A study today in JAMA Network Open offers reassurance that resistance to one of the most effective COVID-19 therapeutics is rare.
The study was based on SARS-CoV-2 isolates collected from March 2020 to January 2023 in Ontario, and it demonstrates very low levels of resistance to Paxlovid, the antiviral drug most commonly used to limit the duration and severity of COVID-19 infections.
Paxlovoid (nirmatrelvir-ritonavir) is one of only two approved antivirals for COVID-19 that has been proven to reduce the risk of hospitalization and death. The drug inhibits the main viral protease encoded by the nsp5 gene, the authors said. The study was conducted by looking at 78,866 clinical samples with next-generation whole-genome sequencing for low-frequency variants in the viral nsp5 gene.
Resistance in 0.16% of isolates
Samples were collected in Ontario from March 1, 2020 through January 12, 2023 from four labs that served multiple community hospitals, other academic tertiary care centers, and COVID-19 assessment centers. Samples were collected before and after the approval of nirmatrelvir-ritonavir in Canada (January 17, 2022).
"Analysis indicated low-frequency variants at positions linked to drug resistance in the nsp5 gene in 128 (0.16%) of the isolates," the authors said.
A similar proportion, but well under 1%, of isolates with low-frequency variants was seen at each of the four laboratories. The highest rate, in one of those labs, was 0.53%, "but this count is likely a result of undersampling bias, because this site had a lower number of sequences," the authors wrote.
The paucity of these variants suggests it may be difficult for resistant variants to be selected, and this may be a contributing factor to why resistance to nirmatrelvir-ritonavir has not yet been observed.
"Studies suggest that only variants present at more than 15% are likely to represent viral adaptation in the face of selective drug pressure. The paucity of these variants suggests it may be difficult for resistant variants to be selected, and this may be a contributing factor to why resistance to nirmatrelvir-ritonavir has not yet been observed," the authors concluded.
Patient histories missing
The authors acknowledged several limitations to the study, namely that they included no patient history in ether analysis. "It cannot be discounted that some patients may have received antiviral treatment before testing," they said.
The authors suggested that future studies include patient histories and consider how to conduct sequencing of isolates from cases with low viral loads. Also, studies should be conducted in regions with heavy Paxlovid use, they said.
