Paxlovid has seen a huge increase in prescriptions recently. It is good news for COVID-19 patients that the pill has been shown to reduce severe disease from the coronaviruses. The most widely used of the two oral antiviral drugs authorized to treat COVID-19 is due to the fact that the coronaviruses can change in ways that make them less susceptible to the drug. Concerns have been raised that one of the best therapies for fighting COVID-19 could soon be lost after researchers found some of theVariants already circulating in people with the disease.
David Ho, a researcher at Columbia University who was one of the first to document drug resistance in HIV, says that the studies show that when you put pressure on the virus it escapes. Ho is doing similar work to the ones done on the new studies. Ho and many other scientists think it is only a matter of time before the newly identified genes are widely used. It is going to come given the amount of infections out there.
Paxlovid is restricted in the United States to people with risk factors, which makes them more likely to develop severe COVID-19. A small percentage of people who receive the normal 5-day course initially feel better, only to have their symptoms come back. Paxlovid was stopped from being used in a large trial because it did not show statistically significant protection against death or hospitalization.
Emergency use authorization for Paxlovid was granted by the FDA. ritonavir slows the breakdown of nirmatrelvir in the body and is part of the drug. Doctors in the United States issued less than 40,000 prescriptions for Paxlovid through April because of manufacturing problems. According to the latest numbers from the Centers for Disease Control and Prevention, prescriptions have more than doubled since then.
The rise causes the virus to be more resistant to the drug. Each person makes trillions of copies of the same strain of the virus.
Paxlovid's effectiveness doesn't seem to have been affected by those genes. An essential step in the reproduction of SARS- CoV-2 is the cutting of a long precursor molecule by the main protease. In February, Pfizer researchers reported in JBC Accelerated Communications that nirmatrelvir remained effective in stopping the activity of M PRO in multiple strains.
The recent studies show that the virus is poised to develop resistance. On 7 June, two preprints were posted on bioRxiv, showing that the lab-grown SARS-coV-2 is able to avoid the attack of nirmatrel. Some but not all of the coronaviruses were killed by two groups of researchers. The tests are meant to show what might happen to a patient if they don't take the full regimen of the drug.
One of those studies, led by Dirk Jochmans, a virologist at KU Leuven in Belgium, found that after 12 rounds of nirmatrelvir treatment, SARS- CoV-2 accumulated three mutations. Potential resistance-conferring mutations at positions 50 and 166 were found in the other study. The virus was 80 times less susceptible to nirmatrel. The information tells us what to look for in patients.
Adam Godzik, a bioinformatics expert at the University of California, Riverside, claims that some of the coronaviruses are already present in people. Godzik and his colleagues searched the database for changes in the M PRO near where nirmatrel interacts with the coronaviruses. Two of the resistance mutations flagged by the Belgian group were already in the viruses that were circulating in people. Godzik says they are likely to have happened randomly because they occurred before Paxlovid was widely used. He says that the virus could be helped by the flexibility of theidase at these positions.
There is a list of potential resistance changes. In a paper posted yesterday on bioRxiv, Jun Wang, a Medicinal chemist at Rutgers University and colleagues report 66 common mutations to M PRO. They scanned the database and found altered versions of the protease, but went a step further. Adding the genes for each variant of M PRO to Escherichia coli allowed them to create supplies of the enzymes for additional tests, first to determine whether each variant still carried out the essential duties of cutting viral proteins, and second to determine whether themutations allowed M PRO to resist nirmatrel One of the 11 that retained the function of the protease was resistant to nirmatrel, requiring at least a 10-fold increase in the drug to kill half the virus. At position 166, one of the variants had a resistancemutation, but the other four had novel workarounds. Wang says that it's just a matter of time before resistance emerges.
Why hasn't it happened yet? There is a chance that not enough people have taken Paxlovid. Wang says that it may take multiple changes in M PRO for the virus to be able to get around Paxlovid. The studies show that patients who have a rebound of symptoms, which happens in 2% or less of those who take the drug, don't seem to be due to resistance. Shah isn't sure if the virus won't find its way around the drug.
Pfizer's Paxlovid regimen may be able to prevent resistance. Patients only take the drug for a short period and typically get a dose manyfold higher than that required to prevent the virus from replicating in cells.
Giving patients multiple antivirals could help prevent resistance by making it harder for the virus to evolve its way around different compounds at the same time. There are two other antivirals authorized in the US. The other oral drug, molnupiravir, has been shown to be less effective than Paxlovid, and has raised safety concerns because it can cause dangerous new strains of the virus. It is only authorized for hospitalized patients and can only be delivered via IV. According to a preprint posted on bioRxiv yesterday, combining molnupiravir and nirmatrelvir is more effective than either of the two antivirals alone. The strategy hasn't been popular with doctors.
More than one company is racing to complete clinical trials on more than one drug at the same time. Those are not available right now. Pfizer has been accused of not making Paxlovid easily available for trials of combination therapies. Some are skeptical of the company's plans to do those studies on its own.
Paxlovid will remain alone until more drugs are available, raising fears that it will lose its punch in the future. Viruses can find a way around a single antiviral. It will happen, if it can happen. The lab results show that it can happen.
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