Anti-Covid Remedies May Generate Resistant Variants, Scientists Warn

The anti-Covid pill from MSD (company known as Merck in the US and Canada) was the first oral drug approved to fight the Sars-CoV-2 virus in the world in early November.

Known as molnupiravir, the antiviral drug was effective in preliminary studies of a 50% reduction in hospitalization and death, a number that later dropped to 30% after new data was evaluated by the company on 26 November.

Even so, a panel of the FDA (the American agency that regulates drugs and food products in the country) recommended in a fierce vote —13 votes in favor and ten against — the emergency authorization of the pill on the last 30th. The panel’s recommendation is not definitive. , but serves as a guideline for the agency to approve the registration of the drug.

In Brazil, the laboratory made an emergency use request to Anvisa (National Health Surveillance Agency) at the end of November. The agency has yet to make a decision.

According to experts, the benefits of using the Covid-19 pill against death, especially against new variants of the virus, such as omicron, outweigh its risks. Among them are that of generating mutations in Sars-CoV-2 that can lead to the appearance of resistant strains with more aggressive potential.

Questions about the likelihood that these forms are perhaps a greater risk than previously thought, however, have been raised by some experts.

The first of them was virologist William Haseltine, a former researcher at Harvard University in the United States, known for his work on HIV. In an interview with Forbes magazine, the scientist said he was “deeply concerned about the new strains”.

Recently, another scientist raising the alert was evolutionist and University of Washington professor Carl Bergstrom. In his Twitter account, the researcher hypothesized that the large-scale use of the MSD pill could cause more risks to the population than benefits to those who use the therapy.

Doubts hover over the drug’s mechanism of action: molnupiravir acts by binding to the RNA of Sars-CoV-2 with an amino acid [parte de uma proteína] exchanged, which causes copy errors and prevents replication. However, precisely because it is a kind of “changed key” of the genome, the drug is mutagenic, that is, it can generate mutations in the virus.

“It does induce copying errors in Sars-CoV-2, but a point to make is that we haven’t observed so far a very high number of changes in the viral genome, so maybe the frequency is too low. But of course there are. this possibility needs to be monitored”, explains Fernando Spilki, virologist and coordinator of the Corona-omics Network, an initiative of the Ministry of Science, Technology and Innovation to observe the evolution of the coronavirus in Brazil.

Because some of these errors lead to forms of the virus that are unviable, the concern that such mutants might be selected by evolutionary pressure and “spread” is minor, though not non-existent.

“All this is still in the field of hypotheses, it is not possible to predict which mutations will emerge and whether there will be selection mechanisms, but some examples in the past show viruses acquiring resistance due to the prolonged use of drugs”, he says.

Spilki cites the case of the antiviral oseltamivir, tested against the H1N1 virus and marketed under the name Tamiflu. Its indiscriminate use led to the emergence of resistant strains.

“Any runny nose, the person would go there and take oseltamivir, so in a matter of months there were samples resistant to the drug, but if there is a correct use, with medical supervision, the risk is negligible”, he says.

For Esper Kallás, infectologist and professor at the Faculty of Medicine at USP, the period of use of the drug, right at the beginning of the infection and for very specific cases in which there is a risk of progression to an aggravated condition of Covid, should make this selective pressure difficult.

“The use of any antiviral will indeed have a small chance of causing mutations, but the biggest concern is when there is a prolonged period of exposure to the drug, because, then yes, the virus can suffer an evolutionary pressure and perpetuate itself”, he explains , who is a columnist for leaf.

As mutations occur randomly, natural selection will only act in those ways that represent some kind of adaptive advantage —because it manages to evade the drug’s mechanism of action or the organism’s defense, for example— or else in the so-called “base selection “.

“It is these mutations that end up being selected together with others that would have an advantage, but this occurs mainly in immunocompromised patients or those who have a chronic infection, and then the selection is no longer related to the use of the drug, but rather with the time of virus replication in the organism, which is debilitated”, he says.

In a note sent to the report, MSD Brasil did not comment on the possibility of resistant strains appearing with the use of the drug. The company highlighted that molnupirvir works by preventing virus replication and has shown consistent clinical efficacy against several variants.

Another antiviral drug used and approved in the treatment of Covid, remdesivir, so far, has not shown the emergence of resistant strains. “However, its use is much more restricted, in hospitals, and it is not as widespread”, explains Spilki.

For specialists, however, the recommendation of treatment with molnupiravir, two pills a day for five days, reduces the risk of occurrence of selective pressure precisely because, at the end of up to four days, the viral load in the body tends to be very low.

“The problem is when there is interruption of treatment or non-adherence to treatment, in these cases, there can be the selection of resistant forms, but from there to leave the field of the individual and spread to the community is a leap of belief” , evaluates Kallás.

In any case, it will be necessary to carry out constant monitoring and sequencing to identify mutations early on, emphasizes Spilki.

“The main question is at what speed or frequency this can occur. If it is as low as the occurrence, for example, of rare clots after the injection of some vaccines against Covid, from 1 to 250,000 cases, still the benefit of use drug outweighs the risks,” says the virologist.