Highlights in this article
Covid-19 has been prevalent for the past couple of years. Although effective vaccines are available and effective in mitigating symptoms of infected people of all generations including children, the medication for infected people was not developed in 2021. The FDA approved a medication called nirmatrelvir developed by Pfizer to treat patients infected with Covid-19. And this has been effective to suppress symptoms. However, this latest research by Dr. David Ho’s group at Columbia University showed the possibility of Covid-19 acquiring resistance to nirmatrelvir. This suggests that we might not combat this virus completely and we might need to keep using the updated vaccine and medications over time, which would be key to protecting our health.
Background
Covid-19 has been a world-wide health crisis for the past years, and although there is no “cure” for the virus yet, there is still much that can be done in terms of treatment and prevention. One of the most important areas of focus when it comes to treating Covid-19 is medication. Medication for Covid-19 can be divided into three categories: antivirals, anti-inflammatories, and immune modulators. Antiviral medications are agents that reduce the ability of the virus to replicate and spread in the body. These medications are used to reduce symptoms, speed up recovery, and may reduce the risk of severe illness. Examples of antiviral medications used to treat Covid-19 include remdesivir and favipiravir. Anti-inflammatory medications are used to reduce inflammation in the body, which can help reduce the severity of symptoms and speed up recovery. Examples of anti-inflammatory medications used to treat Covid-19 include corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). Immune modulators are agents that help to regulate the immune system, which can help improve the body’s ability to fight off the virus. Examples of immune modulators used to treat Covid-19 include interferon and interleukin-6 receptor antagonists. In addition to medications, other treatments for Covid-19 include oxygen therapy, supportive care, and vaccines. Oxygen therapy is used to help maintain adequate levels of oxygen in the blood and can be used to help reduce symptoms of severe illness. Supportive care is used to help manage symptoms and can include things like hydration and nutrition, pain relief, and rest. Vaccines are currently the only way to prevent Covid-19, and there are several different types of vaccines being developed. Overall, there are many different types of medications and treatments available for Covid-19, and it is important to work with your healthcare provider to determine the best treatment plan for you. It is also important to remember that the best way to protect yourself from Covid-19 is to practice social distancing, wear a mask, and get vaccinated when it becomes available to you.
The COVID-19 pandemic has caused great disruption globally, but the development and deployment of vaccines and monoclonal antibody therapeutics has helped to contain its impacts. The virus, however, has evolved to become resistant to antibodies and vaccines, leading to breakthrough infections. In the US, three antivirals have been authorized for use in treating COVID-19: remdesivir, molnupiravir, and nirmatrelvir. These drugs target the RdRp and 3CL protease, respectively, which are essential for the viral life cycle. In vitro and in vivo studies have shown that remdesivir can develop resistance, and that resistance to molnupiravir and nirmatrelvir is currently under investigation. This study found that there are multiple pathways by which SARS-CoV-2 can gain resistance to nirmatrelvir in vitro.
Discovery
Nirmatrelvir, an oral antiviral drug targeting the 3CL protease of SARS-CoV-2, has been demonstrated to be clinically useful against COVID-19. This study examined the potential for the virus to develop resistance to the drug. Through two independent approaches, including one on a large scale, highly resistant viruses emerged with mutations observed at 23 different residues of the enzyme. Common mutational pathways to nirmatrelvir resistance were observed, with a majority of the viruses descending from T21I, P252L or T304I as precursor mutations. Although some of the mutations caused low-level resistance, stronger resistance was found to require additional mutations. E166V mutation conferred the strongest resistance, but with a loss of viral replicative fitness that was restored by compensatory changes. The findings indicate that SARS-CoV-2 resistance to nirmatrelvir does arise readily and provides a foundation from which to study the mechanism of resistance and design next-generation protease inhibitors.
For more information:
Nature 2022 11/9
https://www.nature.com/articles/s41586-022-05514-2
Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir
Dr. Ho’s website:
https://microbiology.columbia.edu/faculty-david-ho
https://www.adarc.cuimc.columbia.edu/profile/david-d-ho-md
Nirmatrelvir (Paxlovid)