As Covid-19 pills roll out, concerns are growing that resistance may develop

Still, viruses are notorious for mutating in ways that allow them to bypass antiviral drugs, especially when the drugs are given alone, as is the case with the new Covid-19 pills.

This is why treatments for other viruses such as HIV and hepatitis C consist of several drugs. Combinations reduce the risk of resistance due to mutations because a virus is forced to do more to survive.

The Covid-19 pills promise to keep people out of the hospital and slow down the spread of coronavirus, but resistance could jeopardize drug use and backfire as businesses and schools push to stay open.

“We know this is likely to happen at some point, so we have to hit it to the tip and nip it in the bud before it runs out of hand and starts taking over,” said Katherine Seley-Radtke, a medic -chemistry professor at the University of Maryland, Baltimore County, whose laboratory studies antiviral combination therapies.

However, some researchers and drug manufacturers say that the risk of developing resistance to the new Covid-19 pills is low because they are taken over just five days, too short a time for the virus to change meaningfully.

HIV is more likely to develop resistance to treatment consisting of a single drug, the researchers say, because it is more prone to mutations when it replicates than the pandemic coronavirus. Another factor: the course of treatment is much longer for a chronic disease than an acute infection.

Pfizer and Merck researchers said they did not see resistance develop during the clinical trials that evaluated the pills. The company’s researchers also said that each of the pills has properties that reduce the risk of resistance, even if they are looking for signs.

Viruses are pieces of genetic code wrapped in protein clothing. They can only survive and thrive by infecting cells whose machinery they hijack to replicate and spread.

Since a virus makes copies of itself, it can mutate to avoid treatments that seek to eliminate it. The genetic changes tend to occur while the virus is replicating early in the course of the disease, which is also when antiviral drugs are usually most effective.

The Food and Drug Administration asked Pfizer and Merck-Ridgeback to monitor for resistance and submit monthly reports on their results as a condition of approving the new pills.

The FDA also said it may require drug manufacturers to assess whether their drugs hold up to any variant of interest and to provide drug samples to the government for its own evaluations.

“As with any virus for which SARS-CoV-2 is no exception, there is a potential for the emergence of resistance that may affect existing treatments,” the agency said. “As such, the FDA put mechanisms in place as part of the approvals to help the agency understand the potential effect of variants on these products.”

Independent researchers say the pandemic virus may be more likely to develop resistance to Paxlovid than to molnupiravir because of the different ways the pills work to prevent the virus from replicating.

Paxlovid, known under its trademark, stops the virus by blocking an enzyme – called protease – involved in replication.

Molnupiravir, which is in another class of antiviral agents, prevents the virus from multiplying by tricking an enzyme that it has to replicate, called polymerase, into inserting defects in the genome of the coronavirus, thereby short-circuiting the process.

Molnupiravir’s structure, which resembles genetic molecules, is more difficult for the virus to deal with, said Dr. Seley-Radtke.

Viruses have developed resistance to both types of drugs, say independent researchers, although it may take longer to emerge for the class of molnupiravir.

“I’ve been in the antiviral field for 35 years and there’s no drug that I know of that is resistant,” said John Mellors, a specialist in infectious diseases at the University of Pittsburgh.

Using a combination of drugs can help ward off the virus’ attempts to break through and avoid treatment by attacking the virus at various stages in its efforts to replicate.

“See it as Swiss cheese,” said Carl Dieffenbach, director of the AIDS division at the National Institute of Allergy and Infectious Disease, which works with Covid-19 antiviral development. “Swiss cheese has holes in it, and if you had overlapping slices of Swiss cheese, nothing could penetrate.”

The National Institutes of Health wants to test combination therapies for Covid-19 when a range of drug options are available, said Dr. Dieffenbach.

Pfizer is working on potential new Covid-19 antiviral drugs and trying to see which combinations may work if necessary, said Annaliesa Anderson, who led Pfizer’s research into Paxlovid.

Research from the company published last year in the journal Nature showed that an infused version of Paxlovid worked well with remdesivir, an antiviral drug from Gilead Sciences Inc.

currently approved for use in inpatients.

“So far we do not see anything that worries us, but we continue to look for, you know, if there is an Achilles’ heel within the strategy we have,” said Dr. Anderson.

Merck is looking at combining molnupiravir with other drugs, including remdesivir, also known as Veklury, said Daria Hazuda, Merck’s vice president of infectious disease detection.

This combination would be attractive, said Dr. Hazuda because resistance mutations associated with Veklury are more susceptible to molnupiravir, making it more effective.

Veklury has just been approved for use in non-hospitalized patients. Still, it would be difficult for people to take molnupiravir at home because it is given as an infusion over three days.

An oral version of Veklury will begin early testing phases this quarter, but even if trials prove successful, it will not be available until next year at the earliest, Gilead CEO Daniel O’Day said.

Merck researchers have not looked at whether molnupiravir could work safely with Paxlovid, although the drugmaker is also developing its own protease inhibitor, said Dr. Hazuda.

“I always say we should never bet against the virus,” she said.

There may eventually be several antiviral drugs that can be tested in combination with either Paxlovid or molnupiravir, including one from Shionogi & Co., which the Japanese company says may soon start a late stage and get results later this year.

The Biden administration is investing $ 3 billion in the development and manufacture of antiviral Covid-19.

There are 18 Covid-19 trials aimed at enrolling more than 100 people to test combinations of antiviral drugs, none involving Paxlovid or molnupiravir, according to a January 7 analysis by Airfinity in London.

—Joseph Walker contributed to this article.

Write to Jared S. Hopkins at jared.hopkins@wsj.com and Felicia Schwartz at felicia.schwartz@wsj.com