tetano
Editor, Senior Moderator
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[SUP] #[/SUP][SUP] 1 2 [/SUP], Keisuke Nishioka[SUP] #[/SUP][SUP] 1 [/SUP], Chie Yamamoto[SUP] #[/SUP][SUP] 2 [/SUP], Yohei Watanabe[SUP] 1 3 [/SUP], Tomo Daidoji[SUP] 1 4 [/SUP], Masataka Kawamoto[SUP] 5 [/SUP], Sayaka Uda[SUP] 6 [/SUP], Shoko Kirito[SUP] 1 [/SUP], Yuta Nakagawa[SUP] 2 [/SUP], Yu Kasamatsu[SUP] 2 [/SUP], Yoshiyuki Kawahara[SUP] 7 [/SUP], Yuri Sakai[SUP] 7 [/SUP], Shuji Nobori[SUP] 8 [/SUP], Tohru Inaba[SUP] 2 [/SUP], Bon Ota[SUP] 9 [/SUP], Naohisa Fujita[SUP] 7 [/SUP], Atsushi Hoshino[SUP] 10 [/SUP], Yoko Nukui[SUP] 2 [/SUP], Takaaki Nakaya[SUP] 1 [/SUP]
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[SUP] #[/SUP][SUP] 1 2 [/SUP], Keisuke Nishioka[SUP] #[/SUP][SUP] 1 [/SUP], Chie Yamamoto[SUP] #[/SUP][SUP] 2 [/SUP], Yohei Watanabe[SUP] 1 3 [/SUP], Tomo Daidoji[SUP] 1 4 [/SUP], Masataka Kawamoto[SUP] 5 [/SUP], Sayaka Uda[SUP] 6 [/SUP], Shoko Kirito[SUP] 1 [/SUP], Yuta Nakagawa[SUP] 2 [/SUP], Yu Kasamatsu[SUP] 2 [/SUP], Yoshiyuki Kawahara[SUP] 7 [/SUP], Yuri Sakai[SUP] 7 [/SUP], Shuji Nobori[SUP] 8 [/SUP], Tohru Inaba[SUP] 2 [/SUP], Bon Ota[SUP] 9 [/SUP], Naohisa Fujita[SUP] 7 [/SUP], Atsushi Hoshino[SUP] 10 [/SUP], Yoko Nukui[SUP] 2 [/SUP], Takaaki Nakaya[SUP] 1 [/SUP]
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.