When US president Joe Biden tested positive for Covid-19 in July, he was prescribed Paxlovid—an antiviral that helps the body fight off the virus. This prescription drug can be taken outside of a hospital, meaning that highly vulnerable people, if infected, can use it at home to stop themselves from developing severe and potentially life-threatening Covid symptoms.

Paxlovid became the world’s first oral Covid antiviral when it was authorized for use by the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare Products Regulatory Agency back in December 2021. With regulators green-lighting the drug less than a year after the first person received it in clinical trials, it has been described as the fastest drug-development project in history.

Since then, Paxlovid has been approved by the European Medicines Agency, and the United Nations struck a deal with manufacturers to produce a generic version of it so that millions of doses can be supplied to low- and middle-income countries, beginning in April 2022.

How Does Paxlovid Work?

Developed by global pharmaceutical giant Pfizer, Paxlovid is a combination therapy, which means it contains two different drugs: nirmatrelvir and ritonavir.

When SARS-CoV-2 infects a cell, it hijacks the cellular machinery to make the proteins it needs to assemble new copies of itself, which allows it to continue spreading inside the body.

Nirmatrelvir is the active antiviral in Paxlovid. It works by targeting an enzyme called Mpro, which is found in many coronaviruses and plays a pivotal role in their ability to reproduce. Nirmatrelvir prevents Mpro from making the active proteins that SARS-CoV-2 needs to replicate. It’s a substance with a bit of history—it was initially developed by Pfizer to combat the original SARS virus back in 2002.

The second drug, ritonavir, is a “boosting agent.” It slows down the rate at which nirmatrelvir is metabolized in the liver, meaning the active antiviral reaches higher concentrations in the body and lasts for longer before being cleared. Ritonavir has previously been used in HIV antiviral therapies to make them more effective.

How Is Paxlovid Taken?

Patients take Paxlovid as three tablets—two 50 mg tablets of nirmatrelvir and one 100 mg tablet of ritonavir—twice daily for five straight days. To be effective at stopping the spread of the virus through the body (and preventing full-blown Covid from developing), Paxlovid has to be taken as soon as possible after someone is infected, and at the very least within the first five days of their symptoms starting.

How Effective Is It?

Paxlovid is currently the most effective oral antiviral available for Covid. In the clinical trial that led to its authorization by regulators, it was found to reduce the risk of hospitalization and death in highly vulnerable Covid patients by 89 percent.

However, in less severe scenarios it hasn’t been found to be as effective. When Pfizer examined whether Paxlovid could help prevent infections in people who had been exposed to a symptomatic household contact within the last four days, the results weren’t statistically significant—meaning there wasn’t a big enough difference between the outcomes of those who had and had not received the drug to tell if it was making a difference.

Hopes that it could be useful for treating people with mild illness have also proved unfounded. In June, a trial of Paxlovid’s effects in standard-risk Covid patients was ended when the treatment failed to significantly relieve the symptoms of those participating.

Paxlovid’s usefulness is in protecting at-risk people from experiencing the very worst effects of Covid—it isn’t used to stop people from developing symptoms altogether, nor to block an infection after someone has been exposed.

Does It Work Against the Newer Variants?

It appears so. In February 2022, Pfizer reported that nirmatrelvir was effective in halting the activity of Mpro across the Alpha, Beta, Delta, Gamma, Lambda, and Omicron variants of SARS-CoV-2, as well as the original viral strain.

Studies in cultured monkey cells conducted by independent researchers at the University of Tokyo also suggest that nirmatrelvir can curb activity of the BA.5 subvariant of Omicron, which is what has been driving infections in recent months.

Who Can Get It?

In the UK and the US, Paxlovid is authorized for people older than 12 years old, weighing more than 40 kg (88 pounds), who if they get Covid are classed as being at a high risk of developing severe symptoms, being admitted to hospital, or dying. They need, though, to have only mild or moderate Covid symptoms and to not have been hospitalized because of their current infection.

People classified as being at high risk from Covid include those who are over 65 as well as people with underlying health conditions, such as HIV, chronic kidney disease, various autoimmune conditions, Down’s syndrome, sickle cell disease, certain types of cancer, and diabetes. Organ transplant patients are also categorized as being at high risk.

