COVID-19 News: SARS-CoV-2 Develops Mutations That Causes Resistance To Any Antivirals Used. In Japan, Use Of Ensitrelvir Resulted In M49L Mutants!

COVID-19 News: Since the onset of the SARS-CoV-2 pandemic in 2020, the quest for effective antiviral therapies has been a focal point of medical research. As witnessed in previous viral outbreaks, such as Influenza and HIV, the development of potent antiviral treatments plays a pivotal role in managing public health crises. Initial hopes were pinned on the repurposing of broad-spectrum antivirals targeting the replication complex. However, clinical trials yielded disappointing results, leading researchers to explore alternative avenues as reported in various past COVID-19 News coverages.


In Japan, Use Of Ensitrelvir (Xocova) Resulted In M49L Mutants
 
Nirmatrelvir (Paxlovid®), a 3CLpro inhibitor, emerged as a promising candidate, demonstrating robustness against variants in clinical trials according to claims by the pharma giant involved i.e. the notorious Pfizer. Another contender, ensitrelvir (Xocova®), developed by the Japanese company Shionogi, claimed encouraging results in Phase 2 trials and gained emergency regulatory approval in Japan in November 2022. However, recent developments raise concerns about the efficacy of these protease inhibitors, as experimental evidence suggests the emergence of resistance mutations.
 
Evidence is emerging that the SARS-CoV-2 virus ultimately develops mutations to confer drug resistance to any antivirals used. In the case of Paxlovid, the mutations T21I, T304I, L50F and E166A emerged.
 
Thailand Medical News had been warning about SARS-CoV-2 drug resistance since the time Remdesivir was being used.
 
https://www.thailandmedical.news/news/covid-19-news-scientists-warn-sars-cov-2-is-mutating-to-escape-all-known-clinical-protease-inhibitors-multi-drug-approach-recommended
 
https://www.thailandmedical.news/news/breaking-sars-cov-2-ba-2-variant-spawning-mutations-on-its-mpro-sites-that-reduce-efficacy-of-the-antiviral-paxlovid-many-such-variants-in-america-no
 
https://www.thailandmedical.news/news/yale-study-reveals-that-enzyme-present-in-sars-cov-2-known-as--coronavirus-3-5-exoribonuclease-exon-is-responsible-for-antiviral-drug-resistance
 
t;>https://www.thailandmedical.news/news/warning-mutations-in-new-emerging-ba-2,-ba-4-subvariants-are-changing-the-main-coronavirus-protease-drastically,-rendering-many-previous-antivirals-ob
 
https://www.thailandmedical.news/news/latest-danish-study-shows-that-mutations-e166v-and-l50f-e166v-on-sars-cov-2-variants-weakens-nirmatrelvir-a-component-of-paxlovid-mpro-binding
 
Experimental Generation of Resistant Strains
Researchers at the Unité des Virus Émergents, UVE: Aix Marseille Univ-France, in collaboration with the Drugs for Neglected Diseases Initiative in Geneva-Switzerland, conducted experiments to generate SARS-CoV-2 strains resistant to nirmatrelvir and ensitrelvir. Through 16 passages in vitro, they successfully produced mutants displaying resistance to these clinical stage protease inhibitors.

Notably, the M49L mutation was identified as a key player, conferring a robust resistance to ensitrelvir. In vitro analyses demonstrated a substantial loss of sensitivity for the resistance mutants, indicating a potential challenge in the effectiveness of these antivirals.
 
In Vivo Implications of the M49L Mutation
Utilizing a Syrian golden hamster infection model, the researchers observed that the ensitrelvir-resistant M49L mutation rendered ensitrelvir treatment ineffective in vivo. The study revealed that the M49L mutation alone significantly reduced the efficacy of ensitrelvir in the hamster model.
 
Furthermore, a noteworthy finding was the identification of an increasing prevalence of naturally occurring M49L-carrying sequences over recent months. This trend raised concerns about potential links between the rise in M49L mutants and the utilization of ensitrelvir in Japan since its approval in November 2022.
 
