默克公司的 COVID 抗病毒药物Molnupiravir可能会导致病毒突变




由美国默克公司开发的抗冠状病毒药物Molnupiravir (Lagevrio)通过打乱病毒的遗传密码来阻止COVID-19病毒的复制。但是,近期一项于1月份发表在medRxiv预印本服务器上的研究,在建立1300多万个COVID-19基因组序列的全球数据库后,筛查发现了带有Molnupiravir相关突变的遗传足迹,这表明接受Molnupiravir治疗的人体内的突变病毒不仅可以存活,而且可以传播。


科学家推测,COVID-19变体会在免疫功能低下的人群中自然产生。一般来说,免疫系统受损的人可能更难以清除病毒感染,这可能会使 COVID-19病毒在人体内长时间停留,从而为其进化和复制提供更多时间。研究人员表示,Molnupiravir这种常用的抗病毒药物将“增强”免疫功能低下患者体内的病毒进化,这也将可能导致产生新的变异并延长大流行。


Merck's COVID Antiviral Drug Might Be Spurring New Variants


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Key Takeaways

  1. Molnupiravir, the antiviral by Merck, spurs mutations in the COVID-19 virus to stop it from replicating.
  2. Researchers found signatures of the drug in mutated COVID-19 sequences from people in countries where the drug is widely used.
  3. The research shows that molnupiravir-associated variants can spread, but it’s not yet clear how much of a concern this is.
  4. Some scientists are now calling for the drug to be discontinued.


One of the last remaining COVID-19 antivirals may be spawning new variants.


The widely used antiviral molnupiravir (Lagevrio) is designed to stop the COVID-19 virus from replicating by jumbling the virus’s genetic code. Researchers now have new evidence that mutated viruses in molnupiravir-treated people are not only viable, but also transmissible.


In a preprint study published in January, a team of British researchers surveyed a global database of more than 13 million COVID-19 genome sequences. They found the genetic footprint of molnupiravir-associated mutations in clusters of cases, indicating these mutants are transmissible. The research has not yet been peer-reviewed.


“A major reason to consider these effects is to judge whether there is a risk to wider public health from any potentially increased rate of SARS-CoV-2 evolution,” Theo Sanderson, PhD, a researcher at the Francis Crick Institute in London and a lead author of the study, told Verywell in an email.


There’s no data yet on whether these variants are more transmissible or pathogenic than prior variants. There’s also no indication that molnupiravir is dangerous for individuals who take it. But the findings raise questions about whether molnupiravir should remain in use.


“We’re mutanizing a virus which we know can rapidly change its fundamental characteristics—its infectivity, its immune suppression, its latency, its ability to evade our best vaccines,” William Haseltine, PhD, a virologist and president of ACCESS Health International, told Verywell.


“It seems to be foolish, in the absence of a convincing argument that this is something we absolutely need, to continue to manufacture, to distribute, and to approve this drug,” he added.


Are Molnupiravir-associated Variants Transmissible?


Some COVID-19 mutations can give the virus a leg up, as seen in the slew of viral variants that quickly overtake their predecessors. But most mutations are likely to harm the virus.


Molnupiravir works by getting into the virus’s RNA and introducing errors. These mutations build up until the virus can no longer efficiently replicate. This helps reduce the level of COVID-19 virus in the body.


Scientists have long raised the possibility that some people who take molnupiravir may not fully clear the mutated virus from their bodies, giving it the opportunity to transmit to others.


The mutations molnupiravir introduces into the body aren’t random. Rather, specific nucleotides—the basic building blocks of RNA and DNA—tend to switch, creating a traceable signature.


According to the analysis, these signature mutations were 100 times more common in countries where molnupiravir was widely used than in those where it was not. Plus, almost all of these mutants appeared in 2022, soon after countries first started distributing molnupiravir.


In tracing these lineages in the countries that widely distribute the drug, the researchers found clusters of COVID-19 cases in which people were infected with the same molnupiravir-implicated mutants. The largest was a group of 20 people in Australia. 

“Our data shows clearly that viruses treated with molnupiravir can be transmitted. How much of a cause for concern this is is an open question,” Christopher Ruis, PhD, a post-doctoral researcher at the University of Cambridge, told Verywell in an email.

In a statement to Verywell, Merck minimized the findings, saying, “the authors assume these mutations were associated with molnupiravir treatment without evidence the viral sequences were isolated from treated patients.”


Are The Variants from Molnupiravir Dangerous?


Scientists have theorized that COVID-19 variants of concern can arise naturally in immunocompromised people. In general, people who have compromised immune systems may have more difficulty clearing infections. That may leave the COVID-19 virus to smolder in their bodies, giving more time for it to evolve and replicate.

A 2022 study that has not yet been peer-reviewed reported that five immunocompromised people treated with molnupiravir started producing mutant viruses within days of treatment.


“Our study demonstrates that this commonly used antiviral can ‘supercharge’ viral evolution in immunocompromised patients, potentially generating new variants and prolonging the pandemic,” the authors concluded.


Sanderson said his team didn’t directly study the immune status of individuals in the sequencing databases. But they acknowledge that people treated with molnupiravir often see some reduction in their viral load and may be less likely to harbor chronic disease. It’s possible, the authors say, that variants arising from chronic infection could be more fit than those related to molnupiravir.


He added that it is unlikely molnupiravir contributed to circulating variants. The mutations seen in Omicron variants are not the same as those observed in molnupiravir-associated variants.


“There is a high degree of uncertainty about what could happen in the future,” Sanderson said.


Should You Avoid Using Molnupiravir?


Molnupiravir isn’t a very potent drug to begin with. A large December 2022 study showed that treatment with molnupiravir had no significant effect on whether COVID-19 patients were hospitalized or died.

Haseltine said he sympathizes with doctors who are treating patients who are immunocompromised or otherwise at risk of severe disease because there are few treatment options left. Paxlovid, the only other oral antiviral on the market, continues to be the most efficacious drug option.


“For a drug that is marginally effective at best—and there’s very little data that the drug is effective in treating those people who need it most—I think that the concerns that it could create a new and more dangerous strain out of immune suppressed people is quite real,” he added.


Haseltine emphasized that the U.S. should invest in the development of new drugs to treat COVID-19.


“We don’t have those drugs, and I can’t see the effort anywhere in the world to develop them,” Haseltine said.


This week, researchers announced positive results of a large phase 3 clinical trial testing the efficacy of a new treatment. A shot of the new antiviral, called interferon lambda, prevented 51% of hospitalizations among people who had been vaccinated—a group that hasn’t seen much benefit from other drug options.


 The treatment may not be available here any time soon, however. The FDA rejected the companies’ application for authorization last spring because no arm of the study was conducted in the United States.



Verywell Health

Published on February 13 2023





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