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Trevor Tamura, BA


Job Title

Technical Research Assistant II

Academic Rank

Staff/Research Assistant


Infectious Diseases


Tamura TJ, Yousuf F, Choudhary MC, Deo R, Edelstein GE, Boucau J, Uddin R, Marino C, Liew MY, Barry M, Gilbert RF, Reynolds Z, Li Y, Tien D, Sagar S, Vyas TD, Kawano Y, Sparks JA, Hammond SP, Wallace Z, Vyas JM, Siedner MJ, Barczak AK, Lemieux JE, Li JZ

Principal Investigator

Jonathan Z. Li



Analysis of emerging drug resistance after nirmatrelvir-ritonavir treatment and during post-treatment virologic rebound

Scientific Abstract

Nirmatrelvir-ritonavir (N-R) is a SARS-CoV-2 antiviral that reduces the risk of hospitalization and progression to severe COVID-19. While N-R resistance has not posed a significant clinical problem, the risk of emerging resistance remains unclear. We performed deep sequencing of the nsp5 gene using anterior nasal swab samples from participants in the POSITIVES study who received N-R (n=53) and who were untreated (n=42) to identify treatment-emergent N-R resistance. Mutations expected to confer moderate resistance (≥2.5-fold reduced susceptibility to N-R in vitro) were significantly more likely to be detected in those who received N-R than those who did not (11% vs 0%, p=0.03). However, these mutations were detected at low frequencies, with all but one mutation found in 0.99). In summary, mutations that confer resistance can emerge after N-R, but the risk of wide-spread dissemination of N-R resistant variants appears low, as they are generally present at minority frequencies, occur transiently, and do not associate with virologic rebound.

Lay Abstract

Paxlovid, currently one of the main treatments for COVID-19, significantly reduces the chances of hospitalization and severe illness. Previous treatments for COVID-19, including monoclonal antibodies, can no longer be used because the virus has become resistant to those treatments. There is concern that COVID-19 could also become resistant to Paxlovid, rendering the drug similarly ineffective. In the POSITIVES study, we examined the emergence of resistance in people who took Paxlovid and those who did not. We discovered some mutations in the virus that made it less sensitive to Paxlovid, especially in those who received treatment (15%), compared to those who did not (0%). However, these resistance mutations were generally found at low frequencies and did not seem to contribute to the instances when the virus returned following initial clearance. In summary, we found that the virus can develop resistance to Paxlovid, but the risk of widespread resistance appears low because these mutations are generally present in a small part of the viral population, come and go quickly, and do not lead to continued illness following the return of the virus.

Clinical Implications

Our study reports that despite discovering the presence of treatment-emerging resistance to Paxlovid, the risk of wide-spread dissemination of resistant variants appears low due to them being generally present at minority frequencies, appearing transiently, and not leading to virologic rebound.