{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T22:27:12Z","timestamp":1788992832990,"version":"build-2803163510"},"reference-count":23,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Although the coronavirus disease 2019 (COVID-19) pandemic is coming to an end, it still poses a threat to the immunocompromised and others with underlying diseases. Especially in cases of persistent COVID-19, new mutations conferring resistance to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapies have considerable clinical implications. We present a patient who independently acquired a T21I mutation in the 3CL protease after nirmatrelvir exposure. The T21I mutation in the 3CL protease is one of the most frequent mutations responsible for nirmatrelvir resistance. However, limited reports exist on actual cases of SARS-CoV-2 with T21I and other mutations in the 3CL protease. The patient, a 55 year-old male, had COVID-19 during chemotherapy for multiple myeloma. He was treated with nirmatrelvir early in the course of the disease but relapsed, and SARS-CoV-2 with a T21I mutation in the 3CL protease was detected in nasopharyngeal swab fluid. The patient had temporary respiratory failure but later recovered well. During treatment with remdesivir and dexamethasone, viruses with the T21I mutation in the 3CL protease showed a decreasing trend during disease progression while increasing during improvement. The impact of drug-resistant SARS-CoV-2 on the clinical course, including its severity, remains unknown. Our study is important for examining the clinical impact of nirmatrelvir resistance in COVID-19.<\/jats:p>","DOI":"10.3390\/v16050718","type":"journal-article","created":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T07:04:14Z","timestamp":1714633454000},"page":"718","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Nirmatrelvir Resistance in an Immunocompromised Patient with Persistent Coronavirus Disease 2019"],"prefix":"10.3390","volume":"16","author":[{"given":"Chie","family":"Yamamoto","sequence":"first","affiliation":[{"name":"Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Taniguchi","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, Kyoto City Hospital, Kyoto 604-8845, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keitaro","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1595-8524","authenticated-orcid":false,"given":"Toru","family":"Inaba","sequence":"additional","affiliation":[{"name":"Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Niiyama","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Ide","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6498-1755","authenticated-orcid":false,"given":"Shinsuke","family":"Mizutani","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6130-1550","authenticated-orcid":false,"given":"Junya","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Tanino","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Nishioka","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7723-8960","authenticated-orcid":false,"given":"Koichi","family":"Takayama","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Nakaya","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6123-5212","authenticated-orcid":false,"given":"Yoko","family":"Nukui","sequence":"additional","affiliation":[{"name":"Department of Infection Control and Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"ref_1","unstructured":"(2024, March 30). Therapeutics and COVID-19 Living Guideline. Available online: https:\/\/www.who.int\/publications\/i\/item\/WHO-2019-nCoV-therapeutics-2023.2."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1056\/NEJMoa2118542","article-title":"Oral nirmatrelvir for high-risk, nonhospitalized adults with COVID-19","volume":"386","author":"Hammond","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1093\/cid\/ciad400","article-title":"Oral nirmatrelvir and ritonavir for coronavirus disease 2019 in Vaccinated, Nonhospitalized Adults Aged 18\u201350 Years","volume":"77","author":"Faust","year":"2023","journal-title":"Clin Infect Dis"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"77","DOI":"10.7326\/M22-2141","article-title":"Nirmatrelvir plus ritonavir for early COVID-19 in a Large U.S. health system: A population-based cohort study","volume":"176","author":"Kim","year":"2023","journal-title":"Ann. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/S1473-3099(23)00118-4","article-title":"Effectiveness of nirmatrelvir-ritonavir in preventing hospital admissions and deaths in people with COVID-19: A cohort study in a large US health-care system","volume":"23","author":"Lewnard","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eabo0718","DOI":"10.1126\/scitranslmed.abo0718","article-title":"Mutations in the SARS-CoV-2 RNA-dependent RNA polymerase confer resistance to remdesivir by distinct mechanisms","volume":"14","author":"Stevens","year":"2022","journal-title":"Sci. