SARS-CoV-2 Strains With Nirmatrelvir Resistance After Antiviral Therapy Present in Patients at Low Frequencies

In a study of patients with COVID-19, some of whom received antiviral therapy, treatment-emergent, resistant mutations persisteed at a higher rate in those who received treatment, especially in patients who were immunosuppressed, though these mutations were unlikely to pose a significant risk to viral spread or contribute to virologic rebound in patients.¹

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Nirmatrelvir (Paxlovid, in combination with ritonavir; Pfizer) and remdesivir (Veklury; Gilead Sciences) are recommended for use in mild-to-moderate COVID-19 in high-risk patients. Concerns remain about the unclear prevalence of nirmatrelvir resistance in clinical settings, with concerns over an association between posttreatment virologic rebound and the emergence of antiviral resistance.¹

Additionally, results from a recent trial of immunocompromised individuals who are persistently infected with SARS-CoV-2 showed that patients could potentially harbor drug-resistant variants towards remdesivir or nirmatrelvir-ritonavir. There were multiple instances of treatment-resistant variants emerging, with 1 individual even developing a strain that was resistant to both treatments at once.²

To avoid low frequency resistance variants spreading in the general population and eventually becoming dominant, the investigators in this current trial assessed the in vivo emergence of mutations that confer resistance to nirmatrelvir and remdesivir. The analysis included patients who are actively participating in the Post-Vaccination Viral Characteristics Study (POSITIVES), an ongoing trial of patients with acute COVID-19.¹

In total, 156 individuals with COVID-19 were included; 79 participants were treated with nirmatrelvir and 14 were treated with remdesivir, while 63 were untreated. Patients treated with nirmatrelvir had more emergent resistance mutations detected in the nsp5 gene (9 [11.4%]) than untreated individuals (2 [3.2%]), though the comparison was not deemed statistically significant. When compared with treated, non-immunosuppressed individuals (4 of 57 [7.0%]), immunosuppressed patients had a higher frequency of mutation emergence (5 of 22 [22.7%]).¹

Importantly, most nirmatrelvir resistance mutations (10 of 11 [90.9%]) were detected at low frequencies within a patient’s viral population. Even in participants with a detectable presence of nirmatrelvir resistance mutation, RNA levels become undetectable within a few days, and all of the mutations were transient in nature.¹

In 2 of 14 individuals (14.3%) treated with remdesivir, emergent resistance mutations were detected. The individuals were determined to be severely immunosuppressed; still, these mutations were present at low frequencies and were transient.¹

Zhuo Zhou and Peng Hong penned a commentary in JAMA Network Open in response to these results, praising the analysis and their use of “a highly sensitive next-generation sequencing approach” to identify treatment-resistant mutations. However, they raised concerns about the implication of these results for immunocompromised patients.³

The authors of the current study discussed that this susceptibility could be due to greater viral genetic diversity and a prolonged duration of active viral replication in patients with a suboptimal immune response.¹

Zhou and Hong point out that if interactions between mutations occur, prolonged infections in immunocompromised hosts would “allow these mutations to accumulate sequentially” and make evolutionary jumps towards becoming the dominant variant.³

“These observations highlight the hidden risk of nirmatrelvir resistance and again stress the importance of proactive viral genomics surveillance in immunocompromised populations,” Zhou and Hong wrote, stressing further research and the optimization of treatment regimens as next steps.³

REFERENCES

1. Tamura TJ, Choudhary MC, Deo R, et al. Emerging SARS-CoV-2 resistance after antiviral treatment. JAMA Netw Open. 2024;7(9):e2435431. doi:10.1001/jamanetworkopen.2024.35431

2. Halpern L. Immunocompromised patients with persistent COVID-19 can harbor drug-resistant variants following treatment. Pharmacy Times. Published September 25, 2024. Accessed September 26, 2024. https://www.pharmacytimes.com/view/immunocompromised-patients-with-persistent-covid-19-can-harbor-drug-resistant-variants-following-treatment

3. Zhou Z, Hong P. SARS-CoV-2 Nirmatrelvir resistance—a concern for immunocompromised populations? JAMA Netw Open. 2024;7(9):e2435439. doi:10.1001/jamanetworkopen.2024.35439