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Infect Drug Resist
. 2024 Feb 8:17:531-541.
doi: 10.2147/IDR.S438915. eCollection 2024. Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient
Yoko Tanino # 1 2 , Keisuke Nishioka # 1 , Chie Yamamoto # 2 , Yohei Watanabe 1 3 , Tomo Daidoji 1 4 , Masataka Kawamoto 5 , Sayaka Uda 6 , Shoko Kirito 1 , Yuta Nakagawa 2 , Yu Kasamatsu 2 , Yoshiyuki Kawahara 7 , Yuri Sakai 7 , Shuji Nobori 8 , Tohru Inaba 2 , Bon Ota 9 , Naohisa Fujita 7 , Atsushi Hoshino 10 , Yoko Nukui 2 , Takaaki Nakaya 1
Affiliations
Introduction: Various therapeutic agents are being developed for the treatment of coronavirus disease 2019 (COVID-19). Therefore, it is crucial to accumulate information regarding the features of drug-resistant viruses to these antiviral drugs.
Methods: We investigated the emergence of dual-drug resistance in a kidney transplant recipient who received sotrovimab (from day 0) and remdesivir (RDV) (from day 8 to day 17). We sequenced the whole viral genomes from nasopharyngeal swabs taken on day 0 and seven points after starting treatment (on days 12, 19, 23, 37, 43, 48, and 58). The genetic traits of the wild-type (day 0) and descendant viruses (after day 12) were determined by comparing the genomes with those of a Wuhan strain and the day 0 wild-type strain, respectively. Three viral isolates (from samples collected on days 0, 23, and 37) were investigated for their escape ability and growth kinetics in vitro.
Results: The sotrovimab resistant mutation (S:E340K) and the RDV resistant mutation RdRp:V792I (nt: G15814A) emerged within 12 days (day 12) and 11 days (day 19) after the treatment, respectively. The day 23 isolate harboring S:E340K/RdRp:V791I was resistant to both sotrovimab and RDV, showing 364- and 2.73-fold higher resistance respectively, compared with the wild-type. Moreover, compared with the day 23 isolate, the day 37 isolate accumulated multiple additional mutations and had a higher level of resistance to both drugs.
Conclusion: Drug-resistant variants with double mutations (S:E340K/RdRp:V791I) became dominant within 23 days after starting treatment, suggesting that even a combination therapy involving sotrovimab and RDV, dual-drug resistant viruses may emerge rapidly in immunocompromised patients. The dual-resistant variants had lower virus yields than those of the wild-type virus in vitro, suggesting that they paid a fitness cost.
Keywords: SARS-CoV-2; drug resistance; immunosuppression therapy; remdesivir; sotrovimab.
. 2024 Feb 8:17:531-541.
doi: 10.2147/IDR.S438915. eCollection 2024. Emergence of SARS-CoV-2 with Dual-Drug Resistant Mutations During a Long-Term Infection in a Kidney Transplant Recipient
Yoko Tanino # 1 2 , Keisuke Nishioka # 1 , Chie Yamamoto # 2 , Yohei Watanabe 1 3 , Tomo Daidoji 1 4 , Masataka Kawamoto 5 , Sayaka Uda 6 , Shoko Kirito 1 , Yuta Nakagawa 2 , Yu Kasamatsu 2 , Yoshiyuki Kawahara 7 , Yuri Sakai 7 , Shuji Nobori 8 , Tohru Inaba 2 , Bon Ota 9 , Naohisa Fujita 7 , Atsushi Hoshino 10 , Yoko Nukui 2 , Takaaki Nakaya 1
Affiliations
- PMID: 38348230
- PMCID: PMC10860503
- DOI: 10.2147/IDR.S438915
Introduction: Various therapeutic agents are being developed for the treatment of coronavirus disease 2019 (COVID-19). Therefore, it is crucial to accumulate information regarding the features of drug-resistant viruses to these antiviral drugs.
Methods: We investigated the emergence of dual-drug resistance in a kidney transplant recipient who received sotrovimab (from day 0) and remdesivir (RDV) (from day 8 to day 17). We sequenced the whole viral genomes from nasopharyngeal swabs taken on day 0 and seven points after starting treatment (on days 12, 19, 23, 37, 43, 48, and 58). The genetic traits of the wild-type (day 0) and descendant viruses (after day 12) were determined by comparing the genomes with those of a Wuhan strain and the day 0 wild-type strain, respectively. Three viral isolates (from samples collected on days 0, 23, and 37) were investigated for their escape ability and growth kinetics in vitro.
Results: The sotrovimab resistant mutation (S:E340K) and the RDV resistant mutation RdRp:V792I (nt: G15814A) emerged within 12 days (day 12) and 11 days (day 19) after the treatment, respectively. The day 23 isolate harboring S:E340K/RdRp:V791I was resistant to both sotrovimab and RDV, showing 364- and 2.73-fold higher resistance respectively, compared with the wild-type. Moreover, compared with the day 23 isolate, the day 37 isolate accumulated multiple additional mutations and had a higher level of resistance to both drugs.
Conclusion: Drug-resistant variants with double mutations (S:E340K/RdRp:V791I) became dominant within 23 days after starting treatment, suggesting that even a combination therapy involving sotrovimab and RDV, dual-drug resistant viruses may emerge rapidly in immunocompromised patients. The dual-resistant variants had lower virus yields than those of the wild-type virus in vitro, suggesting that they paid a fitness cost.
Keywords: SARS-CoV-2; drug resistance; immunosuppression therapy; remdesivir; sotrovimab.