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Torii, S., Kim, K.S., Koseki, J., Suzuki, R., Iwanami, S., Fujita, Y., Jeong, Y.D., Ito, J., Asakura, H., and Nagashima, M. (2023). Increased flexibility of the SARS-CoV-2 RNA-binding site causes resistance to remdesivir. PLOS Pathog., 19.","DOI":"10.1371\/journal.ppat.1011231"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105247","DOI":"10.1016\/j.antiviral.2022.105247","article-title":"Very low levels of remdesivir resistance in SARS-CoV-2 genomes after 18 months of massive usage during the COVID19 pandemic: A GISAID exploratory analysis","volume":"198","author":"Focosi","year":"2022","journal-title":"Antivir. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1038\/s41467-022-29104-y","article-title":"De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report","volume":"13","author":"Gandhi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1093\/cid\/ciac769","article-title":"Remdesivir resistance in transplant recipients with persistent coronavirus disease 2019","volume":"76","author":"Hogan","year":"2023","journal-title":"Clin Infect Dis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41586-022-05514-2","article-title":"Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir","volume":"613","author":"Iketani","year":"2023","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"106708","DOI":"10.1016\/j.ijantimicag.2022.106708","article-title":"Nirmatrelvir and COVID-19: Development, pharmacokinetics, clinical efficacy, resistance, relapse, and pharmacoeconomics","volume":"61","author":"Focosi","year":"2023","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"531","DOI":"10.2147\/IDR.S438915","article-title":"Emergence of SARS-CoV-2 with dual-drug resistant mutations during a long-term infection in a kidney transplant recipient","volume":"17","author":"Tanino","year":"2024","journal-title":"Infect. Drug Resist."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"giy169","DOI":"10.1093\/gigascience\/giy169","article-title":"NanoPipe-a web server for nanopore MinION sequencing data analysis","volume":"8","author":"Shabardina","year":"2019","journal-title":"Gigascience"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100747","DOI":"10.1016\/j.lanepe.2023.100747","article-title":"Impact of COVID-19 on immunocompromised populations during the Omicron era: Insights from the observational population-based INFORM study","volume":"35","author":"Evans","year":"2023","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2211688","DOI":"10.1080\/22221751.2023.2211688","article-title":"Orthogonal dual reporter-based gain-of-signal assay for probing SARS-CoV-23CL protease activity in living cells: Inhibitor identification and mutationinvestigation","volume":"12","author":"Beia","year":"2023","journal-title":"Emerg. Microbes Infect."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ip, J.D., Chu, A.W.H., Chan, W.M., Leung, R.C.Y., Abdullah, S.M.U., Sun, Y., and To, K.K.W. (2023). Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance. eBioMedicine, 91.","DOI":"10.1016\/j.ebiom.2023.104559"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sayan, M., Arikan, A. (2023). Molecular epidemiology of SARS-CoV-2 omicron sub-lineages isolated from Turkish patients infected with COVID-19. Viruses, 15.","DOI":"10.3390\/v15051066"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mohammad, A., Al-Mulla, F., Wei, D.Q., and Abubaker, J. (2021). Remdesivir MD simulations suggest a more favourable binding to SARS-CoV-2 RNA dependent RNA polymerase mutant P323L than wild-type. Biomolecules, 11.","DOI":"10.3390\/biom11070919"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e0022222","DOI":"10.1128\/aac.00222-22","article-title":"Remdesivir and GS-441524 retain antiviral activity against delta, omicron, and other emergent SARS-CoV-2 variants","volume":"66","author":"Pitts","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e0003722","DOI":"10.1128\/jvi.00037-22","article-title":"SARS-CoV-2 nsp5 exhibits stronger catalytic activity and interferon antagonism than its SARS-CoV ortholog","volume":"96","author":"Chen","year":"2022","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1038\/s41598-022-05424-3","article-title":"Pro108Ser mutation of SARS-CoV-2 3CLpro reduces the enzyme activity and ameliorates the clinical severity of COVID-19","volume":"12","author":"Abe","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_23","unstructured":"Covid CG (2024, March 30). COVID-19 CoV Genetics. Available online: https:\/\/covidcg.org\/."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/5\/718\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:37:27Z","timestamp":1760107047000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/16\/5\/718"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":23,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["v16050718"],"URL":"https:\/\/doi.org\/10.3390\/v16050718","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]}}}