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. 2024 Sep 3;7(9):e2435431.
doi: 10.1001/jamanetworkopen.2024.35431.

Emerging SARS-CoV-2 Resistance After Antiviral Treatment

Trevor J Tamura  1 , Manish C Choudhary  1   2 , Rinki Deo  1   2 , Fizah Yousuf  1 , Anadela Navarrete Gomez  1 , Gregory E Edelstein  1   2 , Julie Boucau  3 , Owen T Glover  3 , Mamadou Barry  4 , Rebecca F Gilbert  4 , Zahra Reynolds  4 , Yijia Li  1   4   5 , Dessie Tien  4 , Tammy D Vyas  4 , Eliza Passell  4 , Karry Su  4 , Sarah Drapkin  4 , Emory G Abar  4 , Yumeko Kawano  1   2 , Jeffrey A Sparks  1   2 , Zachary S Wallace  2   4 , Jatin M Vyas  1   4   6 , Robert W Shafer  7 , Mark J Siedner  2   4 , Amy K Barczak  2   3   4 , Jacob E Lemieux  2   4   6 , Jonathan Z Li  1   2 ; POSITIVES Study Team
Affiliations

Emerging SARS-CoV-2 Resistance After Antiviral Treatment

Trevor J Tamura et al. JAMA Netw Open. .

Abstract

Importance: Previous studies have identified mutations in SARS-CoV-2 strains that confer resistance to nirmatrelvir, yet how often this resistance arises and its association with posttreatment virologic rebound is not well understood.

Objective: To examine the prevalence of emergent antiviral resistance after nirmatrelvir treatment and its association with virologic rebound.

Design, setting, and participants: This cohort study enrolled outpatient adults with acute COVID-19 infection from May 2021 to October 2023. Participants were divided into those who received antiviral therapy and those who did not. The study was conducted at a multicenter health care system in Boston, Massachusetts.

Exposure: Treatment regimen, including none, nirmatrelvir, and remdesivir.

Main outcomes and measures: The primary outcome was emergent SARS-CoV-2 antiviral resistance, defined as the detection of antiviral resistance mutations, which were not present at baseline, were previously associated with decreased antiviral efficacy, and emerged during or after completion of a participant's treatment. Next-generation sequencing was used to detect low frequency mutations down to 1% of the total viral population.

Results: Overall, 156 participants (114 female [73.1%]; median [IQR] age, 56 [38-69] years) were included. Compared with 63 untreated individuals, the 79 who received nirmatrelvir were older and more commonly immunosuppressed. After sequencing viral RNA from participants' anterior nasal swabs, nirmatrelvir resistance mutations were detected in 9 individuals who received nirmatrelvir (11.4%) compared with 2 of those who did not (3.2%) (P = .09). Among the individuals treated with nirmatrelvir, those who were immunosuppressed had the highest frequency of resistance emergence (5 of 22 [22.7%]), significantly greater than untreated individuals (2 of 63 [3.1%]) (P = .01). Similar rates of nirmatrelvir resistance were found in those who had virologic rebound (3 of 23 [13.0%]) vs those who did not (6 of 56 [10.7%]) (P = .86). Most of these mutations (10 of 11 [90.9%]) were detected at low frequencies (<20% of viral population) and reverted to the wild type at subsequent time points. Emerging remdesivir resistance mutations were only detected in immunosuppressed individuals (2 of 14 [14.3%]) but were similarly low frequency and transient. Global Initiative on Sharing All Influenza Data analysis showed no evidence of increased nirmatrelvir resistance in the United States after the authorization of nirmatrelvir.

Conclusions and relevance: In this cohort study of 156 participants, treatment-emergent nirmatrelvir resistance mutations were commonly detected, especially in individuals who were immunosuppressed. However, these mutations were generally present at low frequencies and were transient in nature, suggesting a low risk for the spread of nirmatrelvir resistance in the community with the current variants and drug usage patterns.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Barry reported receiving grants from National Institutes of Health (NIH) during the conduct of the study. Ms Reynolds reported receiving grants from Massachusetts Consortium on Pathogen Readiness (MassCPR) and the NIH during the conduct of the study. Dr Y. Li reported serving as a topic editor for DynaMed outside the submitted work and being supported Rustbelt Center for AIDS Research. Ms Su reported receiving grants from the NIH during the conduct of the study. Mr Abar reported receiving grants from the NIH during the conduct of the study. Dr Sparks reported receiving grants from the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Gordon and Llura Gund Foundation, Boehringer Ingelheim, Bristol Myers Squibb, Sonoma Biosciences, and Janssen Pharmaceuticals as well as personal fees from AbbVie, Amgen, Gilead, Pfizer, ReCor, Sobi, and UCB outside the submitted work. Dr Wallace reported receiving grants from the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases during the conduct of the study. Dr Shafer reported serving on the advisory board of and receiving speaking honorarium from Gilead Sciences and receiving speaking honorarium from ViiV Healthcare outside the submitted work. Dr Siedner reported receiving grants from the NIH and MassCPR during the conduct of the study. Dr Barczak reported serving as a consultant for ICON Government and Public Health Solutions outside the submitted work. Dr Lemieux reported receiving grants from MassCPR, the NIH, and the US Centers for Disease Control and Prevention during the conduct of the study as well as receiving grants from Moderna outside the submitted work. Dr J. Z. Li reported consulting for Abbvie and receiving grants from Merck during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Prevalence of Emergent Nirmatrelvir Resistance Mutations in Untreated and Nirmatrelvir-Treated Individuals
Individuals treated with nirmatrelvir were also separated by immunosuppression (IS) and virologic rebound (VR) status. P values were calculated using a 2-sided Boschloo test.
Figure 2.
Figure 2.. Viral Load and Mutational Landscape Graphs for Participants With an Emergent Nirmatrelvir Resistance Mutation
A, An individual with the highest frequency mutation observed. B, An individual with virologic rebound. IS indicates immunosuppressed.
Figure 3.
Figure 3.. Nirmatrelvir Resistance Mutation Prevalence Compiled From Global Initiative on Sharing All Influenza Data (GISAID) SARS-CoV-2 Sequences in the United States
SARS-CoV-2 sequences were downloaded from GISAID between January 2020 and February 2024. Prevalence was calculated by dividing the number of mutated variants of interest by the total number of sequences per month. The dashed line at December 2021 indicates the Food and Drug Administration’s initial Emergency Use Authorization (EUA) for nirmatrelvir.
See this image and copyright information in PMC

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