Genetic Monitoring for Treatment Efficacy
The experimental findings underscore the strategic importance of genetic monitoring of circulating SARS-CoV-2 strains to ensure the continued effectiveness of antiviral treatments. Resistance mutations, such as M49L, pose a substantial limitation to the efficacy of antiviral monotherapies. The study suggests that the emergence of these mutations may occur both naturally and in response to treatment conditions.
 
Nirmatrelvir (Paxlovid) and ensitrelvir (Xocova) demonstrated a certain degree of cross-resistance in vitro, implying that substituting one compound with the other could potentially mitigate the emergence of resistance during treatment. However, the magnitude of resistance observed with the M49L mutation in ensitrelvir raised concerns about the efficacy of this approach.
 
Global Prevalence of M49L-Carrying Sequences
The researchers conducted a comprehensive analysis of the global prevalence of M49L-carrying sequences through data obtained from the Global Initiative on Sharing All Influenza Data (GISAID). The study revealed that, as of October 30, 2023, a small proportion (0.00165%) of SARS-CoV-2 sequences carried the M49L mutation.
 
Notably, the prevalence of M49L has shown a recent increase, with more occurrences reported between May and October 2023 compared to the previous 21 months. The analysis identified Japan as the primary origin of M49L sequences, constituting 59.9% of the total sequences and rising to 88.3% in the specified time frame.
 
Association Between M49L Prevalence and Ensitrelvir Use in Japan
The study established a correlation between the increased prevalence of M49L and the introduction of ensitrelvir (Xocova) in Japan. The drug received emergency regulatory approval in November 2022 and was commercially available from April 2023. The researchers observed that the surge in M49L-carrying sequences coincided with the timeline of ensitrelvir use in the country.
 
Further analysis indicated that M49L sequences were sporadically observed before December 2022, with a significant upswing since June 2023. This temporal alignment strongly suggested a potential link between the selective pressure exerted by ensitrelvir use and the increased prevalence of M49L mutants.

Multiple Lineages and Emergence Events
To delve deeper into the genomic diversity of M49L-carrying sequences, the researchers examined the Pango lineage distribution. Surprisingly, M49L was found in 90 different lineages, including prominent ones like Alpha, Delta, and Omicron. This extensive distribution suggested that M49L had emerged independently on multiple occasions.
 
Phylogenetic analysis revealed 12 distinct emergence events associated with the M49L mutation, further emphasizing the repeated occurrence of this resistance-conferring mutation within the SARS-CoV-2 genome. This finding highlighted the importance of monitoring these emergence events to assess the risk of fixation of the mutation.
 
Implications for Antiviral Therapies
The study's findings have significant implications for the ongoing efforts to combat SARS-CoV-2. The emergence of resistance mutations, particularly the M49L mutation, raises concerns about the long-term efficacy of ensitrelvir. The observed increase in prevalence linked to ensitrelvir use in Japan underscores the need for vigilant genetic monitoring to adapt treatment strategies and prevent the spread of resistant strains.
 
The study advocates for continuous assessment of the risk associated with antiviral treatments, emphasizing the importance of a diversified arsenal of antivirals targeting various viral proteins. Additionally, the identification of resistance mutations like M49L necessitates a nuanced approach in treatment strategies, potentially considering dual therapies to mitigate the risk of resistance emergence.
 
Conclusion
In conclusion, the experimental generation of SARS-CoV-2 mutants resistant to nirmatrelvir and ensitrelvir, particularly the ensitrelvir-resistant M49L mutation, raises critical questions about the sustainability of current antiviral therapies. The study's comprehensive analysis of global prevalence and emergence events provides valuable insights into the dynamics of resistance mutations.

The correlation between ensitrelvir use in Japan and the surge in M49L prevalence highlights the intricate interplay between drug utilization and the evolution of viral strains. This study underscores the urgency of implementing genetic monitoring strategies to adapt antiviral treatments and mitigate the risk of resistance emergence.
 
As the world continues to grapple with the evolving landscape of the SARS-CoV-2 pandemic, ongoing research and surveillance are imperative to stay ahead of emerging challenges and to ensure the effectiveness of antiviral interventions in the face of a dynamic virus.
 
The study findings were published in the peer reviewed journal: Antiviral Research.
https://www.sciencedirect.com/science/article/pii/S0166354224000226
 
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