COVID Update: The Pros and Cons of Paxlovid and Legevrio

COVID cases have been trending down for the last several weeks, but hundreds of people are still dying. Paxlovid (nirmatrelvir + ritonavir) has been promoted as a life-saving treatment, especially for older people. Just how effective is it really?

New Study Offers Disappointing Evaluation of Paxlovid Effectiveness:

A new study in JAMA utilizing data from Ontario, Canada, asked whether Paxlovid reduced hospitalizations and deaths from COVID among vaccinated seniors (Feb. 20, 2025). Ontario records in 2022 provided a natural experiment because during that time the province restricted Paxlovid to those over 70 with a positive COVID-19 test.

Comparing those just under the cut-off age to those just over it allowed for a comparison between Paxlovid treatment and a control group. The vast majority of older Ontarians had received at least two COVID shots by that time. Although the rate of Paxlovid prescriptions was twice as high for people over 70, there were no significant differences in hospitalization or mortality rates. The researchers suggest that further randomized controlled trials on Paxlovid’s ability to protect people at high risk are needed.

How Effective Are Paxlovid and Legevrio?

Last year, as COVID cases rose, there was renewed interest in the oral antiviral medications, Paxlovid and Legevrio. A study published in JAMA Network Open (Sept. 21, 2023) revealed that both drugs reduced the likelihood of hospitalization and death in vulnerable patients. Quick refresher: Paxlovid is a combo pill containing nirmatrelvir (which stops SARS-CoV-2 from replicating) plus ritonavir (an anti-HIV drug that boosts blood levels of nirmatrelvir. Legevrio is the brand name for molnupirivir. It works by fooling SARS-CoV-2 into incorporating the drug into its RNA. This leads to multiple mutations that theoretically stop the virus from replicating. More about that in a minute. The good news is that both drugs save lives.

The bad news is that the benefits were lower than the original clinical trials suggested. That may be because the early studies were carried out in patients who had not been vaccinated and had little, if any, natural immunity against COVID-19. They were more vulnerable to the devastating effects of the virus.

More recent data were collected from patients who may have already been infected with the SARS-CoV-2 virus or received at least one vaccination. The researchers conclude, however, that both drugs remain quite helpful in reducing the risk of death from the virus.

Paxlovid Interactions Are Worrisome!

Before anyone takes Paxlovid, it is essential that both the prescriber and dispenser check and then double check to make sure that there are no dangerous drug interactions!

Here is a recent message from a reader:

Q. I had COVID a few months ago. My doctor prescribed Paxlovid.

I was on four kinds of blood pressure medications twice daily. Paxlovid interacted with my pills. As a consequence, my blood pressure dropped so low that I was not able to take three of them. I stuck with just half of my regular beta blocker. Has anyone else had this problem?

 A. No one should ever take this antiviral medicine without having the prescriber and the pharmacist double check on potential drug interactions. Your experience is not unusual because so many medications can interact with this COVID drug.

Paxlovid Rebound Is Real!

There are some worrisome developments with the oral antiviral drugs. Paxlovid rebound appears to be a real phenomenon.

While Paxlovid can lessen symptoms and speed recovery, the most important contribution of the drug is in keeping people out of the hospital or morgue. The rebound phenomenon occurs when people appear to be recovering and test negative for COVID. Then it comes back!

Researchers don’t know the actual incidence of this problem, but some patients experience a resurgence of symptoms that may last as long as a week or more. While symptoms seem to be milder than during the original infection, people may still be contagious during the rebound phase of the COVID illness.

The Molnupiravir Mess:

Just when we thought that both Paxlovid and Legevrio were going to escape controversy, a report emerged suggestive that molnupiravir might lead to SARS-CoV-2 mutations. Several years ago the renowned geneticist and AIDS researcher, Dr. William Haseltine, warned that molnupiravir could be mutagenic. If the drug led to mutations in the SARS-CoV-2 virus, he cautioned that we might end up with a more virulent variant. Here are links to his 2-part article in Forbes:

“Supercharging New Viral Variants: The Dangers of Molnupiravir (Part 1) (Nov. 1, 2021)

and

Harming Those Who Receive It: The Dangers of Molnupiravir (Part 2) (Nov. 2, 2021)

You can read more a lot more about Paxlovid and Legevrio and Dr. Haseltine’s concerns at this link.

Other virologists have also expressed concerns about mutations to the SARS-CoV-2 virus after exposure to molnupiravir.

The Latest Research on Legevrio:

A study published in Nature (Sept. 25, 2023) confirms that molnupirivir can indeed trigger mutations and that they sometimes show up in other patients. Remember, the way Legevrio works is by causing so many mutations in the virus that it’s not supposed to replicate.

But the researchers discovered that there have been instances where COVID is capable of surviving the antiviral treatment. Then, in its mutated form, it is transmitted to others.

There is no evidence that the new variants are more transmissible or more dangerous than existing infections. And the drug company that markets molnupirivir (Merck) has criticized the research on the grounds that it has not yet been proven the new mutations came from patients treated with Legevrio. Nevertheless, Dr. Haseltine’s warning from 2021 has not been discounted.

Final Words:

We cannot make any final recommendations on Paxlovid and Legevrio other than to say both drugs seem to reduce the likelihood of severe COVID, hospitalization and/or death. For people taking a number of medications that could interact with Paxlovid, Legevrio may be a better option. We have not discovered any new research suggesting that COVID mutations are a big problem with Legevrio. Neither drug should be taken without careful consultation with both a physician and pharmacist!