general informational purposes only. No content in the articles should ever be used as a substitute for medical advice from your doctor or other qualified clinician. Always seek the individual advice of your health care provider with any questions you have regarding a medical condition.