How Do I Access Paxlovid?

This will differ depending on where you live. In the US, if you test positive and think you are eligible for Paxlovid, contact your health care provider. Alternatively, you can go to a Test-to-Treat site, where a state-licensed pharmacist can prescribe the drug to you if you are eligible. Remember to check beforehand what documentation you need to take to these sites.

In the UK, if you think you have Covid and are eligible for Paxlovid, take a test and report your result online. If the result is positive and you are eligible for the treatment, the NHS will contact you about receiving it. If you think you are eligible but don’t receive a call from the NHS, contact your GP, or call 111.

If prescribed in the UK, the pills can be posted to you or picked up for you by a friend, relative, or volunteer. However, it’s worth noting that patients in the UK who meet the eligibility criteria have reported difficulties accessing the drug in time from their local Covid medicines delivery unit.

If you live elsewhere, check the website of your country’s health provider for what to do or contact your GP.

What Is “Paxlovid Rebound”?

This phrase describes when someone appears to have recovered from Covid after taking the drug, tests negative, but then a few days later tests positive again or experiences a second round of the disease. This appears to have happened to both President Biden and Anthony Fauci, the US’s chief medical adviser.

Rebound symptoms tend to be mild, and rebounding doesn’t appear to be very common, though research into the phenomenon is still at an early stage. One initial study—which is in preprint, so its results are still awaiting a formal review by independent researchers—examined 11,000 people who had received Paxlovid and found that seven days after treatment, 3.5 percent of participants rebounded to test positive again, with 2.3 percent seeing their symptoms return. After 30 days, 5.4 percent were testing positive again and 5.9 percent had symptoms.

What Causes Covid to Rebound?

Scientists don’t understand why rebounding occurs, but it is not specific to Paxlovid—it also occurs in some Covid patients who have not received any treatment. Another recent preprint study by infectious disease experts at UC San Diego looked at 568 Covid patients and found that 27 percent of them experienced rebounding symptoms.

One theory for why it happens with Paxlovid relates to how the drug works. Paxlovid does not kill the virus, it merely prevents it from replicating, so it may be that a five-day course does not always give enough time for the immune system to gear up and eradicate the virus from the body. After the Paxlovid has cleared, it may be that remnants of the virus from the initial infection then start reproducing again.

Another possibility is that rebounding occurs in some people because they don’t take Paxlovid as prescribed.

What Should I Do If I Experience Paxlovid Rebound?

If you test positive again or find that your Covid symptoms return, you may again be at risk of passing the virus on to others, so take steps to minimize this risk.

In the US, for example, the Centers for Disease Control and Prevention recommend you isolate for at least five days after your rebound starts—you can end your re-isolation after you’ve experienced five days without a fever, even if you are still testing positive, though you should wear a mask for 10 days following the start of your rebounding symptoms.

Is Paxlovid at Risk of Becoming Less Effective?

While there’s no evidence that Paxlovid rebound is a consequence of the virus developing resistance against the treatment, some scientists believe it is “a matter of time” before this happens.

A series of preprints from virologists at KU Leuven, the University of Copenhagen, and Rutgers University have demonstrated that the coronavirus can mutate in ways that make it less susceptible to nirmatrelvir, the substance that hinders the virus’s ability to reproduce. These studies simulate plausible conditions in the real world where the virus could have a good opportunity to mutate, such as in an immunocompromised patient who has trouble ridding their body of the virus, or an infected person who does not complete their full course of Paxlovid.

In each of these cases, virologists have found that SARS-CoV-2 appears capable of accumulating mutations in the amino acid chains that make up Mpro, enabling it to continue replicating despite the presence of nirmatrelvir.

Some predict that as Paxlovid prescriptions rise, this will increase selective pressure on the virus, by giving it more opportunities to test out mutations that could help it survive in the presence of the drug.

If the virus does develop resistance to Paxlovid, the drug could still have a future as part of a combination therapy with other antivirals. This idea has yet to receive widespread consideration, but should be kept in mind if needed.